Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC([CH2:7][N:8](C)[C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([C:22]4[CH:27]=[C:26]([NH2:28])[C:25]([F:29])=[CH:24][C:23]=4[Cl:30])[C:15](=[O:21])[N:16]3[CH2:19][CH3:20])=[CH:11][N:10]=2)=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:28][C:26]1[C:25]([F:29])=[CH:24][C:23]([Cl:30])=[C:22]([C:14]2[C:15](=[O:21])[N:16]([CH2:19][CH3:20])[C:17]3[C:12]([CH:13]=2)=[CH:11][N:10]=[C:9]([NH:8][CH3:7])[CH:18]=3)[CH:27]=1
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2Cl)cc2cnc(N(C)Cc3ccc(OC)cc3)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCn1c(=O)c(-c2cc(N)c(F)cc2Cl)cc2cnc(NC)cc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 46.5 %

Procedure:
To a solution of Example A4 (3 g, 6.2 mmol) in DCM (100 mL) was added TFA (20 mL) at RT, and the resulting mixture was stirred at RT for 6 h. The mixture was extracted with water (2×) and the combined aqueous layers were neutralized with NH3H2O. The resulting precipitate was collected by filtration and dried to give 3-(5-amino-2-chloro-4-fluorophenyl)-1-ethyl-7-(methylamino)-1,6-naphthyridin-2(1H)-one (1 g, 44% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.46 (s, 1H), 7.75 (s, 1H), 7.1 (d, J=11.2 Hz, 1H), 7.0 (m, 1H), 6.73 (d, J=9.6 Hz, 1H), 6.43 (s, 1H), 4.95 (br s, 2H), 4.14 (m, 2H), 2.92 (s, 3H), 1.14 (t, J=6.8 Hz, 3H); MS (ESI) m/z: 347.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9]1([S:19](Cl)(=[O:21])=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.O>O1CCOCC1>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:19]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)(=[O:21])=[O:20])=[CH:3][CH:4]=1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: Nc1ccc(O)cc1
Solvent: C1COCCO1
Solvent: O
Product: O=S(=O)(Nc1ccc(O)cc1)c1cccc2ccccc12
Reaction time: 4.5 h
Yield: 72.3 %

Procedure:
To a solution of 4-aminophenol (4.5 g) in dioxane (20 ml) was added dropwise a solution of 1-naphthalenesulfonyl chloride (4.4 g) in dioxane (20 ml). The mixture was further stirred at room temperatue for 4.5 hours and poured into water. The precipitate was collected by filtration, recrystallized from ethanol and decolored with activated carbon to give N-(ρ-hydroxyphenyl)-1-naphthalenesulfonamide (4.2 g), mp 195-196° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][NH:23][C:24]2[S:25][C:26]3[CH:32]=[C:31]([N+:33]([O-])=O)[CH:30]=[CH:29][C:27]=3[N:28]=2)=[CH:18][CH:17]=1)([CH3:4])([CH3:3])[CH3:2].O.O.[Sn](Cl)Cl.C([O-])(=[O:44])C.[NH4+]>C1COCC1.CO.O>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:44])[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][NH:23][C:24]2[S:25][C:26]3[CH:32]=[C:31]([NH2:33])[CH:30]=[CH:29][C:27]=3[N:28]=2)=[CH:18][CH:17]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NCc1ccc(CNc2nc3ccc([N+](=O)[O-])cc3s2)cc1
Agent: Cl[Sn]Cl
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(CNc2nc3ccc(N)cc3s2)cc1
Yield: 76.9 %

Procedure:
To a suspension of compound 141 (200 mg, 0.385 mmol) in a mixture of THF/MeOH/H2O (10 mL/10 mL/10 mL) were successively added tin(II) chloride dihydrate (1.35 g, 8.46 mmol) and ammonium acetate (1.09 g, 14.12 mmol). The mixture was refluxed for 2 days, the tin salts were filtered off and the filtrate was concentrated in vacuo. The residue was partitioned between EtOAc and H2O (brine was added to break the emulsion). Organic phase was successively washed with saturated aqueous NaHCO3 and brine, dried over MgSO4, and concentrated in vacuo to afford the title compound 143 (145 mg, 77% yield). 1H NMR: (DMSO-d6) δ (ppm): 12.89 (bs, 1H), 10.79 (s, 1H), 8.12 (d, J=2.0 Hz, 1H), 8.05 (d, J=8.8 Hz, 2H), 7.90-7.68 (m, 3H), 7.62 (d, J=8.4 Hz, 2H), 7.48 (bs, 1H), 7.21 (dd, J=4.9, 3.7 Hz, 1H), 4.65 (s, 2H). m/z: 490.5 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10].[S:19]1[C:23]([S:24](Cl)(=[O:26])=[O:25])=[CH:22][C:21]2[CH:28]=[CH:29][CH:30]=[CH:31][C:20]1=2>C(Cl)Cl.N1C=CC=CC=1>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([S:9]([NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][S:24]([C:23]2[S:19][C:20]3[CH:31]=[CH:30][CH:29]=[CH:28][C:21]=3[CH:22]=2)(=[O:25])=[O:26])(=[O:11])=[O:10])=[CH:17][CH:16]=1
Reactant: Nc1ccccc1NS(=O)(=O)c1ccc(Cl)cc1
Reactant: O=S(=O)(Cl)c1cc2ccccc2s1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1ccccc1NS(=O)(=O)c1cc2ccccc2s1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.2 %

Procedure:
To a solution of N-(2-aminophenyl)-4-chlorobenzenesulfonamide (0.5 mmol, prepared as in Example 11) in DCM (1 mL) and pyridine (1 mL), benzo[b]thiophene-2-sulfonyl chloride (0.55 mmol), prepared as above, was added at RT and the reaction mixture was then allowed to stir at RT overnight or until the reaction was complete as determined by TLC or LC-MS. The reaction mixture was then diluted with DCM (5 mL). The organic phase was washed with 10% HCl aqueous solution (5 mL), water (5 mL) and brine (5 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc to afford 180 mg of benzo[b]thiophene-2-sulfonic acid [2-(4-chlorobenzenesulfonylamino)phenyl]-amide. LC: Tr 1.23 min, MS: 479.8 (M+1)+.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:11])[O:8][CH:7]([CH2:9][OH:10])[CH2:6][O:5]1.Br[C:13]1[N:14]=[CH:15][S:16][CH:17]=1>>[CH3:3][C:4]1([CH3:11])[O:8][CH:7]([CH2:9][O:10][C:13]2[N:14]=[CH:15][S:16][CH:17]=2)[CH2:6][O:5]1
Reactant: Brc1cscn1
Reactant: CC1(C)OCC(CO)O1
Agent: [H-]
Agent: [Na+]
Product: CC1(C)OCC(COc2cscn2)O1

Procedure:
NaH (60% dispersion in mineral oil, 12.19 g, 305.3 mmol) was added portionwise to DL-1,2-isoproylideneglycerol (16.11 g, 1218 mmol) and the mixture was stirred until gas evolution had ceased (ca. 30 min RT, followed by 2 h at 60° C.). Subsequently, 4-bromothiazole (20.00 g, 121.9 mmol) was added and the mixture was stirred at 140° C. for 45 min. Subsequently, the reaction mixture was quenched with aq. sat. NH4Cl and extracted with EtOAc. The comb. org. layers were washed with brine, dried over MgSO4, and conc. in vacuo. The residue was subjected to distillation and the volatiles (HV, 60° C.) were removed. The residue was purified by means of CC (5-40% EtOAc/Hept) to provide a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[N:10][C:5]2=[C:4](Cl)[CH:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO>[Cl:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[N:10][C:5]2=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=1
Reactant: Clc1cc(Cl)c2nc[nH]c2n1
Reactant: Nc1ccccc1
Solvent: CO
Product: Clc1cc(Nc2ccccc2)c2nc[nH]c2n1

Procedure:
5,7-Dichloro-3H-imidazo[4,5-b]pyridine (4.4 g, 23.3 mMol) was heated with 50 mL of aniline at 135° C. under a nitrogen atmosphere. After 48 hours the reaction mixture was cooled and diluted with 50 mL methanol. The 5-chloro-7-anilino-3H-imidazo[4,5-b]pyridine was isolated and washed with methanol. The dried solid weighed 4.8 g. Yield 19.6 mMol, 84%; m.p. >300° C.; NMR (DMSO-d6): 9.23 δ (s, 1H, NH-anilino); 8.24 (s, 1H, H2); 7.44-7.37 (m, 5H, aromatic); 6.69 (s, 1H, H5).
Reaction SMILES: C[O:2][C:3](=[O:38])[CH2:4][CH:5]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[CH3:36])=[O:28])=[CH:22][CH:21]=3)[C:15]2=[O:37])=[CH:9][CH:8]=1)[CH3:6].[OH-].[Li+]>O1CCCC1>[O:37]=[C:15]1[C:16]([C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[CH3:36])=[O:28])=[CH:22][CH:21]=2)=[CH:17][CH:18]=[CH:19][N:14]1[CH2:13][C:10]1[CH:11]=[CH:12][C:7]([CH:5]([CH3:6])[CH2:4][C:3]([OH:38])=[O:2])=[CH:8][CH:9]=1
Reactant: COC(=O)CC(C)c1ccc(Cn2cccc(-c3ccc(NC(=O)Nc4ccccc4C)cc3)c2=O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccccc1NC(=O)Nc1ccc(-c2cccn(Cc3ccc(C(C)CC(=O)O)cc3)c2=O)cc1
Temperature: 65 °C

Procedure:
(±)-3-(4-{2-Oxo-3-[4-(3-o-tolyl-ureido)phenyl]-2H-pyridin-1-ylmethyl}phenyl)-butyric acid methyl ester (0.21 g, 0.41 mmol) was dissolved in tetrahydrofuran (3 mL) and aqueous lithium hydroxide (0.5 M, 3 mL) added with stirring. The mixture was heated at 65° C. for 2 hours and then allowed to cool and concentrated in vacuo. The mixture was acidified with hydrochloric acid (2M), extracted with ethyl acetate (2×25 mL) and the combined organic layers washed with brine and dried over anhydrous magnesium sulfate. After filtration and evaporation to dryness the title compound was obtained as a white solid.
Reaction SMILES: C([O:4][C:5]1[CH:13]=[C:12]([Cl:14])[CH:11]=[C:10]2[C:6]=1[CH2:7][CH2:8][CH2:9]2)C=C.[C:15]1(C)[CH:20]=C(C)C=C(C)[CH:16]=1>>[CH2:20]([C:13]1[C:12]([Cl:14])=[CH:11][C:10]2[CH2:9][CH2:8][CH2:7][C:6]=2[C:5]=1[OH:4])[CH:15]=[CH2:16]
Reactant: C=CCOc1cc(Cl)cc2c1CCC2
Reactant: Cc1cc(C)cc(C)c1
Product: C=CCc1c(Cl)cc2c(c1O)CCC2
Yield: 56 %

Procedure:
Treatment of 4-(allyloxy)-6-chloroindane (8.0 g, 0.038 mol) in refluxing mesitylene (270 mL) generally according to the procedure described for Intermediate 1 afforded 4.5 g (56%) of 5-allyl-6-chloroindan-4-ol as a colorless oil which solidified into a white solid upon standing. mp 37-39° C.; Anal. calcd. for C12H13ClO.0.1H2O: C, 68.48; H, 6.32. Found: C, 68.54; H, 6.29.
Reaction SMILES: C(Cl)CCl.[Br:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=O.[CH3:15][N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[C:17]1[CH2:25][NH:26][CH3:27].C1C=CC2N(O)N=NC=2C=1.O>CN(C=O)C>[Br:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([N:26]([CH3:27])[CH2:25][C:17]1[N:16]([CH3:15])[C:24]2[C:19]([CH:18]=1)=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:10]
Reactant: O=C(O)c1ccccc1Br
Reactant: CNCc1cc2ccccc2n1C
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O
Product: CN(Cc1cc2ccccc2n1C)C(=O)c1ccccc1Br
Reaction time: 8 h
Yield: 60.9 %

Procedure:
EDC (660 mg, 3.44 mmole) was added to a solution of 2-bromobenzoic acid (693 mg, 3.45 mmole), 1-methyl-2-(methylaminomethyl)indole (600 mg, 3.45 mmole), and HOBt.H2O (466 mg, 3.45 mmole) in DMF at RT. The reaction was stirred overnight, then was concentrated in vacuo. The residue was diluted with 5% NaHCO3 and extracted with CH2Cl2. The combined organic extracts were washed with brine and dried over MgSO4. Flash chromatography on silica gel (2% MeOH/CH2Cl2) gave the title compound (750 mg, 63%): MS (ES) m/e 357 (M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:7]([Cl:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([NH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:11].Br[C:20]1[S:21][C:22]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:23]([CH3:25])[N:24]=1.C(=O)(O)[O-].[Na+].O>CN(C=O)C>[Cl:2][C:3]1[C:7]([Cl:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([NH:12][CH:13]1[CH2:18][CH2:17][N:16]([C:20]2[S:21][C:22]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:23]([CH3:25])[N:24]=2)[CH2:15][CH2:14]1)=[O:11]
Reactant: Cc1[nH]c(C(=O)NC2CCNCC2)c(Cl)c1Cl
Reactant: CCOC(=O)c1sc(Br)nc1C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1sc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc1C
Temperature: 50 °C
Yield: 30.6 %

Procedure:
3,4-Dichloro-5-methyl-N-piperidin-4-yl-1H-pyrrole-2-carboxamide hydrochloride (Intermediate 1; 0.500 g, 2.00 mmol), ethyl 2-bromo-4-methyl-1,3-thiazole-5-carboxylate (0.625 g, 2.00 mmol) and sodium bicarbonate (0.336 g, 2.00 mmol) were stirred in DMF (5 ml). The reaction was heated to 50° C. overnight. The solution was diluted by the addition of water and the resulting layers were separated. The aqueous layer was extracted with EtOAc (3×), and the organic layers were combined, dried over anhydrous magnesium sulfate, filtered and concentrated. Hexanes were added to the crude material, and the precipitate was filtered and rinsed with EtOAc to give the title compound as a beige solid (0.273 g).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][CH:25]=1)[CH2:7][S:8][C:9]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:10]=1[C:11]([O:13]C)=O.O.Cl>CN(C)C=O>[OH:13][C:11]1[C:10]2[CH:15]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=[CH:18][C:9]=2[S:8][C:7]=1[C:6]1[CH:23]=[CH:24][CH:25]=[C:4]([CH3:3])[CH:5]=1
Reactant: COC(=O)c1cc(C(F)(F)F)ccc1SCc1cccc(C)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(-c2sc3ccc(C(F)(F)F)cc3c2O)c1
Temperature: 75 °C
Reaction time: 0.75 h

Procedure:
To a slurry of sodium hydride (50% dispersion in mineral oil) (253 mg, 5.27 mmol) in N,N-dimethylformamide (3 ml) at 75° C. under a nitrogen atmosphere was added a solution of methyl 2-(m-methylbenzylthio)-5-trifluoromethylbenzoate (885 mg, 2.60 mmol) in N,N-dimethylformamide (12 ml). Gas evolution was observed during the 20 minute addition period. After stirring an additional 45 minutes at 75° C., water (70 ml) was added, and the aqueous mixture was brought to pH5-6 at room temperature with 2N hydrochloric acid. Extraction of the mixture with diethyl ether followed by washing the combined extracts with water and evaporation gave a residue that was chromatographed on a column of silica gel (Merck 7734, packed as a slurry in 15:1 hexane-ether). Elution with 15:1 hexane-ether containing 1% acetic acid and evaporation of the appropriate fractions afforded the product as a white crystalline solid; yield 450 mg (56%); m/z 308 (M+.); m.p. 124°-126°.
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:7][O:6][C:5]([C:8]2[NH:12][C:11]([C:13]3[CH:14]=[C:15]([CH:27]=[C:28]([O:30][C@@H:31]([CH3:35])[CH2:32][O:33]C)[CH:29]=3)[O:16][C:17]3[CH:18]=[CH:19][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[N:21][CH:22]=3)=[CH:10][CH:9]=2)=[N:4]1)[CH3:2].B(Br)(Br)Br.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH2:1]([C@@H:3]1[CH2:7][O:6][C:5]([C:8]2[NH:12][C:11]([C:13]3[CH:29]=[C:28]([CH:27]=[C:15]([O:16][C:17]4[CH:22]=[N:21][C:20]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:19][CH:18]=4)[CH:14]=3)[O:30][C@@H:31]([CH3:35])[CH2:32][OH:33])=[CH:10][CH:9]=2)=[N:4]1)[CH3:2]
Reactant: CC[C@@H]1COC(c2ccc(-c3cc(Oc4ccc(S(C)(=O)=O)nc4)cc(O[C@@H](C)COC)c3)[nH]2)=N1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC[C@@H]1COC(c2ccc(-c3cc(Oc4ccc(S(C)(=O)=O)nc4)cc(O[C@@H](C)CO)c3)[nH]2)=N1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 71.7 %

Procedure:
5-(3-{5-[(4R)-4-Ethyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-[(1S)-2-methoxy-1-methylethoxy]phenoxy)-2-(methylsulfonyl)pyridine (1.06 g, 2.12 mmol) synthesized in Example (85b) was dissolved in methylene chloride (20 mL), followed by cooling to −78° C., and boron tribromide (1.0 mol/L methylene chloride solution, 2.33 mL, 2.33 mmol) was added under nitrogen atmosphere. After the temperature was raised naturally and stirring was carried out at room temperature for 30 minutes, a saturated aqueous sodium hydrogencarbonate solution was added to neutralize the reaction solution, followed by extraction with methylene chloride (80 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=70%-100%) to afford the desired compound (738 mg, 71%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]=O)=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[O-]S([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[CH2:18](/[N:25]=[CH:16]\[C:13]1[CH:14]=[CH:15][C:10]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Br:1])[CH:3]=2)=[CH:11][CH:12]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1ccc(-c2ccc(C=O)cc2)cc1Br
Reactant: NCc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: COc1ccc(-c2ccc(/C=N\Cc3ccccc3)cc2)cc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.9 %

Procedure:
A mixture of 3′-bromo-4′-methoxy-1,1′-biphenyl-4-carbaldehyde (19.4 g, 69 mmol), prepared in step 3 of Example 6, benzylamine (38 mL, 345 mmol) and 60 g of anhydrous MgSO4 in 400 mL of methylene chloride was stirred under nitrogen at room temperature for 18 h. The reaction was filtered and the filtrate concentrated under reduced pressure to give an off-white solid. The solid was triturated with hexane and dried under reduced pressure to give N-benzyl-N-[(1Z)-(3′-bromo-4′-methoxy-1,1′-biphenyl-4-yl)methylidene]amine (23.6 g, 88%) as an off-white solid, MS KESI) m/z 380 [M+H]+. Elemental analysis for C21H18BrNO: Calc'd: C, 66.33; H, 4.77; N, 3.68; Found: C, 63.22; H, 4.85; N, 4.17
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH3:20])[C:7](=[O:19])[CH2:8][N:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])[C:4]=2[CH:3]=1.C1(B(O)O)C=CC=CC=1.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1B(O)O>>[CH3:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH3:20])[C:7](=[O:19])[CH2:8][N:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])[C:4]=2[CH:3]=1
Reactant: CN1C(=O)CN=C(c2cccc(C#N)c2)c2cc(Br)ccc21
Reactant: COc1ccccc1B(O)O
Agent: OB(O)c1ccccc1
Product: COc1ccccc1-c1ccc2c(c1)C(c1cccc(C#N)c1)=NCC(=O)N2C
Yield: 45 %

Procedure:
Prepared from 3-(7-bromo-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)-benzonitrile Intermediate 14 using the same method described for Example 1 and instead of using benzene boronic acid, we used 2-methoxyphenyl boronic acid. The title compound (85 mg) was obtained as a yellow solid, (yield=45%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]=[C:29]=[O:30]>>[F:20][C:21]([F:31])([F:32])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][C:29](=[O:30])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=1
Reactant: O=C=Nc1ccccc1C(F)(F)F
Reactant: NC(=O)c1[nH]c2cnccc2c1-c1ccc(N)cc1
Product: NC(=O)c1[nH]c2cnccc2c1-c1ccc(NC(=O)Nc2ccccc2C(F)(F)F)cc1

Procedure:
80 mg of solid yellow 3-{4-[3-(2-trifluoromethylphenyl)ureido]phenyl}-1H-pyrrolo[2,3-c]pyridine-2-carboxamide are prepared as described in Example 1 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide and 2-trifluoromethylphenyl isocyanate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]([CH3:15])=[C:13]([C:16]([O:18]CC)=[O:17])[CH:12]=[N:11]1.[OH-].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]([CH3:15])=[C:13]([C:16]([OH:18])=[O:17])[CH:12]=[N:11]1
Reactant: CCOC(=O)c1cnn(-c2c(Cl)cc(Cl)cc2Cl)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1c(C(=O)O)cnn1-c1c(Cl)cc(Cl)cc1Cl
Yield: 71.5 %

Procedure:
By the method of Example 1, Step D, 40.0 g (0.12 mole) of 1-(2,4,6-trichlorophenyl)-4-ethoxycarbonyl-5-methyl-1H-pyrazole and 5.75 g (0.14 mole) of sodium hydroxide were reacted in 40 mL of ethanol and 30 mL of water, yielding 26.2 g of 1-(2,4,6-trichlorophenyl)-4-carboxy-5-methyl-1H-pyrazole as a light tan solid; mp 184°-186.5° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][C:5](=[O:10])[CH2:6][C:7]([O-:9])=[O:8].[N:11]([CH2:14][CH2:15][OH:16])=[N+:12]=[N-:13].Cl.[CH2:18]1COC[CH2:19]1>>[CH2:18]([O:9][C:7](=[O:8])[CH2:6][C:5](=[O:10])[CH2:4][O:16][CH2:15][CH2:14][N:11]=[N+:12]=[N-:13])[CH3:19]
Reactant: [N-]=[N+]=NCCO
Reactant: C1CCOC1
Reactant: O=C([O-])CC(=O)CCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC(=O)COCCN=[N+]=[N-]
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
To a slurry of sodium hydride (0.80 g, 60% dispersion, 20 mmol) in anhydrous THF (10 mL) cooled to −30° C. with a dry ice-acetone bath under N2 was slowly added a solution of 4-chloroacetoacetate (3.25 g, 19.75 mmol) in anhydrous THF (10 mL). The mixture was kept cooled at −30° C. and stirred for 30 min. This solution was transferred by cannula to another flask containing a slurry of sodium hydride (0.80 g, 60% dispersion, 20 mmol) and 2-azido-ethanol (1.72 g, 19.8 mmol) in anhydrous THF (30 mL). After the addition, the temperature was allowed to warm up to RT and stirred overnight (ca. 15 h). The mixture was acidified with 1N HCl and then extracted with EtOAc (100 mL). The EtOAc extract was washed with brine (50 mL), dried (Na2SO4), filtered and concentrated in vacuo to afford 4.792 g of crude product as a brown oil. The crude product was purified by chromatography using the ISCO Combiflash SQ16× (120 g Redisep silica gel column, 0 to 70% EtOAc in hexanes for 30 min at 40 mL/min) to afford 2.932 g of purified material as a yellow oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@@H:23]([CH:25](C)[NH:26][C:27]([SH:29])=[S:28])[O:22][C:21]3=[O:31])=[CH:16][C:15]=2[F:32])[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:33]O>>[CH3:33][S:29][C:27](=[S:28])[NH:26][CH2:25][C@@H:23]1[O:22][C:21](=[O:31])[N:20]([C:17]2[CH:18]=[CH:19][C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[C:15]([F:32])[CH:16]=2)[CH2:24]1
Reactant: CO
Reactant: CC(NC(=S)S)[C@@H]1CN(c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)c(F)c2)C(=O)O1
Product: CSC(=S)NC[C@H]1CN(c2ccc(N3CCNCC3)c(F)c2)C(=O)O1
Reaction time: 120 h

Procedure:
A suspension of 510 mg 4-{2-fluoro-4-[(5S)-5-(methyl-sulfanylthiocarbonylamino-methyl)2-oxo-oxazolidin-3-yl]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester (1.05 mmol) in 1.25 M/methanol was stirred for 5 days. The solvent was evaporated and the residue digested in water. The water layer was neutralized at pH 7 with a saturated solution of sodium bicarbonate and evaporated to dryness. The residue was digested in CH2Cl2/MeOH. The salts were filtered and the solvent evaporated:
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CON(C)[C:39]([C:41]1[S:45][CH:44]=[N:43][CH:42]=1)=[O:40]>>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[C:22]([C:39]([C:41]2[S:45][CH:44]=[N:43][CH:42]=2)=[O:40])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CON(C)C(=O)c1cncs1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2F)C[C@H](C)O1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(=O)c3cncs3)c(F)c2F)C[C@H](C)O1

Procedure:
Starting materials: (2R,6S)-4-(6-((tert-butyldiphenylsilyloxy)methyl)-2,3-difluorophenyl)-2,6-dimethylmorpholine (Intermediate 3) and N-methoxy-N-methylthiazole-5-carboxamide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[CH3:12].S([O-])([O-])=O.[Na+:17].[Na+].C(=O)([O-])O.[Na+]>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:12].[Na+:17]
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1Br
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(S(=O)[O-])ccc1Br
Temperature: 90 °C
Yield: 91.7 %

Procedure:
4-Bromo-3-methylbenzenesulfonyl chloride (1.145 g, 4.25 mmol) was added portion wise to a solution of sodium sulfite (0.578 g, 2.29 mmol) and sodium hydrogen carbonate (0.749 g, 2.4 mmol) in water (10 mL) at 80° C. The reaction was heated to 90° C. for 3 h. The cooled reaction mixture was evaporated in vacuo to half-volume, at which point a precipitate appeared. This was removed by filtration. The filtrate was concentrated further then cooled to 5° C. and the precipitate removed by filtration. The combined residues were washed with water and dried to give sodium 4-bromo-3-methylbenzenesulfinate (0.54 g).