Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C([O-])=O.[CH3:8][O:9][C:10](=[O:28])/[CH:11]=[CH:12]/[C:13]1[CH:27]=[CH:26][C:16]2[NH:17][C:18]([C:20]3([NH3+:25])[CH2:24][CH2:23][CH2:22][CH2:21]3)=[N:19][C:15]=2[CH:14]=1.[CH:29]1([C:35]2[C:43]3[C:38](=[CH:39][C:40]([C:44](O)=[O:45])=[CH:41][CH:42]=3)[N:37]([CH2:47][C:48]([N:50]([CH3:52])[CH3:51])=[O:49])[C:36]=2[C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:29]1([C:35]2[C:43]3[C:38](=[CH:39][C:40]([C:44]([NH:25][C:20]4([C:18]5[NH:17][C:16]6[CH:26]=[CH:27][C:13](/[CH:12]=[CH:11]/[C:10]([O:9][CH3:8])=[O:28])=[CH:14][C:15]=6[N:19]=5)[CH2:24][CH2:23][CH2:22][CH2:21]4)=[O:45])=[CH:41][CH:42]=3)[N:37]([CH2:47][C:48]([N:50]([CH3:52])[CH3:51])=[O:49])[C:36]=2[C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: CN(C)C(=O)Cn1c(-c2ccccc2)c(C2CCCCC2)c2ccc(C(=O)O)cc21
Reactant: COC(=O)/C=C/c1ccc2[nH]c(C3([NH3+])CCCC3)nc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ccc2[nH]c(C3(NC(=O)c4ccc5c(C6CCCCC6)c(-c6ccccc6)n(CC(=O)N(C)C)c5c4)CCCC3)nc2c1
Reaction time: 8 h

Procedure:
To a solution of 1-{5-[(1E)-3-methoxy-3-oxoprop-1-en-1-yl]-1H-benzimidazol-2-yl}cyclopentanaminium trifluoroacetate (from Step 4, 1 eq), 3-cyclohexyl-1-[2-(dimethylamino)-2-oxoethyl]-2-phenyl-1H-indole-6-carboxylic acid (from Example 1, Step 6, 1 eq) in DMF (0.02 M), HATU (1 eq) and DIPEA (5 eq) were added. The reaction mixture was left at RT with stirring overnight. The resulting mixture was partitioned between EtOAc and hydrochloric acid. The combined EtOAc layers were washed with saturated aqueous NaCl solution, separated, dried over Na2SO4, filtered and evaporated in vacuo to afford methyl (2E)-3-(2-{1-[({3-cyclohexyl-1-[2-(dimethylamino)-2-oxoethyl]-2-phenyl-1H-indol-6-yl}carbonyl)amino]cyclopentyl}-1H-benzimidazol-5-yl)acrylate, which was used without further purification. MS (ES+) m/z 672 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F-:12].[K+]>CS(C)=O>[F:12][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: [F-]
Reactant: Clc1cnc2ccccc2n1
Agent: [K+]
Solvent: CS(C)=O
Product: Fc1cnc2ccccc2n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 2-chloroquinoxaline (1.65 g, 10 mmol), potassium fluoride (1.16 g, 20 mmol) and dry dimethyl sulfoxide (10 mL) was heated with stirring for 4 h. After cooling to room temperature the mixture was filtered through silica gel with 10% ether/hexane as the eluent to afford 2-fluoroquinoxaline as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH3:12])[CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]1)=[O:4].CO.C(O)C.[BH4-].[Na+]>O>[CH3:1][O:2][C:3]([C:5]1([CH3:12])[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(C)CCC(=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CO
Product: COC(=O)C1(C)CCC(O)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 109.8 %

Procedure:
To a solution of 3.7 g (20.1 mmol) of 1-methyl-4-oxocyclohexanecarboxylic acid methyl ester in mixture of methanol and ethanol (6 mL+15 mL) was added 200 mg (5.29 mmol) of sodium borohydride at 0° C., and stirred for 1 hour at 0° C. After addition of water thereto, the reaction mixture was concentrated under a reduced pressure and the residue was extracted with ethyl acetate. The organic layer was washed with water and saturated brine successively and dried over anhydrous magnesium sulfate. Upon removal of the solvent by evaporation, 3.8 g (yield 100%) of 4-hydroxy-1-methylcyclohexanecarboxylic acid methyl ester was obtained as colorless liquid. Its physical property is shown below.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[F:19][C:20]1[CH:21]=[C:22]([C:26]2[O:30][C:29]([CH3:31])=[N:28][C:27]=2[C:32](O)=[O:33])[CH:23]=[CH:24][CH:25]=1>>[C:2]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:32]([C:27]3[N:28]=[C:29]([CH3:31])[O:30][C:26]=3[C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([F:19])[CH:21]=3)=[O:33])=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: Cc1nc(C(=O)O)c(-c2cccc(F)c2)o1
Reactant: CC1(c2csc(Cn3ccc(N)n3)n2)OCCO1
Product: CC(=O)c1csc(Cn2ccc(NC(=O)c3nc(C)oc3-c3cccc(F)c3)n2)n1

Procedure:
Following general procedure B followed by C, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-(3-fluoro-phenyl)-2-methyl-oxazole-4-carboxylic acid. LC-MS-conditions 05: tR=0.89 min; [M+H]+=426.04.
Reaction SMILES: CS(Cl)(=O)=O.O[CH2:7][CH2:8][CH2:9][C:10]1[N:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:13]2=[N:12][N:11]=1.[CH2:20]([CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.O.C(N(CC)CC)C>[CH2:20]([CH:27]1[CH2:32][CH2:31][N:30]([CH2:7][CH2:8][CH2:9][C:10]2[N:14]3[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:13]3=[N:12][N:11]=2)[CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OCCCc1nnc2n1CCCCC2
Reactant: c1ccc(CC2CCNCC2)cc1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: c1ccc(CC2CCN(CCCc3nnc4n3CCCCC4)CC2)cc1

Procedure:
Triethylamine (1.4 ml) and methanesulfonyl chloride (0.62 ml) were added to a solution of 3-(3-hydroxypropyl)-6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a]azepine (0.98 g) obtained in the same manner as in Example 4 in dimethylformamide (20 ml) with stirring. Then, 4-benzylpiperidine (0.88 g), potassium carbonate (1.38 g) and potassium iodide (0.83 g) were added and the mixture was stirred for 4 hours at 60° C. After the completion of the reaction, the reaction mixture was poured into water, extracted with ethyl acetate, washed with water, and dried over magnesium sulfate. The solution was concentrated under reduced pressure to give 3-(3-(4-benzylpiperidin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a]azepine.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:2].C(N(C(C)C)CC)(C)C.[C:20](Cl)([Cl:22])=[O:21]>C(Cl)Cl>[CH2:1]([N:3]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:20]([Cl:22])=[O:21])[CH3:2]
Reactant: O=C(Cl)Cl
Reactant: CCNCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN(Cc1ccccc1)C(=O)Cl
Temperature: 0 °C
Reaction time: 8 h

Procedure:
N-Ethylbenzylamine (0.56 mL, 3.8 mmol) and diisopropylethylamine (1 mL, 5.7 mmol) were combined in CH2Cl2 (12 mL) and cooled to 0° C. Phosgene (20% in toluene; 2.4 mL, 4.6 mmol) was added, and the reaction was stirred overnight at room temperature. The mixture was concentrated, and the residue was dissolved in Et2O and washed twice with H2O. The organic layer was dried, filtered, and concentrated to give the title compound.
Reaction SMILES: [BH4-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:13][CH:12]([C:14](O)=[O:15])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].II>C1COCC1.CO>[C:3]([O:7][C:8]([N:10]1[CH2:13][CH:12]([CH2:14][OH:15])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(CO)C1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a stirred mixture of 0.56 g (14.91 mmol) sodium borohydride in 10 mL THF was added 1.0 g (4.97 mmol) 1-(tert-butoxycarbonyl)-3-azetidinecarboxylic acid, and the reaction mixture was cooled to 0° C. 1.26 g (4.97 mmol) iodine in 5 mL THF was added dropwise over 15 minutes and the reaction was stirred at 0° C. for 10 minutes, then heated under reflux for 18 hours. The mixture was allowed to cool to room temperature, diluted with 80 mL MeOH and stirred until all effervescence ceased. After evaporation of the solvent, 25 mL 20% (w/w) KOH was added to the residue and the mixture was stirred for 4.5 hours. The mixture was extracted with DCM (3×100 mL) and the combined organic layers were dried over MgSO4. After filtration, the solvent was evaporated to give the desired product, which was used for the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:3]2[S:18][CH:17]=[CH:16][C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH3:15])[N:7]=1.[NH:19]1[CH2:24][CH2:23][CH:22]([NH:25][C:26](=[O:32])[O:27][CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:21][CH2:20]1.CCN(CC)CC>CN(C=O)C.C(Cl)Cl>[CH3:15][O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[N:7]=[C:2]([N:19]2[CH2:20][CH2:21][CH:22]([NH:25][C:26](=[O:32])[O:27][CH2:28][CH:29]([CH3:30])[CH3:31])[CH2:23][CH2:24]2)[C:3]2[S:18][CH:17]=[CH:16][C:4]=2[N:5]=1
Reactant: COc1ccccc1-c1nc(Cl)c2sccc2n1
Reactant: CC(C)COC(=O)NC1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1-c1nc(N2CCC(NC(=O)OCC(C)C)CC2)c2sccc2n1
Yield: 54.6 %

Procedure:
A solution of 4-chloro-2-(2-methoxyphenyl)thieno[3,2-d]pyrimidine (0.15 g, 0.54 mmol), isobutyl piperidin-4-ylcarbamate (0.11 g, 0.54 mmol), and Et3N (0.15 mL, 1.1 mmol) in DMF (1.8 mL) was heated in a microwave oven at 180° C. for 5 min. The reaction was cooled and diluted with CH2Cl2. The solution was washed with water, dried over Na2SO4, and concentrated under vacuum to give isobutyl 1-(2-(2-methoxyphenyl)thieno[3,2-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (0.13 g, 55% yield). LC/MS: m/z 441.5 (M+H)+ at 2.55 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][O:13][N:14]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=2)[CH3:16])=[CH:6][C:5]=1[OH:27].[OH-].[Na+]>C(O)C>[C:23]([C:20]1[CH:21]=[CH:22][C:17](/[C:15](=[N:14]/[O:13][CH2:12][CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:28])=[O:2])=[C:5]([OH:27])[CH:6]=2)/[CH3:16])=[CH:18][CH:19]=1)([CH3:24])([CH3:25])[CH3:26]
Reactant: COC(=O)c1ccc(OCCON=C(C)c2ccc(C(C)(C)C)cc2)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C/C(=N\OCCOc1ccc(C(=O)O)c(O)c1)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Yield: 46.8 %

Procedure:
To a solution of 4-{2-[1-(4-tert-butyl-phenyl)-ethylideneaminooxy]-ethoxy}-2-hydroxy-benzoic acid methyl ester (0.546 g, 1.29 mmol) in ethanol (10 mL) was added 1 M sodium hydroxide solution (2 mL, 2 mmol) and the reaction was heated at reflux for 40 minutes. After cooling to room temperature, it was concentrated to a small volume, acidified to pH 1 with 2M hydrochloric acid solution and extracted with ethyl acetate. The combined organics were dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography using ethyl acetate/hexanes (30/70)+1% formic acid to afford the title compound (0.224 g, 47%) as a white solid. mp=157.4-158.7° C.; mass spectrum (+ESI, M+H) m/z 372. 1H NMR (400 MHz, DMSO-d6); δ 13.60 (bs, 1H), 11.50 (bs, 1H), 7.67 (d, 1H), 7.57 (d, 2H), 7.40 (d, 2H), 6.52 (m, 2H), 4.40 (t, 2H), 4.30 (t, 2H), 2.13 (s, 3H), 1.27 (s, 9H). Elemental analysis: Calcd. for C21H25NO5: C, 67.91; H, 6.78; N, 3.77, Found: C, 67.69; H, 6.81; N, 3.68.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][O:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[Cl:1])[CH3:18]
Reactant: CCOC(=O)CBr
Reactant: O=[N+]([O-])c1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)COc1ccc([N+](=O)[O-])cc1Cl
Reaction time: 10 h
Yield: 64.1 %

Procedure:
A mixture of 2-chloro-4-nitrophenol (63.6 g, 0.367 mol), ethyl bromoacetate (67.0 g, 0.4 mol), potassium carbonate (60.7 g, 0.44 mol) and 2-butanone (400 mL) was refluxed under stirring for 10 h, then filtered and the solvent was evaporated. The residue was fractionated yielding 61.1 g (64%) of 2-chloro-4-nitrophenoxyacetic acid ethyl ester, b.p. 150° C./40 Pa.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[F:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([I:18])[C:11]=1[C:12]#[N:13].[CH:19](OC)=[O:20].O>C1COCC1>[F:9][C:10]1[C:17]([CH:19]=[O:20])=[CH:16][CH:15]=[C:14]([I:18])[C:11]=1[C:12]#[N:13]
Reactant: N#Cc1c(F)cccc1I
Reactant: COC=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1c(I)ccc(C=O)c1F
Reaction time: 1 h
Yield: 71.9 %

Procedure:
LDA (24.3 mL, 2.0 M solution in THF) was added dropwise to a stirred solution of 2-fluoro-6-iodobenzonitrile (10.0 g, 40.5 mmol) in THF (200 mL) at −78° C., and the mixture was stirred for 1 h. Methyl formate (5.0 mL, 81.0 mmol) was added via syringe and the resulting mixture was stirred at −78° C. for 30 min then at rt for 1 h. H2O was added and the mixture was extracted with EtOAc. The extracts were washed with brine, dried (MgSO4) and concentrated. The residue was purified by flash chromatography on silica gel eluting with 20-25% EtOAc/hexanes to give the desired product (8.01 g). MS (ESI(+)) m/e 274.9 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]#[N:19])[CH:16]=3)[NH:11][N:10]=2)=[CH:5][CH:4]=1.[OH-:21].[Na+]>Cl>[CH3:1][N:2]([CH3:20])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([NH2:19])=[O:21])[CH:16]=3)[NH:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: CN(C)c1ccc(-c2n[nH]c3ccc(C#N)cc23)cc1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: CN(C)c1ccc(-c2n[nH]c3ccc(C(N)=O)cc23)cc1
Yield: 52.1 %

Procedure:
A solution of 3-[4-(dimethylamino)phenyl]-1H-indazole-5-carbonitrile (125 mg, 0.476 mmol) in 5.00 mL of concentrated aq. HCl was heated at 47° C. for 1 h, and then added dropwise with stirring to 20 mL of 6.0 N aq. NaOH that was cooled in a water bath. The mixture was extracted with 2× EtOAc, and the combined organics were dried (Na2SO4). Purification by silica gel chromatography using EtOAc as eluent afforded the title compound (69.3 mg, 52.1% yield): 1H NMR (DMSO-d6) δ 13.19 (s, 1H), 8.58 (s, 1H), 8.10 (br s, 1H), 7.9S-7.82 (m, 3H), 7.56 (d, 1H), 7.30 (br s, 1H), 6.84 (d, 2H), 2.98 (s, 6H); ES-MS (m/z) 281 [M+1]+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([NH2:12])=[CH:11][C:5]=2[N:4]=1.N1C=CC=CC=1.Cl[C:22]([O:24][CH2:25][C:26]([Cl:29])([Cl:28])[Cl:27])=[O:23].O>O1CCCC1>[F:14][C:2]([F:1])([F:13])[C:3]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([NH:12][C:22](=[O:23])[O:24][CH2:25][C:26]([Cl:29])([Cl:28])[Cl:27])=[CH:11][C:5]=2[N:4]=1
Reactant: Nc1ccc2[nH]c(C(F)(F)F)nc2c1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1ccc2[nH]c(C(F)(F)F)nc2c1)OCC(Cl)(Cl)Cl
Yield: 68.4 %

Procedure:
To a solution of 2-(trifluoromethyl)-1H-benzimidazol-5-amine (1.00 g, 4.97 mmol) and pyridine (0.473 ml, 5.97 mmol) in tetrahydrofuran (17 ml) was added, under ice-cooling, 2,2,2-trichloroethyl chloroformate (0.826 ml, 5.97 mmol), and the mixture was stirred at room temperature for 1 hour and half. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:3) to give 1.28 g (68.5%) of the desired product as a solid.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:11][CH2:10][S:9][C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=2[C:6]1([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=1)O)[CH3:3].[ClH:26]>>[ClH:26].[CH3:25][O:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)/[CH:17]=[C:6]1/[C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[S:9][CH2:10][CH2:11][CH:5]/1[CH2:4][N:2]([CH3:3])[CH3:1]
Reactant: COc1cccc(CC2(O)c3ccccc3SCCC2CN(C)C)c1
Agent: Cl
Product: COc1cccc(/C=C2/c3ccccc3SCCC2CN(C)C)c1

Procedure:
5.00 g (4RS,5RS)-4-dimethylaminomethyl-5-(3-methoxybenzyl)-2,3,4,5-tetrahydro-benzo[b]thiepin-5-ol (see example 9) were reacted with 230 ml 6N hydrochloric acid by the procedure described in example 13. After processing, separation of the double bond isomers by column chromatography with ethyl acetate/methanol=3/1 and conversion into the hydrochloride, the title compounds were obtained in the form of white crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][C:3]=1[O:14][CH3:15]>CO.Cl.[Pt]=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:4][C:3]=1[O:14][CH3:15]
Reactant: COc1cc(-c2cccnc2)ccc1F
Agent: O=[Pt]
Agent: Cl
Solvent: CO
Product: COc1cc(C2CCCNC2)ccc1F
Reaction time: 7 h
Yield: 71.1 %

Procedure:
To a solution of 12.3 g (60.5 mmole) of 3-(4-fluoro-3-methoxyphenyl)pyridine in a mixture of 160 ml of methanol and 20.2 ml of concentrated hydrochloric acid was added 1.6 g of platinum oxide. The resulting mixture was shaken under an atmosphere of hydrogen at an initial pressure of 50 psig for 7 hours. The reaction mixture was filtered, an additional 1 g of platinum oxide was added, and the mixture was shaken under hydrogen at a pressure of 50 psig for 2 hours. The reaction mixture was then filtered, and the bulk of the methanol was removed by evaporation in vacuo. The residual aqueous system was diluted with water, and the resulting aqueous solution was washed with ether and then basified with 100 ml of 10% sodium hydroxide. The basified mixture was extracted with diethyl ether, and the combined extracts were washed with saturated sodium chloride solution, dried (K2CO3) and evaporated in vacuo. This afforded 9 g (71% yield) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][N:16]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[CH2:17]([NH:24][C:25]([C:27]1[S:31][C:30](Br)=[N:29][C:28]=1[CH3:33])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([NH:24][C:25]([C:27]1[S:31][C:30]([N:16]2[CH:15]=[CH:14][C:4]([C:5](=[O:6])[NH:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:3][C:2]2=[O:1])=[N:29][C:28]=1[CH3:33])=[O:26])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1nc(Br)sc1C(=O)NCc1ccccc1
Reactant: O=C(Nc1ccccc1)c1ccnc(O)c1
Product: Cc1nc(-n2ccc(C(=O)Nc3ccccc3)cc2=O)sc1C(=O)NCc1ccccc1
Yield: 20 %

Procedure:
Following the procedure as described in Example 3, making variations only as required to use 2-hydroxy-N-phenylisonicotinamide in place of 4-aminopyridin-2(1H)-one to react with N-benzyl-2-bromo-4-methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 20% yield: mp 243-245° C. (hexane/ethyl acetate); 1H NMR (300 MHz, DMSO-d6) δ 10.53 (s, 1H), 8.88 (t, J=5.8 Hz, 1H), 8.83 (d, J=7.6 Hz, 1H), 7.72 (d, J=7.6 Hz, 2H), 7.36-7.19 (m, 8H), 7.10 (t, J=7.3 Hz, 1H), 6.98 (dd, J=7.6, 1.8 Hz, 1H), 4.40 (d, J=5.8 Hz, 2H), 2.59 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 163.0, 161.7, 160.2, 153.5, 150.7, 139.8, 132.0, 129.1, 128.7, 127.7, 127.2, 124.7, 124.6, 123.6, 121.0, 119.5, 107.0, 106.1, 43.2, 17.5; (ES+) m/z 445.1 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][C:6]1[CH:19]=[C:9]2[NH:10][C:11](=[O:18])[C:12]3[C:17]([N:8]2[N:7]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25](B(O)O)[CH:24]=1>COCCOC.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>[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:2]2[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=2)[CH2:5][C:6]2[CH:19]=[C:9]3[NH:10][C:11](=[O:18])[C:12]4[C:17]([N:8]3[N:7]=2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:24]=1
Reactant: O=c1[nH]c2cc(Cc3cccc(Br)c3)nn2c2ccccc12
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: O=c1[nH]c2cc(Cc3cccc(-c4cccnc4)c3)nn2c2ccccc12

Procedure:
A mixture of Example 61B (0.05 g, 0.141 mmol), pyridine-3-ylboronic acid (0.018 g, 0.148 mmol) cesium fluoride (0.064 g, 0.423 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.1 g, 0.014 mmol) in DME (2 mL) was heated in a microwave (Personal Chemistry SmithSynthesizer) at 150° C. for 10 minutes. The mixture was filtered evaporated. The residue was purified by HPLC on a C18 column with 0-100% CH3CN/H2O/0.1% TFA to provide the desired product. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.10 (s, 2 H) 5.75 (s, 1 H) 7.41-7.51 (m, 3 H) 7.63-7.73 (m, 2 H) 7.76 (s, 1 H) 7.83-7.88 (m, 1 H) 8.04 (d, J=7.67 Hz, 1 H) 8.12 (dd, J=8.13, 1.38 Hz, 1 H) 8.35 (dt, J=7.98, 1.84 Hz, 1 H) 8.68 (dd, J=5.06, 1.38 Hz, 1 H) 9.01 (d, J=2.15 Hz, 1 H) 12.08 (s, 1 H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:10][C:3]=12.[H-].[Na+].[Li].[B:18](OC(C)C)([O:23]C(C)C)[O:19]C(C)C.[Cl-].[NH4+]>C1COCC1>[CH3:12][C:11]([C:9]1[NH:8][C:4]2=[N:5][CH:6]=[CH:7][C:2]([B:18]([OH:23])[OH:19])=[C:3]2[CH:10]=1)([CH3:14])[CH3:13]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(C)(C)c1cc2c(Br)ccnc2[nH]1
Agent: [Cl-]
Agent: [H-]
Agent: [Li]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc2c(B(O)O)ccnc2[nH]1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
4-Bromo-2-(1,1-dimethylethyl)-1H-pyrrolo[2,3-b]pyridine (430 mg, 1.7 mmol) was dissolved in anhydrous THF (12 ml) under nitrogen and degassed (nitrogen/vacuum 3 times). Sodium hydride (60% dispersion in mineral oil) (88 mg, 2.2 mmol) was added and the reaction stirred at room temperature for 50 mins. The reaction was then cooled to −78° C., further degassed as before and 1.5M nbutyl lithium in hexanes (1.6 ml, 2.4 mmol) was added dropwise over 5 mins. The reaction was stirred for 45 mins then tri-isopropyl borate (1.2 ml) was added. The reaction was stirred for a further hour before warming to room temperature. Saturated ammonium chloride (aq) (20 ml) was added and the reaction was extracted with DCM (2×25 ml). The combined organics were washed with water (50 ml), passed through a hydrophobic frit and concentrated. The residue was dissolved in DCM:MeOH (1:1, v/v) and loaded onto an aminopropyl cartridge (10 g). The cartridge was washed with DCM:MeOH (1:1, v/v) and eluted with 2M ammonia in MeOH, which was concentrated to give title compound, 164 mg.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([NH:10][C:11]1[CH:12]=[C:13]([S:19]([C:22]2[CH:23]=[C:24]([OH:30])[C:25]([OH:29])=[CH:26][C:27]=2[CH3:28])(=[O:21])=[O:20])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18])(=[O:9])[CH3:8].C([O:33][C:34](=[O:38])[CH:35](Cl)Cl)C.Cl>COCCOC.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.CC(C)=O>[C:7]([NH:10][C:11]1[CH:12]=[C:13]([S:19]([C:22]2[C:27]([CH3:28])=[CH:26][C:25]3[O:29][CH:35]([C:34]([OH:38])=[O:33])[O:30][C:24]=3[CH:23]=2)(=[O:21])=[O:20])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18])(=[O:9])[CH3:8]
Reactant: CCOC(=O)C(Cl)Cl
Reactant: COc1ccc(S(=O)(=O)c2cc(O)c(O)cc2C)cc1NC(C)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Solvent: CC(C)=O
Product: COc1ccc(S(=O)(=O)c2cc3c(cc2C)OC(C(=O)O)O3)cc1NC(C)=O
Reaction time: 0.17 h

Procedure:
A suspension of 72.8 g (526 mmol) of freshly calcined potassium carbonate in 300 ml of 1,2-dimethoxyethane is stirred under nitrogen for 10 minutes using a high-speed stirrer and then, while stirring normally, 37.0 g (105.3 mmol) of 4-(3-acetamido-4-methoxyphenylsulphonyl)-5-methyl-1,2-benzenediol, 16.5 g (105.3 mmol) of dichloroacetic acid ethyl ester and 3 g of tetrabutylammonium bromide are added. The mixture is boiled under reflux, 300 ml of acetone are added, the whole is boiled under reflux for 3 more hours, a further 60 g of potassium carbonate and 16.5 g of dichloroacetic acid ethyl ester are added, and the whole is boiled under reflux for 9 more hours. The reaction mixture is poured into water and acidified to pH 1-2 with hydrochloric acid. Some of the solvent is evaporated off in vacuo and the aqueous phase remaining is extracted with ethyl acetate. The combined organic phases are washed with water and saturated sodium chloride solution, dried over sodium sulphate and concentrated by evaporation in a rotary evaporator. The residue is recrystallised four times from acetonitrile, yielding 5-(3-acetamido-4-methoxyphenylsulphonyl)-6-methyl-1,3-benzodioxole-2-carboxylic acid in the form of white crystals having a melting point of 230° (sintering at 150°).