Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2](=O)[C@H:3]([NH:7][C:8]1[N:9]=[N:10][C:11]([C:25]([NH2:27])=[O:26])=[C:12]([NH:14][C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH:17]=[CH:18][N:19]3[CH3:24])[N:13]=1)C(C)C.[NH:29]1[CH:33]=[CH:32]C(CN)=N1.N[C@H](C(C)C)C(N)=O>>[NH:29]1[CH:33]=[CH:32][C:2]([CH2:3][NH:7][C:8]2[N:9]=[N:10][C:11]([C:25]([NH2:27])=[O:26])=[C:12]([NH:14][C:15]3[CH:23]=[CH:22][CH:21]=[C:20]4[C:16]=3[CH:17]=[CH:18][N:19]4[CH3:24])[N:13]=2)=[N:1]1
Reactant: NCc1cc[nH]n1
Reactant: CC(C)[C@@H](Nc1nnc(C(N)=O)c(Nc2cccc3c2ccn3C)n1)C(N)=O
Agent: CC(C)[C@@H](N)C(N)=O
Product: Cn1ccc2c(Nc3nc(NCc4cc[nH]n4)nnc3C(N)=O)cccc21

Procedure:
The title compound was prepared in a similar procedure as described in Example (R)-3-((1-amino-3-methyl-1-oxobutan-2-yl)amino)-5-((1-methyl-1H-indol-4-yl)amino)-1,2,4-triazine-6-carboxamide. Here though, 1H-Pyrazole-3-methanamine was utilized instead of (R)-2-amino-3-methylbutanamide. MS found for C17H17N9O as (M+H)+ 364.4. UV: λ=211, 239 nm. Proton NMR: (CD3OD) δ 7.90 (1H, d, J=8.0 Hz), 7.62 (1H, m), 7.34 (1H, d, J=8.8 Hz), 7.28 (1H, d, J=3.2 Hz), 7.20 (1H, t, J=8.0 Hz), 6.63 (1H, d, J=3.6 Hz), 6.33 (1H, m), 4.76 (2H, m), 3.85 (3H, s) ppm.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:10]=[CH:11][C:12]2[N:13]([C:15]([C:18]([C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[C:22]([O:29][CH3:30])[CH:21]=3)=[O:19])=[N:16][CH:17]=2)[CH:14]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.Cl>>[NH2:8][C:9]1[CH:10]=[CH:11][C:12]2[N:13]([C:15]([C:18]([C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[C:22]([O:29][CH3:30])[CH:21]=3)=[O:19])=[N:16][CH:17]=2)[CH:14]=1
Reactant: COc1cc(C(=O)c2ncc3ccc(NC(=O)OC(C)(C)C)cn23)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)c2ncc3ccc(N)cn23)ccc1[N+](=O)[O-]

Procedure:
This compound is obtained according to the same process as that described in the preceding example 15 by deprotection of the amine of the compound [6-(tert-butoxycarbonylamino)imidazo[1,5-a]pyridin-3-yl](3-methoxy-4-nitrophenyl)methanone with trifluoroacetic acid. A yellow solid is obtained which is salified in the hydrochloride form. Melting point: 252° C.; 1H NMR (d6-DMSO): 4.01 (3H, s), 7.14 (1H, d), 7.79 (1H, s), 7.87 (1H, d), 7.97-8.01 (2H, m), 8.13 (1H, s), 9.41 (1H, s)
Reaction SMILES: [CH2:1]([Sn:5]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:9][CH2:10][CH2:11][CH3:12])[C:6]#[C:7][CH3:8])[CH2:2][CH2:3][CH3:4].[CH2:17]([N:24]=[N+:25]=[N-:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([N:24]1[C:7]([CH3:8])=[C:6]([Sn:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:9][CH2:10][CH2:11][CH3:12])[N:26]=[N:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC#C[Sn](CCCC)(CCCC)CCCC
Reactant: [N-]=[N+]=NCc1ccccc1
Product: CCCC[Sn](CCCC)(CCCC)c1nnn(Cc2ccccc2)c1C
Temperature: 150 °C

Procedure:
Tributyl(1-propynyl)tin (3.87 g, 11.8 mmol) and benzyl azide (2.2 mL, 17.6 mmol) were combined and heated to 150° C. overnight. The mixture was purified by silica gel chromatography eluting with a gradient of 5-40% ethyl acetate in hexanes to afford the title compound. MS (ESI+) m/z 464.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:17](=[O:19])[CH3:18])[C:5]2[N:9]=[CH:8][N:7](C3CCCCO3)[C:6]=2[CH:16]=1.CC1C=CC(S(O)(=O)=O)=CC=1>O.CO>[F:1][C:2]1[CH:3]=[C:4]([C:17](=[O:19])[CH3:18])[C:5]2[N:9]=[CH:8][NH:7][C:6]=2[CH:16]=1
Reactant: CC(=O)c1cc(F)cc2c1ncn2C1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: CC(=O)c1cc(F)cc2[nH]cnc12
Temperature: 80 °C
Yield: 99.6 %

Procedure:
A mixture of 1-(6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-4-yl)ethanone (1.0 g, 3.82 mmol) and TsOH (1.97 g, 11.45 mmol) in water (10 mL) and MeOH (50 mL) was heated at 80° C. for 3 h. The reaction mixture was quenched with EtOAc (50 mL) and water (50 mL). The aqueous phase was extracted with EtOAc (50 mL×2). The combined organic layers were washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo to afford 1-(6-fluoro-1H-benzo[d]imidazol-4-yl)ethanone as a yellow solid (678 mg, 99.8%). MS (ESI): m/z=179.3 [M+1].
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([S:16]([OH:19])(=[O:18])=O)[C:10]=2[CH:9]=[CH:8][N:7]=1.C(=O)([O-])O.[Na+].[NH:25]1[CH2:31][CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>ClCCl.O.CN(C)C=O>[Cl:5][C:6]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([S:16]([N:25]3[CH2:31][CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)(=[O:18])=[O:19])[C:10]=2[CH:9]=[CH:8][N:7]=1
Reactant: C1CNCCNC1
Reactant: O=S(=O)(O)c1cccc2c(Cl)nccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: O=S(=O)(c1cccc2c(Cl)nccc12)N1CCCNCC1
Reaction time: 1 h
Yield: 70.3 %

Procedure:
To 50 ml of thionyl chloride were added 5.85 g of 1-chloro-5-isoquinolinesulfonic acid as obtained in Example 1 and 0.5 ml of N,N-dimethylformamide. Then, the resulting mixture was refluxed while heating at 80° to 85° C. for 2 hours, followed by removal of the thionyl chloride and N,N-dimethylformamide under reduced pressure to obtain a residue. The residue was dissolved in a liquid consisting of 20 ml of water and 50 ml of dichloromethane, and the pH of the aqueous solution was adjusted to 6.0 with an aqueous sodium hydrogencarbonate saturated solution. Then, the dichloromethane layer was added to a 100 ml of a dichloromethane solution containing 6.0 g of homopiperazine for 20 minutes while cooling with ice, followed by stirring for 1 hour at a temperature of 15° C. to 20° C. The obtained reaction mixture was washed thrice with 50 ml of water, dried with anhydrous sodium sulfate and then distilled under reduced pressure to obtain oily residue. The thus obtained oily residue was subjected to purification by the silica gel column chromatography (Wacogel C-200, 150 g; solvent: a 5% methanol solution in chloroform), thereby to obtain 5.5 g of 1-(1-chloro-5-isoquinolinesulfonyl)homopiperazine, i.e., Compound (76), in a 84% yield. Analytical data on Compound (76) are given below.
Reaction SMILES: [CH:1]([S:4]([N:7]1[C:11]2[CH:12]=[C:13]([C:16]3[N:20]([CH:21]4[CH2:26][CH2:25][CH:24]([NH:27]C(OC(C)(C)C)=O)[CH2:23][CH2:22]4)[CH:19]=[N:18][C:17]=3[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH2:41])(=[O:6])=[O:5])([CH3:3])[CH3:2].[ClH:42]>C(O)(=O)C>[ClH:42].[CH:1]([S:4]([N:7]1[C:11]2[CH:12]=[C:13]([C:16]3[N:20]([CH:21]4[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]4)[CH:19]=[N:18][C:17]=3[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH2:41])(=[O:5])=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)S(=O)(=O)n1c(N)nc2ccc(-c3c(-c4ccccc4)ncn3C3CCC(NC(=O)OC(C)(C)C)CC3)cc21
Agent: Cl
Solvent: CC(=O)O
Product: CC(C)S(=O)(=O)n1c(N)nc2ccc(-c3c(-c4ccccc4)ncn3C3CCC(N)CC3)cc21
Yield: 15 %

Procedure:
Stir a solution of 1-isopropylsulfonyl-2-amino-6-(1-(4-(N-[tert-butoxycarbonyl]amino)cyclohex-1-yl)-4-(phenyl)-imidazol-5-yl)-benzimidazole (0.14 g, 0.2 mmol) in 1 M hydrogen chloride in acetic acid (5 mL) at room temperature for 1 hour. Filter the suspension and dry the solid to provide 0.017 g (15%) of the title compound. MS(ES+): m/z=479.0 (M+H)+
Reaction SMILES: Cl.Cl.[CH3:3][NH:4][CH2:5][C:6]1[S:7][C:8]([CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:9][N:10]=1.CCN(C(C)C)C(C)C.[CH3:26][O:27][C:28]1[CH:33]=[C:32]([CH3:34])[C:31]([S:35]([N:38]([CH2:40][C:41]2[O:45][CH:44]=[C:43]([C:46]([OH:48])=O)[CH:42]=2)[CH3:39])(=[O:37])=[O:36])=[C:30]([CH3:49])[CH:29]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH3:49])[C:31]([S:35]([N:38]([CH2:40][C:41]2[O:45][CH:44]=[C:43]([C:46]([N:4]([CH3:3])[CH2:5][C:6]3[S:7][C:8]([CH2:11][N:12]4[CH2:16][CH2:15][CH2:14][CH2:13]4)=[N:9][N:10]=3)=[O:48])[CH:42]=2)[CH3:39])(=[O:36])=[O:37])=[C:32]([CH3:34])[CH:33]=1
Reactant: CNCc1nnc(CN2CCCC2)s1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)N(C)Cc3nnc(CN4CCCC4)s3)co2)c(C)c1
Temperature: 0 °C
Reaction time: 7 h

Procedure:
N-methyl-1-[5-(pyrrolidin-1-ylmethyl)-1,3,4-thiadiazol-2-yl]methanamine dihydrochloride (25 mg, 0.087 mmol) was dissolved in DCM (5 mL), on addition of DIPEA (0.03 mL, 0.17 mmol). 5-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (30 mg, 0.09 mmol) and HOBt (17 mg, 0.12 mmol) were added and the resulting solution was cooled to 0° C. prior to the addition of EDCI (24 mg, 0.13 mmol). The mixture was stirred at ambient temperature for 7 h, quenched with saturated aqueous NaHCO3 (3 mL) and extracted with DCM (2×10 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo. The residue was purified by FCC eluting with 2% MeOH in DCM to afford the title compound.
Reaction SMILES: [CH:1]1([N:6]2[C:10]([NH2:11])=[C:9]([C:12]([NH2:14])=[O:13])[C:8]([CH3:15])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:16]([O:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=O)[CH2:17][CH3:18].CS(O)(=O)=O>O>[CH:1]1([N:6]2[C:10]3=[N:11][C:22]([C:21]4[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=4[O:19][CH2:16][CH2:17][CH3:18])=[N:14][C:12](=[O:13])[C:9]3=[C:8]([CH3:15])[NH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCCOc1ccccc1C=O
Reactant: Cc1nn(C2CCCC2)c(N)c1C(N)=O
Agent: CS(=O)(=O)O
Solvent: O
Product: CCCOc1ccccc1-c1nc2n(C3CCCC3)[nH]c(C)c-2c(=O)n1
Temperature: 180 °C
Yield: 39.9 %

Procedure:
A mixture of 1-cyclopentyl-3-methyl-5-amino-1H-pyrazole-4-carboxamide (3.98 g, 0.019 mol), 2-propoxybenzaldehyde (6.35 g, 0.038 mol), xylenes (150 ml) and methanesulfonic acid (0.5 ml) was heated at reflux for 39 hours with azeotropic removal of water. The reaction mixture was concentrated in vacuo and the residue was treated with 10% K2CO3 and ether. The layers were separated, the aqueous layer was extracted with ether and the combined ether layers were concentrated in vacuo. Analysis of the reaction mixture by TLC indicated that the reaction was not yet complete, therefore, the mixture was heated at 180° C. on an oil bath. The residue was dissolved in chloroform, and purified by column chromatography on silica gel eluting with hexane (100%) followed by ether (100%) to afford 2.67 g (41%) of 1-cyclopentyl-3-methyl-6-(2-propoxyphenyl)-pyrazolo[3,4-d]pyrimidin-4-one, m.p. 130°-132° C.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[N:5]=[C:6]([NH:16][C:17](=[NH:21])SCC)[S:7][C:8]=1[C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][N:10]=1.O.[NH2:23][NH2:24]>C(O)C>[CH3:3][C:4]1[N:5]=[C:6]([NH:16][C:17]([NH:23][NH2:24])=[NH:21])[S:7][C:8]=1[C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][N:10]=1
Reactant: NN
Reactant: CCSC(=N)Nc1nc(C)c(-c2cc(C)ccn2)s1
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1ccnc(-c2sc(NC(=N)NN)nc2C)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
To a suspension of N-(4-methyl-5-(4-methylpyridin-2-yl)thiazol-2-yl)-S-ethylisothiourea dihydrochloride (36.5 mg) in ethanol (0.5 ml) was added hydrazine hydrate (50 mg). The mixture was stirred at 80° C. for 1 hour and cooled to ambient temperature. The precipitate was collected by filtration, washed with ethanol, water and diisopropyl ether to give N-(4-methyl-5-(4-methylpyridin-2-yl)thiazol-2-yl)-N′-aminoguanidine (11 mg).
Reaction SMILES: [C:1]1(/[C:7](/[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:19][CH:18]=2)=[C:8](/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)\[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:28]([S:30]([NH2:33])(=[O:32])=[O:31])[CH3:29]>>[C:1]1([C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:33][S:30]([CH2:28][CH3:29])(=[O:32])=[O:31])=[O:26])=[CH:19][CH:18]=2)=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH3:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCS(N)(=O)=O
Reactant: CC/C(=C(\c1ccccc1)c1ccc(C=CC(=O)O)cc1)c1ccccc1
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)CC)cc1)c1ccccc1

Procedure:
Prepared by coupling 1a and ethanesulfonamide (Synlett, 1997, 375) in accordance with Procedure 1, Method B described hereinabove. Yield (25%); 1H NMR (d6-DMSO) δ 11.67 (br s, 1H), 7.47 (d, J=15.7 Hz, 1H), 7.40-7.09 (m, 12H), 6.86 (d, J=8.4 Hz, 2H), 6.47 (d, J=15.7 Hz, 1H), 3.37 (q, J=7.4 Hz, 2H), 2.36 (q, J=7.3 Hz, 2H), 1.16 (t, J=7.3 Hz, 3H), 0.83 (t, J=7.3 Hz, 3H); APcI m/z: 444 (M−H−)
Reaction SMILES: [F:1][C@:2]12[C@@H:19]([OH:20])[CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH:14]=[C:15]3[S:21][CH3:22])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:24])[CH:4]=[CH:5][C:6](=[O:23])[CH:7]=1.[C:25]1([CH3:33])[CH:30]=[CH:29][C:28]([S:31]Cl)=[CH:27][CH:26]=1>ClCCl>[F:1][C@:2]12[C@@H:19]([OH:20])[CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][C:14]([S:31][C:28]4[CH:29]=[CH:30][C:25]([CH3:33])=[CH:26][CH:27]=4)=[C:15]3[S:21][CH3:22])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:24])[CH:4]=[CH:5][C:6](=[O:23])[CH:7]=1
Reactant: Cc1ccc(SCl)cc1
Reactant: CSC1=CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]12C
Solvent: ClCCl
Product: CSC1=C(Sc2ccc(C)cc2)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]12C
Yield: 106.9 %

Procedure:
A solution of 900 mg of 9-fluoro-11β-hydroxy-17-(methylthio)androsta-1,4,16-trien-3-one in 900 ml of dichloromethane is stirred with 500 mg of p-toluenesulfenyl chloride at room temperature under a nitrogen atmosphere for about 16 hours. The resulting solution is washed with water, dried over anhydrous Na2SO4 and evaporated in vacuo to give 1.3 g of a solid, which is dissolved in chloroform-hexane (3:2) and chromatographed on a 50 g-silica gel column. Elution with chloroform-hexane (3:2) gives 930 mg of a tlc-homogenous material. Two crystallizations from acetone-hexane give 400 mg of an analytical specimen of the title compound, melting point 205°-206° C.
Reaction SMILES: [CH3:1][C:2]([CH3:29])([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)=[O:6])[CH3:3].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]>CCOC(C)=O>[CH3:3][C:2]([CH3:29])([O:4][C:5]([N:7]1[CH2:8][CH2:9][N:10]([C:13]2[CH:14]=[CH:15][C:16]([NH:19][C:20]([C:21]3[CH:22]=[CH:23][C:24]([O:27][CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[CH:25][CH:26]=3)=[O:28])=[CH:17][CH:18]=2)[CH2:11][CH2:12]1)=[O:6])[CH3:1]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(NC(=O)c3ccc(O)cc3)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)COc1ccc(C(=O)Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 108.1 %

Procedure:
To a 100 mL round bottomed flask with a stirring bar and an argon inlet was added N-(4-(4-(1,1-dimethylethoxycarbonyl)piperazin-1-yl)phenyl)-4-hydroxybenzamide (0.56 g, 1.41 mmol) DMF (35 mL), Cs2CO3 (0.49 g, 1.51 nmmol) and tert-butyl bromoacetate (0.28 mL, 1.75 mmol). This mixture was stirred at ambient temperature for 18 h. The mixture was diluted with EtOAc and washed with H2O and brine. Drying (MgSO4), filtration and removal of the solvent in vacuo gave 0.78 g of tert-butyl 4-(4-(4-(1,1-dimethylethoxycarbonyl)piperazin-1-yl)phenylaminocarbonyl)phenoxyacetate which was used in the next step without purification.
Reaction SMILES: [CH:1]1([N:6]2[C@@H:14]3[C@@H:9]([C:10]4[CH:18]=[CH:17][CH:16]=[C:15]([O:19]C)[C:11]=4[CH2:12][CH2:13]3)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:21]>Br>[ClH:21].[CH:1]1([N:6]2[C@@H:14]3[C@@H:9]([C:10]4[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[C:11]=4[CH2:12][CH2:13]3)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cccc2c1CC[C@H]1[C@@H]2CCN1C1CCCC1
Agent: Br
Agent: Cl
Product: Oc1cccc2c1CC[C@H]1[C@@H]2CCN1C1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
1.8 g (0.0066 mol) of rac-cis-3-cyclopentyl-2,3,3a,4,5,9b-hexahydro-6-methoxy-1H-benzo[e]indole were dissolved in 0.2 l of 48% aqueous HBr and boiled under reflux for 1 hour. The mixture was cooled and concentrated, whereupon 100 ml of an aqueous NaHCO3 solution and a small amount of 2N NaOH solution were added thereto, the mixture was extracted three times with CH2Cl2 and the extracts were dried with MgSO4, filtered and concentrated. The brown crystals (1.7 g) were dissolved in 30 ml of ethanol. 1.3 ml (0.0075 mol) of 5.8N ethanolic HCl solution were added dropwise thereto and the mixture was stirred at room temperature for 1 hour and at 0° for 1 hour. The separated crystals were filtered off under suction and washed with ethyl acetate. There were obtained 1.65 g (85%) of rac-cis-3-cyclo-pentyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indol-6-ol hydro-chloride as pale rose crystals with m.p. 256°-258°.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].CN1CCCC1=O.[NH2:19][CH2:20][CH2:21][CH:22]([OH:24])[CH3:23].C(N(CC)CC)C>O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:19][CH2:20][CH2:21][CH:22]([OH:24])[CH3:23])=[C:3]([CH3:11])[CH:4]=1)([O-:10])=[O:9]
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: CC(O)CCN
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cc([N+](=O)[O-])ccc1NCCC(C)O
Temperature: 60 °C
Yield: 82.3 %

Procedure:
2 g of 2-fluoro-5-nitrotoluene were added to a solution of 20 ml of N-methylpyrrolidinone, 1.38 g of 4-amino-2-butanol and 1.57 g of triethylamine. The reaction medium was heated at 60° C. for 12 hours and, after cooling to room temperature, was then poured into a water and ice mixture. The yellow precipitate formed was filtered off, reslurried in water and then dried over P2O5. 2.38 g of 4-(4-nitro-2-methylphenylamino)butan-2-ol (27) were obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:3])[CH3:2].C([O:29][C:30](=O)[CH2:31][C:32](=[O:45])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)[CH:34]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([C:19]([F:21])([F:22])[F:20])=[CH:10][C:9]=1[NH:23][C:30](=[O:29])[CH2:31][C:32](=[O:45])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)[CH:34]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCCC2)c(C(F)(F)F)cc1N
Product: CC(C)(C)OC(=O)Nc1cc(N2CCCC2)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2cccnc2)c1

Procedure:
The title compound was prepared from (2-amino-5-pyrrolidin-1-yl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J27) (259 mg, 0.75 mmol) and 3-oxo-3-(3-pyridin-3-yl-phenyl)-propionic acid tert-butyl ester (Example K1) (223 mg, 0.75 mmol) according to the general procedure M. Obtained as a yellow foam (259 mg, 61%).
Reaction SMILES: B.[CH2:2]([N:4]1[C:23](=O)[C:22](=O)[N:7]2[CH2:8][C@@H:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10]3[C:15]([C@@H:6]2[CH2:5]1)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH3:3].[ClH:26]>O1CCCC1>[ClH:26].[ClH:26].[CH2:2]([N:4]1[CH2:23][CH2:22][N:7]2[CH2:8][C@@H:9]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:10]3[C:15]([C@@H:6]2[CH2:5]1)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH3:3]
Reactant: CCN1C[C@H]2c3ccccc3[C@H](c3ccccc3)CN2C(=O)C1=O
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: CCN1CCN2C[C@@H](c3ccccc3)c3ccccc3[C@@H]2C1

Procedure:
To a stirred solution of 1.0 M borane in tetrahydrofuran (200 ml) maintained under nitrogen at ambient temperature was added cis-1,3,4,6,7,11b-hexahydro-2-ethyl-7-phenyl-2H-pyrazino[2,1-a]isoquinoline-3,4-dione (9.9 g, 0.03 m) and the mixture heated to reflux for 2 hours. The mixture was cooled in an ice bath and carefully treated with 10% HCl (125 ml), refluxed for 1 hour, and the solvent removed on an aspirator. The residue was treated with water (300 ml), basified to pH 11 with 50% NaOH, and extracted with chloroform. The extracts were dried over MgSO4 and evaporated to a pale yellow oil. This oil was dissolved in methanol (100 ml) and isopropanol (100 ml) and acidified with HCl gas. Upon cooling and standing, a white solid crystallized which was collected by filtration. Recrystallization and vacuum drying gave 4.0 g of cis-1,3,4,6,7,11b-hexahydro-2-ethyl-7-phenyl-2H-pyrazino[2,1-a]isoquinoline dihydrochloride, m.p. 276°-277° C. The product has an ad cyc H rating greater than 1×10-5M, a (3H)mepyramine rating of 3.4×10-7 and a (3H)QNB rating of 1.1×10-6M.
Reaction SMILES: C(N(CC)CC)C.C1(O[C:15](=[O:27])[NH:16][C:17]2[CH:18]=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=2)C=CC=CC=1.[NH2:28][C@H:29]([CH2:33][OH:34])[CH:30]([CH3:32])[CH3:31]>C(Cl)(Cl)Cl>[OH:34][CH2:33][C@@H:29]([NH:28][C:15]([NH:16][C:17]1[CH:18]=[N:19][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:22]=1)=[O:27])[CH:30]([CH3:32])[CH3:31]
Reactant: CC(C)[C@H](N)CO
Reactant: O=C(Nc1ccc(C(F)(F)F)nc1)Oc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)[C@@H](CO)NC(=O)Nc1ccc(C(F)(F)F)nc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 113.3 %

Procedure:
Triethylamine (0.54 mL) and phenyl[6-(trifluoromethyl)pyridin-3-yl]carbamate (600 mg) were added to a solution of L-valinol (200 mg) in chloroform, and the mixture was stirred at 80° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel cartridge, hexane/ethyl acetate) to afford 1-[(2S)-1-hydroxy-3-methylbutan-2-yl]-3-[6-(trifluoromethyl)pyridin-3-yl]urea (640 mg).
Reaction SMILES: [C:1]1([NH:7]N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.[CH2:16]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([CH:32]=O)[CH2:28][CH2:27]1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[BH4-].[Na+]>C1(C)C=CC=CC=1.C(#N)C.CO>[N:26]1([C:24]([O:23][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:25])[CH2:27][CH2:28][C:29]2([C:6]3[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=3)[NH:7][CH2:32]2)[CH2:30][CH2:31]1
Reactant: NNc1ccccc1
Reactant: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C(OCc1ccccc1)N1CCC2(CC1)CNc1ccccc12
Temperature: 35 °C
Reaction time: 8 h
Yield: 34.1 %

Procedure:
A solution of phenyl hydrazine (1.29 g, 12.0 mmol) and trifluoroacetic acid (3.0 mL) in a 49/1 solution of toluene/acetonitrile (50 mL) is heated at 35° C. 4-Formyl-piperidine-1-carboxylic acid benzyl ester (2.7 g, 10.91 mmol) is dissolved in a 49/1 solution of toluene/acetonitrile (10 mL) and added dropwise to the mixture (WO2005046682). The mixture is stirred at 35° C. overnight. The resulting solution is cooled to 0° C., and methanol (5 mL) is added. NaBH4 (0.619 g, 16.38 mmol) is added slowly to the solution and the mixture is stirred for 45 min. The mixture is washed with aqueous NH4OH (6%, 25 mL) and brine (30 mL), dried over sodium sulfate, and evaporated to dryness to give a yellow solid. The crude solid is recrystallised from EtOAc to give a pale yellow solid (1.25 g, 1st crop). The mother liquor is evaporated and purified by flash chromatography, eluting with hexane:ethyl acetate (8:2) to give the title compound as a pale yellow solid (1.2 g, 2nd crop) with a total yield (2.4 g, 84%). ESI/MS m/z 323 (M+H)+.