Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][NH:5][C:6](=[NH:22])[CH2:7][C:8]1([N:13]2[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[CH:15]=[CH:14]2)[CH2:12][CH2:11][CH2:10][CH2:9]1)(=[O:3])[CH3:2]>C(O)C.[Pd]>[C:1]([OH:4])(=[O:3])[CH3:2].[N:13]1([C:8]2([CH2:7][C:6]([NH2:22])=[NH:5])[CH2:12][CH2:11][CH2:10][CH2:9]2)[C:17]2=[N:18][CH:19]=[CH:20][CH:21]=[C:16]2[CH:15]=[CH:14]1
Reactant: CC(=O)ONC(=N)CC1(n2ccc3cccnc32)CCCC1
Agent: [Pd]
Solvent: CCO
Product: CC(=O)O
Product: N=C(N)CC1(n2ccc3cccnc32)CCCC1
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
To a stirred degassed solution of 2-(1-{1H-pyrrolo[2,3-b]pyridin-1-yl}cyclopentyl)ethanimidamido acetate (401) (500 mg, 1.67 mmol) in ethanol (20 mL) was added 10% Pd—C (50 mg) and stirring was continued 30 min under H2 (hydrogen-bludder) at room temperature (TLC, 50% ethyl acetate in hexane, Rf=0.1), The reaction mixture was filtered through a celite bed and washed with 10% methanol in dichloromethane (5×50 mL). The organic phase was thereafter dried and concentrated to get 2-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentyl)-acetamidine; compound with acetic acid (402) (437 mg, 87%) as an off-white solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]2[OH:24])=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[F:11][C:12]1[CH:13]=[CH:14][C:15]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19]2=[O:24])=[CH:16][CH:17]=1
Reactant: OC1CCCCC1c1ccc(F)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=C1CCCCC1c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 69.2 %

Procedure:
To a solution of oxalyl chloride (0.45 mL, 5.2 mmol) in dry dichloromethane (15 mL) at −78° C. is added a solution of DMSO (0.73 mL, 10.3 mmol) in dichloromethane (10 mL) dropwise, and the resulting mixture is allowed to stir at −78° C. for 30 minutes. Then a solution of 2-(4-Fluoro-phenyl)-cyclohexanol (500 mg, 2.57 mmol) in dichloromethane (5 mL) is added and stirred for 15 minutes. Then triethylamine (2.87 mL, 15.4 mmol) is added and the reaction is allowed to slowly warm up to 20° C. and stirred for 16 hours. The mixture is poured into ice-water (30 mL) and organic layer is washed with water (10 mL×5), then brine (10 mL×1) and dried over anhdrous sodium sulfate. After concentration, the crude is purified by silica flash column chromatography using EtOAc in Heptane (gradient from 0% to 30%) to give 342 mg of the desired product.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:17]([CH2:18][CH2:19][C@:3]12[CH3:4])[C@@H:16]1[C:11](=[CH:12][C:13](=[O:20])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3.[CH2:21]([O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][C:36](O)=[O:37])=[CH:30][CH:29]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C1CCC(N=C=NC2CCCCC2)CC1.C(O)(=O)C>N1C=CC=CC=1>[CH2:21]([O:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:34][CH2:35][C:36]([O:1][C@H:2]2[CH2:7][CH2:6][C@H:5]3[C@H:8]4[C@H:17]([CH2:18][CH2:19][C@:3]23[CH3:4])[C@@H:16]2[C:11](=[CH:12][C:13](=[O:20])[CH2:14][CH2:15]2)[CH2:10][CH2:9]4)=[O:37])=[CH:32][CH:33]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Reactant: CCCCCCOc1ccc(CCC(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: CCCCCCOc1ccc(CCC(=O)O[C@H]2CC[C@H]3[C@@H]4CCC5=CC(=O)CC[C@@H]5[C@H]4CC[C@]23C)cc1
Reaction time: 8 h
Yield: 87 %

Procedure:
To a solution of 17β-hydroxyestr-4-en-3-one (5.48 g) and 3-(4-hexyloxyphenyl)propionic acid (5.75 g) in dry pyridine (60 ml) pTSA (0.200 g) and DCC (5.77 g) are added. After 72 h stirring at room temperature acetic acid (2 ml) is added, and the reaction mixture is kept overnight at +4° C. The same work-up procedure as in Example 1 gives 17β-[3-(4-hexyloxyphenyl)-propanoyloxy]estr-4-en-3-one (m. p. 52°-3° C.) in a 87% yield after recrystallization from methanol/water.
Reaction SMILES: [CH3:1][I:2].[CH2:3]([O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][C:14]1[C:18]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[N:17][S:16][N:15]=1)[CH2:4][CH2:5][CH3:6]>>[I-:2].[CH2:3]([O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][C:14]1[C:18]([C:19]2[CH:20]=[N+:21]([CH3:1])[CH:22]=[CH:23][CH:24]=2)=[N:17][S:16][N:15]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCOCCOCCOc1nsnc1-c1cccnc1
Reactant: CI
Product: CCCCOCCOCCOc1nsnc1-c1ccc[n+](C)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of methyl iodide (0.5 ml, 9 mmol) and 3-(3-(2-(2-butoxyethoxy)ethoxy)-1,2,5-thiadiazol-4-yl)pyridine (3 mmol) inacetone (5 ml) was stirred at room temperature for 18 h. The title compoundprecipitated from the solution and was collected by filtration.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=2[CH:16](O)[CH:17]=[CH2:18])=[CH:4][CH:3]=1.C(OCC)C.[BrH:25].O>CCCCCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=2[CH:16]=[CH:17][CH2:18][Br:25])=[CH:4][CH:3]=1
Reactant: C=CC(O)c1c(F)cccc1Sc1ccc(F)cc1
Reactant: Br
Solvent: CCOCC
Solvent: O
Solvent: CCCCCC
Product: Fc1ccc(Sc2cccc(F)c2C=CCBr)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1-(2-(4-fluorophenylthio)-6-fluorophenyl)prop-2-en-1-ol (2.29 g, 8.23 mmol) is dissolved in 10 ml of hexane and 10 ml of diethyl ether and cooled in an ice bath. Concentrated HBr acid (4.6 ml, 41.2 mmol) is then added dropwise and the reaction mixture is stirred vigorously for 5 hours at room temperature. The reaction mixture is then poured into water and extracted twice with diethyl ether. The extracts are washed with water and then brine and dried over MgSO4 to afford the subtitle compound.
Reaction SMILES: [CH2:1]([N:4]([CH2:23][CH2:24][CH3:25])[C:5](=O)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:9]([NH2:21])[CH:8]=1)[CH2:2][CH3:3].B.[ClH:27].O>O1CCCC1>[ClH:27].[ClH:27].[CH2:14]([O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][N:4]([CH2:1][CH2:2][CH3:3])[CH2:23][CH2:24][CH3:25])=[CH:8][C:9]=1[NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCCN(CCC)C(=O)Cc1ccc(OCc2ccccc2)c(N)c1
Agent: B
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CCCN(CCC)CCc1ccc(OCc2ccccc2)c(N)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 13.9 g of 2-(3-amino-4-benzyloxyphenyl)acetic acid dipropylamide in 65 ml of tetrahydrofuran is added dropwise under a nitrogen atmosphere into 12 ml of a one-molar solution of borane in tetrahydrofuran, cooled to +5° C., during a period of 20 minutes. Subsequently, the mixture is agitated for 4 hours at room temperature and refluxed for 22 hours. The mixture is combined with semiconcentrated hydrochloric acid and water and the tetrahydrofuran is distilled off. The aqueous solution is then adjusted to a pH value of 10 with sodium hydroxide and extracted by shaking with ether. The ether solution yields, after evaporation and chromatography on silica gel with methylene chloride/acetone (1:1), 8.93 g of pure 2-benzyloxy-5-(2-dipropylaminoethyl)-aniline as an oil. Treatment of this product with 2N HCl in methanol and evaporation yield 2-benzyloxy-5-(2-dipropylaminoethyl)aniline, dihydrochloride, mp 111°-112° C.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:26]=[C:27]=[O:28])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[OH:29][CH2:30][CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][NH:33]1>C(Cl)Cl.C(Cl)(Cl)Cl>[OH:29][CH2:30][CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][N:33]1[N:26]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:27]=[O:28]
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Reactant: OCCC1CCCCN1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCN(C=O)N1CCCCC1CCO
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.1 %

Procedure:
Triethylamine (6.0 ml) and octadecyl isocyanate (11.500 g) were added to a solution of 2-(2-hydroxyethyl)piperidine (5.009 g) in methylene chloride (50 ml). After being stirred for 4 hours at room temperature, the reaction mixture was diluted with chloroform, washed with 1N hydrochloric acid, saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. The residue was purified by silica gel column chromatography (silica gel 200 g, chloroform:methanol=100:1~80:1), thereby yielding the entitled compound (15.662 g) as white solid.
Reaction SMILES: N[CH:2]([OH:6])[CH2:3][CH2:4][OH:5].[CH2:7](Br)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C([N:25](C(C)C)CC)(C)C>C(O)C>[CH2:7]([NH:25][CH:3]([CH2:4][OH:5])[CH2:2][OH:6])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCCCCCBr
Reactant: NC(O)CCO
Reactant: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCCCCCCCCCCCCCNC(CO)CO

Procedure:
3 g of 2 amino-1,3-propanediol were dissolved in 100 ml ethanol, 4 ml tetradecyl bromide were added followed by 5 ml diisopropyl ethylamine. The mixture was heated to reflux for 24 hours in a 250 ml round bottom flask equipped with a reflux condenser and stirred on a magnetic stirrer. The solution was evaporated to dryness and dissolved in 200 ml dichloromethane:methanol, 2:1, transferred to a 500 ml separatory funnel and washed with 75 ml 0.2N HCl. Phases were separated and the organic phase was washed again with 75 ml 0.1N HCl and 15 ml methanol. The organic phase was separated and dried on 5 g magnesium sulfate, filtered and evaporated to dryness. The resulted oil was crystallized from ethanol: H2O. Yield 1.2 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[N:10]([CH:22]=[N:23][N:24]=3)[C:11](SC)=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:31]1([CH2:37][C@H:38]([NH2:41])[CH2:39][NH2:40])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[N:10]([CH:22]=[N:23][N:24]=3)[C:11]([NH:40][CH2:39][C@@H:38]([NH2:41])[CH2:37][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1
Reactant: NC[C@@H](N)Cc1ccccc1
Reactant: CSc1nc(-c2ccncc2)c(-c2ccc(F)cc2)c2nncn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N[C@H](CNc1nc(-c2ccncc2)c(-c2ccc(F)cc2)c2nncn12)Cc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 8-(4-fluorophenyl)-5-methylthio-7-(4-pyridyl)-1,2,4-triazolo[4,3-c]pyrimidine (1.0 g, 3.0 mmole), potassium carbonate (1.5 g) and (2S)-3-phenylpropane-1,2-diamine (540 mg, 3.6 mmole) in 50 ml of DMF was stirred at room temperature (RT) for 48 hours. The reaction solution was poured into water (200 mL), and the resulting precipitate was filtered and washed with water. The crude product was purified by flash chromatography (3%-15% MeOH/NH3 in DCM) to provide 1-(8-(4-fluorophenyl)-7-(4-pyridyl)-1,2,4-triazolo[4,3-c]pyrimidin-5-yl)amino-2(S)-amino-3-phenylpropane was obtained as white solid; MS: m/z (M+H)+ 440.1; C25H22FN7 requir. 439.5.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH2:8])[CH2:4][CH2:3]1.[CH3:9][S:10]([Cl:13])(=[O:12])=[O:11]>C(Cl)Cl>[ClH:13].[NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][S:10]([CH3:9])(=[O:12])=[O:11])[CH2:4][CH2:3]1
Reactant: CS(=O)(=O)Cl
Reactant: N[C@H]1CC[C@H](N)CC1
Solvent: ClCCl
Product: CS(=O)(=O)NC1CCC(N)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
To trans 1,4-diaminocyclohexane (2.0 g, 17.5 mmol) in DCM at 0° C. (ice bath) was added methanesulfonyl chloride (1.63 mL, 21.0 mmol). The reaction was allowed to stir at RT for 1 h when a precipitate formed and was collected on a glass frit, rinsed with DCM, and dried to afford 2.56 g (64%) of 360.
Reaction SMILES: [P:1]([O:10]C(C)C)([O:6]C(C)C)[O:2]C(C)C.[P:14]([CH:18]1[CH2:22][CH2:21][CH:20](Br)[O:19]1)([OH:17])([OH:16])=[O:15].Cl>>[P:14]([CH:18]1[CH2:22][CH2:21][CH:20]([P:1]([OH:2])([OH:6])=[O:10])[O:19]1)([OH:17])([OH:16])=[O:15]
Reactant: O=P(O)(O)C1CCC(Br)O1
Reactant: CC(C)OP(OC(C)C)OC(C)C
Agent: Cl
Product: O=P(O)(O)C1CCC(P(=O)(O)O)O1
Temperature: 170 °C

Procedure:
Triisopropyl phosphite (0.33 ml, 1.2 mmol) was added to the 2-phosphono-5-bromotetrahydrofuran prepared in accordance with the process of Example II. The mixture was heated over a period of one half hour under a nitrogen atmosphere to 170° C. It was held at this temperature for two and one quarter hours and then cooled to room temperature. Concentrated hydrochloric acid (15 ml) was added and the resulting mixture was heated to reflux for five hours. The volatile components were removed under vacuum leaving 2,5-diphosphonotetrahydrofuran ("DPTHF") containing phosphorous acid as an impurity. The identity of the 2,5-diphosphonotetrahydrofuran was established by nuclear magnetic resonance spectroscopy (proton, phosphorus and carbon-13) and fast atom bombardment mass spectroscopy
Reaction SMILES: ClN1C(=O)CCC1=O.[C:9]1([SH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[Li].C([Li])CCC.S1C=CC=C1>C1C=CC=CC=1.O1CCCC1>[C:9]1([S:15][C:17]2[S:16][CH:20]=[CH:19][CH:18]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Sc1ccccc1
Reactant: [Li]c1cccs1
Agent: O=C1CCC(=O)N1Cl
Agent: [Li]CCCC
Solvent: c1ccsc1
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: c1ccc(Sc2cccs2)cc1
Temperature: -15 °C
Reaction time: 1 h

Procedure:
To a suspension of N-chlorosuccinimide (7.8 g) in benzene (30 ml) was added dropwise, a solution of thiophenol (5.51 g) in benzene (20 ml) at room temperature. After 1 hour, the suspension was filtered, the filter pad washed with benzene and the filtrate evaporated under reduced pressure to give an orange oil. The oil was dissolved in dry tetrahydrofuran (20 ml) and added dropwise to a solution of 2-thienyl-lithium (prepared by the addition of n-butyllithium (20 ml, 2.5M) to thiophene (4.2 g) in dry tetrahydrofuran (30 ml) at -15° C. under nitrogen and stirred for 2 hours) at -15° C. under N2. The solution was stirred for 1 hour, allowed to warm to room temperature and stirred overnight. The reaction mixture was poured on to ice, extracted with ether (3×100 ml), dried over MgSO4 and evaporated under reduced pressure to give a brown oil. The oil was flash chromatographed on a Sorbsil C60-40/60H column using petroleum ether (40°-60° C.) to give a colourless oil, b.p. 161° C./20 mm pressure.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[CH:6][N:5]=[C:4]1[SH:8])[CH3:2].[NH2:9][C:10]1[CH:15]=[N:14][C:13]([CH3:16])=[CH:12][N:11]=1.Cl[C:18]1[C:19]2[N:27]=[C:26](Cl)[CH:25]=[CH:24][C:20]=2[N:21]=[CH:22][N:23]=1>>[CH2:1]([N:3]1[CH:7]=[CH:6][N:5]=[C:4]1[S:8][C:26]1[CH:25]=[CH:24][C:20]2[N:21]=[CH:22][N:23]=[C:18]([NH:9][C:10]3[CH:15]=[N:14][C:13]([CH3:16])=[CH:12][N:11]=3)[C:19]=2[N:27]=1)[CH3:2]
Reactant: Clc1ccc2ncnc(Cl)c2n1
Reactant: Cc1cnc(N)cn1
Reactant: CCn1ccnc1S
Product: CCn1ccnc1Sc1ccc2ncnc(Nc3cnc(C)cn3)c2n1

Procedure:
The compound of Example 45 was manufactured by the same method as in Example 31, by a similar method thereto or by a combination of such a method with a conventional method using 1-ethyl-2-mercaptoimidazole, 2-amino-5-methylpyrazine and 4,6-dichloropyrido-[3,2-d]pyrimidine.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[O:31][CH2:32][CH:33]4[CH2:35][CH2:34]4)[C:15]=3[NH:14][C:13]=2[CH3:36])=[O:11])[CH2:5][CH2:4]1.[CH3:37][O:38][CH2:39][C:40](Cl)=[O:41]>>[CH:33]1([CH2:32][O:31][C:22]2[CH:23]=[CH:24][C:25]([C:27]([F:30])([F:29])[F:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:36])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:40](=[O:41])[CH2:39][O:38][CH3:37])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:35]1
Reactant: COCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(C(F)(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@@H](N)CC1
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)(F)F)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-(trifluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f33) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][C:2]([CH2:16][CH2:17][CH:18]=[C:19]([CH3:26])[CH2:20][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])=[CH:3][CH2:4][N:5]1C(=O)C2C(=CC=CC=2)C1=O.CNN.[OH-].[Na+]>C(O)C>[CH2:4]([NH2:5])[CH:3]=[C:2]([CH2:16][CH2:17][CH:18]=[C:19]([CH2:20][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])[CH3:26])[CH3:1]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCN1C(=O)c2ccccc2C1=O
Agent: CNN
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)=CCCC(C)=CCCC(C)=CCN
Temperature: 25 °C
Reaction time: 4 h
Yield: 89 %

Procedure:
A solution 2.50 g (7.1 mmol) of Part (1) compound in 15 ml of absolute ethanol at room temperature under argon was treated with 1.9 ml (35.57 mmol, 5.0 eq.) of methyl hydrazine and stirred for 2 hours at room temperature and 4 hours at reflux. After cooling and the addition of 7.1 ml (7.1 mmol, 1.0 eq.) of 1M NaOH, the ethanol was removed under reduced pressure. The residue was extracted with 350 ml of ethyl ether and the ether layer washed with 100 ml of lM NaOH, 50 ml of H2O and 50 ml of brine, dried (MgSO4) and evaporated to obtain 1.45 g of crude product. Purification by bulb-to-bulb distillation at 120° C./0.005 mm provided 1.405 g (89%) of title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:12]([C:16]1[O:20][N:19]=[C:18]([NH:21][C:22]([CH:24]2[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]2)=[O:23])[CH:17]=1)([CH3:15])([CH3:14])[CH3:13].Cl.C(N(CC)C(C)C)(C)C>CN(C=O)C.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[C:12]([C:16]1[O:20][N:19]=[C:18]([NH:21][C:22]([CH:24]2[CH2:29][CH2:28][CH2:27][N:26]([S:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)(=[O:10])=[O:9])[CH2:25]2)=[O:23])[CH:17]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CC(C)(C)c1cc(NC(=O)C2CCCNC2)no1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1cc(NC(=O)C2CCCN(S(=O)(=O)c3ccc(Cl)cc3)C2)no1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-chlorophenylsulfonyl chloride (117.35 mg; 0.556 mmol) in DMF (2 mL) is added piperidine-3-carboxylic acid (5-tert-butyl-isoxazol-3-yl)-amide; hydrochloride (160 mg; 0.556 mmol), N,N-diisopropylethylamine (0.261 mL; 1.5 mmol) and 4-dimethylaminopyridine (2 mg, 0.016 mmol). The reaction mixture is left stirring at room temperature for 18 hours. After this time, the mixture is diluted with ethyl acetate and washed with water 3 times, then brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography on silica using methanol/methylene chloride provides the title compound, m/z 426/428 [M+H+].
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][O:8][CH:7]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)[O:6][CH2:5]1)[CH2:2][CH3:3].C([Li])CCC.Br[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1.O>C1COCC1.CCCCCC.[Cl-].[Zn+2].[Cl-]>[CH2:1]([CH:4]1[CH2:5][O:6][CH:7]([C:10]2[CH:15]=[C:14]([F:16])[C:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)=[C:12]([F:17])[CH:11]=2)[O:8][CH2:9]1)[CH2:2][CH3:3]
Reactant: CCCC1COC(c2cc(F)cc(F)c2)OC1
Reactant: Clc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC1COC(c2cc(F)c(-c3ccc(Cl)cc3)c(F)c2)OC1
Temperature: -60 °C
Reaction time: 0.83 h
Yield: 56.3 %

Procedure:
5-Propyl-2-(3,5-difluorophenyl)-1,3-dioxane (5.0 g; 20.6 mmol), which had been synthesized in Step 1 of Example 1, was dissolved in THF (50 ml), and the solution was cooled to -60° C. in a nitrogen atmosphere. A solution (16.1 ml; 25.8 mmol) of 1.60M n-butyl lithium in hexane was added dropwise thereto so that the temperature of the mixture did not exceed -55° C. The mixture was stirred for 50 minutes with the temperature being maintained below -55° C. Subsequently, a solution (51.6 ml; 25.8 mmol) of 0.5M zinc chloride in THF was added dropwise so that the temperature of the mixture did not exceed -50° C. Thereafter, the mixture was warmed to room temperature and stirred for 30 minutes. Tetrakistriphenylphosphine palladium (0.5 g) and 1-bromo-4-chlorobenzene (4.94 g; 25.8 mmol) were added, and the mixture was refluxed for 3 hours. Water (100 ml) was added to the resultant reaction mixture, and the material produced was extracted with toluene. The extract was sequentially washed with saturated ammonium chloride solution, saturated sodium bicarbonate solution and saturated brine and dried over magnesium sulfate. Subsequently, the solvent was evaporated. The residue was purified by column chromatography (eluent: toluene). The solvent was evaporated, and the residue was recrystallized twice from heptane, to thereby obtain 4.10 g (11.6 mmol) of 5-propyl-2-(4-(4-chlorophenyl)-3,5-difluorophenyl)-1,3-dioxane. The yield of this compound from 5-propyl-2-(3,5-difluorophenyl)-1,3-dioxane was 56.3%.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[F:16])[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C:18]1([CH3:26])[C:20]([CH3:22])([CH3:21])[CH:19]1[C:23](Cl)=[O:24].[C-:27]#[N:28].[Na+].O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.CCCCCC>[C:27]([CH:11]([O:12][C:23]([CH:19]1[C:18]([CH3:26])([CH3:17])[C:20]1([CH3:22])[CH3:21])=[O:24])[C:10]1[CH:13]=[CH:14][C:15]([F:16])=[C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:9]=1)#[N:28]
Reactant: [C-]#N
Reactant: O=Cc1ccc(F)c(Oc2ccccc2)c1
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)C(C(=O)OC(C#N)c2ccc(F)c(Oc3ccccc3)c2)C1(C)C
Yield: 786 %

Procedure:
5 g (0.0232 mol) of 3-phenoxy-4-fluoro-benzaldehyde and 3.72 g (0.0232 mol) of 2,2,3,3-tetramethylcyclopropanecarboxylic acid chloride were together added dropwise to a mixture of 1.8 g of sodium cyanide, 2.7 ml of water, 100 ml of n-hexane and 0.6 g of tetrabutylammonium bromide at 20°-25° C., while stirring, and the mixture was then stirred at 20°-25° C. for 4 hours. 300 ml of toluene were then added to the reaction mixture and the mixture was extracted twice by shaking with 300 ml of water each time. The organic phase was separated off and dried over magnesium sulphate and the solvent was distilled off under a waterpump vacuum. Last residues of solvent were removed by brief incipient distillation at a bath temperature of 60° C./1 mm Hg. 67 g (78.7% of theory) of 2,2,3,3-tetramethylcyclopropanecarboxylic acid α-cyano-3-phenoxy-4-fluoro-benzyl ester were obtained as a yellow oil with a refractive index nD24 of 1.5732.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:8][C:9]=1[NH:10][CH:11]1[CH2:16][CH2:15][S:14][CH2:13][CH2:12]1)=[O:4].[CH3:23][CH:24]1[CH2:29][CH2:28][CH:27]([C:30](Cl)=[O:31])[CH2:26][CH2:25]1>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:8][C:9]=1[N:10]([C:30]([C@H:27]1[CH2:28][CH2:29][C@H:24]([CH3:23])[CH2:25][CH2:26]1)=[O:31])[CH:11]1[CH2:12][CH2:13][S:14][CH2:15][CH2:16]1)=[O:4]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1NC1CCSCC1
Reactant: CC1CCC(C(=O)Cl)CC1
Product: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCSCC1

Procedure:
Amidation of 5-phenyl-3-(tetrahydro-thiopyran-4-ylamino)-thiophene-2-carboxylic acid methyl ester (0.2 g, 0.6 mmol) and 4-Methyl-cyclohexanecarbonyl chloride was carried out as described for example 19, step 2 gave 3-[(trans-4-methyl-cyclohexanecarbonyl)-(tetrahydro-thiopyran-4-yl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (0.208 g, 75.7%). NMR 1H (CDCl3, 400 MHz): 7.68-7.62 (m, 2H), 7.5-7.4 (m, 3H), 7.04 (s, 1H), 4.68-4.58 (m, 1H), 3.86 (s, 3H), 2.9-1.2 (m, 16H), 0.78 (d, 3H), 0.76-0.56 (m, 2H).s