Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:12][O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1.[Li]CCCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:35])(=O)=O)=CC=1.O>C1COCC1>[F:35][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:12][O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1
Reactant: Brc1c(COC2CCCCO2)ccc2c1CCCC2
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Fc1c(COC2CCCCO2)ccc2c1CCCC2
Temperature: 23 °C
Reaction time: 1 h

Procedure:
To stirring solution of bromide 47.5 (1.0 g, 3.1 mmol) in THF at −78° C. is added n-BuLi (1.6 M, 2.11 mL, 3.4 mmol), and stirring is continued for 1 hour. N-Fluorobenzene sulfonimide (3.7 mmol) is added and the mixture is allowed to warm to 23° C. Water is added to quench the reaction. The aqueous layer is extracted with EtOAc (3×100 mL), and the organic layer is dried over MgSO4 and concentrated in vacuo. The residue is purified by column chromatography (silica, EtOAc/Hexane), to afford fluoride 47.6.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH2:8][CH2:7]2)(=O)[CH3:2].C([O:15][C:16](=O)[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[NH2:19])C.[Al+3].[Cl-].[Cl-].[Cl-].CCCCCC>C1(OC2C=CC=CC=2)C=CC=CC=1.CO>[CH2:9]1[C:10]2[C:6](=[CH:5][C:4]([C:1]3[NH:19][C:18]4[C:17]([C:16](=[O:15])[CH:2]=3)=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:12][CH:11]=2)[CH2:7][CH2:8]1
Reactant: CCOC(=O)c1ccccc1N
Reactant: CC(=O)c1ccc2c(c1)CCC2
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CO
Solvent: CCCCCC
Product: O=c1cc(-c2ccc3c(c2)CCC3)[nH]c2ccccc12
Temperature: 200 °C
Reaction time: 2.5 h
Yield: 89 %

Procedure:
To a mixture of 5-acetylindane (3.0 g, 18.7 mmol) and anthranilic acid ethyl ester (2.8 ml, 18.7 mmol) in diphenylether (47 g) was added portionwise AlCl3 (3.5 g, 26.2 mmol). The reaction mixture was stirred at 200° C. for 2.5 hours and cooled to room temperature. Hexane (100 ml) and MeOH (3 ml) were then added. The so obtained solid was filtered, washed with hexane and stirred in the presence of 5N HCl (85 ml) and acetone (10 ml). After filtration, the solid was again washed with H2O, and stirred with MeOH (15 ml) for 30 min. Filtration provided 2-indan-5-yl-1 H-quinolin-4-one (4.35 g, 89%) as a light yellow solid, MS: m/e=261 (M+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([SH:9])=[C:4]([CH3:10])[CH:3]=1.[NH2:11][C:12]([CH3:16])([CH3:15])[CH2:13]O.[C:17](O)(=[O:20])[CH2:18][CH3:19]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([S:9][CH2:13][C:12]([NH:11][C:17](=[O:20])[CH2:18][CH3:19])([CH3:16])[CH3:15])=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(Cl)c(C)cc1S
Reactant: CC(C)(N)CO
Reactant: CCC(=O)O
Solvent: Cc1ccccc1
Product: CCC(=O)NC(C)(C)CSc1cc(C)c(Cl)cc1C

Procedure:
A mixture of 4-chloro-2,5-dimethylbenzenethiol (17.25 g), 2-amino-2-methylpropanol (8.9 g), propionic acid (7.4 g) and toluene (50 ml) was reacted to give a solid which was recrystallised from petroleum ether, b.p. 60°-80° C. to give N-[2-(4-chloro-2,5-xylylthio)-1,1-dimethylethyl]propionamide, m.p. 78°-81° C. This product (15.0 g) and concentrated hydrochloric acid (18 ml) were boiled under reflux for 25 hours give an oil which was purified by flash column chromatography on silica using ethyl acetate and then ethyl acetate/methanol (4:1) as the mobile phase to give 2-(4-chloro-2,5-xylylthio)-1,1-dimethylethylamine as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:18]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11](Cl)[N:10]=1.[Cl:27][C:28]1[CH:29]=[N:30][CH:31]=[C:32]([OH:34])[CH:33]=1>>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]2[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])=[N:10][C:11]([O:34][C:32]3[CH:31]=[N:30][CH:29]=[C:28]([Cl:27])[CH:33]=3)=[C:12]([CH:17]=2)[C:13]([O:15][CH3:16])=[O:14])=[CH:20][CH:21]=1
Reactant: COC(=O)c1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1Cl
Reactant: Oc1cncc(Cl)c1
Product: COC(=O)c1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1Oc1cncc(Cl)c1

Procedure:
Using the procedure described in Example 84, methyl 6-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-2-chloro-nicotinate Example 83 was reacted with 3-chloro-5-hydroxypyridine to afford the title compound: m/e=521 (M+3); Rt=4.65 min
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([OH:13])=[N:10][S:11][N:12]=2)=[CH:4][CH:3]=1.[C:14](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([O:13][CH3:14])=[N:10][S:11][N:12]=2)=[CH:6][CH:7]=1
Reactant: Oc1nsnc1-c1ccc(Cl)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1nsnc1-c1ccc(Cl)cc1
Yield: 86.3 %

Procedure:
By the method of L. Weinstock, et al., supra, 0.5 g (0.0023 mole) 4-(4-chlorophenyl)-3-hydroxy-1,2,5-thiadiazole, 0.36 g (0.0026 mole) of potassium carbonate and 0.37 g (0.0026 mole) of iodomethane in 15 ml of N,N-dimethylformamide were reacted to produce 0.45 g of 4-(4-chlorophenyl)-3-methoxy-1,2,5-thiadiazole, Compound 25 of Table I. Compounds 22-24, 26-29, 31, 35, 37, and 39-41 were also prepared by this method, except that, in some cases sodium carbonate was used in place of potassium carbonate and/or an appropriate bromide or chloride was used in place of methyl iodide.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[CH2:10][CH:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=2)[C:12]1=[O:23])(=[O:3])[CH3:2].[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][Br:29]>>[Br-:29].[C:1]([C:4]1[CH:5]=[N+:6]([CH2:28][C:27]2[CH:30]=[CH:31][CH:32]=[C:25]([Cl:24])[CH:26]=2)[CH:7]=[CH:8][C:9]=1[CH2:10][CH:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=2)[C:12]1=[O:23])(=[O:3])[CH3:2]
Reactant: COc1ccc2c(c1)CCC(Cc1ccncc1C(C)=O)C2=O
Reactant: Clc1cccc(CBr)c1
Product: COc1ccc2c(c1)CCC(Cc1cc[n+](Cc3cccc(Cl)c3)cc1C(C)=O)C2=O
Product: [Br-]

Procedure:
The title compound 122 is prepared according to the procedure reported in Example 38.1 with compound 103 (62 mg, 0.2 mmol) and 3-chlorobenzyl bromide (39 μL, 0.3 mmol) as reactants. White solid. (Yield 75.0 mg, 73%).
Reaction SMILES: [CH:1]([CH:3]1[CH2:5][CH:4]1[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:2].[BH4-].[Na+].O.CCOC(C)=O>CO>[CH2:9]([O:8][C:6]([CH:4]1[CH2:5][CH:3]1[CH2:1][OH:2])=[O:7])[CH3:10]
Reactant: CCOC(=O)C1CC1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CC1CO
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Ethyl 2-formyl-1-cyclopropanecarboxylate (2 ml, 15.11 mmol) was dissolved in methanol (35 ml) and cooled to 0° C. under N2. Sodium borohydride (1.2 g, 31.7 mmol) was added in portions and resulting solution stirred at 0° C. for 2 h. The solution was then diluted by the dropwise addition of water, followed by the addition of EtOAc (100 mL). The aqueous layer was separated and extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine, dried over sodium sulphate and concentrated in vacuo to give the title compound. TLC: 20% EtOAc/hexanes, high Rf: 0.35, low Rf: 0.3.
Reaction SMILES: C([CH2:3]/[C:4](/[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=2[F:26])=[C:13]([O:27][CH2:28][CH2:29][CH2:30][OH:31])[CH:12]=1)=[C:5](/CC)\[C:6]([NH2:8])=[O:7])C.[C:32]([O-])(=O)[CH3:33].[Na+].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=[CH:48][CH:47]=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH2:47]([N:8]([CH2:32][CH3:33])[C:6](=[O:7])/[CH:5]=[C:4](/[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=2[F:25])=[C:13]([O:27][CH2:28][CH2:29][CH:30]=[O:31])[CH:12]=1)\[CH3:3])[CH3:48]
Reactant: CC(=O)[O-]
Reactant: CCC/C(=C(/CC)C(N)=O)c1ccc(OCc2c(F)cccc2F)c(OCCCO)c1
Reactant: c1cc[nH+]cc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCN(CC)C(=O)/C=C(\C)c1ccc(OCc2c(F)cccc2F)c(OCCC=O)c1
Reaction time: 2.5 h

Procedure:
To a solution of diethyl (E)-3-[4-(2,6-difluorobenzyloxy)-3-(3-hydroxypropoxy)-phenyl]-2-butenamide (2.22 g, 5.13 mmol) and anhydrous sodium acetate (5.05 g, 61.53 mmol) in CH2Cl2 (100 mL) is added pyridinium dichromate (6.63 g, 30.76 mmol) and the mixture is stirred for 2.5 hours. At this time, 2 g celite is added to the mixture, and the resulting mixture is filtered through celite, and the solid is washed with CH2Cl2 (50 mL). The filtrate is concentrated in vacuo, and the residue is filtered through a column of florisil, yielding N,N-diethyl (E)-3-[4-(2,6-difluorobenzyloxy)-3-(3-oxopropyloxy)-phenyl]-2-butenamide, as a brown oil. This crude product is carried on directly to the next step.
Reaction SMILES: Cl.[CH2:2]([O:9][C@H:10]1[C@H:26]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C@@H:25]([CH2:35][O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[O:24][C@H:11]1OC(=O)C1C=CC([N+]([O-])=O)=CC=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([NH:47][C:48]1[N:56]=[C:55]2[C:51]([NH:52][CH:53]=[N:54]2)=[C:50]([NH:57]C(=O)C)[N:49]=1)(=O)C>C(Cl)Cl.C(Cl)CCl>[NH2:47][C:48]1[N:56]=[C:55]2[C:51]([N:52]=[CH:53][N:54]2[C@@H:11]2[O:24][C@H:25]([CH2:35][O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C@@H:26]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C@@H:10]2[O:9][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[C:50]([NH2:57])[N:49]=1
Reactant: O=C(O[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1)c1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)Nc1nc(NC(C)=O)c2[nH]cnc2n1
Agent: Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: Nc1nc(N)c2ncn([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@@H]3OCc3ccccc3)c2n1

Procedure:
Dry HCl gas was bubbled into a solution of 2,3,5-tri-O-benzyl-1-O-p-nitrobenzoyl-β-D-arabinofuranose (17 g, 30 mmol) in CH2Cl2 (187 ml) at -10°-0° for 21/2 hr. The precipitated p-nitrobenzoic acid was removed by filtration and washed with CH2Cl2. The CH2Cl2 solution was evaporated in vacuo. The residue, dissolved in 500 ml of ethylene chloride, was added to a mixture of 2.6-diacetamidopurine (7.03 g, 30 mmol) and molecular sieve (Linde 4A, 75 g) in 500 ml of ethylene chloride. This mixture was refluxed until all the chlorosugar was consumed (TLC) (8-11 days). The mixture was then stirred with Celite and filtered. The solid was washed with CHCl3, and the combined filtrates were evaporated to dryness in vacuo. The residue was dissolved in benzene and filtered (to remove unreacted 2,6-diacetamidopurine). The filtrate was again evaporated to dryness in vacuo and the residue dissolved in 100 ml of 1 N methanolic NaOMe. After a 3-hr reflux period, the solution was chilled, neutralized with acetic acid, and refrigerated overnight. The solid that precipitated was removed by filtration, washed with MeOH, and dried in vacuo; yield 5.6 g (34%); mp 159°-161°; TLC homogenous.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=2[C:13]([OH:15])=[O:14])=[O:10])=[CH:5][CH:4]=1.S(Cl)(Cl)=O.CO.N1CCCC[CH2:28]1>C(Cl)CCl>[CH3:28][O:10][C:9]1([C:6]2[CH:5]=[CH:4][C:3]([N:2]([CH3:20])[CH3:1])=[CH:8][CH:7]=2)[C:11]2[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:13](=[O:15])[O:14]1
Reactant: C1CCNCC1
Reactant: CN(C)c1ccc(C(=O)c2ccccc2C(=O)O)cc1
Solvent: O=S(Cl)Cl
Solvent: CO
Solvent: ClCCCl
Product: COC1(c2ccc(N(C)C)cc2)OC(=O)c2ccccc21

Procedure:
Following a procedure similar to that described in Example 1 above, 4.5 g of 2-(4-dimethylaminophenyl)carbonylbenzoic acid, 1.2 ml of thionyl chloride and 5.0 ml of methyl alcohol were interacted in 30.0 ml of ethylene dichloride in the presence of 1.3 ml of piperidine at ambient temperature for approximately ten minutes to obtain 4.0 g of 3-methoxy-3-(4-dimethylaminophenyl)phthalide (Formula II: R0 =R=R1 =R2 =R5 =H; R4 =R4' =R5 =Y=CH3 ; X=O), a pale peach-colored solid which melted at 112.5° to 114.5° C. A significant infrared maximum appeared at 1773 cm-1 (C=O;s). The nulcear magnetic resonance spectrum was consistent with the assigned structure. Analysis by mass spectrum showed m/e peaks at 283 (M+) and 252 (M+ -OCH3). A toluene solution of the product spotted on an acidic clay-coated paper developed a yellow-colored image.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[C:5]([O:14][CH3:15])(=[O:13])[C:6]1[C:7](=[CH:9][CH:10]=[CH:11][CH:12]=1)[OH:8].C(=O)([O-])[O-].[K+].[K+].O>C1COCC1.CN(C=O)C>[CH2:1]([O:8][C:7]1[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=1[C:5]([O:14][CH3:15])=[O:13])[CH:2]=[CH2:3]
Reactant: COC(=O)c1ccccc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: C=CCOc1ccccc1C(=O)OC

Procedure:
A mixture of allyl bromide (152.4 g, 1.27 mol), methyl salicylate (162.44 g, 1.06 mol), and potassium carbonate (219.75 g, 1.59 mol) in THF (600 ml) and DMF (600 ml) was heated to reflux for 6 hr. The mixture was poured into water (3L) and extracted with ethyl acetate three times. The ethyl acetate extracts were combined and washed with water and dried with brine. The ethyl acetate extracts were concentrated in vacuo to a yellow oil that was vacuum distilled to a clear oil (163.45 g, 80%).
Reaction SMILES: C([O:4][C:5]1[C:14]2[CH:15]=[C:16]([NH2:18])[CH:17]=[C:12]3[C:13]=2[N:8]([CH2:9][CH2:10][O:11]3)[C:7](=[O:19])[C:6]=1[C:20]([N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23]1)=[O:21])(=O)C.[C:31](=[O:34])([O-])[O-].[K+].[K+].Cl.[CH3:38]N(C)C=O>>[C:31]([NH:18][C:16]1[CH:17]=[C:12]2[O:11][CH2:10][CH2:9][N:8]3[C:7](=[O:19])[C:6]([C:20]([N:22]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[CH2:24][CH2:23]4)=[O:21])=[C:5]([OH:4])[C:14]([CH:15]=1)=[C:13]23)(=[O:34])[CH3:38]
Reactant: O=C([O-])[O-]
Reactant: CN(C)C=O
Reactant: CC(=O)Oc1c(C(=O)N2CCc3ccccc32)c(=O)n2c3c(cc(N)cc13)OCC2
Agent: Cl
Agent: [K+]
Product: CC(=O)Nc1cc2c3c(c1)c(O)c(C(=O)N1CCc4ccccc41)c(=O)n3CCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2,3-dihydro-7-acetoxy-9-amino-6-(1-indolinylcarbonyl)-5-oxo-5H-pyrido[1,2,3-de]-1,4-benzoxazine (1.5 g) and potassium carbonate (0.5 g) in N,N-dimethylformamide (10 ml) was stirred at room temperature for 1 hour. The mixture was poured into cold diluted hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and evaporated. The residue (1 g) was purified by column chromatography on silica gel eluting with chloroform-methanol (30:1) to give crystals of 2,3-dihydro-9-acetylamino-7-hydroxy-6-(1-indolinylcarbonyl)-5-oxo-5H-pyrido[1,2,3-de]-1,4-benzoxazine (0.72 g).
Reaction SMILES: C(OC([N:8]1[CH2:37][CH2:36][N:11]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[C:18]([C:19]3[C:20](=O)[O:21][C:22](=[O:34])[C:23]=3[C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]([CH3:33])[CH:25]=3)=[C:10]2[CH2:9]1)=O)(C)(C)C.C([N:40](CC)CC)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>ClCCl>[CH3:45][S:46]([N:8]1[CH2:37][CH2:36][N:11]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[C:18]([C:19]3[C:20](=[O:21])[NH:40][C:22](=[O:34])[C:23]=3[C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]([CH3:33])[CH:25]=3)=[C:10]2[CH2:9]1)(=[O:48])=[O:47]
Reactant: CS(=O)(=O)Cl
Reactant: CCN(CC)CC
Reactant: Cn1cc(C2=C(c3c4n(c5ccccc35)CCN(C(=O)OC(C)(C)C)C4)C(=O)OC2=O)c2ccccc21
Solvent: ClCCl
Product: Cn1cc(C2=C(c3c4n(c5ccccc35)CCN(S(C)(=O)=O)C4)C(=O)NC2=O)c2ccccc21
Reaction time: 17 h
Yield: 66.4 %

Procedure:
A solution of 150 mg of the product of Example 20 in 40 ml of dichloromethane was treated with 40 mg of triethylamine and 44 mg of methanesulfonyl chloride. After 17 hours, the solution was washed with water. The organic phase was dried and evaporated. Chromatography of the residue on silica gel with ethyl acetate/n-hexane (2:1) and ethyl acetate gave 95 mg of 3-[1,2,3,4-tetrahydro-2-methanesulfonylpyrazino[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione of melting point 298°-301° C. (decomposition).
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][C:15]#[N:16])[CH2:10][CH2:9]1)(C)(C)C.C(Cl)(Cl)[Cl:20]>C(O)C.O=[Pt]=O>[ClH:20].[NH2:16][CH2:15][CH2:14][C@H:11]1[CH2:12][CH2:13][C@H:8]([CH2:7][OH:6])[CH2:9][CH2:10]1
Reactant: CC(C)(C)[SiH2]OC(C)(C)[C@H]1CC[C@H](CC#N)CC1
Reactant: ClC(Cl)Cl
Agent: O=[Pt]=O
Solvent: CCO
Product: Cl
Product: NCC[C@H]1CC[C@H](CO)CC1

Procedure:
A solution of 24.2 g (90.5 mmol) of trans-[4-(tert-butyl-dimethyl-silanyloxymethyl)-cyclohexyl]-acetonitrile, 22 mL (270 mmol, 3 eq) of CHCl3 and 2.4 g of PtO2 (Degussa 223) in 250 mL of ethanol was stirred at RT for 20 h under a hydrogen atmosphere. The catalyst was then removed by filtration and the solvent evaporated under reduced pressure to give 17.1 g (97%) of pure trans-[4-(2-amino-ethyl)-cyclohexyl]-methanol-HCl-salt as colorless solid, MS: 158 (MH+).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:46])[N:20]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[CH:40]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>O.C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:46])[N:20]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[CH:40]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCc1nc(C)n(-c2cccc(Cl)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCc1nc(C)n(-c2cccc(Cl)c2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 60.1 %

Procedure:
A mixture of hydroxylammonium chloride (1.2 g), sodium hydrogen carbonate (1.8 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[4-butyl-1-(3-chlorophenyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.96 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.41 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.37 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.65 g, 60%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[I:9]I.CCCCCC>CCO.[O-]S([O-])(=O)=O.[Ag+].[Ag+]>[Br:1][C:2]1[N:7]=[C:6]([I:9])[C:5]([NH2:8])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)nc1
Reactant: II
Agent: [Ag+]
Agent: O=S(=O)([O-])[O-]
Solvent: CCCCCC
Solvent: CCO
Product: Nc1ccc(Br)nc1I
Reaction time: 8 h
Yield: 64.6 %

Procedure:
To a stirred solution of 6-bromo-pyridin-3-ylamine (10.2 g, 0.0580 mol) and Ag2SO4 (18.1 g, 0.0580 mol) in EtOH (150 mL) was added I2 (7.59 g, 0.0580 mol) and the reaction was allowed to stir overnight. At this time hexane (200 mL) was added and the resultant mixture was filtered through Celite. The solvent was removed in vacuo, dissolved in CHCl3 (200 mL), washed with aqueous saturated Na2S2O3 (100 mL), water (1×100 mL), and dried (Na2SO4). The solvent was concentrated in vacuo and the residue was dissolved in hot EtOAc (100 mL), filtered and treated with hexanes (100 mL). Filtration gave 11.2 g (65%) of 6-bromo-2-iodo-pyridin-3-ylamine as a white crystalline material. 1H-NMR (CDCl3; 400 MHz): δ 7.10 (d, 1H, J=8.2 Hz), 6.74 (d, 1H, J=8.2 Hz), 4.06 (br s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[C:6]([CH2:8]O)[CH:7]=1.[BrH:23].[C:24]1([PH+:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(#N)C>[Br-:23].[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[C:6]([CH:7]=1)[CH2:8][P+:30]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Reactant: Br
Reactant: OCc1cc(F)ccc1OCCc1ccc(C(F)(F)F)cc1
Solvent: CC#N
Product: Fc1ccc(OCCc2ccc(C(F)(F)F)cc2)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Product: [Br-]
Yield: 82.5 %

Procedure:
1.7 g (5.41 mmol) of {5-fluoro-2-[2-(4-trifluoromethylphenyl)ethoxy]phenyl}methanol and 1.76 g (5.14 mmol) of triphenylphosphonium hydrobromide are heated under reflux in 20 ml of acetonitrile for three hours. A first product fraction is crystallized at −20° C. The mother liquor is concentrated, the residue is dissolved in dichloromethane, and a second fraction is crystallized with diethyl ether. A total of 2.71 g (76% yield) of the title compound is obtained.
Reaction SMILES: [CH3:1][C:2]1[N:29]=[C:5]2[NH:6][C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1.[CH3:30][C:31]1([CH2:35]O)[CH2:34][O:33][CH2:32]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1.C(OCC)(=O)C>[CH3:1][C:2]1[N:29]=[C:5]2[N:6]([CH2:30][C:31]3([CH3:35])[CH2:34][O:33][CH2:32]3)[C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1
Reactant: CC1(CO)COC1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2nc(C)nn12
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC2(C)COC2)c2nc(C)nn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 1.6 %

Procedure:
To a solution of 4′-[(2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (1.5 g), (3-methyloxetan-3-yl)methanol (0.6 g) and tributylphosphine (1.9 mL) in THF (80 mL) was added 1,1′-(azodicarbonyl)dipiperidine (1.9 g) under ice-cooling, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.03 g, 16%).