Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].C(N)(=[S:11])C>Cl>[N:4]1[CH:5]=[CH:6][CH:7]=[N:8][C:3]=1[C:1](=[S:11])[NH2:2]
Reactant: CC(N)=S
Reactant: N#Cc1ncccn1
Agent: Cl
Product: NC(=S)c1ncccn1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A mixture of 2-cyanopyrimidine (15 g) and thioacetamide (20 g) in 100 mL of 10% concentrated HCl in Miff is heated with stirring at 90° C. for three hours and cooled. The solid is collected by filtration, washed with water and dried to afford the title compound.
Reaction SMILES: [OH:1][C:2]1[C:3]2[C:4](=[N:16][N:17]([CH3:19])[CH:18]=2)[N:5]=[CH:6][C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9].[CH2:20](I)[CH3:21].[OH-].[Na+]>CN(C)C=O>[C:8]([C:7]1[C:2](=[O:1])[C:3]2[C:4](=[N:16][N:17]([CH3:19])[CH:18]=2)[N:5]([CH2:20][CH3:21])[CH:6]=1)(=[O:9])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cn1cc2c(O)c(C(=O)c3ccccc3)cnc2n1
Reactant: CCI
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)c2ccccc2)c(=O)c2cn(C)nc21

Procedure:
25.3 g. of (4-hydroxy-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)phenylmethanone (0.1 mol.), 17.1 g. of ethyl iodide (0.11 mol.) and 5 g. of sodium hydroxide are heated together in 150 ml. of dimethylformamide for 12 hours with continuous stirring at 100°. The mixture is filtered hot, evaporated to dryness and the residue is recrystallized from butanol to obtain 5-benzoyl-7-ethyl-2,7-dihydro-2-methyl-4H-pyrazolo[3,4-b]pyridin-4-one, yield 20.3 g. (72%); m.p. 217°-218°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:13][C:14]([C:17]3[C:18]([CH2:33][CH3:34])=[C:19]([CH2:23][CH2:24][N:25]4[CH2:28][CH:27]([C:29]([O:31]C)=[O:30])[CH2:26]4)[CH:20]=[CH:21][CH:22]=3)=[CH:15][N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+]>C(O)(C)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:13][C:14]([C:17]3[C:18]([CH2:33][CH3:34])=[C:19]([CH2:23][CH2:24][N:25]4[CH2:26][CH:27]([C:29]([OH:31])=[O:30])[CH2:28]4)[CH:20]=[CH:21][CH:22]=3)=[CH:15][N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCc1c(CCN2CC(C(=O)OC)C2)cccc1-c1cnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CCc1c(CCN2CC(C(=O)O)C2)cccc1-c1cnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.3 %

Procedure:
To a solution of methyl 1-{2-[3-(2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-2-ethylphenyl]ethyl}-3-azetidinecarboxylate (D90) (120 mg) in isopropanol (40 mL) and water (10 mL) stirred under nitrogen at room temperature was added a solution of NaOH (9.62 mg) in water in one charge. The reaction mixture was stirred at room temperature overnight. Isopropanol was removed in vacuo. The residue was dissolved in water and acidified with 1N HCl to pH=5. The solvent was removed in vacuo, the residue was dissolved in THF, and filtered. The filtrate was purified by Mass Directed AutoPrep to give 1-{2-[3-(2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-2-ethylphenyl]ethyl}-3-azetidinecarboxylic acid (E41) (12 mg) as a TFA salt (white solid). δH (DMSO-d6, 400 MHz): 1.07 (3H, t), 1.34 (6H, d), 2.70 (2H, m), 2.87 (2H, m), 3.59 (3H, m), 4.29 (4H, m), 4.79 (1H, m), 7.30 (4H, m), 7.82 (1H, s), 7.87 (1H, dd), 7.99 (1H, d), 10.06 (1H, br s), 13.15 (1H, br s). δF (DMSO-d6, 376 MHz): −73.6. MS (ES): C26H29ClN2O3S requires 484. found 485.2 (M+H+).
Reaction SMILES: [H-].[Na+].[CH:3]([C@H:5]1[C@H:12]([O:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][C@H:10]2[C@@H:6]1[CH2:7][C:8](=[O:22])[O:9]2)=O.[CH2:23]([CH2:26][O:27]C)OC>>[O:27]=[C:26]([CH:11]([CH3:10])[CH2:12][CH2:5][C:6]#[C:7][CH3:8])/[CH:23]=[CH:3]/[C@H:5]1[C@H:12]([O:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][C@H:10]2[C@@H:6]1[CH2:7][C:8](=[O:22])[O:9]2
Reactant: O=C[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Reactant: COCCOC
Agent: [H-]
Agent: [Na+]
Product: CC#CCCC(C)C(=O)/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 7.56 g of dimethyl-2-oxo-3 -methyl-6-octynylphosphate in 60 ml of dimethoxyethane is to a suspension of 1.33 g of sodium hydride (55% strength in oil) in 65 ml of dimethoxyethane at room temperature. Then the solution is agitated for 30 minutes at room temperature and cooled to -30° C. Subsequently, at -20° C., a solution of 7.66 g of (1S,5R,6R,7R)-6-formyl-7-benzoyloxy-2-oxabicyclo[3.3.0]octan-3-one in 84 ml of dimethoxyethane is added thereto and the mixture is stirred for another 2 hours at room temperature. The crude product is isolated analogously to Example (1a), thus obtaining 12.95 g of the title compound as an oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15](Br)=[CH:14][CH:13]=[C:12]([CH3:17])[N:11]=2)=[O:9])=[N:3]1.[NH2:18][C:19]1[N:23]([CH3:24])[N:22]=[CH:21][CH:20]=1>>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH:18][C:19]3[N:23]([CH3:24])[N:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=[C:12]([CH3:17])[N:11]=2)=[O:9])=[N:3]1
Reactant: Cn1nccc1N
Reactant: Cc1ccc(Br)c(C(=O)Nc2ccn(C)n2)n1
Product: Cc1ccc(Nc2ccnn2C)c(C(=O)Nc2ccn(C)n2)n1

Procedure:
The title compound, was prepared from 3-Bromo-6-methyl-pyridine-2-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide in accordance with the general method of Example 78, step 3 using 5-Amino-1-methyl-pyrazole instead of 3-Amino-1-methyl-pyrazole to yield the final compound as a yellow solid, MS (ISP): m/e=312.3 (M+H+).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:9]1[CH:13]=[CH:12][S:11][C:10]=1[CH:14]=[O:15]>>[C:1]1([S:7][C:9]2[CH:13]=[CH:12][S:11][C:10]=2[CH:14]=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Reactant: O=Cc1sccc1Br
Product: O=Cc1sccc1Sc1ccccc1

Procedure:
The title compound was prepared by the method of Preparation 1a using benzenethiol and 3-bromothiophene-2-carbaldehyde.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[C:7]2[S:9][C:10]([CH3:12])=[N:11][C:6]2=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:20][S:21]([O:1][CH2:2][C:3]1[N:8]=[C:7]2[S:9][C:10]([CH3:12])=[N:11][C:6]2=[CH:5][CH:4]=1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nc2ccc(CO)nc2s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc2ccc(COS(C)(=O)=O)nc2s1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of the alcohol of Step 6 (303 mg, 1.68 mmol) in 17 mL of CH2Cl2 at -40° C., triethylamine (350 μl, 2.5 mmol) and methane-sulfonyl chloride (170 μl, 2.2 mmol) were added and the solution was stirred at -40° C. for 30 min and at 0° C. for 2 hr. Saturated aq. NaHCO3 was added and the product was extracted in CH2C12, dried over Na2SO4, concentrated, and the remaining water was stripped with toluene twice.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH3:19])[CH2:8][CH2:7][C:6]([N:16]([CH3:18])[CH3:17])([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.[C:29](Cl)(=[O:38])[CH:30]=[CH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>ClCCl>[CH3:17][N:16]([CH3:18])[C:6]1([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)[CH2:5][CH2:4][C:3]([CH2:2][NH:1][C:29](=[O:38])/[CH:30]=[CH:31]/[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([CH3:19])[CH2:8][CH2:7]1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: CN(C)C1(c2cccc(F)c2)CCC(C)(CN)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C1(c2cccc(F)c2)CCC(C)(CNC(=O)/C=C/c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of the title compound of step 4 (polar diastereomer) (250 mg, 0.94 mmol) and Hünig's base (169 μl, 1.0 mmol) in abs. dichloromethane (10 mL) was mixed with cinnamic acid chloride (166 mg 1.0 mmol) and stirred for 24 h at RT. The organic solution was washed with saturated NaHCO3 solution and saturated NaCl solution, dried over Na2SO4, concentrated to low volume in a vacuum and the remaining residue was purified by flash chromatography with ethyl acetate/MeOH 4:1.
Reaction SMILES: [CH3:1][C:2]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=[O:3].[N+:12]([O-])([OH:14])=[O:13]>CS(O)(=O)=O>[C:2]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:6]=1[N+:12]([O-:14])=[O:13])(=[O:3])[CH3:1]
Reactant: CC(=O)Nc1ccc(Br)cc1
Reactant: O=[N+]([O-])O
Agent: CS(=O)(=O)O
Product: CC(=O)Nc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 2 h

Procedure:
A solution of 4-bromoacetanilide (20 g, 93.4 mmol) in methanesulfonic acid is cooled to 10° C. Conc. nitric acid (12.6 ml) is added and the mixture is stirred at 40° C. for 2 hours. The mixture is poured into ice-water. The product is filtered off, washed with water and dried. Yield: 23.59 g (97%). Mp 99-100° C.
Reaction SMILES: [NH:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[CH:6]=[CH:5][N:4]=1)[NH2:2].[C:19](OCC)(OCC)(OCC)[CH2:20][CH3:21]>>[CH2:20]([C:21]1[N:4]2[CH:5]=[CH:6][C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)=[N:8][C:3]2=[N:1][N:2]=1)[CH3:19]
Reactant: CCOC(CC)(OCC)OCC
Reactant: NNc1nccc(-c2cccc(C(F)(F)F)c2)n1
Product: CCc1nnc2nc(-c3cccc(C(F)(F)F)c3)ccn12

Procedure:
A mixture of 1.50 g. of 2-hydrazino-4-(m-trifluoromethylphenyl)pyrimidine and 25 ml. of triethyl orthopropionate is refluxed for 8 hours. On cooling the desired compound is obtained by filtration, m.p. 223°-224° C.
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=3[CH2:6][CH2:5][C:4]=2[N:3]=1.[Cl:17][S:18](O)(=[O:20])=[O:19]>>[CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([S:18]([Cl:17])(=[O:20])=[O:19])[CH:15]=[CH:16][C:7]=3[CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: Cc1nc2c(c(=O)[nH]1)-c1ccccc1CC2
Reactant: O=S(=O)(O)Cl
Product: Cc1nc2c(c(=O)[nH]1)-c1cc(S(=O)(=O)Cl)ccc1CC2
Temperature: 25 °C
Reaction time: 12 h
Yield: 41 %

Procedure:
1,2,5,6-tetrahydro-3-methyl-1-oxobenzo[f]quinazoline (5 g, 0.024 mole) was added to chlorosulfonic acid (50 ml, Aldrich) and stirred for 12 hours at room temperature. The reaction mixture was poured over ice (750 g), and the dark brown solid collected by filtration. The solid was washed with water, suspended in water (500 ml), and the pH of the suspension adjusted to 5.00 by addition of sodium bicarbonate. The suspension was filtered, the product washed with H2O and dried under high vacuum at room temperature to give 1,2,5,6-tetrahydro-3-methyl-oxobenzo[f]quinazolin-9-sulfonyl chloride as a light brown solid (3.054 g, 41%). 1H NMR (DMSO-d6, 300 MHz) δ: 2.60 (s, 3H, CH3); 2.90 (s, 4H, Ar CH2); 7.22 (d, J=9 Hz, 1H, Ar); 7.53 (d, J=9 Hz, 1H, Ar); 8.75 (s, 1H, Ar).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:21])[CH2:4][CH2:3]1.[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[CH3:31])[CH:26]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[CH3:31])[CH2:26][NH:1][CH:2]1[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:21])[CH2:6][CH2:7]1
Reactant: Cc1ccc(C=O)cc1F
Reactant: NC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: Cc1ccc(CNC2CCN(CCn3c(=O)cnc4ccc(F)cc43)CC2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
To 10 mL of a chloroform solution containing 383 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-fluoroquinoxalin-2(1H)-one and 160 mg of 3-fluoro-4-methylbenzaldehyde, 76 μL of acetic acid was added, and stirred at room temperature for 1 hour. To the reaction mixture, 437 mg of sodium triacetoxyborohydride was added, and stirred overnight. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Fuji Silysia Chemical Ltd., Chromatorex-NH, eluent; ethyl acetate:hexane=1:1] to give 429 mg of 1-(2-(4-((3-fluoro-4-methylbenzyl)amino)piperidin-1-yl)ethyl)-7-fluoroquinoxalin-2(1H)-one as a pale yellow solid.
Reaction SMILES: [CH3:1][CH:2]([OH:7])[CH2:3][CH2:4][CH2:5][CH3:6].C[Al](C)C.[CH3:12][O:13][C:14]1[N:19]=[C:18]([CH3:20])[N:17]=[C:16]([NH:21][C:22]([NH:24][S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34](OC)=[O:35])(=[O:27])=[O:26])=[O:23])[N:15]=1>C1(C)C=CC=CC=1>[CH3:12][O:13][C:14]1[N:19]=[C:18]([CH3:20])[N:17]=[C:16]([NH:21][C:22]([NH:24][S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([O:7][CH:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH3:6])=[O:35])(=[O:27])=[O:26])=[O:23])[N:15]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)nc(OC)n1
Reactant: CCCCC(C)O
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CCCCC(C)OC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)nc(OC)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 57.8 %

Procedure:
2-Hexanol (0.61 g) in 2 ml dry toluene was slowly added at room temperature to a solution of 1.5 ml (2M) trimethylaluminum diluted with 5.0 ml dry toluene under nitrogen. The mixture was stirred at room temperature for 15 minutes and 0.95 g of N-[(4-methoxy-6-methyl-1,3,5-triazin-2-yl)aminocarbonyl]-2-methoxycarbonylbenzenesulfonamide was added. The mixture was warmed under N2 to reflux temperature for 2.5 hr. cooled to room temperature and carefully quenched with 20 ml 10% HCl. The organic phase was taken up in methylene chloride, separated, washed with water, dried over magnesium sulfate, filtered and the solvent evaporated under reduced pressure to give 0.65 g of the desired compound which melted at 125°-130° C. The infrared spectrum exhibited characteristic absorption for the product at 3300, 1725, 1730, 1585, 1555 cm-1.
Reaction SMILES: [Na].[O-]CC.[Na+].O=[C:7]1[CH2:14][CH2:13][C:10]2([CH2:12][CH2:11]2)[CH2:9][CH:8]1[C:15]([O:17]CC)=O.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35][C:36](=[NH:38])[NH2:37])[CH2:29][CH2:28]2)=[CH:23][CH:22]=1>O.C(O)C>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([N:27]2[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35][C:36]3[NH:38][C:15](=[O:17])[C:8]4[CH2:9][C:10]5([CH2:11][CH2:12]5)[CH2:13][CH2:14][C:7]=4[N:37]=3)[CH2:29][CH2:28]2)=[CH:25][CH:26]=1
Reactant: CCOC(=O)C1CC2(CCC1=O)CC2
Reactant: N=C(N)CCCN1CCN(c2ccc(Cl)cc2)CC1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CCO
Product: O=c1[nH]c(CCCN2CCN(c3ccc(Cl)cc3)CC2)nc2c1CC1(CC2)CC1
Temperature: 25 °C
Yield: 5.9 %

Procedure:
Sodium (0.094 g, 4.08 mmol) was added to ethanol (15 ml) under stirring condition at room temperature. The resulting mixture was stirred for 30 min. To this freshly prepared clear solution of sodium ethoxide, were added ethyl 6-oxospiro[2.5]octane-5-carboxylate (0.4 g, 2.03 mmol) and 4-(4-(4-chlorophenyl) piperazin-1-yl)butanimidamide (0.343 g, 1.223 mmol) and the reaction mixture was heated at 85° C. for 18 h. The progress of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain crude residue which was dissolved with water (15 ml). Aqueous layer was extracted with ethylacetate (2×30 ml). The combined organic layer was dried over sodium sulphate, filtered and solvent was removed under reduced pressure to obtain a crude product which was purified by flash chromatography over silica gel (100-200 mesh) using 3-4% methanol in dichloromethane as eluent to obtain title compound (0.030 g, 4% yield).
Reaction SMILES: [NH2:1][C:2]1[N:24]([CH2:25][CH2:26][CH2:27][NH:28]C(=O)OC(C)(C)C)[C:6]2[N:7]=[C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)[N:9]=[CH:10][C:5]=2[C:4](=[O:36])[C:3]=1[C:37](=[O:39])[NH2:38].[ClH:40].CCOCC>O1CCOCC1>[ClH:40].[NH2:1][C:2]1[N:24]([CH2:25][CH2:26][CH2:27][NH2:28])[C:6]2[N:7]=[C:8]([NH:11][C:12]3[CH:13]=[CH:14][C:15]([N:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)=[CH:16][CH:17]=3)[N:9]=[CH:10][C:5]=2[C:4](=[O:36])[C:3]=1[C:37]([NH2:38])=[O:39]
Reactant: CC(C)(C)OC(=O)NCCCn1c(N)c(C(N)=O)c(=O)c2cnc(Nc3ccc(N4CCOCC4)cc3)nc21
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: NCCCn1c(N)c(C(N)=O)c(=O)c2cnc(Nc3ccc(N4CCOCC4)cc3)nc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
0.16 g (0.30 mmol) of the product prepared in step 11.4 is suspended in 4 mL of anhydrous dioxane, and 0.74 mL (2.95 mmol) of a 4N solution of hydrogen chloride in dioxane is added. The mixture is stirred at room temperature for 5 hours, and ether is added. The solid is drained by suction, rinsed with pentane and dried in an oven. 0.14 g of the expected product is obtained in the form of a white powder. Yield (dihydrochloride)=quantitative. m.p.=250°C. M+H+=439.
Reaction SMILES: C(=O)([O-])[O-:2].[K+].[K+].F[B-](F)(F)F.[Cl:12][C:13]1[CH:27]=[C:26]([F:28])[C:25]([N:29]2[C:33](=[O:34])[N:32]([CH:35]([F:37])[F:36])[C:31]([CH3:38])=[N:30]2)=[CH:24][C:14]=1[O:15][C:16]1[CH:21]=[CH:20][C:19]([N+]#N)=[CH:18][N:17]=1>FC(F)(F)C(O)=O.O>[Cl:12][C:13]1[C:14]([O:15][C:16]2[CH:21]=[CH:20][C:19]([OH:2])=[CH:18][N:17]=2)=[CH:24][C:25]([N:29]2[C:33](=[O:34])[N:32]([CH:35]([F:36])[F:37])[C:31]([CH3:38])=[N:30]2)=[C:26]([F:28])[CH:27]=1
Reactant: Cc1nn(-c2cc(Oc3ccc([N+]#N)cn3)c(Cl)cc2F)c(=O)n1C(F)F
Reactant: O=C([O-])[O-]
Agent: F[B-](F)(F)F
Agent: [K+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1nn(-c2cc(Oc3ccc(O)cn3)c(Cl)cc2F)c(=O)n1C(F)F
Temperature: 25 °C
Yield: 177.8 %

Procedure:
To a stirred, cold (ice bath) solution of 0.67 g (0.0048 mole) of potassium carbonate in 20 mL of trifluoroacetic acid was added 4.7 g (0.097 mole) of 2-[2-chloro-4-fluoro-5-(4-difluoromethyl-4,5-dihydro -3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenoxy]pyridine-5-diazonium tetrafluoroborate. The reaction mixture was allowed to warm to room temperature and was then heated at reflux for 5.5 hours. The mixture was cooled to room temperature, diluted with 50 mL of water, and the whole was extracted with four portions of methylene chloride. The extracts were combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated under reduced pressure to give a red oil which was purified by column chromatography on silica gel. Elution with n-hexane:ethyl acetate (2:1) gave 3.3 g of 1-[4-chloro-2-fluoro-5-(5-hydroxypyridin-2-yloxy)-phenyl]-4-difluoromethyl-4,5-dihydro -3-methyl,1,2,4-triazol-5(1H)-one as a solid, m.p. 179°-181° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][N:7]=[C:8]([OH:10])[CH:9]=1)=[O:4].[CH3:11][C:12]1[O:16][N:15]=[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]=1[CH2:23]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:23][C:13]2[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:15][O:16][C:12]=2[CH3:11])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(O)n[nH]1
Reactant: Cc1onc(-c2ccccc2)c1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(OCc2c(-c3ccccc3)noc2C)n[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.9 %

Procedure:
To a stirred solution of 5-hydroxy-2H-pyrazole-3-carboxylic acid methyl ester (1.30 g, 9.15 mmol) and (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (1.73 g, 9.15 mmol) in THF (80 mL) at 5° C. under argon was added triphenylphosphine (3.12 g, 11.9 mmol), then diethyl azodicarboxylate (2.07 g, 11.9 mmol) was added dropwise. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was then evaporated. Purification by chromatography (silica, heptane:ethyl acetate=1:1 then dichloromethane:methanol=9:1) gave a colorless oil (800 mg) which was triturated with diisopropylether and further purified using a 5×50 cm Chiralpak AD column at room temperature using an isopropanol:heptane (2:8) mobile phase with UV detection at 220 nM to afford the title compound (250 mg, 9%) as a white solid. MS: m/e=328.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]1[C:14](=[O:15])[N:13]([CH2:16][CH2:17][CH3:18])[N:12]=[N:11]1.CC1C=CC(S(O)(=O)=O)=CC=1.[O:30]1[CH:34]=[CH:33][CH2:32][CH2:31]1.N>O1CCOCC1.CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:31]2[CH2:32][CH2:33][CH2:34][O:30]2)=[CH:4][C:3]=1[N:10]1[C:14](=[O:15])[N:13]([CH2:16][CH2:17][CH3:18])[N:12]=[N:11]1
Reactant: C1=COCC1
Reactant: CCCn1nnn(-c2cc(O)c(Cl)cc2Cl)c1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Solvent: C1COCCO1
Solvent: CO
Product: CCCn1nnn(-c2cc(OC3CCCO3)c(Cl)cc2Cl)c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.1 %

Procedure:
To a stirred solution of 1.0 g (0.0035 mole) of 1-(2,4-dichloro-5-hydroxyphenyl)-1,4-dihydro-4-propyl-5H-tetrazol-5-one (Example 10, Step A) and 0.05 g (0.00026 mole) of 4-methylphenylsulfonic acid in 40 mL of p-dioxane was added slowly 0.88 g (0.0126 mole) of dihydrofuran in 20 mL of p-dioxane. The mixture was stirred at room temperature for approximately 18 hours, and an additional 0.88 g of dihydrofuran was added. The mixture was stirred at room temperature for an additional 48 hours. One mL of methanol saturated with ammonia was added to the mixture and stirring was continued for a short period of time. The reaction mixture was evaporated under reduced pressure to leave a residue. The residue was purified by column chromatography on silica gel, eluting with methylene chloride, to yield 0.58 g of 1-[2,4-dichloro-5-(2-tetrahydrofuranyloxy)phenyl]-1,4-dihydro-4-propyl-5H-tetrazol-5-one as a solid, mp 89°-90° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]([C:13]3[O:17][C:16]([N:18]4[CH2:23][CH2:22][CH2:21][CH:20]([CH3:24])[CH2:19]4)=[N:15][C:14]=3[C:25]([F:28])([F:27])[F:26])=[O:12])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[C:29]1([N:35]=[C:36]=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[CH3:24][CH:20]1[CH2:21][CH2:22][CH2:23][N:18]([C:16]2[O:17][C:13]([C:11]([NH:10][C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[N:1]([C:36]([NH:35][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:37])[N:2]=[CH:3]4)=[O:12])=[C:14]([C:25]([F:28])([F:27])[F:26])[N:15]=2)[CH2:19]1
Reactant: O=C=Nc1ccccc1
Reactant: CC1CCCN(c2nc(C(F)(F)F)c(C(=O)Nc3ccc4[nH]ncc4c3)o2)C1
Solvent: ClCCl
Product: CC1CCCN(c2nc(C(F)(F)F)c(C(=O)Nc3ccc4c(cnn4C(=O)Nc4ccccc4)c3)o2)C1
Temperature: 25 °C
Reaction time: 17 h
Yield: 42 %

Procedure:
To a solution of compound 49 (0.060 g, 0.152 mmol) in anhydrous methylene chloride (1.52 mL) at room temperature under argon was added phenyl isocyanate (0.018 mL, 0.160 mmol). The reaction mixture was stirred at room temperature for 17 h and another portion of phenyl isocyanate (0.018 mL, 0.160 mmol) was added. After additional stirring at room temperature for 17 h, the reaction mixture was quenched with methanol (1.0 mL) and concentrated. Purification by silica gel chromatography (eluant: 100% methylene chloride to 100% EtOAc gradient) gave 32.7 mg (42% yield) of 5-[[2-(3-methyl-1-piperidinyl)-4-(trifluoromethyl)-5-oxazolyl]carbonylamino]-N-phenyl-1H-indazole-1-carboxamide (50) as a white solid. 1H NMR (500 MHz, CD3OD) δ 8.31 (br d, 1H, J=8.8 Hz), 8.24 (m, 2H), 7.70 (m, 3H), 7.39 (br t, 2H, J=7.9 Hz), 7.16 (t, 1H, J=7.4 Hz), 4.90 (br s, 2H), 4.20 (m, 2H), 3.08 (td, 1H, J=12.4, 3.1 Hz), 2.75 (dd, 1H, J=12.3, 12.6 Hz), 1.89 (m, 1H), 1.82 (m, 1H), 1.74 (m, 1H), 1.65 (m, 1H), 1.23 (m, 1H), 1.01 (d, 3H, J=6.6 Hz). MS (M+1): 513.