Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10](O)[CH3:11])=[CH:4][C:3]=2[O:2]1.[C:13]([O:16]C(=O)C)(=[O:15])[CH3:14]>N1C=CC=CC=1>[C:13]([O:16][CH2:11][CH2:10][C:5]1[CH:6]=[CH:7][C:8]2[O:9][CH2:1][O:2][C:3]=2[CH:4]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: CC(O)c1ccc2c(c1)OCO2
Solvent: c1ccncc1
Product: CC(=O)OCCc1ccc2c(c1)OCO2
Temperature: 80 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
To a stirred solution of 2-(3,4-methylenedioxy)phenyl-1-ethanol (1.68 g, 10 mmol) in dry pyridine was added acetic anhydride and the resultant reaction mixture was stirred at 80° C. for 1h. The reaction mixture was poured into ice-water and was extracted with ether (2×75 ml). The combined ether extract was washed with water (2×50 ml), 5% HCl (2×50 ml) and then with 5% NaHCO3 (2×50 ml). The organic layer was dried over magnesium sulfate and the solvent was removed under reduced pressure to give 1-acetoxy-2-[(3,4-methylenedioxy)phenyl]ethane as a solid (1.7 g, 81% yield).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[CH:8]=O)(=[O:3])[CH3:2].C([O-])(=O)C.[NH4+].[N+:23]([CH3:26])([O-:25])=[O:24]>>[CH2:14]([N:13]([C:12]1[CH:11]=[CH:10][C:7]([CH:8]=[CH:26][N+:23]([O-:25])=[O:24])=[CH:6][C:5]=1[NH:4][C:1](=[O:3])[CH3:2])[CH2:16][CH3:17])[CH3:15]
Reactant: CCN(CC)c1ccc(C=O)cc1NC(C)=O
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CCN(CC)c1ccc(C=C[N+](=O)[O-])cc1NC(C)=O
Temperature: 100 °C
Yield: 36 %

Procedure:
A solution was prepared by dissolving 28 grams (0.12 mol) of 3-acetylamino-4-(N,N-diethylamino)benzaldehyde in 120 ml of nitromethane, and added with 4 grams of ammonium acetate. The mixture was heated at 100° C. for 5 hours under agitation. The reaction solution was then cooled on a dry ice-acetone bath until crystallization had been completed. The separated solid (crystal) was filtered off and dried in vacuum. The obtained product was recrystallized from acetonitrile for two times. An amount of 10 grams of red crystals was obtained. The yield was 36%.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][C:10]=1[C:21](=O)[C:22]([N:24]1[CH2:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25]1)=[O:23])=O)(C)(C)C.[F-].[Cs+].C[Si]([N:40]=[C:41]=[N:42][Si](C)(C)C)(C)C.Cl>C(#N)C.ClCCl>[NH2:40][C:41]1[N:42]=[C:21]([C:22]([N:24]2[CH2:25][C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:32]2)=[O:23])[C:10]2[C:9](=[CH:14][CH:13]=[C:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:11]=2)[N:8]=1
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Reactant: CCOC(=O)Cc1ccc(NC(=O)OC(C)(C)C)c(C(=O)C(=O)N2Cc3ccccc3C2)c1
Agent: Cl
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4.9 g of ethyl 2-[4-(tert-butoxycarbonylamino)-3-(2-isoindolin-2-yl-2-oxo-acetyl)phenyl]acetate are dissolved in 100 ml of acetonitrile under argon. 1.7 g of caesium fluoride are added, and 3 ml of bis(trimethylsilyl)carbodiimide are added dropwise to the solution over the course of 5 min. The mixture is stirred at room temperature for 15 min, and 20 ml of dichloromethane are then added. After addition of 20 ml of hydrochloric acid (1N), the product precipitates out as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].[C:27]1([CH:33]2[CH2:38][CH2:37][CH2:36][CH:35]([NH2:39])[CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:17](=[O:19])[NH:39][CH:35]3[CH2:36][CH2:37][CH2:38][CH:33]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:34]3)=[CH:20][CH:21]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Reactant: NC1CCCC(c2ccccc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NC4CCCC(c5ccccc5)C4)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.7 %

Procedure:
To a solution of 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (83.9 mg, 0.223 mmol), N,N-dimethylpyridin-4-amine (2.72 mg, 0.0223 mmol), and 3-phenylcyclohexanamine (41 mg, 0.234 mmol) in DMF (1.2 ml) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (47.0 mg, 0.245 mmol), and the reaction was stirred overnight at ambient temperature. The reaction was diluted with EtOAc and washed with 1M hydrochloric acid, saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified on a Biotage SP1 system to yield 58 mg of the title compound (48.7% yield).
Reaction SMILES: [H-].[Na+].[S:3]1[CH:7]=[CH:6][N:5]=[C:4]1[SH:8].[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19](S(C)(=O)=O)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>CN(C=O)C>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([S:8][C:4]2[S:3][CH:7]=[CH:6][N:5]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCC(S(C)(=O)=O)CC1
Reactant: Sc1nccs1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Sc2nccs2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.5 %

Procedure:
To sodium hydride (60% wt. suspension in mineral oil, 108 mg) in dry DMF (5 ml) was added 1,3-thiazole-2-thiol (315 mg) at 0° C. After 30 minutes, 4-methanesulfonyl-piperidine-carboxylic acid tert-butyl ester (500 mg) was added as a solution in DMF (2 ml) and the reaction mixture was warmed up to room temperature overnight, then heated at 50° C. for 3 hours. Aqueous work-up and purification on silica yielded 4-(thiazol-2-ylsulfanyl)-piperidine-1-carboxylic acid tert-butyl ester (174 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][S:5][CH2:6][C:7]1[CH:19]=[CH:18][C:10]2[S:11][C:12]([S:14](=[O:17])(=[O:16])[NH2:15])=[CH:13][C:9]=2[CH:8]=1.I([O-])(=O)(=O)=[O:22].[Na+]>C(O)C.O>[CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][S:5]([CH2:6][C:7]1[CH:19]=[CH:18][C:10]2[S:11][C:12]([S:14](=[O:17])(=[O:16])[NH2:15])=[CH:13][C:9]=2[CH:8]=1)=[O:22]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CN(C)CCSCc1ccc2sc(S(N)(=O)=O)cc2c1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CN(C)CCS(=O)Cc1ccc2sc(S(N)(=O)=O)cc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64 %

Procedure:
To a partial solution of 5-[2-(dimethylamino)ethylthiomethyl]-2-sulfamoylbenzo[b]thiophene (1.32 g, 0.004 mol) in 20 ml of ethanol and 40 ml of water was added sodium metaperiodate (0.94 g, 0.0044 mol) and the mixture was stirred at room temperature for 16 hours over night. The reaction mixture was filtered and the filtrate was evaporated to dryness in vacuo. The white solid residue was recrystallized twice from 4/1 (V/V) water/ethanol and chromatographed on silica gel eluting with 7.5% (V/V) methanol/CHCl3. There was recovered 0.88 g of white solid, m.p. 180°-183° C., dec. (Yield 64%).
Reaction SMILES: [OH:1][CH:2]([CH2:9][OH:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].[CH2:11](C(Cl)(C1C=CC=CC=1)C1C=CC=CC=1)C1C=CC(OC)=CC=1.O>N1C=CC=CC=1>[OH:10][CH2:9][CH:2]([O:1][CH3:11])[CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8]
Reactant: C=CCCCCC(O)CO
Reactant: COc1ccc(CC(Cl)(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: O
Product: C=CCCCCC(CO)OC
Reaction time: 48 h
Yield: 45.8 %

Procedure:
A mixture of 45 g of 7,8-dihydroxy-1-octene and 101.2 g of p-anisylchlorodiphenylmethane in 200 ml of pyridine was allowed to stand at 10° C. for 48 hours. The mixture was poured into water and extracted with ether. The ether solution was dried and evaporated. The residue was dissolved in 300 ml of dimethylformamide containing 83.1 ml of methyl iodide and this solution was added dropwise to a suspension of 17.75 g of 60t sodium hydride in 500 ml of dimethylformamide over a 2 hour period. After stirring an additional 13 hours the mixture was poured into water and extracted with ether. The ether solution was dried and evaporated. The residue was dissolved in 400 ml of methanol and stirred with 35 g of Amberlyst 15 resin. The solution was filtered and solvent was removed. The residue was purified by chromatography giving 22.6 g of 8-hydroxy-7-methoxy-1-octene as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5](=O)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][C:8]=1[N+:17]([O-])=O)[CH3:2].CCO>[Fe].CC(O)=O>[CH2:1]([O:3][C:4]([C:5]1[NH:17][C:8]2[C:7]([CH:6]=1)=[CH:12][CH:11]=[C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:9]=2)=[O:21])[CH3:2]
Reactant: CCOC(=O)C(=O)Cc1ccc(C(C)(C)C)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1cc2ccc(C(C)(C)C)cc2[nH]1

Procedure:
A mixture of 3-(4-tert-butyl-2-nitro-phenyl)-2-oxo-propionic acid ethyl ester (prepared in Example XX; 9.1 g, 31 mmol), iron powder (15.3 g, 274 mmol), EtOH (70 mL), and glacial AcOH (70 mL) was refluxed for 2 hours. After cooling, the resulting mixture was evaporated. THF (100 mL) was added to the residue, and the suspension was filtered on florisil, eluting with a large amount of THF. The solvents were evaporated, and the residue was purified by flash silica gel chromatography (5%-30% EtOAc in hexanes as eluents). MS(APCI): 246 (M+H).
Reaction SMILES: [N:1]1([C:7]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=2[C:9](Cl)=[O:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[Cl:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[N:27]1[CH2:28][CH2:29][N:30]([C:9]([C:8]2[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:7]=2[N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:10])[CH2:31][CH2:32]1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Reactant: Fc1ccc(N2CCNCC2)c(Cl)c1
Product: O=C(c1cc([N+](=O)[O-])ccc1N1CCOCC1)N1CCN(c2ccc(F)cc2Cl)CC1

Procedure:
The title compound was prepared according to the procedure described for example 46 from 2-Morpholin-4-yl-5-nitro-benzoyl chloride and 1-(2-Chloro-4-fluoro-phenyl)-piperazine (70%, yellow solid, MS (m/e): 449.2 (M+H, 100%)
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([CH3:23])[CH:18]=3)[NH:14][N:13]=2)=[CH:8][C:7]=1[N+:24]([O-:26])=[O:25])[CH:2]([CH3:4])[CH3:3].[C:27]([O:33][CH2:34]Cl)(=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([CH3:23])[CH:18]=3)[N:14]([CH2:34][O:33][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[N:13]=2)=[CH:8][C:7]=1[N+:24]([O-:26])=[O:25])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: Cc1cc(-c2nc(-c3ccc(OCC(C)C)c([N+](=O)[O-])c3)n[nH]2)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(-c2nc(-c3ccc(OCC(C)C)c([N+](=O)[O-])c3)nn2COC(=O)C(C)(C)C)ccn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.4 %

Procedure:
354 mg of the powder obtained in Example 1 was dissolved in 3 ml of DMF, 181 mg of pivaloyloxymethyl chloride and 276 mg of potassium carbonate were added thereto, and the mixture was stirred at room temperature for 18 hours. Ethyl acetate was added to the reaction mixture, which was then washed with water and dried over magnesium sulfate. After the magnesium sulfate was filtered off, the solvent was evaporated under reduced pressure and the residue was subjected to silica gel column chromatography. Chloroform-acetone (95:5) was used as an eluent and 358 mg of the object compound was obtained as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]1[CH:26]=[CH:25][C:24]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])=[CH:23][C:6]=1[CH:7]([C:13]1[S:14][C:15]([C:18]#[C:19][CH2:20][O:21][CH3:22])=[CH:16][CH:17]=1)[O:8]2>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]1[CH:26]=[CH:25][C:24]([NH:27][S:28]([CH3:31])(=[O:29])=[O:30])=[CH:23][C:6]=1[CH:7]([C:13]1[S:14][C:15]([CH2:18][CH2:19][CH2:20][O:21][CH3:22])=[CH:16][CH:17]=1)[O:8]2
Reactant: COCC#Cc1ccc(C2Oc3cccc(OC)c3-c3ccc(NS(C)(=O)=O)cc32)s1
Agent: [Pd]
Solvent: CO
Product: COCCCc1ccc(C2Oc3cccc(OC)c3-c3ccc(NS(C)(=O)=O)cc32)s1
Yield: 72.7 %

Procedure:
A solution of Example 92 (0.05 g, 0.11 mmol) was treated with 10% Pd/C (0.011 g) in MeOH (2 mL) under an atmosphere of hydrogen (50 psi) for 1.5 hour, followed by 10% Pd/C (0.012 g) under an atmosphere of hydrogen 50 psi for 3 hours. The mixture was filtered and concentrated under reduced pressure to afford the titled compound (38 mg, 0.08 mmol, 75%). 1H NMR (500 MHz, CD3OD) δ 8.41 (d, J=8.7 Hz, 1H), 7.25 (dd, J=8.7, 2.5 Hz, 1 H), 7.11 (t, J=8.3 Hz, 1H), 7.05 (d, J=2.2 Hz, 1H), 6.69 (dd, J=8.4, 0.9 Hz, 1H), 6.61 (dd, J=3.4, 0.9 Hz, 1H), 6.57 (m, 2H), 6.25 (s, 1H), 3.92 (s, 3H), 3.35 (t, J=6.2 Hz, 2H), 3.28 (s, 3H), 2.96 (s, 3H), 2.77 (t, J=7.5 Hz, 2H), 1.81 (m, 2H); MS (ESI, −Q1MS) m/e 460 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:7])=[C:4]([OH:17])[CH:3]=1.[OH-].[Na+:19]>CC(C)=O>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([O-:14])=[O:13])=[O:7])=[C:4]([OH:17])[CH:3]=1.[Na+:19]
Reactant: O=C(O)CCCNC(=O)c1ccc(Cl)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C([O-])CCCNC(=O)c1ccc(Cl)cc1O
Temperature: 50 °C
Yield: 97.2 %

Procedure:
A 22 L, five neck round bottom flask, was equipped with an overhead stirrer, reflux condenser, thermocouple temperature read out, and heating mantle. The following reaction was run under a dry nitrogen atmosphere. Reagent acetone (13000 mL) and 4-[(4-chloro-2-hydroxy-benzoyl)amino]butanoic acid (500.0 g, 1.94 mol) were charged to the reactor and stirring was started. The reaction slurry was heated to 50° C. until a hazy brown solution was obtained. The warm solution was pumped through a warm pressure filter dressed with Whatman #1 paper into a clean 22 L reactor. The clear yellow filtrate was heated to 50° C. while stirring. Sodium hydroxide solution (50% aqueous; 155 g, 1.94 mol) was charged to the reactor while maintaining vigorous agitation. After the base addition was complete, the reactor was heated to reflux (60° C.) for 2.5 hours and then allowed to cool slowly to ambient temperature. The product was isolated by vacuum filtration through a sintered glass funnel and dried in a vacuum oven at 50° C. for 24 hours to give 527.3 g of sodium 4-[(4-chloro-2-hydroxybenzoyl)amino]butanoate as an off-white solid. Using acetone in the final stage of the synthesis always resulted in the production of the anhydrous crystalline form. The yield was 97.2%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[CH:12]1(O)[CH2:15][CH2:14][CH2:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH:12]1([O:1][C:2]2[CH:3]=[C:4]([O:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=2)[CH2:15][CH2:14][CH2:13]1
Reactant: CC(=O)Oc1cccc(O)c1
Reactant: OC1CCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)Oc1cccc(OC2CCC2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 20.6 %

Procedure:
Acetic acid 3-hydroxy-phenyl ester (1 ml, 9 mmol) was mixed with cyclobutanol (0.58 g, 8 mmol), triphenylphosphine (2.1 g, 8 mmol) and diisopropyl azodicarboxylate (1.57 ml, 8 mmol) in tetrahydrofuran (20 ml) at 0° C. under a nitrogen atmosphere. The mixture was warmed to room temperature and stirred for 16 hours. The reaction mixture was concentrated in-vacuo the residue was purified by chromatography on silica gel using ethyl acetate in pentane as eluant (gradient from 0:100 to 15:85) to give acetic acid 3-cyclobutoxy-phenyl ester (340 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](F)[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.O.[NH2:12][NH2:13]>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([NH:12][NH2:13])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1
Reactant: NN
Reactant: CSc1nc(F)cc(F)n1
Solvent: CCO
Solvent: O
Product: CSc1nc(F)cc(NN)n1
Yield: 94.7 %

Procedure:
A solution of 15.8 g (0.097 mol) of 4,6-di-fluoro-2-methylthiopyrimidine in 50 ml of ethanol was added slowly with stirring to a solution of 11.6 ml (12.0 g, 0.214 mol) of hydrazine monohydrate in 100 ml of ethanol, keeping the temperature below 0° C. by external cooling. The mixture was allowed to react for an additional 30 min and the volatiles were then removed by evaporation under reduced pressure. The residue was diluted with ethyl acetate and the resulting solution extracted with water, dried over magnesium sulfate, and concentrated under reduced pressure to obtain 16.0 g of the title compound as a white powder melting at 153°-154° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].F[C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1.O>CN(C=O)C>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:1][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=2)[CH:3]=1
Reactant: Oc1cccnc1
Reactant: COC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(Oc2cccnc2)cc1
Temperature: 135 °C
Yield: 32.3 %

Procedure:
3-hydroxypyridine (6.17 g, 64.87 mmol) was dissolved in 100 mL of anhydrous DMF under argon atmosphere. Solid K2CO3 (8.96 g, 64.87 mmol) was added, followed by neat methyl 4-fluorobenzoate (10.0 g, 64.87 mmol). The reaction mixture was heated at 135° C. for 10 hrs. The absence of the starting material was confirmed by LC/MS. The reaction mixture was cooled down to ambient temperature and poured into ca. 500 mL of H2O. The resulting solution was extracted 3 times with ca. 150 mL of EtOAc (during the extraction small volumes of MeOH, Et2O and brine were added to facilitate the separation). Combined EtOAc layers were washed twice with sat. NaHCO3, twice with brine and dried over anhydrous Na2SO4. Solvent was removed in vacuo to give dark-red oil, which was purified by silica gel chromatography using 1:1 mixture of EtOAc/Hexane as eluent to give the title product (4.8 g, 32.3% yield) as yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]([OH:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:14])=[N:7]2.[Se](=O)=[O:16]>O1CCOCC1>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]([OH:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH:14]=[O:16])=[N:7]2
Reactant: O=[Se]=O
Reactant: Cc1ccc2c(Cl)cc(Cl)c(O)c2n1
Solvent: C1COCCO1
Product: O=Cc1ccc2c(Cl)cc(Cl)c(O)c2n1
Temperature: 80 °C

Procedure:
A solution of 5,7-dichloro-2-methyl-quinolin-8-ol 16 (1.5 g, 6.58 mmol) in 1,4-dioxane (20 mL) was added dropwise over 3 h to a stirred suspension of selenium dioxide (1.3 g, 11.72 mmol) in 1,4-dioxane (60 mL) at 50-55° C. The resulting mixture was then heated at 80° C. overnight, cooled, and the solids filtered off (celite). The filtrate was concentrated and the residue, after washing with diethyl ether (10 mL×3), gave 17 as a yellow solid (quantitative yield). This material was used in the subsequent step without further purification. 1H NMR (CDCl3, 400 MHz): δ 10.26 (s, 1 H), 8.69 (d, J=8.8, 1 H), 8.37 (br, 1 H), 8.17 (d, J=8.8, 1 H), 7.76 (s, 1 H).
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C@H:6]([OH:13])[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:21][C:22]1[N:26]([CH2:27][C:28]([N:30]2[CH2:35][CH2:34][CH:33]([C:36]3[S:37][CH:38]=[C:39]([C:41](Cl)=[O:42])[N:40]=3)[CH2:32][CH2:31]2)=[O:29])[N:25]=[C:24]([C:44]([F:47])([F:46])[F:45])[CH:23]=1>ClCCl>[CH3:1][N:2]([C@H:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C@H:6]([OH:13])[CH2:5][CH2:4]1)[C:41]([C:39]1[N:40]=[C:36]([CH:33]2[CH2:34][CH2:35][N:30]([C:28](=[O:29])[CH2:27][N:26]3[C:22]([CH3:21])=[CH:23][C:24]([C:44]([F:45])([F:47])[F:46])=[N:25]3)[CH2:31][CH2:32]2)[S:37][CH:38]=1)=[O:42]
Reactant: CN[C@@H]1CC[C@@H](O)c2ccccc21
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)Cl)cs2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)N(C)[C@@H]3CC[C@@H](O)c4ccccc43)cs2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (1R,4R)-1,2,3,4-tetrahydro-4-(methylamino)-1-naphthalenol and its enantiomer (70 mg, 0.39 mmol) (i.e. the product of Example 28, Step A) and triethylamine (0.082 mL, 0.59 mmol) in 2 mL of dichloromethane was gradually added 2-[1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-4-thiazolecarbonyl chloride (181 mg, 0.43 mmol) (i.e. the product of Example 19, Step D) at 0° C. The reaction mixture was stirred at room temperature for 3 h, diluted with 5 mL of dichloromethane, and washed with water, 1 N aqueous hydrochloric acid, water, saturated solution of sodium bicarbonate and brine. The filtered reaction mixture was dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by medium-pressure liquid chromatography on silica gel using 0-20% of acetone in ethyl acetate as eluant to give 160 mg of the title compounds, compounds of the present invention as a white foam.
Reaction SMILES: [CH3:1][N:2]1[C@@:6]2([CH2:20][C:9]3[CH:10]=[C:11]4[C:16](=[CH:17][C:8]=3[CH2:7]2)[N:15]=[C:14]([CH:18]=[O:19])[CH:13]=[CH:12]4)[C:5](=[O:21])[NH:4][C:3]1=[O:22].[CH3:23]/C=C(/C=O)\C>O>[CH3:23][C:13]1[C:14]([CH:18]=[O:19])=[N:15][C:16]2[C:11]([CH:12]=1)=[CH:10][C:9]1[CH2:20][C@@:6]3([CH2:7][C:8]=1[CH:17]=2)[C:5](=[O:21])[NH:4][C:3](=[O:22])[N:2]3[CH3:1]
Reactant: C/C=C(\C)C=O
Reactant: CN1C(=O)NC(=O)[C@]12Cc1cc3ccc(C=O)nc3cc1C2
Solvent: O
Product: Cc1cc2cc3c(cc2nc1C=O)C[C@]1(C3)C(=O)NC(=O)N1C

Procedure:
Essentially following the procedures described for Intermediate 13, but using trans-2-methyl-2-butenal in place of crotonaldehyde, the title compound was prepared. MS: m/z=327 (M+1+H2O).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:14]2[CH:15]=[CH:16][N:17]([C@@H:18]3[O:22][C@H:21]([CH2:23][OH:24])[C@@H:20]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH2:19]3)[C:13]=2[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[S:34]([NH2:37])(=[O:36])=[O:35]>>[S:34](=[O:36])(=[O:35])([O:24][CH2:23][C@@H:21]1[C@@H:20]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:27])[CH3:28])[CH2:19][C@H:18]([N:17]2[C:13]3[CH:12]=[CH:11][N:10]=[C:9]([NH:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:14]=3[CH:15]=[CH:16]2)[O:22]1)[NH2:37]
Reactant: NS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](n2ccc3c(NCc4ccccc4)nccc32)O[C@@H]1CO
Product: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](n2ccc3c(NCc4ccccc4)nccc32)O[C@@H]1COS(N)(=O)=O
Yield: 29 %

Procedure:
Using essentially the same procedure as example 43, step f, ((2R,3S,5R)-5-[4-(benzylamino)-1H-pyrrolo[3,2-c]pyridin-1-yl]-3-{[tert-butyl(dimethyl)silyl]oxy}tetrahydrofuran-2-yl)methanol (0.0876 g, 0.193 mmol) was reacted with chlorosulfonamide, and the product was purified by flash chromatography (60 to 100% EtOAc/CH2Cl2) to afford the title compound (0.0300 g, 29%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[C:12]([CH:16]=[O:17])[CH:11]=[C:10]([S:18]([NH2:21])(=[O:20])=[O:19])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:22]1([CH2:28][CH2:29][C:30](Cl)=[O:31])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[C:12]([CH:16]=[O:17])[CH:11]=[C:10]([S:18]([NH:21][C:30](=[O:31])[CH2:29][CH2:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:19])=[O:20])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: COc1c(C=O)cc(S(N)(=O)=O)cc1-c1cccc(Cl)c1
Product: COc1c(C=O)cc(S(=O)(=O)NC(=O)CCc2ccccc2)cc1-c1cccc(Cl)c1

Procedure:
Proceeding as in Reference 21, but substituting 3′-chloro-5-formyl-6-methoxy-biphenyl-3-sulfonamide and 3-phenylpropanoyl chloride, gave 3′-chloro-5-formyl-6-methoxy-N-(3-phenylpropanoyl)-biphenyl-3-sulfonamide.