Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13](Cl)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:18]1[CH:19]=[N:20][N:21]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:29]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.NC1C=CC=CC=1C1C=CC=CC=1[Pd]Cl>[CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13]([N:29]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[NH:30][C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:18]1[CH:19]=[N:20][N:21]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(cc(-c3cnn(C4CCCCO4)c3)n2Cc2ccccc2)n1
Reactant: CC(C)(C)OC(=O)NNC(=O)OC(C)(C)C
Agent: Nc1ccccc1-c1ccccc1[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1ccc2c(cc(-c3cnn(C4CCCCO4)c3)n2Cc2ccccc2)n1
Temperature: 110 °C

Procedure:
1-Benzyl-5-chloro-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]-1H-pyrrolo[3,2-b]pyridine (0.106 g, 0.270 mmol, from Step 1), di-tert-butyl hydrazine-1,2-dicarboxylate (0.069 g, 0.30 mmol) and Cs2CO3 (0.088 g, 0.27 mmol) were combined in toluene (2.4 mL) and dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium (1:1) (0.021 g, 0.027 mmol) was added. The mixture was degassed by a stream of nitrogen through the solution for 10 minutes. The reaction was heated to 110° C. for 1.5 hours, at which time additional reagents and catalyst were added (same of each as the initial quantities) and the mixture was degassed again and was heated in the microwave to 140° C. for 10 minutes. The reaction mixture was partitioned between EtOAc and water, extracted three times and the combined extracts were dried over sodium sulfate, filtered, and concentrated. The resulting product was purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH). Yield (71 mg, 44%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(#N)C.[CH3:39][O:40][C:41]1[CH:50]=[C:49]2[C:44]([CH2:45][CH2:46][NH:47][CH:48]2[CH3:51])=[CH:43][C:42]=1[OH:52]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:47]3[CH2:46][CH2:45][C:44]4[C:49](=[CH:50][C:41]([O:40][CH3:39])=[C:42]([OH:52])[CH:43]=4)[CH:48]3[CH3:51])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: COc1cc2c(cc1O)CCNC2C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: COc1cc2c(cc1O)CCN(C(=O)c1cc3ncc(Br)cn3n1)C2C
Temperature: 50 °C
Reaction time: 2 h
Yield: 21.1 %

Procedure:
To a solution of 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (1.4 g, 5.8 mmol, 1.0 equiv) and TBTU (2.0 g, 6.2 mmol, 1.1 equiv) in dry acetonitrile (30 mL) triethylamine (2 mL, 14.5 mmol, 2.5 equiv) is added. 7-Methoxy-1-methyl-1,2,3,4-tetrahydro-isoquinolin-6-ol (1.4 g, 7.25 mmol, 1.25 equiv) is then added. The reaction mixture is stirred at 50° C. for 2 h, then at room temperature for 8 h, and concentrated. The residue is extracted with dichloromethane. The extract is washed with water (20 ml), dried over sodium disulfate, and concentrated. The residue is purified by column chromatography on silica gel (eluent: hexane/ethyl acetate—1/1, Rf 0.3) to provide 0.511 g of the title compound as an oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].CC[O:9]CC.[CH2:12]([CH:18]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:19][O:20][CH2:21][C:22](O)=O)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].OS(O)(=O)=O>O>[CH2:12]([CH:18]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:19][O:20][CH:21]([OH:9])[CH3:22])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCOCC
Reactant: CCCCCCCCC(CCCCCC)COCC(=O)O
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: O
Product: CCCCCCCCC(CCCCCC)COC(C)O

Procedure:
In a three-necked, one-liter, round-bottom flask (equipped with a reflux condenser, nitrogen inlet, dropping funnel, and magnetic stirring bar) 0.15 mole of lithium aluminum hydride was dispersed in 300 ml. of ether at room temperature and under a dry nitrogen atmosphere. The 2-hexyldecyloxyacetic acid from Part A was mixed with 200 ml. of ether and added dropwise with stirring. The resulting mixture was stirred overnight at room temperature. The flask containing the mixture was then cooled in ice, and icecold water was added dropwise to the mixture to react with any excess reducing agents. The reaction mixture was acidified with 10% H2SO4 to a pH of one, and extracted with 300 ml. of ether twice. The ether layers from the two extractions were diluted with an equal volume of water, and washed two times with saturated NaHC3 solution. The mixture was then washed with water and dried with anhydrous magnesium sulfate. 2-hexyldecyloxyethanol was obtained after removing the ether.
Reaction SMILES: C1(CC([NH:10][C@@H:11]2[C:41](=[O:42])[N:13]3[C:14]([C:25]([O:27][CH:28]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:26])=[C:15](/[CH:18]=[C:19]4/[C:20](=[O:24])[O:21][CH2:22][CH2:23]/4)[CH2:16][S:17][C@H:12]23)=O)C=CC=CC=1.CN1CCOCC1.P(Cl)(Cl)Cl.CO>ClCCl.O>[NH2:10][C@@H:11]1[C:41](=[O:42])[N:13]2[C:14]([C:25]([O:27][CH:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)=[O:26])=[C:15](/[CH:18]=[C:19]3/[C:20](=[O:24])[O:21][CH2:22][CH2:23]/3)[CH2:16][S:17][C@H:12]12
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C3\CCOC3=O)CS[C@H]12
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: ClP(Cl)Cl
Product: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C3\CCOC3=O)CS[C@H]12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.3 %

Procedure:
Diphenylmethyl 7β-phenylacetamido-3-[E-2-oxotetrahydrofuran-3-ylidenemethyl)ceph-3-em-4-carboxylate, (0.38 g) in dry dichloromethane (3 mls), cooled to -20° C. under argon, was treated with N-methylmorpholine (0.146 g, 0.158 mls) and a solution of phosphorous trichloride (0.178 g) in dichloromethane (4.4 mls). After 30 mins at -20° C., methanol (5 mls) was added rapidly in one portion. The reaction mixture was allowed to warm slowly to room temperature over 30 mins, and then water (10 mls) added. After vigorous stirring for a further 30 mins the solvents were completely removed in vacuo. The residue was partitioned between ethyl acetate/hexane after adjusting the pH to 8 using aqueous 0.880 ammonia. After washing and drying the organic layer, the solvent was removed and the crude product triturated with ether. Flash chromatography on fine silica gel eluting with ethyl acetate afforded the title compound as a pale yellow foam, (0.116 g, 39%), νmax (CH 2 Cl2) 1780, 1750 and 1720cm-1 ; δH (CDCl3) 2.57-2.72 (1H, m), 2.80-2.96 (1H, m), 3.61 (2H, s), 4.07-4.26 (2H, m), 4.85 (1H, d, J 5.1Hz), 4.98 (1.1Hz), 4.98 (1H, d, J 5.1Hz), 7.04 (1Hz), 7.04 (1H, s) and 7.2-7.5 (10H, m); [mass spectrum: +ve ion (3NOBA, Na+) MNa+ 485].
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].[CH3:16][N:17]([CH2:19][C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1)[CH3:18].[H-].[Na+]>CN(C)C=O.C(Cl)(Cl)Cl>[CH3:18][N:17]([CH2:19][C:20]1[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=1)[O:26][CH2:3][CH:2]([OH:1])[CH2:4][N:5]1[C:6](=[O:15])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:13]1=[O:14])[CH3:16]
Reactant: O=C1c2ccccc2C(=O)N1CC1CO1
Reactant: CN(C)Cc1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CN(C)Cc1cccc(OCC(O)CN2C(=O)c3ccccc3C2=O)c1
Yield: 39.5 %

Procedure:
A solution of 2-(oxiranylmethyl)-1H-isoindole-1,3-(2H)-dione (20.3 g) and 3-(dimethylaminomethyl)phenol (22.3 g) in dimethylformamide (200 ml) with a catalytic amount of sodium hydride (0.2 g) was heated for 6 h at 100° under N2. The solvent was evaporated to give an oil which was dissolved in chloroform and washed with 2N sodium hydroxide and water. The organic solution was evaporated to give an oil (14 g). A portion of the oil (0.8 g) was distilled to give the title compound (0.6 g) as an oil, b.p. 250° (0.08 mmHg).
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C:16]2[C:21]([CH3:22])=[CH:20][C:19](/[C:23](/[CH3:34])=[CH:24]/[C:25]([O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])=[O:26])=[CH:18][C:17]=2[Cl:35])=[N:13][CH:14]=1)(C(C)(C)C)(C)C.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>CCO>[Cl:35][C:17]1[CH:18]=[C:19](/[C:23](/[CH3:34])=[CH:24]/[C:25]([O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])=[O:26])[CH:20]=[C:21]([CH3:22])[C:16]=1[O:15][C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][N:13]=1
Reactant: C/C(=C\C(=O)OCC[Si](C)(C)C)c1cc(C)c(Oc2ccc(O[Si](C)(C)C(C)(C)C)cn2)c(Cl)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: C/C(=C\C(=O)OCC[Si](C)(C)C)c1cc(C)c(Oc2ccc(O)cn2)c(Cl)c1
Temperature: 60 °C
Reaction time: 96 h
Yield: 98.9 %

Procedure:
To a solution of 2-(trimethylsilyl)ethyl (E)-3-{4-[(5-{[tert-butyl(dimethyl)silyl]-oxy}pyridin-2-yl)oxy]-3-chloro-5-methylphenyl}but-2-enoate (0.630 g) in EtOH (12 mL) was added PPTS (0.296 g) at room temperature, then the reaction mixture was stirred for 4 days. The reaction mixture was warmed to 60° C., and stirred over night. The reaction mixture was concentrated under reduced pressure. The residue was diluted with pH 7 phosphate buffer, and extracted with AcOEt. The organic layer was washed with water and saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=8/1 to 2/1) to afford 2-(trimethylsilyl)ethyl (E)-3-{3-chloro-4-[(5-hydroxypyridin-2-yl)oxy]-5-methylphenyl}but-2-enoate as a colorless oil (0.490 g).
Reaction SMILES: [Cl:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([CH2:30][CH3:31])=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21]Cl)=[CH:15][CH:14]=3)=[CH:7][C:5]=2[CH:6]=1.[CH3:32][NH:33][CH3:34]>CO>[Cl:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([CH2:30][CH3:31])=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:33]([CH3:34])[CH3:32])=[CH:15][CH:14]=3)=[CH:7][C:5]=2[CH:6]=1
Reactant: CNC
Reactant: CCC(=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1)c1ccc2oc(Cl)cc2c1
Solvent: CO
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCN(C)C)cc1)c1ccc2oc(Cl)cc2c1
Yield: 38 %

Procedure:
According to the same procedure as example 1, step E described, 4-(2-(2-chlorobenzofuran-5-yl)-1-(4-(2-chloroethoxy)phenyl)but-1-enyl)phenol (70 mg, 1.0 eq, made by example 11, step D) was reacted with dimethylamine (1 mL) in MeOH (8 mL) under reflux to give the desired product (27 mg, 38%, Z/E=1/1.2) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.23 & 7.21 (s, 1H), 7.20 (d, J=8.8 Hz, 1H), 7.08 & 7.06 (d, J=9.2 Hz, 2H), 7.00 & 6.97 (d, J=8.4 Hz, 1H), 6.79 & 6.67 (d, J=8.6 Hz, 2H), 6.66 (d, J=8.4 Hz, 2H), 6.45 & 6.24 (d, J=8.8 Hz, 2H), 6.43 & 6.41 (s, 1H), 4.10 & 3.89 (t, J=5.2 Hz, 2H), 2.86 & 2.75 (t, J=5.2 Hz, 2H), 2.49 (q, J=7.2 Hz, 2H), 2.44 & 2.37 (s, 6H), 0.91 (t, J=7.2 Hz, 3H); m/z=462[M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[OH-].[K+]>C(O)COCCO>[F:17][C:16]([F:18])([F:19])[C:13]1[CH:12]=[C:3]([CH2:4][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2](=[CH:15][CH:14]=1)[NH2:1]
Reactant: Nc1ccc(C(F)(F)F)cc1C(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Product: Nc1ccc(C(F)(F)F)cc1Cc1ccccc1

Procedure:
In the manner given in Preparation 11, 2-amino-5-(trifluoromethyl)benzophenone is refluxed with potassium hydroxide in diethylene glycol to give 4-(trifluoromethyl)-α-phenyl-0-toluidine.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]([CH2:20][CH2:21][C:22]#[N:23])[CH2:15][CH2:14][CH2:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C1COCC1>[C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]([CH2:20][CH2:21][CH2:22][NH2:23])[CH2:15][CH2:14][CH2:13]3)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CCCC1CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Solvent: C1CCOC1
Product: NCCCC1CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Temperature: 25 °C
Yield: 25.4 %

Procedure:
A solution of 3-(6-benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-propionitrile (0.740 g, 2.27 mmol was dissolved in dry THF, and the reaction mixture was stirred under argon at room temperature. BH3 THF (6 mL) was added dropwise, and the reaction mixture was allowed to stir for 15 hours. The reaction mixture was quenched by careful addition of 10% aqueous HCl, followed by stirring for 10 minutes. The reaction mixture was placed under reduced pressure to remove THF. The resulting aqueous solution was diluted with 10 mL of EtOH, made basic by addition of 0.5 M NaOH solution, and warmed to 75° C. for 15 minutes. The solution was cooled and extracted three times with 150 mL of EtOAc. The combined organic layers were washed with water, saturated brine, and dried (MgSO4). Evaporation of the solvent under reduced pressure gave an oil that was purified by elution on silica gel (MeOH:CHCl3 5:95). Removal of the solvent yielded 0.190 g (0.577 mmol, 25.4%) of 3-(6-benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-propylamine as an oil, which was recrystallized from EtOH/EtOAc as an oxalate salt (0.140 g, 0.334 mmol, 14.7% overall yield). MS: 330 (M+H)+.
Reaction SMILES: [OH:1][C:2]12[O:32][CH:25]([CH:26]([O:30][CH3:31])[CH2:27][CH:28]1[CH3:29])[CH:24]([O:33][CH3:34])[CH2:23][CH:22]([CH3:35])[CH2:21][C:20]([CH3:36])=[CH:19][CH:18]([CH2:37][CH2:38][CH3:39])[C:17](=[O:40])[CH2:16][CH2:15][CH:14]([CH3:41])[CH:13]([C:42]([CH3:60])=[CH:43][CH:44]1[CH2:49][CH2:48][CH:47]([O:50]S(C(F)(F)F)(=O)=O)[CH:46]([O:58][CH3:59])[CH2:45]1)[O:12][C:11](=[O:61])[CH:10]1[N:5]([CH2:6][CH2:7][CH2:8][CH2:9]1)[C:4](=[O:62])[C:3]2=[O:63]>ClCCl>[OH:1][C:2]12[O:32][CH:25]([CH:26]([O:30][CH3:31])[CH2:27][CH:28]1[CH3:29])[CH:24]([O:33][CH3:34])[CH2:23][CH:22]([CH3:35])[CH2:21][C:20]([CH3:36])=[CH:19][CH:18]([CH2:37][CH2:38][CH3:39])[C:17](=[O:40])[CH2:16][CH2:15][CH:14]([CH3:41])[CH:13]([C:42]([CH3:60])=[CH:43][CH:44]1[CH2:49][CH2:48][C@H:47]([OH:50])[CH:46]([O:58][CH3:59])[CH2:45]1)[O:12][C:11](=[O:61])[CH:10]1[N:5]([CH2:6][CH2:7][CH2:8][CH2:9]1)[C:4](=[O:62])[C:3]2=[O:63]
Reactant: CCCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OS(=O)(=O)C(F)(F)F)C(OC)C3)C(C)CCC1=O)C(C)CC2OC
Solvent: ClCCl
Product: CCCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CC[C@H](O)C(OC)C3)C(C)CCC1=O)C(C)CC2OC
Reaction time: 16 h
Yield: 30.7 %

Procedure:
Silica (18 g, Merck Kieselgel 60) was added to a solution of the product of step (a) (300 mg) in dichloromethane (100 ml). Volatiles were then removed in vacuo at room temperature and the resulting freely flowing powder was stored at 8° C. for 16 hours. The support was then washed with acetone containing triethylamine and the solvent was evaporated in vacuo to an oil. Chromatography on silica eluting with hexane in an acetone gradient then gave the title compound as a foam (79 mg).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10]O.CS(OS(C)(=O)=O)(=O)=O.CC(=O)OCC.[N:27]1([C:33]2[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=2[C:35]#[N:36])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>C(Cl)Cl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10][N:30]1[CH2:29][CH2:28][N:27]([C:33]2[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=2[C:35]#[N:36])[CH2:32][CH2:31]1
Reactant: OCc1cc2ccccc2s1
Reactant: N#Cc1ccccc1N1CCNCC1
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: N#Cc1ccccc1N1CCN(Cc2cc3ccccc3s2)CC1

Procedure:
The product from Example 8A (150 mg 0.9 mmol), methane sulfonic anhydride (159 mg, 0.9 mmol), and D1 EA (475 μL 2.7 mmol) were combined. After stirring, 2-(1-piperazinyl)benzonitrile (181 mg, 1.0 mmol) in 2 ml DCM was also combined and stirred at room temperature for 18 hours. The mixture was concentrated and the residue was taken up in hot methanol. The methanol was filtered and the filter cake washed with cold methanol to provide the title compound. 1H NMR (300 MHz, CDCl3) δ 2.69 (m, 4H) 3.04 (s, 4H) 3.76 (m, 4H) 3.86 (s, 1H) 6.74 (m, 2H) 7.29 (m, 3H) 7.75 (m, 1H); (ESI) m/z 334 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])=[C:6]([N:8]([CH3:13])[S:9]([CH3:12])(=[O:11])=[O:10])[CH:7]=1.C([N:33]1[CH2:37][CH2:36][NH:35][C:34]1=[O:38])(=O)C.C(=O)([O-])[O-].[Cs+].[Cs+].CNCCNC>[Cu]I.O.O1CCOCC1>[CH3:28][C:27]1[C:22]([N:19]2[CH2:20][CH2:21][N:16]([C:14]([C:5]3[CH:4]=[CH:3][C:2]([N:33]4[CH2:37][CH2:36][NH:35][C:34]4=[O:38])=[CH:7][C:6]=3[N:8]([CH3:13])[S:9]([CH3:12])(=[O:11])=[O:10])=[O:15])[CH2:17][CH2:18]2)=[N:23][CH:24]=[C:25]([CH3:29])[CH:26]=1
Reactant: CC(=O)N1CCNC1=O
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3N(C)S(C)(=O)=O)CC2)c(C)c1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCNC4=O)cc3N(C)S(C)(=O)=O)CC2)c(C)c1
Yield: 60.5 %

Procedure:
To a mixture of N-{5-bromo-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}-N-methylmethanesulfonamide (540 mg) described in Preparation Example 227 and 1-acetylimidazolidin-2-one (144 mg), cesium carbonate (731 mg), copper(I) iodide (107 mg) were added dioxane (3 mL) and N,N′-dimethylethylenediamine (121 μL), and the mixture was stirred under refluxing for 8 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was evaporated, methanol (2 mL) and 1N aqueous sodium hydroxide solution (1.7 mL) were added to the obtained residue, and the mixture was stirred at 40° C. for 3 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was evaporated, and the residue was purified by column chromatography (ethyl acetate:methanol) to give the title compound (330 mg).
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([C:9]2[N:10]=[C:11]([N:14]=[C:15]([NH2:17])[NH2:16])[S:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=1.[SH:18][C:19]1[NH:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[NH:23][C:19]=1[S:18][CH2:2][C:3]1[N:8]=[C:7]([C:9]2[N:10]=[C:11]([N:14]=[C:15]([NH2:17])[NH2:16])[S:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: Sc1nc2ccccc2[nH]1
Reactant: NC(N)=Nc1nc(-c2cccc(CCl)n2)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(N)=Nc1nc(-c2cccc(CSc3nc4ccccc4[nH]3)n2)cs1
Temperature: 25 °C
Reaction time: 15 h
Yield: 77.8 %

Procedure:
A mixture of 4-(6-chloromethylpyridin-2-yl)-2-(diaminomethyleneamino)thiazole (1.1 g), 2-mercaptobenzimidazole (0.74 g) and potassium carbonate (0.68 g) in N,N-dimethylformamide (20 ml) was stirred for 15 hours at ambient temperature. The reaction mixture was added water and extracted with ethyl acetate. The extract layer was washed with brine, dried over magnesium sulfate and evaporated to give 4-[6-(benzimidazol-2-yl)thiomethylpyridin-2-yl]-2-(diaminomethyleneamino)thiazole (1.22 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])=[C:4](Cl)[N:3]=1.[Na].[CH3:19][SH:20].COCCOCCN(CCOCCOC)CCOCCOC>[Cu].C1COCC1>[NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])=[C:4]([S:20][CH3:19])[N:3]=1
Reactant: CS
Reactant: Nc1nc(Cl)c(-c2ccc(Cl)cc2Cl)c(Cl)n1
Agent: [Cu]
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: [Na]
Solvent: C1CCOC1
Product: CSc1nc(N)nc(Cl)c1-c1ccc(Cl)cc1Cl
Temperature: 180 °C
Yield: 51.4 %

Procedure:
A mixture of 2-amino-5-(2,4-dichlorophenyl)-4,6-dichlorohyrimidine (0.5 g) (Example 32) THF (15 ml), methanethiol sodium salt (0.113 g), copper powder (0.05 g) and tris[2-(2-methoxyethoxy)ethyl]amine (0.1 g) was heated in an autoclave at 180° C. for 18 hours. The cooled reaction mixture was filtered, evaporated and the residue purified by flash column chromatography to give the title compound (0.262 g, 52%), mp. 201°-202° C. (softens at 196° C.). Microanalysis:
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[NH2:13][C:14]1[CH:15]=[C:16]2[C:21]3=[C:22]([CH2:24][CH2:25][N:20]3[CH2:19][C@@H:18]3[CH2:26][N:27](C(OC(C)(C)C)=O)[CH2:28][C@H:17]23)[CH:23]=1>>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH:13][C:14]1[CH:15]=[C:16]2[C:21]3=[C:22]([CH2:24][CH2:25][N:20]3[CH2:19][C@@H:18]3[CH2:26][NH:27][CH2:28][C@H:17]23)[CH:23]=1
Reactant: O=Cc1ccccc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CN3CCc4cc(N)cc(c43)[C@H]2C1
Product: FC(F)(F)c1ccccc1CNc1cc2c3c(c1)[C@H]1CNC[C@H]1CN3CC2

Procedure:
Using 2-(trifluoromethyl)benzaldehyde and following the procedures described in EXAMPLE 76, (±)-cis tert-butyl 2-amino-4,5,7a,8,10,10a-hexahydrodipyrrolo[3,4-c:3′,2′,1′-ij]quinoline-9(7H)-carboxylate was converted into (±)-cis-N-[2-(trifluoromethyl)benzyl]-4,5,7,7a,8,9,10,10a-octahydrodipyrrolo[3,4-c:3′,2′,1′-ij]quinolin-2-amine, bis-trifluoroacetic acid salt, after HPLC purification (C18 reverse phase column, elution with a H2O/CH3CN gradient with 0.5% TFA). This material was free-based with aq ammonium hydroxide, extracted with chloroform, washed with brine, dried (K2CO3) and concentrated to the title compound of EXAMPLE 119 as the free base. 1H NMR (CDCl3) δ: 7.69 (d, 1H, J=7.7 Hz), 7.65 (d, 1H, J=7.7 Hz), 7.51 (t, 1H, J=7.4 Hz), 7.37 (t, 1H, J=7.7 Hz), 6.42 (d, 1H, J=1.4 Hz), 6.14 (d, 1H, J=1.8 Hz), 4.47 (s, 2H), 3.70 (dd, 1H, J=11.4, 8.1 Hz), 3.56 (dd, 1H, J=11.9, 7.5 Hz), 3.45 (q, 1H, J=7.7 Hz), 3.28-3.10 (m, 3H), 3.05 (dd, 1H, J=11.5, 8.3 Hz), 2.97-2.85 (m, 4H), 2.72 (dd, 1H, J=11.5, 8.6 Hz). LRMS (ES)+: 374.3 (M+H)+.
Reaction SMILES: [CH3:1][N:2](C)[CH2:3][CH2:4][CH2:5][CH:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][CH2:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]1=2.ClC1C2C=CC=CC=2CCC2C=CC=CC1=2>>[CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH:6]1[C:7]2[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=2[CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]1=2
Reactant: CN(C)CCCC1c2ccccc2CCc2ccccc21
Agent: ClC1c2ccccc2CCc2ccccc21
Product: CNCCCC1c2ccccc2CCc2ccccc21

Procedure:
The starting 10,11-dihydro-5-(3-dimethylaminopropyl)-5H-dibenzo[a,d]cycloheptene used in this example may be prepared by following steps A. and B. in Example 9, but employing 5-chloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene as the starting compound.