Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:11]1[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Br:24]N1C(=O)CCC1=O>ClCCl>[Br:24][C:16]1[C:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:11]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:12]=2[CH:13]=[CH:14][CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCCCCCCn1c2ccccc2c2ccccc21
Solvent: ClCCl
Product: CCCCCCCCCCn1c2ccccc2c2c(Br)cccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.7 %

Procedure:
To a solution of 9-decylcarbazole 15 (3.0 g, 10 mmol) in dichloromethane (90 mL) was added N-bromosuccinimide (1.80 g, 10.1 mmol) at 0° C. in portions. The mixture was warmed to room temperature and stirred overnight. After removal of the solvent, the residue was purified by silica gel column chromatography using petroleum ether/dichloromethane as eluent affording the desired product (3.35 g, 87%). 1H NMR (400 MHz, CDCl3, δ) 8.19 (d, J=1.6 Hz, 1H), 8.04 (d, J=8.0 Hz, 1H), 7.53-7.45 (m, 2H), 7.39 (d, J=8.0 Hz, 1H), 7.24-7.20 (m, 2H), 4.26 (t, J=7.2 Hz, 2H), 1.86-1.79 (m, 2H), 1.30-1.22 (m, 2H), 0.88 (t, J=6.4 Hz, 3H). 13C NMR (100 MHz, CDCl3, δ) 140.7, 139.0, 128.2, 126.3, 124.5, 123.0, 121.8, 120.5, 119.1, 111.5, 110.1, 108.9, 43.2, 31.8, 29.5, 29.4, 29.3, 29.2, 28.9, 27.2, 22.6, 14.1. MS (MALDI-TOF): m/z 387.0912 (M+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[CH2:9][S:8][CH2:7]1.[ClH:12].Cl.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>CC#N>[ClH:12].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([N:22]2[CH2:27][CH2:26][N:25]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:10](=[O:11])[CH2:9][S:8][CH2:7]3)[CH2:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1
Reactant: O=C1CSCN1CCCCBr
Reactant: COc1cccc(N2CCNCC2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: COc1cccc(N2CCN(CCCCN3CSCC3=O)CC2)c1

Procedure:
To a solution of 3-(4-bromobutyl)-4-thiazolidinone (3.0 g) and 1-(3-methoxyphenyl)piperazine dihydrochloride (3.34 g) in 100 ml of anhydrous CH3CN were added K2CO3 (8.7 g) and NaI (200 mg). The mixture was heated to 80° with stirring under N2.
Reaction SMILES: N[C@H](C(O)=O)CC1C=CC([OH:10])=CC=1.[NH2:14][C@H:15]([C:26]([OH:28])=[O:27])[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1>>[OH:10][C:23]1[CH:24]=[C:25]2[C:20]([NH:19][CH:18]=[C:17]2[CH2:16][C@@H:15]([C:26]([OH:28])=[O:27])[NH2:14])=[CH:21][CH:22]=1
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Product: N[C@@H](Cc1c[nH]c2ccc(O)cc12)C(=O)O

Procedure:
The process is conducted as described in the foregoing Example 6, except that instead of tyrosine 0.21 g of tryptophane is used, the reaction medium pH is 4.0. 0.105 g of 5-hydroxytryptophan is obtained (50% as calculated for the starting compound) having melting point of 287°-288° C. The composition, in percent, is as follows:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11](C=O)[CH2:10][CH2:9][C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7][C:6]=2[CH:19]=1.C(=O)([O-])O.[Na+]>Cl.C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH2:10][CH2:9][C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7][C:6]=2[CH:19]=1
Reactant: CCOC(=O)C1=Cc2cc(Br)ccc2N(C=O)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1=Cc2cc(Br)ccc2NCC1
Yield: 59 %

Procedure:
In 1N hydrochloric acid (25 ml) and ethanol (20 ml) was dissolved ethyl 7-bromo-1-formyl-2,3-dihydro-1-benzazepine-4-carboxylate (1165 mg), and the mixture was refluxed for 2 hours. The mixture was neutralized with saturated sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate (300 ml). The organic layer was washed with water (100 ml) and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (150 g, hexane/ethyl acetate=9:1) to give ethyl 7-bromo-2,3-dihydro-1-benzazepine-4-carboxylate (628 mg, 59%).
Reaction SMILES: B.O1CCCC1.[C:7]([N:14]1[CH2:22][CH2:21][CH2:20][C@@H:16]([C:17](O)=[O:18])[CH2:15]1)([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[OH-].[Na+]>C1COCC1>[OH:18][CH2:17][C@@H:16]1[CH2:20][CH2:21][CH2:22][N:14]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)O)C1
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](CO)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.2 %

Procedure:
Borane-tetrahydrofuran complex (1M in THF) (65.4 ml, 65.4 mmol, 3 eq) is added dropwise to a solution of (R)-(−)-N-Boc-nipecotic acid (5 g, 21.8 mmol, 1 eq) in THF (50 ml) and this is stirred at room temperature for 16 hours. The solution is cooled to 0° C. and carefully hydrolysed with 2N aqueous sodium hydroxide (250 ml) the resulting mixture is then heated for 48 hrs. The mixture is cooled to 0° C. and extracted with diethyl ether (3×100 ml). The organic layers are combined, washed with brine (100 ml), dried over magnesium sulphate, filtered and concentrated in vacuo. The residue is purified by flash chromatography, eluting with 50-70% ethyl acetate in iso-hexane to give the tert-butyl (3R)-3-(hydroxymethyl)piperidine-1-carboxylate (4.56 g, 98%). 1H NMR (300 MHz, CDCl3) δH: 4.0-2.7 (6H, br m), 2.17-1.19 (5H, br m) 1.46 (9H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:30](=[O:31])[N:29]([CH3:32])[C:12]2[N:13]([CH3:28])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[CH:24]=[C:23]([CH2:25][OH:26])[N:22]([CH3:27])[N:21]=1)=[CH:16][CH:15]=3.I[CH2:34][CH3:35]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:30](=[O:31])[N:29]([CH3:32])[C:12]2[N:13]([CH3:28])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[CH:24]=[C:23]([CH2:25][O:26][CH2:34][CH3:35])[N:22]([CH3:27])[N:21]=1)=[CH:16][CH:15]=3
Reactant: CCI
Reactant: Cn1nc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)cc1CO
Product: CCOCc1cc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)nn1C

Procedure:
The process is carried out as in Example 101 above, with the compound from Example 82, 3-(2,4-dichlorophenyl)-6-(5-hydroxymethyl-1-methyl-1H-pyrazol-3-yl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and iodoethane.
Reaction SMILES: C1COCC1.[Cl:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=O)[CH:11]([C:18]([N:20]([CH3:22])[CH3:21])=O)[CH2:10]2.Cl>O>[Cl:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH2:12][CH:11]([CH2:18][N:20]([CH3:22])[CH3:21])[CH2:10]2
Reactant: CN(C)C(=O)C1Cc2cc(Cl)ccc2NC1=O
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CN(C)CC1CNc2ccc(Cl)cc2C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 75.4 %

Procedure:
1M Borane/THF complex (33 ml) was added to a THF (300 ml) suspension of 6-chloro-N,N-dimethyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinecarboxamide (2.135 g). The reaction mixture was heated under reflux for 6 hours, and left standing for cooling. The reaction mixture was ice-cooled, to which was added water (5 ml) and 6N hydrochloric acid (30 ml). The mixture was stirred at room temperature for 15 hours, then concentrated. 3N aqueous sodium hydroxide solution was added to the residue to make basic, which was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, then dried and concentrated. The residue was purified by alumina column chromatography (eluent: ethyl acetate/hexane=1/4). The obtained crude crystals were washed with hexane to obtain the entitled compound (1.432 g).
Reaction SMILES: COC([N:5]1[CH2:9][CH:8]([C:10]2[C:18]3[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH:7]2[N:20]([C:23](=[O:39])[CH:24]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:21][CH2:22][CH:6]12)=O.CCN(C(C)C)C(C)C.[CH3:49][S:50](Cl)(=[O:52])=[O:51]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:35]([O:34][C:32](=[O:33])[NH:31][CH:24]([CH:25]1[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1)[C:23]([N:20]1[CH2:21][CH2:22][CH:6]2[N:5]([S:50]([CH3:49])(=[O:52])=[O:51])[CH2:9][CH:8]([C:10]3[C:18]4[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=4)[NH:12][CH:11]=3)[CH:7]12)=[O:39])([CH3:38])([CH3:37])[CH3:36]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)N1CC(c2c[nH]c3cc(F)ccc23)C2C1CCN2C(=O)C(NC(=O)OC(C)(C)C)C1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(C(=O)N1CCC2C1C(c1c[nH]c3cc(F)ccc13)CN2S(C)(=O)=O)C1CCCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 49.4 %

Procedure:
A solution containing 50 (200 mg, 0.41 mmol) and DIPEA (163 mg, 1.26 mmol) in anhydrous DCM (5 mL) was cooled to 0° C. A solution of MsCl (44 mg, 0.41 mmol) in DCM (0.5 mL) was added followed by the addition of DMAP (5 mg, cat.). After 2 h, the reaction mixture was diluted with DCM and washed successively with 1M HCl and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash silica gel chromatography (1:1 hexanes/EtOAc) to afford 114 mg (49%) of 61 as a white solid. Mass spectrum, m/z [563] (M+H)+.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[CH:12]=[CH:13][C:14](=[O:17])[NH:15][CH:16]=3)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[H][H]>C(OCC)(=O)C.[Pd]>[O:4]1[C:5]2([CH2:6][CH2:7][CH:8]([C:11]3[CH:12]=[CH:13][C:14](=[O:17])[NH:15][CH:16]=3)[CH2:9][CH2:10]2)[O:1][CH2:2][CH2:3]1
Reactant: O=c1ccc(C2=CCC3(CC2)OCCO3)c[nH]1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=c1ccc(C2CCC3(CC2)OCCO3)c[nH]1
Reaction time: 2 h

Procedure:
5-(1,4-Dioxa-spiro[4.5]dec-7-en-8-yl)-1H-pyridin-2-one from Step A of Example 37 (5.2 g, 22.1 mmol) in ethyl acetate (30 mL) was treated with 5% Pd/C (Aldrich, 2.6 g) at room temperature. The reaction mixture was then charged with a hydrogen balloon and stirred for 2 hours. The catalyst was removed by filtering the reaction through a pad of Celite. The filtrate was concentrated to give the crude product, which was then purified with a CombiFlash® system using silica gel column and 40% ethyl acetate in hexanes as eluent to give the title compound as a white solid.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.O1CCC[CH2:16]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.CCCCCC.C(OCC)(=O)C>[CH2:16]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C=C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To a solution of 986 mg of methyltriphenylphosphonium bromide in 20 ml of tetrahydrofuran, 1.87 ml of 1.63 M n-butyl lithium/hexane solution was added dropwise at 0° C., under cooling with ice. The temperature then was immediately raised to room temperature, and the system was stirred for 50 minutes. The reaction liquid was again cooled to 0° C., to which a solution of 500 mg of t-butyl 4-oxotetrahydropyridine-1(2H)-carboxylate in 5 ml of tetrahydrofuran was added dropwise, followed by an hour's stirring at the same temperature. The reaction liquid was diluted with ethyl acetate, washed successively with saturated aqueous ammonium chloride solution and saturated brine, and dried over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, the resulting residue was purified on silica gel column chromatography (eluent: hexane/ethyl acetate=5/1) to provide 192 mg of the title compound.
Reaction SMILES: [CH:1]12[CH2:13][CH2:12][CH:8]([CH2:9][NH:10][CH2:11]1)[C:7]1[C:2]2=[CH:3][C:4]([NH2:14])=[CH:5][CH:6]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:22][C:23]#[N:24]>CC(C)=O>[NH2:14][C:4]1[CH:3]=[C:2]2[C:7](=[CH:6][CH:5]=1)[CH:8]1[CH2:12][CH2:13][CH:1]2[CH2:11][N:10]([CH2:22][C:23]#[N:24])[CH2:9]1
Reactant: Nc1ccc2c(c1)C1CCC2CNC1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: N#CCN1CC2CCC(C1)c1cc(N)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.1 %

Procedure:
10-Aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamine (193 mg, 1.02 mmol) was dissolved in acetone (20 mL) and Cs2CO3 (994 mg, 3.06 mmol, 3.0 eq) and bromoacetonitrile (134 mg, 1.13 mmol, 91 μL, 1.1 eq) were added. The reaction was stirred at room temperature for 2 hours and was then concentrated under reduced pressure. The residue was taken up in CH2Cl2 (10 mL) and washed with water (10 mL). The organic layer was dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of 0-10% MeOH/CH2Cl2 as the eluting solvent to obtain (4-amino-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-10-yl)-acetonitrile as a brown oil (123 mg, 53%). LCMS (m/e) 227 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 6.87 (d, 1H, J=7.7 Hz), 6.50 (dd, 1H, J=2.4 and 7.7 Hz), 6.47 (d, 1H, J=2.3 Hz), 3.57 (bs, 2H), 3.52 (s, 2H), 3.00-2.90 (m, 2H), 2.99-2.80 (m, 2H), 2.61-2.50 (m, 2H), 2.20-2.05 (m, 2H), 1.70-1.63 (m, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.CCOCC>CO>[CH:17]1([O:16][CH2:15][CH2:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCOC2CCCCC2)CC1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: C1CCC(OCCC2CCNCC2)CC1
Reaction time: 8 h
Yield: 30.5 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-4-[2-(cyclohexyloxy)ethyl]piperidine (182 mg, 0.59 mmol) in MeOH (2 mL) was added 2N anhydrous HCl/ether (0.75 mL, 1.5 mmol). The reaction mixture was stirred overnight. After evaporation, the residue was dissolved in deionized water. EtOAc was used to wash the aqueous layer before the pH was altered to approx. 9-10. The aqueous layer was extracted three times with CH2Cl2 and dried over Na2SO4. After evaporation, the product (38.0 mg, 30%) was obtained as a colorless oil. 1H NMR (CDCl3, 400 MHz) δ 3.46-3.29 (m, 2H), 3.16 (1, 2H), 3.02 (m, 2H), 2.56 (m, 2H), 2.17 (br, 1H), 1.88 (m, 2H), 1.71-1.64 (m, 4H), 1.52-1.42 (m, 4H), 1.25-1.22 (m, 3H), 1.99-1.13 (m, 2H), 1.11-1.08 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ 64.8, 46.3, 37.0, 33.2, 32.8, 32.0, 27.2, 25.4, 23.9.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[C:5]([N+:11]([O-:13])=[O:12])[CH:4]=1)[CH3:2].C([OH:16])C.OO.[OH-].[Na+]>O>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH2:10])=[O:16])=[C:5]([N+:11]([O-:13])=[O:12])[CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C#N)c([N+](=O)[O-])c1
Reactant: CCO
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1ccc(C(N)=O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.9 %

Procedure:
A mixture of 2 parts of 4-ethyl-2-nitrobenzenecarbonitrile, 31.6 parts of ethanol, 27.8 parts of hydrogen peroxide (30%) and 1.7 ml of sodium hydroxide 6N was stirred for 1 hour at room temperature. The reaction mixture was diluted with water and the product was extracted with dichloromethane (3×). The combined extracts were washed with water, dried, filtered and evaporated. The residue was crystallized from 2,2'-oxybispropane. The product was filtered off and dried, yielding 1.3 parts (60.9%) of 4-ethyl-2-nitrobenzamide; mp. 175.0° C. (interm. 4).
Reaction SMILES: [CH:1]([C:4]1[N:9]=[C:8]([C:10](OCC)=[O:11])[CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].CCOCC>C1COCC1>[CH:1]([C:4]1[N:9]=[C:8]([CH2:10][OH:11])[CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cccc(C(C)C)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)c1cccc(CO)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 54.3 %

Procedure:
Ethyl 6-isopropylpicolinate (prepared as in Preparation C; 75 g, 0.39 mol) was dissolved in 1.5 liters of dry THF, chilled to 0° C. and lithium aluminum hydride (0.39 L, 0.39 mol, 1M in THF) was added slowly over a 20 minute period. The resulting dark solution was stirred at 0° C. for 30 minutes, then allowed to warm to ambient temperature. TLC showed complete consumption of starting material. The reaction mixture was chilled to 0° C. and quenched carefully by the addition of sodium sulfate decahydrate until no gas evolution was observed. A thick mixture resulted. Celite and ether (about 200 mL) were added and the reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give 32 g of brown oil. The filter cake was slurried in IPA/EtOAc overnight and filtered to give an additional 8 g of product (68%).
Reaction SMILES: [CH:1]1([C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]=[C:6]([C:14]([OH:16])=O)[N:5]=2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[CH2:24]([O:31][C:32]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][C:35]1([CH3:41])[CH3:40])=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH2:24]([O:31][C:32]([N:34]1[CH2:39][CH2:38][NH:37][CH:36]([C:14]([C:6]2[N:5]=[C:4]([CH:1]3[CH2:2][CH2:3]3)[C:13]3[C:8]([CH:7]=2)=[CH:9][CH:10]=[CH:11][CH:12]=3)=[O:16])[C:35]1([CH3:41])[CH3:40])=[O:33])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC1(C)CNCCN1C(=O)OCc1ccccc1
Reactant: O=C(O)c1cc2ccccc2c(C2CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)C(C(=O)c2cc3ccccc3c(C3CC3)n2)NCCN1C(=O)OCc1ccccc1

Procedure:
230 mg (1.08 mmol) 1-cyclopropyl-isoquinoline-3-carboxylic acid and 391 mg (1.08 mmol) 2,2-dimethyl-piperazine-1-carboxylic acid benzyl ester trifluoroacetate was stirred with 385 mg (1.20 mmol) TBTU and 640 μL (3.70 mmol) DIPEA in 3 mL DMF at RT for 1 h. The mixture was worked up by adding water, followed by extraction with EtOAc. Then the reaction mixture was washed with saturated aqueous NaHCO3 solution. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. Yield: 600 mg (99%), purity: 80%; ESI-MS: m/z=444 (M+H)+; Rt(HPLC): 1.42 min (method 5)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:7]([O:16][C:17]1[CH:25]=[C:24]2[C:20]([CH2:21][CH2:22][C:23]2=O)=[CH:19][CH:18]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[BH4-].[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH2:7]([O:16][C:17]1[CH:25]=[C:24]2[C:20]([CH2:21][CH2:22][CH:23]2[N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[CH:19][CH:18]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: C1CNCCN1
Reactant: CCCCCCCCCOc1ccc2c(c1)C(=O)CC2
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Product: CCCCCCCCCOc1ccc2c(c1)C(N1CCNCC1)CC2
Yield: 91.1 %

Procedure:
Piperazine (4.4 g, 51 mmol), 6-(1-nonyloxy)indan-1-one (1.4 g, 5.1 mmol), titanium(IV) isopropoxide (2.5 ml. 7.5 mmol) and sodium borohydride (1.8 g, 47 mmol) were reacted by Method B to give the product (1.6 g, 91.2%, mp: 138°-144° C.). Calcd for C22H36N2 O.C4H4O4.0.4H2O: C, 66.75%; H, 8.79%; N, 5.99%. Found: C, 66.76%; H, 8.71%; N, 5.90%.
Reaction SMILES: [CH3:1]OS(OC)(=O)=O.S(C)C.[H-].[Na+].[CH2:13]([C@@H:15]1[C:20]([CH3:22])([CH3:21])[C:19](=[O:23])[C:18]([CH3:24])=[CH:17][CH2:16]1)[CH3:14]>CS(C)=O.O.C(OCC)(=O)C.O1CCCC1>[CH2:13]([C@@H:15]1[C:20]([CH3:22])([CH3:21])[C@:19]2([O:23][CH2:1]2)[C:18]([CH3:24])=[CH:17][CH2:16]1)[CH3:14]
Reactant: COS(=O)(=O)OC
Reactant: CC[C@H]1CC=C(C)C(=O)C1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CC[C@H]1CC=C(C)[C@]2(CO2)C1(C)C

Procedure:
Prepared according to the method described, in a vessel equipped with a CO2 condenser and kept under N2, starting from 6.8 g (0.054 mmol) of (CH3)2SO4, 3.3 g of (CH3)2S, 6 ml of THF (tetrahydrofuran), 8 ml of DMSO and 1.7 g (0.054 mol) of 75% NaH in mineral oil. (+)-(5S)-5-Ethyl-2,6,6-trimethyl-2-cyclohexen-1-one (6.6 g, 0.033 mol, [α]20D =+82.4°) in 2 ml of DMSO was added at ~6°. The mixture was stirred over the week-end and then 21 ml of ethyl acetate were added, followed by 21 ml of water added dropwise. After the usual treatment and distillation on residues, a mixture containing 54% of the desired product was obtained. The desired epoxide was separated from the mixture by further distillation.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:10])=[O:9])=[CH:4][C:3]=1[N+:11]([O-])=O.[BH4-].[Na+].[H][H]>CO.C(OCC)(=O)C.[Pd]>[OH:9][CH:8]([C:5]1[CH:4]=[C:3]([C:2]([CH3:1])=[CH:7][CH:6]=1)[NH2:11])[CH3:10]
Reactant: CC(=O)c1ccc(C)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccc(C(C)O)cc1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice-cold solution of 4-methyl-3-nitroacetophenone (25 g, 139 mmol) in methanol (200 mL) is added sodium borohydride (6.2 g, 163 mmol) over 15 minutes. The mixture is stirred at room temperature for 1 hour, then is quenched with water. The mixture is rotary evaporated and the residue is partitioned between water and ethyl acetate. The organic layer is dried (magnesium sulfate) and rotary evaporated to afford a light brown viscous oil. The oil is diluted with ethyl acetate (200 mL), 5% palladium-on-carbon (5 g) is added and the mixture is treated with hydrogen at 40 psi for 18 hours. The mixture is then filtered on Celite and the filtrate is rotary evaporated to afford 3-(1-hydroxyethyl)-6-methylaniline as a light yellow, pasty solid.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].[Cl:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([NH:19][NH2:20])=[O:18])=[CH:15][CH:14]=1>>[Cl:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([NH:19]/[N:20]=[C:4]2\[C:2](=[O:3])[N:1]([CH2:2][CH2:4][CH2:6][CH2:7][CH2:8][CH3:9])[C:11]3[C:6]\2=[CH:7][CH:8]=[CH:9][CH:10]=3)=[O:18])=[CH:15][CH:14]=1
Reactant: O=C1Nc2ccccc2C1=O
Reactant: NNC(=O)c1ccc(Cl)cc1
Product: CCCCCCN1C(=O)/C(=N\NC(=O)c2ccc(Cl)cc2)c2ccccc21
Yield: 80 %

Procedure:
The title compound was prepared as a yellow solid, using isatin 3 and 4-chlorobenzhydrazide according to the synthetic method E. The resulting solid was washed with ethanol. Yield: 80%. 1H NMR (DMSO-d6): δ 0.85 (t, J=6.9 Hz, 3H), 1.25-1.38 (m, 6H), 1.64 (m, 2H), 3.76 (t, J=7.2 Hz, 2H), 7.18 (t, J=7.8 Hz, 1H), 7.23 (d, J=7.8 Hz, 1H), 7.48 (t, J=7.8 Hz, 1H), 7.64-7.72 (m, 3H), 7.91-7.94 (m, 2H), 13.85 (br s, 1H). 13C NMR (DMSO-d6): δ 14.32 (CH3), 22.41 (CH2), 26.37 (CH2), 27.38 (CH2), 31.31 (CH2), 39.80 (CH2), 110.69 (CH), 119.56 (C), 121.33 (CH), 123.72 (CH), 129.75 (CH), 131.20 (C), 132.35 (CH), 138.23 (C), 143.52 (C═N), 161.55 (C═O). HRMS (ES+) calcd for C21H23N3O2Cl (M+H+), m/e, 384.1484. found, 384.1473.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[N:17]2[CH:21]=[CH:20][CH:19]=[N:18]2)[C:5]([Cl:22])=[CH:4][N:3]=1.[O:23]1[CH2:28][CH2:27][O:26][CH2:25][CH:24]1[CH2:29][N:30]1[CH2:36][CH2:35][C:34]2[CH:37]=[C:38]([O:42][CH3:43])[C:39]([NH2:41])=[CH:40][C:33]=2[CH2:32][CH2:31]1>>[Cl:22][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[N:17]2[CH:21]=[CH:20][CH:19]=[N:18]2)=[N:7][C:2]([NH:41][C:39]2[C:38]([O:42][CH3:43])=[CH:37][C:34]3[CH2:35][CH2:36][N:30]([CH2:29][CH:24]4[CH2:25][O:26][CH2:27][CH2:28][O:23]4)[CH2:31][CH2:32][C:33]=3[CH:40]=2)=[N:3][CH:4]=1.[O:23]1[CH2:28][CH2:27][O:26][CH2:25][CH:24]1[CH2:29][N:30]1[CH2:36][CH2:35][C:34]2[CH:37]=[C:38]([O:42][CH3:43])[C:39]([NH2:41])=[CH:40][C:33]=2[CH2:32][CH2:31]1
Reactant: COc1ccc(Nc2nc(Cl)ncc2Cl)c(-n2cccn2)c1
Agent: COc1cc2c(cc1N)CCN(CC1COCCO1)CC2
Product: COc1ccc(Nc2nc(Nc3cc4c(cc3OC)CCN(CC3COCCO3)CC4)ncc2Cl)c(-n2cccn2)c1

Procedure:
(2,5-Dichloro-pyrimidin-4-yl)-(4-methoxy-2-pyrazol-1-yl-phenyl)-amine, of Example 611c, was reacted with 3-1,4-Dioxinan-2-ylmethyl-8-methoxy-2,3,4,5-tetra hydro-1H-3-benzazepin-7-ylamine, in a similar manner as Example 601b, to yield desired product 3-1,4-Dioxinan-2-ylmethyl-8-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ylamine as a lyophylate (40%); 1H NMR (400 MHz, DMSO-d6) δ 9.91 (s, 2H), 8.20 (s, 1H), 8.13 (s, 1H), 8.09 (s, 1H), 7.87 (d, J=9.01 Hz, 1H), 7.80 (s, 1H), 7.59 (s, 1H), 7.24 (s, 1H), 6.99 (bs, 1H), 6.93 (s, 1H), 6.52 (s, 1H), 4.06 (m, 1H), 3.88 (s, 3H), 3.80 (s, 3H), 3.7-3.4 (H2O+6H), 3.3-2.9 (m, 9H), 2.67 (m, 1H); MS (m/e) 592.24 (M+H).