Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[CH:9]=[C:8]([C:10]2[O:11][CH:12]=[CH:13][N:14]=2)[CH:7]=[C:6]([N:15]([CH2:26][CH:27]=[CH2:28])[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH:5]=1.[Li+].[OH-]>CO.O.Cl.C(Cl)Cl>[CH2:26]([N:15]([C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17])[C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([C:10]2[O:11][CH:12]=[CH:13][N:14]=2)[CH:7]=1)[C:3]([OH:29])=[O:2])[CH:27]=[CH2:28]
Reactant: C=CCN(C(=O)OCc1ccccc1)c1cc(C(=O)OC)cc(-c2ncco2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: C=CCN(C(=O)OCc1ccccc1)c1cc(C(=O)O)cc(-c2ncco2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(Allyl-benzyloxycarbonyl-amino)-5-oxazol-2-yl-benzoic acid methyl ester (300 mg, 757 μmol, 1 eq) is dissolved in methanol (10 ml) and H2O (4 ml). LiOH*H2O (100 mg, 2.37 mmol, 3.13 eq) is added to the reaction mixture, which is stirred for 8 h at rt and then diluted with HCl (1N in H2O) and DCM. The combined organic solvents are separated and washed with brine, dried over sodium sulfate, filtered and concentrated. The resulting crystals are washed with hexane and dried under vacuum to give the product.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N:8]=[CH:9][C:10]2[C:15]([NH:16][C:17]([O:19][CH3:20])=[O:18])=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:21])=[CH:6][CH:5]=[CH:4][N:3]=1.[BH4-].[Na+].O>CO.C(Cl)(Cl)Cl>[NH2:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[C:15]([NH:16][C:17]([O:19][CH3:20])=[O:18])=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:21])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: COC(=O)Nc1cccc(C)c1C=Nc1cccnc1N
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClC(Cl)Cl
Product: COC(=O)Nc1cccc(C)c1CNc1cccnc1N
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 94.1 %

Procedure:
To a solution of 2-amino-3-(2-methyl-6-methoxycarbonylaminobenzylideneamino)pyridine (229 mg) in methanol (4.6 ml) and chloroform (4.6 ml) was added sodium borohydride (200 mg) and the mixture was stirred for 3.5 hours at room temperature. After water was added, organic layer was separated and dried over magnesium chloride. The solvent was evaporated under reduced pressure. The residue was triturated with diethyl ether to give 2-amino-3-(2-methyl-6-methoxycarbonylaminobenzylamino)pyridine (217 mg).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([O:19][C:20]([NH:22][CH2:23][CH:24]1[CH2:28][CH2:27][NH:26][CH2:25]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].[Cl:29][C:30]1[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:31]=1[CH:32]=O>ClC(Cl)C>[C:15]([O:19][C:20]([NH:22][CH2:23][CH:24]1[CH2:28][CH2:27][N:26]([CH2:32][C:31]2[CH:34]=[CH:35][CH:36]=[C:37]([Cl:38])[C:30]=2[Cl:29])[CH2:25]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)NCC1CCNC1
Reactant: O=Cc1cccc(Cl)c1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)NCC1CCN(Cc2cccc(Cl)c2Cl)C1
Reaction time: 8 h
Yield: 80.7 %

Procedure:
Sodium triacetoxyborohydride (3.2 g, 15 mmol, 1.5 equiv.) was added in one portion to a stirred solution of 3-(RS)-(N-tert-butoxycarbonylaminomethyl)pyrrolidine (2.0 g, 10 mmol) and 2,3-dichlorobenzaldehyde (1.9 g, 11 mmol, 1.1 equiv.) in dichloroethane (60 mL) at room temperature. The suspension was stirred overnight, then concentrated in vacuo. The residue was diluted with ether and quenched with 1 M hydrochloric acid. The aqueous phase was basified with 4 M sodium hydroxide to pH 12, then extracted with ethyl acetate. The organic extracts were combined and washed with brine, then dried over sodium sulfate and concentrated. Flash chromatography of the residue afforded 3-(RS)-(N-tert-butoxycarbonylaminomethyl)-1-(2,3-dichlorobenzyl)-pyrrolidine as a colorless oil (2.9 g). The oil was taken up into methylene chloride (30 mL) and treated with neat trifluoroacetic acid (5 mL). After 1 h, the volatile components were removed on a vacuum pump, then concentrated further under high vacuum to give 3-(RS)-aminomethyl-1-(2,3-dichlorobenzyl)pyrrolidine which was used directly without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][C:11]([NH2:13])=[O:12])=[C:4]([C:14]([F:17])([F:16])[F:15])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:24][C:25]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[CH:27][N:26]=1.O>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:24][C:25]1[CH:30]=[C:29]([C:2]2[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][C:11]([NH2:13])=[O:12])=[C:4]([C:14]([F:17])([F:16])[F:15])[CH:3]=2)[CH:28]=[CH:27][N:26]=1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Reactant: NC(=O)CCSc1ccc(Br)cc1C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccc(SCCC(N)=O)c(C(F)(F)F)c2)ccn1
Temperature: 50 °C
Reaction time: 20 h
Yield: 74 %

Procedure:
3-(4-Bromo-2-trifluoromethyl-phenylsulfanyl)-propionamide (300 g, 914 mmol) was dissolved in N,N-dimethylformamide (3.0 L) and potassium carbonate (300 g, 2.17 mol). Then, 2-methylpyridine-4-boronic acid pinacol ester (285 g, 1.3 mol) and water (240 mL) were added. The solution was degassed and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (30 g, 41 mmol) was added. The mixture was stirred for 20 h at 50° C. After cooling to room temperature, it was poured onto ice cold water (5° C., 5 L) and extracted with ethyl acetate (1×3.5 L, 2×1.5 L). The combined organic extracts were washed with brine/water (1:1 v/v, 750 mL) and brine (750 mL), before methanol (600 mL) was added and the mixture was dried over sodium sulfate. Silica gel (400 g) was added, the slurry was filtered and washed with ethyl acetate/methanol (9:1 v/v, 1.5 L). The combined filtrates were concentrated in vacuo. The residue was suspended in toluene (600 mL) and n-heptane (300 mL) and stirred for 5 min at 60° C. and for 1 h at room temperature. The precipitate was filtered off, washed with toluene/n-heptane (4:1 v/v, 300 mL) and n-heptane (300 mL), and dried in vacuo to afford 230.3 g of brown crystalline material. The crystals were further purified by trituration in isopropanol/heptane (1:1 v/v, 600 mL) for 30 min at room temperature and 30 min at 0-4° C. (ice bath). The precipitate was filtered off, washed with n-heptane/isopropanol (4:1 v/v, 300 mL), and dried in vacuo at 65° C. to yield the title compound as a light brown crystalline solid (215.7 g, 69%). MS (EI): m/z=341.1 [M+H]. 1H NMR (d6-DMSO, 400 MHz): δ 2.48 (t, J=7.2 Hz, 2H), 2.54 (s, 3H), 3.32 (t, J=7.2 Hz, 2H), 6.95 (bs, 1H), 7.41 (bs, 1H), 7.58 (dd, J=1.6 Hz, 5.4 Hz, 1H), 7.68 (s, 1H), 7.77 (d, J=9.1 Hz, 1H), 8.02-8.08 (m, 2H), 8.52 (d, J=5.1 Hz, 1H).
Reaction SMILES: Cl.[NH2:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:18])[CH2:13][CH2:14][C:15]([OH:17])=O)=[CH:7][CH:6]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[CH3:34][O:35][C:36](=[O:45])[CH2:37][CH:38]([NH2:44])[CH2:39][C:40]([O:42][CH3:43])=[O:41].CN(C1C=CC=CN=1)C>CN(C=O)C>[NH2:2][N:3]=[CH:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:18])[CH2:13][CH2:14][C:15]([NH:44][CH:38]([CH2:37][C:36]([O:35][CH3:34])=[O:45])[CH2:39][C:40]([O:42][CH3:43])=[O:41])=[O:17])=[CH:9][CH:10]=1
Reactant: COC(=O)CC(N)CC(=O)OC
Reactant: NN=Cc1ccc(NC(=O)CCC(=O)O)cc1
Agent: CC(C)COC(=O)Cl
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)CC(CC(=O)OC)NC(=O)CCC(=O)Nc1ccc(C=NN)cc1
Reaction time: 0.08 h
Yield: 52.5 %

Procedure:
4-[[4-(aminoiminomethyl)phenyl]-amino]-4-oxobutanoic acid hydrochloride prepared in Example 1, Step 1 (4.6 g, 17 mmol) was added to dry DMF (225 ml) followed by N-methylmorpholine (1.2 g, 17 mmol) and isobutyl chloroformate (2.3 g, 17 mmol) at 25° C. The mixture was stirred for 5 min. Dimethyl-3-aminoglutarate (3.0 g, 17 mmol) was added followed by dimethylaminopyridine. After 1 hr, the solvent was removed under reduced pressure and the product purified by reverse phase chromatography (0.05% TFA water/acetonitrile) to result in 3.5 g of a white solid: 1H NMR (d6 -DMSO) δ2.37 (t, 2H, J=7.3 Hz), 2.55 (m, 2H), 2.57 (t, 2H, J=7.1 Hz), 3.57 (s, 6H), 4.35 (m, 1H), 7.79 (s, 4H), 7.99 (d, 1H,J=8.1 Hz), 9.1(bs, 2H), 9.19 (bs, 2H), 10.42 (s, 1H); MS (FAB) m/z 393.2 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[N:10][N:11]([CH2:14]C2C=CC(C(OC)=O)=CC=2)[C:12]=1[Cl:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(C1C=NN(C[C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([C:45]([O:47][CH3:48])=[O:46])[CH:40]=2)C=1N)=O)(C)(C)C>>[C:1]([O:5][C:6]([C:8]1[CH:9]=[N:10][N:11]([CH2:14][C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([C:45]([O:47][CH3:48])=[O:46])[CH:40]=2)[C:12]=1[Cl:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cccc(Cn2ncc(C(=O)OC(C)(C)C)c2N)c1
Reactant: COC(=O)c1ccc(Cn2ncc(C(=O)OC(C)(C)C)c2Cl)cc1
Product: COC(=O)c1cccc(Cn2ncc(C(=O)OC(C)(C)C)c2Cl)c1

Procedure:
Compound prepared in an analogous manner to Intermediate #48, replacing 5-Amino-1-(4-methoxycarbonyl-benzyl)-1H-pyrazole-4-carboxylic acid tert-butyl ester with 5-Amino-1-(3-methoxycarbonyl-benzyl)-1H-pyrazole-4-carboxylic acid tert-butyl ester (Intermediate #51)
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:4][C@@H:3]1[C:5]1[O:9][N:8]=[C:7]([C:10]2[CH:11]=[CH:12][C:13]([CH3:28])=[C:14]([NH:16][C:17]([C:19]3[N:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]4=[N:21][CH:20]=3)=[O:18])[CH:15]=2)[N:6]=1.F[C:31]1(F)C[C@H]1C1ON=C(C2C=CC(C)=C(NC(C3N4C=CC=CC4=NC=3)=O)C=2)N=1.F[C@@H]1C[C@H]1C1ON=C(C2C=CC(C)=C(NC(C3N4C=CC=CC4=NC=3)=O)C=2)N=1.F[C@H]1C[C@@H]1C1ON=C(C2C=CC(C)=C(NC(C3N4C=CC=CC4=NC=3)=O)C=2)N=1>>[F:1][C:2]1([F:29])[CH2:4][CH:3]([C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:11]=[CH:12][C:13]([CH3:28])=[C:14]([NH:16][C:17]([C:19]4[N:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]5=[N:21][CH:20]=4)=[O:18])[CH:15]=3)[N:6]=2)[CH2:31]1
Reactant: Cc1ccc(-c2noc([C@H]3CC3(F)F)n2)cc1NC(=O)c1cnc2ccccn12
Reactant: Cc1ccc(-c2noc([C@@H]3CC3(F)F)n2)cc1NC(=O)c1cnc2ccccn12
Agent: Cc1ccc(-c2noc([C@@H]3C[C@H]3F)n2)cc1NC(=O)c1cnc2ccccn12
Agent: Cc1ccc(-c2noc([C@H]3C[C@@H]3F)n2)cc1NC(=O)c1cnc2ccccn12
Product: Cc1ccc(-c2noc(C3CC(F)(F)C3)n2)cc1NC(=O)c1cnc2ccccn12

Procedure:
N-(5-{5-[(1R)-2,2-difluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide; N-(5-{5-[(1S)-2,2-difluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide; N-(5-{5-[(1S,2R)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide, and N-(5-{5-[(1R,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][CH2:11][OH:12].N[C:14](N)=[O:15].[OH-].[Na+]>>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]2[N:9]([CH2:10][CH2:11][OH:12])[C:14](=[O:15])[NH:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(Cl)ccc1NCCO
Reactant: NC(N)=O
Agent: [Na+]
Agent: [OH-]
Product: O=c1[nH]c2cc(Cl)ccc2n1CCO
Reaction time: 8 h

Procedure:
A mixture of 9 parts of 2-[(2-amino-4-chlorophenyl)amino]-ethanol and 9 parts of urea is stirred and heated for 2 hours at 180°-190° C. After cooling the reaction mixture is treated with concentrated sodium hydroxide solution. The obtained solution is filtered from some unsoluble matter. It is then treated with activated charcoal and filtered again. The filtrate is acidified with concentrated hydrochloric acid. After keeping overnight at room temperature, the precipitated solid is filtered off, washed and dried, to yield 5 parts of 5-chloro-1-(2-hydroxyethyl)-1,3-dihydro-2H-benzimidazol-2-one; mp. 176°-178.2° C; pale-brown, amorphous powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][NH:24]1)=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[Cl:54][C:55]1[N:60]=[C:59]([CH3:61])[C:58]([S:62](Cl)(=[O:64])=[O:63])=[CH:57][CH:56]=1.Cl>>[CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:62]([C:58]1[C:59]([CH3:61])=[N:60][C:55]([Cl:54])=[CH:56][CH:57]=1)(=[O:64])=[O:63])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][CH:17]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: Cc1nc(Cl)ccc1S(=O)(=O)Cl
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1ccc(Cl)nc1C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Yield: 79.8 %

Procedure:
(S)-2-({(S)-7-(6-Chloro-2-methyl-pyridine-3-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (80 mg) was prepared from (S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-propionic acid methyl ester (80 mg) and 6-Chloro-2-methyl-pyridine-3-sulfonyl chloride (29 mg) according to General Procedure E (except that the 1 N HCl wash was omitted). LCMS (m/z) 937.
Reaction SMILES: [CH:1]([OH:3])=O.[NH2:4][C:5]1[C:12]([N+:13]([O-])=O)=[C:11]([CH3:16])[C:10]([N+:17]([O-])=O)=[CH:9][C:6]=1[C:7]#[N:8].N[C:21]1C([N+]([O-])=O)=C(C)C([N+]([O-])=O)=CC=1C#N.O.C(O)=O>[Pt].O>[CH:1]([NH:17][C:10]1[CH:9]=[C:6]([C:7]#[N:8])[C:5]2[N:4]=[CH:21][NH:13][C:12]=2[C:11]=1[CH3:16])=[O:3]
Reactant: O=CO
Reactant: Cc1c([N+](=O)[O-])cc(C#N)c(N)c1[N+](=O)[O-]
Agent: [Pt]
Solvent: O
Product: Cc1c(NC=O)cc(C#N)c2nc[nH]c12
Temperature: 95 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
A mixture of platinum on carbon (sulfided) catalyst (5.3 kg of Engelhard C3759), formic acid (86.8 kg) and water (28.4 L) is heated to about 95° C. A mixture of 2-amino-4-methyl-3,5-dinitrobenzonitrile (5) (10.9 kg), formic acid (28 kg) and water (8 L) is then added to the catalyst-containing solution over about 45 minutes, while maintaining the temperature of the catalyst-containing mixture at about 95° C. The vessel that formerly contained the initial 2-amino-4-methyl-3,5-dinitrobenzonitrile/water/formic acid mixture is then rinsed with water (5.5 L) and the rinse solution is added to the catalyst-containing mixture. The resultant catalyst-containing mixture is then agitated at about 95° C. for about 30 minutes. After the mixture is cooled to about 35-45° C., the mixture is filtered to remove the catalyst and the filtered catalyst is washed with 96% formic acid (32.3 kg). The combined product-containing filtrate is placed under vacuum and heated (from about 25° C. to about 60° C.), and formic acid/water is distilled off, until about 98.4 kg of distillate is collected. At this point, methanol (109.1 kg) is added to the product-containing mixture. The mixture is gradually cooled to about 5° C., over a period of about 1 hour, and held at this temperature for about 1 hour. The mixture is then filtered and the product filter cake is washed with methanol (42.5 kg). The product is then dried in a vacuum tray dryer, at a temperature of about 45-50° C. and a vacuum of about 70 torr until dry to obtain 6-(Formylamino)-7-methyl-1H-benzimidazole-4-carbonitrile (9) (6.4 kg, 65% yield).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:12]([O:14][CH3:15])=[O:13])[NH:6]2.[H-].[Na+].Br[CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].[NH4+].[Cl-]>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:12]([O:14][CH3:15])=[O:13])[N:6]2[CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: COC(=O)c1cc2c(Br)cc(F)cc2[nH]1
Reactant: CCOC(=O)CCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCn1c(C(=O)OC)cc2c(Br)cc(F)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
To a solution of methyl 4-bromo-6-fluoro-1H-indole-2-carboxylate (10 g, 36.8 mmol) in DMF (100 mL) at 0° C. was added NaH (1.8 g, 44.2 mmol, 60% in oil). The mixture was stirred at r.t. for 30 minutes and tetra-n-butylammonium iodide (500 mg) was added, followed by the addition of ethyl 4-bromobutyrate (10.1 g, 51.5 mmol). The reaction mixture was stirred at r.t. for 3 h, poured into saturated aqueous NH4Cl and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluted with 20% EtOAc to give 13.2 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH:14](OS(C)(=O)=O)[CH2:13][CH2:12][CH:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:25]=[N+:26]=[N-:27].[Na+]>CS(C)=O.C(OCC)(=O)C>[N:25]([CH:14]1[CH2:13][CH2:12][CH:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:10][CH:9]1[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[N+:26]=[N-:27]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)C1CCC(OS(C)(=O)=O)C(NC(=O)OC(C)(C)C)C1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOC(=O)C1CCC(N=[N+]=[N-])C(NC(=O)OC(C)(C)C)C1
Temperature: 90 °C
Reaction time: 8 h
Yield: 43.8 %

Procedure:
To a solution of Racemate-ethyl 3-(tert-butoxycarbonylamino)-4-(methylsulfonyloxy)cyclohexanecarboxylate (11.0 g, 30 mmol) in dimethyl sulfoxide (110 mL) was added sodium azide (20 g, 300 mmol), and the mixture was stirred at 90° C. overnight under N2. The solution was cooled to ˜30° C., dissolved in ethyl acetate (˜500 mL), washed with water (500 mL×5) and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=4:1˜2:1) to thereby give the title compound (4.1 g, 44%) as an colorless oil. MS (ES+) C14H24N4O4 requires: 312, found: 213 [M+H−100]+.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N+:14]([C:17]1[CH:18]=[C:19]([CH2:23][C:24](O)=[O:25])[CH:20]=[CH:21][CH:22]=1)([O-:16])=[O:15].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[N+:14]([C:17]1[CH:18]=[C:19]([CH2:23][C:24]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)=[O:25])[CH:20]=[CH:21][CH:22]=1)([O-:16])=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)Cc2cccc([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An oven-dried, round-bottom flask was charged with tert-butyl piperazine-1-carboxylate (1.1 eq), 3-nitrophenylacetic acid (7A, 1.0 eq), EDC (1.2 eq), and HOBT (1.2 eq). The flask was flushed with nitrogen, and A, N-dimethylfomamide (about 0.5 M 7A in DMF) and triethylamine (2.0 eq) were added by syringe. The resulting reaction mixture was stirred overnight at room temperature. The reaction mixture was then diluted with EtOAc, and washed 4 times with H2O, twice with 1 N aq. KHSO4, once with saturated NaHCO3, and once with brine. The organic layer was dried over Na2 SO4, filtered and concentrated in vacuo. Tert-butyl 4-(2-(3-nitrophenyl)acetyl)piperazine-1-carboxylate (7B) was isolated as a solid (80%) and used without further purification.
Reaction SMILES: [N:1]1([C:10]2[N:15]=[C:14](Cl)[CH:13]=[C:12]([Cl:17])[N:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.C(Cl)Cl>CN(C=O)C.O>[N:1]1([C:10]2[N:11]=[C:12]([Cl:17])[CH:13]=[C:14]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:15]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: C1COCCN1
Reactant: Clc1cc(Cl)nc(-n2cnc3ccccc32)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Clc1cc(N2CCOCC2)nc(-n2cnc3ccccc32)n1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 76.7 %

Procedure:
The obtained 2-(benzimidazol-1-yl)-4,6-dichloropyrimidine (2.08 g, 7.85 mmol) dissolved in DMF(30 ml) was cooled to −5° C., added with anhydrous potassium carbonate (3.0 g, 22 mmol) and morpholine (0.68 g. 7.85 mmol) and stirred for 30 minutes. The reaction mixture was further stirred at room temperature overnight and condensed under reduced pressure. The residue was added with methylene chloride and water and shaken for mixing. The organic layer was separated out and washed with water, dried over anhydrous magnesium sulfate and condensed. The obtained residue was purified by silica gel column chromatography to obtain 1.90 g (yield 77%) of 2-(benzimidazol-1-yl)-4-chloro-6-morpholinopyrimidine with melting point of 178° C.-181° C.
Reaction SMILES: Br.[NH2:2][CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)[C:4]#[N:5].[CH3:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]1[C:22]([NH:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[C:31](O)=[O:32])=[O:23]>>[C:4]([CH:3]([NH:2][C:31]([C@@H:26]1[CH2:27][CH2:28][CH2:29][CH2:30][C@@H:25]1[NH:24][C:22]([C:14]1[N:13]([CH3:12])[C:21]2[C:16]([CH:15]=1)=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:23])=[O:32])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)#[N:5]
Reactant: N#CC(N)c1ccccn1
Reactant: Cn1c(C(=O)NC2CCCCC2C(=O)O)cc2ccccc21
Agent: Br
Product: Cn1c(C(=O)N[C@H]2CCCC[C@H]2C(=O)NC(C#N)c2ccccn2)cc2ccccc21

Procedure:
Amino-pyridin-2-yl-acetonitrile hydrobromide and 2-[(1-Methyl-1H-indole-2-carbonyl)-amino]-cyclohexanecarboxylic acid were coupled as described in Example 1 to provide methyl-1H-indole-2-carboxylic acid {(1S,2R)-2-[(cyano-pyridin-2-yl-methyl)-carbamoyl]-cyclohexyl}-amide.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[C:9]=1Cl.[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[SH:26]>C1(C)C(C)=CC=CC=1>[Cl:7][C:8]1[C:9]([S:26][C:20]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:19]=2[Cl:18])=[C:10]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:12][CH:13]=1
Reactant: O=[N+]([O-])c1cccc(Cl)c1Cl
Reactant: Sc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: O=[N+]([O-])c1cccc(Cl)c1Sc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium carbonate (13.8 g) is added to a solution of 1,2-dichloro-3-nitrobenzene (19.29 g) and 2,4-dichlorothio-phenol (17.9 g) in xylene (250 ml), and the resulting mixture is heated for 5 hours at reflux temperature. The precipitate is separated by filtration, washed with xylene and the combined organic phases are concentrated. The resultant residue is mixed with petroleum ether and stirred for 1 hour at room temperature. Following this, the crystalline material is suction filtered and washed with petroleum ether, and any remaining solvent is removed in a vacuum. Yield: 25.6 g of colourless crystals (76.6%).