Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[NH:20][CH:21]=[C:22]([NH:23][C:24](=[O:28])[CH2:25][CH2:26][CH3:27])[C:15]=23)[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.Cl.[Pd]>[N:11]1([C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[NH:20][CH:21]=[C:22]([NH:23][C:24](=[O:28])[CH2:25][CH2:26][CH3:27])[C:15]=23)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CCCC(=O)Nc1c[nH]c2nccc(N3CCN(Cc4ccccc4)CC3)c12
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCCC(=O)Nc1c[nH]c2nccc(N3CCNCC3)c12
Yield: 91.6 %

Procedure:
N-(4-(4-Benzylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)butyramide (0.070 g, 0.19 mmol) was dissolved in MeOH (1 mL). Pd/C (0.0197 g, 0.0185 mmol) was then added, followed by the addition of 3 drops of concentrated HCl. The reaction was then placed under a H2 balloon for 18 hours. The reaction was then filtered, washed with MeOH, and concentrated to give the crude product N-(4-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)butyramide (0.050 g, 93.8% yield).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][C:9]1([C:15]([NH:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[NH:31][C:32](=[O:38])[C:33]([CH3:37])([CH3:36])[CH2:34]Cl)[CH2:20][CH:19]2[OH:39])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7].CC(C)([O-])C.[Na+]>ClCCl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][C:9]1([C:15]([NH:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[N:31]3[CH2:34][C:33]([CH3:37])([CH3:36])[C:32]3=[O:38])[CH2:20][CH:19]2[OH:39])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7]
Reactant: CC(C)(CCl)C(=O)Nc1cc(F)ccc1N1CCC(NC(=O)C2(NC(=O)c3ccco3)CCCCC2)C(O)C1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)CN(c2cc(F)ccc2N2CCC(NC(=O)C3(NC(=O)c4ccco4)CCCCC3)C(O)C2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.1 %

Procedure:
The solution of 4-[N-[1-[N-(furan-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-1-[4-fluoro-2-(3-chloro-2,2-dimethylpropionyl)aminophenyl]piperidin-3-ol (1.1 g) obtained in Step 1 in 40 ml of dichloromethane was cooled to 0° C. and was added sodium tert-butoxide (NaOtBu, 600 mg) thereto. The reaction mixture was stirred overnight at room temperature, diluted with dichloromethane, and washed with brine. The resulting organic layer was dried and concentrated on sodium sulfate. The resulting residue was purified with column chromatography to give 762 mg of the titled compound.
Reaction SMILES: FC(F)(F)C([NH2:5])=O.[O-2].[Mg+2].[C:10]([Si:14]([CH3:23])([CH3:22])[O:15][CH2:16][CH2:17][CH2:18][S:19]([CH3:21])=[O:20])([CH3:13])([CH3:12])[CH3:11].C(OI(C1C=CC=CC=1)OC(=O)C)(=O)C>ClCCl.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[C:10]([Si:14]([CH3:22])([CH3:23])[O:15][CH2:16][CH2:17][CH2:18][S:19]([CH3:21])(=[NH:5])=[O:20])([CH3:13])([CH3:12])[CH3:11]
Reactant: NC(=O)C(F)(F)F
Reactant: CS(=O)CCCO[Si](C)(C)C(C)(C)C
Agent: [Rh+2]
Agent: CC(=O)OI(OC(C)=O)c1ccccc1
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCCS(C)(=N)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 65.5 %

Procedure:
To a 1-L round-bottom flask containing 2,2,2-trifluoroacetamide (17.43 g), magnesium oxide (12.1 g), and rhodium(II) acetate (0.99 g) in anhydrous dichloromethane (500 mL) was added tert-butyldimethyl(3-(methylsulfinyl)propoxy)silane (17.65 g) and (diacetoxyiodo)benzene (36.1 g). The resulting reaction mixture was stirred at room temperature for 24 hours and then filtered through a short pad of celite. The filtrate was concentrated, the brown oily residue was taken up in MeOH (˜500 mL), and potassium carbonate (51.7 g) was added. The reaction mixture was stirred at RT for 2 hours. The mixture was then filtered through a pad of celite, the pad was washed with MeOH, and the filtrate was concentrated. The resulting soft brown solid was treated with DCM-EtOAc (4:1), the mixture was stirred at room temperature for 1 hour, and it was filtered again through a pad composed of silica gel and celite. The pad was washed with DCM-EtOAc (2:1) first and then with neat EtOAc only. The filtrate was concentrated and the brown oily residue was subject to a column chromatography (EtOAc-Hex 1:2 to neat EtOAc). Concentration of the product eluting fractions gave the title compound as a light brown oil (12.3 g).
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH3:10])[C:5]([CH2:11][S:12]([C:14]2[N-:18][C:17]3[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:16]=3[N:15]=2)=[O:13])=[N:4][CH:3]=1.[CH3:25][C:26]1[C:31]([O:32][CH3:33])=[C:30]([CH3:34])[C:29]([CH2:35][S:36]([C:38]2[N-:42][C:41]3[CH:43]=[CH:44][C:45]([O:47][CH3:48])=[CH:46][C:40]=3[N:39]=2)=[O:37])=[N:28][CH:27]=1.O.O.O.[Mg+2:52]>ClCCl.C(O)C>[CH3:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][S+:12]([O-:13])[C:14]2[N-:18][C:17]3[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:16]=3[N:15]=2)=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].[CH3:25][C:26]1[CH:27]=[N:28][C:29]([CH2:35][S+:36]([O-:37])[C:38]2[N-:42][C:41]3[CH:43]=[CH:44][C:45]([O:47][CH3:48])=[CH:46][C:40]=3[N:39]=2)=[C:30]([CH3:34])[C:31]=1[O:32][CH3:33].[Mg+2:52]
Reactant: COc1ccc2[n-]c(S(=O)Cc3ncc(C)c(OC)c3C)nc2c1
Agent: [Mg+2]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: COc1ccc2[n-]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Yield: 62.6 %

Procedure:
Esomeprazole magnesium trihydrate (10 g) was dissolved in a mixture of dichloromethane (50 ml) and ethanol (70 ml) at 25-30° C. Any undissolved material was filtered off. The clear solution thus obtained was spray dried with an inlet temperature of 70-80° C. and an outlet temperature of 22-42° C. The solid was further dried under vacuum at 60-65° C. for 14 to 15 hours to yield 5.82 g of esomeprazole magnesium of amorphous form.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]2[CH:10]=[N:9][NH:8][C:6]=2[N:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:23]([CH3:25])[CH3:24]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]2[CH:10]=[N:9][N:8]([CH:23]([CH3:25])[CH3:24])[C:6]=2[N:7]=1
Reactant: CC(C)Br
Reactant: CCOC(=O)c1cc(Br)nc2[nH]ncc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cc(Br)nc2c1cnn2C(C)C
Yield: 58.2 %

Procedure:
To a stirred solution of ethyl 6-bromo-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (20 g, 74.3 mmol) in acetonitrile (200 mL), K2CO3 (15.39 g, 111.52 mmol) and 2-bromopropane (18.13 g, 148.64 mmol) was added to it. The reaction mixture was refluxed for 8 h. On completion, acetonitrile was removed under reduced pressure and water was added to it. Extraction was carried out using ethyl acetate; the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4. Solvent was removed under reduced pressure and residue was purified by silica gel column chromatography to obtain the desired intermediate (13.5 g, 58.3%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.F[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1.C([O-])([O-])=O.[Cs+].[Cs+].CN(C)C=O>CN1CCCC1=O>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: Fc1ccccn1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ccccn5)ccc(F)c43)ccc21
Temperature: 130 °C
Reaction time: 0.5 h

Procedure:
A microwave vial is charged with a stir bar, {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (0.10 g), 2-fluoro-pyridine (27 mg), Cs2CO3 (91 mg) and N,N-dimethylformamide (2 mL; alternatively N-methyl-pyrrolidinone is used). The mixture is stirred at 130° C. for 30 min by irradiation in a microwave oven. After cooling to room temperature, the mixture is concentrated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 99:1→80:20) to give the title compound. LC (method 2): tR=1.15 min; Mass spectrum (ESI+): m/z=436 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:3]([F:15])=[C:4]([C:11]([F:14])([F:13])[F:12])[C:5]([F:10])=[C:6]([F:9])[C:7]=1[F:8].C([O-])(=O)C.[Na+].[H][H]>C(O)(=O)C.[Pd]>[F:10][C:5]1[C:6]([F:9])=[C:7]([F:8])[CH:2]=[C:3]([F:15])[C:4]=1[C:11]([F:14])([F:13])[F:12]
Reactant: Fc1c(F)c(Cl)c(F)c(C(F)(F)F)c1F
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Fc1cc(F)c(C(F)(F)F)c(F)c1F
Yield: 96.3 %

Procedure:
252.5 g (1 mol) of 3-chloro-2,4,5,6-tetrafluorobenzotrifluoride (cf., for example, Zh. obshch. Khim., 37, 1686-1687 [1967]) and 86 g (1.05 mol) of sodium acetate in 1000 ml of glacial acetic acid are hydrogenated in the presence of 10 g of palladium-on-activated charcoal (5% strength) at a hydrogen pressure of 30 to 50 bar and 120° C. to constant pressure. For working-up, the catalyst is removed from the cold reaction mixture by filtration, and the residue is distilled. 210 g (96% of theory) of 2,3,4,6-tetrafluorobenzotrifluoride of boiling point 105°-106° C. and of refraction index nD20 =1.3770 are obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].C(=O)([O-])[O-].[Na+].[Na+].[NH2:16][C:17](=[NH:22])S(O)(=O)=O>O>[NH:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])[C:17]([NH2:22])=[NH:16]
Reactant: NCCCCCC(=O)O
Reactant: N=C(N)S(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: N=C(N)NCCCCCC(=O)O
Reaction time: 20 h

Procedure:
6.5 g (50 mmol) 6-aminohexanoic acid and 6.9 g (50 mmol) sodium carbonate were dissolved in 50 mL water. 6.2 g (50 mmol) amino-iminomethane sulphonic acid was added under stirring to the solution. After 20 hours, the product was filtered and washed with acetic acid, methanol and then ether. Yield: 6.6 g (76%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[OH:13])([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[Br:20][CH2:21][CH:22]=[CH:23][CH2:24]Br>CN1C(=O)CCC1>[Br:20][CH2:21][CH:22]=[CH:23][CH2:24][O:13][C:5]1[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)c([N+](=O)[O-])c1
Reactant: BrCC=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc(OCC=CCBr)c([N+](=O)[O-])c1
Temperature: 45 °C
Yield: 46.7 %

Procedure:
A mixture of 2,4-dinitrophenol (4.6 g, 80 wt %), potassium carbonate (4.2 g), NMP (40 mL) and 1,4-dibromo-2-butene (12.8 g) was heated to 45° C. for 2 hr. Extraction in the normal fashion and Kugelrohr distillation of the excess dibromide (0.1 mm Hg, 80° C.) gave 1-bromo-4-(2,4-dinitrophenyloxy)but-2-ene (3.7 g, mp 55-57° C.).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:16][CH:17]1[CH2:19][CH2:18]1.O>CN(C=O)C>[CH:17]1([CH2:16][O:8][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[N:7][CH:6]=2)[CH2:19][CH2:18]1
Reactant: BrCC1CC1
Reactant: Cc1ccc(O)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(OCC2CC2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.9 %

Procedure:
To a solution of 6-methylpyridin-3-ol (5.0 g, 46 mmol) in DMF (45 mL) were added cesium carbonate (16.5 g, 53 mmol) and (bromomethyl)cyclopropane (7.1 g, 53 mmol) at room temperature. After being stirred at room temperature for 18 hours, the mixture was poured into H2O, and the aqueous phase was extracted with ethyl acetate (twice). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (3:1 (v/v)) to give 3.9 g (52% yield) of the title compound as a yellow oil:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1.[Cl:23][C:24]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[C:26]([Cl:39])[C:25]=1[OH:40]>>[Cl:23][C:24]1[CH:29]=[C:28]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][CH:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[CH:27]=[C:26]([Cl:39])[C:25]=1[OH:40]
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1NC1CCN(C)CC1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)nc2c1NC1CCN(C)CC1
Yield: 53.1 %

Procedure:
Following general procedure II, 1-{6-chloro-4-[(1-methylpiperidin-4-yl)amino]-1,5-naphthyridin-3-yl}ethanone (70 mg, 0.22 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (95 mg, 0.33 mmol) to afford the desired product (52 mg, 53%) as a yellow solid: 1H NMR (500 MHz, CD3OD) δ 8.85 (s, 1H), 8.09-8.01 (m, 2H), 7.94 (s, 2H), 5.74-5.70 (m, 1H), 2.95-2.92 (m, 2H), 2.68 (s, 3H), 2.51 (t, J=11.7 Hz, 2H), 2.37 (s, 3H), 2.33-2.25 (m, 2H), 1.73-1.71 (m, 2H); ESI MS m/z 445 [M+H]+; HPLC>99% (AUC), tR=9.03 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([I:10])[C:7]([NH2:11])=[C:6]([NH2:12])[CH:5]=1.[CH:14](OC)(OC)OC>C1COCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]([I:10])[C:7]2[N:11]=[CH:14][NH:12][C:6]=2[CH:5]=1)=[O:13]
Reactant: COC(OC)OC
Reactant: COC(=O)c1cc(N)c(N)c(I)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(I)c2nc[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.1 %

Procedure:
To a solution of 3,4-diamino-5-iodo-benzoic acid methyl ester (1.68 g, 5.75 mmol) in THF (20 mL) was added trimethyl orthoformate (1.26 mL, 11.5 mmol) and 4-toluenesulfonic acid (11 mg, 0.057 mmol). The mixture was stirred at room temperature overnight, then partitioned between ethyl acetate and water. The organic layer was separated, dried over MgSO4, filtered and concentrated under reduced pressure to give 783 mg (45%) of 7-Iodo-3H-benzoimidazole-5-carboxylic acid methyl ester, MS (M+H)=303.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([NH:13][CH2:14][CH3:15])[CH:4]=1)#[N:2].[C:16](OC)(=[O:24])[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[SH:19].C(N(CC)CC)C>C1(C)C(C)=CC=CC=1>[CH2:14]([NH:13][C:5]1[CH:4]=[C:3]([C:1]2[S:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[C:16](=[O:24])[N:2]=2)[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])[CH3:15]
Reactant: COC(=O)c1ccccc1S
Reactant: CCNc1cc(C#N)ccc1C(=O)OC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1C
Product: CCNc1cc(-c2nc(=O)c3ccccc3s2)ccc1C(=O)OC
Temperature: 145 °C
Reaction time: 18 h
Yield: 22 %

Procedure:
A mixture of methyl 4-cyano-2-(ethylamino)benzoate (1.23 g, 6.02 mmol), methyl thiosalicylate (1.52 g, 9.04 mmol), triethylamine (1.7 mL, 12 mmol) and xylene (6 mL) was stirred at 145° C. for 18 hours under a nitrogen flow. After the reaction mixture was allowed to cool, the crystals were taken by filtration and recrystallized from methanol to give the title compound (450 mg, 22%).
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:10]=[CH:11][C:12]([O:31]CC3C=CC=CC=3)=[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[O:26][C:27]([CH3:30])=[CH:28][CH:29]=4)=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:14]=2)[CH2:3]1.[OH-]>C(O)C.CN(C)C=O>[CH3:8][C@H:6]1[NH:7][C@@H:2]([CH3:1])[CH2:3][N:4]([C:9]2[CH:10]=[CH:11][C:12]([OH:31])=[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[O:26][C:27]([CH3:30])=[CH:28][CH:29]=4)=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:14]=2)[CH2:5]1
Reactant: Cc1ccc(-c2ccc(S(=O)(=O)Nc3cc(N4C[C@@H](C)N[C@@H](C)C4)ccc3OCc3ccccc3)cc2)o1
Agent: [OH-]
Solvent: CCO
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc(S(=O)(=O)Nc3cc(N4C[C@@H](C)N[C@@H](C)C4)ccc3O)cc2)o1
Reaction time: 3.75 h

Procedure:
A solution of N-{5-(cis-3,5-dimethyl-1-piperazinyl)-2-[(phenylmethyl)oxy]phenyl}-4-(5-methyl-2-furanyl)benzenesulfonamide (D43) (100 mg, 0.19 mmol) in ethanol (4 ml) and N,N-dimethylformamide (2.5 ml) was treated with palladiwn hydroxide on carbon (25 mg) and the mixture stirred under an atmosphere of hydrogen for 3.75 h. The mixture was then filtered through celite, washing with ethanol and the filtrate reduced in vacuo and the residue purified by mass directed autoprep HPLC to afford the title compound. MS (ES+) m/e 442 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:27])=[C:14]([C:24]([O-])=[O:25])[C:15](=[O:23])[N:16]3[CH2:19][CH:20]([CH3:22])[CH3:21])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:28][O:29][CH2:30][CH2:31][NH2:32]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:27])=[C:14]([C:24]([NH:32][CH2:31][CH2:30][O:29][CH3:28])=[O:25])[C:15](=[O:23])[N:16]3[CH2:19][CH:20]([CH3:21])[CH3:22])=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CC(C)Cn1c(=O)c(C(=O)[O-])c(O)c2ncc(Cc3ccc(F)cc3)cc21
Reactant: COCCN
Product: COCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(C)C)c1=O
Yield: 79 %

Procedure:
A solution of 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-(2-methylpropyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (20 mg, 0.05 mmol) in 2-methoxyethylamine (1 mL) was heated with a microwave at 140° C. for 20 minutes. The solvent was removed in vacuo and the residue was purified by reverse phase preparative HPLC to give the title compound (17 mg, 79%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 10.35 (br, 1 H), 8.54 (s, 1 H), 7.25 (s, 1 H), 7.15 (dd, J=8.5, 5.4 Hz, 2 H), 7.03 (t, J=8.5 Hz, 2 H), 4.12 (s, 2 H), 3.97 (br, 2 H), 3.63 (m, 2 H), 3.57 (m, 2 H), 3.39 (s, 3 H), 1.95 (m, 1 H), 0.87 (d, J=6.8 Hz, 6 H); HRMS m/z calcd for C23H27N3O4 (M+H)+ 428.1986, found 428.1977.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:10][S:11]([CH2:14][CH2:15][CH3:16])(=[O:13])=[O:12])=[N:4][CH:5]=[C:6]([F:9])[C:7]=1[I:8].[H-].[Na+].[CH3:19][Si:20]([CH2:23][CH2:24][O:25][CH2:26]Cl)([CH3:22])[CH3:21]>CN(C=O)C>[F:1][C:2]1[C:3]([N:10]([CH2:26][O:25][CH2:24][CH2:23][Si:20]([CH3:22])([CH3:21])[CH3:19])[S:11]([CH2:14][CH2:15][CH3:16])(=[O:13])=[O:12])=[N:4][CH:5]=[C:6]([F:9])[C:7]=1[I:8]
Reactant: CCCS(=O)(=O)Nc1ncc(F)c(I)c1F
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)N(COCC[Si](C)(C)C)c1ncc(F)c(I)c1F
Reaction time: 0.17 h

Procedure:
To a solution of N-(3,5-difluoro-4-iodopyridin-2-yl)propane-1-sulfonamide (0.68 g, 1.88 mmol) in anhydrous DMF (25 ml) at 0° C. was added sodium hydride (60% dispersion in mineral oil, 0.15 g, 3.8 mmol). The reaction mixture was stirred for 10 min, and then SEMCl (0.47 g, 2.8 mmol) was added. The mixture was stirred for 1 h and was then concentrated. Water was added and the mixture was extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, and concentrated. The residue was chromatographed on silica gel (5 to 20% ethyl acetate in hexanes eluant) to provide the title compound. MS m/z 515.1 (M+Na).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:21])[NH:10][C@H:11]1[CH2:16][CH2:15][C@@H:14]([OH:17])[CH2:13][C@@H:12]1[CH:18]=[CH:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:21])[NH:10][C@H:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][C@@H:12]1[CH:18]=[CH:19][CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC=C[C@H]1C[C@H](O)CC[C@@H]1NC(=O)OCc1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC=C[C@H]1CC(=O)CC[C@@H]1NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 67.8 %

Procedure:
A solution of [(1S,2R,4R)-(4-hydroxy-2-propenyl-cyclohexyl)]-carbamic acid benzyl ester as a colorless oil (0.56 g, 1.9 mmol) in CH2Cl2 (20 mL) was charged with pyridine (0.8 mL, 9.5 mmol) and Dess-Martin Periodinane (0.9 g, 2.1 mmol). The reaction was stirred at RT for 12 h and concentrated in vacuo. Purification of the residue via flash chromatography afforded the desired [(1S,2R)-(4-oxo-2-propenyl-cyclohexyl)]-carbamic acid benzyl ester (0.37 g) as a 3:1 mixture of Z and E diastereomers. This material was dissolved in titanium tetraisopropoxide (2 mL) and N-methylisopropylamine (3 mL) with agitation. The resultant solution was stirred for 1 h at RT and then charged with MeOH (6 mL) and sodium borohydride (100 mg; added slowly—vigorous gas evolution was observed). The reaction was stirred for 1.5 h and then quenched with 0.2 N NaOH. The resultant mixture was diluted with CH2Cl2 and stirred vigorously before being filtered through Celite. The phases were separated and the organic phase was washed with brine, dried (MgSO4), filtered, and concentrated in vacuo to give the desired [(1S,2R,4R)-4-(isopropyl-methyl-amino)-2-propenyl-cyclohexyl]-carbamic acid benzyl ester (295 mg, mixture of olefin diastereomers, some 4S diastereomer present) as a light yellow oil. MS found: (M+H)+=345.31.
Reaction SMILES: Cl.[CH3:2][CH:3]([C:9](=O)[CH3:10])[C:4](OCC)=[O:5].[SH:12][CH2:13][C:14]([O:16][CH3:17])=[O:15]>ClCCl>[CH3:2][C:3]1[C:4]([OH:5])=[C:13]([C:14]([O:16][CH3:17])=[O:15])[S:12][C:9]=1[CH3:10]
Reactant: CCOC(=O)C(C)C(C)=O
Reactant: COC(=O)CS
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1sc(C)c(C)c1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Dry hydrogen chloride gas was bubbled through a mixture of ethyl 2-methyl-3-oxobutanoate (7.6 g, 50 mmol) and methyl 2-mercaptoacetate (11.2 g, 100 mmol) at -10° C. until saturated. The oil was allowed to stand for 3 hours at room temperature, diluted with dichloromethane and washed with brine. After drying with sodium sulphate and evaporation of solvent the oil was dissolved in methanol (10 ml) and added dropwise to methanolic potassium hydroxide (2N; 75 ml), stirring at room temperature for 1 hour. The solution was diluted with iced water (125 ml) and acidified with 3N hydrochloric acid at -3° to 0° C. to pH1. The precipitate was filtered and washed with water (5.5 g, m.p. 50°-51° C., methanol).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10].C(N(CC)CC)C.Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>C(Cl)Cl>[CH2:22]([O:21][C:19]([NH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10])=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCCCN1CCCC1=O
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCN1CCCC1=O)OCc1ccccc1
Reaction time: 1.5 h
Yield: 87.8 %

Procedure:
To a 0° C. solution of 1-(3-aminopropyl)-2-pyrrolidinone (25.0 g; 176 mmol) and triethylamine (26.7 g; 264 mmol) in CH2Cl2 (500 mL) was added benzyl chloroformate (33.1 g; 194 mmol) dropwise over a period of 15 minutes. The mixture was stirred for 1.5 hr. at 0° C. and then for 15 hr. at ambient temperature, before the mixture was diluted with CH2Cl2 and extracted with 5% aqueous HCl (200 mL), H2O (200 mL), and saturated aqueous NaHCO3. The organic phase was dried (MgSO4), filtered, and the solvents were removed under reduced pressure, then the oil which resulted was flash chromatographed (SiO2 ; 2-5% MeOH/Ch2Cl2) to give the title compound as a colorless oil (42.7 g; 88% yield).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[C:4]([NH:6][C:7]1[C:8]([C:12]2[NH:16][C:15]3[CH:17]=[CH:18][C:19]([CH2:21][OH:22])=[CH:20][C:14]=3[N:13]=2)=[N:9][NH:10][CH:11]=1)=[O:5]>C(Cl)Cl.CO.O=[Mn]=O>[F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[C:4]([NH:6][C:7]1[C:8]([C:12]2[NH:16][C:15]3[CH:17]=[CH:18][C:19]([CH:21]=[O:22])=[CH:20][C:14]=3[N:13]=2)=[N:9][NH:10][CH:11]=1)=[O:5]
Reactant: O=C(Nc1c[nH]nc1-c1nc2cc(CO)ccc2[nH]1)c1c(F)cccc1F
Agent: O=[Mn]=O
Solvent: ClCCl
Solvent: CO
Product: O=Cc1ccc2[nH]c(-c3n[nH]cc3NC(=O)c3c(F)cccc3F)nc2c1
Temperature: 25 °C
Reaction time: 120 h
Yield: 47.7 %

Procedure:
A mixture of 2,6-difluoro-N-[3-(5-hydroxymethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-benzamide (800 mg, 2.17 mmol) and MnO2 (5.00 g, 57.5 mmol) in CH2Cl2/MeOH (10:1, 110 ml) was stirred at ambient temperature for 5 days. The mixture was filtered through a plug of Celite washing with MeOH and the filtrate reduced in vacuo to give 2,6-difluoro-N-[3-(5-formyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-benzamide (380 mg, 48%) as a yellow solid. (LC/MS: Rt 3.41, [M+H]+ 368.04).