Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:12]1[CH:13]=[C:14]([C:31](=[O:33])[CH3:32])[CH:15]=[C:16]([N:20]2[CH2:24][C@@H:23]([O:25][CH2:26][O:27][CH3:28])[C@H:22]([O:29][CH3:30])[CH2:21]2)[C:17]=1[O:18][CH3:19])([CH3:11])([CH3:10])[CH3:9].[Br:34]N1C(=O)CCC1=O>O1CCCC1.C(=O)([O-])O.[Na+].C(OCC)(=O)C>[Br:34][CH2:32][C:31]([C:14]1[CH:15]=[C:16]([N:20]2[CH2:24][C@@H:23]([O:25][CH2:26][O:27][CH3:28])[C@H:22]([O:29][CH3:30])[CH2:21]2)[C:17]([O:18][CH3:19])=[C:12]([C:8]([CH3:11])([CH3:9])[CH3:10])[CH:13]=1)=[O:33]
Reactant: O=C1CCC(=O)N1Br
Reactant: COCO[C@@H]1CN(c2cc(C(C)=O)cc(C(C)(C)C)c2OC)C[C@H]1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COCO[C@@H]1CN(c2cc(C(=O)CBr)cc(C(C)(C)C)c2OC)C[C@H]1OC
Reaction time: 0.33 h
Yield: 89.6 %

Procedure:
Triethylamine (0.46 ml, 3.3 mmol) and tert-butyl dimethylsilyltrifluoromethanesulfonate (0.37 ml, 1.6 mmol) were added dropwise in that order to a solution of 1-{3-(tert-butyl)-4-methoxy-5-[(3R,4R)-3-methoxy-4-(methoxymethoxy)tetrahydro-1H-1-pyrrolyl]phenyl}-1-ethanone (397 mg, 1.09 mmol) in tetrahydrofuran (4 ml) while cooling on ice, and the mixture was stirred at the same temperature for 20 minutes. N-Bromosuccinimide (290 mg, 1.63 mmol) was then added and stirring was continued at the same temperature for 15 minutes. After completion of the reaction, the mixture was diluted with saturated aqueous sodium hydrogencarbonate and ethyl acetate and the organic layer was separated. The organic layer was washed with brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (434 mg, 90%) as a light yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:26])=[C:5]([C:17]([O:24][CH3:25])=[C:18]([O:22][CH3:23])[C:19]=1[O:20][CH3:21])[CH2:6][C:7]1[C:8]([OH:16])=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11].O.[C:28](OC(=O)C)(=[O:30])[CH3:29]>>[CH3:1][O:2][C:3]1[C:4]([CH3:26])=[C:5]([C:17]([O:24][CH3:25])=[C:18]([O:22][CH3:23])[C:19]=1[O:20][CH3:21])[CH2:6][C:7]1[C:8]([O:16][C:28](=[O:30])[CH3:29])=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11]
Reactant: CC(=O)OC(C)=O
Reactant: COc1c(C)c(Cc2cccc(C(=O)O)c2O)c(OC)c(OC)c1OC
Solvent: O
Product: COc1c(C)c(Cc2cccc(C(=O)O)c2OC(C)=O)c(OC)c(OC)c1OC
Temperature: 65 °C
Yield: 68 %

Procedure:
3-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-hydroxybenzoic acid (0.288 g, 0.795 mmol) was dissolved in acetic anhydride (5 ml) and the resulting solution was stirred under heating at 65° C. for 3 hours. The reaction solution was cooled and after adding thereto water (20 ml) and stirring at room temperature for 1 hour, extracted with ethyl acetate. The extract was washed with saturated brine and then dried, and the solvent was removed by distillation. The residue was purified by silica gel column chromatography (chloroform:methanol=9:1) to obtain the titled compound (0.245 g, 0.541 mmol, 68%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:6][C:5]([C:13]2[CH:21]=[C:20]3[C:16]([CH:17]=[N:18][N:19]3S(C3C=CC(C)=CC=3)(=O)=O)=[C:15]([C:32]3[O:33][C:34]([CH3:37])=[N:35][N:36]=3)[CH:14]=2)=[CH:4][N:3]=1.[OH-].[Na+]>C(O)(C)C>[Cl:1][C:2]1[C:7]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:6][C:5]([C:13]2[CH:21]=[C:20]3[C:16]([CH:17]=[N:18][NH:19]3)=[C:15]([C:32]3[O:33][C:34]([CH3:37])=[N:35][N:36]=3)[CH:14]=2)=[CH:4][N:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2ncc3c(-c4nnc(C)o4)cc(-c4cnc(Cl)c(NS(C)(=O)=O)c4)cc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: Cc1nnc(-c2cc(-c3cnc(Cl)c(NS(C)(=O)=O)c3)cc3[nH]ncc23)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.2 %

Procedure:
N-(2-chloro-5-{4-(5-methyl-1,3,4-oxadiazol-2-yl)-1-[(4-methylphenyl)sulfonyl]-1H-indazol-6-yl}-3-pyridinyl)methanesulfonamide (16 mg, 0.029 mmol) and 2M sodium hydroxide (1 ml, 2.0 mmol) were placed in isopropanol (5 ml) and the mixture stirred at room temperature overnight. The solvent was removed and the residue partitioned between water (5 ml) and dichloromethane (5 ml). The aqueous was acidified to ˜pH 1 with 2M hydrogen chloride, then extracted with dichloromethane (20 ml). The organic layer was concentrated to give the title compound as a white solid (10 mg).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].N1C=CC=CC=1.[OH:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29]>CN(C1C=CN=CC=1)C.CC#N.C(Cl)Cl>[OH:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28]([NH:1][C:2]1[S:3][C:4]([S:10]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)(=[O:12])=[O:11])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8])=[O:29]
Reactant: NC(=O)c1cc(S(=O)(=O)N2CCOCC2)sc1N
Reactant: O=C(Cl)c1ccccc1O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CC#N
Product: NC(=O)c1cc(S(=O)(=O)N2CCOCC2)sc1NC(=O)c1ccccc1O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
2-Amino-5-(morpholine-4-sulfonyl)-thiophene-3-carboxylic acid amide (150 mg, 0.51 mmol) is mixed with pyridine (63 μL, 0.77 mmol) and DMAP (15 mg, 0.12 mmol) in MeCN (1 mL). 2-Hydroxy-benzoyl chloride (103 mg, 0.65 mmol) is dissolved in 2 mL of MeCN and added to the reaction mixture. The resulting solution is stirred at 60° C. for 2 h, then diluted with DCM and finally washed with aqueous NaHCO3. The organic phase is evaporated to yield a residue which is purified by preparative chromatography to afford the desired product.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]Br.C([NH:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)(=O)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:23][C:20]2[CH:19]=[CH:18][C:17]([NH2:16])=[CH:22][CH:21]=2)=[CH:19][CH:18]=1
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: BrCCCCCCCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Product: Nc1ccc(OCCCCCCCCCCOc2ccc(N)cc2)cc1

Procedure:
Tetrabutylammonium bromide was used as the phase transfer catalyst. It was added to the contents of the flask immediately following addition of the second portion of the 1,10-dibromodecane. The amount of catalyst was 0.50 grams, or 2.5 parts per hundred parts of 4-acetamidophenol.
Reaction SMILES: C(C(C)(CCCCCO)C)#N.[OH:12][C:13]1[C:20](O)=[C:19](CC)[CH:18]=[CH:17][C:14]=1[CH:15]=[O:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C([O:52][CH2:53][CH3:54])=O)=NC(OCC)=O>C1COCC1>[CH2:19]([C:18]1[C:53]([OH:52])=[CH:54][C:15]([OH:16])=[C:14]([CH:17]=1)[CH:13]=[O:12])[CH3:20]
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: CCc1ccc(C=O)c(O)c1O
Agent: CC(C)(C#N)CCCCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1cc(C=O)c(O)cc1O
Temperature: 25 °C

Procedure:
A 50 mL dry THF solution of the above prepare 2-cyano-2-methyl-7-hydroxyheptane and 2,3-dihydroxy-4-ethylbenzaldehyde was stirred at room temp. To this solution added triphenylphosphine (17.91 g, 68.3 mmol) and finally diethyl azodicarboxylate (11.89 g, 68.3 mmol). The reaction was stirred at room temp for 2 h 15 min. and then quenched with saturated NH4Cl solution. The THF was removed under vacuum and the resulting residue was dissolved in EtOAc and the EtOAc solution was washed with brine. The organic layer was dried over MgSO4. Filtration and solvent removal gave an orange solid. The product was purified by Waters Prep 500 chromatography using silica gel as a solid support and eluting with a gradient of 10% to 30% EtOAc/Hexane over 50 min. The desired product was obtained as a yellow oil (10.50 g, 51%).
Reaction SMILES: [NH2:1][CH:2]([CH2:13][O:14][CH:15]([F:17])[F:16])[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].C(N(CC)CC)C.[C:25](OC(=O)C)(=[O:27])[CH3:26]>C1COCC1.C(OCC)(=O)C>[C:25]([NH:1][CH:2]([CH2:13][O:14][CH:15]([F:16])[F:17])[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4])(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: NC(COC(F)F)C(=O)NCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)NC(COC(F)F)C(=O)NCc1ccccc1
Reaction time: 1 h
Yield: 59.1 %

Procedure:
2-Amino-N-benzyl-3-difluoromethoxy-propionamide (195 mg, 0.80) was mixed with triethylamine (322 mg, 3.19 mmol) in THF (5 mL). Acetic anhydride (98.5 mg, 0.96 mmol) was then added and the reaction mixture was stirred for 1 hour. The mixture was then diluted with ethyl acetate and washed with water. The organic layer was dried and concentrated. The residue was purified by column chromatography using hexanes:ethyl acetate (50:50 to 0:100). The isolated product was triturated with diethyl ether to give 2-acetylamino-N-benzyl-3-difluoromethoxy-propionamide (135 mg, 59%) as a white solid. 1H NMR (300 MHz, CDCl3): δ (ppm) 7.33 (m, 5H), 6.68 (br, 1H), 6.37 (br, 1H), 6.24 (t, 1H), 4.72 (q, 1H), 4.87 (d, 2H), 4.23 (dd, 1H), 4.01 (dd, 1H), 2.05 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([OH:10])[N:5]=[C:4]([CH3:11])[CH:3]=1.CO.[NH3:14]>>[NH2:14][C:2]1[C:7]([C:8]#[N:9])=[C:6]([OH:10])[N:5]=[C:4]([CH3:11])[CH:3]=1
Reactant: N
Reactant: Cc1cc(Cl)c(C#N)c(O)n1
Solvent: CO
Product: Cc1cc(N)c(C#N)c(O)n1
Temperature: 100 °C
Reaction time: 16 h
Yield: 66 %

Procedure:
To a pressure vessel were added 4-chloro-2-hydroxy-6-methylnicotinonitrile (600 mg, 3.6 mmol), ammonia methanol solution (7 mol/L, 15 mL) and magnetic stirrer. The pressure vessel was sealed, and stirred at 100° C. for 16 hours. After being cooled to room temperature, the solvent and excess ammonia were removed by rotary evaporation. The residue was purified by silica gel column chromatography with dichloromethane/methanol=10:1 to afford 4-amino-2-hydroxy-6-methylnicotinonitrile (350 mg, 66% yield) as a brown solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH2:20])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[C:21](Cl)(=[O:23])[CH3:22].C(=O)([O-])O.[Na+]>CN(C)C1C=CN=CC=1.CN(C)C(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:20][C:21](=[O:23])[CH3:22])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(-c2nc(N)sc2-c2ccnc(C)n2)c1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(=O)Nc1nc(-c2cccc(C)c2)c(-c2ccnc(C)n2)s1
Temperature: 80 °C
Reaction time: 14 h
Yield: 59.9 %

Procedure:
To a solution of [4-(3-methylphenyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-2-yl]amine (0.50 g, 1.8 mmol) and 4-dimethylaminopyridine (0.065 g, 0.53 mmol) in N,N-dimethylacetamide (10 mL) was added acetylchloride (0.19 mL, 2.7 mmol), and the mixture was stirred at 80° C. for 14 hrs. Into the reaction mixture was poured aqueous sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried and concentrated. The resulting crystals were recrystallized from ethyl acetate to give the title compound (0.35 g, yield 61%).
Reaction SMILES: [CH3:1][CH:2]([C:8]([O:10]CC)=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].N1C=CC=CC=1.[Br:19][C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH2:22]>>[Br:19][C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH:22][C:8](=[O:10])[CH:2]([CH3:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: Nc1ccccc1Br
Solvent: c1ccncc1
Product: CCOC(=O)C(C)C(=O)Nc1ccccc1Br

Procedure:
The ester was prepared according to Procedure A using diethyl 2-methylmalonate (6.00 mL, 34.9 mmol), pyridine (3.76 mL, 46.5 mmol) and 2-bromoaniline (4.00 g, 23.3 mmol). The residue was purified by column chromatography on silica gel (0-30% EtOAc/hexane) to give ethyl 3-(2-bromophenylamino)-2-methyl-3-oxopropanoate as a yellow solid. Mass Spectrum (ESI) m/e=300.0 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([S:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.[NH2:14][C:15]1[NH:16][C:17](=[O:23])[NH:18][C:19](=[O:22])[C:20]=1[NH2:21].O>CN(C)C=O>[NH2:14][C:15]1[NH:16][C:17](=[O:23])[NH:18][C:19](=[O:22])[C:20]=1[NH:21][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([S:12][CH3:13])=[CH:11][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(SC)ccc1C(=O)O
Reactant: Nc1[nH]c(=O)[nH]c(=O)c1N
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(SC)ccc1C(=O)Nc1c(N)[nH]c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Twenty grams of 2-methoxy-4-methylmercapto-benzoic acid is dissolved in 260 ml of dimethylformamide, mixed with 13 gm of N,N'-carbonyl-diimidazole, and stirred for 30 minutes at ambient temperature. Then, 13 gm of 4,5-diamino-pyrimidin-2,6-dione are added, and the reaction mixture is refluxed for three hours with stirring. After cooling, it is poured into 1 liter of water. The product precipitated is suction filtered, washed with water, and dried at 70° C. in a circulating air drier.
Reaction SMILES: [O:1]1[C:6]2=[CH:7][C:8]3[C:9](=[O:15])[C:10](=[O:14])[NH:11][C:12]=3[CH:13]=[C:5]2[O:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH:19]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O.O.C(OCC)(=O)C>[C:20]1([CH:19]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:11]2[C:12]3[CH:13]=[C:5]4[O:4][CH2:3][CH2:2][O:1][C:6]4=[CH:7][C:8]=3[C:9](=[O:15])[C:10]2=[O:14])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: O=C1Nc2cc3c(cc2C1=O)OCCO3
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2cc3c(cc21)OCCO3
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.4 %

Procedure:
To a cooled (0° C.) solution of 2,3-dihydro-6H-[1,4]dioxino[2,3-f]indole-7,8-dione (Lackey and Sternbach, Synthesis 1993:993-997) (1.73 g, 8.42 mmol) in anhydrous N,N-dimethylformamide (28 mL) was added sodium hydride (60% in mineral oil, 0.37 g, 9.26 mmol). The mixture was stirred at ambient temperature for 1 h and bromodiphenylmethane (2.39 g, 9.69 mmol) was added. After stirring at ambient temperature for 16 h, further bromodiphenylmethane (0.42 g, 1.68 mmol) was added. The mixture was stirred at ambient temperature for 8 h and then diluted with water (200 mL) and ethyl acetate (200 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous magnesium sulfate, filtered, concentrated in vacuo. The residue was purified by column chromatography, eluted with a 35% to 50% gradient of ethyl acetate in hexanes to afford 6-(diphenylmethyl)-2,3-dihydro-6H-[1,4]dioxino[2,3-f]indole-7,8-dione (0.7 g, 22%) as a red solid: 1H NMR (300 MHz, CDCl3) δ 7.41-7.28 (m, 10H), 7.16 (s, 1H), 6.94-6.91 (m, 1H), 5.96 (s, 1H), 4.27-4.14 (m, 4H); MS (ES+) m/z 371.9 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=2)[C:18](O)=[O:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:24][C:25]1[CH:26]=[C:27]([NH:32][C:33](=[O:45])[C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([N:40]3[CH2:44][CH2:43][CH2:42][CH2:41]3)[CH:35]=2)[CH:28]=[CH:29][C:30]=1[CH3:31]>>[CH3:31][C:30]1[CH:29]=[CH:28][C:27]([NH:32][C:33](=[O:45])[C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([N:40]3[CH2:41][CH2:42][CH2:43][CH2:44]3)[CH:35]=2)=[CH:26][C:25]=1[NH:24][C:18](=[O:19])[C:17]1[CH:21]=[CH:22][CH:23]=[C:15]([O:14][CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)[CH:16]=1
Reactant: Cc1ccc(NC(=O)c2cccc(N3CCCC3)c2)cc1N
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(C(=O)O)c2)CC1
Product: Cc1ccc(NC(=O)c2cccc(N3CCCC3)c2)cc1NC(=O)c1cccc(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Yield: 69 %

Procedure:
Using an analogous procedure to that described in the first paragraph of Example 25, 3-(1-tert-butoxycarbonylpiperidin-4-yloxy)benzoic acid was reacted with N-(3-amino-4-methylphenyl)-3-pyrrolidin-1-ylbenzamide to give N-[2-methyl-5-(3-pyrrolidin-1-ylbenzamido)phenyl]-3-(1-tert-butoxycarbonylpiperidin-4-yloxy)benzamide in 69% yield; NMR Spectrum: (DMSOd6) 1.39 (s, 9H), 1.56 (m, 2H), 1.87 (m, 2H), 3.2 (m, 2H), 3.64 (m, 2H), 4.62 (m, 1H), 6.69 (d, 1H), 7.02 (s, 1H), 7.2 (m, 4H), 7.42 (t, 1H). 7.56 (m, 3H), 7.79 (s, 1H), 9.83 (s, 1H), 10.05 (s, 1H); Mass Spectrum: M+H+ 599.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:36])[C:9]([C:11]1[S:35][C:14]2[C:15]3[CH:23]=[CH:22][C:21]([C:24]4[CH:25]=[C:26]([CH2:30][C:31]([O:33]C)=[O:32])[CH:27]=[CH:28][CH:29]=4)=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10].[OH-].[Li+]>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:36])[C:9]([C:11]1[S:35][C:14]2[C:15]3[CH:23]=[CH:22][C:21]([C:24]4[CH:25]=[C:26]([CH2:30][C:31]([OH:33])=[O:32])[CH:27]=[CH:28][CH:29]=4)=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10]
Reactant: COC(=O)Cc1cccc(-c2ccc3c(c2)OCCc2cc(C(=O)N(C)c4ccccc4Cl)sc2-3)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C(=O)c1cc2c(s1)-c1ccc(-c3cccc(CC(=O)O)c3)cc1OCC2)c1ccccc1Cl

Procedure:
Methyl 2-(3-(2-((2-chlorophenyl)(methyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)phenyl)acetate 200 was treated with lithium hydroxide in THF and water to give 198. MS: (ESI+) 503.7
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2)=[NH:4].[Cl:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[O:24][CH:25]([CH3:27])[CH3:26])[C:18](O)=O.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:14][C:15]1[CH:16]=[C:17]([C:18]2[O:1][N:2]=[C:3]([C:5]3[CH:6]=[C:7]4[C:11](=[CH:12][CH:13]=3)[NH:10][CH:9]=[CH:8]4)[N:4]=2)[CH:21]=[CH:22][C:23]=1[O:24][CH:25]([CH3:26])[CH3:27]
Reactant: N=C(NO)c1ccc2[nH]ccc2c1
Reactant: CC(C)Oc1ccc(C(=O)O)cc1Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4[nH]ccc4c3)no2)cc1Cl
Reaction time: 8 h
Yield: 11.9 %

Procedure:
D1 (500 mg), D4 (611 mg) and PyBOP (1.66 g) were dissolved in DMF and stirred overnight. The reaction mixture was then evaporated and partitioned between EtOAc and H2O. The organic layer was washed with H2O (×2) then brine, dried over MgSO4, filtered and evaporated to give the crude product. This was purified on a silica cartridge, eluting with a 0 to 50% mixture of Et2O in hexane to give the title compound (120 mg) as a white solid. δH (CDCl3, 400 MHz): 1.43 (6H, d), 4.69 (1H, septet), 6.92 (1H, s), 7.04 (1H, d), 7.25 (1H, s), 7.48 (1H, d), 8.00 (1H, d), 8.07 (1H, d), 8.25 (1H, s), 8.39 (1H, br. s), 8.50 (1H, s). MS (ES): C19H16ClN3O2 requires 353; found 354 (MH+).
Reaction SMILES: [C@@H:1]1([O:12][C:13]2[C:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]([CH3:28])[CH3:27])=[CH:21][CH:20]=3)=[C:16]([CH3:29])[NH:15][N:14]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].C(=O)([O-])[O-].[Cs+].[Cs+].[CH:36]1(Br)[CH2:40][CH2:39][CH2:38][CH2:37]1.O>CN(C)C=O>[CH:36]1([N:15]2[C:16]([CH3:29])=[C:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]([CH3:27])[CH3:28])=[CH:21][CH:20]=3)[C:13]([O:12][C@@H:1]3[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]3[OH:3])=[N:14]2)[CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: Cc1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(OC(C)C)cc1
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(Cc2ccc(OC(C)C)cc2)c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)nn1C1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.3 %

Procedure:
To a suspension of 3-(β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-5-methyl-1H-pyrazole (0.050 g) and cesium carbonate (0.20 g) in N,N-dimethylformamide (1 mL) was added cyclopentyl bromide (0.055 g) at 80° C., and the mixture was stirred for 30 minutes. After cooling to room temperature, water was added to the reaction mixture, and the mixture was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol), and successively by column chromatography on silica gel (eluent: dichloromethane/methanol=8/1) to give 1-cyclopentyl-3-(β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-5-methyl-1H-pyrazole (0.034 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]([CH:8]([CH2:16][CH3:17])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:4](=[O:18])[CH:3]=1.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:29]#[N:30])=[C:24](B(O)O)[CH:25]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:29]#[N:30])=[C:22]([C:2]2[CH:7]=[CH:6][N:5]([CH:8]([CH2:16][CH3:17])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:4](=[O:18])[CH:3]=2)[CH:21]=1
Reactant: N#Cc1ccc(Cl)cc1B(O)O
Reactant: CCC(C(=O)OC(C)(C)C)n1ccc(Br)cc1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCC(C(=O)OC(C)(C)C)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
600 mg (purity 82%, 1.56 mmol) of tert-butyl 2-(4-bromo-2-oxopyridin-1(2H)-yl)butanoate (racemate) and 325 mg (1.8 mmol) of 5-chloro-2-cyanophenylboronic acid in the presence of tetrakis(triphenylphosphine)palladium(0) were reacted according to General Method 2A. Yield: 543 mg (purity 59%, 55% of theory)
Reaction SMILES: [Cl:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([CH:15]=[O:16])=[CH:11][CH:10]=3)[NH:8][C:4]=2[CH:3]=1.I[CH3:21]>>[Cl:19][C:18]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]([CH3:21])[C:7]([C:9]3[CH:10]=[CH:11][C:12]([CH:15]=[O:16])=[CH:13][CH:14]=3)=[N:6][C:5]=2[CH:17]=1
Reactant: O=Cc1ccc(-c2nc3cc(Cl)c(Cl)cc3[nH]2)cc1
Reactant: CI
Product: Cn1c(-c2ccc(C=O)cc2)nc2cc(Cl)c(Cl)cc21

Procedure:
5,6-Dichloro2-(4-formylphenyl)-1-methylbenzimidazole was prepared from 5,6-dichloro-2-(4-formylphenyl)benzimidazole obtained in Example 13 and iodomethane by following General Procedure 3.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=[N:6][CH:7]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:9]=1)[CH3:2].Br[C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37]([NH:39][C:40]2[CH:45]=[CH:44][C:43]([CH2:46][N:47]([CH3:49])[CH3:48])=[C:42]([C:50]([F:53])([F:52])[F:51])[CH:41]=2)=[O:38])=[C:32]([F:54])[CH:31]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:48][N:47]([CH2:46][C:43]1[CH:44]=[CH:45][C:40]([NH:39][C:37](=[O:38])[CH2:36][C:33]2[CH:34]=[CH:35][C:30]([C:8]3[CH:7]=[N:6][C:5]([O:19][CH2:20][C:21]4[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=4)=[C:4]([O:3][CH2:1][CH3:2])[CH:9]=3)=[CH:31][C:32]=2[F:54])=[CH:41][C:42]=1[C:50]([F:51])([F:52])[F:53])[CH3:49]
Reactant: CCOc1cc(B2OC(C)(C)C(C)(C)O2)cnc1OCc1ccc(OC)cc1
Reactant: CN(C)Cc1ccc(NC(=O)Cc2ccc(Br)cc2F)cc1C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCOc1cc(-c2ccc(CC(=O)Nc3ccc(CN(C)C)c(C(F)(F)F)c3)c(F)c2)cnc1OCc1ccc(OC)cc1
Temperature: 110 °C
Yield: 79.9 %

Procedure:
To a solution of 3-ethoxy-2-((4-methoxybenzyl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (3.52 g, 9.14 mmol), 2-(4-bromo-2-fluorophenyl)-N-(4-((dimethylamino)methyl)-3-(trifluoromethyl)phenyl)acetamide (5.5 g, 9.14 mmol) and Cs2CO3 (7.45 g, 22.85 mmol) in 1,4-dioxane (30 mL) and H2O (10.00 mL) stirred under a N2 atmosphere at 20° C. was added PdCl2(dppf) (0.334 g, 0.457 mmol) in one charge. The reaction vessel was heated in 110° C. for 3 h. Then the solution was concentrated and distributed between EA and H2O. The combined organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by silica column chromatography (PE/EA=1:1). All fractions found to contain product by TLC (PE/EA=1:1, Rf 0.3) were combined and concentrated to yield a white solid of N-(4-((dimethylamino)methyl)-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (5.8 g, 7.30 mmol, 80.0% yield): 1H NMR (400 MHz, CDCl3) δ 7.80-7.98 (m, 3H), 7.67 (d, J=8.6 Hz, 1H), 7.37-7.47 (m, 3H), 7.26-7.35 (m, 2H), 7.20 (d, J=2.0 Hz, 1H), 6.89 (d, J=8.6 Hz, 2H), 5.44 (s, 2H), 4.13 (q, J=7.0 Hz, 2H), 3.75-3.86 (m, 5H), 3.70 (br. s., 2H), 2.35 (br. s., 6H), 1.46 (t, J=7.0 Hz, 3H) ES-LCMS m/z 612.2 (M+H).