Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:16]1[NH:17][C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=1>C1(C)C=CC=CC=1>[N:17]1[C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[NH:20][C:16]=1[N:6]1[CH2:7][CH2:8][CH:3]([CH2:2][NH2:1])[CH2:4][CH2:5]1
Reactant: NCC1CCNCC1
Reactant: Clc1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: NCC1CCN(c2nc3ccccc3[nH]2)CC1

Procedure:
45 g of 4-aminomethylpiperidine are placed in 500 ml of anhydrous toluene in the presence of 55 g of potassium carbonate and of 50 g of 2-chlorobenzimidazole. The mixture is subjected to reflux overnight. Aver evaporation and crystallization of the oily residue, the expected product is obtained after washing with dichloromethane.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]#[N:38])[CH:32]=2)[CH:9]2[CH2:14][CH2:13][N:12]([CH:15]([CH3:29])[CH2:16][CH2:17][NH:18][C:19](=[O:28])[C:20]3[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:27])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:45][N:46]([CH3:50])[C:47](Cl)=[O:48]>CN(C=O)C>[C:37]([C:33]1[CH:32]=[C:31]([CH:36]=[CH:35][CH:34]=1)[CH2:30][N:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:47]([N:46]([CH3:50])[CH3:45])=[O:48])=[CH:3][CH:4]=1)[CH:9]1[CH2:10][CH2:11][N:12]([CH:15]([CH3:29])[CH2:16][CH2:17][NH:18][C:19](=[O:28])[C:20]2[C:21]([CH3:27])=[CH:22][CH:23]=[CH:24][C:25]=2[CH3:26])[CH2:13][CH2:14]1)#[N:38]
Reactant: CN(C)C(=O)Cl
Reactant: Cc1cccc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(N)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(NC(=O)N(C)C)cc2)CC1
Temperature: 25 °C
Reaction time: 76 h
Yield: 76 %

Procedure:
A mixture of COMPOUND 142 (61 mg, 0.12 mmol), K2CO3 (50 mg, 0.36 mmol) and dimethylcarbamoyl chloride (23 μL, 0.24 mmol) in DMF (1 mL) was stirred at room temperature for 76 hours to afford COMPOUND 155 as a white solid (53 mg, 76%) following work-up and purification. 1H NMR (CDCl3) δ 0.93-1.17 (m, 2H), 0.99 (d, 3H, J=6.0 Hz), 1.49-1.59 (m, 1H), 1.69-1.78 (m, 3H), 2.14 (t, 1H, J=11.1 Hz), 2.31 (s, 6H), 2.54 (t, 1H, J=10.8 Hz), 2.73-2.85 (m, 3H), 2.98 (s, 6H), 3.27 (t, 1H, J=10.5 Hz), 3.52 (m, 1H), 3.73 (s, 2H), 3.90 (m, 1H), 6.04 (s, 1H), 6.50 (d, 2H, J=8.1 Hz), 6.94-6.99 (m, 3H), 7.09 (d, 2H, J=8.1 Hz), 7.39-7.58 (m, 4H), 8.44 (br s, 1H). 13C NMR (CDCl3) δ 13.81, 19.54, 29.38, 30.74, 31.29, 36.79, 40.28, 43.97, 48.67, 52.61, 57.72, 61.01, 112.75, 115.27, 119.44, 122.87, 127.66, 128.76, 129.49, 130.39, 130.59, 130.76, 131.54, 134.46, 139.03, 142.81, 144.99, 156.69, 170.24. ES-MS m/z 581 (M+H). Anal. Calcd. for C35H44N6O2.0.2CH2Cl2: C, 70.73; H, 7.49; N, 14.06. Found. C, 70.74; H, 7.57; N, 13.74.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.O.Cl.[NH:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([C:6]([C:17]3[CH2:18][CH2:19][NH:14][CH2:15][CH:16]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1CCNCC1
Reactant: Clc1ccc2cc[nH]c2c1Cl
Agent: Cl
Solvent: O
Product: Clc1ccc2c(C3=CCNCC3)c[nH]c2c1Cl

Procedure:
The title compound was prepared in a fashion similar to that described in Preparation 30 from 6,7-dichloroindole (1.4 g, 7.5 mmol) and 4-piperidone hydrochloride hydrate (2.3 g, 15 mmol). The product was isolated as a white solid. Yield 1.8 g (89%). mp 252°-254° C. FDMS m/e=268 (M+ of free base).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:7]=1.[C:23]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].B(O)O>>[C:26]([O:25][C:23]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:2]2[C:3]3[CH2:16][CH2:15][N:14]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=4)[C:4]=3[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=2)=[CH:34][CH:33]=1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: Clc1nc(N2CCOCC2)nc2c1CCN2c1ccncc1
Reactant: CC(C)(C)OC(=O)NCc1ccc(B(O)O)cc1
Agent: OBO
Product: CC(C)(C)OC(=O)NCc1ccc(-c2nc(N3CCOCC3)nc3c2CCN3c2ccncc2)cc1

Procedure:
In the same manner as Example 1-B-10, using 4-chloro-2-morpholin-4-yl-7-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine, and [4-(N-Boc-aminomethyl)phenyl]boronic acid as a boronic acid, 4-(4-tert-butoxycarbonylaminomethyl-phenyl)-2-(morpholin-4-yl)-7-(pyridin-4-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine was obtained. This was dissolved in 1N hydrochloric acid-acetic acid, followed by stirring at room temperature for 40 minutes, and diethyl ether was added to the reaction mixture, to filter off a solid, whereby the desired compound was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[NH:21][N:20]=4)=[CH:15][CH:14]=3)=[N:11][N:10]=[N:9]2)=[CH:5][CH:4]=1.CC([O-])(C)C.[K+].[Cl:36][C:37]1[CH:45]=[CH:44][CH:43]=[C:42]([Cl:46])[C:38]=1[C:39](Cl)=[O:40]>C1COCC1>[Cl:36][C:37]1[CH:45]=[CH:44][CH:43]=[C:42]([Cl:46])[C:38]=1[C:39]([N:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19]([C:16]2[CH:15]=[CH:14][C:13]([C:12]3[N:8]([CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:29][CH:28]=4)[N:9]=[N:10][N:11]=3)=[CH:18][CH:17]=2)=[N:20]1)=[O:40]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: COc1ccc(Cn2nnnc2-c2ccc(-c3n[nH]c4ccccc34)cc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(Cn2nnnc2-c2ccc(-c3nn(C(=O)c4c(Cl)cccc4Cl)c4ccccc34)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of a mixture of regio-isomers of 3-(4-(1-(4-Methoxybenzyl)-1H-tetrazol-5-yl)phenyl)-1H-indazole (Example 20, step i) (50 mg, 0.13 mmol) was dissolved in anhydrous THF (1 ml). After addition of t-BuOK (16 mg, 0.14 mmol,) the reaction mixture was stirred at room temperature for 15 min. Subsequently, 2,6-dichlorobenzoyl chloride (21 μl, 0.14 mmol) was added and the reaction mixture was stirred for another 2 h at room temperature. The solvent was evaporated under reduced pressure, the residue was dissolved in dichloromethane and washed with water, an aqueous solution of 5% K2CO3 and water. The organic solvent was evaporated under reduced pressure and the residue was dried in vacuo. The product was purified by preparative HPLC to afford (2,6-dichlorophenyl)(3-(4-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)phenyl)-1H-indazol-1-yl)methanone as a mixture of 2 regioisomers in a 98 to 2 ratio (59 mg, 74%).
Reaction SMILES: FC(F)(F)[C:3]([NH:5][C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1)[C:9]([O:11]C)=[O:10])=O.C[Si]([N-][Si](C)(C)C)(C)C.[K+].IC.[OH-].[Li+].Cl>C1COCC1>[CH3:3][NH:5][C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:15]=1)[C:9]([OH:11])=[O:10]
Reactant: COC(=O)c1cc(NC(=O)C(F)(F)F)cc(C(F)(F)F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CNc1cc(C(=O)O)cc(C(F)(F)F)c1
Reaction time: 16 h

Procedure:
Methyl 3-(trifluoromethylcarbonyl)amino-5-(trifluoromethyl)benzoate (cf. procedures (116a) and (80a); 131 mg, 0.42 mmol) was dissolved in THF (5 mL), and the resultant solution was charged successively with KHMDS (0.83 mL of a 0.5 M solution) and iodomethane (0.03 mL, 0.42 mL). The mixture was stirred for 16 h, quenched with sat. NaHCO3, and extracted with EtOAc (2×). The organic extracts were combined, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. This product was dissolved in 3:1:1 THF/MeOH/water (5 mL) and the resultant solution was charged with lithium hydroxide (20 mg, 0.84 mmol). The reaction was stirred for 14 h, acidified with 1N HCl, and extracted with EtOAc (2×). The organic extracts were combined, washed with water, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide 3-methylamino-5-(trifluoromethyl)benzoic acid.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH2:9]1)=O)(C)(C)C.[ClH:22].CO>>[ClH:22].[NH:8]1[CH2:9][CH:10]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CC(c2ccc3ccccc3n2)C1
Agent: Cl
Solvent: CO
Product: c1ccc2nc(C3CNC3)ccc2c1
Yield: 100 %

Procedure:
A solution of 3-quinolin-2-yl-azetidine-1-carboxylic acid tert-butyl ester (2.2 g, 7.75 mmol) in 4N HCl/MeOH (20 mL) was stirred at room temperature for 30 min. The reaction mixture was concentrated to give the crude product (1.70 g, 7.75 mmol, yield 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([NH2:15])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:26][O:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Cl)=[CH:30][CH:29]=1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([C@H:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([NH2:15])=[O:14])[CH2:32][C:31]2[CH:34]=[CH:35][C:28]([O:27][CH3:26])=[CH:29][CH:30]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CC(C)C[C@@H](NS(=O)(=O)c1ccc(Cl)cc1)C(N)=O
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(CN([C@H](CC(C)C)C(N)=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Yield: 69.9 %

Procedure:
(2R)-2-(4-Chlorobenzenesulfonylamino)-4-methylpentanoic acid amide (300 mg, 1 mmol), K2CO3 (170 mg, 1.2 mmol), and 4-methoxybenzyl chloride (170 mg, 1.1 mmol) in DMF (25 mL) was heated to 60° C. for 18 h. The reaction was then diluted with EtOAc (150 mL) and washed with H2O, brine, dried over MgSO4 and concentrated to give a crude white wax. Further purification by flash chromatography (SiO2, 25% EtOAc/hexanes) afforded the titled compound (297 mg) as a white solid in 70% yield. [α]D=+44.2 (c 1.00, MeOH); MS (ESI), (M−H)− 422.9; 1H NMR (CDCl3) δ 7.63 (d, 2H, J=7.0), 7.42 (d, 2H, J=7.0), 7.25 (d, 2H, J=8.0), 6.79 (d, 2H, J=8.0), 6.25 (br s, 1H), 5.35 (br s, 1H), 4.36 (dd, 2H, J=50, 15), 4-26 (t, 1H, J=7.2), 3.78 (s, 3H), 1.83 (m, 1H), 1.18-1.34 (m, 2H), 0.75 (d, 3H, J=7.0), 0.67 (d, 3H, J=7.0); IR (KBr) 3480, 2959, 1693, 1674, 1514, 1333, 1158 cm−1.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[O:4][C@@H:3]([CH2:11][OH:12])[CH2:2]1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[CH3:20][S:21]([O:12][CH2:11][C@H:3]1[O:4][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:10]2[O:1][CH2:2]1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: OC[C@H]1COc2cccnc2O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@@H]1COc2cccnc2O1
Temperature: 0 °C
Yield: 88.6 %

Procedure:
A mixture of intermediate (2-a) (0.023 mol) and triethylamine (0.046 mol) in DCM (40 ml) was stirred at 0° C. A mixure of methanesulfonyl chloride (0.035 mol) in DCM (10 ml) was added dropwise. The mixture was stirred on an ice bath for 2 hours and then washed with H2O/NaCl. The organic layer was dried, filtered and the solvent was evaporated. The residue (oil) was solidified in DIPE. The precipitate was filtered off and dried, yielding 5 g of (S)-2,3-dihydro-1,4-dioxino[2,3-b]pyridine-3-methanol methanesulfonate (ester) (intermediate 3) ([α]D−27.89°; c=25.10 mg/5 ml in methanol; mp. 136° C.).
Reaction SMILES: [CH:1]12[CH2:7][CH:6]1[N:5](C(OCC1C3C=CC=CC=3C3C1=CC=CC=3)=O)[CH2:4][CH2:3][N:2]2[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C(S)CCCCCCC.C1CCN2C(=NCCC2)CC1>CCOCC>[CH:1]12[CH2:7][CH:6]1[NH:5][CH2:4][CH2:3][N:2]2[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)C2CC21
Agent: CCCCCCCCS
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCNC2CC21
Reaction time: 4 h

Procedure:
tert-Butyl (±)-9H-fluoren-9-ylmethyl 2,5-diazabicyclo[4.1.0]heptane-2,5-dicarboxylate (1.05 g, 2.50 mmol) was dissolved in Ether (25 mL) and was treated with 1-octanethiol (3.65 g, 24.97 mmol) at room temperature for 10 minutes. Then DBU (0.151 mL, 0.999 mmol) was added. Let mixture stir for 4 hours. Then solvent and extra 1-Octanethiol was removed under reduced pressure. And residue was put on 40 gram silica gel column and eluted on ISCO (0-15% MeOH/EtOAc). Removing solvent gave the title compound. 1H NMR (ppm) (500 MHz, CDCl3): δ 3.51-3.45 (1H, m), 3.05-2.58 (5H, m), 1.71 (1H, s), 1.45 (9H, s), 0.88-0.77 (1H, m), 0.53-0.44 (1H, m).
Reaction SMILES: [C:1]([O:9][CH3:10])(=[O:8])/[CH:2]=[CH:3]/[C:4]([O:6][CH3:7])=[O:5].C([O:13][C:14]1O[CH:17]=[N:16][CH:15]=1)C>>[CH3:7][O:6][C:4]([C:3]1[CH:17]=[N:16][CH:15]=[C:14]([OH:13])[C:2]=1[C:1]([O:9][CH3:10])=[O:8])=[O:5]
Reactant: CCOc1cnco1
Reactant: COC(=O)/C=C/C(=O)OC
Product: COC(=O)c1cncc(O)c1C(=O)OC

Procedure:
Dimethyl fumarate (781 mg; 1.1 eq.) was added to 5-ethoxyoxazole (557.3 mg; 4.9 mmol), and the mixture was reacted at 120° C. for 1.5 hours. The reaction residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane 2:1), to give crude crystals of the title compound. Yield: 730 mg (70.2%). The crude crystals were recrystallized from dichloromethane-hexane, to give colorless plates.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:22])[CH:7]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1.[CH3:23][CH:24]([CH3:40])[C:25]([NH:27][C:28]1[CH:29]=[N:30][CH:31]=[C:32]([CH:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH:33]=1)=[O:26]>>[F:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:6]([NH:5][CH2:4][CH2:3][CH2:2][N:37]2[CH2:38][CH2:39][CH:34]([C:32]3[CH:33]=[C:28]([NH:27][C:25](=[O:26])[CH:24]([CH3:23])[CH3:40])[CH:29]=[N:30][CH:31]=3)[CH2:35][CH2:36]2)=[O:22])=[CH:9][CH:10]=1
Reactant: O=C(NCCCBr)C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CC(C)C(=O)Nc1cncc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cncc(C2CCN(CCCNC(=O)C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c1

Procedure:
Example 172 was prepared from N-(3-bromopropyl)-2,2-bis(4-fluoro phenyl) acetamide and 2-methyl-N-[5-(4-piperidinyl)-3-pyridinyl]propanamide according to the procedures described in Scheme 14: 1H NMR (400 MHz, CDCl3) δ 8.39 (s, 1 H), 8.19 (s, 1 H), 8.17 (S, 1 H), 7.95 (s, 1 H), 7.31–7.20 (m, 5 H), 7.04–6.94 (m, 4 H), 4.82 (s, 1 H), 3.46–3.35 (m, 2 H), 2.98–2.92 (m, 2 H), 2.62–2.48 (m, 2 H), 2.48–2.38 (m, 2 H), 2.09–1.95 (m, 2 H), 1.87–1.76 (m, 2 H), 1.76–1.55 (m, 4 H), 1.25 (d, 6 H, J=7.6 Hz); ESMS m/e: 535.4 (M+H)+.
Reaction SMILES: C(OC([N:8]([CH2:16][CH2:17][CH2:18][C:19]12[BH:30][CH:27]([BH:28][BH:29]1)[BH:26][BH:25][BH:24][BH:23][BH:22][BH:21][BH:20]2)C(OC(C)(C)C)=O)=O)(C)(C)C>Cl.CCOC(C)=O>[C:19]12([CH2:18][CH2:17][CH2:16][NH2:8])[BH:30][CH:27]([BH:28][BH:29]1)[BH:26][BH:25][BH:24][BH:23][BH:22][BH:21][BH:20]2
Reactant: CC(C)(C)OC(=O)N(CCCC12BBBBBBBC(BB1)B2)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: NCCCC12BBBBBBBC(BB1)B2
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
Di-tert-butyl[3-(2,3,4,5,6,7,8,10,11,12-decaborabicyclo[7.2.1]dodec-1-yl)propyl]imidodicarbonate from Example 1 (2.21 g, 5.50 mol) was dissolved in a saturated solution of HCl in EtOAc (100 ml). The solution was stirred overnight at r.t. and then evaporated. The white fluffy precipitate was washed with dry ether. The precipitate was then dissolved in water and the solution was basified with an aqueous saturated solution of Na2CO3 (40 ml). The aqueous layer was extracted with ether and the combined organic extracts were washed with brine (3×10 ml). Removing of the solvent under vacuum afforded the free amine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[N:36]1([C:42]([NH2:44])=[O:43])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.[C:45]1([C:51]2([C:57]([OH:59])=[O:58])[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]2)[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.C(OCC)(=O)C.CCCCCC>CO.ClCCl>[N:36]1([C:42]([NH2:44])=[O:43])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][N:54]3[CH2:53][CH2:52][C:51]([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)([C:57]([OH:59])=[O:58])[CH2:56][CH2:55]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: O=C(O)C1(c2ccccc2)CCNCC1
Agent: Cl
Agent: NC(=O)N1CCCCC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 27.3.1 using 2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (0.21 g, 0.4 mmol) and 4-phenyl-piperidine-4-carboxylic acid piperidine-amide hydrochloride (0.12 mmol, 0.4 mmol). Chromatograph on silica gel eluting sequentially with 50% ethyl acetate/hexane, 2% methanol/dichloromethane, and then 4% methanol/dichloromethane to give the title compound: Rf =0.41 (silica gel, 5% methanol/dichloromethane). Exact Mass (FAB+): calculated for C39H48Cl2N3O5 calculated 708.2937. Found 708.2971.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]2[C:15](=[O:16])[NH:14][CH:13]([CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:12](=[O:28])[NH:11][C:10]=2[CH:29]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1COCC1>[C:24]([O:23][C:21](=[O:22])[NH:20][CH2:19][CH2:18][CH2:17][CH:13]1[C:12](=[O:28])[NH:11][C:10]2[CH:29]=[C:6]([CH2:4][OH:3])[CH:7]=[CH:8][C:9]=2[C:15](=[O:16])[NH:14]1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CCOC(=O)c1ccc2c(c1)NC(=O)C(CCCNC(=O)OC(C)(C)C)NC2=O
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCC1NC(=O)c2ccc(CO)cc2NC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.7 %

Procedure:
The compound (35.1 mg) obtained in Example 14-3 was dissolved in anhydrous THF (1.0 ml) and added with Lithium aluminum hydride (6.8 mg) and the whole was stirred at room temperature for 30 minutes. After completion of the reaction, an aqueous potassium sodium tartrate solution was added thereto and the whole was vigorously stirred at room temperature, followed by extraction with chloroform. The extract was dried with magnesium sulfate and the solvent was distilled off. The residue was purified through silica gel column chromatography (chloroform/methanol) thereby obtaining the subject compound (16.9 mg) as a white solid.
Reaction SMILES: [CH2:1]([C:5]1[N:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:35][N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[C:8]2[CH:9]([C:13]([O:15][CH3:16])=[O:14])[NH:10][CH2:11][CH2:12][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[CH2:36]([O:38][C:39]([CH2:41][C:42](Cl)=[O:43])=[O:40])[CH3:37]>>[CH2:1]([C:5]1[N:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:35][N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[C:8]2[CH:9]([C:13]([O:15][CH3:16])=[O:14])[N:10]([C:42](=[O:43])[CH2:41][C:39]([O:38][CH2:36][CH3:37])=[O:40])[CH2:11][CH2:12][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnn[nH]3)cc1)C(C(=O)OC)NCC2
Reactant: CCOC(=O)CC(=O)Cl
Product: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnn[nH]3)cc1)C(C(=O)OC)N(C(=O)CC(=O)OCC)CC2

Procedure:
Methyl 2-n-butyl-3-{2'-(1H-tetrazol-5-yl)-biphenyl-4-yl}methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate and ethoxycarbonylacetyl chloride are treated in the same manner as in Example 1-(2) to give methyl 2-n-butyl-5-ethoxycarbonylacetyl-3-{2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[N:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:9]=1[C:10](O)=[O:11].N.CO>O1CCCC1>[Cl:7][C:8]1[C:9]([CH2:10][OH:11])=[CH:13][CH:14]=[C:15]([Cl:17])[N:16]=1
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Agent: N
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CO
Product: OCc1ccc(Cl)nc1Cl

Procedure:
Lithium aluminum hydride (1.78 g) was suspended in dry tetrahydrofuran (10 ml), and 2,6-dichloronicotinic acid was added under ice-cooling at an inside temperature of not more than 10° C. The mixture was stirred under ice-cooling for 1 hr and 28% aqueous ammonia was added dropwise to the reaction mixture until foams disappeared. Methanol was added and the mixture was stirred at room temperature for 3 hr, and filtered through celite. The mother liquor was concentrated and the residue was applied to flash silica gel column chromatography (silica gel, 200 ml) and eluted with chloroform:ethyl acetate=8:1 to give 2,6-dichloro-3-hydroxymethylpyridine as colorless crystals (2.89 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:12](=[C:13](Cl)[CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][C:7]([CH2:25][NH:26][C@@H:27]([CH:30]([CH3:32])[CH3:31])[CH2:28][OH:29])([CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:6][C:5]2=1.ClC1C=C(Cl)C=CC=1NN>>[CH3:31][CH:30]([CH3:32])[C@H:27]([NH:26][CH2:25][C:7]1([CH2:16][CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:6][C:5]2[C:4]3[C:12](=[CH:13][CH:14]=[CH:2][CH:3]=3)[NH:11][C:10]=2[CH2:9][CH2:8]1)[CH2:28][OH:29]
Reactant: CC(C)[C@@H](CO)NCC1(CCCc2ccccc2)CCc2[nH]c3c(Cl)cc(Cl)cc3c2C1
Agent: NNc1ccc(Cl)cc1Cl
Product: CC(C)[C@@H](CO)NCC1(CCCc2ccccc2)CCc2[nH]c3ccccc3c2C1

Procedure:
17 mg of (2S)-2-[[[6,8-dichloro-2,3,4,9-tetrahydro-3-(3-phenylpropyl)-1H-carbazol-3-yl]methyl]amino]-3-methyl-1-butanol 286 is produced analogously with use of 2,4-dichlorophenylhydrazine.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[O:24][CH:25]=[C:26]([C:28]([O:30]C)=[O:29])[N:27]=1.[OH-].[Na+]>O.CO>[O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[O:24][CH:25]=[C:26]([C:28]([OH:30])=[O:29])[N:27]=1
Reactant: COC(=O)c1coc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1coc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 75.4 %

Procedure:
A suspended mixture of methyl 2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxylate (0.88 g, 2.1 mmol) and sodium hydroxide (4.00 g, 10.0 mmol) in water (50 mL) and methanol (50 mL) was stirred at 60° C. for 2 h. The reaction mixture was concentrated in vacuo to remove most of methanol and acidified with concentrated hydrochloric acid to pH 1-2. The solid residue was filtered off, washed with water (50 mL) and dried in vacuo to afford 2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxylic acid (0.64 g, 75%) as a colorless solid: 1H NMR (300 MHz, DMSO-d6) δ 8.24 (s, 1H), 7.29-6.95 (m, 4H), 6.55 (s, 1H), 6.37 (s, 1H), 5.08 (ABq, 2H), 4.74 (ABq, 2H), 4.44 (t, J=8.7 Hz, 2H), 3.01-2.80 (m, 2H); MS (ES−) m/z 403.4 (M−1).
Reaction SMILES: [CH2:1]1[CH:5]2[C:6]3[C:11]([CH:3]([CH2:4]2)[CH2:2]1)=[N:10][C:9](Cl)=[N:8][CH:7]=3.[NH2:13][NH2:14]>N1C=CC=CC=1>[CH2:1]1[CH:5]2[C:6]3[C:11]([CH:3]([CH2:4]2)[CH2:2]1)=[N:10][C:9]([NH:13][NH2:14])=[N:8][CH:7]=3
Reactant: NN
Reactant: Clc1ncc2c(n1)C1CCC2C1
Solvent: c1ccncc1
Product: NNc1ncc2c(n1)C1CCC2C1

Procedure:
2-Chloro-5,8-methano-5,6,7,8-tetrahydroquinazoline was dissolved in anhydrous pyridine (30 mL) and treated with anhydrous hydrazine (15 mL) at 120° C. for 5 h. The solvent was removed under vacuum. The residue was partitioned between chloroform and 1M aqueous potassium carbonate solution. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 2-hydrazino-5,8-methano-5,6,7,8-tetrahydroquinazoline as a tan solid, 2.68 g; 1H NMR (CDCl3, 300 MHz) 7.99 (s, 1H), 7.93 (br s, 1H), 3.90 (br s, 2H), 3.48 (s, 1H), 3.23 (s, 1H), 1.97 (m, 2H), 1.76 (d, 1H), 1.55 (d, 1H), 1.20-1.35 (m, 2H) ppm; 13C NMR (CDCl3, 75 MHz ) 179.48, 163.48, 147.10, 129.57, 47.58, 45.45, 39.86, 27.82, 25.46; MS(ES) 177 (M+H).