Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19](Cl)[N:18]=[C:17]([C:31]3[N:36]=[C:35]([O:37][CH3:38])[CH:34]=[C:33]([O:39][CH3:40])[N:32]=3)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl>CN(C)C=O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:37][CH2:35][CH2:34][CH2:33][OH:39])[N:18]=[C:17]([C:31]3[N:36]=[C:35]([O:37][CH2:38][CH2:22][CH2:23][OH:28])[CH:34]=[C:33]([O:39][CH2:40][CH2:19][CH2:20][OH:21])[N:32]=3)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(OC)nc(-c2nc(Cl)c(Oc3ccccc3OC)c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)n2)n1
Agent: Cl
Solvent: CN(C)C=O
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(-c2nc(OCCCO)cc(OCCCO)n2)nc1OCCCO
Yield: 100.4 %

Procedure:
A solution of 4-t-butyl-N-[6-chloro-2-(4,6-dimethoxy-2-pyrimidinyl)-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide (409 mg) in anhydrous dimethylformamide (2.4 ml) was added dropwise to the above mixture while being cooled on ice. The resultant mixture was stirred for 3.5 hours at 60° C. The reaction mixture was poured into cold 1N HCl, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=20/1) to give obtain 4-t-butyl-N-[2-(4,6-di(3-hydroxypropyloxy)-2-pyrimidinyl)-6-(3-hydroxypropyloxy)-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide (250 mg) as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([N:5]1[CH:9]=[CH:8][C:7]([C:10]2[CH:17]=[C:16]([F:18])[C:13]([C:14]#[N:15])=[C:12]([F:19])[CH:11]=2)=[N:6]1)[CH3:4].[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:30]=[C:29]([C:31](O)=[O:32])[NH:28][N:27]=2)[CH:21]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>C(Cl)Cl>[C:14]([C:13]1[C:16]([F:18])=[CH:17][C:10]([C:7]2[CH:8]=[CH:9][N:5]([C@@H:3]([CH3:4])[CH2:2][NH:1][C:31]([C:29]3[NH:28][N:27]=[C:26]([C:22]4[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=4)[CH:30]=3)=[O:32])[N:6]=2)=[CH:11][C:12]=1[F:19])#[N:15]
Reactant: C[C@@H](CN)n1ccc(-c2cc(F)c(C#N)c(F)c2)n1
Reactant: O=C(O)c1cc(-c2cccnc2)n[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](CNC(=O)c1cc(-c2cccnc2)n[nH]1)n1ccc(-c2cc(F)c(C#N)c(F)c2)n1

Procedure:
The title compound was synthesized from (S)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2,6-difluorobenzonitrile (0.277 g, 1.06 mmol), 3-(pyridin-3-yl)-1H-pyrazole-5-carboxylic acid (0.2 g, 1.06 mmol), HOBt (0.17 g, 1.27 mmol), DIPEA (0.22 mL, 1.27 mmol) and EDCI (0.243 g, 1.27 mmol) using DCM as the solvent using the method of Example 34(d). Yield 0.13 g. 1H NMR (400 MHz; d6-DMSO): δ 1.50 (d, 3H), 3.66 (m, 2H), 4.72 (m, 1H), 7.00 (d, 1H), 7.20 (s, 1H), 7.48 (m, 1H), 7.78 (m, 2H), 7.93 (d, 1H), 8.13 (m, 1H), 8.55 (dd, 1H), 8.97 (s, 1H).
Reaction SMILES: [O:1]=[C:2]([NH:9][CH:10]([C:12]1[O:13][C:14]2[CH:20]=[C:19]([CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH3:32])=[CH:25][CH:24]=3)[CH:18]=[CH:17][C:15]=2[CH:16]=1)[CH3:11])[CH2:3][C:4]([O:6]CC)=[O:5].[OH-].[Na+].Cl>C1COCC1.CO>[O:1]=[C:2]([NH:9][CH:10]([C:12]1[O:13][C:14]2[CH:20]=[C:19]([CH2:21][CH2:22][C:23]3[CH:24]=[CH:25][C:26]([O:29][CH2:30][CH2:31][CH3:32])=[CH:27][CH:28]=3)[CH:18]=[CH:17][C:15]=2[CH:16]=1)[CH3:11])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CCCOc1ccc(CCc2ccc3cc(C(C)NC(=O)CC(=O)OCC)oc3c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCOc1ccc(CCc2ccc3cc(C(C)NC(=O)CC(=O)O)oc3c2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78.9 %

Procedure:
To a solution of ethyl 3-oxo-3-[(1-{6-[2-(4-propoxyphenyl)ethyl]-1-benzofuran-2-yl}ethyl)amino]propanoate (214 mg, 0.489 mmol) obtained in Example 34 in THF-methanol (5 mL-3 mL) was added 1N aqueous sodium hydroxide solution (0.750 mL, 0.750 mmol), and the mixture was stirred at room temperature for 15 min. The reaction mixture was acidified with 1N hydrochloric acid and extracted twice with ethyl acetate, and the combined organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was washed with diethyl ether to give the title compound (158 mg, yield 79%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:24]([C:31](OCC)=[O:32])[N:23]=[C:22]2[CH2:36][CH2:37][CH2:38][CH3:39])=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:24]([CH2:31][OH:32])[N:23]=[C:22]2[CH2:36][CH2:37][CH2:38][CH3:39])=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCc1nc(C(=O)OCC)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: CCCCc1nc(CO)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1

Procedure:
Following a procedure similar to that described in Example 1(b), but using 1.50 g or diethyl 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butylimidazole-4,5-dicarboxylate [prepared as described in step (a) above] and 3.9 ml or diisobutylaluminum hydride (as a 1.5M solution in toluene), 1.1 g of the title compound was obtained as a gum.
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].CC([O-])(C)C.[K+].[CH2:18]1[C:21]2([CH2:24][CH2:23][CH2:22]2)[CH2:20][C:19]1=O>C1COCC1>[CH2:20]1[C:21]2([CH2:24][CH2:23][CH2:22]2)[CH2:18][C:19]1=[CH:3][C:1]#[N:2]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=C1CC2(CCC2)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#CC=C1CC2(CCC2)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 55.1 %

Procedure:
Diethyl cyanomethylphosphonate (3.15 mL, 20.0 mmol) was suspended in THF (30 mL) and cooled to 0° C. Potassium 2-methylpropan-2-olate (2.35 g, 21.0 mmol) was added portion-wise and stirred at 0° C. for 15 minutes. Spiro[3.3]heptan-2-one (2.100 g, 19.06 mmol) as a solution in THF (20 mL) was added dropwise and the reaction mixture was allowed to warm to ambient temperature overnight. The reaction mixture was partitioned between water, saturated aqueous NH4Cl and EtOAc. The organic layer was washed with saturated aqueous NH4Cl, brine, dried (MgSO4), filtered and concentrated under reduced pressure to afford the crude material. The crude was purified by flash column chromatography, eluting with 2.5% EtOAc/Hexanes to provide 2-(spiro[3.3]heptan-2-ylidene)acetonitrile (1.40 g, 10.5 mmol, 55% yield). 1H NMR (CDCl3) δ 5.14-5012 (m, 1H), 2.93-2.91 (m, 2H), 2.82-2.80 (m, 2H), 2.10-2.04 (m, 4H), 1.91-1.85 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][O:9][CH2:8][C:7]1=O)=[O:5])[CH3:2].[CH3:13][C@@H:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([O:3][C:4]([C:6]1[CH2:11][CH2:10][O:9][CH2:8][C:7]=1[NH:21][C@@H:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCOCC1=O
Reactant: C[C@@H](N)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)C1=C(N[C@H](C)c2ccccc2)COCC1
Yield: 104.2 %

Procedure:
A solution of 3-oxo-tetrahydro-pyran-4-carboxylic acid ethyl ester (3.03 g, 17.6 mmol), R-(+)-α-methylbenzylamine (2.35 g, 19.4 mmol) and p-toluenesulfonic acid hydrate (67 mg, 230 μmol) in benzene (60 mL) was heated at reflux under a Dean-Stark trap for 16 h. The cooled mixture was concentrated in vacuo to provide the product as a yellow oily semisolid (5.05 g), used without further purification.
Reaction SMILES: C([O:9][C@H:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@@H:12]([CH2:13][CH2:14][C@@H:15]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:36])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:11]1)(=O)C1C=CC=CC=1.[OH-].[Na+]>C1COCC1.CO>[CH3:26][CH:24]([CH2:23][CH2:22][CH2:21][C@H:20]([C@@H:19]1[C@:28]2([CH3:36])[C@H:16]([C@H:15]3[C@H:31]([CH2:30][CH2:29]2)[C@:32]2([CH3:35])[C@H:12]([CH2:11][C@@H:10]([OH:9])[CH2:34][CH2:33]2)[CH2:13][CH2:14]3)[CH2:17][CH2:18]1)[CH3:27])[CH3:25]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 16 h
Yield: 76 %

Procedure:
A solution of pyridazine 12 (113 mg, 0.22 mmol) in THF (1 mL) and MeOH (2 mL) was treated with 1M NaOH (0.29 mL, 0.29 mmol) and allowed to stand at ambient temperature for 16 h. The solvent was evaporated at reduced pressure and the residue was treated with CH2Cl2 (50 mL) and a 10% Na2CO3 solution (20 mL). The organic layer was separated, dried over MgSO4, filtered, and evaporated to dryness. The residue was purified by flash chromatography on 4 g of silica gel 60 using MeOH/CHCl3 (5:95) giving 65 mg (72%) of 13, which crystallized from CH2Cl2 /acetone, mp 203°-205° C. 1H NMR: δ3.71 (m, 1H), 3.13 (dd, 1H, J=5.6, 13.4 Hz), 3.10 (dd, 1H, J=6.8, 16.5 Hz), 2.95 (dd, 1H, J=10.6, 16.3 Hz), 2.61 (dd, 1H, J=12.8, 17.9 Hz), 2.27 (dd, 1H, J=6.1, 11.0 Hz), 2.23 (ddd, 1H, J=3.6, 3.6, 13.4 Hz), 1.06 (s, 3H), 0.99 (d, 3H, J=6.2 Hz), 0.89 (d, 6H, J=6.6 Hz), 0.80 (s, 3H). IR (Nujol): 3301, 1626, 1554, 1035 cm-1. EIMS (m/z): 410 (M+), 395 (M-Me). Anal. (C27H42N2O): C, H, N.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11](=[S:22])[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[O-][CH2:24][CH3:25].[Na+].II>C(O)C>[S:22]([C:11]1[NH:12][C:13]([C:25]2[CH:24]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=2)=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][CH:7]=2)[N:10]=1)[C:11]1[NH:10][C:9]([C:6]2[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][CH:7]=2)=[C:13]([C:14]2[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=2)[N:12]=1
Reactant: CSc1ccc(-c2[nH]c(=S)[nH]c2-c2ccc(SC)cc2)cc1
Reactant: CC[O-]
Agent: II
Agent: [Na+]
Solvent: CCO
Product: CSc1ccc(-c2nc(Sc3nc(-c4ccc(SC)cc4)c(-c4ccc(SC)cc4)[nH]3)[nH]c2-c2ccc(SC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 4,5-bis(4-methylthiophenyl)-1H-imidazole-2-thione (5.2 g, 0.015 mol), sodium ethoxide (1.0 g, 0.015 mol) and iodine (1.9 g, 0.0075 mol) in ethanol (70 ml) was stirred at ambient temperature for three hours. The resulting solid was collected, washed with ethanol and then ether. Recrystallization from N,N-dimethylformamide give the title compound, m.p. 297°-298°.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Cl:23][C:24]1[C:32]2[N:31]=[C:30]3[N:33]([C:37]4[C:38]([CH3:46])=[N:39][C:40]([O:44][CH3:45])=[N:41][C:42]=4[CH3:43])[CH2:34][CH2:35][CH2:36][N:29]3[C:28]=2[C:27]([CH2:47][OH:48])=[CH:26][CH:25]=1>CS(C)=O.C(#N)C.C(=O)([O-])O.[Na+]>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([CH:47]=[O:48])=[C:28]2[C:32]=1[N:31]=[C:30]1[N:33]([C:37]3[C:38]([CH3:46])=[N:39][C:40]([O:44][CH3:45])=[N:41][C:42]=3[CH3:43])[CH2:34][CH2:35][CH2:36][N:29]21
Reactant: COc1nc(C)c(N2CCCn3c2nc2c(Cl)ccc(CO)c23)c(C)n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CS(C)=O
Product: COc1nc(C)c(N2CCCn3c2nc2c(Cl)ccc(C=O)c23)c(C)n1
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 79.2 %

Procedure:
Dess-Martin reagent (10.1 g, 23.8 mmol) was added to a stirred solution of [9-chloro-1-(2-methoxy-4,6-dimethylpyrimidin-5-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]methanol (8.08 g, 21.6 mmol) in dimethyl sulfoxide (5.0 mL) and acetonitrile (100 mL) at 0 ° C., and the mixture was stirred at 0 ° C. for 50 min. Additional Dess-Matrin reagent (4.00 g, 9.43 mmol) was added to the stirred mixture, and the mixture was stirred at 0 ° C. for 60 min. The mixture was diluted with saturated aqueous sodium hydrogen carbonate, filtrated and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the title compound as a yellow solid (6.35 g, 17.1 mmol, 79%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12](=[N:27][OH:28])[CH2:13][NH:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:24])[F:23])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].I[CH:36]([CH3:38])[CH3:37].O>CN(C)C=O>[Cl:1][C:2]1[C:3](/[C:12](=[N:27]/[O:28][CH:36]([CH3:38])[CH3:37])/[CH2:13][NH:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:24])([F:25])[F:23])=[N:4][CH:5]=[C:6]([C:8]([F:10])([F:9])[F:11])[CH:7]=1
Reactant: O=C(NCC(=NO)c1ncc(C(F)(F)F)cc1Cl)c1ccccc1C(F)(F)F
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)O/N=C(\CNC(=O)c1ccccc1C(F)(F)F)c1ncc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 50.1 %

Procedure:
To a suspension of 20.00 g of N-[2-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-2-(hydroxyimino)ethyl]-2-(trifluoromethyl)benzamide and 19.48 g of potassium carbonate in 105 ml of N,N-dimethylformamide, 10.38 g of 2-iodopropane was added, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was mixed with 200 ml of water and extracted with ethyl acetate (100 ml×3), the resulting organic layers were combined, washed with water (100 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 1:9 to 3:7) as the eluent to obtain 11.00 g of the desired product as white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=O)[CH2:13]Cl)[CH2:7][CH2:6][CH2:5]2.C(=O)([O-])[O-].[K+].[K+].[CH3:22][NH:23][CH2:24][CH2:25][OH:26]>C(#N)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][N:23]([CH3:22])[CH2:24][CH2:25][OH:26])[CH2:7][CH2:6][CH2:5]2
Reactant: O=C(CCl)N1CCCc2cc(Br)ccc21
Reactant: CNCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CN(CCO)CCN1CCCc2cc(Br)ccc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 83.9 %

Procedure:
A solution of 6-bromo-1-(2-iodoethyl)-1,2,3,4-tetrahydroquinoline (compound 1, 0.475 g, 1.298 mmol) in acetonitrile (19 mL) and water (1 mL) in a 50 mL pressure vessel fitted with a stir-bar was treated with potassium carbonate (1.793 g, 12.98 mmol) and 2-(methylamino)ethanol (0.975 g, 12.98 mmol) and the sealed vessel stirred at 80° C. overnight. After 18 hours the mixture was partitioned between CH2Cl2 (100 mL) and water (20 mL) and transferred to a separatory funnel. The organic layer was separated and the aqueous layer (pH=12); extracted further with CH2Cl2. The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to a brown residue. Purification on silica gel eluting with 5% 2M NH3 in methanol/95% dichloromethane yielded a pale yellow oil, 2 (341 mg, 84%). 1H-NMR (DMSO-d6) δ 7.06 (dd, 1H, J=8.8, 2.5 Hz), 6.99 (d, 1H, J=2.4 Hz), 6.48 (d, 1H, J=8.8), 4.34 (t, 1H, J=5.3 Hz), 3.44 (q, 2H, J=6.2 Hz), 3.32-3.25 (m, 4H), 2.64 (t, 2H, J=6.2 Hz), 2.47-2.41 (m, 4H), 2.23 (s, 3H), 1.83-1.76 (m, 2H). MS (ESI+): 313/315 (MH+, 100).
Reaction SMILES: C[O:2][C:3]1[CH:13]=[CH:12][C:6]2[CH2:7][CH2:8][NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=1.[BrH:14]>>[BrH:14].[OH:2][C:3]1[CH:13]=[CH:12][C:6]2[CH2:7][CH2:8][NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)CCNCC2
Agent: Br
Product: Oc1ccc2c(c1)CCNCC2
Temperature: 100 °C
Reaction time: 4 h

Procedure:
7-Methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (10 g) (known from M. Kanao et al., Chem. Pharm. Bull. 1982, 30, 180-188) in 48% aqueous hydrobromic acid (350 ml) was allowed to stir at 100° C. for 4 h. The mixture was cooled to 20° C. then evaporated to dryness in vacuo to give the title compound (14.5 g) as a brown solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:26])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:25])([CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)[CH2:6][CH2:5]2.[C:27](OC(=O)C)(=[O:29])[CH3:28]>N1C=CC=CC=1>[C:27]([O:1][C:2]1[C:3]([CH3:26])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:25])([CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)[CH2:6][CH2:5]2)(=[O:29])[CH3:28]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(COc1ccc([N+](=O)[O-])cc1)O2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(COc1ccc([N+](=O)[O-])cc1)O2
Temperature: 0 °C

Procedure:
20.4 g of 6-hydroxy-2,5,7,8-tetramethyl-2-(4-nitrophenoxymethyl)chroman were dissolved in 60 ml of pyridine, and, while stirring, 30 ml of acetic anhydride were added dropwise at 10° C. The mixture was gradually restored to room temperature and then reacted for 1 hour at 30° C. The reaction mixture was cooled and then poured into ice-water and extracted with a 1:1 by volume mixture of benzene and cyclohexane. The extract was washed well with a 2% w/v aqueous solution of hydrochloric acid and then with water, after which it was dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure, giving the desired 6-acetoxy-2,5,7,8-tetramethyl-2-(4-nitrophenoxymethyl)chroman. Rf value on thin layer chromatography: 0.64 [silica gel; developing solvent; benzene and ethyl acetate=10:1 by volume]
Reaction SMILES: [NH2:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([S:12]([NH2:15])(=[O:14])=[O:13])[C:6]=2[CH:5]=[CH:4][C:3]=1[N:16]=NC1C=CC(Cl)=CC=1>Cl>[NH2:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([S:12]([NH2:15])(=[O:13])=[O:14])[C:6]=2[CH:5]=[CH:4][C:3]=1[NH2:16]
Reactant: Nc1c(N=Nc2ccc(Cl)cc2)ccc2c(S(N)(=O)=O)cccc12
Agent: Cl
Product: Nc1ccc2c(S(N)(=O)=O)cccc2c1N
Temperature: 70 °C
Reaction time: 3 h
Yield: 101.9 %

Procedure:
To a solution of 18,1 g (80 mmol) stannous chloride dihydrate in 100 ml concentrated hydrochloric acid was added 10,0 g (27,7 mmol) 1-amino-2-(4-chlorophenylazo)-naphthalene-5-sulphonamide. The mixture was stirred at 70° C. for 3 h. After cooling to 25° C., the mixture was poured into 200 ml ice-water. The precipitate was filtered off and washed with 4N hydrochloric acid. The crude product was stirred with ice-water. The precipitate was filtered off and washed with ice-water and ethanol to give 6,7 g 1,2-diamino-naphthalene-5-sulphonamide as a hydrochloride salt.
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=2[S:5][CH:6]=1.[N+:11]([O-])([OH:13])=[O:12]>C(O)(=O)C>[Br:1][C:2]1[C:3]2[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=2[S:5][C:6]=1[N+:11]([O-:13])=[O:12]
Reactant: O=[N+]([O-])O
Reactant: Brc1csc2ccccc12
Solvent: CC(=O)O
Product: O=[N+]([O-])c1sc2ccccc2c1Br
Temperature: 25 °C
Reaction time: 5 h
Yield: 71.4 %

Procedure:
Into a solution of 3-bromobenzo[b]thiophene (40 g, 190 mmol) in glacial acetic acid (140 ml) was added a solution of nitric acid (74 ml, 1760 mmol) in glacial acetic acid (40 mL) over a period of 45 min. The reaction mixture was stirred at room temperature for 5 hours before quenching with water. The precipitate was isolated by filtration, washed with water and recrystallized from ethyl acetate/hexane (1/1, v/v) to yield 3-bromo-2-nitrobenzo[b]thiophene (35 g, 72%) as yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:13]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:26][CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[CH2:12][C:11]([C:34]([C:40]([F:43])([F:42])[F:41])([C:36]([F:39])([F:38])[F:37])[OH:35])=[N:10]1.[ClH:44]>C(OCC)(=O)C>[ClH:44].[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:13]([C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH2:26][CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[CH:18][CH:19]=2)[CH2:12][C:11]([C:34]([C:40]([F:41])([F:42])[F:43])([C:36]([F:38])([F:37])[F:39])[OH:35])=[N:10]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccc(F)cc3F)cc2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: OC(C1=NN(c2ccc(F)cc2F)C(c2ccc(N3CCCNCC3)cc2)C1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(2,4-Difluoro-phenyl)-5-[4-(4-BOC-homopiperazin-1-yl)-phenyl]-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole (340.0 mg, 0.6 mmol) prepared in Example 408 was added to a saturated solution of hydrochloric acid in ethyl acetate (5.0 mL). The reaction mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure to give 250.0 mg of the titled compound as a pale yellow solid.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].[CH:9]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1)([CH3:11])[CH3:10]>C(O)C>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[NH:1][N:2]=[CH:16][C:15]1[CH:18]=[CH:19][C:12]([CH:9]([CH3:11])[CH3:10])=[CH:13][CH:14]=1
Reactant: CC(C)c1ccc(C=O)cc1
Reactant: NNc1ccccn1
Solvent: CCO
Product: CC(C)c1ccc(C=NNc2ccccn2)cc1
Temperature: 100 °C
Reaction time: 0.02 h
Yield: 76 %

Procedure:
In 20 ml of ethanol was dissolved 5.46 g of 2-hydrazinopyridine. With 7.41 g of 4-isopropylbenzaldehyde added, the solution was agitated. Fine crystals started precipitating within about 30 seconds and the entire solution solidified within about 1 minute. 10 ml of ethanol was added to the mass, which was refluxed at 100° C. for 40 minutes. The reaction solution was allowed to cool at room temperature and further cooled down to 5° to 10° C. to cause crystals to fully precipitate, which were collected by suction filtration. The crystals were washed with ethanol and dried in vacuum for 40 minutes, obtaining 9.09 g (yield 76%) of pale yellow acicular crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH2:9][CH2:8][N:7]4[CH2:15][CH2:16][CH2:17][CH:6]4[C:5]=3[C:4]=2[CH:3]=1.[H-].[Na+].[CH3:20][C:21]1[N:26]=[CH:25][C:24]([CH2:27][CH2:28]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:23][CH:22]=1>CN(C=O)C>[CH3:1][C:2]1[CH:14]=[CH:13][C:12]2[N:11]([CH2:28][CH2:27][C:24]3[CH:25]=[N:26][C:21]([CH3:20])=[CH:22][CH:23]=3)[C:10]3[CH2:9][CH2:8][N:7]4[CH2:15][CH2:16][CH2:17][CH:6]4[C:5]=3[C:4]=2[CH:3]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)C1CCCN1CC3
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(C)nc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CCN2CCCC12
Reaction time: 0.08 h

Procedure:
To a solution of 9-methyl-2,3,4,5,6,10c-hexahydro-1H-3a,6-diaza-cyclopenta[c]fluorene (100 mg, 0.422 mmol) in DMF (1 mL) was added sodium hydride (53 mg, 1.326 mmol). After stirring for 5 min, a solution of toluene-4-sulfonic acid 2-(6-methyl-pyridin-3-yl)-ethyl ester (386 mg, 1.326 mmol) in DMF (1 mL) was added dropwise at 0° C. and the reaction mixture stirred at RT for 6 h. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was poured into ice-cold water and extracted with EtOAc (3×25 mL). The combined organic layer was washed with water (5×20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase HPLC to yield 9-methyl-6-[2-(6-methyl-pyridin-3-yl)-ethyl]-2,3,4,5,6,10c-hexahydro-1H-3a,6-diaza-cyclopenta[c]fluorene. 1H NMR, (CDCl3, freebase) δ (ppm): 8.07 (s, 1H), 7.28 (m, 2H), 7.07 (d, 1H), 7.0 (s, 2H), 4.72 (m, 1H), 4.3 (m, 1H), 4.18 (m, 1H), 3.31 (m, 1H), 3.2 (m, 1H), 3.12 (m, 1H), 3.0 (m, 2H), 2.7 (m, 1H), 2.51 (m, 1H), 2.5 (s, 3H), 2.48 (s, 3H), 2.4 (d, 1H), 2.28 (m, 1H), 2.2 (m, 1H), 2.0 (m, 1H), 1.8 (m, 1H). Chiral HPLC provided enantiomers 197a and 197b.