Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][N:10]1[C:14]2=[CH:15][N:16]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([Cl:31])[CH:29]=4)[CH:24]=[C:17]3[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:13]2[CH:12]=[N:11]1.O>CN(C)C=O>[Cl:1][C:26]1[CH:27]=[C:28]([Cl:31])[CH:29]=[C:30]2[C:25]=1[CH:24]=[C:17]1[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:13]3[CH:12]=[N:11][N:10]([CH3:9])[C:14]3=[CH:15][N:16]12
Reactant: CN1N=CN2C1=Cn1c(cc3ccc(Cl)cc31)-c1ccccc12
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: CN1N=CN2C1=Cn1c(cc3c(Cl)cc(Cl)cc31)-c1ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.7 %

Procedure:
A solution of 1.91 g N-chlorosuccinimide in 45 ml dimethylformamide was added dropwise to a solution of 3.33 g 1-methyl-12-chloro-4H-indolo[1,2-d][1,2,4]triazolo[4,3-a][1,4]benzodiazepine in 100 ml dimethylformamide. The reaction mixture was stirred for three hours at room temperature. Upon addition of water and stirring overnight, a solid precipitated. This was collected, triturated with hexane and dried to yield 1.72 g. Recrystallization from methanol/water yielded 1.17 g solid, m.p. 266°-270° C.
Reaction SMILES: [CH:1]1[C:13]2[N:12]([C:14]3[CH:15]=[C:16]([C:33]4[O:34][C:35]([C:38]5[CH:43]=[CH:42][CH:41]=[C:40]([O:44]C)[CH:39]=5)=[N:36][N:37]=4)[CH:17]=[C:18]([N:20]4[C:32]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[C:26]5[C:21]4=[CH:22][CH:23]=[CH:24][CH:25]=5)[CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.B(Br)(Br)Br.C(=O)=O.CC(C)=O>ClCCl>[CH:22]1[C:21]2[N:20]([C:18]3[CH:17]=[C:16]([C:33]4[O:34][C:35]([C:38]5[CH:39]=[C:40]([OH:44])[CH:41]=[CH:42][CH:43]=5)=[N:36][N:37]=4)[CH:15]=[C:14]([N:12]4[C:13]5[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=5[C:6]5[C:11]4=[CH:10][CH:9]=[CH:8][CH:7]=5)[CH:19]=3)[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]=2[CH:25]=[CH:24][CH:23]=1
Reactant: COc1cccc(-c2nnc(-c3cc(-n4c5ccccc5c5ccccc54)cc(-n4c5ccccc5c5ccccc54)c3)o2)c1
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: Oc1cccc(-c2nnc(-c3cc(-n4c5ccccc5c5ccccc54)cc(-n4c5ccccc5c5ccccc54)c3)o2)c1
Temperature: 0 °C
Reaction time: 5.5 h

Procedure:
To a solution of 2-(3,5-dicarbazol-9-ylphenyl)-5-(3-methoxyphenyl)-1,3,4-oxadiazole (0.95 g, 1.63 mmol) in dichloromethane (20.0 ml) was dropwise added BBr3 (7.0 ml, 1M in dichloromethane) at −78° C. (dry-ice/acetone) under nitrogen. After addition of BBr3 solution, the reaction was taken to room temperature and kept at room temperature for 5.5 h. The reaction mixture was poured into ice-water (70.0 ml). Dichloromethane was evaporated under reduced pressure. The white solid was collected by filtration. After drying under vacuum, product as white solid was obtained in 0.92 g (98.9%) yield. 1H NMR (400 MHz, DMSO-d6, δ): 10.01 (s, br, 1H, OH), 8.46 (d, J=1.6 Hz, 2H), 8.28 (d, J=8.0 Hz, 4H), 8.17 (t, J=1.6 Hz, 111), 7.66 (d, J=8.0 Hz, 4H), 7.59 (d, J=8.0 Hz, 1H), 7.50 (m, 5H), 7.34 (m, 5H), 7.00 (dd, J1=8.4 Hz, J2=2.4 Hz, 1H). MS-EI (m/z): [M]+ calcd for C38H24N4O2, 568.2. found 568.2.
Reaction SMILES: C(OC([N:8]1[CH2:26][CH2:25][N:11]2[C:12](=[O:24])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][C:20]([F:23])([F:22])[F:21])=O)(C)(C)C.[ClH:27]>CCOCC.O>[ClH:27].[F:23][C:20]([F:21])([F:22])[O:19][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[C:12](=[O:24])[N:11]1[CH2:25][CH2:26][NH:8][CH2:9][C@H:10]12
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)c3c(OC(F)(F)F)cccc3[C@@H]2C1
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: O=C1c2c(OC(F)(F)F)cccc2[C@@H]2CNCCN12
Reaction time: 1 h

Procedure:
To a stirring solution of N-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-one (181 mg, 0.5 mmol) in dry ether (5 mL) was added hydrochloric acid (1 mL). The reaction was stirred for 1 h and then conc. in vacuo to a white solid. The solid was dissolved in water and lyophilized to 147 mg of a white solid. MS (ESI) 309 (M−Cl).
Reaction SMILES: [CH2:1]([O:4][C@@H:5]1[CH2:10][O:9]C(C)(C)[O:7][C@H:6]1[CH:13]=[CH2:14])C=C.Cl.C([O-])(O)=O.[Na+]>CO.CCOC(C)=O>[OH:9][CH2:10][C@H:5]1[C@H:6]([OH:7])[CH:13]=[CH:14][CH2:1][O:4]1
Reactant: C=CCO[C@@H]1COC(C)(C)O[C@H]1C=C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: OC[C@@H]1OCC=C[C@H]1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of trans-5-allyloxy-2,2-dimethyl-4-vinyl-[1,3]dioxane (48 mg, 0.28 mmol) in MeOH (5 mL) was added a solution of methanolic HCl (0.5 mL, prepared from 0.5 mL conc. HCl in 30 mL of MeOH). The mixture was stirred for 30 min at ambient temperature. Aqueous saturated NaHCO3 (5 mL) was added and the mixture was diluted with EtOAc (50 mL). The organic layer was washed with saturated NaHCO3 (30 mL). The aqueous layer was washed with EtOAc (30 mL×2). The combined organic layers were washed with brine, dried over Na2SO4, concentrated in vacuo, and the residue was purified by flash chromatography with 100% EtOAc.
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[C:15]([C:32]#[C:33][Si](C)(C)C)[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(=O)([O-])[O-].[K+].[K+].Cl>CCO.C1COCC1>[C:32]([C:15]1[N:14]=[C:13]([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH:8]=2)[N:17]([CH3:18])[C:16]=1[C:19]([N:21]1[CH2:26][CH2:25][CH:24]([N:27]2[CH2:28][CH2:29][CH2:30][CH2:31]2)[CH2:23][CH2:22]1)=[O:20])#[CH:33]
Reactant: CCCCCCc1cccc(-c2nc(C#C[Si](C)(C)C)c(C(=O)N3CCC(N4CCCC4)CC3)n2C)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCO
Product: C#Cc1nc(-c2cccc(CCCCCC)c2)n(C)c1C(=O)N1CCC(N2CCCC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.5 %

Procedure:
To a solution of 0.52 g (1.00 mmol) of [2-(3-hexyl-phenyl)-3-methyl-5-trimethylsilanylethynyl-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 12) in 10 ml EtOH:THF 5:1 was added 0.277 g (2.0 mmol) of solid potassium carbonate and the reaction mixture was stirred at RT for 18 hours. It was then poured into crashed ice, acidified with HCl (25% in water) and extracted twice with CH2Cl2; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0 to 9:1) to give 0.27 g (60%) of the title compound as light brown solid. MS: 447.4 (MH+).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH3:12])=[N:9][CH:10]=1)(=O)C.[OH-].[Na+]>CO>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH3:12])=[N:9][CH:10]=1
Reactant: COc1ccc(OC(C)=O)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(O)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.4 %

Procedure:
To a solution of the 5acetoxy-2-methoxypyridine (600 mg, 3.59 mmol) in MeOH (10 mL) was added 1M aq. NaOH (10 mL, 10 mmol). After stirring at r.t. for 30 min, volatile solvent was removed in vacuo, acidified with HOAc and extracted with CHCl3(3×). The combind CHCl3 extracts were washed with H2O, dried (anhydrous MgSO4) and evaporated to give the title compound as a brown oil (240 mg, solidified on standing).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4](S(C)=O)[N:3]=1.[O:22]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]1.O>CN1CCCC1=O>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:28][CH:25]2[CH2:26][CH2:27][O:22][CH2:23][CH2:24]2)[N:3]=1
Reactant: NC1CCOCC1
Reactant: COc1ccc(F)cc1C(=O)c1cnc(S(C)=O)nc1N
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCOCC2)nc1N

Procedure:
A solution of (4-amino-2-methanesulfinyl-pyrimidin-5-yl)-(5-fluoro-2-methoxy-phenyl)-methanone (235 mg, 0.73 mmol, Example 157) and tetrahydro-pyran-4-ylamine (Combi-Blocks) (260 mg, 2.3 mmol) in N-methylpyrrolidinone (15 ml) was heated for 30 minutes at 100° C. The solution was cooled, poured into water and extracted into ethyl acetate (2×). The combined organic extracts were washed with 5% sodium bicarbonate and saturated sodium chloride. The solution was dried (Na2SO4) and solvent was removed under vacuum to give a crude solid. Purification was by silica gel chromatography to give [4-amino-2-(tetrahydro-pyran-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone as a white solid. HRMS, observed: 346.1445; Calcd for M+: 346.1441.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:11])[CH:3]=1.[CH:12]1([C:15]2[CH:16]=[CH:17][C:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[N:19][CH:20]=2)[CH2:14][CH2:13]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:24]2[CH2:25][CH2:26][N:21]([C:18]3[CH:17]=[CH:16][C:15]([CH:12]4[CH2:14][CH2:13]4)=[CH:20][N:19]=3)[CH2:22][CH2:23]2)=[O:8])=[C:4]([F:11])[CH:3]=1
Reactant: c1cc(N2CCNCC2)ncc1C1CC1
Reactant: O=C(O)c1ccc(Br)cc1F
Product: O=C(c1ccc(Br)cc1F)N1CCN(c2ccc(C3CC3)cn2)CC1
Yield: 85.3 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 90 and using 4-bromo-2-fluorobenzoic acid (1.2 g) and 1-(5-cyclopropylpyridin-2-yl)piperazine (1.02 g) described in Preparation Example 187, the title compound (1.73 g) was obtained.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH:5]([CH3:7])[CH3:6].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH3:6][CH:5]([CH3:7])[CH2:4][C@H:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:2]=[O:1]
Reactant: CC(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)C[C@@H](C=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (S)-tert-butyl (1-hydroxy-4-methylpentan-2-yl)carbamate (2 g, 9.20 mmol) in DCM (30 mL) was added Dess-Martin Periodinane (5.86 g, 13.81 mmol) at 0° C. The reaction mixture was allowed to stir at RT for 16 h. The reaction mixture was quenched with NaHCO3, diluted with water and extracted in ethyl acetate. Organic layer was dried over Na2SO4 and concentrated which afforded (S)-tert-butyl (4-methyl-1-oxopentan-2-yl)carbamate as colorless oil (1.4 g, 6.50 mmol, 71% crude yield). The material was carried on without further purification. 1H NMR (300 MHz, DMSO-d6): δ 0.8-0.96 (m, 6H), 1.31-1.49 (m, 11H), 1.57-1.66 (m, 1H), 3.81-3.89 (m, 1H). 7.27 (d, 1H), 9.43 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]2[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].N1C=CC=CC=1.[C:27](Cl)(=[O:29])[CH3:28]>C1COCC1>[C:27]([NH:1][C:2]1[CH:10]=[C:9]([C:11]2[C:16]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5])(=[O:29])[CH3:28]
Reactant: NC(=O)c1ccc(-c2ncccc2C(F)(F)F)cc1N
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)Nc1cc(-c2ncccc2C(F)(F)F)ccc1C(N)=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-amino-4-(3-trifluoromethyl-pyridin-2-yl)-benzamide (0.5 mmol) and pyridine (0.55 mmol) in THF (5 ml) add acetyl chloride (0.55 mmol). Stir the mixture 10 minutes at room temperature. Concentrate under vacuum, extract with EtOAc, wash with brine, dry over Na2SO4, and concentrate under vacuum. Triturate with ether to give 2-acetylamino-4-(3-trifluoromethyl-pyridin-2-yl)-benzamide.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.C(N(CC)CC)C.[O:19]1[C:27]2[C:22](=[CH:23][C:24]([C:28](Cl)=[O:29])=[CH:25][CH:26]=2)[CH2:21][CH2:20]1>O1CCCC1>[O:19]1[C:27]2[C:22](=[CH:23][C:24]([C:28]([N:9]3[CH2:8][CH2:7][N:6]([C:2]4[S:1][CH:5]=[CH:4][N:3]=4)[CH2:11][CH2:10]3)=[O:29])=[CH:25][CH:26]=2)[CH2:21][CH2:20]1
Reactant: c1csc(N2CCNCC2)n1
Reactant: O=C(Cl)c1ccc2c(c1)CCO2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(c1ccc2c(c1)CCO2)N1CCN(c2nccs2)CC1
Temperature: 60 °C
Yield: 76.3 %

Procedure:
To a solution of 9 g of 1-(2-thiazolyl) piperazine and 5 g of anhydrous triethylamine in 200 ml of anhydrous tetrahydroduran, there were added dropwise, a solution of 9.1 g of 5-coumaranyl carboxylic acid chloride in 20 ml of tetrahydrofuran. After the completion of the addition, the reaction mixture was heated at 60° C for two hours, then, the so-formed precipitate was suction-filtered off. The filtrate was evaporated under reduced pressure and the crystalline residue was washed with water then recrystallized in 70 ml of ethanol. There were obtained 12 g of 1-(5-coumaranyl carbonyl)-4-(2-thiazolyl) piperazine, melting (K) at 150°-151° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[C:18](OC(C)(C)C)(=[O:26])[C:19](OC(C)(C)C)=[O:20].CC(C)([O-])C.[K+].Cl>C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:19](=[O:20])[C:18]([OH:26])=[C:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9]1
Reactant: CC(C)(C)OC(=O)CCNc1ccccc1F
Reactant: CC(C)(C)OC(=O)C(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)C1=C(O)C(=O)N(c2ccccc2F)C1
Temperature: 25 °C
Reaction time: 84 h
Yield: 47.8 %

Procedure:
To a solution of the title compound of Example C (5.41 g, 22.6 mmol) in dry THF (100 ml) was added di-tert-butyl oxalate (4.57 g, 22.6 mmol), followed by potassium tert-butoxide (5.07 g, 45.2 mmol) and the resulting dark yellow solution was stirred for 84 h at room temperature. The reaction mixture was then acidified with 1N HCl to pH=3, followed by the addition of H2O (35 ml) and the mixture was then extracted with CH2Cl2. The combined organic layers were dried with MgSO4, filtered and dried to give a solid which was chromatographed on silica gel eluting with 1/1/98 MeOH/HOAc/CH2Cl2 to give the title compound (3.166 g, 48%). Anal calcd for C15H16NO4F: C, 61.43; H, 5.50; N, 4.78. Found: C, 61.16; H, 5.50; N, 4.77.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][CH2:8][O:7][C:6]=2[CH:5]=[CH:4][C:3]=1[NH:11]C(=O)OC(C)(C)C.Cl.O1CCOCC1>>[Cl:1][C:2]1[C:10]2[O:9][CH2:8][O:7][C:6]=2[CH:5]=[CH:4][C:3]=1[NH2:11]
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1Cl)OCO2
Agent: Cl
Solvent: C1COCCO1
Product: Nc1ccc2c(c1Cl)OCO2
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
To a vial containing tert-butyl 4-chlorobenzo[d][1,3]dioxol-5-ylcarbamate (307.2 mg, 1.1 mmol, 1 equiv.) was added 5.5 mL of 4N HCl in dioxane (22 mmol, 20 equiv.). The mixture was stirred at room temperature for 5.5 h, the solvent removed under vacuum, the residue dissolved in ethyl acetate, washed with saturated NaHCO3, and brine. The combined organic layers was dried over anhydrous Na2SO4, filtered and the solvent removed under to give a quantitative yield 4-chlorobenzo[d][1,3]dioxol-5-amine.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[CH:18][N:19]2[C@@H:22]2[CH2:26][C@H:25]([CH2:27][OH:28])[CH:24]=[CH:23]2)=[C:15](Cl)[N:14]=1.[OH-].[Na+]>CO>[NH2:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[CH:18][N:19]2[C@@H:22]2[CH2:26][C@H:25]([CH2:27][OH:28])[CH:24]=[CH:23]2)=[C:15]([NH:10][C@@H:8]2[CH2:9][C@H:7]2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:14]=1
Reactant: Nc1nc(Cl)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1nc(N[C@@H]2C[C@H]2c2ccccc2)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1

Procedure:
A solution of trans-2-phenyl cyclopropylamine.HCl (1.02 g, 6 mmol) in methanol (10 ml) was stirred with basic ion exchange resin for 5 minutes. The resin was filtered off and the filtrate was concentrated to a colorless oil. To this was added (±)-(cis)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopentene-1-methanol (0.549 g, 2 mmol). The resulting solution was stirred in a Parr bomb at 80° C. for 12 hours 1 N NaOH 12 ml) was added and the solvent evaporated. The residual oil was chromatographed on silica gel. Title compound was eluted with 5% methanol-chloroform to give tan crystals after crystallization from acetonitrile-methanol (0.221 g, 30%), m.p.=188-190° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]3[CH2:11][C:12]4[C:17]([C:9]3=[C:8]([CH:18]=O)[C:7]=2[N:20]=1)=[CH:16][CH:15]=[CH:14][CH:13]=4.[H-].[Na+].C(OP([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])(OCC)=O)C>C1COCC1>[CH2:36]([O:35][C:33](=[O:34])[CH2:32][CH:31]=[CH:18][C:8]1[C:7]2[N:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[N:10]2[CH2:11][C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9]=12)[CH3:37]
Reactant: COc1ccc2c(n1)c(C=O)c1n2Cc2ccccc2-1
Reactant: CCOC(=O)CCP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC=Cc1c2n(c3ccc(OC)nc13)Cc1ccccc1-2

Procedure:
10.7 mmol of the compound obtained in Step E of Preparation 1 in 20 ml of anhydrous THF are placed in the presence of 1.2 eq of NaH (60% in oil) in 25 ml of anhydrous THF and of 1.2 eq of ethyl 3-(diethoxyphosphoryl)propanoate. The title compound is obtained after 3 hours' stirring at room temperature and gentle refluxing overnight.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1[CH:5]=O.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH2:25][C:26]#[N:27])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]>>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([C:25](=[CH:5][C:4]2[CH:7]=[CH:8][C:9]([O:13][CH3:14])=[C:10]([O:11][CH3:12])[C:3]=2[O:2][CH3:1])[C:26]#[N:27])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: COc1ccc(C=O)c(OC)c1OC
Product: COc1ccc(C(C#N)=Cc2ccc(OC)c(OC)c2OC)cc1OC
Yield: 90 %

Procedure:
Following the Procedure A, the reaction was performed with 1.96 g of 2,3,4-trimethoxybenzaldehyde (10 mmol) and 1.77 g 3,4-dimethoxyphenyl-acetonitrile (10 mmol), affording 2-(3,4-dimethoxy-phenyl)-3-(2,3,4-trimethoxy-phenyl)-acrylonitrile as yellow powder (yield 3.2 g, 90%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[CH2:13])[C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[SH:21]>C(O)C>[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21][CH2:13][CH:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[C:10]([OH:12])=[O:11]
Reactant: Nc1ccccc1S
Reactant: C=C(C(=O)O)c1ccc(OC)cc1
Solvent: CCO
Product: COc1ccc(C(CSc2ccccc2N)C(=O)O)cc1

Procedure:
A solution of 125 ml of ethanol, 8.9 g of 4-methoxy-α-methylene benzeneacetic acid and 5.35 ml of 2-amino thiophenol was refluxed for 7 hours. The ethanol was evaporated off and the residue was crystallized from 500 ml of isopropyl ether to obtain 11 g of the desired product melting at 118° C. and used as is for the following step.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[CH3:14].[Cl:20][S:21](O)(=[O:23])=[O:22]>>[Cl:20][S:21]([C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:6]([CH3:14])[N:5]([CH2:4][C:3]3[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:2]=3[Cl:1])[C:9]=2[CH:10]=1)(=[O:23])=[O:22]
Reactant: O=S(=O)(O)Cl
Reactant: Cc1nc2ccccc2n1Cc1ccc(Cl)cc1Cl
Product: Cc1nc2ccc(S(=O)(=O)Cl)cc2n1Cc1ccc(Cl)cc1Cl
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
In an ice bath, 1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (4.00 g) is added to chlorosulfonic acid (20 ml) and the solution is stirred for 24 hours at room temperature and at 1.5 hours at 80° C. The reaction solution is poured into ice water, precipitated gummy solids are separated through filtration, and thus, a mixture of 5-chlorosulfonyl-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole and 6-chlorosulfonyl-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole is obtained. This material is immediately used for the following reaction.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH:8]1([N:13]2[C:17]3[N:18]=[C:19]([NH2:22])[N:20]=[CH:21][C:16]=3[C:15]3[CH:23]=[CH:24][N:25]=[CH:26][C:14]2=3)[CH2:12][CH2:11][CH2:10][CH2:9]1.Cl[C:28]1[N:33]=[CH:32][C:31]([S:34]([N:37]2[CH2:42][CH2:41][N:40](C(OC(C)(C)C)=O)[CH2:39][CH2:38]2)(=[O:36])=[O:35])=[CH:30][CH:29]=1>>[CH:8]1([N:13]2[C:17]3[N:18]=[C:19]([NH:22][C:28]4[CH:29]=[CH:30][C:31]([S:34]([N:37]5[CH2:38][CH2:39][NH:40][CH2:41][CH2:42]5)(=[O:36])=[O:35])=[CH:32][N:33]=4)[N:20]=[CH:21][C:16]=3[C:15]3[CH:23]=[CH:24][N:25]=[CH:26][C:14]2=3)[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(Cl)nc2)CC1
Reactant: Nc1ncc2c3ccncc3n(C3CCCC3)c2n1
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1ccc(Nc2ncc3c4ccncc4n(C4CCCC4)c3n2)nc1)N1CCNCC1

Procedure:
Compound 359 was prepared as a white solid (TFA salt) from compound 4 and compound 360 using chemistry similar to that described in example 200. 1H NMR (500 MHz, CD3OD) δ ppm 9.59 (1 H, s), 9.29 (1 H, s), 8.72-8.78 (2 H, m), 8.63-8.66 (1 H, m), 8.61 (1 H, d), 8.22 (1 H, dd, J=8.8, 2.4 Hz), 5.51 (1 H, quin, J=8.9 Hz), 3.37 (8 H, s), 2.46-2.60 (2 H, m), 2.13-2.34 (4 H, m), 1.87-2.01 (2 H, m). LCMS-ESI (POS), M/Z, M+1. Found 478.9.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH:4]([CH3:8])[N:3]1[C:9]1[S:10][C:11]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:12]=2[N:13]=1.Br[CH2:23][CH2:24][O:25][Si](C(C)(C)C)(C)C.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:8][CH:4]1[N:3]([C:9]2[S:10][C:11]3[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:2]([CH3:1])[CH2:7][N:6]([CH2:23][CH2:24][OH:25])[CH2:5]1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: CC1CNCC(C)N1c1nc2ccc(C(F)(F)F)cc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1CN(CCO)CC(C)N1c1nc2ccc(C(F)(F)F)cc2s1
Temperature: 60 °C
Reaction time: 20 h
Yield: 65 %

Procedure:
A mixture of 2-(2,6-dimethyl piperazine-1-yl)-6-trifluoromethyl benzothiazole (360 mg), (2-bromoethoxy)-t-butyldimethyl silane (257 uL), potassium carbonate (157 mg) and dimethylformamide (2 mL) was stirred at 60° C. for 20 hours. To the reaction solution was added water and extracted with ethyl acetate. The organic layer was washed with water and dried over sodium carbonate. After evaporating the solvent, the residue was purified by column chromatograph on silica gel to give the title compound (265 mg). Yield: 65%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH:9]([CH3:11])[CH3:10])[N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20]3)=[C:15]([O:25][CH3:26])[CH:14]=2)[N:3]=1.[OH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]([F:37])([F:36])[F:35]>C(OCC)(=O)C>[CH:9]([O:8][C:6]1[N:7]=[C:2]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:35])([F:36])[F:37])[N:3]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20]3)=[C:15]([O:25][CH3:26])[CH:14]=2)[N:5]=1)([CH3:11])[CH3:10]
Reactant: Oc1ccccc1C(F)(F)F
Reactant: COc1cc(Nc2nc(Cl)nc(OC(C)C)n2)ccc1-n1cnc(C)c1
Solvent: CCOC(C)=O
Product: COc1cc(Nc2nc(Oc3ccccc3C(F)(F)F)nc(OC(C)C)n2)ccc1-n1cnc(C)c1
Yield: 99 %

Procedure:
This compound was prepared from (4-chloro-6-isopropoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine and 2-hydroxy benzotrifluoride in analogy to example 3. Chromatography on silica gel using ethyl acetate as an eluent gave the title compound as a colorless solid in 99% yield.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH2:21])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>C(OCC)(=O)C.CCCCCC>[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:21][C:16]2[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]3[O:12][C:11]([CH3:24])([CH3:23])[CH:10]([C:7]4[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=4)[C:14]=3[C:15]=2[CH3:22])=[O:31])=[CH:28][CH:27]=1
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(C)c2c(c(C)c1NC(=O)c1ccc(Cl)cc1)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Yield: 71 %

Procedure:
By using 3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine and 4-chlorobenzoyl chloride, the title compound was synthesized according to Example 1b. Yield: 71%. Melting point: 201-203° C. (Ethyl acetate-hexane)