Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2]S([O-])(=O)=O.[NH2:7][C:8]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:9]=1[C:10](O)=[O:11].CCN(CC)CC>CN(C=O)C>[NH2:7][C:8]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:9]=1[C:10]([O:2][CH3:1])=[O:11]
Reactant: COS(=O)(=O)[O-]
Reactant: Nc1ccc(Br)cc1C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(Br)ccc1N
Temperature: 25 °C
Reaction time: 48 h
Yield: 56.7 %

Procedure:
MeSO4 (26.3 mL, 0.280 mol) was added to a solution of 2-amino-5-bromobenzoic acid (50.0 g, 0.230 mol) in DMF and Et3N (40 mL, 0.28 mol). The reaction mixture was stirred at rt for 48 h. The mixture was quenched with water, extracted with EtOAc and dried over MgSO4. The solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel (5% EtOAc in petroleum ether) to afford methyl 2-amino-5-bromobenzoate (30 g, 56% yield). 1H NMR (300 MHz, DMSO) δ 7.74 (d, J=2.7, 1H), 7.35 (dd, J=9.0, 2.1, 1H), 6.78-6.73 (m, 3H), 3.77 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([OH:15])[C:12]=1[O:13][CH3:14])[CH:9]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1)[NH:8][CH2:7][CH2:6]2.[CH3:25][N:26]=[C:27]=[O:28]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([OH:15])[C:12]=1[O:13][CH3:14])[CH:9]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1)[N:8]([C:27](=[O:28])[NH:26][CH3:25])[CH2:7][CH2:6]2
Reactant: CN=C=O
Reactant: COc1cccc(CC2NCCc3cc(OC)c(OC)c(O)c32)c1
Solvent: ClCCl
Product: CNC(=O)N1CCc2cc(OC)c(OC)c(O)c2C1Cc1cccc(OC)c1
Reaction time: 3.5 h
Yield: 0.1 %

Procedure:
To a solution of 6,7-dimethoxy-1-(3-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-8-ol (350 mg, 1.06 mole) in dichloromethane (11 ml) was added methyl isocyanate (69 μl, 1.17 mole) at room temperature under an argon atmosphere, and the reaction mixture was stirred for 3.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel/chloroform:methanol=20:l) to give the desired compound (410 mg) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([CH3:9])[N:3]=1.[OH-].[NH4+:11]>COCCOC.O>[Cl:1][C:2]1[N:3]=[C:4]([CH3:9])[N:5]=[C:6]([NH2:11])[CH:7]=1
Reactant: [NH4+]
Reactant: Cc1nc(Cl)cc(Cl)n1
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: Cc1nc(N)cc(Cl)n1
Temperature: 23 °C
Reaction time: 336 h
Yield: 60 %

Procedure:
A stirred suspension of 4,6-dichloro-2-methylpyrimidine (39.5 g, 244 mmol) in 1,2-dimethoxyethane (50 mL) in a sealable pressure reaction vessel was treated with concentrated aqueous ammonium hydroxide (40 mL). The mixture was vigorously stirred at 23° C. for 14 days in the sealed vessel. The mixture was then diluted with water and filtered. The isolated white solids were rinsed with water and dried in vacuo to afford 6-chloro-2-methyl-4-aminopyrimidine (20.94 g, 146 mmol, 60% yield): mp 191°-192° C.; Rf 0.49 (EtOAc); 1H NMR (DMSO-D6, 200 MHz)δ7.09 (br s, 2H, NH), 6.24 (s, 1H), 2.26 (s, 3H).
Reaction SMILES: [Cl:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][C:5]([O:7]CC)=[O:6].[OH-].[Na+].Cl>>[Cl:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)CCC(F)(F)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCC(F)(F)Cl
Yield: 79.7 %

Procedure:
18.6 g of ethyl 4-chloro-4,4-difluorobutyrate are stirred with 100 ml of 2N-NaOH at room temperature until a homogeneous solution has been produced. The solution is then poured into 150 ml of 2N-HCl. The organic phase which has separated out is taken up in diethyl ether, dried with sodium sulfate and, after removal of the ether by distillation, distilled in vacuo. 12.6 g of 4-chloro-4,4-difluorobutyric acid are obtained in the form of a colourless oil of boiling point 88°-90° C./11 mbar.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][N:11]([C:13]([O:15][C:16](C)(C)C)=O)[C@H:10](CO)[CH2:9]2)=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:40])[NH:29][C@@H:30]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=2)[CH2:31][OH:32])=[C:24]([F:41])[CH:23]=1.CCN(C(C)C)C(C)C.C(C1NC=CN=1)(C1NC=CN=1)=[S:52]>C(#N)C.CN(C=O)C>[NH2:1][C:2]1[C:3]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([NH:29][C@@H:30]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=3)[CH2:31][OH:32])=[O:40])=[C:24]([F:41])[CH:23]=2)=[CH:4][C:5]([C@@H:8]2[CH2:12][N:11]3[C:13](=[S:52])[O:15][CH2:16][C@@H:10]3[CH2:9]2)=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](c2cnc(N)c(-c3ccc(C(=O)N[C@H](CO)c4cccc(Cl)c4)c(F)c3)c2)C[C@H]1CO
Reactant: S=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Nc1ncc([C@H]2C[C@H]3COC(=S)N3C2)cc1-c1ccc(C(=O)N[C@H](CO)c2cccc(Cl)c2)c(F)c1
Reaction time: 2 h
Yield: 9.6 %

Procedure:
To a solution of (2S,4R)-tert-butyl 4-(6-amino-5-(4-(((S)-1-(3-chlorophenyl)-2-hydroxyethyl)carbamoyl)-3-fluorophenyl)pyridin-3-yl)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (45 mg, 0.063 mmol) (see Example 7) in acetonitrile (0.75 mL) and DMF (0.5 mL) was added DIEA (42 μL, 0.240 mmol) and thiocarbonyl diimidazole (15.6 mg, 0.088 mmol). After 2 h, the reaction was quenched with 1 N aqueous solution. NaOH (1 mL) and stirred vigorously to effect decomposition of a mixed thiocarbamate byproduct. The reaction was then diluted with ethyl acetate (10 mL), washed with water (5 mL) and brine (5 mL), then dried over sodium sulfate and concentrated. The crude material was purified by reverse phase prep HPLC yielding 4-(2-amino-5-((6R,7aS)-3-thioxohexahydropyrrolo[1,2-c]oxazol-6-yl)pyridin-3-yl)-N—((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-2-fluorobenzamide (3.2 mg, 11% yield). LCMS (m/z): 527.3, 529.3 (MH+), 0.67 min; 1H NMR (400 MHz, CD3OD) δ ppm 8.64 (dd, J=3.91, 7.04 Hz, 1H), 7.85 (d, J=1.96 Hz, 2H), 7.83-7.77 (m, 3H), 7.39-7.32 (m, 5H), 7.30-7.26 (m, 3H), 7.25-7.19 (m, 2H), 5.15-5.07 (m, 2H), 4.73-4.69 (m, 2H), 4.45-4.35 (m, 3H), 3.85-3.65 (m, 8H), 2.38 (td, J=5.58, 11.54 Hz, 2H), 1.80-1.70 (m, 1H).
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([NH:24][CH:25]([CH3:27])[CH3:26])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[N:6][CH:5]=1.Cl.O>CO.[OH-].[Na+]>[CH:25]([NH:24][C:23]1[C:18]([N:15]2[CH2:16][CH2:17][N:12]([C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:28])=[O:2])=[CH:5][N:6]=3)=[O:11])[CH2:13][CH2:14]2)=[N:19][CH:20]=[CH:21][CH:22]=1)([CH3:27])[CH3:26]
Reactant: COC(=O)c1ccc(C(=O)N2CCN(c3ncccc3NC(C)C)CC2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cn2)CC1
Reaction time: 2 h
Yield: 91 %

Procedure:
6-[1-[3-(Isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]nicotinic acid methyl ester (3 g) was dissolved in methanol (30 ml) and with the addition of aqueous 1N sodium hydroxide (16 ml), the mixture was hydrolyzed at 25°C. for 2 hours. 2N hydrochloric acid was slowly added to the mixture for neutralization (pH=˜5), followed by the slow addition of excess of water to precipitate. After 2-hours stirring, the precipitate was filtered, washed with water and dried to give a desired compound of 2.63 g (yield: 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH2:21][CH2:22][N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[CH:14]=3)=[CH:11][C:10]([C:28]([O:30]CC)=[O:29])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(N2C(C3C=C(F)C=C(Cl)C=3)=CC(C(O)=O)=N2)C=CC=1F>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH2:21][CH2:22][N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[CH:14]=3)=[CH:11][C:10]([C:28]([OH:30])=[O:29])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2cccc(OCCCN3CCCC3)c2)n(-c2cccc(Cl)c2)n1
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1
Product: O=C(O)c1cc(-c2cccc(OCCCN3CCCC3)c2)n(-c2cccc(Cl)c2)n1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 70A in analogy to the synthesis of the compound of Example 71A. 10 mg of the title compound with 79% purity (44% of theory) are obtained.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[CH:14][C:15]([F:33])=[C:16]([NH:18][C:19](=[O:32])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4([C:29]#[N:30])[CH2:28][CH2:27]4)[C:21]=3[Cl:31])[CH:17]=1)[N:5]=2.[CH3:34][CH:35]([CH3:39])[C:36](Cl)=[O:37].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Cl:31][C:21]1[C:22]([C:26]2([C:29]#[N:30])[CH2:28][CH2:27]2)=[CH:23][CH:24]=[CH:25][C:20]=1[C:19]([NH:18][C:16]1[CH:17]=[C:12]([O:11][C:6]2[N:5]=[C:4]3[S:3][C:2]([NH:1][C:36](=[O:37])[CH:35]([CH3:39])[CH3:34])=[N:10][C:9]3=[CH:8][CH:7]=2)[CH:13]=[CH:14][C:15]=1[F:33])=[O:32]
Reactant: N#CC1(c2cccc(C(=O)Nc3cc(Oc4ccc5nc(N)sc5n4)ccc3F)c2Cl)CC1
Reactant: CC(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)C(=O)Nc1nc2ccc(Oc3ccc(F)c(NC(=O)c4cccc(C5(C#N)CC5)c4Cl)c3)nc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.8 %

Procedure:
To a solution of N-{5-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-2-fluorophenyl}-2-chloro-3-(1-cyanocyclopropyl)benzamide (0.16 g, 0.33 mmol) produced in Example C71(iv) and N,N-dimethylpyridine-4-amine (0.12 g, 1.00 mmol) in pyridine (2 mL) was added dropwise 2-methylpropanoyl chloride (0.12 g, 1.00 mmol) under ice-cooling, and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added water (50 mL), and the mixture was extracted with ethyl acetate (50 mL×2). The ethyl acetate layers were combined, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in methanol (5 mL), 8N aqueous sodium hydroxide solution (1 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water (50 mL), and the mixture was extracted with ethyl acetate (50 mL×2). The ethyl acetate layers were combined, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100→100/0), and recrystallized from methanol to give the title compound (114 mg, 63%) as white crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=[C:6](OS(C(F)(F)F)(=O)=O)[C:5]=1[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[CH3:2].[CH:30]1(B(O)O)[CH2:32][CH2:31]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.C1(C)C=CC=CC=1>[CH:30]1([C:6]2[CH:7]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:9]=[C:4]([O:3][CH2:1][CH3:2])[C:5]=2[C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[CH2:32][CH2:31]1
Reactant: CCOC(=O)c1cc(OCC)c(-c2ccc(F)cc2)c(OS(=O)(=O)C(F)(F)F)c1
Reactant: OB(O)C1CC1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1cc(OCC)c(-c2ccc(F)cc2)c(C2CC2)c1
Temperature: 25 °C
Yield: 89.4 %

Procedure:
A mixture of ethyl 2-ethoxy-4′-fluoro-6-(((trifluoromethyl)sulfonyl)oxy)biphenyl-4-carboxylate (15.6 g), cyclopropylboronic acid (7.67 g), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (2.20 g), a 2 M aqueous sodium carbonate solution (53.6 mL), tris(dibenzylideneacetone)dipalladium(0) (2.29 g), and toluene (60 mL) was stirred at 100° C. for 2 hours in an argon atmosphere. The reaction mixture was allowed to cool to room temperature and then poured to water, followed by extraction with ethyl acetate. The obtained organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (10.5 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10]CC[C:7]2=[O:12].C([O:17]O)(C)(C)C.C[O-].[Na+].O>CO.C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([C:7]([OH:12])=[O:17])[C:11]=1[NH2:10]
Reactant: CC(C)(C)OO
Reactant: O=C1CCNc2c(F)cccc21
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: Nc1c(F)cccc1C(=O)O
Yield: 51.6 %

Procedure:
A solution of 0.25 g (1.5 mmol) of 8-fluoro-2,3-dihydroquinolin-4-one, 0.8 g (6.2 mmol) of 70 percent t-butyl hydroperoxide, 2 mL of 25 percent sodium methoxide in methanol and 3 mL of methanol were stirred at 75° C. for 72 hr. An additional 1 mL of 70 percent t-butyl hydroperoxide and 2 mL of 25 percent sodium methoxide in methanol were added and heating was continued for 72 more hr. The reaction mixture was cooled, poured into water and neutralized with acetic acid. The mixture was extracted with methylene chloride and the organic phase was collected. Evaporation of the solvent gave 0.12 g (51 percent yield) of 3-fluoroanthranilic acid, identical in all respects to an authentic sample.
Reaction SMILES: O[C:2]([CH:4]([C:6]1[CH:19]=[CH:18][CH:17]=[C:8]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])[CH:7]=1)[CH3:5])=[O:3].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.C([O:36][C:37](=[O:47])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][S:43](=[O:46])(=[O:45])[NH2:44])C>ClCCl>[C:9]([C:8]1[CH:7]=[C:6]([CH:4]([CH3:5])[C:2]([NH:44][S:43]([CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][C:37]([OH:47])=[O:36])(=[O:45])=[O:46])=[O:3])[CH:19]=[CH:18][CH:17]=1)(=[O:10])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C(=O)O)c1cccc(C(=O)c2ccccc2)c1
Reactant: CCOC(=O)CCCCCS(N)(=O)=O
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C(=O)NS(=O)(=O)CCCCCC(=O)O)c1cccc(C(=O)c2ccccc2)c1
Yield: 46.3 %

Procedure:
To a suspension of racemic ketoprofen (3.81 g, 15.0 mmol) in dichloromethane (50 ml) were added HOAt (2.04 g, 15.0 mmol) and EDC (2.88 g, 15.0 mmol), and the mixture was stirred until a clear solution resulted. To this solution was added a solution of 6-sulfamoylhexanoic acid ethyl ester (2.23 g, 10.0 mmol) and DI PEA (2.56 ml) in dichloromethane, and the mixture was stirred at room temperature for 3 d. The mixture was washed with 1N aqueous HCl, dried over MgSO4, and concentrated. Purification by column chromatography yielded 2.0 g (44%) of the title compound. An analytical sample was obtained by preparative HPLC.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[N:29]=4)=[O:26])=[CH:20][CH:19]=3)[CH:9]=[C:10]([C:11]([O:13]CCCC)=[O:12])[N:6]2[N:5]=[CH:4][N:3]=1.[OH-].[Na+].Cl>C1COCC1.CO>[NH2:1][C:2]1[C:7]2=[C:8]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[N:29]=4)=[O:26])=[CH:20][CH:19]=3)[CH:9]=[C:10]([C:11]([OH:13])=[O:12])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CCCCOC(=O)c1cc(-c2ccc(NC(=O)Nc3cccc(C(F)(F)F)n3)cc2)c2c(N)ncnn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ncnn2c(C(=O)O)cc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)n4)cc3)c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.5 %

Procedure:
A mixture of butyl 4-amino-5-{4-[({[6-(trifluoromethyl)pyridin-2-yl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazine-7-carboxylate (96.0 mg, 0.19 mmol) and 1 N aqueous sodium hydroxide solution (0.94 mL, 0.94 mmol) in THF (4 mL) and MeOH (5 mL) was stirred at rt for 4 h and acidified to pH 3 using 2N hydrochloric acid. The organic solvents were evaporated under reduced pressure and the residue was suspended in water (5 mL). The solid was filtered, washed with water and air-dried to give 63.0 mg (74%) of the title compound. 1H-NMR (DMSO-d6) δ 12.76 (s, 1 H), 9.87 (s, 1 H), 9.71 (s, 1 H), 8.08 (s, 1 H), 8.04-7.97 (m, 2 H), 7.57 (d, J=8.6 Hz, 2 H), 7.50-7.49 (m, 1 H), 7.43 (d, J=8.5 Hz, 2 H), 7.20 (s, 1 H); MS [M+H]+=458.0; LCMS RT=2.90 min.
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[N:15][O:16][CH:17]([F:19])[F:18])[C:13]#[N:14].C(N)(N)=[O:26].OO.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O>[F:19][CH:17]([F:18])[O:16][N:15]=[C:12]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH2:5][O:4][C:3]1[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:2]=1[CH3:1])[C:13]([NH2:14])=[O:26]
Reactant: Cc1ccc(C)c(OCc2ccccc2C(C#N)=NOC(F)F)c1
Reactant: NC(N)=O
Agent: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1ccc(C)c(OCc2ccccc2C(=NOC(F)F)C(N)=O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4.72 g of 2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-difluoromethoxyimino-acetonitrile in 15 ml of acetone is added dropwise to a solution of 4.88 g of hydrogen peroxide-urea adduct and 0.20 g of potassium carbonate in 15 ml of water and the reaction mixture is stirred at room temperature for 16 hours. The reaction mixture is then diluted with water and the precipitated crystalline material is filtered off with suction. Chromatography on silica gel with hexane/ethyl acetate (3:1) yields pure 2-(2,5-dimethylphenoxymethyl)-phenylglyoxalic acid amide O-difluoromethyl oxime in the form of white crystals; m.p. 153°-156° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](OS(C(F)(F)F)(=O)=O)=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][N:7]=[CH:6]2.[CH2:22]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:23][CH2:24][C:25]#[CH:26].C(N(CC)CC)C.O>CN(C=O)C>[CH3:1][O:2][C:3]1[C:4]([C:26]#[C:25][CH2:24][CH2:23][CH2:22][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][N:7]=[CH:6]2
Reactant: C#CCCCc1ccccc1
Reactant: COc1ccc2c(=O)[nH]ncc2c1OS(=O)(=O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc2c(=O)[nH]ncc2c1C#CCCCc1ccccc1
Temperature: 90 °C
Yield: 65.3 %

Procedure:
A mixture under N2 of trifluoro-methanesulfonic acid 6-methoxy-1-oxo-1,2-dihydrophthalazin-5-yl ester (2 g, 6.16 mmoles), prepared as described in example 59, pent-4-ynyl-benzene (1.33 g, 9.24 mmoles), bis(triphenylphosphine)PdCl2 (216 mg, 0.308 mmole) and triethylamine (3.42 ml, 24.64 mmoles) in DMF (40 ml) was heated to 90° C. for 3 hours, then poured into water (200 ml), filtered and the precipitate was washed with water to give 1.28 g of the title compound (yield: 65%).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C@@:7]([OH:32])([CH2:8][CH2:9][C@@H:10]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:22])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:6]1)(=[O:3])[CH3:2].C(OCC)(=[O:35])C.C(OO)(=O)C>C(O)(=O)C>[C:1]([O:4][C@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C@@:7]([OH:32])([CH2:8][CH2:9][C@@H:10]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:22])[CH2:16][CH2:17][CH2:18][C:19]([OH:35])([CH3:21])[CH3:20])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@H]4[C@@H]3CC[C@@]2(O)C1
Agent: CC(=O)OO
Solvent: CC(=O)O
Product: CC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H]([C@H](C)CCCC(C)(C)O)CC[C@H]4[C@@H]3CC[C@@]2(O)C1

Procedure:
A solution of 50 g 3β-acetoxy-5-α-hydroxy-cholestane (II), in 25 ml. of ethyl acetate was treated with 100 ml. of peracetic acid (70%) in acetic acid and was irradiated with ultra-violet light of about 300 mμ wavelength for 12 hours. The resulting reaction mixture was washed with a solution of aqueous sodium bisulfite, sodium bicarbonate and then with water. After evaporation of the solvent in vacuo, the residue was chromatographed on a column of silica gel to give 10 g of the novel 3β-acetoxy-5α,25-dihydroxy cholestane (IV) which was recrystallized from methanol, m.p. 180°-182°C.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[F:6][CH:7]([F:21])[C:8]1[N:12]=[CH:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=2[CH3:20])[N:9]=1>C(Cl)Cl>[F:21][CH:7]([F:6])[C:8]1[N:12]=[CH:11][N:10]([C:13]2[C:14]([CH3:20])=[CH:15][C:16]([CH3:19])=[C:17]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:18]=2)[N:9]=1
Reactant: Cc1ccc(-n2cnc(C(F)F)n2)c(C)c1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: Cc1cc(C)c(S(=O)(=O)Cl)cc1-n1cnc(C(F)F)n1
Temperature: 45 °C
Reaction time: 5 h

Procedure:
Under a nitrogen atmosphere, 14.2 g of chlorosulphonic acid are introduced and are admixed at room temperature, in portions, with 4 g of 3-(difluoromethyl)-1-(2,4-dimethylphenyl)-1H-1,2,4-triazole. The exothermic reaction raises the temperature of the mixture to around 45° C. The mixture is subsequently stirred at 70° C. for 5 hours and then cooled, and diluted with 20 ml of methylene chloride. The mixture is added with stirring to 40 g of ice and then the phases are separated and extracted with twice 20 ml of methylene chloride. The combined organic phases are concentrated on a rotary evaporator. This gives 4.5 g of brown oil. This oil is chromatographed using CH2Cl2. A white solid (2.9 g; 52% of theory) is isolated.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C:24]1[C:28]([C:29]2C=CC=CC=2)=[CH:27]SC=1C(OC)=O.C(OCC)(OCC)OCC.C(C1CCC(N)CC1)(C)(C)C>C(O)(=O)C>[C:28]([CH:4]1[CH2:5][CH2:6][CH:1]([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:10]=3[N:9]=[CH:8]2)[CH2:2][CH2:3]1)([CH3:29])([CH3:24])[CH3:27]
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: COC(=O)c1scc(-c2ccccc2)c1N
Agent: CC(C)(C)C1CCC(N)CC1
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: CC(C)(C)C1CCC(n2cnc3c(-c4ccccc4)csc3c2=O)CC1
Yield: 65.4 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (100 mg, 0.43 mmol), triethyl orthoformate (1 ml), 4-t-butylcyclohexylamine (0.161 ml, 0.90 mmol), and acetic acid (0.1 ml) were used to give 103.1 mg (0.28 mmol, 65.4% yield) of the title compound.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:7]=1[C:8](Cl)=O.[CH3:16][C:17]1[CH:18]=[C:19]2[N:24]([CH:25]=1)[CH:23]=[C:22]([C:26]([O:28][CH3:29])=[O:27])[CH:21]=[CH:20]2>ClCCl>[Cl:5][C:6]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:7]=1[CH2:8][C:25]1[N:24]2[C:19]([CH:20]=[CH:21][C:22]([C:26]([O:28][CH3:29])=[O:27])=[CH:23]2)=[CH:18][C:17]=1[CH3:16]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: COC(=O)c1ccc2cc(C)cn2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)c1ccc2cc(C)c(Cc3ccc(Cl)cc3Cl)n2c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 68.7 %

Procedure:
To a suspension of anhydrous aluminum chloride (3.18 g) in dichloromethane (19 ml) was added 2,4-dichlorobenzoyl chloride (2.93 g) under ice-cooling, and the mixture was stirred for 10 min. To this solution was added methyl 2-methylindolizine-6-carboxylate (1.89 g) and the mixture was stirred for 4 hr at room temperature. The reaction mixture was slowly poured into ice water and the resulting product was extracted with ethyl acetate. The organic layer was washed successively with water, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1) to give the objective compound (2.39 g) as a pale-yellow solid.