Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30]([OH:32])=O)[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:63][S:64]([C:67]1[CH:73]=[CH:72][C:70]([NH2:71])=[CH:69][CH:68]=1)(=[O:66])=[O:65]>>[CH3:63][S:64]([C:67]1[CH:73]=[CH:72][C:70]([NH:71][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:35])([CH3:36])[CH3:37])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:32])=[CH:69][CH:68]=1)(=[O:65])=[O:66]
Reactant: CS(=O)(=O)c1ccc(N)cc1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(S(C)(=O)=O)cc2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.33 g, 0.57 mmol), was reacted with diisopropylethylamine (0.59 g, 4.6 mmol), diphenylphosphinic chloride (0.54 g, 2.3 mmol), then reacted with 4-(methylsulfonyl)aniline (Oakwood) (0.098 g, 0.57 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-methanesulfonyl-phenyl)-amide as a off white foam (Yield 0.11 g, 31%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C.CCOC(C)=O>[CH2:18]([O:11][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][C:6]=1[C:8](=[O:10])[CH3:9])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: CC(=O)c1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)c1cc(Br)ccc1OCc1ccccc1
Reaction time: 8 h
Yield: 98.9 %

Procedure:
To a mixture of 1-(5-bromo-2-hydroxyphenyl)ethanone (505 mg, 2.348 mmol) and cesium carbonate (1339 mg, 4.11 mmol) in DMF (5 ml) was added benzyl bromide (0.351 ml, 2.94 mmol) and the resulting mixture was stirred overnight. The reaction mixture was diluted with EtOAc and washed 2 times with water, followed by brine. The organic layer was dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc in hexanes to afford 709 mg of 1-[2-(benzyloxy)-5-bromophenyl]ethanone, 703 mg (2.304 mmol) of which were combined with BISPIN (731 mg, 2.88 mmol), PdCl2(dppf) (202 mg, 0.276 mmol), and potassium acetate (452 mg, 4.61 mmol) in 1,4-dioxane (2 ml)/DMSO (10 ml). The mixture was heated at 80° C. overnight. The solids were filtered through a silica plug washing with EtOAc. Water was added and the filtrate was extracted 3 times with EtOAc. The combined organics were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc in hexanes to afford 634 mg of 1-[2-(benzyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethanone. A mixture of 64 mg (0.182 mmol) of 1-[2-(benzyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethanone, 63 mg (0.105 mmol) of (4S,5R)-3-{[6-azetidin-1-yl-3-(5-chloro-2-methoxyphenyl)pyridin-2-yl]methyl}-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (EXAMPLE 27), potassium carbonate (1M aqueous) (0.400 ml, 0.400 mmol), and 1,1′-bis(di-t-butylphosphino)ferrocene palladium dichloride (15 mg, 0.023 mmol) in 1,4-dioxane (1.5 ml) was heated at 120° C. with microwaves for 4 hours, then transferred to an oil bath at 120° C. overnight. The mixture was filtered through a silica plug, washing with EtOAc. The filtrate was concentrated and purified by flash column chromatography on silica gel, eluting with EtOAc in hexanes to afford the title compound. Mass spectrum (ESI) 790.6 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([NH2:14])=[C:9](CC)[C:10]=1[CH3:11])=[O:5])[CH3:2].[Cl:15][CH2:16][CH2:17][N:18]=[C:19]=[O:20]>C(#N)C>[Cl:15][CH2:16][CH2:17][NH:18][C:19](=[O:20])[NH:14][C:8]1[S:7][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:10]([CH3:11])[CH:9]=1
Reactant: O=C=NCCCl
Reactant: CCOC(=O)c1sc(N)c(CC)c1C
Solvent: CC#N
Product: CCOC(=O)c1sc(NC(=O)NCCCl)cc1C
Temperature: 70 °C
Reaction time: 20 h
Yield: 82 %

Procedure:
A mixture of ethyl 5-amino-3-methylthiophene-2-carboxylic acid ethyl ester (4.75 g, 25.6 mmol) and 2-chloroethyl-isocyanate (2.63 ml, 30.8 mmol) in anhydrous acetonitrile (50 mL) was stirred under nitrogen atmosphere at 70° C. for 20 h, then was cooled to ambient temperature and concentrated in vacuo. The residue was triturated with hexanes/ethyl acetate to afford an off-white solid. The filtrate was concentrated in vacuo, and the residue was triturated with hexanes/ethyl acetate to afford an off white solid. The combined solid was dried to afford the title compound in 82% yield (6.11 g): 1H NMR (300 MHz, CDCl3) δ 7.73 (br s, 1H), 6.31 (s, 1H), 5.60 (t, J=5.0 Hz, 1H), 4.27 (q, J=7.1 Hz, 2H), 3.69-3.59 (m, 4H), 2.44 (s, 3H), 1.33 (t, J=7.1 Hz, 3H); MS (ES+) m/z 291.2 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:19]=[C:18]([CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:17]=[CH:16][C:4]=1[O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1.N1C=CC=CC=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl.C(OCC)(=O)C.Cl>[C:24]([O:23][C:21](=[O:22])[CH2:20][C:18]1[CH:17]=[CH:16][C:4]([O:5][C:6]2[CH:7]=[CH:8][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:14][CH:15]=2)=[C:3]([CH2:2][NH:1][S:35]([CH3:34])(=[O:37])=[O:36])[CH:19]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: COC(=O)c1ccc(Oc2ccc(CC(=O)OC(C)(C)C)cc2CN)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Oc2ccc(CC(=O)OC(C)(C)C)cc2CNS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.2 %

Procedure:
To a stirred solution of the methyl 4-(2-(aminomethyl)-4-(2-tert-butoxy-2-oxoethyl)phenoxy)benzoate (690 mg, 1.86 mmol) in dichloromethane (6 ml) was added pyridine (225 μL, 2.78 mmol) followed by methanesulfonyl chloride (287 μL, 3.71 mmol). The reaction was stirred at ambient temperature for 4 hours, after which time additional pyridine (1.5 eq) and methanesulfonyl chloride (2 eq) were added. The reaction was stirred for an additional hour and then diluted with ethyl acetate and 1M HCl. The aqueous layer was extracted with ethyl acetate and the combined organics washed with brine and dried over MgSO4. The crude product was then purified on the Biotage Horizon (40+M, 5% to 75% B:ethyl acetate) to give methyl 4-(4-(2-tert-butoxy-2-oxoethyl)-2-(methylsulfonamidomethyl)phenoxy)benzoate (0.754 g).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:18]=[C:17]([CH3:19])[C:12]3[NH:13][C:14]([CH3:16])=[N:15][C:11]=3[CH:10]=2)[CH:3]=1.[NH:20]1[CH2:25][CH2:24][CH:23]([N:26]2[C:30]3[CH:31]=[N:32][C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:38]=4[C:29]=3[NH:28][C:27]2=[O:39])[CH2:22][CH2:21]1.CCN(C(C)C)C(C)C>CN(C=O)C.CO>[CH3:16][C:14]1[NH:13][C:12]2[C:17]([CH3:19])=[CH:18][C:9]([NH:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([N:20]4[CH2:21][CH2:22][CH:23]([N:26]5[C:30]6[CH:31]=[N:32][C:33]7[CH:34]=[CH:35][CH:36]=[CH:37][C:38]=7[C:29]=6[NH:28][C:27]5=[O:39])[CH2:24][CH2:25]4)[CH:3]=3)=[CH:10][C:11]=2[N:15]=1
Reactant: Cc1nc2cc(Nc3cc(Cl)ncn3)cc(C)c2[nH]1
Reactant: O=c1[nH]c2c3ccccc3ncc2n1C1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Cc1nc2cc(Nc3cc(N4CCC(n5c(=O)[nH]c6c7ccccc7ncc65)CC4)ncn3)cc(C)c2[nH]1

Procedure:
150 mg (0.548 mmol) (6-chloro-pyrimidin-4-yl)-(2,7-dimethyl-1H-benzimidazol-5-yl)-amine, 150 mg (0.559 mmol) 3-piperidin-4-yl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one and 1.00 mL (5.81 mmol) DIPEA were refluxed in 1.0 mL DMF. After the reaction had ended the reaction mixture was diluted with MeOH and purified by preparative HPLC. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[N:11][C:12]([C:15]([O:17][CH3:18])=[O:16])=[N:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]([CH3:19])[C:9]1[CH:14]=[N:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[N:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ncc(NC(=O)OC(C)(C)C)cn1
Agent: [Cs+]
Solvent: ClCCl
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ncc(N(C)C(=O)OC(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 84.1 %

Procedure:
A solution of methyl 5-((tert-butoxycarbonyl)amino)pyrimidine-2-carboxylate (1.31 g, 5.16 mmol) in DMF (13 mL) was treated with cesium carbonate (2.19 g, 6.71 mmol) followed by iodomethane (0.64 mL, 10.32 mmol). The resulting suspension was stirred at ambient temperature for 5 h. The suspension was diluted with DCM (50 mL), filtered, concentrated, and purified by flash chromatography on silica gel eluting with a gradient of 0 to 40% EtOAc in DCM to give methyl 5-((tert-butoxycarbonyl)(methyl)amino)pyrimidine-2-carboxylate (1.16 g, 84% yield) as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.91 (s, 2H), 4.07 (s, 3H), 3.38 (s, 3H), 1.52 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[CH2:8][CH:7]([NH:13][CH:14]([CH2:18][CH2:19][CH3:20])[C:15]([OH:17])=O)[CH2:6][CH2:5]2.[CH3:21][C:22]([N:30]1[CH:34]=[C:33]([N+:35]([O-])=O)[N:32]=[CH:31]1)([CH3:29])[CH2:23][N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH3:29][C:22]([N:30]1[CH:34]=[C:33]([NH:35][C:15](=[O:17])[CH:14]([NH:13][CH:7]2[CH2:6][CH2:5][C:4]3[C:9](=[C:10]([F:12])[CH:11]=[C:2]([F:1])[CH:3]=3)[CH2:8]2)[CH2:18][CH2:19][CH3:20])[N:32]=[CH:31]1)([CH3:21])[CH2:23][N:24]1[CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)O
Reactant: CC(C)(CN1CCCC1)n1cnc([N+](=O)[O-])c1
Product: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1

Procedure:
Following the procedure for Example 86, 2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid (diastereomer 1) was reacted with 1-(1,1-Dimethyl-2-pyrrolidin-1-yl-ethyl)-4-nitro-1H-imidazole to afford the title compound: C13 NMR (100 MHz, CDCl3) 14.2, 19.6, 24.3, 26.6, 28.2, 28.6, 29.6, 36.6, 51.9, 56.0, 59.3, 60.3, 67.2, 100.8, 101.0, 101.3, 104.9, 110.7, 112.5, 130.8, 172.6; MS m/z 474.3 (M+1).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][N:39]1[CH:43]=[CH:42][CH:41]=[C:40]1[C:44]([N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1)=[O:45]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:49]3[CH2:48][CH2:47][N:46]([C:44]([C:40]4[N:39]([CH3:38])[CH:43]=[CH:42][CH:41]=4)=[O:45])[CH2:51][CH2:50]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cn1cccc1C(=O)N1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(C(=O)c2cccn2C)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with (1-methyl-1H-pyrrol-2-yl)-piperazin-1-yl-methanone (Enamine) to give the title compound. HR-MS (ES, m/z) calculated for C39H45Cl2N6O3 [(M+H)+] 715.2925, observed 715.2926.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[S:22]([NH:25][C:26]2[CH:35]=[CH:34][C:33]3[CH2:32][CH2:31][CH2:30][CH2:29][C:28]=3[C:27]=2[C:36]([OH:38])=[O:37])(=[O:24])=[O:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Si](C=[N+]=[N-])(C)(C)[CH3:40]>C1C=CC=CC=1.CO>[CH3:40][O:37][C:36]([C:27]1[C:28]2[CH2:29][CH2:30][CH2:31][CH2:32][C:33]=2[CH:34]=[CH:35][C:26]=1[NH:25][S:22]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[NH:15][CH2:14][CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1)(=[O:24])=[O:23])=[O:38]
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2ccccc2S(=O)(=O)Nc2ccc3c(c2C(=O)O)CCCC3)CC1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)c1c(NS(=O)(=O)c2ccccc2NCC2CCN(C(=O)OC(C)(C)C)CC2)ccc2c1CCCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of Example 396 (2.69 g, 5.0 mmol) in benzene (40 mL) and methanol (10 mL) was treated with TMSCHN2 (3.0 mL, 6.0 mmol, 2.0M solution in hexanes). The reaction was stirred at room temperature for 1 hour, then quenched with acetic acid, and diluted with ethyl acetate. The organic layer was washed with aqueous NaHCO3, dried (MgSO4), filtered, concentrated, and purified by column chromatography (25% ethyl acetate/hexanes) to provide the desired product. MS (ESI(+)) m/e 528 (M+H)+.
Reaction SMILES: [CH2:1]([N:9]1[C:17]2[C:12](=[CH:13][C:14](Br)=[C:15]([CH3:21])[C:16]=2[N+:18]([O-:20])=[O:19])[CH2:11][CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Cu](C#N)[C:24]#[N:25].C(OCC)(=O)C.O>CN1CCCC1=O>[CH2:1]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([C:24]#[N:25])=[C:15]([CH3:21])[C:16]=2[N+:18]([O-:20])=[O:19])[CH2:11][CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCN1CCc2cc(Br)c(C)c([N+](=O)[O-])c21
Reactant: N#C[Cu]C#N
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: CCCCCCCCN1CCc2cc(C#N)c(C)c([N+](=O)[O-])c21
Temperature: 190 °C
Reaction time: 1 h
Yield: 70.3 %

Procedure:
1-Octyl-5-bromo-6-methyl-7-nitroindoline (4.0 g) was dissolved in N-methylpyrrolidone (40 ml), and copper cyanide (1.9 g) was added, which was followed by stirring at 190° C. for 1 hr. Ethyl acetate (100 ml) and water (100 ml) were added to the reaction mixture. The insoluble matter was filtered off. The ethyl acetate layer was washed with water and dried over anhydrous sodium sulfate. Ethyl acetate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5-1/3) to give 2.4 g of oily 1-octyl-5-cyano-6-methyl-7-nitroindoline.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[S:27])=[CH:21][CH:20]=1.C1(C)C=CC=CC=1>CCOCC>[Cl:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([F:16])[C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:26]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([CH3:18])=[CH:20][CH:21]=2)=[S:27])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(N=C=S)cc1
Reactant: Nc1ncccc1OCc1c(F)cccc1Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Cc1ccc(NC(=S)Nc2ncccc2OCc2c(F)cccc2Cl)cc1

Procedure:
A mixture of 2-amino-3-(2-chloro-6-fluorobenzyloxy)pyridine (2g, 0.008 mol), 4methylphenyl isothiocyanate (1.43g, 0.0096 mol) and toluene (10 ml) was heated under reflux for 5 hours, then cooled and diluted with ether to induce crystallisation of the product. Yield 2.61g (82%) m.p. 138°-140 ° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][CH2:10][CH:9]2[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.C[O-].[Na+]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[CH2:13][C:12](=[O:14])[NH:11][CH2:10][C@H:9]2[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CNC(=O)CC1c1ccc(F)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CCOC(=O)[C@@H]1CNC(=O)C[C@H]1c1ccc(F)cc1
Temperature: 110 °C

Procedure:
3.8 g of the cis/trans mixture of ethyl 4-(p-fluorophenyl)-6-oxo-3-piperidinecarboxylate obtained in Examples 4 to 6 was added to 100 mL of toluene, and 2.7 mL of a 28% methanol solution of sodium methoxide was added. The reaction mixture was heated at 110° C. for 2.5 hours, then poured into ice water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated to obtain 3.28 g of ethyl trans-4-(p-fluorophenyl)-6-oxo-3-piperidinecarboxylate.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][CH:3]=1.[OH-].[K+].[CH3:14][CH2:15][CH2:16]Br.O>CS(C)=O>[CH2:14]([O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)[CH2:15][CH3:16]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CCCBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCCOc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96 %

Procedure:
Methyl 4-hydroxybenzoate (15.4 g: 101.2 mmol) was dissolved in 150 ml of dimethylsulfoxide (DMSO), and an aqueous solution of potassium hydroxide (KOH/H2O: 7 g/15 ml) was added to the mixture. The resultant mixture was stirred until dissolving homogeneously. Next, 12.5 g (101.6 mmol) of n-propyl bromide was added thereto, and the reaction was carried out at a room temperature for 24 hours. The reaction mixture was poured into 1 L of an iced water and the resultant precipitate was collected by filtration. The obtained precipitate was dissolved in 300 ml of ethanol, and an aqueous solution of sodium hydroxide (NaOH/H2O: 5 g/100 ml) was added thereto. Thus obtained mixture was refluxed by heating for 1 hour, and water (the amount of the water: about 300 ml) was added thereto with removing ethanol (EtOH). After cooling to a room temperature, the transparent solution was acidified by adding a concentrated hydrochloric acid. The resultant white precipitate was filtered and recrystallized from toluene to give 17.5 g (97.2 mmol) of 4-n-propyloxybenzoic acid.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][N:4]1[C:13](=[O:15])[CH3:14].Br[CH2:17][CH2:18][O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([O:19][CH2:18][CH2:17][O:1][CH2:2][C@@H:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][N:4]1[C:13](=[O:15])[CH3:14])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(=O)N1Cc2ccccc2C[C@H]1CO
Reactant: BrCCOCc1ccccc1
Product: CC(=O)N1Cc2ccccc2C[C@H]1COCCOCc1ccccc1
Yield: 63.3 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 116B, (S)-1-(3-(hydroxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (Intermediate 116A, 40.0 mg, 0.20 mmol) and ((2-bromoethoxy)methyl)benzene (92 μl, 0.58 mmol) were converted to the title compound (43 mg, 65%) after purification by flash column chromatography (gradient from 0% to 50% EtOAc/hexanes). 1H NMR (CDCl3, 2:1 mixture of amide rotamers) δ 7.41-7.25 (m, 5H), 7.24-7.06 (m, 4H), 5.10 (d, J=18.0 Hz, 1H), 4.66-4.44 (m, 3H), 4.39 (q, J=5.9 Hz, 0.5H), 4.26 (d, J=17.8 Hz, 0.5H), 3.68-3.47 (m, 5H), 3.44-3.27 (m, 1.5H), 3.10 (dd, J=5.8, 16.0 Hz, 0.5H), 3.01-2.80 (m, 1H), 2.24 (s, 2H), 2.19 (s, 1H); MS(ESI+) m/z 340.2 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH2:9][C:10]([OH:12])=[O:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[ClH:13].[CH2:14](O)[CH3:15]>>[NH2:1][CH2:2][C:3]1([CH2:9][C:10]([O:12][CH2:14][CH3:15])=[O:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[ClH:13]
Reactant: NCC1(CC(=O)O)CCCCC1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)CC1(CN)CCCCC1
Reaction time: 8 h

Procedure:
10 g. of the 1-aminomethyl-1-cyclohexane-acetic acid, prepared according to Example 1, are dissolved in 50 ml. anhydrous ethanol and saturated at 0° C. with gaseous hydrogen chloride. The reaction mixture is left to stand overnight at ambient temperature, then evaporated in a vacuum and the residue recrystallised from ethanol/ether. Ethyl 1-aminomethyl-1-cyclohexane-acetate is obtained in the form of its hydrochloride; m.p. 161°-163° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11][CH2:12][CH2:13][C:14]1[CH:24]=[CH:23][C:17]([O:18][CH2:19][C:20]([OH:22])=O)=[CH:16][CH:15]=1)=[O:4].[F:25][C:26]1[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=1[CH2:28][NH:29][CH2:30][CH3:31].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH2:30]([N:29]([CH2:28][C:27]1[CH:32]=[CH:33][CH:34]=[CH:35][C:26]=1[F:25])[C:20](=[O:22])[CH2:19][O:18][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][S:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:3]([O:2][CH3:1])=[O:4])=[CH:24][CH:23]=1)[CH3:31]
Reactant: COC(=O)c1ccccc1SCCc1ccc(OCC(=O)O)cc1
Reactant: CCNCc1ccccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCN(Cc1ccccc1F)C(=O)COc1ccc(CCSc2ccccc2C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.3 %

Procedure:
[4-(2-{[2-(Methoxycarbonyl)phenyl]thio}ethyl)phenoxy]acetic acid (0.250 g, 0.722 mmol) was dissolved in DCM (10 ml), N-(2-fluorobenzyl)ethanamine (0.105 g, 0.686 mmol) was added. N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate (0.255 g, 0.0.794 mmol) and N-ethyl-N,N-diisopropylamine (0.187 g, 1.443 mmol) were added. The solution was stirred for 2 hours at room temperature. The crude was purified by flash chromatography (started with isocratic DCM 100% and then the MeOH concentration was increased from 0.5% to 20%, (silica gel 60 0.004-0.063 mm). The product containing fractions were pooled and the EtOAc was removed by evaporation. The substance needed to be purified once more and it was purified by preparative HPLC (started with isocratic acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product containing fractions were pooled and the acetonitrile was removed by evaporation. The ammonium acetate was removed by freeze drying the product overnight to give 0.1 g of methyl 2-{[2-(4-{2-[ethyl(2-fluorobenzyl)amino]-2-oxoethoxy}phenyl)ethyl]thio}benzoate (yield 29.1%).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[CH:9]=[C:8]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH:20]([CH3:22])[CH3:21])=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:14]=3)[CH:7]=[CH:6][C:5]=2[N:4]2[CH2:27][CH2:28][C@H:29]([CH2:30][C:31]([OH:33])=[O:32])[C:3]=12.[OH-].[Na+:35]>CC(O)C>[OH2:11].[Na+:35].[Cl:1][C:2]1[C:10]2[CH:9]=[C:8]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH:20]([CH3:22])[CH3:21])=[C:15]([C:23]([F:24])([F:25])[F:26])[CH:14]=3)[CH:7]=[CH:6][C:5]=2[N:4]2[CH2:27][CH2:28][C@H:29]([CH2:30][C:31]([O-:33])=[O:32])[C:3]=12
Reactant: CC(C)Oc1ccc(COc2ccc3c(c2)c(Cl)c2n3CC[C@@H]2CC(=O)O)cc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CC(C)Oc1ccc(COc2ccc3c(c2)c(Cl)c2n3CC[C@@H]2CC(=O)[O-])cc1C(F)(F)F
Product: O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(R)-2-(9-Chloro-7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid (20 mg) was dissolved in IPA (0.5 mL) with heating, and 2.0 M NaOH (21 uL) was added. The solution was allowed to cool to room temperature and stir for 24 h. The resultant solids that had formed were collected after decanting off the IPA.