Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:6])(=O)[CH2:2][CH2:3][CH3:4].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:19][C:20](=[N:51]O)[C:21]1[CH:49]=[CH:48][C:24]([O:25][CH2:26][CH2:27][CH2:28][N:29]2[CH2:35][CH2:34][CH2:33][N:32]([C:36](=[O:47])[C@H:37]([NH:39][C:40]([C:42]3[O:43][CH:44]=[CH:45][CH:46]=3)=[O:41])[CH3:38])[CH2:31][CH2:30]2)=[CH:23][C:22]=1[F:50]>CN(C=O)C>[F:50][C:22]1[CH:23]=[C:24]([CH:48]=[CH:49][C:21]=1[C:20]1[N:51]=[C:1]([CH2:2][CH2:3][CH3:4])[O:6][N:19]=1)[O:25][CH2:26][CH2:27][CH2:28][N:29]1[CH2:35][CH2:34][CH2:33][N:32]([C:36](=[O:47])[C@H:37]([NH:39][C:40]([C:42]2[O:43][CH:44]=[CH:45][CH:46]=2)=[O:41])[CH3:38])[CH2:31][CH2:30]1
Reactant: CCCC(=O)O
Reactant: C[C@@H](NC(=O)c1ccco1)C(=O)N1CCCN(CCCOc2ccc(C(N)=NO)c(F)c2)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CCCc1nc(-c2ccc(OCCCN3CCCN(C(=O)[C@@H](C)NC(=O)c4ccco4)CC3)cc2F)no1
Temperature: 115 °C

Procedure:
Butyric acid (0.2 mmol) was treated with 0.5 mL of a 0.46 M solution (0.23 mmol) of 1,1′-carbonyldiimidazole (CDI) in DMF in a 4 mL vial. After mixing for 30 minutes, 0.75 mL of a 0.17 M solution of Example 141F (0.13 mmol) in DMF was added to the vial. The resulting solution was mixed for 4 hours at room temperature. A further 0.5 mL of 0.35 M solution of CDI (0.175 mmol) in DMF was added to the vial. The resulting mixture was heated at 115° C. for 6 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to provide the desired products. 1H NMR (CDCl3) δ1.05 (t, 3H), 1.50 (m, 5H), 1.90 (m, 2H), 2.41 (m, 2H), 2.92 (t, 2H), 3.30-3.70 (m, 4H), 4.10-4.50 (m, 8H), 4.95 (m, 1H), 6.50 (m, 1H), 6.75 (m, 2H), 7.10 (m, 2H), 7.50 (m, 1H), 7.98 (m, 1H);
Reaction SMILES: [N:1]1[C:2]([C:10]([OH:12])=O)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[N:6][C:5]=12.[NH2:13][C@@H:14]([CH3:31])[CH2:15][N:16]1[CH:20]=[CH:19][C:18]([C:21]2[CH:28]=[C:27]([F:29])[C:24]([C:25]#[N:26])=[C:23]([Cl:30])[CH:22]=2)=[N:17]1>>[Cl:30][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[CH:20][N:16]([CH2:15][C@@H:14]([NH:13][C:10]([C:2]3[N:1]=[C:5]4[N:6]=[CH:7][CH:8]=[CH:9][N:4]4[CH:3]=3)=[O:12])[CH3:31])[N:17]=2)[CH:28]=[C:27]([F:29])[C:24]=1[C:25]#[N:26]
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1cn2cccnc2n1
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1cn2cccnc2n1
Yield: 46 %

Procedure:
The title compound was prepared using the method of Example 34(d) starting from Imidazo[1,2-a]pyrimidine-2-carboxylic acid (0.076 g, 0.466 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (0.1 g, 0.359 mmol). The product was purified by recrystallization from acetonitrile. Yield 46.0%. 1H-NMR (400 MHz; CDCl3): δ 1.32 (d, 3H), 4.33 (dd, 1H), 4.44 (dd, 1H), 4.57-4.67 (m, 1H), 6.57 (dd, 1H), 6.97 (dd, 1H), 7.50 (d, 1H), 7.59 (dd, 1H), 7.71 (dd, 1H), 7.80 (d, 1H), 8.08 (s, 1H), 8.47 (dd, 1H), 8.66 (dd, 1H).
Reaction SMILES: Cl[S:2]([C:5]1[C:16]([CH3:17])=[CH:15][C:8]([O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:7][C:6]=1[CH3:18])(=[O:4])=[O:3].[CH3:19][O:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[C:23]([N+:28]([O-:30])=[O:29])[CH:22]=1.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:19][O:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][S:2]([C:5]2[C:16]([CH3:17])=[CH:15][C:8]([O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:7][C:6]=2[CH3:18])(=[O:4])=[O:3])=[C:23]([N+:28]([O-:30])=[O:29])[CH:22]=1
Reactant: COC(=O)COc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COC(=O)COc1cc(C)c(S(=O)(=O)Nc2ccc(OC)cc2[N+](=O)[O-])c(C)c1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
A mixture of methyl (4-chlorosulfonyl-3,5-dimethylphenoxy)acetate (Intermediate A1, 7.6 g, 0.026 mol), 4-methoxy-2-nitroaniline (4.0 g, 0.024 mol), and pyridine (50 mL) was stirred at room temperature for 16 hr, in a 90° C. bath for 5 hr, and in a 130° C. bath for 30 min. The mixture was cooled and stirred with toluene for 10 min. The resulting suspension was filtered, and the filtrate was concentrated, diluted with 150 mL toluene and 100 mL ethyl acetate, washed with 1 M hydrochloric acid and water, and concentrated to about 50 mL. The mixture was left overnight in a freezer. The solid was collected and washed with several portions of cold toluene. After drying, it weighed 8.2 g (74%). Another 0.45 g portion of the title compound was recovered from extraction of aqueous phases and crystallization of a second crop from the toluene filtrate.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[C:4]([N:6]1[CH2:17][CH2:16][C:9]2[N:10]=[N:11][C:12]([NH:14][NH2:15])=[CH:13][C:8]=2[CH2:7]1)=[O:5].[CH3:22][C:23]([CH3:25])=O>>[F:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[C:4]([N:6]1[CH2:17][CH2:16][C:9]2[N:10]=[N:11][C:12]([NH:14][N:15]=[C:23]([CH3:25])[CH3:22])=[CH:13][C:8]=2[CH2:7]1)=[O:5]
Reactant: NNc1cc2c(nn1)CCN(C(=O)c1ccccc1F)C2
Reactant: CC(C)=O
Product: CC(C)=NNc1cc2c(nn1)CCN(C(=O)c1ccccc1F)C2

Procedure:
1.0 g of 6-(o-fluorobenzoyl)-3-hydrazino-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine is heated in 10 cc of acetone on a water bath at reflux for 30 minutes. The title compound has a M.P. of 200°-203° (decomp., from absolute ethanol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([CH:10]=[CH:11][C:12]([CH3:22])=[CH:13][CH:14]=[CH:15][C:16]([CH3:21])=[CH:17][C:18](Cl)=[O:19])=[C:5]([CH3:23])[C:4]=1[CH3:24].[CH3:25][NH2:26]>>[CH3:25][NH:26][C:18](=[O:19])[CH:17]=[C:16]([CH3:21])[CH:15]=[CH:14][CH:13]=[C:12]([CH3:22])[CH:11]=[CH:10][C:6]1[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH3:24])[C:5]=1[CH3:23]
Reactant: CN
Reactant: COc1cc(C)c(C=CC(C)=CC=CC(C)=CC(=O)Cl)c(C)c1C
Product: CNC(=O)C=C(C)C=CC=C(C)C=Cc1c(C)cc(OC)c(C)c1C

Procedure:
9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid chloride is reacted with methyl-amine to produce 9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid methyl amide, m.p. 206° C.;
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)=[C:7]([Cl:20])[CH:6]=1.[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([BH3-])#N.[Na+]>C(O)(=O)C.CO>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([Cl:20])[CH:6]=1
Reactant: O=Cc1ccccc1
Reactant: COC(=O)Cc1cc(Cl)c(Oc2ccc(N)cc2)c(Cl)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)Cc1cc(Cl)c(Oc2ccc(NCc3ccccc3)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 120 h
Yield: 88.1 %

Procedure:
A stirred mixture consisting of methyl[3,5-dichloro-4-(4-aminophenoxy)phenyl]acetate (0.32 g), benzaldehyde (0.20 g), sodium cyanoborohydride (0.03 g), methanol (15 mL) and one drop of acetic acid was stirred at room temperature for 5 days. The reaction mixture was concentrated and the residue partionated between ethyl acetate and sodium hydrogen-carbonate (saturated aqueous solution). The aqueous phase was further extracted with ethyl acetate. The collected organic phases were purified on column (silica gel, n-heptane/ethyl acetate, 9:1) to give 0.36 g of methyl[3,5-dichloro-4-(4-benzylaminophenoxy)phenyl]acetate.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[CH:31][C:32]([NH:34][C:35](=[O:39])[CH2:36][CH2:37][CH3:38])=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O.C(Cl)Cl>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[CH:31][C:32]([NH:34][C:35](=[O:39])[CH2:36][CH2:37][CH3:38])=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cc(NC(=O)CCC)ccc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCc1nc2cc(NC(=O)CCC)ccc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-5-butanoylamino-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid/methylene chloride.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[C:10]([C:18](=[O:20])[CH3:19])=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[C:22]([O-])([O-])=O.[K+].[K+].IC>CC#N>[C:1]([O:5][C:6](=[O:21])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:22])=[CH:14][CH:15]=2)[C:10]([C:18](=[O:20])[CH3:19])=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1cn(CC(=O)OC(C)(C)C)c2ccc(O)cc12
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: COc1ccc2c(c1)c(C(C)=O)cn2CC(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of (3-acetyl-5-hydroxy-indol-1-yl)-acetic acid tert-butyl ester (500 mg, 1.73 mmol) in CH3CN (15 mL) was added K2CO3 (358 mg, 2.59 mmol) and iodomethane (0.162 mL, 2.59 mmol). The reaction mixture was stirred at 50° C. overnight. Additional K2CO3 (716 mg, 5.18 mmol) and iodomethane (0.324 mL, 5.18 mmol) were added and heating was continued for an additional 2 days. Volatiles were evaporated, the reaction mixture was taken up in water and extracted twice with AcOEt. The combined organic phases were dried (Phase separator) and evaporated to give the title compound. MS (LC/MS): 304.0 [M+H]+, 629.0 [2M+Na]+; tR (HPLC conditions c): 4.92 min.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6](O)[CH:7]([CH3:10])[CH:8]=[CH2:9].C(=O)([O-])[OH:13].[Na+]>CC(C)=O.O>[OH:1][CH:5]1[CH:4]=[CH:3][C:2](=[O:13])[CH:6]1[CH:7]([CH3:10])[CH:8]=[CH2:9]
Reactant: O=C([O-])O
Reactant: C=CC(C)C(O)c1ccco1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: C=CC(C)C1C(=O)C=CC1O
Reaction time: 48 h
Yield: 61 %

Procedure:
1-(2-Furyl)-2-methyl-3-buten-1-ol (122 g, 0.8 mole) was dissolved in a 2:1 mixture (1.2 liter) of acetone and water in a reactor, and polyphosphoric acid (20 g) was then added. Thereafter, reaction was carried out at 50° to 60° C. for about 48 hours with stirring. After completion of the reaction, the reaction solution was cooled and neutralized with addition of a saturated aqueous solution (200 ml) of sodium hydrogen carbonate, followed by extraction with a solvent. The extract was washed with water, dried and concentrated. The residue obtained was distilled under reduced pressure to obtain 74 g (yield, 61%) of pure (±)-3-hydroxy-2-(1-methyl-2-propenyl)-4-cyclopenten-1-one having a boiling point of 122°-130° C./3 mmHg.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][N:3]2[CH2:6][CH:7]([C:9]3[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=3)[NH:12]C(=O)C)[N:8]=[C:2]12.[ClH:19]>CO.CC(O)C>[ClH:19].[ClH:19].[NH2:12][C:11]1[CH:10]=[C:9]([CH:7]2[CH2:6][N:3]3[C:2]([S:1][CH2:5][CH2:4]3)=[N:8]2)[CH:18]=[CH:17][CH:16]=1
Reactant: CC(=O)Nc1cccc(C2CN3CCSC3=N2)c1
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Product: Nc1cccc(C2CN3CCSC3=N2)c1
Reaction time: 8 h

Procedure:
A solution of 1.00 g. (0.0038 mole) of 3'-(2,3,5,6-tetrahydroimidazo[2,1-b]thiazol-6-yl)acetanilide (Example 8) in 17 ml. of 6N hydrochloric acid is heated at reflux for 2.5 hours and then allowed to stand overnight at room temperature. The solution is concentrated at reduced pressure, made basic with concentrated aqueous sodium hydoxide while cooling and then extracted with 3 portions of chloroform. The combined organic layers are washed with brine, dried (sodium sulfate) and evaporated to give 0.84 g. of an oil, i.e., m-aminotetramisole free base. The oil is dissolved in hot methanol and strongly acidified with hydrogen chloride in 2-propanol. Evaporation of the solution and crystallization of the residue from 2-propanol gives 0.91 g. (81%) of cream colored solid, melting point 198°-201°C., dec.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)CCC.[CH2:20]([O:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[C:30](Br)[CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCOCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:20]([O:27][C:28]1[CH:29]=[C:30]([C:6]2[CH:7]=[CH:8][N:9]=[CH:10][CH:11]=2)[CH:31]=[C:32]([F:34])[CH:33]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Fc1cc(Br)cc(OCc2ccccc2)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Fc1cc(OCc2ccccc2)cc(-c2ccncc2)c1
Temperature: 100 °C

Procedure:
A mixture of 4-tributylstannylpyridine (250 mg), O-benzyl-3-bromo-5-fluorophenol (200 mg; EP 385,662) and tetrakis (triphenylphosphine) palladium (8 mg) in dioxane (3 mL) was heated at 100° C. for 15 h. The solvent was evaporated and the residue chromatographed (silica gel; hexane/EtOAc acetate (4:1-3:2)) to provide the title compound as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](OC)=[O:13])[O:8][CH2:7][CH2:6][CH:5]2[N:16]([C@H:31]1[CH2:36][CH2:35][C@H:34]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:33][CH2:32]1)[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=1)=[O:18].[Li+].[OH-].[NH2:43][C:44]1[NH:48][N:47]=[N:46][N:45]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([NH:43][C:44]1[NH:48][N:47]=[N:46][N:45]=1)=[O:13])[O:8][CH2:7][CH2:6][CH:5]2[N:16]([C@H:31]1[CH2:36][CH2:35][C@H:34]([C:37]([CH3:39])([CH3:40])[CH3:38])[CH2:33][CH2:32]1)[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:29])([F:28])[F:30])=[CH:22][CH:21]=1)=[O:18]
Reactant: COC(=O)c1cc2c(cc1Br)C(N(C(=O)Nc1ccc(OC(F)(F)F)cc1)[C@H]1CC[C@H](C(C)(C)C)CC1)CCO2
Reactant: Nc1nnn[nH]1
Agent: [Li+]
Agent: [OH-]
Product: CC(C)(C)[C@H]1CC[C@H](N(C(=O)Nc2ccc(OC(F)(F)F)cc2)C2CCOc3cc(C(=O)Nc4nnn[nH]4)c(Br)cc32)CC1

Procedure:
Enantiomer A of methyl 6-bromo-4-[(trans-4-tert-butylcyclohexyl)({[4-(trifluoromethoxy)phenyl]amino}carbonyl)amino]chromane-7-carboxylate (25 mg) was saponified with aqueous LiOH and then coupled to 5-amino tetrazole following the procedure described (Step D., Example 1/2) to give 6-bromo-4-[(trans-4-tert-butylcyclohexyl)({[4-(trifluoromethoxy)phenyl]amino}carbonyl)amino]-N-1H-tetrazol-5-ylchromane-7-carboxamide. HPLC/MS: m/z=680.2 (M+1), Rt=2.55 min. 1H NMR (DMSO-d6): δ 12.58 (1H, br s), 8.61 (1H, s), 7.47 (2H, dd, J=2.5 Hz, 8.5 Hz), 7.29 (1H, s), 7.21 (2H, d, J=8.5 Hz), 7.05 (1H, s), 4.71 (1H, m), 4.40 (1H, dt, J=2.5 Hz, 10.5 Hz), 4.25 (1H, t, J=10.5 Hz), 3.93 (1H, m), 2.77 (1H, m), 2.02 (1H, m), 1.90-1.67 (6H, m), 1.29-1.03 (4H, m), 0.88 (9H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([C:22](=[O:35])[C:23]3[CH:28]=[C:27]([N:29]4[CH:33]=[CH:32][CH:31]=[N:30]4)[CH:26]=[CH:25][C:24]=3[Cl:34])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)COC)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:36]([F:39])([F:38])[F:37]>Cl.O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:15]2[C:16]([C:22](=[O:35])[C:23]3[CH:28]=[C:27]([N:29]4[CH:33]=[CH:32][CH:31]=[N:30]4)[CH:26]=[CH:25][C:24]=3[Cl:34])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:36]([F:37])([F:38])[F:39]
Reactant: COCN(c1cc(Cl)cnc1C(=O)c1cc(-n2cccn2)ccc1Cl)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: O=C(c1cc(-n2cccn2)ccc1Cl)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 85 °C

Procedure:
4-Chloro-N-[5-chloro-2-(2-chloro-5-pyrazol-1-yl-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide from step 5 was dissolved in a mixture of 4 M HCl in dioxane (8 mL) and water (2 mL) and heated at 85° C. for 2 h. The solvent was evaporated and the residue was purified via HPLC to give 4-chloro-N-[5-chloro-2-(2-chloro-5-pyrazol-1-yl-benzoyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide: 1H NMR (400 MHz, CDCl3) δ 8.2 (m, 3H), 8.0 (m, 1H), 7.9 (s, 1H), 7.7 (m, 4H), 7.45 (d, 1H), 6.45 (s, 1H); MS m/z: 576.9 (M+H)+.
Reaction SMILES: N[N:2]1[CH:6]=[N:5][N:4]=[CH:3]1.Cl[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])=[O:10]>>[N:5]1([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])=[O:10])[CH:6]=[N:2][CH:3]=[N:4]1
Reactant: O=C(CCl)c1ccc(F)cc1F
Reactant: Nn1cnnc1
Product: O=C(Cn1cncn1)c1ccc(F)cc1F

Procedure:
A process for preparing fluconazole, including the steps of (1) acylating 1,3-difluorobenzene (DFB) to obtain 2-chloro-2',4'-difluoroacetophenone (CAP); (2) alkylating 4-amino-4H-1,2,4-triazole (4-AT) with CAP to obtain 2-(1H-1,2,4-triazol-1-yl)-2',4'-difluoroacetophenone (TAAP) salt; (3) deaminating TAAP salt to obtain TAAP; and (4) reacting TAAP with 1,2,4-triazole to obtain fluconazole.
Reaction SMILES: [C:1]12([NH:11][C:12]([NH2:14])=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Cl[CH:16]([C:22]([C:24]([F:27])([F:26])[F:25])=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[C:1]12([NH:11][C:12]3[O:13][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:22]([C:24]([F:25])([F:27])[F:26])[N:14]=3)[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: CCOC(=O)C(Cl)C(=O)C(F)(F)F
Reactant: NC(=O)NC12CC3CC(CC(C3)C1)C2
Product: CCOC(=O)c1oc(NC23CC4CC(CC(C4)C2)C3)nc1C(F)(F)F
Yield: 39.1 %

Procedure:
By the procedure of Example 4, 11.6 g (60 mmol) of adamantyl urea was reacted with 10.9 g (50 mmol) of ethyl 2-chloro-4,4,4-trifluoroacetoacetate at 140°-150° C. for 24 hours. The product was separated and then recrystallized from methylcyclohexane to yield 7.0 g of a white solid product (m.p.=109°-111° C.) identified in Table I.
Reaction SMILES: Br[C:2]1[C:3](=[O:23])[O:4][C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][C:7]=1[OH:8].[CH3:24][C:25]1[CH:26]=[CH:27][C:28]([CH:32]([CH3:34])[CH3:33])=[C:29]([SH:31])[CH:30]=1.N1CCCCC1>ClCCl>[OH:8][C:7]1[CH2:6][C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:4][C:3](=[O:23])[C:2]=1[S:31][C:29]1[CH:30]=[C:25]([CH3:24])[CH:26]=[CH:27][C:28]=1[CH:32]([CH3:34])[CH3:33]
Reactant: O=C1OC(CCc2ccccc2)(c2ccccc2)CC(O)=C1Br
Reactant: Cc1ccc(C(C)C)c(S)c1
Solvent: C1CCNCC1
Solvent: ClCCl
Product: Cc1ccc(C(C)C)c(SC2=C(O)CC(CCc3ccccc3)(c3ccccc3)OC2=O)c1

Procedure:
The title compound was prepared as described in General Method 6 from 2.0 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one (prepared in example BBB), 2.1 mmol of 5-methyl-2-isopropylbenzenethiol, and 2.1 mmol of piperidine in 30 mL of dichloromethane. The product was chromatographed on silica gel, eluting first with chloroform and then with 5% methanol in chloroform (m.p. 66°-67° C.). 1H NMR (DMSO-d6) δ 1.16 (m, 6 H), 1.87 (s, 3 H), 2.26 (m, 3 H), 2.57 (m, 1 H), 3.23 (m, 1 H), 3.43 (q, 2 H), 6.01 (bs, 1 H), 6.78 (d, 1 H), 7.03-7.27 (m, 6 H), 7.37-7.47 (m, 5 H).
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:24])[C:11]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([Cl:23])[CH:18]=2)([OH:16])[C:12]([F:15])([F:14])[F:13])=[C:6]([Cl:25])[CH:5]=1.[Li+].[OH-]>C1COCC1.CO>[Cl:25][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[CH:10]([CH3:24])[C:11]([C:17]1[CH:22]=[CH:21][N:20]=[C:19]([Cl:23])[CH:18]=1)([OH:16])[C:12]([F:15])([F:14])[F:13])[C:3]([OH:26])=[O:2]
Reactant: COC(=O)c1ccc(C(C)C(O)(c2ccnc(Cl)c2)C(F)(F)F)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(c1ccc(C(=O)O)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Temperature: 65 °C
Reaction time: 2 h

Procedure:
3-Chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-benzoic acid methyl ester (Example 135, 62 mg) in THF (1.5 mL) and MeOH (0.3 mL) was treated with 1M aqueous LiOH (0.228 mL) and stirred for 2 h at 65° C. (bath-temperature). The organic solvents were evaporated in vacuo and the residue was diluted with water (2 mL) and acidified with 1M aqueous HCl (0.3 mL). The precipitate was filtered and dried under high vacuum, leading to the title compound as white solid (54 mg). MS (m/e)=392.2 (M−H).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C(NC(C)C)(C)C.[Li]CCCC.[Br:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1.[CH2:32]=[O:33]>C1COCC1>[Br:21][C:22]1[C:31]([CH2:32][OH:33])=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1
Reactant: Brc1ccc2ccccc2n1
Reactant: C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: OCc1cc2ccccc2nc1Br
Reaction time: 1 h

Procedure:
To a solution of LDA, freshly prepared from diisopropylamine (0.42 mL, 2.97 mmol) and n-BuLi (2.97 mmol), in THF (10 mL) at -78° C. was added 2-bromoquinoline (T. Young and E. Amstutz, J. Am. Chem. Soc. 73, 4773 (1951)) (570 rag, 2.7 mmol) and stirring was continued for 1 h. This mixture was cannulated into a solution of formaldehyde in THF at -78° C., which was prepared by cracking paraformaldehyde (1.24 g, 14.8 mmol) under 140°-180° C. and releasing the gas into THF (25 mL) at -23 ° C. Stirring was continued for 6.5 h at -78° C. The reaction was quenched with water (5 mL) and extracted with EtOAc (3×25 mL). After drying (MgSO4), concentration gave a light yellow solid (660 mg) which was purified by recrystallization and chromatography (silica gel, 15% EtOAc/hexanes) to give 373 mg (58%) of the product as a white solid: mp 173°-4° C. 1H NMR (300 MHz, CDCl3) δ8.24 (s, 1H), 8.05 (d, 1 H, J=8 Hz), 7.84 (d, 1 H, J=8 Hz), 7.75 (m, 1 H), 7.59 (m, 1 H). 4.90 (d, 2 H, J=6 Hz), 2.36 (rt, 1 H, J=6 Hz). Analysis calculated for C10H8BrNO was as follows: C, 50.45; H, 3.39; N, 5.88. Found: C, 50.72; H, 3.35; N, 5.94 .
Reaction SMILES: [F:1][C:2]1([F:18])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][NH:14][C:13](=[O:17])[N:12]=3)[C:4]=2[O:3]1.[H-].[Na+].Br[CH2:22][CH2:23][CH2:24][CH2:25][Cl:26].O>CN(C=O)C>[Cl:26][CH2:25][CH2:24][CH2:23][CH2:22][N:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:4]3[O:3][C:2]([F:1])([F:18])[O:6][C:5]=3[CH:7]=[CH:8][CH:9]=2)=[N:12][C:13]1=[O:17]
Reactant: O=c1nc(-c2cccc3c2OC(F)(F)O3)cc[nH]1
Reactant: ClCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1nc(-c2cccc3c2OC(F)(F)O3)ccn1CCCCCl
Temperature: 100 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
To a solution of 4-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-1H-pyrimidin-2-one (232 mg, 0.92 mmol) in dry DMF (18 ml), 60% NaH (47 mg, 1.19 mmol) was added portionwise under inert atmosphere. After heating the mixture at 100° C. for 1 hour, 1-bromo-4-chloro-butane (137 μl 1.19 mmol) was added and the mixture was stirred overnight at room temperature. Water was added and the mixture extracted with diethyl ether. The organic layer was dried (Na2SO4) and evaporated. The residue purified by flash chromatography with hexane-ethyl acetate (8-2) to give 123 mg of the title compound (39% yield).
Reaction SMILES: [CH3:1][C:2]([CH3:13])([C:10](O)=[O:11])[CH2:3][C:4]([CH3:9])([CH3:8])[C:5](O)=[O:6].[NH2:14]C(N)=O>O>[CH3:1][C:2]1([CH3:13])[CH2:3][C:4]([CH3:9])([CH3:8])[C:5](=[O:6])[NH:14][C:10]1=[O:11]
Reactant: CC(C)(CC(C)(C)C(=O)O)C(=O)O
Reactant: NC(N)=O
Solvent: O
Product: CC1(C)CC(C)(C)C(=O)NC1=O
Temperature: 160 °C
Reaction time: 10 h
Yield: 98.4 %

Procedure:
The mixture of 2.6 g of tetramethylglutaric acid and 8.3 g of urea was stirred for 10 hours at 160° C. Into the reaction mixture was added water at 100° C., and the mixture was cooled to near room temperature. The mixture was extracted with ethyl acetate three times. The organic layers were washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 2.3 g of 3,3,5,5-tetramethylpiperidin-2,6-dione.