Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([C:7]([O:22][CH2:23][C@H:24]2[O:28][C@@H:27]([N:29]3[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]3=[O:31])[CH2:26][C@@H:25]2[OH:38])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.N1C=CN=C1.N1C=CC=CC=1.[CH:52]([Si:55](Cl)([CH:59]([CH3:61])[CH3:60])[CH:56]([CH3:58])[CH3:57])([CH3:54])[CH3:53]>CN(C)C=O.C(OCC)(=O)C>[CH:52]([Si:55]([CH:59]([CH3:61])[CH3:60])([CH:56]([CH3:58])[CH3:57])[O:38][C@@H:25]1[C@@H:24]([CH2:23][O:22][C:7]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[C:6]2[CH:39]=[CH:40][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[O:28][C@@H:27]([N:29]2[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]2=[O:31])[CH2:26]1)([CH3:54])[CH3:53]
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2O[Si](C(C)C)(C(C)C)C(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.3 %

Procedure:
1.485 g (2.73 mmol) of 5'-O-(4,4'-dimethoxytrityl)thymidine and 0.37 g (5.45 mmol) of imidazole were first dried by azeotropic distillation under reduced pressure with pyridine and then dissolved in 6 ml of dimethylformamide. 875 μl (4.09 mmol) of triisopropylsilyl chloride were added to this solution, and the resulting mixture was stirred overnight at room temperature. At the end of this time, 875 μl of triisopropylsilyl chloride and 0.37 g of imisazole were added to the mixture, which was then stirred for one day. The reaction mixture was then diluted with 100 ml of ethyl acetate and the diluted mixture was washed twice, each time with 100 ml of a 5% w/v aqueous solution of sodium hydrogencarbonate. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through 100 g of silica gel (70-230 mesh), using methylene chloride containing from 0 to 3% by volume of methanol as the eluent, to give 1.861 g (yield 97%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][OH:9])[C:3]1=[O:10].[C:11](OC(=O)C)(=[O:13])[CH3:12].C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][N:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:11](=[O:13])[CH3:12])[C:3]1=[O:10]
Reactant: CN1CCN(CCO)C1=O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCCN1CCN(C)C1=O

Procedure:
Reaction of 1-methyl-3-(2-hydroxyethyl)-2-imidazolidinone (13 g) with acetic anhydride (9.2 g) in dichloromethane (60 ml) in the presence of triethylamine (9 g) and 4-dimethylaminopyridine (0.1 g) for 18 hours at ambient temperature gave 1-methyl-3-(2-acetoxyethyl)-2-imidazolidinone as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]=[S:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])([CH3:13])=[O:12])=[O:9])=[CH:4][C:3]=1I.[C:23]([C:25]1[CH:26]=[C:27]([NH:31][C:32]([C:34]2[O:35][CH:36]=[CH:37][C:38]=2[CH3:39])=[O:33])[CH:28]=[CH:29][CH:30]=1)#[CH:24].C(N(CC)CC)C>CN(C=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.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]=[S:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])([CH3:13])=[O:12])=[O:9])=[CH:4][C:3]=1[C:24]#[C:23][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][C:32]([C:34]2[O:35][CH:36]=[CH:37][C:38]=2[CH3:39])=[O:33])[CH:26]=1
Reactant: C#Cc1cccc(NC(=O)c2occc2C)c1
Reactant: COC(=O)CCCCS(C)(=O)=NC(=O)c1cnc(N)c(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CCCCS(C)(=O)=NC(=O)c1cnc(N)c(C#Cc2cccc(NC(=O)c3occc3C)c2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 69.9 %

Procedure:
The solution of methyl 5-{N-[(6-amino-5-iodopyridin-3-yl)carbonyl]-S-methylsulfonimidoyl}pentanoate, (565 mg, 1.28 mmol) in anhydrous DMF (7 mL) was degassed with anhydrous nitrogen and then to the solution was added 3-methyl-furan-2-carboxylic acid (3-ethynyl-phenyl)-amide (376.5 mg, 1.3 eq), bis(triphenylphosphine)palladium(II) dichloride (90.3 mg, 0.1 eq), triphenyl phosphine (8.4 mg, 0.025 eq), triethylamine (0.75 mL, 4 eq) and lastly copper(I) iodide (50 mg, 0.2 eq) under anhydrous nitrogen atmosphere. The reaction mixture was stirred at RT for about 15 minutes and then partitioned between saturated aq NaHCO3 and EtOAc. The organic layer was washed one more time with saturated aq NaHCO3, then with aq NH4Cl (1×), brine (1×), and dried with anhydrous Na2SO4 overnight. The upper solution layer was decanted and concentrated. The oily residue was subject to gradient column chromatography. Concentration of the product eluting fractions gave the title compound as white foam (480 mg, 70%).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6].[Nd].[Li][CH2:9][CH2:10][CH2:11][CH3:12].CC(C[AlH]CC(C)C)C.[Nd].[Li]CCCC.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[CH2:1]=[CH2:2].[CH2:9]=[CH:10][CH:11]=[CH2:12].[CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: [Li]CCCC
Agent: CC(C)C[AlH]CC(C)C
Agent: [Nd]
Solvent: C=CCCCC
Solvent: Cc1ccccc1
Product: C=C
Product: C=CC=C

Procedure:
A solution composed of 10 ml of toluene, 100 ml of hexene, 33 mg of this known complex of the formula [Me2Si(Me3SiC5H3)2]NdCl and 20 molar equivalents relative to the neodymium of co-catalyst consisting of a “BuLi/DiBAH” mixture with neodymium/BuLi/DiBAH=1/10/10, then a quantity of a butadiene/ethylene mixture (containing 20 mol % of butadiene), so as to obtain a total pressure in the reactor of P=4 bar when the temperature T was 80° C. were introduced in succession into the reactor under an argon atmosphere. The internal pressure of the reactor was then maintained at 4 bar.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:16]([C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21])#[CH:17]>C(O)(C)(C)C.C(O)(C)C>[ClH:1].[C:12]([C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[C:18]([C:16]#[CH:17])[CH:19]=3)=[N:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1)([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1ccc2c(Cl)ncnc2c1
Reactant: C#Cc1cccc(N)c1
Solvent: CC(C)O
Solvent: CC(C)(C)O
Product: C#Cc1cccc(Nc2ncnc3cc(C(=O)OC)ccc23)c1
Product: Cl

Procedure:
4-Chloro-7-carbomethoxyquinazoline (202 mg, 0.907 mmol) and 3-ethynylaniline (110 mg, 0.939 mmol) were refluxed in 4 mL of tert-butyl alcohol for 2 hours, cooled, diluted with 4 mL of isopropyl alcohol and filtered to afford solid title product which was washed with 10 mL of diethyl ether and dried, in vacuo, at 70° C., 248 mg (80%); mp 219.5°-221° C.
Reaction SMILES: [N+:1]([CH:4]([N+:6]([O-:8])=[O:7])[CH3:5])([O-:3])=[O:2].[OH-].[K+].[C:11]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])(=[O:14])[CH:12]=[CH2:13].CO>O>[N+:1]([C:4]([N+:6]([O-:8])=[O:7])([CH3:5])[CH2:13][CH2:12][C:11]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:14])([O-:3])=[O:2]
Reactant: C=CC(=O)OCCCCCCC
Reactant: CC([N+](=O)[O-])[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCCCOC(=O)CCC(C)([N+](=O)[O-])[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.7 %

Procedure:
Dinitroethane (2.4 g, 0.02 mol) and potassium hydroxide (1.2 g, 0.22 mol) were dissolved in 50 mL of water to form a first solution. 50 mL of water was added to the first solution to dissolve a salt remaining in the first solution to form a second solution. Heptyl acrylate (9.5 mL, 0.05 mol) was mixed with 50 mL of methanol, and then the mixture was slowly added to the second solution to form a third solution. The third solution was stirred at room temperature for 3 hours. The reaction product was extracted by diethyl ether, and was then distilled under reduced pressure to obtain yellow liquid heptyl 4,4-dinitropentanoate (4.8 g, yield: 83%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH:18]([C:19]([NH:21][O:22][CH2:23][C:24](O)=[O:25])=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:27])[N:10]1[CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]1[NH:34][S:35]([CH3:38])(=[O:37])=[O:36].[NH:39](C(OC(C)(C)C)=O)[NH2:40].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[ClH:69]>O.C(OCC)(=O)C.CN(C=O)C>[Cl:69][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[CH:2][C:3]=1[CH:9]1[CH:18]([C:19]([NH:21][O:22][CH2:23][C:24]([NH:39][NH2:40])=[O:25])=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:27])[N:10]1[CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]1[NH:34][S:35]([CH3:38])(=[O:36])=[O:37]
Reactant: CC(C)(C)OC(=O)NN
Reactant: Cl
Reactant: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCC(=O)O)C1c1ccc(Cl)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCC(=O)NN)C1c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.9 %

Procedure:
To 591 mg of [({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]acetic acid were added 8 ml of DMF, 200 mg of tert-butyl hydrazinecarboxylate, 205 mg of HOBt, and 388 mg of WSC hydrochloride, followed by stirring at room temperature for 3 hours. Ethyl acetate and water were added thereto to carry out a liquid separation operation. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure. 7.7 ml of dichloromethane was added thereto, followed by cooling to 0° C., and 1.2 ml of trifluoroacetic acid was added thereto, followed by stirring at room temperature for 5 hours. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol) and recrystallized from ethyl acetate to obtain 417 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-N-(2-hydrazino-2-oxoethoxy)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white powder crystal.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[N:7]([CH2:16][C:17]([OH:19])=O)[N:6]=1)=[O:4].C1C=CC2N(O)N=NC=2C=1.[CH2:32]([NH:34][CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38])[CH3:33].CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[CH3:21][C:2]([CH3:20])([CH3:1])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[N:7]([CH2:16][C:17]([N:34]([CH2:32][CH3:33])[CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38])=[O:19])[N:6]=1)=[O:4]
Reactant: COc1ccc2c(C(=O)C(C)(C)C)nn(CC(=O)O)c2c1
Reactant: CCNCCC(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCN(CCC(C)C)C(=O)Cn1nc(C(=O)C(C)(C)C)c2ccc(OC)cc21
Temperature: 25 °C

Procedure:
To a solution of 29.0 mg [3-(2,2-dimethylpropanoyl)-6-methoxy-1H-indazol-1-yl]acetic acid in 1 mL DMF was added 23.0 mg HOBt, 17.3 mg N-ethyl-iso-amylamine, 38.3 mg EDC, and 45.2 mg DIEA in that order. The mixture was stirred at room temperature over night and purified by RP-HPLC using 60-100% MeCN gradient. The pure product fractions were pooled and lyophilized to give the title compound. LC-MS: 4.16 min. (m/Z=388.3, 4.10.2).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].F[B-](F)(F)F.[O:15]=[N+:16]=[O:17].O>ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([N+:16]([O-:17])=[O:15])[CH:5]=[CH:4][C:3]=1[O:8][CH3:9]
Reactant: O=[N+]=O
Reactant: COc1ccccc1C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: O
Product: COc1ccc([N+](=O)[O-])cc1C
Reaction time: 48 h

Procedure:
2-Methylanisole (20 g) in 500 ml dichloromethane chilled in an ice bath is treated with 27.2 g of nitronium tetrafluoroborate and stirred two days. The mixture is poured into water, the layers are separated, and the aqueous phase is washed with dichloromethane. The combined organic layers are dried, filtered, stripped, and chromatographed on silica gel with 9:1 to 8:2 hexane:ethyl acetate to give 2-methyl-4-nitroanisole. NMR (CDCl3): δ2.3 (3H,s), 3.9 (3H,s), 6.9 (1H,d), 8.0 (1H,d), 8.1 (1H,d of d).
Reaction SMILES: [C:1](=[O:22])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][CH2:6]1.CCN(CC)CC.Cl.Cl.[CH3:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[CH:35][CH:34]=1>CN(C=O)C>[NH3:5].[CH3:32][C:33]1[CH:34]=[CH:35][C:36]([N:39]2[CH2:44][CH2:43][N:42]([C:1]([O:2][CH2:3][CH2:4][N:5]3[CH2:6][CH2:7][N:8]([CH3:11])[CH2:9][CH2:10]3)=[O:22])[CH2:41][CH2:40]2)=[CH:37][CH:38]=1
Reactant: Cc1ccc(N2CCNCC2)cc1
Reactant: CN1CCN(CCOC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(N2CCN(C(=O)OCCN3CCN(C)CC3)CC2)cc1
Product: N
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.4 %

Procedure:
2-(4-Methylpiperazin-1-yl)ethyl 4-nitrophenyl carbonate (Intermediate 4; 866 mg, 2.8 mmol) was dissolved in DMF (25 mL). NEt3 (1.5 mL, 10.8 mmol) and 4-(4-methyl-phenyl)piperazine dihydrochloride (724 mg, 2.9 mmol) were added and the reaction mixture was stirred at room temperature for 24 hours, and the reaction mixture was then concentrated in vacuo. The resulting residue was dissolved in EtOAc (50 mL) and washed with 1M aq Na2CO3 solution (5×50 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by normal phase column chromatography (eluting with DCM, followed by a 200:8:1 mixture of DCM:EtOH:NH3) to give 2-(4-methylpiperazin-1-yl)-ethyl 4-(4-methylphenyl)piperazine-1-carboxylate (293 mg, 30%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:15][C:14]=3I)=[O:9])=[CH:4][CH:3]=1.[CH2:31]([OH:34])[C:32]#[CH:33]>C(NCC)C.C(Cl)Cl.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.[Cu]I>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13]4=[C:14]([CH:33]=[C:32]([CH2:31][OH:34])[N:12]4[CH:11]=2)[CH:15]=[C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:17]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: C#CCO
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(I)cc(CN3CCOCC3)cc2c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClCCl
Solvent: CCNCC
Product: O=C(NCc1ccc(Cl)cc1)c1cn2c(CO)cc3cc(CN4CCOCC4)cc(c1=O)c32
Temperature: 25 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
To a solution of N-(4-chlorobenzyl) -4-hydroxy-8-iodo-6-(4-morpholinylmethyl)-3-quinolinecarboxamide (0.15 g), PdCl2(PPh3)2 (0.0098 g) and CuI (0.0027 g) in diethylamine (5.2 mL) and CH2Cl2 (5 mL) is added propargyl alcohol (0.016 mL). The reaction is stirred at room temperature overnight, then concentrated. The crude residue is partitioned between CH2Cl2 and water. The aqueous layer is extracted with CH2Cl2 (3×). The combined organic layers are dried over Na2SO4 and condensed. The crude product is adsorbed onto silica and chromatographed (Biotage flash 40S, gradient from CH2Cl2 to 2.5% MeOH/ICH2Cl2) Product containing fractions are combined and concentrated. The resulting solid is triturated with CH2Cl2/hexanes, filtered and dried to yield 0.029 g (23%) of N-(4-chlorobenzyl)-2-(hydroxymethyl)-8-(4-morpholinylmethyl)-6-oxo-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxamide, m.p. 210-212° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[C:10]1([C@@H:16]2[CH2:18][C@H:17]2[NH2:19])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:20]=O>CCOCC>[N:1]1([CH2:20][NH:19][C@@H:17]2[CH2:18][C@H:16]2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Reactant: C=O
Solvent: CCOCC
Product: c1ccc([C@@H]2C[C@H]2NCn2nnc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.3 %

Procedure:
To the mixture of 6.7 g (0.056 mole) benzotriazole and 7.4 g (0.056 mole) of trans-2-phenyl-cyclopropylamine in 150 mL of ether was added dropwise 4.5 mL (0.056 mole) of 37% aqueous formaldehyde. The reaction mixture was stirred at room temperature overnight. The solution was dried over calcium chloride, filtered and concentrated under pressure. Hexane was added under ice-cooled bath and the resulting solid was collected by filtration and washed with hexane dried to give 15 g of benzotriazol-1-ylmethyl-(trans-2-phenyl-cyclopropyl)-amine as an oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[CH:10]=[N:9][CH2:8][CH2:7]2.Cl.C1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19]N=1.CC(C1CCCC=1)=[O:29]>CC(C)=O>[CH3:2][O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[CH:10]3[N:9]([CH2:8][CH2:7][C:6]=2[CH:5]=1)[CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26][CH:21]1[C:20](=[O:29])[CH2:19]3
Reactant: CC(=O)C1=CCCC1
Reactant: COc1cc2c(cc1OC)CCN=C2
Reactant: C1=NCCc2ccccc21
Agent: Cl
Solvent: CC(C)=O
Product: COc1cc2c(cc1OC)C1CC(=O)C3CCCCC3N1CC2

Procedure:
When in Example 32 appropriate amounts of 3,4-dihydro-6,7-dimethoxyisoquinoline hydrochloride and 1-chylohexen-1-yl methyl ketone respectively are substituted for 3,4-dihydroisoquinoline hydrochloride and 1-cyclopenten-1-yl methyl ketone, 2,3,4,4a,6,7,11b,12,13,13a-decahydro-9,10-dimethoxy-1H-dibenzo[a,f]quinolizin-13-one is obtained M.P. 129°-141° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>CN(C=O)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:4][CH2:3]1
Reactant: CCOC(=O)CBr
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCN(C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.4 %

Procedure:
To a solution of 1-methylpiperazine (1 g, 8.771 mmol, 1.0 eq) in DMF were added K2CO3 (265 m g, 21.927 mmol, 2.5 eq) and ethyl 2-bromoacetate (167 mg, 13.15 mmol, 1.5 eq). The mixture was stirred at RT for 16 h and quenched and extracted as in Intermediate Example 5(a). The solvent was distilled off to afford the product in 76.4% yield. (1.3 g).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[C:8]([NH2:10])=[O:9].C(N(CC)CC)C.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>ClCCl>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:1][C@H:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]2[C:8]([NH2:10])=[O:9])(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: NC(=O)[C@@H]1CCCC[C@@H]1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)[C@@H]1CCCC[C@@H]1NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.1 %

Procedure:
To a solution of cis-2-aminocyclohexanecarboxylic acid amide (2.0 g, 14.0 mmol), and triethylamine (3.9 mL, 28 mmol) in dichloromethane (100 mL) was added 4-chlorobenzenesulfonyl chloride (2.95 g, 14.0 mmol). The resulting solution was stirred at room temperature for 18 h. The reaction was then diluted with dichloromethane (200 mL) and washed with H2O, 1.0 M HCl, brine, and dried over Na2SO4. Further purification by flash chromatography (silica gel, 1% to 10% MeOH/CHCl3) afforded cis-2-(4-chlorobenzenesulfonylamino)-cyclohexanecarboxylic acid amide (2.0 g) as a white solid in 45% yield over three steps: 1H NMR (DMSO-d6) δ 7.82 (m, 2 H), 7.63 (m, 2 H), 7.56 (d, 1 H, J=7.0 Hz), 7.22 (s br, 1 H), 6.80 (s br, 1 H), 3.43 (m, 1 H), 2.37 (m,1 H), 1.72 (m, 2 H), 1.45 (m, 3 H), 1.15 (m, 3 H); MS m/e 317.05 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]([CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[C:13]4[C:18]([C:10]=3[CH2:9][CH2:8][N:7]([CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)[C:6]=2[CH:38]=1)=[CH:17][C:16]([C:19]([O:21]CC)=[O:20])=[CH:15][CH:14]=4.[OH-].[Na+].[OH-].[Li+].O>O1CCCC1.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]([CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[C:13]4[C:18]([C:10]=3[CH2:9][CH2:8][N:7]([CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)[C:6]=2[CH:38]=1)=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15][CH:14]=4
Reactant: CCOC(=O)c1ccc2c(c1)c1c(n2C2CCCCC2)-c2ccc(Cl)cc2N(CCN2CCCCC2)CC1
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(c1)c1c(n2C2CCCCC2)-c2ccc(Cl)cc2N(CCN2CCCCC2)CC1
Temperature: 70 °C
Reaction time: 2 h
Yield: 72.4 %

Procedure:
To a solution of ethyl 3-chloro-12-cyclohexyl-5-[2-(piperidin-1-yl)ethyl]-5,6,7,12-tetrahydrobenzo[2,3]azepino[4,5-b]indole-9-carboxylate (309 mg, 0.579 mmol) in tetrahydrofuran (4 ml) and methanol (4 ml) was added 1N aqueous sodium hydroxide solution (2 ml), and the mixture was stirred at 70° C. for 2 hr. The mixture was allowed to cool to room temperature, 4N aqueous lithium hydroxide solution (2 ml) was added, and the mixture was stirred at 70° C. for 2 hr. The mixture was allowed to cool to room temperature, water (100 ml) was added, and the mixture was extracted with ethyl acetate (20 ml) and ether (10 ml). The aqueous layer was adjusted to pH 7 with 1N hydrochloric acid, and the precipitated solid was collected by filtration. The obtained solid was washed with water and dried in vacuo to give 3-chloro-12-cyclohexyl-5-[2-(piperidin-1-yl)ethyl]-5,6,7,12-tetrahydro-benzo[2,3]azepino[4,5-b]indole-9-carboxylic acid (212 mg, yield 72%).
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[CH:10]=[N:9][CH:8]=[C:7]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)[C:6]=2[CH2:5][CH2:4][CH2:3]1.[C:20](Cl)(=[O:22])[CH3:21].CCN(CC)CC.CO>C(Cl)Cl>[C:16]([C:15]1[CH:14]=[CH:13][C:12]([C:7]2[C:6]3[CH2:5][CH2:4][CH2:3][CH:2]([NH:1][C:20](=[O:22])[CH3:21])[C:11]=3[CH:10]=[N:9][CH:8]=2)=[CH:19][CH:18]=1)#[N:17]
Reactant: CC(=O)Cl
Reactant: N#Cc1ccc(-c2cncc3c2CCCC3N)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: CC(=O)NC1CCCc2c(-c3ccc(C#N)cc3)cncc21
Reaction time: 0.5 h
Yield: 43.9 %

Procedure:
A cooled (−20° C.) solution of (rac)-4-(8-amino-5,6,7,8-tetrahydroisoquinolin-4-yl)benzonitrile (example 1) (62.3 mg, 250 μmol) in CH2Cl2 (3.6 ml) was treated with acetyl chloride (21.3 μL, 275 μmol) and Et3N (41.8 μL, 300 μmol). After ½ h, an additional drop of acetyl chloride was added and after 5 min. the mixture was treated with MeOH (0.2 mL) and extracted with water/AcOEt (3×). The organic phases were dried over Na2SO4, filtered and evaporated under reduced pressure. Purification by flash chromatography (50 g SiO2, Telos-cartridge, CH2Cl2/MeOH (2 to 3%)) and precipitation from CH2Cl2 with n-pentane gave the title compound (32 mg, 44%) as off-white powder. MS: 292.1 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C.C(OCC)(=O)C>[CH3:17][O:15][C:14]([C@H:9]1[CH2:10][CH2:11][CH2:12][CH2:13][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:16]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1C(=O)O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)[C@H]1CCCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To (R)-Piperidine-1,2-dicarboxylic acid 1-tert-butyl ester (5.1 g, 22.2 mmol) in DMF (60 mL) were added K2CO3 (12.3 g, 88.8 mmol) and MeI (1.7 mL, 26.6 mmol). After stirring at room temperature overnight, the reaction mixture was diluted with ethyl acetate. The organic layer washed with water (6 times) and brine, dried over anhydrous Na2SO4, filtered and concentrated to give the title product (5.4 g, 99%).