Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][O:16][C:17]1[C:18](N)=[CH:19][CH:20]=[CH:21][CH:22]=1.N1C=CC=CC=1>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:16][CH3:15])(=[O:9])=[O:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: COc1ccccc1N
Reactant: NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccccc1NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reaction time: 16 h

Procedure:
4-Chloro-3-nitrobenzenesulfonamide (1.73 g, 6.78 mmol) was dissolved in CH2Cl2 (7.0 mL). o-Anisidine (1.00 g, 8.13 mmol) was added dropwise at room temperature, followed by a slow addition of pyridine (2.0 mL). After 16 h of continued stirring, the reaction mixture was diluted with EtOAc (50 mL) and washed with 1 M HCl (3×50 mL).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[C:5]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31]CC2C=CC=CC=2)=[CH:27][CH:26]=1)([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:6](OC(=O)C(F)(F)F)[CH2:7][CH2:8][CH3:9])[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:39])[C:5]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([OH:31])=[CH:29][CH:30]=1)([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:6][CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: CCCC(OC(=O)C(F)(F)F)C(Cc1ccc(OCc2ccccc2)cc1)(Oc1ccccc1)C(=O)OCC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCC(Cc1ccc(O)cc1)(Oc1ccccc1)C(=O)OCC
Reaction time: 20 h

Procedure:
2-(4-Benzyloxybenzyl)-2-phenoxy-3-(2,2,2-trifluoroacetoxy)hexanoic acid ethyl ester (2.1 mmol) was dissolved in ethyl acetate (30 mL) and treated with 5% palladium on carbon (300 mg), and stirred under an atmosphere of hydrogen for 20 h. The suspension was filtered through celite and concentrated in vacuo to an oil.
Reaction SMILES: [C:1]([O:5][C@H:6]1[CH2:11][CH2:10][C@H:9]2[C@H:12]3[C@H:27]([CH2:28][CH2:29][C@:7]12[CH3:8])[C@:20]1([CH2:21][O:22]C(=O)CC)[C:15](=[CH:16][CH2:17][CH2:18][CH2:19]1)[CH2:14][CH2:13]3)(=[O:4])[CH2:2][CH3:3].C(O[C@H]1CC[C@H]2[C@H]3[C@H](CC[C@]12C)[C@]1(COC(=O)CC)C(=CCC[C@@H]1C)CC3)(=O)CC>>[C:1]([O:5][C@H:6]1[CH2:11][CH2:10][C@H:9]2[C@H:12]3[C@H:27]([CH2:28][CH2:29][C@:7]12[CH3:8])[C@:20]1([CH2:21][OH:22])[C:15](=[CH:16][CH2:17][CH2:18][CH2:19]1)[CH2:14][CH2:13]3)(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)OC[C@]12CCCC=C1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OC(=O)CC)CC[C@@H]12
Agent: CCC(=O)OC[C@@]12C(=CCC[C@@H]1C)CC[C@H]1[C@@H]3CC[C@H](OC(=O)CC)[C@@]3(C)CC[C@@H]12
Product: CCC(=O)O[C@H]1CC[C@H]2[C@@H]3CCC4=CCCC[C@]4(CO)[C@H]3CC[C@]12C

Procedure:
Substituting 4-androstene-17β,19-diol dipropionate for the 1α-methyl- 4-androstene-17β,19-diol dipropionate above results in the preparation of 4-androstene-17β,19-diol 17-propionate.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[CH2:22][CH2:23][NH2:24].[OH-].[NH4+].O>>[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[CH2:22][CH2:23][NH:24][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: Clc1ncnc2ccccc12
Reactant: NCCc1ccc2ccccc2c1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: c1ccc2cc(CCNc3ncnc4ccccc34)ccc2c1
Yield: 26.4 %

Procedure:
A mixture of 1.0 g of 4-chloroquinazoline and 2.0 g of 2-(2-naphthyl)ethyl amine was heated under nitrogen to 165°-170° C. for one hour. The mixture was cooled and then 200 ml of a 50/50 mixture of ammonium hydroxide/water was added. The product was extracted into CH2Cl2, and the resulting solution was treated with charcoal and filtered. The solution was then concentrated to dryness, and the residue was recrystallized from a mixture of pentane and CH2Cl2 to give: 0.480 g of the title product. Yield: 26.7%. M.P. 172°-174° C.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:8]([NH:10][C@H:11]([C:20]([NH:22][C@H:23]([C:31]([O:33][CH3:34])=[O:32])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:21])[CH2:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].[H][H].[ClH:47].O1CCOCC1>[Pd]>[NH2:1][C@H:2]([C:8]([NH:10][C@H:11]([C:20]([NH:22][C@H:23]([C:31]([O:33][CH3:34])=[O:32])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:21])[CH2:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].[ClH:47]
Reactant: [H][H]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)[C@@H](N)CCC(N)=O

Procedure:
4.4 g of Z-Gln-Asp(OtBu)-Phe-OCH3 are decarbobenzoxylated with hydrogen at room temperature in a duck-shaped shaking flask after adding 2.4 ml of hydrogen chloride in dioxane (3.0 N, 7.2 mmols) amd 900 mg of 10% strength palladium on charcoal catalyst. After completion of the hydrogen uptake the mixture is filtered and the filtrate evaporated to dryness in vacuo. The yellowish solid residue is twice triturated with ether and used for the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.[OH:11][C:12]1[C:13]([O:20][CH3:21])=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=O.N1C=CC=CC=1.O>C1COCC1.[Ti](Cl)(Cl)(Cl)Cl>[OH:11][C:12]1[C:13]([O:20][CH3:21])=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=[C:5]1[C:6](=[O:8])[O:7][C:2]([CH3:10])([CH3:1])[O:3][C:4]1=[O:9]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: COc1c(O)cccc1C=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: COc1c(O)cccc1C=C1C(=O)OC(C)(C)OC1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.8 %

Procedure:
To a solution of titanium (IV) chloride (11.1 g) in THF (50 mL) was added dropwise under ice-cooling a solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (4.26 g) and 3-hydroxy-2-methoxybenzaldehyde (3.0 g) in THF (50 mL) at 0° C., and then a solution of pyridine (4.00 g) in THF (20 mL) was added dropwise. The reaction mixture was stirred at 0° C. for 1 hr, and water was added. The mixture was extracted with ethyl acetate, and the extract was washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (3.50 g) as a yellow solid. This compound was used for the next step without further purification.
Reaction SMILES: Cl.C[O:3][C:4](=[O:24])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[CH:10][CH:9]=1)[NH2:6].[CH3:25][C:26]1[C:30]([C:31](=[O:33])[CH3:32])=[C:29]([CH3:34])[NH:28][C:27]=1[C:35](O)=[O:36]>>[Cl:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:16]=1[CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][C@@H:5]([C:4]([OH:3])=[O:24])[NH:6][C:35]([C:27]2[NH:28][C:29]([CH3:34])=[C:30]([C:31](=[O:33])[CH3:32])[C:26]=2[CH3:25])=[O:36])=[CH:9][CH:10]=1
Reactant: CC(=O)c1c(C)[nH]c(C(=O)O)c1C
Reactant: COC(=O)[C@@H](N)Cc1ccc(OCc2c(Cl)cccc2Cl)cc1
Agent: Cl
Product: CC(=O)c1c(C)[nH]c(C(=O)N[C@@H](Cc2ccc(OCc3c(Cl)cccc3Cl)cc2)C(=O)O)c1C

Procedure:
from O-(2,6-dichlorobenzyl)-L-tyrosine methyl ester hydrochloride and 3,5-dimethyl-4-acetylpyrrole-2-carboxylic acid. Freeze drying afforded the title compound as a light cream amorphous solid (550 mg). δH (DMSO-d6) 11.56, (1H, s), 7.61 (1H, d, J 7.8 Hz), 7.51 (2H, d, J 8.0 Hz), 7.41 (1H, t, J 8.0 Hz), 7.21 (2H, d, J 85 Hz), 6.96 (2H, d, J 8.5 Hz), 5.16 (2H, s), 4.69-4.55 (1H, m), 3.12 (1H, dd, J 13.7, 4.7 Hz), 2.99 (1H, dd, J 13.7, 9.1 Hz), 2.43 (3H, s), 2.38 (3H, s), 2.31 (3H, s); m/z (ESI, 60V) 503 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8]N)=[N:6][CH:7]=1.[C:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=O)[CH2:11][CH3:12]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:11]([CH3:12])=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: NNc1ccc(Br)cn1
Reactant: CCC(=O)c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccc2)[nH]c2ncc(Br)cc12

Procedure:
5-Bromo-2-hydrazinopyridine (15.6 g, 0.083 mol) and propiophenone (11.1 ml) was heated at 90° C. (steam bath) for 30 min. Then toluene (100 ml) was added and the resulting solution was refluxed for 2 h to remove water by azeotropic distillation (Dean Stark apparatus). Evaporation of solvent gave 26.4 g of crude product, assumed to be the desired hydrazone. Crude hydrazone (3.02 g) was dissolved in diethylene glycol (30 ml) and heated at 245° C. under argon for 24 h. The reaction mixture was poored crushed ice and extracted with methylene chloride. Drying over MgSO4 and evaporation of solvent left a tary residue which was triturated with diethyl ether to produce 0.84 g (30%) of a brownish, semi-crystalline product.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:24])[C:6]([NH:8][C:9]2[C:10]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([F:23])[CH:17]=3)=[N:11][CH:12]=[CH:13][CH:14]=2)=O)[CH2:3][CH2:2]1.C(O)CO>O.[OH-].[Na+]>[CH:1]1([NH:4][C:5]([C:6]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([F:23])[CH:17]=3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[N:8]=2)=[O:24])[CH2:3][CH2:2]1
Reactant: Cc1ccc(Nc2ncccc2NC(=O)C(=O)NC2CC2)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: Cc1ccc(-n2c(C(=O)NC3CC3)nc3cccnc32)cc1F
Temperature: 200 °C
Reaction time: 1 h

Procedure:
A mixture of N-cyclopropyl-N′-{2-[(3-fluoro-4-methylphenyl)amino]pyridin-3-yl}ethanediamide (C3) (from the preceding step, 8.86 g, ≦16.6 mmol) and ethane-1,2-diol (27 mL) was stirred at 200° C. for 1 hour. After cooling to room temperature, the reaction mixture was diluted with water (100 mL) and aqueous sodium hydroxide solution (1 M, 100 mL), then extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification using silica gel chromatography (Gradient: 5% to 50% ethyl acetate in heptane) was followed by recrystallization from 3:1 toluene/heptane, to afford the product as a solid. Yield: 2.52 g, 8.12 mmol, 49% over three steps. LCMS m/z 311.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.50 (dd, J=4.7, 1.5 Hz, 1H), 8.13 (dd, J=8.1, 1.5 Hz, 1H), 7.68 (br s, 1H), 7.37 (dd, J=8.1, 4.7 Hz, 1H), 7.34-7.40 (m, 1H), 7.10-7.15 (m, 2H), 2.83-2.90 (m, 1H), 2.37 (br d, J=2 Hz, 3H), 0.83-0.89 (m, 2H), 0.67-0.72 (m, 2H).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH3:10][O:11][C:12](=[O:49])[CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][C@@H:19]1[C@@H:23](/[CH:24]=[CH:25]/[C@@H:26]([O:34]C2CCCCO2)[C:27]([CH3:33])([CH3:32])[CH2:28][CH2:29][CH2:30][CH3:31])[C@H:22]([O:41]C2CCCCO2)[CH2:21][C@@H:20]1O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.N1C=CC=CC=1>[CH3:10][O:11][C:12](=[O:49])[CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][C@@H:19]1[C@@H:23](/[CH:24]=[CH:25]/[C@@H:26]([OH:34])[C:27]([CH3:33])([CH3:32])[CH2:28][CH2:29][CH2:30][CH3:31])[C@H:22]([OH:41])[CH2:21][C@H:20]1[F:7]
Reactant: CCN(CC)S(F)(F)F
Reactant: CCCCC(C)(C)[C@@H](/C=C/[C@@H]1[C@@H](CC/C=C\CCC(=O)OC)[C@@H](O)C[C@H]1OC1CCCCO1)OC1CCCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCC(C)(C)[C@H](O)/C=C/[C@@H]1[C@@H](CC/C=C\CCC(=O)OC)[C@H](F)C[C@H]1O
Temperature: -70 °C
Reaction time: 3.5 h

Procedure:
0.56 ml of diethylaminosulfur trifluoride (DAST) is instilled in a solution of 2.05 g of (4Z,13E)-(9S,11R,15R)-9-hydroxy-16,16-dimethyl-11,15-bis-(tetrahydropyran-2-yloxy)-4,13-prostadienoic acid methyl ester in 43 ml of methylene chloride and 1.1 ml of pyridine at −70° C. and stirred for 3.5 hours at −70° C. Then it is added to 200 ml of 5% sodium bicarbonate solution cooled to 0° C. and allowed to stir vigorously for 10 minutes. Then it is extracted several times with methylene chloride, the extract is washed with water, dried over MgSO4 and concentrated by evaporation in a vacuum. The residue is stirred for 24 hours at 20° C. with 60 ml of a mixture of acetic acid/water/tetrahydrofuran (65/35/10), concentrated by evaporation in a vacuum after addition of toluene and the raw product is purified by chromatography on silica gel with toluene/0-10% isopropanol. 306 mg of the title compound is obtained as oil.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].C(N(CC)CC)C.[Br:12][C:13]([CH3:18])([CH3:17])[C:14](Br)=[O:15].O>O1CCCC1>[Br:12][C:13]([CH3:18])([CH3:17])[C:14]([O:3][CH2:2][CH2:1][OH:4])=[O:15]
Reactant: OCCO
Reactant: CC(C)(Br)C(=O)Br
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(Br)C(=O)OCCO
Reaction time: 16 h
Yield: 85.3 %

Procedure:
Anhydrous ethylene glycol (301.3 g, 4.85 mol) and triethylamine (28 mL, 200 mmol) were diluted with dry tetrahydrofuran (100 mL). The reaction mixture was cooled in an ice-water bath and a solution of α-bromoisobutyryl bromide (12 mL, 97.1 mmol) in dry tetrahydrofuran (50 mL) was slowly added while stirring. The mixture was stirred in the cooling bath for 1 h and then at room temperature for 16 h. The reaction mixture was then poured into water (800 mL) and extracted with dichloromethane (6×100 mL). The organic fractions were combined, washed with acidic water (pH=4), dried over MgSO4 and evaporated to dryness to afford 17.477 g (yield=85.3%) of a very pale yellow liquid. 1H NMR (CDCl3, δ, ppm): 4.30-4.19 (m, 2H), 3.86-3.75 (m, 2H), 2.86-2.47 (broad peak, 1H, OH), 1.89 (s, 6H). 13C NMR (CDCl3, δ): 171.95, 67.40, 60.63, 55.89, 30.72.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH2:13])[C:7](=[CH:11][CH:12]=1)[C:8]([OH:10])=[O:9])([O-:3])=[O:2].[F:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:16]=1[C:17](Cl)=O.C(N(CC)CC)C.C1(C)C=CC=CC=1.C(NC1C=CC2N=C(C3C(F)=CC=CC=3F)OC(=O)C=2C=1)(=O)C>C1COCC1>[F:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:16]=1[C:17]1[O:9][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=2[N:13]=1
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: CC(=O)Nc1ccc2nc(-c3c(F)cccc3F)oc(=O)c2c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=c1oc(-c2c(F)cccc2F)nc2cc([N+](=O)[O-])ccc12

Procedure:
4-Nitroanthranilic acid (0.6 g), 2,6-difluorobenzoyl chloride (0.93 mL) and triethyl amine/toluene (1/1) (18 mL) were reacted as described under (10). reaction time 2 days. Extraction between ethyl acetate (100 mL) and HCl (2N, 100 mL), followed by separation of the organic layer, drylng over MgSO4, filtering and evaporation gave a crude product which was dissolved in warm THF (20 mL) and precipitated with hexane twice to get the pure product 2-(2,6-difluoro-phenyl)-7-nitro-benzo[d][1,3]oxazin-4-one (0.417 g), mp. 187 C, MS m/e: 304 M+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]([C:17](=[O:27])[CH:18]=[C:19]2[C:23](=O)[O:22]C(C)(C)[O:20]2)[O:15][CH3:16])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C=O.CN.ClC1C=C(C=CC=1Cl)[CH2:37][N:38](C)[C:39](C1CN(C)C(=O)C=1O)=O>CO>[C:1]([O:5][C:6](=[O:28])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]([C:17]([C:18]2[CH2:37][N:38]([CH3:39])[C:23](=[O:22])[C:19]=2[OH:20])=[O:27])[O:15][CH3:16])=[CH:9][CH:8]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CON(Cc1ccc(C(=O)OC(C)(C)C)cc1)C(=O)C=C1OC(C)(C)OC1=O
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Agent: C=O
Agent: CN
Solvent: CO
Product: CON(Cc1ccc(C(=O)OC(C)(C)C)cc1)C(=O)C1=C(O)C(=O)N(C)C1
Yield: 40 %

Procedure:
4-({[2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-acetyl]-methoxyamino}-methyl)-benzoic acid tert-butyl ester, prepared using the methods described in the previous examples, was treated in methanol with paraformaldehyde and methylamine as described in the preparation of Compound 12 to give the title compound as a white solid (40% yield); mp 157–160° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.58 (9H, s, t-Bu), 3.11 (3H, s, NCH3), 3.72 (3H, s, OCH3), 4.16 (2H, s, NCH2), 4.92 (2H, s, NCH2), 7.37 (2H, d, J=8 Hz, aromatics), 7.97 (2H, d, J=8 Hz, aromatics), 11.55 (1H, broad s, OH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([NH2:12])=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].[N:13]([O-])=O.[Na+].Cl[Sn]Cl.O>Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([NH:12][NH2:13])=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: COc1ccc(N)c(C(=O)O)c1
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: COc1ccc(NN)c(C(=O)O)c1
Reaction time: 1 h
Yield: 284 %

Procedure:
Part A: 5-(Furan-2-yl)-3-trifluoromethyl-1-(2-carboxyl-4-methoxyphenyl)-1H-pyrazole: 3-Methoxy-6-aminobenzoic acid (23 g, 138 mmol) in conc. HCl (300 mL) was cooled to 0° C. and NaNO2 (11.4 g, 165 imnol) in H2O (50 mL) was added dropwise while the temperature of the reaction was maintained below 10° C. The reaction was stirred at or below 10° C. for 1 h, then SnCl2.H2O (92.3 g, 413 mmol) in conc. HCl (125 mL) was added dropwise. The reaction was allowed to thaw to ambient temperature and stirred for 3 h. The precipitate was filtered and air-dried then heated in a vacuum oven for 18 h. There was obtained 71.4 g of 3-methoxy-6-hydrazinobenzoic acid entrained with tin (II) salts.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([Si:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.[Br:32]N1C(=O)CCC1=O.CN(C)C=O.CCOC(C)=O>O>[Br:32][C:12]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([Si:13]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:3]=1[O:2][CH3:1]
Reactant: COc1cc2ccccc2cc1[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1c([Si](c2ccccc2)(c2ccccc2)c2ccccc2)cc2ccccc2c1Br
Yield: 94.9 %

Procedure:
A 150 mL Schlenk flask was charged with 4.68 g of (3-methoxy-2-naphthyl)(triphenyl)silane (11.23 mmol) and 2.20 g of N-bromosuccinimide (NBS) (12.36 mmol) under argon followed by addition of 10 mL of dimethylformamide (DMF). The resultant mixture was stirred overnight at room temperature, then diluted with 500 mL of water and extracted with 3 times 50 mL of CH2Cl2. The combined organic extracts were washed with 200 mL of water, brine and dried over Na2SO4. The product was purified by passing through short column (silica) using a mixture heptane:EtOAc in a ratio of 15:1 as eluent to afford 5.28 g of product as off-white solid (10.66 mmol) with a yield of 96%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:9]=[CH:10][C:3]=12.[Li]C(CC)C.Cl[C:27]([O:29][CH3:30])=[O:28].C(Cl)Cl>C1COCC1>[Cl:1][C:2]1[C:7]([C:27]([O:29][CH3:30])=[O:28])=[CH:6][N:5]=[C:4]2[N:8]([Si:11]([CH:15]([CH3:17])[CH3:16])([CH:18]([CH3:20])[CH3:19])[CH:12]([CH3:13])[CH3:14])[CH:9]=[CH:10][C:3]=12
Reactant: COC(=O)Cl
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Cl)ccnc21
Agent: [Li]C(C)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)c1cnc2c(ccn2[Si](C(C)C)(C(C)C)C(C)C)c1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
4-Chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (0.50 g, 1.612 mmol, see Example 1) was dissolved in THF (15 mL) and cooled to −78° C. s-BuLi (2.54 mL, 3.56 mmol) was then added dropwise, and the solution was stirred at −78° C. for 30 minutes. Methyl chloroformate (0.38 mL, 4.98 mmol) was then added as a THF (2 mL) solution, and the reaction was stirred for an additional 30 minutes. The reaction was then quenched with saturated NH4Cl and allowed to warm to room temperature. The reaction was then extracted with DCM (3×50 mL), dried, and filtered to give a crude residue. The crude residue was purified by column chromatography with 5:1 hexane:DCM to give methyl 4-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.55 g, 91% yield).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.Br[CH2:10][C:11](=O)[CH2:12][CH3:13]>C(O)CC>[CH2:12]([C:11]1[N:1]=[C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[N:4][N:3]2[CH:10]=1)[CH3:13]
Reactant: Cc1ccc(N)nn1
Reactant: CCC(=O)CBr
Solvent: CCCO
Product: CCc1cn2nc(C)ccc2n1
Temperature: 25 °C

Procedure:
3-Amino-6-methylpyridazine (4.00 g, 27.5 mmol) and 1-bromo-2-butanone (90%, 7.38 g, 44.0 mmol) were heated in 1-propanol (40.0 ml) for 13 hours under reflux. The reaction solution was cooled to room temperature and concentrated under reduced pressure, and then the residues were dissolved in acetone (50.0 ml) and neutralized with 20% aqueous sodium hydroxide solution. The reaction solution was concentrated under reduced pressure, and then the residues were dissolved in chloroform, dried over anhydrous magnesium sulfate and concentrated. The residues were purified by silica gel column chromatography (isopropanol:hexane=1:2), to give the title compound as gray crystals. The yield was 2.33 g (39.4%).
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:21]=[CH:20][C:7]([C:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:9])=[CH:6][CH:5]=1>ClCCl>[Br:1][CH:10]([C:8](=[O:9])[C:7]1[CH:6]=[CH:5][C:4]([Cl:3])=[CH:21][CH:20]=1)[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: BrBr
Reactant: CCOC(=O)CCCCCC(=O)c1ccc(Cl)cc1
Solvent: ClCCl
Product: CCOC(=O)CCCCC(Br)C(=O)c1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
Bromine(21.1 g) was added dropwise to a dichloromethane solution (200 ml) of ethyl 6-(4-chlorobenzoyl)hexanoate (37.3 g) at room temperature. After stirring for 30 minutes, the reaction mixture was washed with sodium hydrogensulfite, saturated sodium bicarbonate and water in turn. The dichloromethane layer was dried(MgSO4). The solvent was evaporated to give ethyl 6-bromo-6-(4-chlorobenzoyl)hexanoate(47.6 g, quant.) as an oily substance.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8]3[CH2:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][C:9]=3[S:22][C:6]=2[N:5]=[CH:4][N:3]=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[Cl:31])[NH2:27]>>[Cl:23][C:24]1[CH:25]=[C:26]([NH:27][C:2]2[C:7]3[C:8]4[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][C:9]=4[S:22][C:6]=3[N:5]=[CH:4][N:3]=2)[CH:28]=[CH:29][C:30]=1[Cl:31]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCCc2c(sc3ncnc(Cl)c23)C1
Product: Clc1ccc(Nc2ncnc3sc4c(c23)CCCNC4)cc1Cl

Procedure:
The title compound was synthesized in analogy to Example 12A from tert-butyl 4-chloro-5,6,7,9-tetrahydro-8H-pyrimido[5′,4′:4,5]thieno[2,3-c]azepine-8-carboxylate from Example 80A (1.74 g, 5.11 mmol) and 3,4-dichloroaniline (870 mg, 5.37 mmol) to yield 820 mg (44%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1.[OH-].[Na+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:11]#[N:12])=[CH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(CC#N)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C(C#N)=Cc2ccccc2)cc1

Procedure:
is prepared by treating a toluene solution of 4-cyanomethyl-benzoic acid methyl ester (CAS-Number: 76469-88-0), 4-chlorobenzaldheyde, tetrabutylammonium iodide with an aqueous solution of sodium hydroxide according to the following literature: I. P. Beletskaya, N. S. Gulyukina, M. Ali Ali, A. A. Solov'yanov, O. A. Reutov J. Org. Chem. USSR (Engl. Transl.) 1987, 23, 657-661.