Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:21])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:8][N:7]=1.C(O)[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(OCC)(=O)C>S(=O)(=O)(O)O.C1(C)C=CC=CC=1>[CH2:1]([O:2][C:3](=[O:22])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:21])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:8][N:7]=1)[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: OCCc1ccccc1
Reactant: COC(=O)COc1ccc(C(=O)Nc2ccc(F)cc2)cn1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(COc1ccc(C(=O)Nc2ccc(F)cc2)cn1)OCCc1ccccc1
Yield: 4.2 %

Procedure:
A solution of [5-(4-fluoro-phenylcarbamoyl)-pyridin-2-yloxy]-acetic acid methyl ester (0.020 g, 0.66 mmole), phenethyl alcohol (0.078 mL, 0.66 mmol) and sulfuric acid (1 drop) in toluene (3 mL) was heated at reflux. After 4 h the reaction mixture was poured into ethyl acetate and washed with saturated sodium bicarbonate and dried over sodium sulfate. Removal of the solvents provided a solid. Purification by trituration using ethyl acetate/hexanes gave 0.011 g (42%) of the titled product as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 10.29 (s. H); 8.65 (m, 1H); 8.23 (m, 1H); 7.74 (m, 2H); 7.01–7.27 (m, 8H); 4.94 (s, 2H); 4.27 (m, 2H); 2.85 (m, 2H); MS (EI) m/z 393.03 (M−H)−.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[N:14]=[CH:13][N:12]=[C:11]3[C:7]=2[N:8]=[CH:9][N:10]3[C@H:15]2[CH2:19][CH2:18][C@@H:17]([CH2:20][OH:21])[O:16]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:29](Cl)(=[O:35])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>CN(C)C1C=CN=CC=1.C(#N)C>[CH:1]1([CH2:4][NH:5][C:6]2[N:14]=[CH:13][N:12]=[C:11]3[C:7]=2[N:8]=[CH:9][N:10]3[C@H:15]2[CH2:19][CH2:18][C@@H:17]([CH2:20][O:21][C:29](=[O:35])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[O:16]2)[CH2:2][CH2:3]1
Reactant: CCCCCC(=O)Cl
Reactant: OC[C@@H]1CC[C@H](n2cnc3c(NCC4CC4)ncnc32)O1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCCC(=O)OC[C@@H]1CC[C@H](n2cnc3c(NCC4CC4)ncnc32)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 40.7 %

Procedure:
6-(Cyclopropylmethylamino)-9-[(2R,5S)-tetrahydro-5-(hydroxymethyl)-2-furyl]-9H-purine (0.503 g, 1.7 mmoles), triethylamine (2.0 mL, 14 mmoles, Aldrich Chemical Co., Madison, Wis.), and 4-dimethylaminopyridine (10 mg, 0.1 mmoles, Aldrich Chemical Co., Madison, Wis.) were dissolved in 50 mL acetonitrile. Hexanoyl chloride (980 μl, 7.0 mmoles, Aldrich Chemical Co., Madison, Wis.) was added and the reaction was stirred at room temperature for 3 hours. The reaction was quenched with methanol and solvents were evaporated in vacuo. The residue was dissolved in 25 mL ethyl acetate and undissolved salts were removed by filtration. After evaporation of the ethyl acetate, the residue was dissolved in methanol and passed over a silica gel column (4.8×13 cm). The product containing fractions were combined, concentrated, and chromatographed on a Chromatotron (4 mm silica gel plate) with a mixture of hexane:acetone (8:2). The product was further purified on the Chromatotron (2 mm silica gel plate) with a mixture of chloroform:acetone (99:1). Lyophilization afforded 0.268 g of 6-(cyclopropylmethylamino)-9-[(2R,5S)-5-[(hexanoyloxy)methyl]-tetrahydro-2-furyl]-9H-purine as an oil (40% yield).
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([N:19]2[C:20]3[C:16](=[CH:15][C:14]([C:12]([N:9]4[CH2:8][CH2:7][N:6]([CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5]5)[CH2:11][CH2:10]4)=[O:13])=[CH:22][CH:21]=3)[CH:17]=[C:18]2[C:23]([N:25]2[CH2:30][CH2:29][S:28](=[O:31])(=[O:32])[CH2:27][CH2:26]2)=[O:24])=[CH:36][CH:35]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCS(=O)(=O)CC1)n2-c1ccc(Cl)cc1)N1CCN(C2CCCC2)CC1
Yield: 34 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone (example 34), 4-chlorophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless solid (34%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[CH:6]=[CH:5][CH:4]=1.[C:20](Cl)(=[O:23])[CH2:21][CH3:22].CN(C)C(=O)C>O>[CH3:1][N:2]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[N:8]=1)[C:20](=[O:23])[CH2:21][CH3:22]
Reactant: CCC(=O)Cl
Reactant: CNc1cccc(-c2nc(=O)c3ccccc3s2)n1
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCC(=O)N(C)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 50.1 %

Procedure:
A mixture of 2-(6-methylamino-2-pyridyl)-4H-1,3-benzothiazine-4-one (0.25 g, 0.92 mmol), propionyl chloride (0.29 g, 3.1 mmol) and N,N-dimethylacetamide (10 ml) was stirred at 80° C. for 2 hrs. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was successively washed with saturated aqueous sodium hydrogen carbonate solution and brine and dried. The solvent was evaporated. The residue was recrystallized from tetrahydrofuran-hexane to give the titled compound (0.15 g, 49%).
Reaction SMILES: S(=O)(=O)(O)[OH:2].[F:6][C:7]1[CH:22]=[CH:21][C:10]2[N:11]([C:16](=[O:20])[CH:17]=NO)[CH:12]([CH3:15])[CH2:13][O:14][C:9]=2[C:8]=1[F:23]>O>[F:23][C:8]1[C:7]([F:6])=[CH:22][C:21]2=[C:10]3[C:9]=1[O:14][CH2:13][CH:12]([CH3:15])[N:11]3[C:16](=[O:20])[C:17]2=[O:2]
Reactant: CC1COc2c(ccc(F)c2F)N1C(=O)C=NO
Reactant: O=S(=O)(O)O
Solvent: O
Product: CC1COc2c(F)c(F)cc3c2N1C(=O)C3=O
Temperature: 80 °C

Procedure:
A solution of 45 mL of 98% sulfuric acid in 18 mL of water is heated to 50° C. to 60° C. and treated portionwise over 30 minutes with 10.5 g (41 mmol) of (7,8-difluoro-3-methyl-2,3-dihydro-1,4-benzoxazin-4-yl)oxoacetaldehyde oxime (Example 29). After the addition is complete, the reaction is heated to 80° C. for 15 minutes and poured onto 200 mL of ice and water. The mixture is stirred until the ice melts and the solid is removed by filtration, washed with water and the wet filter cake is dissolved in dichloromethane. The organic solution is washed with water (2×200 mL), dried (MgSO4), filtered and concentrated in vacuo affording 7.1 g of the title compound, mp 169–171° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11]O.C(Br)(Br)(Br)[Br:14]>>[Br:14][CH2:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1cc([N+](=O)[O-])ccc1CO
Reactant: BrC(Br)(Br)Br
Product: Cc1cc([N+](=O)[O-])ccc1CBr
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4.55 g (27.2 mmol) (2-methyl-4-nitro-phenyl)-methanol 10.8 g (40.8 mmol) triphenylphosphine and 13.7 g (40.8 mmol) carbon tetrabromide is added at 0° C. The reaction mixture is stirred at room temperature for 1 h. After that the reaction mixture is filtered and the filtrate is concentrated in vacue. The residue is purified by chromatography (silicagel, 100% hexane=>100% EtOAc) to afford the title compound as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[NH:5][C:6](=[O:9])[CH2:7][Br:8].[C:13](Cl)(=[O:16])[CH2:14][CH3:15].N1C=CC=CC=1>C(Cl)Cl>[C:13]([O:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[NH:5][C:6](=[O:9])[CH2:7][Br:8])(=[O:16])[CH2:14][CH3:15]
Reactant: O=C(CBr)Nc1cccc(O)c1
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(=O)Oc1cccc(NC(=O)CBr)c1
Reaction time: 0.33 h

Procedure:
The anilide, 3'-hydroxy bromoacetanilide, 6.9 g. and propionyl chloride (3.1 g., 0.033 mole) are combined in 120 ml. of methylene chloride as a solvent. Pyridine (2.6 g., 0.033 mole) is added dropwise. A slightly exothermic reaction takes place during the addition. Stirring is continued at room temperature for 20 minutes. A clear solution is obtained. The material is washed sucessively with water, dilute hydrochloric acid and again with water. The organic layer is dried over anhydrous magnesium sulfate and the solvent evaporated. The resulting material is recrystallized from a mixture of ethylacetate and ether. There is obtained 6.5 g. of the title compound, m.p. 85°-88° C.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[CH:25]=[CH:24][C:19]([C:20]([NH:22][CH3:23])=[O:21])=[CH:18][CH:17]=4)[S:15][C:8]=23)=[C:4]([F:28])[CH:3]=1.[CH3:29][N:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36](O)=[O:37])[C:31]1=[O:39]>>[F:28][C:4]1[CH:3]=[C:2]([NH:1][C:36]([C:32]2[C:31](=[O:39])[N:30]([CH3:29])[CH:35]=[CH:34][CH:33]=2)=[O:37])[CH:27]=[CH:26][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]3[CH:25]=[CH:24][C:19]([C:20](=[O:21])[NH:22][CH3:23])=[CH:18][CH:17]=3)[S:15][C:8]=12
Reactant: CNC(=O)c1ccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)cc1
Reactant: Cn1cccc(C(=O)O)c1=O
Product: CNC(=O)c1ccc(-c2cc3nccc(Oc4ccc(NC(=O)c5cccn(C)c5=O)cc4F)c3s2)cc1
Yield: 30 %

Procedure:
Prepared from 4-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)-N-methylbenzamide (Example 95, Step A) and 1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid according to the procedure of Example 89. The crude was purified by silica gel flash column chromatography (3% MeOH in CH2Cl2) to afford 11.1 mg (30%) of the desired product. LRMS (ESI pos) m/e 529.2 (M+1). 1H NMR (400 MHz, CDCl3/CD3OD) δ 8.59 (dd, 1H), 8.46 (d, 1H), 8.01 (dd, 1H), 7.94 (m, 2H), 7.88 (m, 3H), 7.67 (s, 1H), 7.47 (m, 1H), 7.36 (t, 1H), 6.64 (m, 2H), 3.75 (s, 3H), 2.98 (s, 3H); 19F NMR (376 MHz, CDCl3/CD3OD) 6-128.2.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:29])[CH2:14][CH2:15][C:16]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]=[N:27][OH:28])[CH:21]=1)=[O:17])(C)(C)C>ClCCl>[OH:28][N:27]=[CH:26][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[CH2:19][NH:18][C:16](=[O:17])[CH2:15][CH2:14][C:13]([OH:29])=[O:12]
Reactant: CC(C)(C)OC(=O)CCC(=O)NCc1cccc(C=NO)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCC(=O)NCc1cccc(C=NO)c1
Temperature: 25 °C
Reaction time: 0.92 h
Yield: 145 %

Procedure:
Trifluoroacetic acid (7 ml) was added to a solution of crude N-[3-((hydroxyimino)methyl)benzyl]succinamic acid tert-butyl ester (249 mg, 0.81 mmol) in dichloromethane (7 ml). The reaction mixture was stirred for 55 min at room temperature. The solvent was removed in vacuo. The residue was redissolved in dichloromethane (50 ml). The solvent was removed in vacuo. The latter procedure was repeated twice to give 294 mg of crude N-[3-(hydroxyiminomethyl)benzyl]succinamic acid, which was used in the next step without further purification.
Reaction SMILES: [C:1]([O-])([O-])=O.[K+].[K+].[CH3:7][C:8]([CH3:28])([CH3:27])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]1[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19]1)=[O:10].IC>CN(C=O)C>[CH3:7][C:8]([CH3:28])([CH3:27])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]1[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]1[CH3:1])=[O:10]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)C(=O)Nc1ccccc1C1Cc2ccccc2N1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1c2ccccc2CC1c1ccccc1NC(=O)C(C)(C)C
Temperature: 25 °C
Yield: 46.2 %

Procedure:
To a mixture of 9.40 g K2CO3 and 10.05 g 2,2-dimethyl-N-[2-(2,3-dihydro-1H-indol-2-yl)phenyl]propanamide in 125 ml DMF at 0° C., was added 3.64 ml iodomethane. The resulting mixture was stirred twenty-eight hours at room temperature. Upon dilution with water, a solid precipitated, which was collected and washed with water. Recrystallization from EtOH/water yielded 4.86 g solid, m.p. 133°-135° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[CH2:7][CH2:8][CH2:9][CH:10]([NH2:12])[CH2:11][C:5]=2[CH:4]=1.[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][C:26]([C@@H:29]([O:32][Si](CC)(CC)CC)[CH2:30]I)=[CH:25][C:24]=1[NH:40][S:41]([CH3:44])(=[O:43])=[O:42])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)C(C)C)(C)C.S([O-])(O)=O.[Na+]>CN(C)C(=O)C>[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][C:26]([C@@H:29]([OH:32])[CH2:30][NH:12][CH:10]2[CH2:9][CH2:8][CH2:7][C:6]3[CH:13]=[CH:14][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[CH2:11]2)=[CH:25][C:24]=1[NH:40][S:41]([CH3:44])(=[O:42])=[O:43])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC[Si](CC)(CC)O[C@@H](CI)c1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1
Reactant: COc1ccc2c(c1)CC(N)CCC2
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CC(NC[C@H](O)c1ccc(OCc3ccccc3)c(NS(C)(=O)=O)c1)CCC2
Yield: 20 %

Procedure:
Under nitrogen, a solution of 3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-ylamine (720 mg), N-[2-benzyloxy-5-[(1R)-2-iodo-1-(triethylsilyloxy)ethyl]phenyl]-methanesulfonamide (2.1 g) and N,N-diisopropylethylamine (2.6 ml) in N,N-dimethylacetamide (10 ml) was stirred at 110° C. for 96 hours. The resulting mixture was poured into aqueous 10% sodium hydrogensulfite and extracted with ethyl acetate. The organic layer was successively washed with saturated aqueous sodium hydrogencarbonate and brine, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (chloroform:methanol=40:1 to 20:1) to give N-[2-benzyloxy-5-[(1R)-1-hydroxy-2-(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-ylamino)ethyl]phenyl]methanesulfonamide (381 mg).
Reaction SMILES: [CH3:1][CH:2]([NH:12][C:13](=[O:24])[CH:14]=[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=1)[CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[C:25]1(=[O:32])[O:31][C:29](=[O:30])[CH2:28][CH2:27][CH2:26]1>C1(C)C=CC=CC=1>[CH3:1][CH:2]([NH:12][C:13](=[O:24])[CH:14]=[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:25](=[O:32])[CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])[CH:18]=1)[CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCC(C)NC(=O)C=C(C)c1cccc(N)c1
Reactant: O=C1CCCC(=O)O1
Solvent: Cc1ccccc1
Product: CCCCCCCCCC(C)NC(=O)C=C(C)c1cccc(NC(=O)CCCC(=O)O)c1
Reaction time: 0.08 h

Procedure:
A stirred solution of 0.61 g. of N-(1-methyldecyl)-3-(3-aminophenyl)-2-butenamide, prepared in a manner analogous to Preparation 27, in 25 ml. of toluene, was heated on a steam bath and then 0.23 g. of glutaric anhydride was added in one portion. After 5 minutes, the reaction mixture was cooled and the solvent was removed by evaporation in vacuo. The residue was recrystallized twice from acetonitrile, to give 370 mg. of the title compound, m.p. 136°-140° C. This latter material was recrystallized from isopropanol/water to give 196 mg. of material having a melting point of 140°-141.5° C. The IR spectrum (KBr disc) showed absorptions at 3390, 2895, 1724, 1681, 1613 and 1575 cm-1. The NMR spectrum (DMSO-d6) showed absorptions at 0.90 (m, 3H), 1.08 (m, 3H), 1.26 (s, 16H), 1.89 (m, 2H), 2.40 (m, 7H, under DMSO-d6), 3.80 (m, 1H), 6.19 (s, 1H), 7.51 (m, 6H), and 9.90 (s, 1H) ppm.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:17](=O)[CH3:18])=[CH:4][S:5][C:6]=1[C:7]1[CH:16]=[CH:15][C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=1.[NH:20]([C:22]([C:24]1[S:28][C:27]([C:29]([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([C:39](=[O:44])[NH:40][CH2:41][CH2:42][OH:43])=[CH:35][CH:34]=2)=[O:30])=[CH:26][CH:25]=1)=[O:23])[NH2:21]>>[OH:1][C:2]1[C:3]([C:17](=[N:21][NH:20][C:22]([C:24]2[S:28][C:27]([C:29]([NH:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([C:39](=[O:44])[NH:40][CH2:41][CH2:42][OH:43])=[CH:35][CH:34]=3)=[O:30])=[CH:26][CH:25]=2)=[O:23])[CH3:18])=[CH:4][S:5][C:6]=1[C:7]1[CH:16]=[CH:15][C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=1
Reactant: CC(=O)c1csc(-c2ccc3c(c2)CCCC3)c1O
Reactant: NNC(=O)c1ccc(C(=O)NCc2ccc(C(=O)NCCO)cc2)s1
Product: CC(=NNC(=O)c1ccc(C(=O)NCc2ccc(C(=O)NCCO)cc2)s1)c1csc(-c2ccc3c(c2)CCCC3)c1O
Yield: 64.9 %

Procedure:
Synthesis was carried out in the same manner as in Synthetic Example 1 by using 24.4 mg (0.0895 mmol) of 1-[4-hydroxy-5-(5,6,7,8-tetrahydronaphthalen-2-yl)thiophen-3-yl]ethanone and 32.6 mg (0.0900 mmol) of 5-(hydrazinecarbonyl)-N-[4-(2-hydroxyethylcarbamoyl)benzyl]thiophene-2-carboxamide to obtain the desired product (35.8 mg, yield 65%).
Reaction SMILES: C1(C2C3C=CC=CC=3OC=2)C=CC=CC=1.C(Cl)(=O)C1C=CC(OC)=CC=1.C[O:28][C:29]1[CH:51]=[CH:50][C:32]([C:33]([C:35]2[O:36][C:37]3[CH:49]=[CH:48][CH:47]=[CH:46][C:38]=3[C:39]=2[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:34])=[CH:31][CH:30]=1>>[OH:28][C:29]1[CH:30]=[CH:31][C:32]([C:33]([C:35]2[O:36][C:37]3[CH:49]=[CH:48][CH:47]=[CH:46][C:38]=3[C:39]=2[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:34])=[CH:50][CH:51]=1
Reactant: COc1ccc(C(=O)c2oc3ccccc3c2-c2ccccc2)cc1
Agent: COc1ccc(C(=O)Cl)cc1
Agent: c1ccc(-c2coc3ccccc23)cc1
Product: O=C(c1ccc(O)cc1)c1oc2ccccc2c1-c1ccccc1

Procedure:
Acylation of 3-phenylbenzofuran with p-anisoyl chloride over a 4 hour period as described in the procedure of Example 1 followed by demethylation of the 2-(4-methoxybenzoyl)-3-phenylbenzofuran thus formed as previously described gives 2-(4-hydroxybenzoyl)-3-phenylbenzofuran.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([CH3:12])=[CH:10][C:9]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)=[N:8][C:7]=12)#[CH:2].[NH2:23][C:24]1[CH:29]=[CH:28][C:27](Br)=[CH:26][N:25]=1>>[CH3:12][C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:27]3[CH:28]=[CH:29][C:24]([NH2:23])=[N:25][CH:26]=3)=[C:7]2[N:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:15][CH:14]=2)[CH:10]=1
Reactant: C#Cc1cnn2c(C)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Nc1ccc(Br)cn1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc2c(C#Cc3ccc(N)nc3)cnn12

Procedure:
The title compound was prepared from 3-ethynyl-7-methyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.12) (151 mg, 0.5 mmol) and 2-amino-5-bromopyridine (87 mg, 0.5 mmol) according to general procedure II. Obtained as an orange solid (37 mg, 19%). MS (ISP) 394.0 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([NH:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19](I)[CH:18]=4)[N:14]=[CH:15][C:10]=3[CH2:9][C:8](=[O:24])[NH:7][C:6]=2[CH:25]=1.[CH2:26]([N:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1)[C:27]#[CH:28]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([NH:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:28]#[C:27][CH2:26][N:29]5[CH2:33][CH2:32][CH2:31][CH2:30]5)[CH:18]=4)[N:14]=[CH:15][C:10]=3[CH2:9][C:8](=[O:24])[NH:7][C:6]=2[CH:25]=1
Reactant: O=C1Cc2cnc(Nc3cccc(I)c3)nc2-c2ccc(Cl)cc2N1
Reactant: C#CCN1CCCC1
Product: O=C1Cc2cnc(Nc3cccc(C#CCN4CCCC4)c3)nc2-c2ccc(Cl)cc2N1

Procedure:
In a manner similar to that described for Method O, 9-chloro-2-(3-iodo-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one (v-j) and 1-(prop-2-ynyl)pyrrolidine were converted to I-89 (46%): MS (AA) Rt=1.32 min, m/z=444 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4](OS(C)(=O)=O)[CH2:3]1.[N-:13]=[N+:14]=[N-:15].[Na+].O>CN(C=O)C>[N:13]([CH:4]1[CH2:5][CH2:6][CH2:7][N:2]([CH3:1])[CH2:3]1)=[N+:14]=[N-:15]
Reactant: [N-]=[N+]=[N-]
Reactant: CN1CCCC(OS(C)(=O)=O)C1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCCC(N=[N+]=[N-])C1
Temperature: 80 °C

Procedure:
To a stirred solution of methanesulfonic acid 1-methyl-piperidin-3-yl ester (A) (3 g, 0.17 mmol) in DMF (35 cm3) was added sodium azide (11 g, 0.17 mol). The reaction was then heated to 80° C. for 16 h, and allowed to cool before water (80 cm3) was added and the organic material was extracted into ethyl acetate (80 cm3). The aqueous layer was then extracted with a further portion ethyl acetate (60 cm3) and the combined organic collections and washed with saturated aqueous sodium chloride solution (100 cm3). The organic mixture was and dried over sodium sulfate and then evaporated under reduced pressure to afford the title compound as a crude oil, which was used as crude in next reaction.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@H:3]([NH2:10])[C@@H:2]1[OH:11].C(N(CC)CC)C.[C:19](Cl)(=[O:23])[CH2:20][CH2:21][CH3:22]>C1COCC1>[OH:11][C@@H:2]1[CH2:1][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@H:3]1[NH:10][C:19](=[O:23])[CH2:20][CH2:21][CH3:22]
Reactant: N[C@H]1c2ccccc2C[C@H]1O
Reactant: CCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCC(=O)N[C@H]1c2ccccc2C[C@H]1O
Temperature: 0 °C

Procedure:
(1S, 2R)-cis-1-Amino-2-indanol (XIV, 1.5 g) was dissolved with triethylamine (1.5 mL) in dry THF (45 mL), and cooled to 0° C. Butyryl chloride (XIII, 1.05 mL) was added by syringe, and the resultant solution stirred 0° C. for 20 min, whereupon the reaction mixture was partitioned between half-saturated NH4Cl (45 mL) and EtOAc (2×45 mL). The combined organic layers were dried dried (MgSO4), filtered, and concentrated under reduced pressure to give a solid, which was taken to the next reaction without further purification.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=4)[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[NH:29]1[CH2:34][CH2:33][CH:32]([CH2:35][NH:36]C(=O)OC(C)(C)C)[CH2:31][CH2:30]1>>[CH3:22][N:20]1[CH:21]=[C:17]([C:14]2[CH:15]=[C:16]3[C:8]([C:6]4[N:7]=[C:2]([N:29]5[CH2:34][CH2:33][CH:32]([CH2:35][NH2:36])[CH2:31][CH2:30]5)[CH:3]=[CH:4][CH:5]=4)=[N:9][NH:10][C:11]3=[CH:12][N:13]=2)[CH:18]=[N:19]1
Reactant: Cn1cc(-c2cc3c(-c4cccc(F)n4)nn(C4CCCCO4)c3cn2)cn1
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Product: Cn1cc(-c2cc3c(-c4cccc(N5CCC(CN)CC5)n4)n[nH]c3cn2)cn1
Yield: 63 %

Procedure:
Following the procedures as described in Example 189, 3-(6-fluoropyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine and tert-butyl piperidin-4-ylmethylcarbamate were reacted and the product was deprotected to give 182 as a white solid (63% over two steps). 1H NMR (400 MHz, DMSO) δ 9.03 (s, 1H), 8.54 (s, 1H), 8.11 (s, 1H), 7.82 (s, 1H), 7.63 (t, J=8.0 Hz, 1H), 7.41 (d, J=7.4 Hz, 1H), 6.84 (d, J=8.5 Hz, 1H), 4.50 (d, J=12.1 Hz, 2H), 3.91 (s, 3H), 2.99 (t, J=12.5 Hz, 2H), 2.53-2.44 (m, 4H), 1.92-1.74 (m, 3H), 1.58 (s, 1H), 1.31-1.18 (m, 2H). LC/MS: m/z 389.2 [M+1]
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Br)=[O:4].CN(C)C1C=CC=CC=1.S(=O)(=O)(O)O.[C:21]([OH:25])([CH3:24])([CH3:23])[CH3:22]>C(Cl)(Cl)Cl>[Br:1][CH:2]([CH3:6])[C:3]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:4]
Reactant: CC(Br)C(=O)Br
Reactant: CC(C)(C)O
Agent: O=S(=O)(O)O
Solvent: CN(C)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(Br)C(=O)OC(C)(C)C
Yield: 86.7 %

Procedure:
(a) A solution of 2-bromopropionyl bromide (25 g.) in dry chloroform (50 ml.) was dropwise added with stirring and ice-cooling to a solution of N,N-dimethylaniline (24 g.) in t-butanol (11 g.) and the mixture was refluxed for 2 hours. After cooling, the reaction mixture was poured into 6N sulfuric acid (150 ml.) and extracted with ether. The extract was in turn washed with 6N sulfuric acid, water, a 10% potassium carbonate aqueous solution and water and dried over magnesium sulfate. The solvent was distilled off to give oil of t-butyl 2-bromopropionate (21 g.).
Reaction SMILES: C(O[CH:4]=[C:5]1[C:16]2[C:8](=[CH:9][CH:10]=[C:11]3[C:15]=2[S:14][CH:13]=[N:12]3)[NH:7][C:6]1=[O:17])C.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][S:26]([NH2:29])(=[O:28])=[O:27])=[CH:21][CH:20]=1>>[O:17]=[C:6]1[C:5](=[CH:4][NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][S:26]([NH2:29])(=[O:27])=[O:28])=[CH:21][CH:20]=2)[C:16]2[C:8](=[CH:9][CH:10]=[C:11]3[C:15]=2[S:14][CH:13]=[N:12]3)[NH:7]1
Reactant: Nc1ccc(CS(N)(=O)=O)cc1
Reactant: CCOC=C1C(=O)Nc2ccc3ncsc3c21
Product: NS(=O)(=O)Cc1ccc(NC=C2C(=O)Nc3ccc4ncsc4c32)cc1
Yield: 25 %

Procedure:
The title compound was prepared in 25% yield from 8-ethoxymethylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one and 4-aminophenylmethane sulfonamide according to Procedure J: 1H NMR (DMSO-d6): δ 11.1 (d,1H), 10.9 (s, 1H), 9.3 (s, 1H), 8.1 (d, 1H), 7.8 ( d, 1H), 7.5 (q, 4H), 7.2 (d, 1H), 6.9 (s, 2H), 4.2 (s, 2H); APCI−MS m/z 387 (M+H)+.