Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:22]([O:23][CH3:24])=[CH:21][C:7]2[C:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:9][CH2:10][C:11](=[O:14])[N:12]([CH3:13])[C:6]=2[CH:5]=1)[CH3:2].[N+](C1C=CC=CC=1CBr)([O-])=O.Br[CH2:37][C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][CH:45]=1)[C:41]#[N:42]>>[CH2:1]([O:3][C:4]1[C:22]([O:23][CH3:24])=[CH:21][C:7]2[C:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:9][CH:10]([CH2:37][C:38]3[CH:39]=[C:40]([CH:43]=[CH:44][CH:45]=3)[C:41]#[N:42])[C:11](=[O:14])[N:12]([CH3:13])[C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCOc1cc2c(cc1OC)C(c1ccccc1)=NCC(=O)N2C
Reactant: N#Cc1cccc(CBr)c1
Agent: O=[N+]([O-])c1ccccc1CBr
Product: CCOc1cc2c(cc1OC)C(c1ccccc1)=NC(Cc1cccc(C#N)c1)C(=O)N2C
Yield: 35 %

Procedure:
By replacing 1-ethyl-7,8-dimethoxy-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (IIbd) in example IIbh by 8-ethoxy-7-methoxy-1-methyl-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (IIIda), and 2-nitrobenzyl bromide by 3-bromomethyl-benzonitrile, and proceeding in the same manner, the abovenamed product is obtained. Yield: 35%. M: 148–150° C. 1H-NMR (CDCl3, 200 MHz): d 1.53 (s, 3H, CH3), 3.40 (s, 3H, NCH3), 3.58–3.62 (m, 2H, 1H —CH2Ph+CH), 3.72 (s, 3H, OCH3), 3.75–3.80 (m, 1H CH2Ph), 4.17 (q, 2H, CH2), 6.66 (s, 1H Ar), 6.76 (s, 1H Ar), 7.35–7.67 (m, 9H Ar).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5](Cl)[C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][N:8]=2)[N:3]=1.[CH3:17][N:18]([CH2:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1)[CH3:19]>>[Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]2[NH:25][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][N:18]([CH3:19])[CH3:17])=[CH:27][CH:26]=1
Reactant: CS(=O)(=O)c1cnc2ccc(Cl)nc2c1Cl
Reactant: CN(C)Cc1ccc(N)cc1
Product: CN(C)Cc1ccc(Nc2c(S(C)(=O)=O)cnc3ccc(Cl)nc23)cc1
Yield: 72.4 %

Procedure:
Following general procedure I, 2,8-dichloro-7-(methylsulfonyl)-1,5-naphthyridine (150 mg, 0.53 mmol) was acted with 4-[(dimethylamino)methyl]aniline (120 mg, 0.80 mmol) to afford the desired product (150 mg, 80%) as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 9.05 (s, 1H), 8.95 (s, 1H), 8.18 (d, J=8.8 Hz, 1H), 7.52 (d, J=8.7 Hz, 1H), 7.34-7.27 (m, 2H), 7.12-7.04 (m, 2H), 3.49 (s, 2H), 3.17 (s, 3H), 2.30 (s, 6H); ESI MS m/z 391 [M+H]+
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7](NC2SC=CN=2)[CH:6]=C[CH:4]=1.Cl[C:16]1[C:17](F)=C(C=C[CH:29]=1)C(N1CCNCC1)=O>CN(C)C=O>[CH:16]([N:8]([CH2:7][CH3:6])[CH:3]([CH3:2])[CH3:4])([CH3:17])[CH3:29]
Reactant: ClCc1cccc(Nc2nccs2)n1
Reactant: O=C(c1cccc(Cl)c1F)N1CCNCC1
Solvent: CN(C)C=O
Product: CCN(C(C)C)C(C)C

Procedure:
A mixture of 2.70 g of 6-(chloromethyl)-N-thiazol-2-ylpyridin-2-amine, 4.00 g of 1-(3-chloro-2-fluorobenzoyl)piperazine obtained in Reference Example 1, 6.25 ml of N,N-diisopropylethylamine and 30 ml of dimethylformamide was stirred at 90° C. for 2 hours. The reaction solution was diluted with ethyl acetate and then washed with water and brine. The resulting organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated. The resulting residue was purified by a silica gel column chromatography (eluent: chloroform to chloroform/methanol=10/1). Then, the obtained compound was suspended in ethyl acetate, and filtered and collected to give the title compound as a colorless amorphous substance.
Reaction SMILES: [Na].N.[CH2:3]([O:5][C:6](=[O:24])[CH2:7][C:8]1[CH:23]=[CH:22][C:11]2[S:12][CH2:13][C:14]3[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=3[C:16](=[O:17])[C:10]=2[CH:9]=1)[CH3:4].[CH3:25]I>CCOCC.[N+]([O-])([O-])=O.[Fe+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>[CH2:3]([O:5][C:6](=[O:24])[CH:7]([CH3:25])[C:8]1[CH:23]=[CH:22][C:11]2[S:12][CH2:13][C:14]3[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=3[C:16](=[O:17])[C:10]=2[CH:9]=1)[CH3:4]
Reactant: CI
Reactant: CCOC(=O)Cc1ccc2c(c1)C(=O)c1ccccc1CS2
Agent: [Fe+3]
Agent: N
Agent: O=[N+]([O-])[O-]
Solvent: CCOCC
Product: CCOC(=O)C(C)c1ccc2c(c1)C(=O)c1ccccc1CS2
Reaction time: 0.25 h

Procedure:
2.4 G of finely cut sodium are added portionwise to 300 cc of ammonia condensed at -40°, with the addition of 200 mg of iron (III) nitrate. Stirring is effected for 30 minutes at the same temperature and 300 cc of ether are subsequently allowed to flow slowly into the reaction mixture. 31.2 g of 6,11-dihydro-11-oxo-dibenzo[b,e]thiepine-2-acetic acid ethyl ester are subsequently added portionwise. After 15 minutes, the salt formation is complete. 17.0 G of methyl iodide in 100 cc of ether are added dropwise at -40°. After a further 15 minutes, the reaction is complete. The ammonia is removed by evaporation and successively replaced by 300 cc of ether. The organic phase is finally shaken with 50 g of ammonium chloride dissolved in water and is washed with water until neutral. The solution which has been purified with charcoal and dried over sodium sulphate, is concentrated at reduced pressure and pentane is added thereto, whereby 6,11-dihydro-(α-methyl)- 11-oxo-dibenzo[b,e]thiepine-2-acetic acid ethyl ester crystallies. M.P. 91°-93°.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:25]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[C:8]([NH2:27])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH2:29][CH2:30][CH2:31][CH3:32]>>[NH2:27][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:25])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]1[CH2:20][CH2:21][N:22]([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:23][CH2:24]1
Reactant: CCCCI
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCC3CCNCC3)c2n1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCC3CCN(CCCC)CC3)c2n1

Procedure:
Prepared similarly to Example 82 from 2-(butyloxy)-8-(methyloxy)-9-[4-(4-piperidinyl)butyl]-9H-purin-6-amine and 1-iodobutane.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[CH2:22]([S:24][C:25]1[N:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](O)=[O:28])[CH3:23].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl.CN(C)C=O>[CH2:22]([S:24][C:25]1[N:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([NH:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23)=[O:28])[CH3:23]
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Reactant: CCSc1ncccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCSc1ncccc1C(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Yield: 16.7 %

Procedure:
Preparation of example 66 from the title compound of Example 7 (hydrochloride) (30 mg, 0.096 mmol), 2-ethylsulfanyl-nicotinic acid (22 mg, 0.12 mmol), triethylamine (0.020 mL, 0.14 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (46 mg, 0.12 mmol) in CH2Cl2 (0.4 mL) and N,N-dimethylformamide (0.4 mL) was carried out analogously to Example 11. Silica gel chromatography (pre-rinsed silica with 3% triethylamine in ethyl acetate, eluted with 3% triethylamine in 19:6:1 ethyl acetate:hexane:methanol), also in an analogous manner, afforded the title compound (7 mg, 0.016 mmol) as a yellow powder in 17% yield.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([S:28][CH3:29])[CH:23]=2)[C:8](N([C@H](C)[C@H](O)C2C=CC=CC=2)C)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.S(=O)(=O)(O)[OH:31].C(Cl)Cl>O1CCOCC1.O>[CH:1]1([CH2:6][C@H:7]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([S:28][CH3:29])[CH:23]=2)[C:8]([OH:9])=[O:31])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CSc1cccc([C@@H](CC2CCCC2)C(=O)N(C)[C@H](C)[C@H](O)c2ccccc2)c1
Reactant: O=S(=O)(O)O
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: CSc1cccc([C@@H](CC2CCCC2)C(=O)O)c1
Temperature: 110 °C
Reaction time: 18 h
Yield: 96 %

Procedure:
To a stirred solution of (R)-3-cyclopentyl-N-((1R,2R)-2-hydroxy-1-methyl-2-phenyl-ethyl)-N-methyl-2-(3-methylsulfanyl-phenyl)-propionamide (1.16 g, 2.82 mmol) in 1,4-dioxane (10 mL) was added 9 N aqueous sulfuric acid (10 mL) and the reaction was stirred at 110° C. for 18 h. The reaction was cooled to 25° C. and diluted with water (25 mL) and poured into methylene chloride (30 mL). The layers were separated and the aqueous layer was extracted with methylene chloride (2×30 mL). The combined methylene chloride layers were washed with water and saturated sodium chloride solution and then dried over magnesium sulfate. Filtration and concentration afforded the crude product which was purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 0% ethyl acetate/hexanes to 50% ethyl acetate/hexanes) to yield (R)-3-cyclopentyl-2-(3-methylsulfanyl-phenyl)-propionic acid (712 mg, 96%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:11]([C:13]2[C:21]3[CH:20]=[N:19][CH:18]=[N:17][C:16]=3[N:15]([CH:22]([CH3:24])[CH3:23])[CH:14]=2)=[O:12])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH3:10].[NH3:25]>CN1C(=O)CCC1.O.[Cu-]=O>[NH2:25][C:2]1[CH:3]=[C:4]([C:11]([C:13]2[C:21]3[CH:20]=[N:19][CH:18]=[N:17][C:16]=3[N:15]([CH:22]([CH3:24])[CH3:23])[CH:14]=2)=[O:12])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH3:10]
Reactant: CCOc1ncc(C(=O)c2cn(C(C)C)c3ncncc23)cc1Br
Reactant: N
Agent: O=[Cu-]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOc1ncc(C(=O)c2cn(C(C)C)c3ncncc23)cc1N
Temperature: 130 °C
Yield: 24 %

Procedure:
Copper(I) oxide (38.6 mg, 0.27 mmol) was added to (5-Bromo-6-ethoxy-pyridin3-yl)-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone (Preparation 241, 350 mg, 0.89 mmol) in concentrated ammonia solution (6 mL) and NMP (1 mL). The mixture was heated in a sealed vessel at 130° C. for 17 hours. The reaction mixture was cooled to room temperature and diluted with water (10 ml). It was extracted with 20% i-PrOH in DCM (6×50 mL), dried (Na2SO4) and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (MeOH:DCM 5:95) to afford the title compound as a yellow solid in 24% yield, 70 mg. LCMS (system 10): Rt=2.99 min; m/z 326 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[N+:19]([O-:21])=[O:20])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].[H-].[Na+].[CH3:24]I.O>CN(P(N(C)C)(N(C)C)=O)C>[CH3:1][O:2][C:3]([C:5]1[C:10]([N:11]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[N+:19]([O-:21])=[O:20])[CH3:24])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1nccnc1Nc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)c1nccnc1N(C)c1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3.1 g 3-(4-chloro-2-nitrophenylamino)-pyrazine-2-carboxylic acid methyl ester in 15 ml absolute hexamethylphosphorotriamide is treated portionwise with 0.3 g sodium hydride. The reaction mixture is stirred at room temperature for 1 hour and then treated dropwise with 2.8 g methyl iodide, and the temperature is maintained under 20° C. After the reaction mixture has been stirred for 1 hour at room temperature 10 ml water are added dropwise. The mixture is extracted with ethyl acetate. The organic phase is washed with water, dried over sodium sulphate and evaporated. The residue is recrystallised from ethyl acetate to give the heading compound, m.p. 111°-112°.
Reaction SMILES: [CH2:1]([O:8][C:9]([C@H:11]1[NH:15][C:14](=[O:16])[C@H:13](OS(C)(=O)=O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][SH:29])=[CH:26][CH:25]=1.C1CCN2C(=NCCC2)CC1.C(OCC)(=O)C>CN(C=O)C>[CH2:1]([O:8][C:9]([C@H:11]1[NH:15][C:14](=[O:16])[CH:13]([S:29][CH2:28][C:27]2[CH:30]=[CH:31][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)OCc2ccccc2)NC1=O
Reactant: COc1ccc(CS)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(CSC2C[C@@H](C(=O)OCc3ccccc3)NC2=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 111.6 %

Procedure:
16.3 g (52.1 mmol) of (3R,5S)-5-benzyloxycarbonyl-3-mesyloxypyrrolidin-2-one was dissolved in 82 ml of DMF, and 7.95 ml (57.3 mmol) of p-methoxybenzylmercaptan was added to the solution under cooling with ice, then 8.48 ml (56.7 mmol) of DBU was added dropwise thereto. The mixture was stirred for 15 minutes at room temperature. Ethyl acetate was added to the reaction mixture, which was washed sequentially with water, 1 N HCl, a saturated sodium hydrogencarbonate aqueous solution and a saturated sodium chloride aqueous solution. The ethyl acetate solution was dried over anhydrous magnesium sulfate and the solvent was distilled off to obtain 21.6 g of (3RS,5S)-5-benzyloxycarbonyl-3-p-methoxybenzylthiopyrrolidin-2-one as an oily substance. This oily substance was dissolved in 122 ml of methanol, and 36.5 ml of 2N NaOH was added thereto under cooling with ice, and then the mixture was stirred for 1 hour at the same temperature. After the reaction mixture was washed twice with ethyl acetate, the aqueous layer was adjusted to pH 2.0 with 2N HCl, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was triturated with isopropyl ether to obtain 10.6 g of (3RS,5S)-3-p-methoxybenzylthio-2-oxopyrrolidin-5-carboxylic acid. This was dissolved in 348 ml of THF, and 6.17 g (75.7 mmol) of dimethylamine hydrochloride and 11.5 g (94.3 mmol) of 4-dimethylaminopyridine were added thereto under cooling with ice. And then, a solution of 11.7 g (56.8 mmol) of DCC in 37 ml of THF was added dropwise thereto. The mixture was stirred for 3 hours at the same temperature, and then for 1 day at room temperature. After the precipitate was filtered off, ethyl acetate was added to the filtrate, which was washed with lN HCl. The solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (Wakogel® C-300, elution with 1-2% methanol-chloroform) to obtain 5.33 g (yield: 28.4%) of (3S,5S)-5-dimethylcarbamoyl-3-p-methoxybenzylthiopyrrolidin-2-one as an oil and 4.41 g (yield: 23.5%) of (3R,5S)-5-dimethylcarbamoyl-3-p-methoxybenzylthiopyrrolidin-2-one as a powder.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]2[C:13](Br)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.C([Li])CCC.[CH3:20][N:21]([CH3:29])[CH:22]1[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]1.O>CCCCCC.O1CCCC1>[C:4]1([CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=2[C:25]2([OH:28])[CH2:26][CH2:27][CH:22]([N:21]([CH3:29])[CH3:20])[CH2:23][CH2:24]2)[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: CN(C)C1CCC(=O)CC1
Reactant: Brc1ccccc1Cc1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C1CCC(O)(c2ccccc2Cc2ccccc2)CC1
Temperature: 0 °C
Yield: 30.6 %

Procedure:
To 24.7 g of 2-bromodiphenylmethane and 100 ml of dry tetrahydrofuran (THF, hereinafter) is added 55 ml of 2.4 molar solution of n-butyllithium in hexane dropwise with stirring at -40° to 50° C. under a dry nitrogen atmosphere. The resultant solution is stirred one hour after addition of the n-butyllithium is completed. A solution of 15.5 g 4-dimethylaminocyclohexanone in 50 ml of dry THF is added dropwise with stirring while maintaining the temperature below -40° C. The resultant solution is stirred at -40°0 to -50° C. for two hours after addition of the ketone is completed and further stirred under N2 atmosphere overnight (16 hours) at room temperature. The solution is cooled to 0° C. and 350 ml of water and 400 ml of hexane are added thereto. The aqueous phase of the resultant mixture is removed and the product crystallized out of the organic phase. After filtration (washing the filter cake with hexane) the organic phase is washed three times with 100°ml portions of water and cooled overnight. A second crop is obtained, combined with the first crop and recrystallized from 50 ml of toluene to yield 9.46 g (30.6% yield) of 1-[2-(phenylmethyl)phenyl]-4-dimethylaminocyclohexanol, m.p. 140°-141° C.
Reaction SMILES: [C:1](#[N:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH3:11].CO>CCO>[C:4]1(/[CH:3]=[CH:2]/[C:1](=[NH:11])[NH2:10])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: N
Reactant: N#CC=Cc1ccccc1
Solvent: CO
Solvent: CCO
Product: N=C(N)/C=C/c1ccccc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Cinnamonitrile (25.0 g, 194 mmol) was dissolved in EtOH (ethanol) (200 mL). The solution was cooled to 0° C. and HCl gas bubbled through the solution for 30 minutes. The solution was stirred at ambient temperature for 16 h and then concentrated under vacuum. The residue was dissolved in EtOH (100 mL), cooled to 0° C. and a solution of NH3/MeOH (7M, 69 mL, 484 mmol) was added dropwise through an addition funnel. Once added, the solution was allowed to warm to ambient temperature and the resulting NH4Cl was filtered off. The solution was concentrated under vacuum and the resulting white solid was used without further purification (26 g crude).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH:12]=2)[CH:2]=1>C(O)C.[OH-].[OH-].[Pd+2]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:12]2)[CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cccnc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2cccnc2)CC1
Reaction time: 6.5 h

Procedure:
The tert-Butyl 3′,6′-dihydro-3,4′-bipyridine-1′(2′H)-carboxylate prepared in Step A (1.14 g, 4.38 mmol) was dissolved in 20 mL of ethanol and added to a flask containing palladium hydroxide on carbon powder (20% Pd). The reaction mixture was subjected to 50 psi of H2 (g) for 6.5 h with vigorous shaking. The reaction was then filtered and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, 0-1% MeOH/EtOAc gradient eluent) afforded tert-butyl 4-pyridin-3-ylpiperidine-1-carboxylate. ESI-MS calc. for C15H22N2O2: 262.37, found 263 (M+H).
Reaction SMILES: CN1C(=O)CCC1.Br[CH2:9][CH2:10][C:11]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:12]#[N:13].[Cl:26][C:27]1[CH:28]=[C:29]([CH:37]=[CH:38][CH:39]=1)[CH2:30][O:31][CH:32]1[CH2:36][CH2:35][NH:34][CH2:33]1>C(N(CC)CC)C>[Cl:26][C:27]1[CH:28]=[C:29]([CH:37]=[CH:38][CH:39]=1)[CH2:30][O:31][CH:32]1[CH2:36][CH2:35][N:34]([CH2:9][CH2:10][C:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:12]#[N:13])[CH2:33]1
Reactant: N#CC(CCBr)(c1ccccc1)c1ccccc1
Reactant: Clc1cccc(COC2CCNC2)c1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: N#CC(CCN1CCC(OCc2cccc(Cl)c2)C1)(c1ccccc1)c1ccccc1
Temperature: 140 °C
Reaction time: 20 h
Yield: 49.7 %

Procedure:
To 20 ml of NMP was added 2,54 g of 4-bromo-2,2-diphenylbutyronitrile, 1.79 g of 3-(3-chlorobenzyloxy)pyrrolidine and 1.29 g of triethylamine, and the mixture was stirred for 20 hours at 140° C. The reaction mixture was concentrated under reduced pressure and water was added to the residue, and then extracted with methylene chloride. The extract was dried over anhydrous sodium sulfate. The organic layer was concentrated and the residue was purified by silica gel column chromatography (ethyl acetate) to obtain 1.81 g of the aimed compound as a brown oil.
Reaction SMILES: [OH-].[Na+:2].CO.[CH3:5][C:6]1[O:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:17][O:18][C:19]1[CH:36]=[CH:35][C:22]([CH2:23][O:24][C:25]2[C:30]([CH2:31][C:32]([OH:34])=[O:33])=[CH:29][CH:28]=[CH:27][N:26]=2)=[CH:21][CH:20]=1>CC(C)=O>[CH3:5][C:6]1[O:10][C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[N:8][C:7]=1[CH2:17][O:18][C:19]1[CH:36]=[CH:35][C:22]([CH2:23][O:24][C:25]2[C:30]([CH2:31][C:32]([O-:34])=[O:33])=[CH:29][CH:28]=[CH:27][N:26]=2)=[CH:21][CH:20]=1.[Na+:2]
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ncccc2CC(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(C)=O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ncccc2CC(=O)[O-])cc1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
1N Sodium hydroxide-methanol solution (2.4 ml) was added to 2-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]acetic acid (1.0 g) and the mixture was heated to 40° C. The obtained solution was allowed to cool and acetone (10 ml) was added. The mixture was stirred at room temperature for 30 min and acetone (5 ml) was further added. The mixture was stirred at room temperature for 1 hr, and under ice-cooling for 1 hr. The precipitated crystals were collected by filtration, washed with acetone (10 ml) ice-cooled in advance, and dried under reduced pressure to give sodium 2-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]acetate as white crystals.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:42]=[CH:41][C:17]3[S:18][C:19]([S:22]([N:25]4[CH2:30][CH2:29][N:28]([C:31]5[C:36]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:34]=[CH:33][N:32]=5)[CH2:27][CH2:26]4)(=[O:24])=[O:23])=[C:20]([CH3:21])[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:21][C:20]1[C:16]2[CH:15]=[C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH:42]=[CH:41][C:17]=2[S:18][C:19]=1[S:22]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[C:36]([C:37]([F:39])([F:38])[F:40])=[CH:35][CH:34]=[CH:33][N:32]=2)[CH2:27][CH2:26]1)(=[O:24])=[O:23]
Reactant: Cc1c(S(=O)(=O)N2CCN(c3ncccc3C(F)(F)F)CC2)sc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(S(=O)(=O)N2CCN(c3ncccc3C(F)(F)F)CC2)sc2ccc(N3CCNCC3)cc12
Yield: 53.9 %

Procedure:
To a solution of 4-{3-methyl-2-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-benzo[b]thiophen-5-yl}-piperazine-1-carboxylic acid tert-butyl ester (95 mg, 0.18 mmol) in DCM (4 mL) was added TFA (1 mL). The resultant mixture was stirred at ambient temperature for 3 hours. The solvent was removed under vacuum. The crude product was triturated with ether then water to give 1-(3-Methyl-5-piperazin-1-yl-benzo[b]thiophene-2-sulfonyl)-4-(3-trifluoromethyl-pyridin-2-yl)-piperazine as a light yellow solid (51 mg, 66%).