Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:25](Br)[CH:26]=[CH2:27]>C1COCC1>[CH2:27]([C:2]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:1][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1)[CH:26]=[CH2:25]
Reactant: CCOC(=O)C1Cc2ccccc2C1
Reactant: C=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCC1(C(=O)OCC)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl indane-2-carboxylate [Schaaf et al., J. Med. Chem. 1983, 26, 328-334] (6.87 g, 36.1 mmol) in THF (100 mL) at −78° C. was added sodium bis(trimethylsilyl)amide (1.0 M in THF, 39.7 mL, 39.7 mmol) dropwise over 20 min. The resulting yellow solution was stirred for 1 h, and then allyl bromide (3.75 mL, 43.3 mmol) was added over 5 min. Stirring was continued for 1.5 h at −78° C., and then the reaction was quenched by the addition of saturated NH4Cl and warmed to ambient temperature. The reaction mixture was partitioned between saturated NH4Cl (100 mL) and EtOAc (100 mL). The aqueous phase was further extracted with EtOAc (2×50 mL), and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 75:25, to give the title compound. MS: m/z=231 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[NH:9][C:10](=[O:25])[N:11]([CH:12]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)[C:6]2=[CH:5][CH:4]=1.Cl>CO.CCOCC>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[NH:9][C:10](=[O:25])[N:11]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:6]2=[CH:5][CH:4]=1
Reactant: COc1ccc2c(n1)[nH]c(=O)n2C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: COc1ccc2c(n1)[nH]c(=O)n2C1CCNCC1
Reaction time: 2 h
Yield: 85.6 %

Procedure:
5-Methoxy-2-oxo-1-(1-t-butoxycarbonylpiperidin-4-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine (100 mg, 0.287 mmol) was dissolved in methanol (2.5 mL) and a solution of 2N hydrochloric acid in ether (3 mL) was added at room temperature. After 2 h, the volatiles were removed in vacuo, to give the title compound (61 mg). MS 249.1 (M+1).
Reaction SMILES: [NH2:1][C@H:2]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:17]([CH2:22][CH:23]2[CH2:25][CH2:24]2)[S:18]([CH3:21])(=[O:20])=[O:19])[CH2:7][CH2:6]1)=[O:4].[C:34]([N:41]1[CH2:44][CH:43]([C:45](O)=[O:46])[CH2:42]1)([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].CCN=C=NCCCN(C)C.CI.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][C@@H:2]([NH:1][C:45]([CH:43]2[CH2:44][N:41]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:42]2)=[O:46])[C:3]([N:5]2[CH2:6][CH2:7][N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:17]([CH2:22][CH:23]3[CH2:24][CH2:25]3)[S:18]([CH3:21])(=[O:19])=[O:20])[CH2:9][CH2:10]2)=[O:4])=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Reactant: CS(=O)(=O)N(CC1CC1)c1ccccc1N1CCN(C(=O)[C@H](N)Cc2ccc(Cl)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CI
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(C(=O)N[C@H](Cc2ccc(Cl)cc2)C(=O)N2CCN(c3ccccc3N(CC3CC3)S(C)(=O)=O)CC2)C1

Procedure:
tert-Butyl 3-{N-[(1R)-1-[(4-Chlorophenyl)methyl]-2-(4-{2-[(cyclopropylmethyl)(methylsulfonyl)amino]phenyl}-piperazinyl)-2-oxoethyl]carbamoyl}-azetidine-carboxylate was prepared from (2R)-2-amino-3-(4-chlorophenyl)-1-(4-{2-[(cyclopropylmethyl)-(methylsulfonyl)amino]phenyl}piperazinyl)propan-1-one (Step 3) (220 mg, 0.46 mmol), according to the procedure for Preparation XIX using Boc-azetidine-3-carboxylic acid (100 mg, 0.50 mmol) (Peptech)., 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide methiodide (275 mg, 0.925 mmol), HOAT (64 mg, 0.470 mmol), and DMF (7 mL). The compound was isolated (294 mg). MS (ESI, pos. ion) m/z: 674 (M+H), (ESI, neg. ion) m/z: 672 (M−H). Calc'd for C33H44ClN5O6S: 674.25.
Reaction SMILES: C(OC([NH:11][C:12]1[C:13](=[O:48])[N:14]([CH2:24][C:25]([NH:27][CH:28]([CH:45]([CH3:47])[CH3:46])[C:29](=[O:44])[C:30]([F:43])([F:42])[C:31](=[O:41])[NH:32][CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:26])[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:16][CH:17]=1)=O)C1C=CC=CC=1.FC(F)(F)S(O)(=O)=O>ClCCl.C1(OC)C=CC=CC=1>[NH2:11][C:12]1[C:13](=[O:48])[N:14]([CH2:24][C:25]([NH:27][CH:28]([CH:45]([CH3:46])[CH3:47])[C:29](=[O:44])[C:30]([F:43])([F:42])[C:31](=[O:41])[NH:32][CH2:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)=[O:26])[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:16][CH:17]=1
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ccc(NC(=O)OCc2ccccc2)c1=O)C(=O)C(F)(F)C(=O)NCCc1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: COc1ccccc1
Product: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ccc(N)c1=O)C(=O)C(F)(F)C(=O)NCCc1ccccc1
Reaction time: 1.5 h
Yield: 33.1 %

Procedure:
To a solution of 2-(3-benzyloxycarbonylamino-2-oxo-6-phenyl-1,2-dihydro-1-pyridyl)-N-[3,3-difluoro-1-isopropyl-2-oxo-3-(N-phenethylcarbamoyl)propyl]acetamide (0.451 g) in dichloromethane (7 mL) and anisole (0.22 mL) was added trifluoromethanesulfonic acid (0.30 mL). After 1.5 h, the reaction was quenched with saturated sodium bicarbonate. The mixture was extracted with dichloromethane, and the extracts were washed (saturated sodium bicarbonate, brine), dried, and evaporated. The crude product was purified by chromatography, twice, with dichloromethane:methanol (first column: gradient, 99:1, 92:8; second column: gradient, 99:1, 92:8) as the eluent. The resulting material was crystallized from ether and petroleum ether to give the title compound (0.119 g) as a tan solid; TLC: Rf =0.27, dichloromethane:methanol (98:2); 300 MHz NMR: 9.20 (t,1), 8.42 (d,1), 7.38-7.18 (m,10), 6.51 (d,1), 5.97 (d,1), 5.15 (d,2), 4.80 (dd,1), 4.43 (broad s,2), 3.43-3.29 (m,2), 2.76 (t,2), 2.29-2.13 (m,1), 0.85 (d,3), 0.74 (d,3); MS: m/z=525(M+1).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:40])[CH:10]=[CH:11][CH:12]([OH:39])[CH2:13][O:14][C:15](=[O:38])[C@H:16]([CH:35]([CH3:37])[CH3:36])[NH:17][C:18]([O:20][CH2:21][CH:22]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:47](Cl)(=[O:65])[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH3:64].C(=O)([O-])O.[Na+]>ClCCl>[CH2:1]([O:8][C:9](=[O:40])[CH:10]=[CH:11][CH:12]([O:39][C:47](=[O:65])[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH3:64])[CH2:13][O:14][C:15](=[O:38])[C@H:16]([CH:35]([CH3:37])[CH3:36])[NH:17][C:18]([O:20][CH2:21][CH:22]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OCC(O)C=CC(=O)OCc1ccccc1
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCC(=O)OC(C=CC(=O)OCc1ccccc1)COC(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Reaction time: 8 h

Procedure:
To a solution of benzyl-5-(N-FMOC-L-valyloxy)-4-hydroxy-2-pentenoate (6.5 g, 12 mmol) and pyridine (2.0 g, 25 mmole) in 100 ml dichloromethane at 10° C. was added dropwise a solution of stearoylchloride (4.55 g, 15 mmol) in 25 ml dichloromethane. The mixture was stirred overnight. 100 ml of 5% sodium hydrogencarbonate solution was added and the mixture was stirred for 30 minutes. The organic phase was separated and the water phase was extracted two times with dichloromethane. The combined organic phases were dried with sodium sulfate and concentrated in vacuo. The product was isolated by silica gel column chromatography Yield: 7.8 g=80%
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[CH3:20])[CH:10]([NH2:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([O-])([O-])=O.[K+].[K+].ClC(OCC)=O.B>C1COCC1.O>[CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[CH3:20])[C@H:10]([NH:21][CH3:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(F)ccc1C1CN(Cc2ccccc2)CC1N
Reactant: O=C([O-])[O-]
Agent: B
Agent: CCOC(=O)Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CN[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(F)cc1C
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 56.1 %

Procedure:
To a solution of rac-(3S,4R)-1-benzyl-4-(4-fluoro-2-methyl-phenyl)-pyrrolidin-3-ylamine (130 mg, 0.46 mmol) in THF (6 ml) was added a solution of K2CO3 (126 mg, 0.91 mmol) in H2O (2 ml). After 10 minutes, ethyl chloroformate (0.05 ml, 0.48 mmol) was added and stirring was continued at RT for an additional 2 h. The intermediate carbamate was then extracted with Et2O, dried over Na2SO4 and concentrated under vacuo to give viscous oil. The oil was taken up in THF (5 ml) and a solution of borane in THF (1M) was added (1.9 ml). The reaction mixture was then heated at 65° C. over night, cooled to RT and carefully quenched with conc. HCl (2 ml). The mixture was then heated at 80° C. for 2 h, cooled to RT, concentrated under vacuo, diluted with Et2O (30 ml) and neutralized with an aqueous solution of NaHCO3. The organic phases were dried over Na2SO4 and the product purified by flash chromatography (SiO2, CH2Cl2/MeOH 9:1) to afford 77 mg (56%) of rac-[(3S,4R)-1-benzyl-4-(4-fluoro-2-methyl-phenyl)-pyrrolidin-3-yl]-methyl-amine as a colorless oil. ES-MS m/e: 299.3 (M+H+).
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7]C(N)=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[NH2:12].C1(=O)CCCCC1>CCC(=O)CC>[Br:9][C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[NH:12][CH:2]([CH2:8][CH3:7])[CH2:3][CH3:4]
Reactant: Nc1ccc(Br)cc1
Reactant: Nc1ccccc1Br
Solvent: CCC(=O)CC
Solvent: O=C1CCCCC1
Product: CCC(CC)Nc1ccccc1Br
Yield: 61 %

Procedure:
The same procedure was carried out as in Example 2 except that 4-bromoaniline and 3-pentanone were used instead of 2-bromoaniline and cyclohexanone to obtain a colorless oil compound (61%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[CH:11]=[CH:10][NH:9][C:5]=2[N:6]=[CH:7][N:8]=1.[I:12]N1C(=O)CCC1=O.O>ClCCl>[I:12][C:11]1[C:4]2[C:3]([O:2][CH3:1])=[N:8][CH:7]=[N:6][C:5]=2[NH:9][CH:10]=1
Reactant: COc1ncnc2[nH]ccc12
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Solvent: O
Product: COc1ncnc2[nH]cc(I)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
To 4-methoxy-7H-pyrrolo[2,3-d]pyrimidine (3, 3.20 g, 21.4 mmol) in 280 mL of dichloromethane, N-iodosuccinimide (5.3 g, 24.0 mmol) suspended in dichloromethane was added. The reaction was stirred at room temperature for 2 hours, then poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was washed with ethyl acetate and hexane to provide the desired compound (35, 4.80 g).
Reaction SMILES: [Cl:1][Si:2]([CH3:8])([CH3:7])[Si:3](Cl)([CH3:5])[CH3:4].[CH3:9][C-:10]1[CH:14]=[C:13]([CH3:15])[C:12]([CH3:16])=[C:11]1[CH3:17].[Na+]>COC>[Cl:1][Si:2]([CH3:8])([CH3:7])[Si:3]([CH:14]1[C:13]([CH3:15])=[C:12]([CH3:16])[C:11]([CH3:17])=[C:10]1[CH3:9])([CH3:5])[CH3:4]
Reactant: C[Si](C)(Cl)[Si](C)(C)Cl
Reactant: Cc1c[c-](C)c(C)c1C
Agent: COC
Agent: [Na+]
Product: CC1=C(C)C([Si](C)(C)[Si](C)(C)Cl)C(C)=C1C

Procedure:
To a solution of 4.802 g (25.7 mmol) 1,2-dichloro-1,1,2,2-tetramethyldisilane in 50 mL dimethylether was slowly added a solution of 2.285 g (12.8 mmol) sodium 1,2,3,4-tetramethylcyclopentadienide in 30 mL dimethylether. The reaction mixture was stirred several hours, then the solvent was removed, the residue was extracted with pentane and filtered. The pentane was removed under reduced pressure to give the product as a light-yellow oil. Mass spec: m/e 272 (8%). 1H NMR (C6D6) δ 2.70 (s, 1H), 1.83 (s, 6H), 1.69 (s, 6H), 0.28 (s, 6H), 0.23 (s, 6H); 13C NMR (C6D6) δ 135.8, 134.0, 54.4, 14.6, 11.4, 3.2, −2.4.
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][C:6](=[N:11]O)[C:5]=2[CH:4]=[CH:3][N:2]=1>C(O)C.C(OCC)(=O)C.[Pd]>[CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH:6]([NH2:11])[C:5]=2[CH:4]=[CH:3][N:2]=1
Reactant: ON=C1CCCc2cnccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: NC1CCCc2cnccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 103.7 %

Procedure:
To a solution of 7,8-dihydroisoquinolin-5-(6H)-one oxime [Synth. Commun., 26(12), 2305-2308, (1996)] (1 g, 6.2 mmol) in ethanol (20 ml) and ethyl acetate (1 ml) was added 10% palladium on carbon (250 mg). The resulting slurry was stirred under a hydrogen balloon at room temperature for 20 hours. The catalyst was removed by filtration and the solvent evaporated to give the title compound as a brown oil (953 mg, 100%). m/z (ES+) 149 (M+H+).
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][C:6]1[CH:7]=[C:8]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[CH:9]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=1)C.O.O[Li].O>C1COCC1>[CH2:13]([O:12][C:10]1[CH:11]=[C:6]([CH2:5][C:4]([OH:30])=[O:3])[CH:7]=[C:8]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:28])([F:29])[F:27])=[CH:22][CH:21]=2)[CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)Cc1cc(OCc2ccccc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cc1cc(OCc2ccccc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.7 %

Procedure:
To a solution of (5-benzyloxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester (120 g, 0.29 mol) in THF (1.2 L) was added water (240 mL), LiOH.H2O (16 g, 0.32 mol) and stirred at room temperature for 16 h. The solution was filtered and concentrated in vacuo to remove THF. The resulting thick liquid was acidified to pH 2 by adding 2N aqueous HCl solution and the white suspension was mechanically stirred for 1 h at room temperature. The wet white product was recovered after filtration and dissolved in EtOAc (500 mL). The organic layer was separated from water, dried (MgSO4) and concentrated in vacuo to obtain (5-benzyloxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid (105 g, 94%).
Reaction SMILES: [CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([OH:17])=O)=[CH:12][CH:13]=2)[CH:8]=[C:7]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[N:6]=1)([CH3:3])[CH3:2].[CH3:25][NH:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][O:29]1>>[CH3:25][N:26]([CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][O:29]1)[C:15]([C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[C:5]([O:4][CH:1]([CH3:2])[CH3:3])=[N:6][C:7]([NH:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=1)=[CH:8]2)=[O:17]
Reactant: CNCC1CCCCO1
Reactant: Cc1cc(Nc2cc3cc(C(=O)O)ccc3c(OC(C)C)n2)n[nH]1
Product: Cc1cc(Nc2cc3cc(C(=O)N(C)CC4CCCCO4)ccc3c(OC(C)C)n2)n[nH]1

Procedure:
Similar procedure as described in example 384 was used, starting from 1-Isopropoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinoline-6-carboxylic acid and Methyl-(tetrahydro-pyran-2-ylmethyl)-amine to give 1-Isopropoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinoline-6-carboxylic acid methyl-(tetrahydro-pyran-2-ylmethyl)-amide. LC-MS: m/e 438 (MH+).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1Cl)[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][Cl:16])[N:14]=1)=[O:8].Cl.ClCC1N=C(N)SC=1.[F:30]C1C=C(C=CC=1)CN=C=O>>[Cl:16][CH2:15][C:13]1[N:14]=[C:10]([NH:9][C:7]([NH:6][CH2:5][C:4]2[CH:17]=[CH:18][CH:19]=[C:2]([F:30])[CH:3]=2)=[O:8])[S:11][CH:12]=1
Reactant: O=C(NCc1ccc(Cl)c(Cl)c1)Nc1nc(CCl)cs1
Reactant: O=C=NCc1cccc(F)c1
Agent: Cl
Agent: Nc1nc(CCl)cs1
Product: O=C(NCc1cccc(F)c1)Nc1nc(CCl)cs1

Procedure:
Prepared by same procedure described for Intermediate 2 with 4-(chloromethyl)thiazol-2-amine hydrochloride and 3-fluorobenzyl isocyanate. 1H-NMR (ppm, DMSO-d6): 10.70 (bs, 1H), 7.36 (dd, 1H), 7.07 (m, 4H), 4.63 (s, 2H), 4.34 (d, 2H).
Reaction SMILES: [CH3:1][CH:2]([S:4](Cl)(=[O:6])=[O:5])[CH3:3].C(N(CC)CC)C.Cl.[C@@H:16]12[CH2:23][NH:22][CH2:21][C@@H:20]1[CH2:19][N:18]([C:24]1[NH:25][C:26]3[CH:32]=[C:31]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH:30]=[CH:29][C:27]=3[N:28]=1)[CH2:17]2>C1COCC1>[CH:2]([S:4]([N:22]1[CH2:21][C@@H:20]2[C@@H:16]([CH2:17][N:18]([C:24]3[NH:25][C:26]4[CH:32]=[C:31]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[CH:30]=[CH:29][C:27]=4[N:28]=3)[CH2:19]2)[CH2:23]1)(=[O:6])=[O:5])([CH3:3])[CH3:1]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: c1ccc(-c2ccc3nc(N4C[C@H]5CNC[C@H]5C4)[nH]c3c2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)S(=O)(=O)N1C[C@H]2CN(c3nc4ccc(-c5ccccc5)cc4[nH]3)C[C@H]2C1
Reaction time: 0.25 h

Procedure:
2-Propanesulfonyl chloride and triethylamine were added to the THF suspension (5 mL) containing 2-(cis-3,7-diazabicyclo[3.3.0]oct-3-yl)-5-phenylbenzimidazole hydrochloride (26 mg) at room temperature, followed by stirring for 15 min. The reaction mixture was concentrated under reduced pressure, and the residue was separated and purified on a collective thin-layer chromatograph (chloroform:methanol=10:1) to give the title compound (12 mg).
Reaction SMILES: [C:1](#[N:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:10][OH:11].C([O-])([O-])=O.[K+].[K+].O>C(O)C>[OH:11][NH:10][C:1](=[NH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccccc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N=C(NO)c1ccccc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 305.6 %

Procedure:
Benzonitrile (1 ml, 9.79 mmol) was mixed with hydroxylamine hydrochloride (1.36 g, 1.96 mmol) and K2CO3 (2.71 g, 1.96 mmol) in anhydrous ethanol (15 ml). The solution was stirred at 80° C. for 16 hr. Water was added and the aqueous phase was extracted with EtOAc (3×), dried over MgSO4 and the volatiles removed in vacuo to give a viscous oil (816 mg, 5.99 mmol, 62%). The compound 10A was used for next step without any further purification. HPLC (4 minutes gradient) tR 0.62 min; MS m/z 137.06 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:14]=[C:13]([C:15]3[C:20]([Cl:21])=[CH:19][CH:18]=[C:17]([NH:22][CH2:23][CH:24]4[CH2:29][CH2:28][O:27][C:26]([CH3:31])([CH3:30])[CH2:25]4)[N:16]=3)[C:12]([Cl:32])=[CH:11][N:10]=2)[CH2:4][CH2:3]1.[F:33][C:34]([F:39])([F:38])[C@H:35]1[O:37][CH2:36]1>CC(O)C>[Cl:21][C:20]1[C:15]([C:13]2[C:12]([Cl:32])=[CH:11][N:10]=[C:9]([NH:8][C@H:5]3[CH2:6][CH2:7][C@H:2]([NH:1][CH2:36][C@H:35]([OH:37])[C:34]([F:39])([F:38])[F:33])[CH2:3][CH2:4]3)[CH:14]=2)=[N:16][C:17]([NH:22][CH2:23][CH:24]2[CH2:29][CH2:28][O:27][C:26]([CH3:30])([CH3:31])[CH2:25]2)=[CH:18][CH:19]=1
Reactant: CC1(C)CC(CNc2ccc(Cl)c(-c3cc(N[C@H]4CC[C@H](N)CC4)ncc3Cl)n2)CCO1
Reactant: FC(F)(F)[C@@H]1CO1
Solvent: CC(C)O
Product: CC1(C)CC(CNc2ccc(Cl)c(-c3cc(N[C@H]4CC[C@H](NC[C@H](O)C(F)(F)F)CC4)ncc3Cl)n2)CCO1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a solution of N2′-(trans-4-aminocyclohexyl)-3,5′-dichloro-N6-((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine (19 mg, 0.040 mmol) in 2-propanol (0.3 mL) was added (S)-(−)-3,3,3-trifluoro-1,2-epoxypropane (3.4 uL, 0.040 mmol). The mixture was stirred at 70° C. for 2 hr. The reaction mixture was concentrated. The resulting residue was purified by reverse phase HPLC and lyophilized to give 9.1 mg of (2S)-3-(trans-4-(3,5′-dichloro-6-((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)amino-2,4′-bipyridin-2′-yl-amino)cyclohexylamino)-1,1,1-trifluoropropan-2-ol as its TFA salt. LCMS (m/z): 590.5 (MH+), retention time=0.71 min; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.81-1.32 (m, 12H) 1.33-1.66 (m, 4H) 1.82-1.99 (m, 1H) 1.99-2.21 (m, 4H) 2.89-3.04 (m, 2H) 3.04-3.19 (m, 2H) 3.27 (d, J=2.35 Hz, 2H) 4.40 (br. s., 1H) 6.38 (s, 1H) 6.55 (d, J=9.00 Hz, 1H) 6.77 (br. s., 1H) 6.91 (br. s., 1H) 7.21 (br. s., 1H) 7.48 (d, J=9.00 Hz, 1H) 8.03 (s, 1H)
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][C:8]1[CH:9]=[N:10][C:11]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:12][C:13]=1[CH2:14][CH2:15]Br)([CH3:4])([CH3:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC>O1CCCC1>[CH3:20][C:19]([CH3:22])([CH3:21])[C:18]([NH:17][C:11]1[N:10]=[CH:9][C:8]2[CH:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:24])[CH2:15][CH2:14][C:13]=2[CH:12]=1)=[O:23]
Reactant: CC(C)(C)OC(=O)Cc1cnc(NC(=O)C(C)(C)C)cc1CCBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1CCc2cc(NC(=O)C(C)(C)C)ncc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of tert-butyl{4-(2-bromoethyl)-6-[(2,2-dimethylpropanoyl)amino]pyridin-3-yl}acetate (6.5 g, 16.3 mmol) in tetrahydrofuran (50 mL) cooled in a dry ice-acetone bath was treated with a solution of lithium diisopropylamide in tetrahydrofuran (50 mL) (prepared from diisopropylamine (3.79 g, 34.7 mmol) and n-butyllithium (2.5 M, 13.7 mL) dropwise via addition funnel over 1 h. After complete addition, the reaction stirred an additional 1 h, then was quenched with saturated sodium bicarbonate solution and allowed to warm to room temperature. The resulting mixture was diluted with ethyl acetate and water and transferred to a reparatory funnel. The layers were separated and the aqueous extracted with ethyl acetate (2×). The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated. Purification of the resulting residue (2−>25% EtOAc/hexanes eluent) provided tert-butyl 3-[(2,2-dimethylpropanoyl)amino]-6,7-dihydro-5H-cyclopenta[c]pyridine-7-carboxylate. 1H NMR (500 MHz, CDCl3), δ 8.27 (s, 1H), 8.16 (s, 1H), 8.06 (br s, 1H), 3.96 (dd, J=5.0, 5.5 Hz, 1H), 3.06 (m, 1H), 2.90 (m, 1H), 2.45 (m, 1H), 2.32 (m, 1H)-1), 1.47 (s, 9H), 1.32 (s, 9H); LC/MS (M+1)+=319.0;
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH:12]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([N:25]3[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[CH2:29][N:28]4[CH:36]=[CH:37][CH:38]=[C:27]4[CH2:26]3)=[O:24])=[CH:19][CH:18]=2)=[N:13]1.C(NC(C)C)(C)C>ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([N:12]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([N:25]3[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[CH2:29][N:28]4[CH:36]=[CH:37][CH:38]=[C:27]4[CH2:26]3)=[O:24])=[CH:19][CH:18]=2)=[N:13]1)=[O:5]
Reactant: O=C(c1ccc(-c2cc[nH]n2)cc1)N1Cc2cccn2Cc2ccccc21
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: O=C(c1ccc(-c2ccn(C(=O)c3ccc(F)cc3Cl)n2)cc1)N1Cc2cccn2Cc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
Portionwise, 2-chloro-4-fluorobenzoyl chloride (0.82 g) was added to a solution of [4-(1H-pyrazol-3-yl)-phenyl]-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (1.0 g) and diisopropylamine (0.55g) in dichloromethane (25 ml) which was cooled in an ice bath. The reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was washed with water and saturated sodium bicarbonate and dried over anhydrous sodium sulfate. The dichloromethane solution was passed through a short column of hydrous sodium magnesium silicate, eluting several additional volumes of dichloromethane. The eluent was evaporated to dryness to yield 1.06 g of the product as a solid, m.p. 150-157° C.; MS, m/z: 510 (M)+.