Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([O:17][CH3:18])=[C:14]([NH2:16])[CH:15]=1.[N:19]([C:22]1[CH:36]=[CH:35][C:25]([CH2:26][P:27](=[O:34])([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30])=[CH:24][CH:23]=1)=[C:20]=[S:21]>O1CCCC1>[CH2:29]([O:28][P:27]([CH2:26][C:25]1[CH:24]=[CH:23][C:22]([NH:19][C:20]([NH:16][C:14]2[CH:15]=[C:10]([C:2]3[NH:1][C:9]4[C:4]([CH:3]=3)=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH:11]=[CH:12][C:13]=2[O:17][CH3:18])=[S:21])=[CH:36][CH:35]=1)(=[O:34])[O:31][CH2:32][CH3:33])[CH3:30]
Reactant: COc1ccc(-c2cc3ccccc3[nH]2)cc1N
Reactant: CCOP(=O)(Cc1ccc(N=C=S)cc1)OCC
Solvent: C1CCOC1
Product: CCOP(=O)(Cc1ccc(NC(=S)Nc2cc(-c3cc4ccccc4[nH]3)ccc2OC)cc1)OCC
Temperature: 50 °C
Reaction time: 6 h

Procedure:
The product from Example 1 (0.119 g, 0.5 mmol) and the product from Example 23, Step A (0.157 g, 0.54 mmol) were combined in tetrahydrofuran (8 mL), briefly heated to 50° C., and then allowed to stand for 6 hours at room temperature. The reaction mixture was concentrated to dryness and the residue triturated with hexanes/ethyl acetate. The product was collected by filtration (0.14 g), mp softening at 120° C., gradual decomposition.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:21]3[N:20]4[C:16](=[CH:17][CH:18]=[CH:19]4)[C:15](=[O:22])[C:14]=3[S:13][CH:12]=2)=[CH:7][CH:6]=1>C(Cl)(Cl)Cl>[Br:1][C:18]1[CH:17]=[C:16]2[N:20]([C:21]3[C:11]([C:8]4[CH:7]=[CH:6][C:5]([O:4][CH3:3])=[CH:10][CH:9]=4)=[CH:12][S:13][C:14]=3[C:15]2=[O:22])[CH:19]=1
Reactant: COc1ccc(-c2csc3c2-n2cccc2C3=O)cc1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2csc3c2-n2cc(Br)cc2C3=O)cc1
Reaction time: 2 h

Procedure:
2.1 mmol of bromine are added to a solution of 1.8 mmol of 3-(4-methoxyphenyl)-8H-thieno[2.3-b]pyrrolizin-8-one in 50 ml of chloroform. After two hours' stirring the solvent is evaporated off under reduced pressure. Chromatography on silica gel (dichloromethane) allows the expected product to be isolated.
Reaction SMILES: Br[CH:2]([CH3:17])[C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[CH:11]=2)[CH:6]=1)=[O:4].[CH2:18]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[BH4-].[Na+].NO>>[CH2:18]([N:25]1[CH2:30][CH2:29][N:28]([CH:2]([CH3:17])[C:3]([C:5]2[CH:14]=[CH:13][C:12]3[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[CH:11]=3)[CH:6]=2)=[O:4])[CH2:27][CH2:26]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: COc1ccc2cc(C(=O)C(C)Br)ccc2c1
Agent: NO
Agent: [BH4-]
Agent: [Na+]
Product: COc1ccc2cc(C(=O)C(C)N3CCN(Cc4ccccc4)CC3)ccc2c1
Yield: 54 %

Procedure:
From 2-bromo-1-(6-methoxy-2-naphtyl)-1-propanone and 1-benzylpiperazine, the compound 2-(4-benzyl-1-piperazinyl)-1-(6-methoxy-2-naphtyl)-1-propanone is prepared (MG 14256; m.p. 89°-91° C., which is reduced with NaBH4 to the corresponding amino alcohol as a mixture of the two stereoisomeric forms which are separated by flash chromatography.
Reaction SMILES: [C:1]1([CH2:7][C@H:8]([CH3:16])[CH2:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:17]([C@@H:19]1[C@@H:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:22][N:21]([C@H:30]([CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)[C:31]([O:33]CC2C=CC(OC)=CC=2)=[O:32])[CH2:20]1)=O>>[CH3:16][C@@H:8]([CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:9][CH:10]1[CH2:11][CH2:12][N:13]([CH2:17][C@@H:19]2[C@@H:23]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:22][N:21]([C@H:30]([CH:43]3[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]3)[C:31]([OH:33])=[O:32])[CH2:20]2)[CH2:14][CH2:15]1
Reactant: C[C@@H](Cc1ccccc1)CC1CCNCC1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Product: C[C@@H](Cc1ccccc1)CC1CCN(C[C@H]2CN([C@@H](C(=O)O)C3CCCCC3)C[C@@H]2c2ccccc2)CC1

Procedure:
The title compound was prepared from 15 mg (0.07 mmol) of 4-(3-phenyl-2-(R)-methylpropyl)piperidine (from EXAMPLE 99, Step C) and 31 mg (0.07 mmol) of 2-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-2-(cyclohexyl)acetic acid, (4-methoxy)benzyl ester (from EXAMPLE 33, Step E) using procedures analogous to those described in EXAMPLE 1, Step J and EXAMPLE 10, Step F. For the title compound: ESI-MS 517 (M+H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[Cl:15][C:16]1[N:21]=[C:20](Cl)[CH:19]=[CH:18][N:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[Cl:15][C:16]1[N:21]=[C:20]([O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)[CH:19]=[CH:18][N:17]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccnc(Cl)n2)CC1
Temperature: 80 °C
Yield: 80.7 %

Procedure:
To tert-butyl 4-hydroxypiperidine-1-carboxylate (389 mg, 1.933 mmol) and 2,4-dichloropyrimidine (240 mg, 1.611 mmol) in N,N-dimethylformamide (6.4 mL) was added cesium carbonate (1050 mg, 3.22 mmol) and the mixture was heated at 80° C. for 1 hour and then to 70° C. overnight. The reaction was then cooled to ambient temperature, diluted with ethyl acetate, and washed with water (3×) and brine (1×). The organic layer was dried, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-50% ethyl acetate/hexanes) to provide 410 mg (1.3 mmol, 81%) of tert-butyl 4-[(2-chloropyrimidin-4-yl)oxy]piperidine-1-carboxylate as white solid. MS APCI: [M+H]+ m/z 314.2.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[N:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[N:15]=1.[C:22](=[O:24])=[O:23].Cl>CCCCCC.O1CCCC1.[Cl-].[Na+]>[C:22]([C:17]1[C:16]([Cl:21])=[N:15][C:14]([Cl:13])=[N:19][C:18]=1[Cl:20])([OH:24])=[O:23]
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: O=C=O
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: O=C(O)c1c(Cl)nc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of diisopropylamine 2.54 g, a 1.6M solution of n-butyl lithium in hexane 15.7 ml and tetrahydrofuran 100 ml is stirred for 30 minutes on a dry ice-acetone bath. Thereto is added 2,4,6-trichloropyrimidine 2.00 g in tetrahydrofuran 8 ml over a period of 30 minutes, followed by further one hour agitation. The reaction mixture is poured into dry ice, and the mixture is stirred for a hour at room temperature. The reaction mixture is made acidic with 10% hydrochloric acid 20 ml, diluted with an aqueous saturated sodium chloride solution and extracted with ethyl acetate. The organic layer is washed, dried and concentrated in vacuo. The solvent is removed by azeotrope with chloroform and the resulting hemisolid is triturated with hexane to give 5-carboxy-2,4,6-trichloropyrimidine as a crystalline powder, 1.51 g. mp 150-153° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]([CH3:23])[C:12]2[CH:22]=[CH:21][C:15]([C:16]([O:18]CC)=[O:17])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.C(O)C.[OH-].[K+].Cl>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][N:11]([CH3:23])[C:12]2[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:21][CH:22]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(N(C)CCCc2ccc(Cl)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN(CCCc1ccc(Cl)cc1)c1ccc(C(=O)O)cc1

Procedure:
A 1.80 g. portion of 4-[[3-(p-chlorophenyl)propyl]methylamino]benzoic acid, ethyl ester is dissolved in 15 ml. of 95% ethanol. A 1 g. portion of potassium hydroxide is added, and the mixture is refluxed overnight. The solution is poured into 30 ml. of water, the pH is adjusted to 6 using 37% hydrochloric acid, and the solid is collected and dried. This solid is dissolved in benzene, filtered, and evaporated, giving 750 mg. of the desired product.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[C:7]([C:18]2[N:26]([S:27]([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[C:21]3=[N:22][CH:23]=[CH:24][CH:25]=[C:20]3[CH:19]=2)=[CH:6]1.[I-:37].[Na+]>C(C(C)=O)C>[I:37][CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[C:7]([C:18]2[N:26]([S:27]([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[C:21]3=[N:22][CH:23]=[CH:24][CH:25]=[C:20]3[CH:19]=2)=[CH:6]1
Reactant: [I-]
Reactant: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(CCCCl)c2cc1OC
Agent: [Na+]
Solvent: CCC(C)=O
Product: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(CCCI)c2cc1OC
Reaction time: 16 h

Procedure:
2-[1-(3-Chloropropyl)-5,6-dimethoxy-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.395 g; 753.8 μmol) and sodium iodide (0.169 g; 1.13 mmol) in methyl ethyl ketone (10 ml) are placed in a 50 ml single-necked flask, at reflux. After 16 hours, sodium iodide (0.169 g; 1.13 mmol) is added and reflux is maintained for a further 5 hours. The reaction mixture is evaporated under reduced pressure and the residue is then dissolved in 50 ml of ethyl acetate, transferred into a separating funnel and washed with 2 times 30 ml of distilled water. The organic extract is dried over magnesium sulfate, filtered and evaporated under reduced pressure, to give the crude compound, which is purified by chromatography on silica gel (10 g, silica 20-40 μm), elution being carried out at 10 ml/min with a mixture of cyclohexane and ethyl acetate (70/30; v/v). The fractions containing the expected compound are combined and evaporated to give 2-[1-(3-iodopropyl)-5,6-dimethoxy-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine in the form of an amorphous solid (0.287 g, 62%), the characteristics of which are as follows:
Reaction SMILES: C(O)(C)C.Cl.Cl[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[F:13].[CH3:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([NH2:24])[CH:16]=1.C([O-])([O-])=O.[Na+].[Na+]>O>[F:13][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:7]=1[NH:24][N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15]([CH3:14])=[CH:16]1
Reactant: Fc1cnccc1Cl
Reactant: Cc1cn(N)c2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: Cc1cn(Nc2ccncc2F)c2ccccc12
Temperature: 90 °C
Reaction time: 4 h
Yield: 63.7 %

Procedure:
To 200 ml isopropanol was added 4-chloro-3-fluoropyridine hydrochloride (10 g) and 3-methyl-1H-indole-1-amine (5.9 g). The mixture was stirred at 90° C. for four hours, cooled; then poured into 500 ml iced-water, pH adjusted to 10 with Na2CO3 solution, then extracted with ethyl acetate. The organic layer was washed with water, then dried (saturated NaCl, anhydrous MgSO4). After filtering, the solvent was evaporated to an oil, which was eluted on a silica gel column with CH2Cl2 (DCM) then with ether:petroleum ether (1:1) via flash chromatography. The desired fractions were combined then evaporated to yield 6.2 g of a solid, 45° C. A sample of this material was recrystallized from isopropyl ether/hexanes (1:1) to give a solid, m.p. 141°-142° C.
Reaction SMILES: [O-]CC.[Na+].Cl[C:6]1[N:7]([CH2:14][CH2:15][CH:16]([OH:29])[CH2:17][O:18]S(C2C=CC(C)=CC=2)(=O)=O)[CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[N:10]=1.[Cl:30][C:31]1[CH:50]=[CH:49][C:34]([O:35][CH2:36][C:37]2[O:38][CH:39]=[C:40]([C:42]3[CH:47]=[CH:46][C:45](O)=[CH:44][CH:43]=3)[N:41]=2)=[CH:33][CH:32]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[H-].[Na+]>CN(C)C=O.O.C(O)C>[Cl:30][C:31]1[CH:50]=[CH:49][C:34]([O:35][CH2:36][C:37]2[O:38][CH:39]=[C:40]([C:42]3[CH:47]=[CH:46][C:45]([O:18][CH2:17][CH:16]4[O:29][C:6]5=[N:10][C:9]([N+:11]([O-:13])=[O:12])=[CH:8][N:7]5[CH2:14][CH2:15]4)=[CH:44][CH:43]=3)[N:41]=2)=[CH:33][CH:32]=1
Reactant: Oc1ccc(-c2coc(COc3ccc(Cl)cc3)n2)cc1
Reactant: Cc1ccc(S(=O)(=O)OCC(O)CCn2cc([N+](=O)[O-])nc2Cl)cc1
Agent: CC[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1cn2c(n1)OC(COc1ccc(-c3coc(COc4ccc(Cl)cc4)n3)cc1)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.1 %

Procedure:
An ethanol solution (0.45 ml) of 20% sodium ethoxide was added to an ethanol solution (10 ml) of toluene-4-sulfonic acid 4-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxybutyl ester (0.52 g), and the mixture was stirred at room temperature for 30 minutes. 4-[2-(4-Chlorophenoxymethyl)oxazol-4-yl]phenol (0.40 g) and tripotassium phosphate (0.34 g) were added to the reaction mixture, and the resulting mixture was heated under reflux for 2 hours. Water was added thereto and the precipitated solid was collected by filtration and dried at 60° C. The residue thus obtained was dissolved in dimethylformamide (3 ml), and sodium hydride (53 mg) was added thereto, followed by stirring at room temperature for 1 hour. Water was added to the reaction mixture, followed by extraction with methylene chloride. The organic layer was dried over magnesium sulfate. After filtering, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride:methanol=10:0→methylene chloride:methanol=9:1) to afford the title compound as a pale yellow powder (0.34 g).
Reaction SMILES: Br[C:2]([F:19])([C:15]([F:18])([F:17])[F:16])[C:3]([F:14])([F:13])[O:4][C:5]1[C:10](Cl)=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12]>CS(C)=O.[Cu].C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:12][C:6]1[C:5]2[O:4][C:3]([F:14])([F:13])[C:2]([F:19])([C:15]([F:18])([F:17])[F:16])[C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: FC(F)(F)C(F)(Br)C(F)(F)Oc1c(Cl)cccc1Cl
Agent: [Cu]
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CS(C)=O
Product: FC(F)(F)C1(F)c2cccc(Cl)c2OC1(F)F
Yield: 47.1 %

Procedure:
In a manner similar to Step C of Example 2, the reaction of 12.8 g (0.033 mole) 2-(2-bromo-1,1,2,3,3,3-hexafluoropropanoxy)-1,3-dichlorobenzene, 10.4 g (0.16 mole) activated copper powder, and 2.3 g (0.0033 mole) bis(triphenylphosphine)palladium II chloride in 225 ml of dimethyl sulfoxide produced 4.3 g of 7-chloro-2,2,3-trifluro-3-trifluoromethyl-2,3-dihydrobenzofuran as an oil. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[CH:20][C:21]3[N:22]([C:24]([C:27]([F:30])([F:29])[F:28])=[N:25][N:26]=3)[N:23]=2)[CH2:14][CH2:13]1.Br.Br[CH2:33][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1>CC(N(C)C)=O>[CH3:10][N:11]([CH2:33][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1)[CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[CH:20][C:21]3[N:22]([C:24]([C:27]([F:30])([F:28])[F:29])=[N:25][N:26]=3)[N:23]=2)[CH2:14][CH2:13]1
Reactant: BrCc1cccnc1
Reactant: CNC1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CN(Cc1cccnc1)C1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Temperature: 150 °C
Yield: 84.9 %

Procedure:
DIPEA (0.174 mL, 1.00 mmol) was added to N-methyl-1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-amine (100 mg, 0.34 mmol) and 3-(bromomethyl)pyridine hydrobromide (127 mg, 0.50 mmol) in DMA (2 mL) and the mixture was sealed into a microwave tube. The reaction was heated to 150° C. for 15 minutes in the microwave reactor and cooled to ambient temperature. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford N-methyl-N-(pyridin-3-ylmethyl)-1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-amine (113 mg, 78%) as a solid.
Reaction SMILES: [NH:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3].[OH-].[Na+].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.Cl>O.C(#N)C>[S:18]([N:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3])([C:15]1[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=1)(=[O:20])=[O:19]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2cc(C)c(=O)[nH]c2=O)cc1
Temperature: 2.5 °C
Reaction time: 0.83 h
Yield: 97.4 %

Procedure:
To a mechanically stirred solution of 200.0 g thymine (1.586 mol) in a mixture of 1.33 l water and 65 g sodium hydroxide (1.6 mol) under nitrogen atmosphere were added simultaneously a solution of 378.1 g p-toluenesulphonyl chloride (1.98 mol) in 1.0 l acetonitrile over 60 min and a solution of 95.16 g NaOH (2.38 mol) in 0.330 l water added over 65 min while cooling the reaction in a water bath from an initial temperature of 40° C. to about 35° C. The reaction was stirred an additional 50 min following completion of the additions, and then cooled to 0-5° C. The reaction mixture was then acidified by adding 242 g conc. HCl (2.45 mol) over 10 min. The reaction mixture was stirred an additional 20 min at 0-5° C. followed by vacuum filtration. The solid was vacuum dried at 55° C. overnight. 433.1 g 1-tosylthymine (97% yield, white crystals) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.Br[CH2:13][CH2:14]Br.[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([C:10]#[N:11])[CH2:14][CH2:13]2)[CH:6]=[CH:7][CH:8]=1
Reactant: BrCCBr
Reactant: COc1cccc(CC#N)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1cccc(C2(C#N)CC2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.6 %

Procedure:
To a mixture of 2-(3-methoxyphenyl)acetonitrile (100 mg, 0.679 mmol), 1,2-dibromoethane (88 μL, 1.02 mmol) and tetrabutylammonium bromide (50 mg, 0.16 mmol) in toluene (1.0 mL) was added an aqueous solution of sodium hydroxide (50%, 500 mg in 0.5 mL of water, 12.5 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate (2 mL) and washed with water (0.5 mL×2) and brine (0.5 mL). The organics were dried over magnesium sulfate, filtered, concentrated under reduced pressure and dried under high vacuum. The residue was purified via flash chromatography (0-60% ethyl acetate in heptanes) to afford 1-(3-methoxyphenyl)cyclopropanecarbonitrile as an oil (56 mg, 48%). 1H NMR (500 MHz, CDCl3) δ 1.38-1.44 (m, 2H), 1.69-1.76 (m, 2H), 3.83 (s, 3H), 6.74-6.96 (m, 3H), 7.22-7.31 (m, 1H).
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([S:19][CH2:20][C:21]4[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=4)[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.S(=O)(=O)(O)O.[CH3:35]O>>[C:1]12([C:11]3[CH:12]=[C:13]([S:19][CH2:20][C:21]4[CH:29]=[CH:28][C:24]([C:25]([O:27][CH3:35])=[O:26])=[CH:23][CH:22]=4)[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: COc1ccc(SCc2ccc(C(=O)O)cc2)cc1C12CC3CC(CC(C3)C1)C2
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(CSc2ccc(OC)c(C34CC5CC(CC(C5)C3)C4)c2)cc1

Procedure:
5 g (12.3 mmol) of 4-[3-(1-adamantyl)-4-methoxyphenylthiomethyl]benzoic acid and 50 ml of methanol were introduced into a round-bottomed flask and 330 μl of concentrated sulfuric acid were added. The mixture was heated at reflux for eight hours and the reaction medium was then evaporated to dryness. The residue was taken up in water, neutralized with sodium bicarbonate and extracted with ethyl ether. The organic phase was separated out after settling had taken place, dried over magnesium sulfate and evaporated. The residue obtained was purified by chromatography on a column of silica, eluted with a mixture of dichloromethane and hexane (40/60). After evaporation of the solvents, 4.1 g (79%) of methyl 4-[3-(1-adamantyl)-4-methoxyphenylthiomethyl]benzoate were recovered.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]2[C:16](=[O:17])[C:15]3[CH:18]=[CH:19][C:20]([OH:22])=[CH:21][C:14]=3[O:13]2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[C:23](Cl)(=[O:26])[CH2:24][CH3:25].C(OCC)(=O)C>N1C=CC=CC=1>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH:11]=[C:12]2[C:16](=[O:17])[C:15]3[CH:18]=[CH:19][C:20]([O:22][C:23](=[O:26])[CH2:24][CH3:25])=[CH:21][C:14]=3[O:13]2)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: CCC(=O)Cl
Reactant: COc1cc(C=C2Oc3cc(O)ccc3C2=O)cc(OC)c1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCC(=O)Oc1ccc2c(c1)OC(=Cc1cc(OC)cc(OC)c1)C2=O
Temperature: 25 °C

Procedure:
After 2-[(3,5-dimethoxyphenyl)methylene]-6-hydroxy-3(2H)-benzofuranone 0.525 g was dissolved in pyridine 5 ml, propionyl chloride 0.218 ml was added, and the mixture was refluxed for 1.5 hours. The reaction mixture was cooled to room temperature, ethyl acetate 50 ml was added, and the mixture was washed with 2N-hydrochloric acid 50 ml, saturated sodium bicarbonate solution 50 ml, and a saturated sodium chloride solution 50 ml. The ethyl acetate solution was dehydrated with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was fractionated by silica gel column chromatography (silica gel: 50 g, eluted with solvent 500 ml of hexane:ethyl acetate=1:1) and the fraction was concentrated to dryness at a temperature of 40° C. under reduced pressure to obtain crystals. The crystals were recrystallized with ethyl acetate 5 ml/hexane 10 ml and filtered. The crystals were dried over phosphorous pentoxide at a temperature of 60° C. for five hours under reduced pressure to obtain the desired compound 275.1 mg.
Reaction SMILES: [NH2:1][C:2]1[N:9]=[C:8]([CH2:10][O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[N-:13]=[N+:14]=[N-:15].[Na+].Cl.C(N(CC)CC)C>CN1C(=O)CCC1>[CH3:12][O:11][CH2:10][C:8]1[N:9]=[C:2]([NH2:1])[C:3]([C:4]2[N:13]=[N:14][NH:15][N:5]=2)=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COCc1ccc(C#N)c(N)n1
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: COCc1ccc(-c2nn[nH]n2)c(N)n1
Temperature: 160 °C
Reaction time: 2 h
Yield: 67.3 %

Procedure:
2-Amino-6-methoxymethyl-nicotinonitrile (0.20 g) described in Manufacturing Example 6-2, sodium azide (0.40 g), triethylamine hydrochloride (1.7 g), and NMP (25 mL) were stirred for 2 hours at 160° C. The reaction solution was directly purified by silica gel chromatography (ethyl acetate, then ethyl acetate:methanol:concentrated aqueous ammonia=6:2:1). The organic layer thus obtained was concentrated and purified by silica gel chromatography (ethyl acetate:methanol=4:1) to obtain the titled compound (170 mg).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:11][C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]([OH:12])[CH2:4]1>O1CCOCC1.[O-2].[O-2].[Mn+4]>[OH:1][CH2:2][CH:3]1[CH2:11][C:7]2[S:8][CH:9]=[CH:10][C:6]=2[C:5](=[O:12])[CH2:4]1
Reactant: OCC1Cc2sccc2C(O)C1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: O=C1CC(CO)Cc2sccc21
Reaction time: 0.67 h
Yield: 61 %

Procedure:
6-(Hydroxymethyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-4-ol (1.2 g, 6.7 mmol) was dissolved in 1,4-dioxane (30 mL) and manganese dioxide (5.8 g, 67 mmol) was added portion-wise at room temperature. The mixture was stirred for 1 h 40 min. The solution was filtered through celite, washed with 1,4-dioxane and concentrated in vacuo. The crude residue was purified on silica gel using a gradient elution of 40-60% ethyl acetate in 40-60 petroleum ether to yield the title compound as a yellow oil (0.745 g, 62%).
Reaction SMILES: [C:1]1([C@H:7]2[C:12]3[NH:13][C:14]4[C:19]([C:11]=3[CH2:10][C@@H:9]([C:20](OC)=[O:21])[NH:8]2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:24]1([N:30]=[C:31]=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([N:30]2[C:20](=[O:21])[C@@H:9]3[N:8]([C@@H:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C:12]4[NH:13][C:14]5[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=5[C:11]=4[CH2:10]3)[C:31]2=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: COC(=O)[C@@H]1Cc2c([nH]c3ccccc23)[C@H](c2ccccc2)N1
Reactant: O=C=NC1CCCCC1
Product: O=C1[C@H]2Cc3c([nH]c4ccccc34)[C@H](c3ccccc3)N2C(=O)N1C1CCCCC1

Procedure:
The same method as employed in the preparation of Example 1 but starting from cis methyl 1,2,3,4-tetrahydro-1-phenyl-9H-pyrido[3,4-b]indole-3-carboxylate and cyclohexyl isocyanate gave after recrystallisation from methanol, the title compound as white crystals m.p.:267-270° C.