Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[N:3]=[C:4]([C@@H:7]2[CH2:11][C@H:10]([CH3:12])[CH2:9][N:8]2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[NH:5][CH:6]=1.[CH3:20][C@@H:21]1[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@H:23]([C:33]2[NH:37][C:36]3C=C[C:40]([C:42]4[CH:47]=[CH:46][C:45]([C:48]#[C:49][Si](C)(C)C)=[CH:44][CH:43]=4)=[CH:41][C:35]=3[N:34]=2)[CH2:22]1.C(Cl)Cl.[CH2:57]1CCN2C(=NCCC2)C[CH2:58]1.O>CN(C=O)C.[Cu]I>[C:16]([O:15][C:13]([N:8]1[CH2:9][C@@H:10]([CH3:12])[CH2:11][C@H:7]1[C:4]1[NH:5][C:6]2[CH:57]=[CH:58][C:48]([C:45]3[CH:46]=[CH:47][C:42]([C:40]#[C:41][C:35]4[N:34]=[C:33]([C@@H:23]5[CH2:22][C@H:21]([CH3:20])[CH2:25][N:24]5[C:26]([O:28][C:29]([CH3:32])([CH3:30])[CH3:31])=[O:27])[NH:37][CH:36]=4)=[CH:43][CH:44]=3)=[CH:49][C:2]=2[N:3]=1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: C1CCC2=NCCCN2CC1
Reactant: C[C@H]1C[C@@H](c2nc3cc(-c4ccc(C#C[Si](C)(C)C)cc4)ccc3[nH]2)N(C(=O)OC(C)(C)C)C1
Reactant: C[C@H]1C[C@@H](c2nc(I)c[nH]2)N(C(=O)OC(C)(C)C)C1
Agent: [Cu]I
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H]1C[C@@H](c2nc(C#Cc3ccc(-c4ccc5[nH]c([C@@H]6C[C@H](C)CN6C(=O)OC(C)(C)C)nc5c4)cc3)c[nH]2)N(C(=O)OC(C)(C)C)C1
Yield: 61.9 %

Procedure:
The well-degassed solution of tert-butyl (2S,4S)-2-(4-iodo-1H-imidazol-2-yl)-4-methyl-pyrrolidine-1-carboxylate (38.21 mg, 0.1013 mmol), tert-butyl (2S,4S)-4-methyl-2-[5-[4-(2-trimethylsilylethynyl)phenyl]-1H-benzimidazol-2-yl]pyrrolidine-1-carboxylate (40 mg, 0.08444 mmol), Pd(DPPF)(Cl)2.CH2Cl2 (6.896 mg, 0.008444 mmol), CuI (3.217 mg, 0.01689 mmol), DBU (128.5 mg, 126.2 μL, 0.8444 mmol), and water (4.563 mg, 4.563 μL, 0.2533 mmol) in DMF (3 mL) is stirred at 70° C. under N2 overnight. After removal of the solvent under reduced pressure, the residue is purified by flash column chromatography on silica gel using methanol/CH2Cl2 (0-6%) to provide the desired tert-butyl (2S,4S)-2-[4-[2-[4-[2-[(2S,4S)-1-tert-butoxycarbonyl-4-methyl-pyrrolidin-2-yl]-1H-benzimidazol-5-yl]phenyl]ethynyl]-1H-imidazol-2-yl]-4-methyl-pyrrolidine-1-carboxylate (34 mg, 61.8% yield). LC/MS: m/z=651.42 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[CH:3]=1.[Cl:10]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:1][C:2]1[C:7]([Cl:10])=[CH:6][N:5]=[C:4]([O:8][CH3:9])[CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1cc(Cl)ccn1
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(Cl)c(Cl)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.1 %

Procedure:
10.0 g (69.9 mmol) of crude 4-chloro-2-methoxypyridine obtained in Step (d) was dissolved in 100 ml of dimethylformamide, and 37.2 g (279 mmol) of N-chlorosuccinimide was added, followed by stirring at room temperature for 12 hours. 400 ml of water was added to terminate the reaction, followed by extraction with ethyl ether. The organic layer was washed with a saturated sodium chloride solution, dried over sodium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure to obtain 9.10 g (crude yield: 73%) of crude 4,5-dichloro-2-methoxypyridine.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>C(#N)C>[Br-:8].[CH2:1]([N+:3]([CH2:6][CH3:7])([CH2:4][CH3:5])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CCCCCCCCBr
Solvent: CC#N
Product: CCCCCCCC[N+](CC)(CC)CC
Product: [Br-]
Temperature: 80 °C
Reaction time: 48 h
Yield: 72.4 %

Procedure:
A 100 ml flask was purged with nitrogen before 8.84 g (0.087 mol) of triethylamine, 20.33 g (0.105 mol) of 1-bromoctane and 31.04 g of acetonitrile were introduced into the flask. The mixture was stirred under protective nitrogen gas at 80° C. for 48 hours. Volatiles were then drawn off under reduced pressure. The crude product was crystallized from an ethyl acetate/acetone mixture to obtain 18.55 g (0.063 mol) of triethyloctylammonium bromide (white hygroscopic crystals). The yield was 72%, based on triethylamine.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:24][O:25][C:26]1[C:27](=[O:50])[C:28]([CH3:49])=[C:29]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([O:45][C:46](=[O:48])[CH3:47])=[C:40]([CH:44]=2)[C:41](O)=[O:42])[C:30](=[O:34])[C:31]=1[O:32][CH3:33]>C(Cl)Cl>[CH:1]1([NH:7][C:41](=[O:42])[C:40]2[CH:44]=[C:36]([CH2:35][C:29]3[C:30](=[O:34])[C:31]([O:32][CH3:33])=[C:26]([O:25][CH3:24])[C:27](=[O:50])[C:28]=3[CH3:49])[CH:37]=[CH:38][C:39]=2[O:45][C:46](=[O:48])[CH3:47])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)NC3CCCCC3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 55 %

Procedure:
Cyclohexylamine (0.159 g, 1.604 mmol), triethylamine (0.162 g, 1.604 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.271 g, 1.604 mmol) were added to a methylene chloride solution (50 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.200 g, 0.535 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:1) and then recrystallized from ether to obtain the titled compound (0.134 g, 0.294 mmol, 55%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:27]#[N:28])=[C:4]([CH:24]=[CH:25][CH:26]=1)[O:5][CH2:6][C:7]([CH3:23])([CH3:22])[CH2:8][NH:9][C:10]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)=[O:11].[S:29](Cl)(=[O:32])(=[O:31])[NH2:30]>>[S:29]([NH:1][C:2]1[C:3]([C:27]#[N:28])=[C:4]([CH:24]=[CH:25][CH:26]=1)[O:5][CH2:6][C:7]([CH3:23])([CH3:22])[CH2:8][NH:9][C:10]([NH:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)=[O:11])(=[O:32])(=[O:31])[NH2:30]
Reactant: NS(=O)(=O)Cl
Reactant: COc1ccc(CNC(=O)NCC(C)(C)COc2cccc(N)c2C#N)cc1
Product: COc1ccc(CNC(=O)NCC(C)(C)COc2cccc(NS(N)(=O)=O)c2C#N)cc1
Yield: 100 %

Procedure:
Prepared as in Example 197a from 1-(3-(3-amino-2-cyanophenoxy)-2,2-dimethylpropyl)-3-(4-methoxybenzyl)urea (Example 218b) and sulfamoyl chloride in 100% yield. MS 462 (MH+).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:25][CH:26]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=1)[CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+].Cl>CN(C)C(=O)C.O>[Cl:37][C:33]1[CH:32]=[C:31]([CH:26]([NH:25][C:3]([C:5]2[N:6]=[C:7]([C:23]#[N:24])[C:8]3[C:13]([C:14]=2[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:9]=3)=[O:4])[CH2:27][C:28]([OH:30])=[O:29])[CH:36]=[CH:35][CH:34]=1
Reactant: NC(CC(=O)O)c1cccc(Cl)c1
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: N#Cc1nc(C(=O)NC(CC(=O)O)c2cccc(Cl)c2)c(O)c2ccc(Oc3ccccc3)cc12
Yield: 25 %

Procedure:
To a mixture of 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (50 mg, 0.16 mmol) and 3-amino-3-(3-chloro-phenyl)-propionic acid (156 mg, 0.78 mmol) (commercially available from Alfa Aesar L19797) in N,N-dimethylacetamide (DMA) (2 mL) was added sodium methoxide (34 mg, 0.62 mmol). The resultant suspension mixture was heated in a 150° C. oil bath for 4 h. After cooled, reaction mixture was diluted with water (50 mL), acidified by 1 N HCl to pH=3-4, and then extracted with EtOAc. Organic layer was washed with brine, dried over MgSO4, filtered and concentrated. Crude product was purified by silica gel chromatography, eluting with EtOAc/hexanes (10%-100%), to provide the title compound 20 mg (0.04 mmol) in 26% yield. LC-MS ESI−: 486 (M−1)−.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([CH2:14][OH:15])[CH2:3]1.CCN(CC)CC.[CH3:23][C:24]([Si:27](Cl)([CH3:29])[CH3:28])([CH3:26])[CH3:25]>ClCCl.CN(C1C=CN=CC=1)C>[Si:27]([O:15][CH2:14][C@@H:4]1[CH2:3][C@@H:2]([OH:1])[CH2:6][N:5]1[C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])([C:24]([CH3:26])([CH3:25])[CH3:23])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1CO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a 0° C. solution of (2S,4R)-tert-butyl 4-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate (1.0 equiv) and Et3N (1.05 equiv) in dichloromethane (0.5 M) was added TBSCl (1.05 equiv), followed by a few crystals of DMAP. The solution was allowed to warm to room temperature and stirred overnight. The reaction mixture was then diluted with dichloromethane, and washed with sat'd. aq. NaHCO3. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide the title compound (95%), which was used without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CN(C=O)C.[H-].[Na+].I[CH:15]1[CH2:21][C:20]([CH3:23])([CH3:22])[C:19]2[CH:24]=[CH:25][C:26]([N+:28]([O-:30])=[O:29])=[CH:27][C:18]=2[NH:17][C:16]1=[O:31]>>[CH3:22][C:20]1([CH3:23])[C:19]2[CH:24]=[CH:25][C:26]([N+:28]([O-:30])=[O:29])=[CH:27][C:18]=2[NH:17][C:16](=[O:31])[CH:15]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[CH2:21]1
Reactant: CC1(C)CC(I)C(=O)Nc2cc([N+](=O)[O-])ccc21
Reactant: C1COCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)CC(N2CCOCC2)C(=O)Nc2cc([N+](=O)[O-])ccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Morpholine (0.0726 mL, 0.000833 mol) was dissolved in DMF (45 mL, 0.58 mol) and cooled to 0° C., and to this solution was added Sodium hydride, 60% disp. in mineral oil (40.0 mg). This mixture was allowed to stir for 30 minutes, followed by the addition of 3-Iodo-5,5-dimethyl-8-nitro-1,3,4,5-tetrahydro-1-benzazepin-2-one (300 mg, 0.0008 mol). The reaction was allowed to warm to rt for 16 h. The reaction was quenched by the addition of ice & water, partitioned between water and EtOAc, extracted 3× with 30 mL portions of EtOAc, was dried over MgSO4, filtered, and concentrated under reduced pressure. (87 mg, 30%). LCMS 320 (M+H)
Reaction SMILES: [F:1][C:2]([F:40])([CH2:36][CH2:37][CH2:38][CH3:39])[C:3](=[O:35])[CH2:4][CH2:5][C@H:6]1[C@H:10]([O:11]C2CCCCO2)[CH2:9][C:8](=[O:18])[C@@H:7]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>O1CCCC1.C(O)(=O)C.O>[F:1][C:2]([C@:3]1([OH:35])[O:11][C@@H:10]2[CH2:9][C:8](=[O:18])[C@H:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])[C@H:6]2[CH2:5][CH2:4]1)([F:40])[CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCC(F)(F)C(=O)CC[C@H]1[C@H](OC2CCCCO2)CC(=O)[C@@H]1CCCCCCC(=O)OCc1ccccc1
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CCCCC(F)(F)[C@@]1(O)CC[C@H]2[C@@H](CC(=O)[C@@H]2CCCCCCC(=O)OCc2ccccc2)O1
Temperature: 40 °C
Reaction time: 4 h
Yield: 75.8 %

Procedure:
To a solution of benzyl 7-[(1R,2R,3R)-2-(4,4-difluoro-3-oxooctyl)-5-oxo-3-(2-tetrahydropyranyloxy) cyclopentyl]heptanoate (1) (39.84 g, 70.54 mmol) in tetrahydrofuran (40 ml), acetic acid (260 ml) and water (140 ml) were added. The mixture was stirred at about 40° C. for 4 hours. The reaction was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (Fuji Silysia BW-300 1600 g, ethyl acetate:hexane=1:3). Fractions containing impurities were purified again by silica gel column chromatography (Fuji Silysia FL-60D 1600 g, ethyl acetate:hexane=1:4). Fractions still containing impurities were collected and further purified repeatedly with silica gel column chromatography (Fuji Silysia FL-60D 1000 g, IPA:hexane=8:100), (Fuji Silysia FL-60D 1600 g, IPA:hexane=7.5:100→3:40), (Fuji Silysia FL-60D 1600 g, IPA:hexane=3:40). Fractions containing substantially no impurities were collected and evaporated to give benzyl 7-[(2R,4aR,5R,7aR)-2-(1,1-difluoropentyl)-2-hydroxy-6-oxooctahydrocyclopenta[b]pyran-5-yl]heptanate (2) (25.68 g, 53.44 mmol, yield: 75.8%).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:13][CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1.C[N:22](C=O)C>>[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([NH2:22])[CH:8]=[C:7]2[CH2:13][CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: Fc1ccc2[nH]cc(CCc3cccnc3)c2c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: Nn1cc(CCc2cccnc2)c2cc(F)ccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of NaH (600 mg, 15 mmol, 60% in mineral oil) in DMF (10 mL) at 0° C. is treated with 5-fluoro-3-(2-pyridin-3-yl-ethyl)-1H-indole (240 mg, 1 mmol) and stirred at 0° C. for 0.5 h. The mixture is treated with HOSA (565 mg, 5 mmol) portion wise and warmed to rt over 2 h. The mixture is then poured over ice, filtered through a pad of Celite, and extracted with EtOAc (3×1050 mL). The combined organic layer is dried (Na2SO4), filtered and concentrated in vacuo to afford 5-fluoro-3-(2-pyridin-3-yl-ethyl)-indol-1-ylamine, which is used in the next step without further purification.
Reaction SMILES: C[C:2]([OH:5])([CH3:4])[CH3:3].[Cl:6][C:7]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]([Cl:14])[C:8]=1[CH:15]([O:17][C:18]1[C:19]([NH2:26])=[N:20][CH:21]=C(C=C)[CH:23]=1)[CH3:16].[OH2:27]>>[NH2:26][C:19]1[N:20]=[CH:21][C:3]([C@H:2]([OH:5])[CH2:4][OH:27])=[CH:23][C:18]=1[O:17][CH:15]([C:8]1[C:9]([Cl:14])=[CH:10][CH:11]=[C:12]([F:13])[C:7]=1[Cl:6])[CH3:16]
Reactant: O
Reactant: CC(C)(C)O
Reactant: C=Cc1cnc(N)c(OC(C)c2c(Cl)ccc(F)c2Cl)c1
Product: CC(Oc1cc([C@H](O)CO)cnc1N)c1c(Cl)ccc(F)c1Cl
Temperature: 0 °C
Yield: 53 %

Procedure:
(S)-1-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl)ethane-1,2-diol was prepared as follow: To a solution of asymmetic dihydroxylation-mix α (2.33 g) in a 1:1 mixture of t-BuOH and water (8 mL each) cooled to 0° C. was added 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-vinyl-pyridin-2-ylamine (500 mg, 1.67 mmol). The reaction mixture was stirred at 0° C. until consumption of the starting material. Three more loadings of AD-mix α was added periodically to increase the reaction rate. Water was added (5 mL) and the mixture was extracted with EtOAc (3×20 mL). The combined organic layer was dried over Na2SO4, and concentrated. The crude product was purified by reverse phase HPLC to provide (S)-1-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl)-ethane-1,2-diol (320 mg, 53% yield).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([OH:9])[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:17]1([S:27](Cl)(=[O:29])=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1.O>C(Cl)(Cl)Cl>[C:17]1([S:27]([NH:2][CH:3]2[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]2)(=[O:29])=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: O=S(=O)(NC1CCC(O)CC1)c1cccc2ccccc12
Reaction time: 15 h
Yield: 89 %

Procedure:
To 18.6 g of trans-4-aminocyclohexanol hydrochloride suspended in 700 ml of chloroform are added, at 5° C., 34 ml of triethylamine, followed by a solution containing 18.6g of 1-naphthylsulfonyl chloride in 100 ml of chloroform. After reacting for 15 hours, the reaction mixture is poured onto 500 ml of water. The expected product is obtained by filtration of the precipitate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH2:8][CH2:9][NH:10][CH:11]([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].Br[C:16]1([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)[C:24]2[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=2)[NH:18][C:17]1=[O:26].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.C(#N)C>[C:1]([O:5][C:6](=[O:14])[NH:7][CH2:8][CH2:9][N:10]([C:16]1([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)[C:24]2[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=2)[NH:18][C:17]1=[O:26])[CH:11]([CH3:12])[CH3:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1Nc2cc(Cl)ccc2C1(Br)Cc1cccc(Cl)c1
Reactant: CC(C)NCCNC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)N(CCNC(=O)OC(C)(C)C)C1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.1 %

Procedure:
A mixture of (2-Isopropylamino-ethyl)-carbamic acid tert-butyl ester (100 mg, 0.5 mmol), rac-3-bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (185 mg, 0.5 mmol) and K2CO3 (138 mg, 1 mmol) in DCM (1 mL) and acetonitrile (2 mL) was stirred at room temperature overnight. The mixture was concentrated and purified by column chromatography to give 180 mg rac-(2-{[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-isopropyl-amino}-ethyl)-carbamic acid tert-butyl ester. MS: [M+H]+=492
Reaction SMILES: CN(C)CCNC.BrC1OC(C=O)=CC=1.[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[O:27][C:26]([CH:28]=O)=[CH:25][CH:24]=2)[CH2:19][CH2:18]1.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][C:40]=1[O:41][CH3:42])[CH2:35][C:36]#[N:37]>>[CH3:30][O:31][C:32]1[CH:33]=[C:34](/[C:35](=[CH:28]/[C:26]2[O:27][C:23]([N:20]([CH2:21][CH2:22][N:17]([CH3:16])[CH3:18])[CH3:19])=[CH:24][CH:25]=2)/[C:36]#[N:37])[CH:38]=[CH:39][C:40]=1[O:41][CH3:42]
Reactant: CN1CCN(c2ccc(C=O)o2)CC1
Reactant: COc1ccc(CC#N)cc1OC
Agent: CNCCN(C)C
Agent: O=Cc1ccc(Br)o1
Product: COc1ccc(/C(C#N)=C/c2ccc(N(C)CCN(C)C)o2)cc1OC
Yield: 96.9 %

Procedure:
Through the procedure as employed in Production step 1, an amine moiety derived from N,N,N′-trimethylethylenediamine (3.06 g) was introduced into 5-bromo-2-furaldehyde (1.75 g), to thereby yield 5-(4-methyl-piperazin-1-yl)-furan-2-carbaldehyde (yield: 1.18 g, 60%). The produced 5-(4-methyl-piperazin-1-yl)-furan-2-carbaldehyde (1.18 g) was condensed with 3,4-dimethoxybenzyl cyanide (1.06 g) through Method A (production step 2), to thereby yield the target product (yield: 2.06 g, 96%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[N:3]=1.[S:16]([O-:19])([OH:18])=[O:17].[Na+:20].C(O)C>O>[F:9][C:8]([F:11])([F:10])[C:6]1[CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[N:3]=[C:2]([S:16]([O-:19])(=[O:18])=[O:17])[CH:7]=1.[Na+:20]
Reactant: FC(F)(F)c1cc(Cl)nc(C(F)(F)F)c1
Reactant: O=S([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=S(=O)([O-])c1cc(C(F)(F)F)cc(C(F)(F)F)n1
Yield: 66.5 %

Procedure:
A mixture of 2-chloro-4,6-bis(trifluoromethyl)pyridine (2.50 g, 10 mmol), sodium hydrogen sulfite (4.2 g, 40 mmol), ethanol (40 ml) and water (40 ml) was heated under reflux for 96.5 hours. The reaction mixture was evaporated to dryness under reduced pressure. To the residue, conc. hydrochloric acid was added and the mixture was again evaporated to dryness. The residued was extracted with methanol, and a methanol phase was filtered. The filtrate was evaporated to dryness under reduced pressure to obtain sodium 4,6-bis(trifluoromethyl)pyridine-2-sulfonate (2.11 g). Yield, 66%.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][C:21]1[C:22](=[O:39])[N:23]([C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-])=O)=[CH:29][C:28]=2[CH2:36][O:37][CH3:38])[CH:24]=[CH:25][CH:26]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])=O.[NH4+]>C(OCC)(=O)C.C(O)C.[Pd]>[NH2:33][C:30]1[CH:31]=[CH:32][C:27]([N:23]2[CH:24]=[CH:25][CH:26]=[C:21]([CH2:20][CH2:19][O:18][Si:1]([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:22]2=[O:39])=[C:28]([CH2:36][O:37][CH3:38])[CH:29]=1
Reactant: COCc1cc([N+](=O)[O-])ccc1-n1cccc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COCc1cc(N)ccc1-n1cccc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1=O

Procedure:
25 g (48 mmol) of the compound from Example 39A are dissolved in 500 ml of ethyl acetate and 500 ml of ethanol. 18 g (286 mmol) of ammonium formate and 1 g of palladium on carbon are added, and the mixture is heated at reflux for 45 min. The reaction solution is then allowed to cool and filtered through silica gel. The filtrate is concentrated to dryness under reduced pressure. This gives 25 g (100% of theory) of the desired product.
Reaction SMILES: [C:1]([S:5][CH2:6][C:7]1([C:17]([NH:19][C@H:20]([C:24]([O:26]CC2C=CC=CC=2)=[O:25])[CH:21]([CH3:23])[CH3:22])=[O:18])[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8]1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)S(O)(=O)=O>CSC.O>[C:1]([S:5][CH2:6][C:7]1([C:17]([NH:19][C@H:20]([C:24]([OH:26])=[O:25])[CH:21]([CH3:22])[CH3:23])=[O:18])[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)[C@H](NC(=O)C1(CSC(C)(C)C)CCc2ccccc2C1)C(=O)OCc1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CSC
Solvent: O
Product: CC(C)[C@H](NC(=O)C1(CSC(C)(C)C)CCc2ccccc2C1)C(=O)O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Dissolve N-[[1,2,3,4-tetrahydro-2-[[(t-butyl)thio]methyl]-2-naphthalenyl]carbonyl]-L-valine, benzyl ester (256 mg, 0.547 mmol) in dimethylsulfide (3 mL) and add trifluoromethanesulfonic acid (0.2 mL). Stir at room temperature under an argon atmosphere for 6 hours. Dilute with water and extract into ethyl ether. Wash with water, then brine and dry (MgSO4). Evaporate the solvent in vacuo to give the title compound.
Reaction SMILES: O=[C:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=O.O.[NH2:26][NH2:27].C(O)C>C1COCC1>[C:19]1([C:2]2[CH:3]=[C:4]([CH:6]3[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]3)[NH:27][N:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)CC(=O)c2ccccc2)CC1
Reactant: NN
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2cc(-c3ccccc3)n[nH]2)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of tert-butyl 4-(3-oxo-3-phenylpropanoyl)piperidine-1-carboxylate (3.1 g), hydrazine monohydrate (0.5 mL), ethanol (30 mL), and THF (30 mL) was stirred at room temperature for about 15 hours, and at 60° C. for 1 hour. Hydrazine monohydrate (0.5 mL) was further added thereto, followed by stirring again at 60° C. for 3 hours. Hydrazine monohydrate (4.0 mL) was added thereto again, followed by stirring at 60° C. for 8 hours. After leaving to be cooled, the solvent was evaporated under reduced pressure, and to the residue were added diisopropyl ether and methanol, followed by stirring. The resulting solid was collected by filtration and dried under reduced pressure to obtain tert-butyl 4-(3-phenyl-1H-pyrazol-5-yl)piperidine-1-carboxylate (2.46 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([NH2:6])=O.CN(C)C=O.N1C=CC=CC=1.C1(S(Cl)(=O)=O)C=CC=CC=1>O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]#[N:6]
Reactant: NC(=O)c1cc([N+](=O)[O-])ccc1Cl
Agent: O=S(=O)(Cl)c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Solvent: c1ccncc1
Product: N#Cc1cc([N+](=O)[O-])ccc1Cl
Yield: 89.3 %

Procedure:
Further, 2-chloro-5-nitrobenzamide (100 g) was added to dimethylformamide (240 ml) and pyridine (100 ml). To the mixture was dropwise added benzenesulfonyl chloride at room temperature with stirring, and the mixture was stirred at 145° C. for 3 h. The reaction mixture was ice-cooled, and water (240 ml) was added thereto. The precipitated crystals were recrystallized from hydrous ethanol to give 2-chloro-5-nitrobenzonitrile (81.3 g), melting point: 108–110° C.