Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:15][CH:16]2[CH:20]3[O:21][CH2:22][CH:23]([N:24]4C(=O)C5C(=CC=CC=5)C4=O)[CH:19]3[O:18][CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1.O.NN>CCO>[NH2:24][CH:23]1[CH:19]2[O:18][CH2:17][CH:16]([NH:15][C:3]3[C:2]([Cl:1])=[CH:7][N:6]=[C:5]([NH:8][C:9]4[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=4)[N:4]=3)[CH:20]2[O:21][CH2:22]1
Reactant: Cn1cc(Nc2ncc(Cl)c(NC3COC4C3OCC4N3C(=O)c4ccccc4C3=O)n2)cn1
Agent: NN
Solvent: CCO
Solvent: O
Product: Cn1cc(Nc2ncc(Cl)c(NC3COC4C(N)COC34)n2)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.7 %

Procedure:
To a solution of 2-(6-((5-chloro-2-((l-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)hexahydrofuro[3,2-b]furan-3-yl)isoindoline-1,3-dione (140.0 mg, 0.29 mmol) in EtOH (5 mL) was added hydrazine hydrate (198.6 mg, 2.94 mmol). The mixture was stirred at room temperature for 4 h. The mixture was concentrated in vacuo, the residue was purified with a silica gel column chromatography ((7M NH3 in MeOH)/DCM (v/v)=1/20) to give the target product as a white solid (65.0 mg, 63.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH:13]=[O:14])=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]([CH2:13][OH:14])=[CH:11][N:12]=2)=[CH:6][CH:7]=1
Reactant: O=Cc1cnc(-c2ccc(Cl)cc2)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cnc(-c2ccc(Cl)cc2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.3 %

Procedure:
To a suspension of 2-(4-chlorophenyl)thiazole-5-carbaldehyde (3.26 g, 14.6 mmol) in methanol (50 ml) is added the sodium borohydride (568 mg, 15 mmol) portionwise at room temperature. The reaction mixture is stirred at room temperature for 2 h. The reaction mixture is quenched with 50 ml of an aqueous saturated solution of ammonium chloride, extracted with dichloromethane (2×100 ml). The combined organic extracts are dried with magnesium sulphate, filtered and evaporated to dryness to give [2-(4-chlorophenyl)thiazol-5-yl]methanol (3.24 g).
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[O:10][CH2:11][C:12]1[N:17]=[CH:16][C:15]([C:18]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[O:19])=[CH:14][CH:13]=1.[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30]>ClCCl>[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].[CH:3]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[O:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]([NH:20][S:21]([CH3:24])(=[O:22])=[O:23])=[O:19])=[CH:16][N:17]=1)=[O:2]
Reactant: COC(OC)c1ccncc1OCc1ccc(C(=O)NS(C)(=O)=O)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)c1ccc(COc2cnccc2C=O)nc1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
Into a 50-mL round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 6-([[4-(dimethoxymethyl)pyridin-3-yl]oxy]methyl)-N-methanesulfonylpyridine-3-carboxamide (80 mg, 0.21 mmol, 1.00 equiv) in dichloromethane (5 mL), and trifluoroacetic acid (2 mL). The resulting solution was stirred for 3 h at 40° C. in an oil bath, and then it was concentrated under vacuum. The crude product (60 mg) was purified by Flash-Prep-HPLC with the following conditions (CombiFlash-1): Column, C18 silica gel; mobile phase, CH3CN/H2O=1/99 increasing to CH3CN/H2O=40/60 within 20 min; Detector, UV 254 nm. This resulted in 20 mg (17%) of 6-[[(4-formylpyridin-3-yl)oxy]methyl]-N-methanesulfonylpyridine-3-carboxamide; bis(trifluoroacetic acid) as a white solid. The compound exhibited a melting point of 102-104° C. LC-MS: (ES, m/z):336 [M+1]+/354 [M+1+18]+. H-NMR (300 MHz, DMSO, ppm): 10.53 (s, 1H), 9.07 (s, 1H), 8.78 (s, 1H), 8.43 (d, J=4.5 Hz, 1H), 8.36 (dd, J=8.1 Hz, 1H), 7.84 (d, J=8.4 Hz, 1H), 7.62 (d, J=4.5 Hz, 1H), 5.60 (s, 2H), 3.37 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.[Br:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]OS(C)(=O)=O)[CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)P(N(C)C)(N(C)C)=O>O>[Br:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)CCc1ccc(N)cc1
Reactant: CS(=O)(=O)OCCCCCC=Cc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)CCc1ccc(NCCCCCC=Cc2cccc(Br)c2)cc1

Procedure:
A mixture of 5.0 g. of ethyl 4-aminohydrocinnamate, 10.0 g. of 7-(3-bromophenyl)-1-methanesulfonyloxy-6-heptene (prepared by the method of Example 9), 4.2 g. of anhydrous powdered potassium carbonate and 40 ml. hexamethylphosphoramide is heated to 80° for 17 hours. The mixture is then cooled, diluted with water and extracted with ethyl ether. The ether extracts are washed with water, dried and evaporated. The residue is recrystallized from ethanol yielding the title compound as white crystals.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][CH:10]([F:28])[O:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([N:18]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=3)[CH:20]=2)[N:17]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:20]1[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)=[N:18][N:16]2[C:15]=1[CH:14]=[CH:13][C:12]([O:11][CH:10]([F:9])[F:28])=[N:17]2
Reactant: O=C1CCC(=O)N1Br
Reactant: Fc1cccc(-c2cc3ccc(OC(F)F)nn3n2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Fc1cccc(-c2nn3nc(OC(F)F)ccc3c2Br)c1
Reaction time: 18 h
Yield: 91 %

Procedure:
N-bromo succinimide (195 mg) was added to a solution of 6-difluoromethoxy-2-(3fluoro-phenyl)-pyrazolo[1,5-b]pyridazine (251 mg) and sodium bicarbonate (185 mg) in anhydrous DMF (10 ml) and stirred for 18 h. The reaction mixture was diluted with ethyl acetate (300 ml) and washed with water (10×20 ml), brine (20 ml), dried (Na2SO4) and concentrated to give the title compound as a solid (293 mg, 91%).
Reaction SMILES: [CH2:1]1[C:7]2=[CH:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[N:6]2[CH2:5][CH2:4][CH2:3][NH:2]1.B.C1COCC1>FC(F)(F)C(O)=O.O1CCCC1>[CH2:1]1[CH:7]2[CH2:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[N:6]2[CH2:5][CH2:4][CH2:3][NH:2]1
Reactant: c1ccc2c(c1)cc1n2CCCNC1
Agent: B
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: c1ccc2c(c1)CC1CNCCCN21
Reaction time: 0.17 h

Procedure:
70 milligrams of 2,3,4,5-tetrahydro-1H-[1,4]-diazepino [1,2-a]indole (prepared as described in U.S. Pat. No. 3,867,374) was dissolved in 3 milliliters of trifluoroacetic acid and the mixture was stirred for 10 minutes under nitrogen. Thereafter, 1.5 milliliters of a 1 M solution of BH3.THF in tetrahydrofuran was added dropwise with stirring and the resulting mixture stirred for 40 minutes to obtain a 2,3,4,5,11,11a-hexahydro-1H-[1,4]-diazepino[1,2-a]indole product in the reaction mixture. Water (0.5 milliliter) then was added dropwise to the mixture cooled in an ice bath, followed by 10 percent NaOH until pH tested about 9 (pH test paper). The alkaline solution was extracted with methylene chloride and the methylene chloride solution washed with saturated sodium chloride solution and dried over potassium carbonate. The dried solution was filtered to remove the drying agent and evaporated in vacuo to obtain 60 milligrams (85 percent yield) of 2,3,4,5,11,11a-hexahydro-1H-[1,4]diazepino[ 1,2-a]indole product as an oil having NMR and mass spectra appropriate for the compound. The hydrochloride salt of the product melted 238°-240° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[C:20]1[N:25]=[C:24]([CH:26]=O)[CH:23]=[CH:22][CH:21]=1.[C:28]([NH2:32])([CH3:31])([CH3:30])[CH3:29].[BH3-]C#N.[Na+].ClCCl>C(O)C>[C:28]([NH:32][CH2:26][C:24]1[N:25]=[C:20]([C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:18]=[CH:19][C:10]=2[CH2:9][NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[CH:21]=[CH:22][CH:23]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: Cc1ccccc1NCc1ccc2ccccc2c1-c1cccc(C=O)n1
Reactant: CC(C)(C)N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: Cc1ccccc1NCc1ccc2ccccc2c1-c1cccc(CNC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1.79 g (5.09 mmol) of 6-(2-{[(2-methylphenyl)amino]methyl}-1-naphthyl)pyridine-2-carbaldehyde, 1.85 g (25.4 mmol) of tert-butylamine and 0.641 g (10.2 mmol) of NaBH3CN in 100 ml of dry ethanol was stirred overnight at room temperature. The resulting mixture was evaporated to dryness. The product was isolated from the residue by flash chromatography on neutral alumina (eluent: dichloromethane, then dichloromethane-ether=1:1, vol.). Yield 1.10 g (53%) of yellowish oil. Anal. calc. for C28H31N3: C, 82.11; H, 7.63; N, 10.26. Found: C, 82.34; H, 7.79; N, 10.11. 1H NMR (CDCl3): 7.90 (d, J=8.6 Hz, 1H, 4-H in naphthyl), 7.88 (m, 1H, 8-H in naphthyl), 7.79 (m, 1H, 4-H in Py), 7.65 (d, J=8.6 Hz, 1H, 3-H in naphthyl), 7.38-7.48 (m, 4H, 3-H in Py and 5,6,7-H in naphthyl), 7.32 (m, 1H, 5-H in Py), 7.01-7.04 (m, 2H, 3,5-H in ortho-tolyl), 6.63 (m, 1H, 4-H in ortho-tolyl), 6.52 (m, 1H, 6-H in ortho-tolyl), 4.22 (m, 2H, Naph-CH2N), 4.01 (m, 2H, Py-CH2N), 3.50 (br. s, 2H, NH), 2.11 (s, 3H, Me in ortho-tolyl), 1.18 (s, 9H, tBu).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:3]=1.[NH:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:21]1.C(N(CC)CC)C>C(Cl)Cl>[OH:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:4]1[N:3]=[C:2]([N:20]2[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:21]2)[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=1
Reactant: Cc1ccc2c(Cl)nc(-c3ccccc3O)nc2c1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)nc(-c3ccccc3O)nc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.5 %

Procedure:
To a solution of 2-(4-chloro-7-methylquinazolin-2-yl)phenol (0.5 g, 1.84 mmol) in CH2Cl2 (10 mL) at 0° C. was added dropwise a solution of tert-butyl(R)-piperidin-3-ylcarbamate (0.37 g, 1.84 mmol) in CH2Cl2 (5 mL), then triethylamine (0.51 mL, 3.68 mmol). The mixture was allowed to warm to room temperature and was stirred for 3 h. After quenching with water, it was extracted with CH2Cl2. The organic layers were combined, dried over MgSO4, and concentrated. Purification via silica gel chromatography using 5:1 CH2Cl2: hexanes gave tert-butyl(R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-ylcarbamate (0.54 g, 68%). LC/MS: m/z 435.5 (M+H)+ at 2.80 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[C:11]([O:13]C)[CH:10]=[CH:9][C:8]=1[CH3:15].C(OCC)(=O)C.[OH-].[Na+]>CCCCC>[OH:6][C:7]1[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][C:8]=1[CH3:15]
Reactant: COc1ccc(C)c(OC)c1
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCCCC
Product: Cc1ccc(O)cc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.1 %

Procedure:
Boron tribromide (3.1 ml, 3.2 mmol) was added to a solution of 2,4-dimethoxytoluene (1 g, 6.5 mmol) in pentane (10 ml) at −70° C. The reaction mixture was allowed to warm to ambient temperature and the mixture stirred for a further 2 hours. Ice water and ethyl acetate were then added and the aqueous layer basified to pH9.5 with 2M aqueous sodium hydroxide. After stirring for 10 minutes, the organic layer was separated and the aqueous layer extracted with ethyl acetate. The combined organic extract was washed with brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by flash chromatography eluting with methylene chloride/ethyl acetate (9/1) to give 2,4-dihydroxytoluene (759 mg, 94%) as a white solid.
Reaction SMILES: [C:1]1([C:7]2[C:15]([CH:16]=[CH:17][C:18]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]3[CH2:26][OH:27])=[O:19])=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29].C(OCC)(=O)C>N1C=CC=CC=1>[C:1]1([C:7]2[C:15]([CH:16]=[CH:17][C:18]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]3[CH2:26][O:27][C:28](=[O:30])[CH3:29])=[O:19])=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=C(C=Cc1c(-c2ccccc2)nn2ccccc12)N1CCCCC1CO
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCC1CCCCN1C(=O)C=Cc1c(-c2ccccc2)nn2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.7 %

Procedure:
1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-hydroxymethylpiperidine (trans isomer) (0.50 g) was added to a stirred solution of acetic anhydride (0.16 g) in pyridine (5 ml) at room temperature, and stirred at room temperature for 3 hours. Ethyl acetate was added to the reaction mixture and washed with 1N aqueous sodium hydroxide solution, water and saturated sodium chloride aqueous solution, then dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (50 g) with a mixture of chloroform and acetone (20: 1) as an eluent. The fractions containing the objective compound were combined and evaporated in vacuo to give 1-[3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-acetoxymethylpiperidine (trans isomer) (0.35 g) as an oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:24]2[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[CH:26][CH:25]=2)=[CH:7][CH:8]=[C:9]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[N:15]=2)[CH:10]=1)=[O:4].[F:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37][NH2:38]>>[Cl:23][C:18]1[CH:17]=[C:16]([C:14]2[N:15]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:24]4[CH:25]=[CH:26][C:27]([C:30](=[O:31])[NH:38][CH2:37][C:36]5[CH:39]=[CH:40][CH:41]=[C:34]([F:33])[CH:35]=5)=[CH:28][CH:29]=4)=[CH:7][CH:8]=3)[S:12][CH:13]=2)[CH:21]=[CH:20][C:19]=1[Cl:22]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(=O)O)cc1
Reactant: NCc1cccc(F)c1
Product: O=C(NCc1cccc(F)c1)c1ccc(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)cc1
Yield: 73.4 %

Procedure:
Using the conditions of General Procedure E for Amide Coupling in Parallel Mode, 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2,4′-dicarboxylic acid 2-methyl ester (which may be prepared as described for Intermediate 8; 100 mg, 0.21 mmol) was reacted with 3-fluorobenzylamine (available from Aldrich Chemical Company, Inc.; 78 mg, 0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC Purification Conditions B to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4′-(3-fluoro-benzylcarbamoyl)-biphenyl-2-carboxylic acid (89 mg, 74%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.17 (br s, 1H), 9.14 (t, J=6.0 Hz, 1H), 8.46 (s, 1H), 8.39 (d, J=1.8 Hz, 1H), 8.33 (d, J=2.0 Hz, 1H), 8.24 (dd, J=8.0, 1.8 Hz, 1H), 8.09 (dd, J=8.5, 2.0 Hz, 1H), 7.97 (d, J=8.3 Hz, 2H), 7.76 (d, J=8.3 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.51 (d, J=8.3 Hz, 2H), 7.35-7.43 (m, 1H), 7.13-7.23 (m, 2H), 7.04-7.11 (m, 1H), 4.53 (d, J=6.0 Hz, 8H).
Reaction SMILES: CC(C)([O-])C.[K+].Cl.[Cl:8][C:9]1[CH:10]=[N:11][C:12](=[O:15])[NH:13][CH:14]=1.Br[CH2:17][S:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1>CN(C=O)C>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([S:18][CH2:17][N:11]2[CH:10]=[C:9]([Cl:8])[CH:14]=[N:13][C:12]2=[O:15])=[CH:20][CH:21]=1
Reactant: Clc1ccc(SCBr)cc1
Reactant: O=c1ncc(Cl)c[nH]1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1ncc(Cl)cn1CSc1ccc(Cl)cc1

Procedure:
Potassium tert-butoxide (40 mmol) in DMF (25 ml) was added to a solution of 5-chloropyrimidin-2-one hydrochloride (20 mmol) in DMF (125 ml). The mixture was stirred at room temperature for 15 min before 1-bromomethylsulfenyl-4-chlorobenzene [see U.S. Pat. No. 2,827,492; Chem. Abstract 52 Pl 6296 d (1958)](25 mmol) was added. The resultant mixture was stirred at room temperature at 60° C. for 3h, the solvent removed at reduced pressure and the residue triturated with water and dried. The residual product was a mixture of the N- and O-alkylated isomers in the ratio 3:1 (1H NMR); yield 4.2 g (73%). The isomers were separated by their different solubilities in acetone, the less polar O-isomer being the more soluble isomer. The title compound, the N- isomer had m.p. 191° C. (acetone). (Found C45.90; H2.78. Calc. for C11H8Cl2N2OS: C46.00; H2.81) 1 H NMR (CDCl3): δ 5.25 (CH2), 7.35 (Ph, s), 8.20 and 8.50 (H-4, H-6, d, J 4 Hz). IR (KBr): 1660 cm-1 (CO). MS (70 eV; m/z (% rel. int)): 286 (4, M), 157 (11), 156 (11), 145 (33), 143 (100), 116 (27).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[C:12]([OH:14])=O)=[CH:5][CH:4]=1.C(Cl)(=O)C([Cl:18])=O>C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[C:12]([Cl:18])=[O:14])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(C(=O)O)CC2
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc2c(c1)C(C(=O)Cl)CC2
Reaction time: 2 h

Procedure:
6-Methoxy-indane-1-carboxylic acid, 6.0 g (31 mmol), a compound of Formula 3, was dissolved in 50 ml of methylene chloride and reacted at ambient temperature with 4.0 ml (46 mmol) of oxalyl chloride in the presence of one drop of DMF. After 2 hours, the reaction mixture was brought to reflux and maintained for 15 minutes. It was then concentrated under vacuum and stirred for about 30 minutes, yielding 6-methoxy-indane-1-carboxylic acid chloride, which was sufficiently pure to be used for the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[N:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[C:6]([Cl:26])[CH:5]=1)([O-])=O.C([O-])(O)=O.[Na+].C(O)(=O)C>C(O)C>[NH2:1][C:4]1[CH:25]=[CH:24][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[N:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[C:6]([Cl:26])[CH:5]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1Cl)N1Cc2ccnn2Cc2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1ccc(C(=O)N2Cc3ccnn3Cc3ccccc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.7 %

Procedure:
A mixture of 0.553 g of 5,10-dihydro-5-(4-nitro-2-chlorobenzoyl)-4H-pyrazolo[5,1-c][1,4]benzodiazepine, 1.70 g of stannous chloride dihydrate in 20 ml of ethanol is heated at 70°-80° C. for 1 hour. The mixture is chilled, made basic with 1M NaHCO3 and then stirred at room temperature for 0.5 hour. The mixture is brought to pH 5 with acetic acid and extracted (several times) with ethyl acetate. The combined extracts are dried Na2SO4) and passed through a pad of hydrous magnesium silicate. The filtrate is evaporated and the residue dissolved in dichloromethane and the solution passed through a thin pad of hydrous magnesium silicate. The filtrate is evaporated in vacuo to give 0.40 g of a glass, m.p. 98°-117° C.; Anal. Calc'd: C, 62.9; H, 4.7; N, 16.3; Cl, 11.6. Found: C, 62.4; H, 4.3; N, 15.6; Cl, 11.7.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1C(OC)=O.[C:11](Cl)(=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13]>N1C=CC=CC=1>[S:4]1[CH:5]=[CH:6][C:2]([NH:1][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:3]1
Reactant: COC(=O)c1sccc1N
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Nc1ccsc1
Temperature: 25 °C
Yield: 44 %

Procedure:
To an oven dried flask was charged with methyl 3-aminothiophene-2-carboxylate (30 g, 191 mmol) and pyridine (300 ml), followed by addition of pivaloyl chloride (25.3 g, 210 mmol) at room temperature. A mild exotherm occurred, and solid was formed. 10 min later, the reaction mixture was refluxed under N2 overnight (˜20 hr), and stirred at rt on weekend. Most of the solvent was removed on rotary vacuo. The brown residue was partitioned between 1N HCl and CH2Cl2(100 mL/150 mL). After seperation, the aqueous solution was extracted with CH2Cl2(100 mL), the combined organic layers were washed with brine (70 mL), dried on MgSO4, concentrated on rotary vacuo, the residue as a brown solid, was triturated with Et2O (30 mL), filtered and washed with Et2O (2×10 mL) to afford the expected product, N-(thiophen-3-yl)pivalamide (15.4 g, 50%) as an off white solid. 1H-NMR (400 MHz, CHLOROFORM-D) δ ppm 1.28 (s, 9 H) 6.98 (dd, J=5.16, 1.39 Hz, 1 H) 7.20 (dd, J=5.29, 3.27 Hz, 1 H) 7.57-7.66 (m, 2 H); Mass spec. C184.05 (MH+) calc. for C9H13NOS 183.07.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:23][CH:24]([S:26](Cl)(=[O:28])=[O:27])[CH3:25].C(OCC)(=O)C>N1C=CC=CC=1>[CH3:19][C:17]1([CH3:18])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=2)[NH:9][CH:8]1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][S:26]([CH:24]([CH3:25])[CH3:23])(=[O:28])=[O:27])[CH:3]=1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(N)c1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)S(=O)(=O)Nc1cccc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)c1
Reaction time: 8 h
Yield: 36.5 %

Procedure:
2-(3-Aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid (100 mg, 0.34 mmol) was dissolved in 2 mL of dry pyridine under nitrogen. Then propane-2-sulfonyl chloride (0.1 mL, 0.89 mmol) was added drop wise to the reaction mixture. The reaction mixture was allowed to stir overnight. Thin layer chromatography (petroleum ether:ethyl acetate=1:1, Rf=0.5) showed the reaction was complete. Pyridine was removed in vacuo and the residue was purified by column chromatography (petroleum ether:ethyl acetate=1:1) to afford 50 mg of 3,3-dimethyl-2-(3-(1-methylethylsulfonamido)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid. Yield: 36.8%. MS (ES+APCI) M+1=403.1.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH:15][C:16]1[CH:17]=[C:18]([CH:23]=[C:24]([O:26][C:27]2[CH:39]=[CH:38][C:30]3[C:31](=[O:37])[N:32]([CH3:36])[CH2:33][CH2:34][O:35][C:29]=3[CH:28]=2)[CH:25]=1)[C:19]([O:21][CH3:22])=[O:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:59][O:60][CH2:61][C@H:62](O)[CH3:63]>C1COCC1>[CH3:63][C@H:62]([O:15][C:16]1[CH:17]=[C:18]([CH:23]=[C:24]([O:26][C:27]2[CH:39]=[CH:38][C:30]3[C:31](=[O:37])[N:32]([CH3:36])[CH2:33][CH2:34][O:35][C:29]=3[CH:28]=2)[CH:25]=1)[C:19]([O:21][CH3:22])=[O:20])[CH2:61][O:60][CH3:59]
Reactant: COC[C@@H](C)O
Reactant: COC(=O)c1cc(O)cc(Oc2ccc3c(c2)OCCN(C)C3=O)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC[C@H](C)Oc1cc(Oc2ccc3c(c2)OCCN(C)C3=O)cc(C(=O)OC)c1
Reaction time: 0.5 h
Yield: 116 %

Procedure:
DIAD (1.18 mL, 6.0 mmol) was added to a stirred solution of methyl 3-hydroxy-5-[(4-methyl-5-oxo-2,3,4,5-tetrahydro-1,4-benzoxazepin-8-yl)oxy]benzoate (1.72 g, 5.0 mmol) and triphenylphosphine (2.62 g, 10.0 mmol) in THF (50 mL) at 0° C.-5° C. The mixture was stirred for 30 minutes, then treated with (R)-1-methoxy-2-propanol (675 mg, 7.5 mmol) and the mixture stirred at RT for 18 hours. The mixture was evaporated in vacuo to a residue which was chromatographed on silica, eluting with 50% ethyl acetate in isohexane. The residue was slurried in ether (25 mL), filtered, and the filtrates evaporated in vacuo to give the desired compound (2.41 g) with a small amount of contaminating triphenylphosphine present. The material was used in the next steps without further purification. 1H NMR δ (CDCl3): 1.25 (d, 3H), 3.15 (s, 3H), 3.3 (s, 3H), 3.4-3.5 (m, 2H), 3.5 (t, 2H), 3.8 (s, 3H), 4.3 (t, 2H), 4.5 (m, 1H), 6.5 (d, 1H), 6.7 (d, 1H), 6.75 (d, 1H), 7.2 (d, 1H), 7.35 (d, 1H), 7.8 (d, 1H); m/z 416 (M+H)+