Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C@@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@H:24]([O:31][C:32]3[CH:33]=[CH:34][C:35]4[N:36]([C:38]([N:41]5[CH2:45][CH2:44][C@@H:43]([O:46][Si](C(C)C)(C(C)C)C(C)C)[CH2:42]5)=[N:39][N:40]=4)[CH:37]=3)[CH2:23][CH2:22]2)=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C@@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@H:24]([O:31][C:32]3[CH:33]=[CH:34][C:35]4[N:36]([C:38]([N:41]5[CH2:45][CH2:44][C@@H:43]([OH:46])[CH2:42]5)=[N:39][N:40]=4)[CH:37]=3)[CH2:23][CH2:22]2)=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CC[C@@H](O[Si](C(C)C)(C(C)C)C(C)C)C5)n4c3)c3ccccc32)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CC[C@@H](O)C5)n4c3)c3ccccc32)cc1
Temperature: 25 °C

Procedure:
To a solution of Intermediate 38d (80 mg, 0.10 mmol) in THF (1 mL) at −30° C. was added TBAF (1M in THF, 150 μL, 0.150 mmol) and the mixture was allowed to warm to RT over 1 h. The reaction mixture was applied to an SCX-2 cartridge (5 g) and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. Purification by HPLC (C6-Ph column, 35-75% MeCN in H2O, 0.1% HCO2H) gave the title compound as a white powder after freeze-drying (22 mg, 35%). LCMS (Method 5): Rt 4.01 min, m/z 621 [MH+]. 1H NMR (400 MHz, d4-MeOH): 1.29 (9H, s), 1.86-2.13 (4H, m), 2.14-2.28 (2H, m), 2.38 (3H, s), 3.40-3.45 (1H, m), 3.49-3.56 (1H, m), 3.66-3.71 (1H, m), 3.74-3.81 (1H, m), 4.50-4.55 (1H, m), 4.85-4.91 (1H, m), 5.37 (1H, t J 4.2), 6.33 (1H, s), 7.10 (1H, dd, J 9.8, 2.2), 7.19-7.36 (8H, m), 7.43 (1H, d, J 9.8), 7.76 (1H, d, J 1.6).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:37])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]3[O:29][CH:30]([C:33]([O:35]C)=[O:34])[CH2:31][N:32]=3)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1.[OH-].[Na+].Cl.C(OCC)(=O)C>C(O)C>[CH3:1][O:2][CH2:3][C@H:4]([CH3:37])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]3[O:29][CH:30]([C:33]([OH:35])=[O:34])[CH2:31][N:32]=3)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C3=NCC(C(=O)OC)O3)[nH]2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C3=NCC(C(=O)O)O3)[nH]2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 118.1 %

Procedure:
Methyl 2-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-4,5-dihydro-1,3-oxazole-5-carboxylate (60.5 mg, 0.114 mmol) synthesized in Example (27b) was dissolved in ethanol (4 mL). An aqueous sodium hydroxide solution (5M, 2 mL) was added, and stirring was carried out at 70° C. for 2.5 hours. After cooling to room temperature, hydrochloric acid (2M, 5 mL) and ethyl acetate (10 mL) were added, and the solution was separated. The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to afford the desired compound (69.3 mg, yield ˜100%) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].Br[CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Reactant: BrCc1ccc2ccccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCc2ccc3ccccc3c2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.50 g in 5 mL of dimethylformamide was treated with 60% sodium hydride (0.112 g) and after 15 minutes, 2-bromomethylnaphthalene (0.61 g) was added. The reaction mixture was stirred 45 minutes at room temperature, was quenched with 0.1 mL of acetic acid and was diluted with diethyl ether-ethyl acetate (10: 1, 50 mL). The mixture was washed with water (2×10 mL) and brine (1×10 mL), dried (1MgSO4) and chromatographed over 100 g of silica gel eluting with dichloromethane-hexane (1:1) to give 0.61 g of 4-[(2-naphthalenyl)methoxy]alpha-oxobenzeneacetic acid methyl ester, mp 101°-102° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:13][C:12]([C:14]([O:16]CC)=O)=[N:11][N:10]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:13][C:12]([C:14]([NH:32][CH:29]2[CH2:28][CH2:27][N:26]([C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])[CH2:31][CH2:30]2)=[O:16])=[N:11][N:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CCOC(=O)c1nnc(Nc2ccccc2F)o1
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2nnc(Nc3ccccc3F)o2)CC1
Yield: 74 %

Procedure:
(intermediate 40) (102 mg, 0.41 mmol) and tert-butyl-4-aminopiperidine-1-carboxylate (81 mg, 0.41 mmol) was heated to 85° C. for 18 hours. Upon cooling the solid was filtered and washed with EtOH (10 mL), Et2O (10 mL) then hexane (10 mL) to leave the title compound (123 mg, 74%) as a white solid; 1H NMR δ 1.41 (9H, s), 1.46-1.54 (2H, m), 1.73-1.76 (2H, m), 2.81 (2H, s), 3.93-3.96 (3H, m), 7.13-7.17 (1H, m), 7.23-7.32 (2H, m), 7.99-8.04 (1H, m), 9.02 (1H, d), 10.63 (1H, s); MS m/e (M−H)− 404.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[NH:12][C:11]([C:13]3[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=3[CH3:20])=[C:10]([C:21]([OH:23])=O)[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[CH3:24][N:25](C=O)C.C1COCC1.C1COCC1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN.O>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[NH:12][C:11]([C:13]3[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=3[CH3:20])=[C:10]([C:21]([NH:25][CH3:24])=[O:23])[CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CN(C)C=O
Reactant: Cc1ccc(Cl)cc1-c1[nH]c(-c2ccnc(N)n2)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)c1cc(-c2ccnc(N)n2)[nH]c1-c1cc(Cl)ccc1C
Temperature: 0 °C
Yield: 84.4 %

Procedure:
To a solution of 5-(2-aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-1H-pyrrole-3-carboxylic acid (142 mg, 0.43 mmol) in DMF/THF 1/1 (4 mL) DIPEA (0.301 mL, 1.72 mmol) and MeNH2 2 M in THF (0.432 mL, 0.86 mmol) were added and the solution was stirred at 0° C. EDCl (157 mg, 0.86 mmol) and HOBT (117 mg, 0.86 mmol) were added and the reaction mixture was stirred for 4 h at room temperature. The mixture was diluted with water and extracted with DCM (4×10 mL). The organic phase was washed with brine, water and then dried over sodium sulfate and concentrated. The crude material was chromatographed on silica gel (DCM/MeOH 90/10) to afford the title compound (124 mg, 84%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.[CH3:13][C:14]1[CH:29]=[N:28][CH:27]=[CH:26][C:15]=1[C:16](N(C)C1C=CC=CC=1)=[O:17].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[K+]>O1CCCC1.CO>[CH3:13][C:14]1[CH:29]=[N:28][CH:27]=[CH:26][C:15]=1[CH:16]=[O:17]
Reactant: Cc1cnccc1C(=O)N(C)c1ccccc1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cnccc1C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.7 %

Procedure:
1M Lithium aluminium hydride in tetrahydrofuran (6.96 ml, 6.96 mmol) in anhydrous tetrahydrofaran (15 ml) under a nitrogen atmosphere, was cooled to -10° C. and treated with ethyl acetate (0.61 g, 6.96 mmol) dropwise. After 10 minutes this solution was treated with dropwise addition of 3,N-dimethyl-N-phenyl-isonicotinamide (1.50 g, 6.63 mmol, J. Chem. Res., Synop. 1986, 20-21) in tetrahydrofuran (15 ml). After 2 hours at -10° C. the mixture was allowed to warm to room temperature. Methanol (10 ml) was added, followed by a saturated solution of potassium tartrate. The organic layer was separated and the aqueous layer was exhaustively extracted with dichloromethane. The combined organics were washed with water (2×10 ml), dried (sodium sulphate) then evaporated. The residue was purified by chromatography on silica using dichloromethane/methanol (40:1) to afford the aldehyde (560 mg, 70%) as a gum. MS, ES+, m/z=122 for (M+H)+, δH (360 MHz, DMSO-d6) 2.59 (3H, s), 7.68 (1H, d, J=5 Hz), 8.66 (1H, s), 8.70 (1H, d, J=5 Hz), 10-30 (1H, s).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH:29]=O)=[CH:21]1>>[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH2:29][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:21]1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4c[nH]c5ccccc45)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 1H-indole-3-carbaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(1H-indol-3-ylmethyl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: CO[C:3]1[CH:23]=[CH:22][C:6]([CH2:7][CH:8]2[C:17]3[C:12](=[CH:13][C:14](OC)=[C:15](OC)[CH:16]=3)CCN2)=C[CH:4]=1.C([BH3-])#N.[Na+]>>[C:17]1([C:8]([C:7]2[CH:4]=[CH:3][CH:23]=[CH:22][CH:6]=2)([CH2:7][CH2:6][CH3:22])[CH2:4][CH2:3][CH3:23])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC)cc32)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCCC(CCC)(c1ccccc1)c1ccccc1

Procedure:
The 1,2,3,4-tetrahydro-1-(4-methoxybenzyl)-6,7-dimethoxyisoquinoline was reacted with 7-[N-3-(4-fluorophenyl)propionyl]amino-4,4-diphenylheptanal in the presence of sodium cyanoborohydride as described in example 1 to give 7-[N-3-(4-fluorophenyl)propionyl]amino- I1-N-[ 1,2,3,4-tetrahydro-1-(4-methoxybenzyl)] -6,7-dimethoxyisoquinolinyl]-4,4-diphenylheptane as a film: MS showed (M+H)+ @ 729; 1H-NMR (CDCl3, δ): 1.0-1.22 (m, 4H), 1.91-2.10 (m, 4H), 2.3-2.4 (m, 2H), 2.4-2.85 (m, 6H), 2.85-2.94 (t, 2H), 2.94-3.2 (m, 4H). 3.51-3.67 (m, 1H), 3.55 (s, 31H). 3.76 (s, 3H), 3.82 (s, 3H), 1H. (broad s, 5.13), 5.92 (s, 1H), 6.52 (s, 1H), 6.75-6.97 (m, 6H), 7.07-7.30 (m, 12H); IR (MIC) u 3300, 2950. 1650, 1510 cm-1. The hydrochloride salt was prepared as in example 4 to give 7-[N-3-(4-fluorophenyl)propionyl]-1-[N-(l.2,3,4-tetra- hydro-1-(4-methoxybenzyl)-6,7-dimethoxyisoquinolinyl)]-4,4-diphenylheptane hydrochloride: mp 100-108° C.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:10]([C:12]([C:14]3[NH:18][C:17]4[CH:19]=[CH:20][C:21]([C:23]#[N:24])=[CH:22][C:16]=4[N:15]=3)=[O:13])=[C:9]([CH3:25])[CH:8]=[C:7]([CH3:26])[C:6]=2[NH:5][CH:4]=1)=O.[BH4-].[Na+]>CO.CCOC(C)=O.FC(F)(F)CO>[CH3:1][C:3]1[C:11]2[C:10]([C:12]([C:14]3[NH:18][C:17]4[CH:19]=[CH:20][C:21]([C:23]#[N:24])=[CH:22][C:16]=4[N:15]=3)=[O:13])=[C:9]([CH3:25])[CH:8]=[C:7]([CH3:26])[C:6]=2[NH:5][CH:4]=1
Reactant: Cc1cc(C)c2[nH]cc(C=O)c2c1C(=O)c1nc2cc(C#N)ccc2[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: OCC(F)(F)F
Product: Cc1cc(C)c2[nH]cc(C)c2c1C(=O)c1nc2cc(C#N)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(3-formyl-5,7-dimethyl-1H-indole-4-carbonyl)-1H-benzo[d]imidazole-5-carbonitrile (20 mg, 0.058 mmol) in MeOH (2 mL) was added NaBH4 (11.05 mg, 0.292 mmol), and then the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with EtOAc/2,2,2-trifluoroethanol (c.a. 9/1). The organic phase was successively washed by H2O and brine, dried over Na2SO4, and filtered. Concentration of the filtrate gave the title compound, which was used in the next reaction without any further purification. MS (ESI+) m/z 329.1 (M+H).
Reaction SMILES: C([O:8][CH2:9][C:10]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][CH2:12][CH2:11]1)C1C=CC=CC=1>[Pd].C(O)C>[OH:8][CH2:9][C:10]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][CH2:12][CH2:11]1
Reactant: CCOC(=O)C1(COCc2ccccc2)CCC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1(CO)CCC1
Reaction time: 4 h

Procedure:
A mixture of ethyl 1-benzyloxymethylcyclobutanecarboxylate (6.57 g, 26.5 mmol), 10% palladium on carbon (0.4 g) and ethanol (100 ml) was hydrogenated on a Parr Shaker for 4 hours. The catalyst was removed by filtration. The filtrate was evaporated in vacuo to leave the desired product as a colorless oil: NMR (CDCl3) δ32 1.26 (3H, t, J=7 Hz), 1.8~2.6 (6H, m), 2.61 (H, s), 3.78 (2H, s), 4.15 (2H, q, J=7 Hz).
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[C:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:12]([C:16]([F:19])([F:18])[F:17])[O:13]2)=[CH:8][CH:7]=1)([CH3:5])[CH:3]=[O:4].[BH4-].[Na+].CC(O)=O>CO>[OH:4][CH2:3][C:2]([C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[C:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:12]([C:16]([F:18])([F:19])[F:17])[O:13]2)=[CH:8][CH:7]=1)([CH3:5])[CH3:1]
Reactant: CCOC(=O)C1=Cc2ccc(C(C)(C)C=O)cc2OC1C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)C1=Cc2ccc(C(C)(C)CO)cc2OC1C(F)(F)F
Reaction time: 0.42 h

Procedure:
To a solution of ethyl 7-(1,1-dimethyl-2-oxoethyl)-2-(trifluoromethyl)-2H-chromene-3-carboxylate (6.90 g, 20.2 mmoles) in 200 mL of MeOH stirring in an ice bath, was added portionwise NaBH4 (763 mg, 20.2 mmoles) as a solid. After 25 min, HOAc was cautiously added, and the solution concentrated. The residue was partitioned between DCM and water, and the organic extract dried over Na2SO4, filtered, and evaporated. Chromatography of the residue over silica gel using a gradient of 0-10% EtOAc—DCM as eluent gave the title compound, 5.4 g, as a very pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][N:14]3C(=O)C4=CC=CC=C4C3=O)=[C:11]([CH3:25])[N:10]=[C:9]2[CH2:26][N:27]([CH3:29])[CH3:28])=[C:4]([C:30](=O)[C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=2)[CH:3]=1.O.NN>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]3[C:9]([CH2:26][N:27]([CH3:29])[CH3:28])=[N:10][C:11]([CH3:25])=[C:12]3[CH2:13][N:14]=[C:30]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=3)[C:4]=2[CH:3]=1
Reactant: Cc1nc(CN(C)C)n(-c2ccc(F)cc2C(=O)c2cccc(Cl)c2)c1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1nc(CN(C)C)n2c1CN=C(c1cccc(Cl)c1)c1cc(F)ccc1-2

Procedure:
In the manner given in Example 4, N-[[1-[4-fluoro-2-(m-chlorobenzoyl)phenyl]-2-[(dimethylamino)methyl]-4-methylimidazol-5-yl]methyl]phthalimide in ethanol is heated with hydrazine hydrate to give 8-fluoro-6-(m-chlorophenyl)-1-[(dimethylamino)methyl]-3-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine.
Reaction SMILES: C(C(CC)CNCC1SC(C2C=C3C(=C(C(N)=O)C=2)NC=C3C2CCN(S(CC)(=O)=O)CC2)=CC=1)C.[CH:37]([C:39]1[S:43][C:42]([B:44]([OH:46])[OH:45])=[CH:41][CH:40]=1)=O.[CH2:47]([O:49][CH2:50][CH2:51][CH2:52][NH2:53])[CH3:48].[BH3-]C#N.[Na+]>>[CH2:47]([O:49][CH2:50][CH2:51][CH2:52][NH:53][CH2:37][C:39]1[S:43][C:42]([B:44]([OH:46])[OH:45])=[CH:41][CH:40]=1)[CH3:48]
Reactant: CCOCCCN
Reactant: O=Cc1ccc(B(O)O)s1
Agent: CCC(CC)CNCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)s1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCOCCCNCc1ccc(B(O)O)s1
Yield: 38.6 %

Procedure:
Following the general procedure of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), [3-(ethyloxy)propyl]amine (34 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 30 mg of crude [5-({[3-(ethyloxy)propyl]amino}methyl)-2-thienyl]boronic acid. The crude [5-({[3-(ethyloxy)propyl]amino}methyl)-2-thienyl]boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K2CO3 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.0079 mmol) to give 8.1 mg of the title compound (10%).
Reaction SMILES: [C:1]1([C:7]2[N:11]([S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:10]=[C:9]([CH2:21][OH:22])[C:8]=2[CH2:23][CH2:24][CH3:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[N+]1([O-])CCOCC1>[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[C:1]1([C:7]2[N:11]([S:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)(=[O:13])=[O:14])[CH:10]=[C:9]([CH:21]=[O:22])[C:8]=2[CH2:23][CH2:24][CH3:25])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCc1c(CO)cn(S(=O)(=O)c2ccccc2)c1-c1ccccc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Product: CCCc1c(C=O)cn(S(=O)(=O)c2ccccc2)c1-c1ccccc1
Yield: 49 %

Procedure:
Using [5-phenyl-1-(phenylsulfonyl)-4-propyl-1H-pyrrol-3-yl]methanol (2.73 g), tetra-n-propylammonium perruthenate (142 mg), N-methylmorpholine N-oxide (1.04 g) and molecular sieves 4A powder (1.5 g), a procedure as in Reference Example 6 was performed to give the title compound as a pale-red oil (yield 1.33 g, 47%).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CC(C)([O-])C.[K+]>CS(C)=O.O>[C:15]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[NH:13][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Nc1ccccc1-c1ccccc1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1cc([N+](=O)[O-])ccc1Nc1ccccc1-c1ccccc1
Reaction time: 16 h
Yield: 55.9 %

Procedure:
To a solution of 2-fluoro-5-nitrobenzonitrile (690 mg, 4.13 mmol, 1 equiv) and 2-aminobiphenyl (700 mg, 4.13 mmol, 1 equiv) in anhydrous DMSO (20 mL) at room temperature was added potassium tert-butoxide (930 mg, 8.26 mmol, 2 equiv). After 16 h, the reaction mixture was diluted with water, and extracted into EtOAc (×3). The EtOAc extractions were combined, washed with water (×5), brine, dried (Na2SO4), filtered and concentrated. The crude residue was dry-loaded onto silica gel and purified by flash column chromatography (CH2Cl2/Hex/EtOAc, 10:10:1) to afford 2-([1,1′-biphenyl]-2-ylamino)-5-nitrobenzonitrile as an orange solid (728 mg, 56%): δH (CDCl3, 400 MHz) 8.31 (d, J=2.4, 1H, Ar), 8.10 (dd, J=9.6, 2.4, 1H, Ar), 7.50-7.24 (m, 9H, Ar), 6.92 (d, J=9.6, 1H, Ar), 6.79 (s, 1H, NH); δC (CDCl3, 100 MHz) 152.2, 138.5, 137.9, 137.5, 134.4, 131.6, 129.7, 129.5, 128.9, 128.8, 128.6, 128.2, 127.6, 125.4, 115.2, 112.5, 96.7), which was subsequently hydrolyzed (1.17 mmol scale) with NaOH (140 mg, 3.52 mmol, 2 equiv) in a 1:1:1 mixture of dioxane/EtOH/H2O (12 mL) at reflux for 48 h. The reaction mixture was concentrated to dryness, and then partitioned between Et2O and H2O to remove neutral organics. The aqueous layer was acidified with 1M HCl, and then extracted with EtOAc (×3). The EtOAc extractions were combined, washed with brine, dried (Na2SO4), filtered and concentrated. The crude residue was dry-loaded onto silica gel and purified by flash column chromatography (CH2Cl2/MeOH/AcOH, 92:7:1) to deliver the title compound 2-([1,1′-biphenyl]-2-ylamino)-5-nitrobenzoic acid (SF-3-103B) as an orange solid (293 mg, 75%): δH (CDCl3+MeOH-d4, 400 MHz) 10.01 (s, 1H, OH), 8.80 (d, J=2.4, 1H, NH), 7.98 (dd, J=9.6, 2.4, 1H, Ar), 7.43-7.17 (m, 11H, Ar), 6.82 (d, J=9.6, 1H, Ar); δC (CDCl3, 100 MHz) 169.2, 153.2, 138.3, 138.2, 137.0, 135.4, 131.4, 129.5, 129.1, 128.8, 128.5, 128.4, 127.5, 126.9, 126.0, 113.0, 110.2.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][C@@H:10]([CH2:14][CH3:15])[C:11]([NH2:13])=[O:12].Br[CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>C1(C)C=CC=CC=1>[NH2:13][C:11]([C@@H:10]([NH:9][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:14][CH3:15])=[O:12]
Reactant: CC[C@H](N)C(N)=O
Reactant: CCOC(=O)CCCBr
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCN[C@@H](CC)C(N)=O

Procedure:
143.6 ml (1.035 mole) of triethylamine are added to a suspension of 47.75 g (0.345 mole) of (S)-2-amino-butanamide hydrochloride ([alpha]D25 : +26.1°; c=1, methanol) in 400 ml of toluene. The mixture is heated to 80° and 67.2 g (0.345 mole) of ethyl 4-bromobutyrate are introduced dropwise.
Reaction SMILES: FC(F)(F)C(O)=O.[I:8][C:9]1[N:10]=[CH:11][N:12]([CH2:14][CH2:15][C:16]([NH:19]C(=O)OC(C)(C)C)([CH3:18])[CH3:17])[CH:13]=1>ClCCl>[I:8][C:9]1[N:10]=[CH:11][N:12]([CH2:14][CH2:15][C:16]([NH2:19])([CH3:17])[CH3:18])[CH:13]=1
Reactant: CC(C)(CCn1cnc(I)c1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(N)CCn1cnc(I)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.2 %

Procedure:
10 mL (130 mmol) trifluoroacetic acid were added to a solution of 1.90 g (5.00 mmol) tert-butyl [3-(4-iodo-imidazol-1-yl)-1,1-dimethyl-propyl]-carbamate in 90 mL dichloromethane at ambient temperature with vigorous stirring. The reaction mixture was stirred for 16 h at ambient temperature and the solvent was eliminated using the rotary evaporator. The residue was taken up in 100 mL sodium hydroxide solution (1M) and 100 mL dichloromethane. The phases were separated and the aqueous phase was extracted three times with 100 mL dichloromethane. The combined organic phases were dried over magnesium sulphate and the solvent was eliminated using the rotary evaporator. 1.37 g (4.91 mmol, 98%) 3-(4-iodo-imidazol-1-yl)-1,1-dimethyl-propylamine were obtained as a colourless oil.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]([C:14]3[C:15]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[CH:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)=[CH2:31].C(O)(=O)C>CO>[N:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[CH2:30][CH2:31][N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]3[C:15]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][CH:21]=4)=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:13])[CH:6]=2)[CH2:1]1
Reactant: C=Cc1ccccn1
Reactant: O=C(Nc1ccc2c(c1)CCNC2)c1ccccc1-c1ccc(C(F)(F)F)cc1
Solvent: CO
Solvent: CC(=O)O
Product: O=C(Nc1ccc2c(c1)CCN(CCc1ccccn1)C2)c1ccccc1-c1ccc(C(F)(F)F)cc1

Procedure:
Compound (II) (300 mg, 0.76 mmole), 2-vinylpyridine (95 mg, 0.91 mmole) and glacial acetic acid (24 mg, 0.40 mmole) were combined in 15 mL of methanol and heated to reflux for 24 hrs. The solvent was removed under vacuum and the residue was purified using silica gel chromatography with a gradient of 0 to 3% methanol in ethyl acetate as the eluent.