Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[OH:7][C@@:8]([CH3:16])([C:12]([F:15])([F:14])[F:13])[C:9](O)=[O:10].[Cl:17][C:18]1[CH:24]=[C:23]([S:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:22]=[CH:21][C:19]=1[NH2:20].C(OCC)(=O)C>ClCCl.CN(C=O)C>[Cl:17][C:18]1[CH:24]=[C:23]([S:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:22]=[CH:21][C:19]=1[NH:20][C:9](=[O:10])[C@:8]([OH:7])([CH3:16])[C:12]([F:15])([F:14])[F:13]
Reactant: Nc1ccc(Sc2ccccc2)cc1Cl
Reactant: C[C@@](O)(C(=O)O)C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@](O)(C(=O)Nc1ccc(Sc2ccccc2)cc1Cl)C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 67.1 %

Procedure:
Oxalyl chloride (0.063 ml) was added to a stirred suspension of (R)-(+)-2-hydroxy-2-methyl-3,3,3-trifluoropropanoic acid (Method 9) (0.106 g) in dichloromethane (2 ml) containing DMF (1 drop). The mixture was stirred at ambient temperature for 90 minutes and was then added to a solution of 2-chloro-4-phenylthioaniline (Method 11) (0.143 g) in dichloromethane (4 ml) and stirred a further 3 hours. Ethyl acetate (30 ml) was added and the mixture was washed with water (2×30 ml) and brine then dried. Volatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column eluting with 15% ethyl acetate/hexane to give the title compound (0.153 g) as a gum. NMR: 1.57 (s, 3H), 7.26-7.41 (m, 6H), 7.44 (d, 1H), 7.82 (s, 1H), 7.95 (d, 1H), 9.74 (s, 1H); MS: 374 (M−H)−.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:15]=[CH:14][C:6]([C:7]([NH:9][CH2:10][C:11]([OH:13])=O)=[O:8])=[CH:5][C:4]=1[N+:16]([O-:18])=[O:17].[CH3:19][NH:20][CH3:21].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1.CN(C=O)C>[CH3:19][N:20]([CH3:21])[C:11]([CH2:10][NH:9][C:7](=[O:8])[C:6]1[CH:14]=[CH:15][C:3]([NH:2][CH3:1])=[C:4]([N+:16]([O-:18])=[O:17])[CH:5]=1)=[O:13]
Reactant: CNC
Reactant: CNc1ccc(C(=O)NCC(=O)O)cc1[N+](=O)[O-]
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CNc1ccc(C(=O)NCC(=O)N(C)C)cc1[N+](=O)[O-]

Procedure:
N-Dimethylcarbamoylmethyl-4-methylamino-3-nitro-benzamide (800 mg) was prepared by following General Procedure F starting from (4-methylamino-3-nitro-benzoylamino)-acetic acid (800 mg), 2 M dimethylamine in THF (3 mL), HBTU (1.5 g), and DIEA (1.3 mL) in DMF (2 mL).
Reaction SMILES: [OH:1][C:2]1([C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[CH:15]([C@:18]1([C:24]([N:26]2[CH2:35][CH2:34][C:33]3[C:28](=[CH:29][C:30]([C:36]([F:39])([F:38])[F:37])=[CH:31][CH:32]=3)[CH2:27]2)=[O:25])[CH2:22][CH2:21][C@@H:20]([NH2:23])[CH2:19]1)([CH3:17])[CH3:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:15]([C@:18]1([C:24]([N:26]2[CH2:35][CH2:34][C:33]3[C:28](=[CH:29][C:30]([C:36]([F:39])([F:37])[F:38])=[CH:31][CH:32]=3)[CH2:27]2)=[O:25])[CH2:22][CH2:21][C@@H:20]([NH:23][CH:5]2[CH2:6][CH2:7][C:2]([C:9]3[N:14]=[CH:13][CH:12]=[CH:11][N:10]=3)([OH:1])[CH2:3][CH2:4]2)[CH2:19]1)([CH3:17])[CH3:16]
Reactant: O=C1CCC(O)(c2ncccn2)CC1
Reactant: CC(C)[C@]1(C(=O)N2CCc3ccc(C(F)(F)F)cc3C2)CC[C@@H](N)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)[C@]1(C(=O)N2CCc3ccc(C(F)(F)F)cc3C2)CC[C@@H](NC2CCC(O)(c3ncccn3)CC2)C1
Reaction time: 8 h

Procedure:
To a solution of 4-hydroxy-4-pyrimidin-2-yl-cyclohexanone (59.8 mg, 0.31 mmol) and (1R,3S)-3-isopropyl-3-{[7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}cyclopentanamine (110 mg, 0.31 mmol) of Step C-2 of Example 1 in CH2Cl2(10 mL) was added sodium triacetoxyborohydride (131 mg, 0.62 mmol). After being stirred overnight, more sodium triacetoxyborohydride was added to bring the equivalents of the reducing agent to 5 equivalents. After stirring for another 5 hrs, the reaction was quenched with aqueous NaOH. The resulting solution was extracted with EtOAc three times. The combined extracts were dried over MgSO4 and concentrated. Purification by flash chromatography followed by HPLC gave two isomers. Isomer 1 and isomer 2: MS calculated for C29H37F3N4O2: (M+H)+531; found 531.1.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH:7]([CH2:12][C:13]([OH:15])=[O:14])[C:8]2=[O:11])=[CH:4][CH:3]=1.CO.O1CCCC1.[BH4-].[Na+]>O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH:7]([CH2:12][C:13]([OH:15])=[O:14])[CH:8]2[OH:11])=[CH:4][CH:3]=1
Reactant: O=C(O)CC1Cc2ccc(Br)cc2C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)CC1Cc2ccc(Br)cc2C1O
Reaction time: 0.75 h

Procedure:
6-Bromo-2-carboxymethyl-1-indanone (139 g, 650 mmol), methanol (1100 mL), and tetrahydrofuran (200 mL) were stirred at 0° C. Sodium borohydride (9.30 g, 245 mmol) was added in portions over 45 minutes and stirred another 45 minutes. More sodium borohydride (12.4 g, 326 mmol) was added in portions over 45 minutes and stirred another 60 minutes. Water was added and the solvent was removed under vacuum at 35° C. The residue was partitioned between diethyl ether and water. The organic layer was washed with water and brine and then dried over sodium sulfate. Flash chromatography of the crude product on a 30×7 cm silica gel column, eluting with dichloromethane/ethyl acetate/hexane (1:2:5), yielded an orange wax (99.6 g, 57%). 1H-NMR (300 MHz, CDCl3) (a ratio of approximately 1:1 cis to trans diastereomers) 7.55 (s, 0.43H), 7.51 (s, 0.57H), 7.39 (t, 0.57H, J=8.1), 7.39 (t, 0.43H, J=8.1), 7.13 (d, 0.43H, J=8.1), 7.08 (d, 0.57H, J=8.1), 5.44 (d, 0.57H, J=6.9), 5.30 (d, 0.43H, J=6.0), 3.79 (s, 1.71H), 3.77 (s, 1.29H), 3.45-2.95 (m, 3H), 2.87 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:11]2[CH:15]3[CH2:16][CH2:17][CH:12]2[CH2:13][CH2:14]3)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH3:18][N:19]([CH3:23])[CH2:20][C:21]#[CH:22]>CN(C=O)C.C(N(CC)CC)C.C(OCC)(=O)C.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>[CH:15]12[N:11]([C:4]3[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([C:22]#[C:21][CH2:20][N:19]([CH3:23])[CH3:18])[CH:3]=3)[CH:12]([CH2:17][CH2:16]1)[CH2:13][CH2:14]2
Reactant: O=[N+]([O-])c1ccc(N2C3CCC2CC3)cc1Br
Reactant: C#CCN(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)CC#Cc1cc(N2C3CCC2CC3)ccc1[N+](=O)[O-]
Yield: 79.4 %

Procedure:
To 7-(3-bromo-4-nitro-phenyl)-7-azabicyclo[2.2.1]heptane 25 (500 mg, 1.683 mmol), Pd(PPh3)2Cl2 (59 mg, 0.08 mmol), and cuprous iodide (9.616 mg, 1.708 μL, 0.05049 mmol) was added a solution of N,N-dimethylprop-2-yn-1-amine (420 mg, 538 μL, 5.05 mmol) in degassed DMF (5 mL) and triethylamine (5 mL). The reaction mixture was microwaved under N2 for 10 min at 100° C. The reaction was diluted with ethyl acetate, washed with 50% saturated sodium bicarbonate solution (2×20 mL), water, and brine. The solution was dried over anhydrous Na2SO4 and filtered, leaving a red solid. Purification by silica gel chromatography (0-50% dichloromethane in ethyl acetate) yielded 3-[5-(7-azabicyclo[2.2.1]heptan-7-yl)-2-nitro-phenyl]-N,N-dimethyl-prop-2-yn-1-amine 26 (400 mg, 79% yield). LC/MS m/z 300.5 [M+H]+, retention time 1.11 min (RP-C18, 10-99% CH3CN/0.05% TFA over 3 min).
Reaction SMILES: [H-].[Na+].Cl[C:4]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][CH2:5]1.CCO[CH2:21][CH3:22].[CH3:23][N:24]([CH:26]=[O:27])[CH3:25]>>[CH3:23][N:24]([CH3:25])[C:26]([C:9]1[C:21]2[C:22](=[CH:17][CH:12]=[CH:13][C:14]=2[O:11][CH2:10][C:7]2[CH:8]=[CH:9][C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:5][CH:6]=2)[CH:6]=[CH:5][CH:4]=1)=[O:27]
Reactant: CN(C)C=O
Reactant: CCOCC
Reactant: OCC1=CCC(Cl)(c2ccccc2)C=C1
Agent: [H-]
Agent: [Na+]
Product: CN(C)C(=O)c1cccc2cccc(OCc3ccc(-c4ccccc4)cc3)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 8-hydroxynaphthalene-1-(N,N-dimethyl)carboxamide (68 mg, 0.32 mmol) in dry DMF (4 mL) was added sodium hydride (8 mg, 0.35 mmol, 1.1 eq). The sodium hydride was added as 14 mg of a 60% dispersion in mineral oil that had been previously washed with 3×heptane portions under an inert atmosphere. The mixture was stirred for 30 minutes at room temperature and 1-chloro-(4-biphenyl)methanol (71 mg, 0.35 mmol, 1.1 eq) was added. The resulting mixture was stirred at room temperature overnight. The reaction mixture was poured onto ice/water (100 mL), and the aqueous-DMF layer was extracted into ethyl acetate portions. The combined organic layers were washed (brine), dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by column chromatography (silica gel, eluant:ethyl acetate/heptane mixtures) to give the desired ether (yield: 99 mg, 0.25 mmol, 79%);
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:21])[NH:10][C@H:11]([C:16]1[N:17]=[N:18][NH:19][N:20]=1)[C:12]([CH3:15])([CH3:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH2:1]([O:8][C:9](=[O:21])[NH:10][C@H:11]([C:16]1[N:20]=[N:19][N:18]([CH3:22])[N:17]=1)[C:12]([CH3:15])([CH3:14])[CH3:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)[C@H](NC(=O)OCc1ccccc1)c1nn[nH]n1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: Cn1nnc([C@@H](NC(=O)OCc2ccccc2)C(C)(C)C)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 68.3 %

Procedure:
A suspension of benzyl[(1S)-2,2-dimethyl-1-(2H-tetrazol-5-yl)propyl]carbamate (0.41 g, 1.4 mmol), potassium carbonate (1.0 g, 7.0 mmol) and methyl iodide (0.35 mL, 5.6 mmol) in acetone (7 mL) was stirred at 0° C. for 10 min and warmed to rt. After 5 h, the reaction mixture was filtered and concentrated. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (8/1-4/1-1/1) to afford 0.29 g (68%) of the title compound.
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1.O>C(O)C.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.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>[F:20][C:21]([F:32])([F:31])[C:22]1[CH:27]=[C:26]([C:2]2[C:12]3[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
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: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2-c2cccc(C(F)(F)F)c2)C1
Yield: 88.2 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (200 mg, 0.605 mmol), a solution of 3-trifluoromethylphenylboronic acid (173 mg, 0.912 mmol) in ethanol (0.7 ml), 2N aqueous sodium carbonate solution (2.5 ml), and tetrakis(triphenylphosphine)palladium(0) (84.0 mg, 0.0730 mmol) in toluene (5 ml) was stirred under a nitrogen atmosphere at 95° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product (210 mg, 88.2%) as an oil.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:6]#[N:7].CO.[H][H]>[Pd]>[F:1][C:2]([F:15])([F:16])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:12])[F:13])[CH:10]=1)[CH2:6][NH2:7]
Reactant: N#Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 87 %

Procedure:
At first, a 1-liter autoclave equipped with a mechanical stirrer was charged with 50 g (0.21 mol) of 3,5-bis(trifluoromethyl)benzonitrile, 200 ml of 2M-ammoniacal methanol solution (containing 400 mmol of ammonia), and 3 g of a catalyst (i.e., a carbon powder (50% wet) carrying thereon 5% palladium), followed by introduction of hydrogen to have a pressure of 1 MPa. Then, the reaction mixture was stirred, while the reaction temperature was maintained at 20° C. and while hydrogen was gradually introduced into the autoclave in a manner to maintain the total pressure at 1 MPa. After conducting the reaction for 5.3 hr, the reaction was stopped, followed by removing the catalyst by filtration. As a result of analyzing the obtained reaction liquid by gas chromatography, 3,5-bis(trifluoromethyl)benzylamine was formed at a yield of 87.0%.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:9]([CH2:18][C:19]3[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][C:20]=3[O:27][CH:28]([CH3:30])[CH3:29])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[C:34]([F:45])[CH:33]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(OCC)(=O)C>[C:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:9]([CH2:18][C:19]3[CH:26]=[CH:25][C:22]([CH2:23][NH:31][C:32]4[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[C:34]([F:45])[CH:33]=4)=[CH:21][C:20]=3[O:27][CH:28]([CH3:30])[CH3:29])[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCc1ccc(N)cc1F
Reactant: CC(C)Oc1cc(C=O)ccc1Cn1nc(-c2ccccc2)cc1-c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCOC(=O)CCc1ccc(NCc2ccc(Cn3nc(-c4ccccc4)cc3-c3ccccc3)c(OC(C)C)c2)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
To a solution of 4-[(3,5-diphenyl-1H-pyrazol-1-yl)methyl]-3-isopropoxybenzaldehyde (0.38 g, 0.95 mmol) and ethyl 3-(4-amino-2-fluorophenyl)propanoate (0.20 g, 0.95 mmol) in 1,2-dichloroethane (7.0 mL) was added acetic acid (0.16 mL, 2.86 mmol) and the mixture was stirred at room temperature for 3 hr. Sodium triacetoxyborohydride (0.61 g, 2.86 mmol) was added, and the mixture was further stirred for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1-hexane/ethyl acetate=1/1) to give the title compound (0.52 g, yield 92%) as a colorless oil.
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:22])([CH3:21])[CH2:4][CH2:5][C:6]1[CH:20]=[CH:19][C:9]([O:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)=[CH:8][CH:7]=1.C(=O)([O-])[O-:24].[K+].[K+].OO.O>CS(C)=O>[NH2:2][C:3]([CH3:22])([CH3:21])[CH2:4][CH2:5][C:6]1[CH:20]=[CH:19][C:9]([O:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]([NH2:16])=[O:24])=[CH:13][CH:12]=2)=[CH:8][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(N)CCc1ccc(Oc2ccc(C#N)cc2)cc1
Agent: Cl
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(N)CCc1ccc(Oc2ccc(C(N)=O)cc2)cc1
Reaction time: 0.17 h
Yield: 9.3 %

Procedure:
4-(4-(3-Amino-3-methylbutyl)phenoxy)benzonitrile hydrochloride (1.04 g, 32.8 mmol) was dissolved in DMSO (30 ml) and treated with potassium carbonate (0.68 g, 49.2 mmol, 1.5 eq.) with stirring. After 10 minutes, hydrogen peroxide (7 ml, 30% aqueous solution) was added dropwise slowly. The mixture was allowed to stir for 16 hours and then added to 300 ml of water, causing a white precipitate. The material was filtered and dried to give a white solid (908 mg, 93%). NMR, MS
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:12]1[O:14][C@H:13]1[CH2:15]Cl.ClCCl.CCCCCC>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@:9]2([C:10]#[N:11])[CH2:15][CH:13]2[CH2:12][OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Reactant: ClC[C@H]1CO1
Solvent: CCCCCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: N#C[C@@]1(c2ccc(Cl)c(Cl)c2)CC1CO
Temperature: -25 °C
Yield: 64.2 %

Procedure:
3,4-Dichlorophenyl acetonitrile (40 g, 215 mmole) was dissolved in dry tetrahydrofuran (THF, 350mL) under nitrogen atmosphere, The solution was cooled to −25° C. and soda amide (8.3 g, 215 mmol) was added portion wise maintaining the temperature of the reaction mass −25° C. The reaction mixture was allowed to warm to room temperature and maintained for 2 hours. It was then cooled to −25° C. A solution of R-(−) epichlorohydrin (19.89 g, 215 mmol) in tetrahydrofuran (50 mL) was added drop wise at −25° C. followed by the portion wise addition of soda amide (8.3 g, 250 mmol). The temperature of the reaction mass was then gradually raised to room temperature over a period of 8 hours. The reaction was monitored by TLC (dichloromethane/hexane (1:1)). The reaction mass was quenched with saturated ammonium chloride solution. The aqueous layer was extracted with ethyl acetate (3×500 mL).The combined organic layer was dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to yield 58 g of crude oil. The crude oil was purified by column chromatography (silica gel, dichloromethane/hexane (9:1) to yield 33.4 g (64%) of product. 1H NMR δ(300 MHz,CDCl3): 1.59-1.67 (3H,m), 1.88-1.97 (1H,m), 3.72-3.79 (1H,m), 4.06-4.12 (1H,m), 7.13-7.17 (1H,m) 7.39-7.52 (2H,m).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[N:21]=[C:20]3[C:16]([N:17]=[CH:18][N:19]3[C@@H:22]3[CH2:26][C@H:25]([NH:27][C:28](=[O:31])[CH2:29][CH3:30])[C@@H:24]([OH:32])[C@H:23]3[OH:33])=[C:15]([NH:34][CH2:35][CH:36]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:14]=2)[CH2:9]1)(C)(C)C.[ClH:50]>CO>[ClH:50].[ClH:50].[NH2:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[N:21]=[C:20]3[C:16]([N:17]=[CH:18][N:19]3[C@@H:22]3[CH2:26][C@H:25]([NH:27][C:28](=[O:31])[CH2:29][CH3:30])[C@@H:24]([OH:32])[C@H:23]3[OH:33])=[C:15]([NH:34][CH2:35][CH:36]([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:14]=2)[CH2:9]1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)OC(C)(C)C)C4)nc32)[C@H](O)[C@@H]1O
Agent: Cl
Solvent: CO
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](N)C4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
{(R)-1-[9-((1R,2S,3R,4S)-2,3-Dihydroxy-4-propionylamino-cyclopentyl)-6-(2,2-diphenyl-ethylamino)-9H-purin-2-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (ca 4.80 mmol) is dissolved in 1.25 M HCl in MeOH (60 mL). After stirring at RT for 3 days, the solvent is removed in vacuo to yield the title compound as a brown solid. This is used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:24])[C:5]2[C:13]3[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=3[N:7]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[CH3:22])[C:6]=2[N:23]=1.[C:25](Cl)(=[O:28])[CH2:26][CH3:27]>ClC(Cl)C>[C:25]([N:24]([C:25](=[O:28])[CH2:26][CH3:27])[C:4]1[C:5]2[C:13]3[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=3[N:7]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[CH3:22])[C:6]=2[N:23]=[C:2]([CH3:1])[CH:3]=1)(=[O:28])[CH2:26][CH3:27]
Reactant: CCC(=O)Cl
Reactant: Cc1cc(C)c(-n2c3c(c4c(N)cc(C)nc42)CCCC3)c(C)c1
Solvent: CC(Cl)Cl
Product: CCC(=O)N(C(=O)CC)c1cc(C)nc2c1c1c(n2-c2c(C)cc(C)cc2C)CCCC1

Procedure:
2-Methyl-6,7,8,9-tetrahydro-9-(2,4,6-trimethylphenyl)-5H-pyrido[2,3-b]indol-4-amine (1b) (470 mg) dissolved in 10 mL dichloroethane is refluxed for 3 hours with propionyl chloride (0.5 mL). The residual reagents are evaporated under reduced pressure. The crude product is partitioned between aqueous sodium carbonate solution and dichloromethane. The organic extract is dried over sodium sulfate and concentrated. The solid, diacylated product is triturated with hexanes and collected by filtration to afford N,N-Dipropionyl-2-methyl-6,7,8,9-tetrahydro-9-(2,4,6-trimethyl phenyl)-5H-pyrido[2,3-b]indol-4-amine 1c as white solid.
Reaction SMILES: [CH3:1][C:2]1([OH:15])[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7]SC1C=CC=CC=1.C([O-])(O)=O.[Na+].[CH:21]1[CH:26]=[C:25](Cl)[CH:24]=[C:23](C(OO)=O)[CH:22]=1.[O-:32][S:33]([O-:36])(=S)=O.[Na+].[Na+]>C(Cl)Cl.O>[C:25]1([S:33]([CH2:7][CH:3]2[CH2:4][CH2:5][CH2:6][C:2]2([CH3:1])[OH:15])(=[O:36])=[O:32])[CH:24]=[CH:23][CH:22]=[CH:21][CH:26]=1
Reactant: O=S([O-])([O-])=S
Reactant: CC1(O)CCCC1CSc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC1(O)CCCC1CS(=O)(=O)c1ccccc1
Reaction time: 0.33 h

Procedure:
To a mixture of 9a (1.84 g, 8.28 mmol) and NaHCO3 (2.45 g, 29.2 mmol) in a mixture of CH2Cl2 (40mL) and water (17 mL) was added mCPBA (85%, 3.36 g, 16.5 mmol) in portionwise with stirring vigorously in an ice bath. The mixture 19 was stirred for 15 min. To the mixture were added water (16 mL), NaHCO3 (2.45 g) and mCPBA (1.68 g), and stirring was continued for 20 min. The excess amount of peracid was decomposed with Na2S2O3 solution in the presence of a catalytic mount of KI. The organic layer was separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with NaCl solution, and dried over Na2SO4. Filtration and concentration gave 2.69 g of 10a, as white solids, which was used in the next reaction without further purification.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([NH:19][S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:22])=[O:21])([C:6]1[N:10]([CH3:11])[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[N:8][N:7]=1)[CH3:5].[CH3:29]I>CN(C=O)C.O>[CH3:29][N:19]([C:4]([CH3:3])([C:6]1[N:10]([CH3:11])[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[N:8][N:7]=1)[CH3:5])[S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:22])=[O:21]
Reactant: CI
Reactant: Cc1ccccc1-c1nnc(C(C)(C)NS(=O)(=O)c2ccccc2)n1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1-c1nnc(C(C)(C)N(C)S(=O)(=O)c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 7 h

Procedure:
Sodium hydride (55% oily, 13 mg) was suspended in DMF (2 ml) and then N-{1-methyl-1-[4-methyl-5-(2-methylphenyl)-1,2,4-triazol-3-yl]ethyl}benzensulfonamide (100 mg) and methyl iodide (0.017 ml) were added thereto under ice cooling, followed by stirring at room temperature for 7 hours. The reaction solution was diluted with water (30 ml) and then extracted with chloroform (15 ml×2). The organic layer was dried over anhydrous sodium sulfate and filtered and then the solvent was removed by evaporation under reduced pressure. The resulting solid washed with diethyl ether to obtain 81 mg of N-methyl-N-{1-methyl-1-[4-methyl-5-(2-methylphenyl)-1,2,4-triazol-3-yl]ethyl}benzensulfonamide (white solid).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10]#[N:11])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[CH3:24][O:25][CH2:26][CH2:27][Br:28]>>[Br-:28].[C:10]([C:9]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:4]12[CH2:5][CH2:6][N+:1]([CH2:27][CH2:26][O:25][CH3:24])([CH2:2][CH2:3]1)[CH2:8][CH2:7]2)#[N:11]
Reactant: N#CC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Reactant: COCCBr
Product: COCC[N+]12CCC(C(C#N)(c3ccccc3)c3ccccc3)(CC1)CC2
Product: [Br-]
Yield: 23.3 %

Procedure:
Following the general procedure outlined in Example 7, 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)acetonitrile (0.0497 g, 0.164 mmol) and 2-bromoethyl methyl ether (0.030 mL, 0.319 mmol) in 2CH3CN/3CHCl3 (4.0 mL) were reacted to give the desired product (0.0169 g, 23.3%). EI-MS m/z 361(M+) Rt (1.84 min).