Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:15][CH:16]=[C:17]([CH3:25])[CH2:18][CH2:19][CH2:20][CH:21]([CH3:24])[CH:22]=[O:23])[C:6]([CH3:14])=[CH:7][C:8]1[N:9]=[C:10]([CH3:13])[S:11][CH:12]=1)(=[O:3])[CH3:2].[CH3:26][O:27][C:28](=[O:47])[CH2:29][C@H:30]([O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])[C:31]([CH3:38])([CH3:37])[C:32](=[O:36])[CH:33](Br)[CH3:34]>C1COCC1.[Cl-].[Na+].O>[CH3:26][O:27][C:28](=[O:47])[CH2:29][CH:30]([O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:41])[CH3:42])[C:31]([CH3:37])([CH3:38])[C:32](=[O:36])[CH:33]([CH3:34])[CH:22]([OH:23])[CH:21]([CH3:24])[CH2:20][CH2:19][CH2:18][C:17]([CH3:25])=[CH:16][CH2:15][CH:5]([O:4][C:1](=[O:3])[CH3:2])[C:6]([CH3:14])=[CH:7][C:8]1[N:9]=[C:10]([CH3:13])[S:11][CH:12]=1
Reactant: CC(=O)OC(CC=C(C)CCCC(C)C=O)C(C)=Cc1csc(C)n1
Reactant: COC(=O)C[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)C(=O)C(C)Br
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CC(O[Si](C)(C)C(C)(C)C)C(C)(C)C(=O)C(C)C(O)C(C)CCCC(C)=CCC(OC(C)=O)C(C)=Cc1csc(C)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 240 mg (1.95 mmol) CrCl2 and 125 mg (0.93 mmol) in 10.0 mL absolute THF was added 322 mg (0.886 mmol) 3-acetoxy-2,6,10-trimethyl-1-(2-methyl-thiazol-4-yl)-11-oxo-undeca-1,5-diene (8 b) in 1.0 mL absolute THF and 384 mg (0.971 mmol) (3S)-6-bromo-3-(tert-butyl-dimethyl-silanyloxy)-4,4-dimethyl-5-oxo-heptanoic acid methyl ester (235) at ambient temperature. After stirring for 2 h 15 min at ambient temperature, 12 mL brine were added and stirring was continued for five minutes. The waterphase was extracted five times with 15 mL of a pentane-diethylether-mixture (1:5) and the combined organic layers were washed twice with 20 mL demi water and twice with 20 mL brine. After drying over Na2SO4, filtration and concentrating in vacuo, the obtained oil was purified by flash chromatography (column dimensions: 2.0×20.0 cm, diethylether/petroleum ether=5:4).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:23])[C:5]([CH3:22])=[C:6]([CH2:12][C:13]2[CH:14]=C(C=CC=2)C(O)=O)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:24]1CC[S:27][CH2:26][CH2:25]1>>[CH3:1][O:2][C:3]1[C:4](=[O:23])[C:5]([CH3:22])=[C:6]([CH2:12][CH:13]2[CH2:14][S:27][CH2:26][CH2:25][NH:24]2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: C1CSCCN1
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)O)c2)=C(C)C1=O
Product: COC1=C(OC)C(=O)C(CC2CSCCN2)=C(C)C1=O
Yield: 55.6 %

Procedure:
3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)benzoic acid (85 mg, 0.27 mmol) obtained in Example 41 and thiomorpholine (0.041 ml, 0.41 mmol) were used, and a method similar to that described in Example 42 was employed to obtain the title compound (61 mg, 0.15 mmol, yield 54%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]2)=[CH:9][CH:10]=1)=[O:4].Br[CH2:25][C:26]1[C:27]([C:34]2[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][C:35]=2[Cl:41])=[N:28][O:29][C:30]=1[CH:31]1[CH2:33][CH2:32]1.[H-].[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[C:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:7][C:8]([N:11]2[CH2:12][CH2:13][CH:14]([O:17][CH2:25][C:26]3[C:27]([C:34]4[C:35]([Cl:41])=[CH:36][CH:37]=[CH:38][C:39]=4[Cl:40])=[N:28][O:29][C:30]=3[CH:31]3[CH2:33][CH2:32]3)[CH2:15][CH2:16]2)=[CH:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1ccc(N2CCC(O)CC2)cc1-c1ccccc1
Reactant: Clc1cccc(Cl)c1-c1noc(C2CC2)c1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N2CCC(OCc3c(-c4c(Cl)cccc4Cl)noc3C3CC3)CC2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 41.6 %

Procedure:
A mixture of 5-(4-hydroxy-piperidin-1-yl)-biphenyl-2-carboxylic acid methyl ester (318 mg, 1.02 mmol), 4-bromomethyl-5-cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazole (375 mg, 1.08 mmol), and sodium hydride (52 mg, 1.30 mmol) in dimethylformamide (4 mL) is stirred at room temperature for 2.5 h. The mixture is partitioned between saturated aqueous ammonium chloride and ethyl acetate. The layers are separated and the aqueous layer is extracted with ethyl acetate (3×). The ethyl acetate layers are washed with brine (3×), dried (MgSO4), and concentrated under reduced pressure. The crude material is purified on silica (40 g) eluting with a gradient of ethyl acetate in heptane (0-60%) to provide the title compound (245 mg, 42%) as a glassy film. LC-ES/MS m/z 579.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][C@H:17]([CH2:21]OS(C)(=O)=O)[O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[N-:27]=[N+:28]=[N-:29].[Na+]>CN1C(=O)CCC1>[F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][C@H:17]([CH2:21][N:27]=[N+:28]=[N-:29])[O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OC[C@H]1CCc2ccc(S(=O)(=O)c3cccc(F)c3)cc2O1
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: [N-]=[N+]=NC[C@H]1CCc2ccc(S(=O)(=O)c3cccc(F)c3)cc2O1
Temperature: 75 °C
Reaction time: 2 h
Yield: 101.5 %

Procedure:
To a solution of methanesulfonic acid (R)-7-(3-fluoro-benzenesulfonyl)-chroman-2-ylmethyl ester (2.0 g, 4.99 mmol) in 30 mL of NMP was added sodium azide (1.55 g, 0.024 mol). The reaction mixture was heated to 75° C. with stirring for two hours. The reaction was quenched by addition of water, and the resulting mixture was extracted with diethyl ether. The combined organic layers were washed with water and brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (hexanes:EtOAc 3:2) to give 1.76 g (quantitative) of C—[(R)-7-(3-fluoro-benzenesulfonyl)-chroman-2-yl]-methyl azide.
Reaction SMILES: C(N[C:10]1[CH:41]=[CH:40][N:13]([C@@H:14]2[O:29][C@H:18]([CH:19]([C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[OH:20])[C@@:16]([C:30](=[O:37])[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([OH:17])[C@:15]2([F:39])[CH3:38])[C:12](=[O:42])[N:11]=1)(=O)C1C=CC=CC=1.CC(O)=[O:45]>>[C:30]([C@@:16]1([OH:17])[C@@H:18]([CH:19]([C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[OH:20])[O:29][C@@H:14]([N:13]2[CH:40]=[CH:41][C:10](=[O:45])[NH:11][C:12]2=[O:42])[C@@:15]1([F:39])[CH3:38])(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(=O)O
Reactant: C[C@]1(F)[C@H](n2ccc(NC(=O)c3ccccc3)nc2=O)O[C@H](C(O)C(=O)c2ccccc2)[C@]1(O)C(=O)c1ccccc1
Product: C[C@]1(F)[C@H](n2ccc(=O)[nH]c2=O)O[C@H](C(O)C(=O)c2ccccc2)[C@]1(O)C(=O)c1ccccc1
Yield: 91 %

Procedure:
N4,3′,5′-tribenzoyl-2′-Deoxy-2′-fluoro-2′-C-methylcytidine (2.0 g, 1 eq) was refluxed in 80% aqueous AcOH overnight. After cooling and standing at room temperature (15° C.), most of the product precipitated and then was filtered through a sintered funnel. White precipitate was washed with water and co-evaporated with toluene to give a white solid. The filtrate was concentrated and co-evaporated with toluene to give additional product which was washed with water to give a white solid. Combining the two batches of white solid gave 1.50 g of 3′,5′-dibenzoyl-2′-Deoxy-2′-fluoro-2′-C-methyluridine (Yield: 91%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1.O1CCCC1.C([Li])(C)(C)C.[B:29](OC)([O:32]C)[O:30]C>CCCCC>[CH3:10][C:7]1([CH3:11])[C:6]2[CH:12]=[C:2]([B:29]([OH:32])[OH:30])[CH:3]=[C:4]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:5]=2[O:9][CH2:8]1
Reactant: COB(OC)OC
Reactant: CCCCCCc1cc(Br)cc2c1OCC2(C)C
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCCCCCc1cc(B(O)O)cc2c1OCC2(C)C

Procedure:
Following General Procedure A and using 5-bromo-7-hexyl-3,3-dimethyl-2,3-dihydro-benzofuran (Intermediate 53, 1.32 g, 4.26 mmol), anhydrous tetrahydrofuran, 1.7M solution of t-butyllithium in n-pentane and trimethyl borate, the title compound was obtained as a foam that was used as such for the next step without purification and characterization.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[CH3:25][N:26]([CH3:39])[S:27]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)(=[O:29])=[O:28]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:33]4[CH:32]=[CH:31][C:30]([S:27]([N:26]([CH3:39])[CH3:25])(=[O:28])=[O:29])=[CH:35][CH:34]=4)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: CN(C)S(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(-c4ccc(S(=O)(=O)N(C)C)cc4)cc32)N=C1N
Temperature: 120 °C
Yield: 9.4 %

Procedure:
Pd(PPh3)2Cl2 (10 mg) in a 10 mL CEM test tube under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 4-(N,N-dimethylsulfamoyl)phenylboronic acid (23.8 mg, 0.104 mmol). The mixture was heated in a microwave reactor at 120° C. for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC and preparative HPLC to give pure 4-(2′-amino-1′-methyl-5′-oxo-2-phenyl-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)-N,N-dimethylbenzenesulfonamide (2.4 mg, 9%). 1H-NMR (CDCl3): 2.31 (t, 1H), 2.57 (t, 1H), 2.78 (s, 6H), 3.33 (d, 3H), 3.56 (s, 2H), 5.88 (d, 1H), 7.20 (d, 1H), 7.26 (s, 1H), 7.48 (m, 5H), 7.57 (m, 1H), 7.62 (d, 2H), 7.80 (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([CH3:9])[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]=1
Reactant: Cc1cc(Cl)nc(Cl)n1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1cc(-c2ccccc2)nc(Cl)n1
Temperature: 90 °C

Procedure:
A mixture of 2,4-dichloro-6-methylpyrimidine (5 g, 30.7 mmol), benzeneboronic acid (3.74 g, 30.7 mmol), K2CO3 (12.72 g, 92 mmol) and Pd(PPh3)4 (1.06 g, 0.92 mmol) in toluene (150 ml) and methanol (35 ml) was degassed with nitrogen and heated at 90° C. overnight. The mixture was cooled and water (200 ml) added. The organic layer was separated and the aqueous extracted with EtOAc (×2). The organic layers were combined and dried over MgSO4, filtered and evaporated. The residue was purified by MPLC (Biotage Horizon: FLASH 40+M) eluent: 100% Hexanes (180 ml), gradient rising from 100% Hexanes to 20% EtOAc in Hexanes (1800 ml), then 20% EtOAc in Hexanes (1000 ml) to give 3 g (48%). 1H NMR (CDCl3): 2.61 (s, 3H), 7.52 (m, 4H), 8.08 (m, 2H).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:11](=[O:15])[CH:12]([CH3:14])[CH3:13])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH:16]12[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH:17]1[N:26]=[C:27]=[O:28])[CH2:23]2>>[CH:18]12[CH2:24][CH:22]3[CH2:21][CH:20]([CH2:25][CH:16]([CH2:23]3)[CH:17]1[NH:26][C:27]([NH:2][CH:3]([CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:11](=[O:15])[CH:12]([CH3:13])[CH3:14])=[O:28])[CH2:19]2
Reactant: CC(C)C(=O)C(N)Cc1ccccc1
Reactant: O=C=NC1C2CC3CC(C2)CC1C3
Agent: Cl
Product: CC(C)C(=O)C(Cc1ccccc1)NC(=O)NC1C2CC3CC(C2)CC1C3

Procedure:
This material was obtained in analogy to example 7, step A] from known 2-amino-4-methyl-1-phenyl-pentan-3-one hydrochloride (CAS 472995-82-7, see J. Heterocyclic Chem. 39 (2), 2002, 375-382, 249 mg) and 2-adamantyl isocyanate (194 mg). 1-Adamantan-2-yl-3-(1-benzyl-3-methyl-2-oxo-butyl)-urea was obtained as a white solid (245 mg). MS (ISP): 369.5 (MH+).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH3:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=1>CCO>[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH:18][C:2]2[CH:3]=[C:4]([CH3:11])[CH:5]=[CH:6][C:7]=2[N+:8]([O-:10])=[O:9])=[CH:15][CH:14]=1
Reactant: NCc1ccc(Br)cc1
Reactant: Cc1ccc([N+](=O)[O-])c(F)c1
Solvent: CCO
Product: Cc1ccc([N+](=O)[O-])c(NCc2ccc(Br)cc2)c1
Temperature: 25 °C
Yield: 72.6 %

Procedure:
To a solution of 3-fluoro-4-nitrotoluene (0.30 g, 1.93 mmol) in EtOH (18 ml) at rt under nitrogen was added 4-bromobenzylamine (0.36 g, 1.93 mmol) slowly. The reaction was warmed to reflux where it was maintained for 2 d. After this time, the mixture was cooled to rt and concentrated under reduced pressure. The crude product was partitioned between H2O and EtOAc and the organic phase was separated, washed with 5N HCl, dried (Na2SO4) and concentrated under reduced pressure to provide (4-bromo-benzyl)-(5-methyl-2-nitro-phenyl)-amine (0.45 g, 72%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=1>CN(C)C=O.O>[N+:30]([C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[CH2:23][NH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH:5]=[CH:6][CH:7]=1)([O-:32])=[O:31]
Reactant: CC(C)(C)OC(=O)Nc1cccc(N)c1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cccc(NCc2cccc([N+](=O)[O-])c2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.8 %

Procedure:
A solution of tert-butyl (3-aminophenyl)carbamate (0.51 g, 2.4 mmol) and potassium carbonate (0.61 g, 4.4 mmol) in N,N-dimethylformamide (7 mL) was treated with a solution of 1-(bromomethyl)-3-nitrobenzene (0.50 g, 2.3 mmol) in N,N-dimethylformamide (3 mL) and stirred at 25° C. for 16 h. The reaction mixture was diluted with water (80 mL) and extracted with ethyl acetate (3×75 mL). The combined organic layers were washed with water (3×50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to give a crude residue. This material was purified by flash column chromatography to give the desired product (0.78 g, 88% [90% pure]) as a solid. LCMS for C18H22N3O4 (M+H)+: m/z=344.2.
Reaction SMILES: [BH4-].[Na+].[CH:3]([Si:6]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[O:7][CH2:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=[O:14])([CH3:5])[CH3:4]>O1CCCC1.O>[CH:18]([Si:6]([CH:3]([CH3:5])[CH3:4])([CH:21]([CH3:23])[CH3:22])[O:7][CH2:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:13][OH:14])[CH:15]=[CH:16][CH:17]=1)([CH3:19])[CH3:20]
Reactant: CC(C)[Si](OCCc1cccc(C=O)c1)(C(C)C)C(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[Si](OCCc1cccc(CO)c1)(C(C)C)C(C)C
Yield: 99 %

Procedure:
Sodium borohydride (0.062 g, 1.63 mmol) was added to a mixture of 14 (0.500 g, 1.63 mmol) in tetrahydrofuran (4 mL) and water (0.25 mL). The reaction mixture was heated to reflux temperature for 2 h. After cooling, water was added and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue so obtained was dried under high vacuum to afford the desired compound as colorless oil. Yield: 99%.
Reaction SMILES: ClCCl.[Cl:4][C:5]1[C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([S:15]([N:18]3[CH2:23][CH2:22][CH:21](OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:20][CH2:19]3)(=[O:17])=[O:16])[C:9]=2[CH:8]=[CH:7][N:6]=1.[CH3:35][NH2:36]>CO>[Cl:4][C:5]1[C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([S:15]([N:18]3[CH2:23][CH2:22][CH:21]([NH:36][CH3:35])[CH2:20][CH2:19]3)(=[O:17])=[O:16])[C:9]=2[CH:8]=[CH:7][N:6]=1
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(S(=O)(=O)c3cccc4c(Cl)nccc34)CC2)cc1
Reactant: CN
Solvent: CO
Solvent: ClCCl
Product: CNC1CCN(S(=O)(=O)c2cccc3c(Cl)nccc23)CC1
Temperature: 70 °C
Yield: 71 %

Procedure:
To 50 ml of dichloromethane were added 4.0 g of the thus obtained 1-(1-chloro-5-isoquinolinesulfonyl)-4-p-toluenesulfonyloxypiperidine and 1 ml of a 40% methylamine solution in methanol. The mixture was heated at 70° C. for 6 hours in a sealed vessel. Then, the dichloromethane was removed under reduced pressure to obtain an oily residue. The thus obtained oily residue was subjected to purification by silica gel column chromatography (Wacogel C-200, 100 g; solvent: a 5% methanol solution in chloroform) to obtain 2.28 g of 1-(1-chloro-5-isoquinolinesulfonyl)-4-methylaminopiperidine [Compound (94)] in a yield of 71%. Compound (94) was analyzed to give the following data.
Reaction SMILES: Br[CH:2]1[CH2:8][NH:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]2[C:13]([CH3:16])=[N:14][N:15]=[C:3]12.[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:16][C:13]1[N:4]2[C:5]3[CH:12]=[CH:11][C:10]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:9][C:6]=3[NH:7][CH2:8][CH2:2][C:3]2=[N:15][N:14]=1
Reactant: Cc1nnc2n1-c1ccccc1NCC2Br
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nnc2n1-c1ccc(-c3ccccc3)cc1NCC2
Yield: 52.6 %

Procedure:
A solution of bromo-1-methyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine (30 mg, 0.11 mmol), phenylboronic acid (26 mg, 0.22 mmol), Tetrakis(triphenylphosphine)palladium(0) (10 mg) and Cs2CO3 (72 mg, 0.22 mmol) in dioxane (5 mL) and water (1 mL) was heated at 120° C. under microwave for 20 min. The reaction mixture was concentrated to give the crude product, which was purified by prep-TLC (DCM:MeOH=10:1) to afford 1-methyl-8-phenyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine (16 mg, yield 55%).
Reaction SMILES: C([Li])CCC.[S:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1.CON(C)[C:18](=[O:20])[CH3:19]>C1COCC1>[S:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:18](=[O:20])[CH3:19]
Reactant: c1ccc2scnc2c1
Reactant: CON(C)C(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)c1nc2ccccc2s1
Temperature: -78 °C
Reaction time: 3 h
Yield: 38.1 %

Procedure:
Butyllithium (10.2 mL, 16.3 mmol, 1.6 M, 1.1 Eq) was added dropwise to a stirred solution of benzothiazole (1.6 mL, 14.8 mmol, 1.0 Eq) in anhydrous THF (15 mL) at −78° C. under nitrogen. The resultant solution was stirred at −78° C. for one hour. N-Methoxy-N-methylacetamide (1.7 mL, 16.3 mmol, 1.1 Eq) was added in one portion and the reaction stirred at −78° C. for 3 hours. The resultant solution was allowed to warm to room temperature overnight. The reaction was quenched by the addition of 1M HCl (10 mL) and extracted with ethyl acetate (3×15 mL). The combined organic extracts were dried over solid MgSO4 and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (10% ethyl acetate in hexanes) to give the title compound as a yellow solid (1.0 g, 39% yield): 1H NMR (400 Mhz, CDCl3) δ 2.85 (3H, s), 7.54-7.62 (2H, m), 8.01 (1H, d), 8.21 (1H, d); MS: ES+ 178.0 (100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][N:14]2[CH:22]=[CH:23][CH:24]=[C:13]2[CH2:12]1)=[O:10].[H-].[Na+].CCCCCC.[NH:33]1[CH:37]=[CH:36][CH:35]=[N:34]1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([N:33]2[CH:37]=[CH:36][CH:35]=[N:34]2)[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][N:14]2[CH:22]=[CH:23][CH:24]=[C:13]2[CH2:12]1)=[O:10]
Reactant: O=C(c1ccc(F)cc1Cl)N1Cc2cccn2Cc2ccccc21
Reactant: c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: O=C(c1ccc(-n2cccn2)cc1Cl)N1Cc2cccn2Cc2ccccc21

Procedure:
In the manner of Example 9's Method 1, employing (2-chloro-4-fluorophenyl)-(5H, 11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (1.0 g), 60% sodium hydride in oil (0.2 g, degreased with hexane), pyrazole (0.20 g) and dimethylformamide (25 ml), the title compound was obtained as an amorphous solid, MS, m/z: 389.2 (M+H)+, 777.1 (2M+H)+.
Reaction SMILES: O([CH:8]=[CH:9][C:10](=[N:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C1C=CC=CC=1.[CH3:25][NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(#N)C>[CH3:25][N:26]([CH:8]=[CH:9][C:10](=[N:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[O:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: C(=CC(=Nc1ccccc1)Oc1ccccc1)Oc1ccccc1
Reactant: CNc1ccccc1
Solvent: CC#N
Product: CN(C=CC(=Nc1ccccc1)Oc1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 41.9 %

Procedure:
phenyl 3-(phenoxy)-N-phenylacrylimidate (0.39 g) was dissolved to acetonitrile (5 ml), and N-methylaniline (0.20 g) and catalytic amount of N,N-dimethylaminopyridine were added at room temperature. It was stirred for two hours at the same temperature and for eight hours under heat refluxing. It was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain phenyl 3-(N′-methyl-N′-phenylamino)-N-phenylacrylimidate (0.17 g) as light brown crystal.
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N:9]=2)=[O:7])=[CH:4][CH:3]=1.[N-:17]=[N+]=[N-].[Na+].O>CS(C)=O>[NH2:17][C:2]1[CH:16]=[CH:15][C:5]([CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N:9]=2)[OH:7])=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cccc(C(=O)c2ccc(F)cc2)n1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cccc(C(O)c2ccc(N)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.3 %

Procedure:
A solution of 2-(4-fluorobenzoyl)-6-methylpyridine (2.0 g) and sodium azide (3.36 g) in DMSO (40 ml) and the mixture was stirred for 24 hours at 90° C. To the reaction mixture was added water, and the mixture was extracted with diethylether. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and a solution of the residue (1.88 g) in THF (40 ml) was added dropwise to a suspension of aluminum lithium hydride (0.60 g) in. THF (20 ml) at 0° C. The mixture was stirred at room temperature for 30 minutes, and water (0.6 ml), 15% aqueous solution of sodium hydroxide (0.6 ml) and water (1.8 ml) were sequentially and slowly added dropwise to the solution at 0° C. The mixture was stirred at room temperature for 4 days, magnesium sulfate was added to the mixture, and the precipitates were removed by filtration (Celite). The reaction mixure was concentrated under reduced pressure, and the obtained residue was separated and purified by column chromatography (ethyl acetate), to give (4-aminophenyl)(6-methylpyridin-2-yl)methanol (1.44 g) as pale yellow crystals.