Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.[CH3:41][CH:42]1[CH2:47][CH2:46][CH2:45][CH2:44][N:43]1[CH2:48][C:49]([OH:51])=O>>[CH3:20][C@:17]12[C@@:16]3([CH3:21])[C@@H:7]([C@:8]4([CH3:34])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:22])([CH3:23])[C:11]([C:24]3[CH:33]=[CH:32][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)=[CH:10][CH2:9]4)[CH2:6][CH2:5][C@@H:4]1[C@H:3]1[C@H:35]([C:38]([CH3:40])=[CH2:39])[CH2:36][CH2:37][C@:2]1([NH:1][C:49](=[O:51])[CH2:48][N:43]1[CH2:44][CH2:45][CH2:46][CH2:47][CH:42]1[CH3:41])[CH2:19][CH2:18]2
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CC1CCCCN1CC(=O)O
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)CN3CCCCC3C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the general procedure described for the parallel synthesis of C-17 amides above, using (2-methylpiperidin-1-yl)acetic acid as the reacting carboxylic acid. LCMS: m/e 669.7 (M+H)+, 4.73 min (method 3).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6]([CH3:20])([CH3:19])[CH2:7][CH:8]([NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.Cl[C:24]1[N:29]=[C:28]([NH:30][C:31]2[C:42]([F:43])=[CH:41][CH:40]=[CH:39][C:32]=2[C:33]([NH:35][CH2:36][C:37]#[CH:38])=[O:34])[C:27]([Cl:44])=[CH:26][N:25]=1>>[Cl:44][C:27]1[C:28]([NH:30][C:31]2[C:42]([F:43])=[CH:41][CH:40]=[CH:39][C:32]=2[C:33]([NH:35][CH2:36][C:37]#[CH:38])=[O:34])=[N:29][C:24]([NH:1][C:2]2[CH:22]=[CH:21][C:5]3[C:6]([CH3:19])([CH3:20])[CH2:7][CH:8]([NH:12][C:13](=[O:18])[C:14]([F:17])([F:15])[F:16])[C:9](=[O:11])[NH:10][C:4]=3[CH:3]=2)=[N:25][CH:26]=1
Reactant: C#CCNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CC1(C)CC(NC(=O)C(F)(F)F)C(=O)Nc2cc(N)ccc21
Product: C#CCNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)NC(=O)C(NC(=O)C(F)(F)F)CC3(C)C)ncc1Cl

Procedure:
Title compound was prepared from N-(8-Amino-5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl)-2,2,2-trifluoro-acetamide and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-prop-2-ynyl-benzamide in an analogous manner to Example 1221d. Title compound was isolated as a white solid (67 mg, 24%) LCMS 564.12 (M−C3NH4), 1H-NMR (CDCl3, 400 MHz) δ 9.71 (bs, 1H), 9.60 (d, J=7.9 Hz, 1H), 9.43 (bs, 1H), 9.20 (s, 1H), 8.93 (bt, 1H), 7.50-7.47 (m, 2H), 7.37-7.34 (m, 1H), 7.28 (d, J=7.7 Hz, 1H), 7.17 (s, 1H), 7.10 (d, J=8.8 Hz, 1H), 4.26-4.22 (m, 4H), 4.03-3.99 (m, 2H), 2.18-2.13 (m, 2H), 1.35 (s, 3H), 1.26 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([OH:15])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:16]([N:23]1[CH2:28][CH2:27][CH:26](O)[CH2:25][CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:1]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([O:15][CH:26]2[CH2:27][CH2:28][N:23]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:24][CH2:25]2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: COC(=O)c1ccc(C(C)(C)C)cc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(C)(C)C)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 72 h

Procedure:
To a stirring solution of methyl 4-tert-butyl-2-hydroxybenzoate (9.45 g, 45.4 mmol), 1-Boc-piperidin-4-ol (9.6 g, 47.7 mmol) and triphenylphosphine (12.5 g, 47.7 mmol) in THF (125 mL) was added, dropwise via an addition funnel, a solution of diisopropyl azodicarboxylate (9.4 mL, 47.7 mmol) in THF (25 mL). After 72 h, the solvent was removed in vacuo and the residue was dissolved in a minimal amount of chloroform and vacuum filtered through a pad of silica gel, eluting with a solution of 20% ethyl acetate in hexanes. The filtrate was then concentrated in vacuo and the residue was chromatographed over silica gel, eluting with a gradient of 5% ethyl acetate in hexanes through 20% ethyl acetate in hexanes. The product containing fractions were combined and concentrated in vacuo to give the ether (12.9 g, 73%) as a thick colorless oil.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[C:9]([C:13]3[CH:17]=[C:16]([CH2:18][CH:19]([CH3:21])[CH3:20])[S:15][C:14]=3[S:22]([NH:25]C(C)(C)C)(=[O:24])=[O:23])[CH:10]=[CH:11][CH:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.B(Cl)(Cl)Cl.N1(C2C=CC=CN=2)CCCC1.Cl[C:46]([O:48][CH2:49][CH2:50][CH2:51][CH3:52])=[O:47].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[CH2:49]([O:48][C:46]([NH:25][S:22]([C:14]1[S:15][C:16]([CH2:18][CH:19]([CH3:20])[CH3:21])=[CH:17][C:13]=1[C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([CH2:6][N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)[CH:8]=1)(=[O:23])=[O:24])=[O:47])[CH2:50][CH2:51][CH3:52]
Reactant: CCCCOC(=O)Cl
Reactant: CC(C)Cc1cc(-c2cccc(Cn3cccn3)c2)c(S(=O)(=O)NC(C)(C)C)s1
Agent: ClB(Cl)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: c1ccc(N2CCCC2)nc1
Solvent: ClCCl
Product: CCCCOC(=O)NS(=O)(=O)c1sc(CC(C)C)cc1-c1cccc(Cn2cccn2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
To a solution of 3-(3-pyrazol-1-ylmethylphenyl)-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (82.4 mg, 0.191 mmol; see step (a)) in CH2Cl2 (2 mL) was added BCl3 (0.6 mL, 1.0 M in hexane) and the reaction mixture was stirred for 1 h at ambient temperature. The reaction mixture was concentrated in vacuo. Water (5 mL) was added to the residue and this was then extracted with EtOAc. The combined organic phase was washed with water and brine, dried (over anhydrous MgSO4) and concentrated in vacuo. To the crude product dissolved in pyridine (1.5 mL) was added pyrrolidinopyridine (42.7 mg, 0.288 mmol) and butyl chloroformate (192.6 μL, 1.91 mmol) and the reaction mixture was stirred overnight. Citric acid (5 mL, 10% aq) was added to the reaction mixture, which was then extracted with EtOAc, dried (over anhydrous MgSO4), concentrated in vacuo, and the residue was purified by LCMS (30-100% CH3CN in water) to give the title compound in 69% yield, over two steps, (62.7 mg, 0.132 mmol).
Reaction SMILES: [Br:1][C:2]1[C:11]([C@H:12]([OH:15])[CH2:13][OH:14])=[C:10]([CH3:16])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:17])=[N:7]2.[CH3:18][C:19]([CH3:24])([CH3:23])[C:20](Cl)=[O:21]>ClCCl.N1C=CC=CC=1>[C:20]([O:14][CH2:13][C@H:12]([C:11]1[C:2]([Br:1])=[C:3]2[C:8](=[CH:9][C:10]=1[CH3:16])[N:7]=[C:6]([CH3:17])[CH:5]=[CH:4]2)[OH:15])(=[O:21])[C:19]([CH3:24])([CH3:23])[CH3:18]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1ccc2c(Br)c([C@H](O)CO)c(C)cc2n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc2c(Br)c([C@H](O)COC(=O)C(C)(C)C)c(C)cc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (S)-1-(5-bromo-2,7-dimethylquinolin-6-yl)ethane-1,2-diol (290 mg, 0.98 mmol) in dichloromethane (12 mL) and pyridine (2 mL) was added trimethyl acetylchloride (0.24 mL, 1.97 mmol) at 0° C. The mixture was stirred at room temperature for 2 hours, and quenched with slow addition of NaHCO3 solution. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide (S)-2-(5-bromo-2,7-dimethylquinolin-6-yl)-2-hydroxyethyl pivalate. LCMS-ESI+ (m/z): [M+H]+ calc'd for C18H23BrNO3: 380.1; Found: 380.2.
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)C.CO.[OH-].[Li+].Cl>O>[C:12]([N:9]1[CH2:8][CH2:7][N:6]([CH2:5][C:4]([OH:20])=[O:3])[CH2:11][CH2:10]1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)CN1CCN(C(=O)c2ccccc2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CN1CCN(C(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 116.9 %

Procedure:
To (4-benzoylpiperazin-1-yl)acetic acid ethyl ester (8.19 g) were added methanol (300 ml) and water (50 ml), and lithium hydroxide (1.34 g) was added thereto in an ice water bath, followed by stirring for 10 min. The reaction mixture was allowed to warm up to room temperature and stirred for 24 hr. After addition of 1N hydrochloric acid (55.9 ml), the reaction mixture was concentrated under reduced pressure, and ethanol (200 ml) was added to the resultant residue. Precipitated insoluble matter was filtered through celite. The filtrate was concentrated to provide a crude product of (4-benzoylpiperazin-1-yl)acetic acid as a white solid (8.6 g). To (4-benzoylpiperazin-1-yl)acetic acid (2 g) was added N,N-dimethylformamide (80 ml) under a nitrogen atmosphere at room temperature, and azetidine hydrochloride (1.51 g), triethylamine (4.49 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.09 g) and 1-hydroxybenzotriazole (2.18 g) were added thereto in this order, followed by stirring at room temperature for 66 hr. Liquid-liquid separation was carried out after addition of ethyl acetate (100 ml) and a saturated aqueous solution of sodium hydrogencarbonate (50 ml) to the reaction mixture. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (50 ml), water (50 ml) and brine (50 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate). Fractions containing the target compound were concentrated under reduced pressure, the resultant residue was suspended in diethyl ether (10 ml). The solid was collected by filtration, and dried under aeration to provide the titled compound as white powder (731.5 mg).
Reaction SMILES: [OH:1][CH2:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:12]=2)[NH:7][CH:6]=1)=[O:4]>C(O)C.C(O)(=O)C.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:12]=2)[NH:7][CH:6]=1)(=[O:4])[CH:2]=[O:1]
Reactant: O=C(CO)c1c[nH]c2ccc(OCc3ccccc3)cc12
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: O=CC(=O)c1c[nH]c2ccc(OCc3ccccc3)cc12

Procedure:
A solution of 20 in ethanol was treated with copper(II) acetate monohydrate in 50% aqueous acetic acid as described above for 15. Work-up gave nearly pure 3-glyoxalyl-5-(benzyloxy)indole 21.
Reaction SMILES: Cl.[C:2]1([C:8]2[CH:9]=[N:10][NH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Cl[C:23](Cl)([O:25]C(=O)OC(Cl)(Cl)Cl)Cl.Cl.[NH2:35][CH2:36][C:37]([N:39]1[CH2:44][CH2:43][CH:42]([O:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=2[Cl:52])[CH2:41][CH2:40]1)=[O:38]>C(Cl)Cl.O>[Cl:52][C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=1[O:45][CH:42]1[CH2:43][CH2:44][N:39]([C:37](=[O:38])[CH2:36][NH:35][C:23]([N:10]2[CH:9]=[C:8]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:12]=[N:11]2)=[O:25])[CH2:40][CH2:41]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NCC(=O)N1CCC(Oc2ccccc2Cl)CC1
Reactant: c1ccc(-c2cn[nH]c2)cc1
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CNC(=O)n1cc(-c2ccccc2)cn1)N1CCC(Oc2ccccc2Cl)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.6 %

Procedure:
A mixture of 4-phenyl-1H-pyrazole hydrochloride (70 mg, 0.387 mmol), DIPEA (100 mg, 0.81 mmol) and DCM (5 mL) was added to a stirred solution of triphosgene (36 mg, 0.12 mmol) in DCM (2 mL) at room temperature. After 30 minutes, to the above solution, a mixture of 2-amino-1-[4-(2-chloro-phenoxy)-piperidin-1-yl]-ethanone hydrochloride (prepared by method used for the synthesis of Intermediate 15) 118 mg, 0.3875 mmol), DIPEA (100 mg, 0.81 mmol) and DCM (5 mL) was added and the resulting mixture was stirred at room temperature for 1 hr. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure The residue was purified by preparative HPLC to afford 60 mg (17.6% Yield) of 4-phenyl-pyrazole-1-carboxylic acid {2-[4-(2-chloro-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]++: 439.15, 93.19%. 1H NMR (300 MHz, DMSO-d6): δ 8.8 (s, 1H), 8.4 (t, 1H), 8.35-8.3 (s, 1H), 7.8-7.72 (d, 2H), 7.48-7.38 (m, 3H), 7.35-7.24 (m, 3H), 7.0 (t, 1H), 4.8 (m, 1H), 4.2 (d, 2H), 3.8-3.6 (m, 2H), 3.6-3.4 (m, 2H), 2.1-1.8 (m, 2H), 1.8-1.6 (m, 2H).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8](/[C:11](/[C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[C:12](\[CH:15]2[CH2:24][CH2:23][C:18]3([O:22][CH2:21][CH2:20][O:19]3)[CH2:17][CH2:16]2)/[CH2:13][CH3:14])=[CH:7][CH:6]=1.[CH3:32][NH2:33]>CO>[CH3:32][NH:33][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8](/[C:11](/[C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[C:12](\[CH:15]2[CH2:24][CH2:23][C:18]3([O:22][CH2:21][CH2:20][O:19]3)[CH2:17][CH2:16]2)/[CH2:13][CH3:14])=[CH:7][CH:6]=1
Reactant: CN
Reactant: CC/C(=C(\c1ccc(O)cc1)c1ccc(OCCCl)cc1)C1CCC2(CC1)OCCO2
Solvent: CO
Product: CC/C(=C(\c1ccc(O)cc1)c1ccc(OCCNC)cc1)C1CCC2(CC1)OCCO2
Temperature: 85 °C

Procedure:
A mixture of (Z)-4-(1-(4-(2-chloroethoxy)phenyl)-2-(1,4-dioxaspiro[4.5]decan-8-yl)but-1-enyl)phenol (90 mg, 0.20 mol), 30% aqueous of CH3NH2 (5 mL), and MeOH (5 mL) was heated at 85° C. in a sealed tube overnight, concentrated, and purified by column chromatography to give the desired product (90 mg).
Reaction SMILES: S(Cl)(Cl)=O.C1(CCC(O)=O)C=CC=CC=1.C1(CCC(Cl)=O)C=CC=CC=1.[C:27]1([CH2:33][CH2:34][C:35]([N:37]=[C:38]=[S:39])=[O:36])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[CH3:40][O:41][C:42]1[CH:43]=[C:44]2[C:49](=[CH:50][C:51]=1[O:52][CH3:53])[N:48]=[CH:47][CH:46]=[C:45]2[O:54][C:55]1[CH:61]=[CH:60][C:58]([NH2:59])=[C:57]([F:62])[CH:56]=1>C(O)C.C1(C)C=CC=CC=1>[CH3:40][O:41][C:42]1[CH:43]=[C:44]2[C:49](=[CH:50][C:51]=1[O:52][CH3:53])[N:48]=[CH:47][CH:46]=[C:45]2[O:54][C:55]1[CH:61]=[CH:60][C:58]([NH:59][C:38]([NH:37][C:35](=[O:36])[CH2:34][CH2:33][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[S:39])=[C:57]([F:62])[CH:56]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Reactant: O=C(CCc1ccccc1)N=C=S
Agent: O=C(Cl)CCc1ccccc1
Agent: O=C(O)CCc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)CCc4ccccc4)c(F)c3)c2cc1OC
Temperature: 100 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 3-phenylpropanoic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 3-phenylpropanoyl isothiocyanate was prepared using the resultant 3-phenylpropanoyl chloride as a starting compound according to the description of the literature. 3-Phenylpropanoyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (60 mg, yield 74%).
Reaction SMILES: C1(CNCC2C=C(C3C=C4C(=C(C(N)=O)C=3)NC=C4C3CCN(S(CC)(=O)=O)CC3)C=NC=2)CC1.[CH3:36][C:37]1([CH3:52])[C:41]([CH3:43])([CH3:42])[O:40][B:39]([C:44]2[CH:45]=[C:46]([CH:50]=O)[CH:47]=[N:48][CH:49]=2)[O:38]1.[CH3:53][C:54]([CH3:58])([CH3:57])[CH2:55][NH2:56].[BH3-]C#N.[Na+]>>[CH3:53][C:54]([CH3:58])([CH3:57])[CH2:55][NH:56][CH2:50][C:46]1[CH:47]=[N:48][CH:49]=[C:44]([B:39]2[O:38][C:37]([CH3:52])([CH3:36])[C:41]([CH3:43])([CH3:42])[O:40]2)[CH:45]=1
Reactant: CC1(C)OB(c2cncc(C=O)c2)OC1(C)C
Reactant: CC(C)(C)CN
Agent: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cncc(CNCC5CC5)c4)cc23)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC(C)(C)CNCc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Yield: 63.7 %

Procedure:
Following the general procedure of 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-pyridinyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinecarbaldehyde (30 mg, 0.129 mmol), (2,2-dimethylpropyl)amine (0.015 mL, 0.129 mmol), and NaCNBH3 (16 mg, 0.258 mmol) were reacted to give 25 mg of crude (2,2-dimethylpropyl){[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine. The crude (2,2-dimethylpropyl){[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (30 mg, 0.0723 mmol), potassium carbonate (60 mg, 0.434 mmol), and chloro-2-(dimethylaminormethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium(II) (4.4 mg, 0.00723 mmol) to give 12.7 mg of the title compound (34%).
Reaction SMILES: Cl.CO[C:4](=[NH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[NH2:12][CH2:13][CH:14]([NH2:16])[CH3:15]>CO>[NH3:11].[CH3:15][CH:14]1[CH2:13][NH:12][C:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[N:16]1
Reactant: CC(N)CN
Reactant: COC(=N)c1ccccc1
Agent: Cl
Solvent: CO
Product: CC1CNC(c2ccccc2)=N1
Product: N
Temperature: 25 °C

Procedure:
To a solution of benzimidic acid methyl ester hydrochloride (1 g) in MeOH (25 ml) was added 1,2-diaminopropane (545 μL) then the mixture was heated to reflux. After 16 h the mixture was cooled to room temperature and concentrated. The residue was taken up in MeOH then passed through Dowex 1×2-400 ion exchange resin (prewashed with 1M NaOH, H2O, MeOH) washing with MeOH. The filtrate was concentrated. Flash column chromatography (gradient, 0-10% MeOH/CHCl3 saturated with NH3) gave 4-methyl-2-phenyl-4,5-dihydro-1H-imidazole as a white solid (1.04 g) which was sufficiently pure for use in the next step. 1H-NMR (400 MHz, CDCl3) δ 7.84 (m, 2 H), 7.55-7.38 (m, 3 H), 4.16 (m, 1 H), 3.95 (dd, J=9.98 and 1.83 Hz, 1 H), 3.40 (m, 1 H), 1.32 (d, J=6.41 Hz, 3 H).
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[N:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]([NH2:29])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.C(N(CC)CC)C.[NH2:37][C:38]1[CH:39]=[C:40]2[C:44](=[CH:45][CH:46]=1)[NH:43][CH:42]=[C:41]2[CH:47]1[CH2:52][CH2:51][N:50]([CH3:53])[CH2:49][CH2:48]1.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH3:53][N:50]1[CH2:51][CH2:52][CH:47]([C:41]2[C:40]3[C:44](=[CH:45][CH:46]=[C:38]([NH:37][C:5]([NH:29][C:22]4[C:23]5[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=5)[C:19]([C:16]5[CH:15]=[CH:14][N:13]=[CH:18][CH:17]=5)=[CH:20][CH:21]=4)=[O:11])[CH:39]=3)[NH:43][CH:42]=2)[CH2:48][CH2:49]1
Reactant: Nc1ccc(-c2ccncc2)c2ccccc12
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)Nc4ccc(-c5ccncc5)c5ccccc45)cc23)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of triphosgene (0.09 g, 0.31 mmole) in dichloromethane (15 ml) under argon, was added dropwise a solution of 4-(pyridin-4-yl)naphth-1-ylamine (D3, 0.17 g, 0.77 mmole) and triethylamine (0.12 ml, 0.83 mmole) in dichloromethane (10 ml). The mixture was then stirred at room temperature for 20 minutes, then a solution of 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole (D2, 0.15 g, 0.66 mmole) in dichloromethane (10 ml) was slowly added. After stirring the mixture for 1 hour, dilute potassium carbonate solution (10 ml) was added. The precipitated solid mass was collected and purified by flash chromatography on silica gel eluting with CH2Cl2/MeOH/NH4OH (100:10:1) to afford the title compound as a buff powder (0.14 g).
Reaction SMILES: N#N.[CH3:3][C:4]1([CH3:15])[C:8]2([CH3:14])[C:9]([O:11][C:12](=[O:13])[CH:5]1[CH2:6][CH2:7]2)=O.[OH:16][CH2:17][CH2:18][CH2:19][CH2:20][NH2:21].C1(C)C=CC=CC=1>O>[OH:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[C:12](=[O:13])[CH:5]2[C:4]([CH3:3])([CH3:15])[C:8]([CH3:14])([CH2:7][CH2:6]2)[C:9]1=[O:11]
Reactant: NCCCCO
Reactant: CC12CCC(C(=O)OC1=O)C2(C)C
Agent: N#N
Solvent: O
Solvent: Cc1ccccc1
Product: CC12CCC(C(=O)N(CCCCO)C1=O)C2(C)C

Procedure:
To a 125 ml round-bottomed flask equipped with Dean-Stark trap, condenser, and N2 inlet were added 5.35 g (29 mmol) of d-camphoric anhydride, 2.49 g (28 mmol) of 4-hydroxybutylamine, and 60 ml of toluene. The reaction was refluxed with separation of water for 20 hours. It was then cooled, concentrated to an oil, and the oil dissolved in ethyl acetate. The ethyl acetate solution was washed with 5% HCl, 5% NaOH, and brine, dried over sodium sulfate, and evaporated to an oil, 6.0 g (85%).
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:35])[CH2:15][NH:16][C:17]([C:19]2[N:20]=[C:21]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[S:22][C:23]=2[NH:24][CH2:25][CH2:26][CH2:27][OH:28])=[O:18])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].C(OC1C(OC(=O)C)=C(I)C=CC=1)(=[O:38])C.CC1(C)N([O])C(C)(C)CCC1.Cl>O.CC#N.O>[CH2:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:35])[CH2:15][NH:16][C:17]([C:19]2[N:20]=[C:21]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[S:22][C:23]=2[NH:24][CH2:25][CH2:26][C:27]([OH:38])=[O:28])=[O:18])[CH2:12][CH2:13]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)Oc1cccc(I)c1OC(C)=O
Reactant: CCCCOC(=O)N1CCN(C(=O)CNC(=O)c2nc(-c3ccccc3)sc2NCCCO)CC1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: Cl
Solvent: CC#N
Solvent: O
Product: CCCCOC(=O)N1CCN(C(=O)CNC(=O)c2nc(-c3ccccc3)sc2NCCC(=O)O)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 31.1 %

Procedure:
To a suspension of Example 27 (25 mg) in H2O/CH3CN (0.2 mL, 1:1) was added at 0° C. diacetoxyiodobenzene (35 mg) and 2,2,6,6-tetramethylpiperidine-1-oxyl (3 mg), and the reaction mixture was stirred at 0° C. for 2 h. The reaction mixture was diluted with H2O, acidified with aq. HCl (1M, 0.5 mL) and extracted with EtOAc (3×5 mL) The combined organic layers were dried over Na2SO4 and concentrated to dryness. Purification by CC (CH2Cl2/MeOH 97:3) gave 8 mg of the desired product.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]3[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH:18]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.CO>CO>[CH:18]1([NH:24][CH:14]2[CH2:15][CH2:16][CH:11]([NH:10][C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[NH:1][N:2]=[CH:3]4)[CH2:12][CH2:13]2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: NC1CCCCC1
Reactant: O=C1CCC(Nc2ccc3[nH]ncc3c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: c1cc2[nH]ncc2cc1NC1CCC(NC2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 28.3 %

Procedure:
4-(1H-5-Indazolylamino)-1-cyclohexanone (intermediate 3) (57 mg) and cyclohexylamine (50 mg) were dissolved in methanol (1 ml), and sodium triacetoxyborohydride (105 mg) was added by portions to the solution at room temperature. The reaction mixture was stirred at room temperature for 18 hr. Hydrochloric acid-methanol was then added thereto, and the reaction mixture was stirred and was then concentrated. The residue was purified by HPLC [0.5% aqueous trifluoroacetic acid solution/acetonitrile]. A saturated aqueous sodium hydrogencarbonate solution (2 ml) was then added to fractions containing respective compounds, followed by extraction with chloroform-propanol (3/1). The organic layers were dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure to give an antiform compound (22 mg) and a syn-form compound (23 mg).