Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]C1C=C(OC)C(OC)=CC=1C1N=C(C2C=C(C(OC)=S)SC=2C)SC=1.[Cl:27][C:28]1[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[CH:33][C:29]=1[C:30](O)=[O:31].P(Cl)(Cl)(Cl)(Cl)Cl>>[Cl:27][C:28]1[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[CH:33][C:29]=1[C:30]([Cl:1])=[O:31]
Reactant: COc1cc(Cl)c(C(=O)O)cc1OC
Reactant: COC(=S)c1cc(-c2nc(-c3cc(OC)c(OC)cc3Cl)cs2)c(C)s1
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: COc1cc(Cl)c(C(=O)Cl)cc1OC
Temperature: 120 °C
Yield: 96 %

Procedure:
Methyl 4-[4-(2-chloro-4,5-dimethoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate: 2-Chloro-4,5-dimethoxybenzoic acid (0.5 g, 2.3 mmol) and PCl5 (0.54 g, 2.6 mmol) were placed in a round bottomed flask fitted with a reflux condenser. The mixture was heated in an oil bath at 120° C. for 70 min. The mixture was allowed to cool and the formed phosphorus oxychloride was removed under vacuum to give 0.52 g (96%) of 2-chloro-4,5-dimethoxybenzoyl chloride as a solid. 2-Chloro-4,5-dimethoxybenzoyl chloride (0.52 g, 2.2 mmol) was treated in a manner similar to that for Example 32 step (a) to give 2-bromo-1-(2-chloro-4,5-dimethoxyphenyl)ethan-1-one. The dry solid (0.65 g, 2.2 mmol) was dissolved in acetone (25 ml). To this solution 5-(methoxycarbonyl)-2-(methylthio)-thiophene-3-thiocarboxamide (0.55 g, 2.2 mmol) was added and heated at reflux for 5 h. At this point the solid that precipitated was filtered off and washed with acetone and dried under vacuum to give 0.53 g (54%) of methyl 4-[4-(2-chloro-4,5-dimethoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate. 1H-NMR (DMSO-d6; 300 MHz) δ 2.73 (s, 3H), 3.83 (s, 3H), 3.84 (s, 3H), 3.85 (s, 3H), 7.13 (s, 1H), 7.69 (s, 1H), 8.13 (s, 1H), 8.17 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:6]1[CH:15]=[CH:14][C:13]2[CH2:12][CH:11]([C:16]([O:18]C)=[O:17])[CH2:10][CH2:9][C:8]=2[N:7]=1)([CH3:5])[CH3:4].[OH-].[Na+]>CO>[CH3:1][O:2][C:3]([C:6]1[CH:15]=[CH:14][C:13]2[CH2:12][CH:11]([C:16]([OH:18])=[O:17])[CH2:10][CH2:9][C:8]=2[N:7]=1)([CH3:5])[CH3:4]
Reactant: COC(=O)C1CCc2nc(C(C)(C)OC)ccc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(C)(C)c1ccc2c(n1)CCC(C(=O)O)C2
Yield: 157.8 %

Procedure:
A 4-mL vial with stir bar was charged with methyl 2-(2-methoxypropan-2-yl)-5,6,7,8-tetrahydroquinoline-6-carboxylate (16 mg, 0.061 mmol), methanol (450 μL) and 4M sodium hydroxide (150 μL, 0.61 mmol). The mixture was stirred at room temperature for 1 hour then quenched into 1M NaH2PO4 (2 mL) and 1M citric acid was added to obtain pH 4-5. The mixture was extracted with EtOAc (3 mL×3), dried (Na2SO4), filtered and evaporated to obtain a colorless oil (24 mg), which was used directly in the next step. m/z=250.3 (M+H)+. 1H NMR (400 MHz; CD3OD) δ 8.32 (d, J=8.3 Hz, 1H), 7.83 (d, J=8.3 Hz, 1H), 3.3.0 (s, 3H), 3.29-3.15 (m, 4H), 3.00-2.90 (m, 1H), 2.41-2.31 (m, 1H), 2.17-2.04 (m, 1H), 2.04 (s, 2H), 1.66 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:13]=[C:12]([C:14]4[CH:18]=[CH:17][NH:16][N:15]=4)[N:11]([CH2:19][C:20]4[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=4)[C:23](O)=[O:24])[C:8]=3[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.B>C1COCC1>[CH3:1][C:2]1[N:6]2[C:7]3[CH:13]=[C:12]([C:14]4[CH:18]=[CH:17][NH:16][N:15]=4)[N:11]([CH2:19][C:20]4[CH:21]=[C:22]([CH2:23][OH:24])[CH:26]=[CH:27][CH:28]=4)[C:8]=3[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: Cc1nnc2ccc3c(cc(-c4cc[nH]n4)n3Cc3cccc(C(=O)O)c3)n12
Agent: B
Solvent: C1CCOC1
Product: Cc1nnc2ccc3c(cc(-c4cc[nH]n4)n3Cc3cccc(CO)c3)n12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 3-{[1-methyl-7-(1H-pyrazol-3-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-6-yl]methyl}benzoic acid (0.40 g, from Step 5) in THF (40. mL) at 0° C. was treated with 1.0 M borane in THF (1.7 mL, 1.7 mmol, Aldrich) dropwise. The mixture was stirred for 1.5 hours, with warming to room temperature. Additional 1.0 M borane in THF (45 mL, 45 mmol) was added portionwise to the reaction mixture at room temperature over the course of 48 hours. The reaction mixture was cooled to 0° C. and cautiously quenched by the dropwise addition of water, followed by the addition of 1N HCl (55 mL). The mixture was then neutralized by the addition of solid NaHCO3, and the product was extracted with 10% iPrOH in CHCl3. Precipitate was dissolved in MeOH and combined with the organic extracts. The resulting solution was dried over sodium sulfate, filtered and concentrated. The product was purified by flash chromatography, eluting with a gradient from 0-10% MeOH in DCM. Yield: (0.12 g, 31%).
Reaction SMILES: [CH3:1][C:2]([CH3:19])([O:4][C:5]([CH2:7][CH:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:6])[CH3:3].[H-].[Na+].[CH3:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([CH3:31])[CH:30]=1)[CH2:26]Br.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.O>[CH2:17]([O:16][C:14]([C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])([CH2:22][C:23]1[CH:24]=[C:25]([CH3:26])[CH:28]=[C:29]([CH3:31])[CH:30]=1)[CH2:7][C:5]([O:4][C:2]([CH3:1])([CH3:3])[CH3:19])=[O:6])=[O:15])[CH3:18]
Reactant: Cc1cc(C)cc(CBr)c1
Reactant: CCOC(=O)C(CC(=O)OC(C)(C)C)C(=O)OCC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(CC(=O)OC(C)(C)C)(Cc1cc(C)cc(C)c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 13.8 g (50.2 mMol) of diethyl [(1,1-dimethyl-ethoxycarbonyl)methyl]-malonoate in 400 ml of anhydrous tetrahydrofuran, 2.3 g (52.7 mMol) of sodium hydride was added whilst being externally cooled with iced water. After stirring for 30 minutes, and maintaining a reaction temperature of 0 to +5° C., the solution of 10.0 g (50.2 mMol) of 3,5-dimethylbenzylbromide in 80 ml tetrahydrofuran was added dropwise and the mixture allowed to warm to room temperature within 14 hours. The reaction mixture was freed from the solvent in vacuo, 200 ml of 10% citric acid was added to the residue and the resulting mixture was thoroughly extracted with ethyl acetate. After the usual working up, the combined extracts yielded 19.7 g (100% of theory) of a colourless oil of Rf=0.67 (eluant:dichloromethane), which was used in the following steps without further purification.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[C:21]([C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)=[N:22][C:23]([CH3:27])=[C:24]([CH3:26])[CH:25]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:34][CH3:35])C1C=CC=CC=1.CS(O)(=O)=O>FC(F)(F)C(O)=O>[CH3:26][C:24]1[CH:25]=[C:20]([O:19][C:13]2[C:12]3[C:17](=[CH:18][C:9]([OH:8])=[C:10]([O:34][CH3:35])[CH:11]=3)[N:16]=[CH:15][CH:14]=2)[C:21]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)=[N:22][C:23]=1[CH3:27]
Reactant: COc1cc2c(Oc3cc(C)c(C)nc3-c3cccnc3)ccnc2cc1OCc1ccccc1
Agent: CS(=O)(=O)O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3cccnc3)ccnc2cc1O
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 120 %

Procedure:
3-(7-Benzyloxy-6-methoxy-quinolin-4-yloxy)-5,6-dimethyl-[2,3′]bipyridine (compound 344) (804 mg) was dissolved in trifluoroacetic acid (8 ml) to prepare a solution. Methanesulfonic acid (0.8 ml) was added to the solution, and the mixture was stirred at 70° C. for 1.5 hr. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. An aqueous sodium hydrogencarbonate solution was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform-methanol to give the title compound (777 mg, yield 100%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][OH:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[H-].[Na+].[CH:14]1([CH2:17]Br)[CH2:16][CH2:15]1>CN(C=O)C.O>[CH:14]1([CH2:17][O:11][CH2:10][C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH:2]=[CH:3][C:4]=3[CH:9]=2)[CH2:16][CH2:15]1
Reactant: BrCC1CC1
Reactant: OCc1ccc2occc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1cc2cc(COCC3CC3)ccc2o1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of benzofuran-5-ylmethanol (1.0 g, 6.8 mmol), and sodium hydride (0.25 g, 10.0 mmol) in DMF (20 mL) was stirred at 0° C. for 30 minutes. Cyclopropylmethyl bromide (0.97 g, 7.0 mmol) was the added and resultant reaction mixture was slowly warmed to room temperature and left stirring over night. Reaction mixture was diluted to 100 mL with water. The solution was extracted with Et2O (20 mL×3); the combined extracts were washed with 1N NaOH solution, water and brine, dried, and concentrated under reduced pressure to yield the desired product after purification on silica (4/1 hexane/ethyl acetate). 1H NMR (400 MHz, CDCl3) δ 7.61 (d, 2H), 7.44 (d, 1H), 7.27 (d, 1H), 6.76 (s, 1H), 4.62 (s, 2H) 3.37 (d, 2H), 1.41 (m, 1H), 0.58 (m, 2H), 0.21 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8](F)[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5].Cl.[NH2:13][C@H:14]([CH:18]1[CH2:20][CH2:19]1)[C:15]([NH2:17])=[O:16].CCN(C(C)C)C(C)C.O>CS(C)=O.CCOC(C)=O>[Br:1][C:2]1[C:3]([C:4]#[N:5])=[CH:6][C:7]([F:11])=[C:8]([NH:13][C@H:14]([CH:18]2[CH2:20][CH2:19]2)[C:15]([NH2:17])=[O:16])[CH:9]=1
Reactant: NC(=O)[C@H](N)C1CC1
Reactant: N#Cc1cc(F)c(F)cc1Br
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(F)c(N[C@@H](C(N)=O)C2CC2)cc1Br
Yield: 80.9 %

Procedure:
A solution of 2-bromo-4,5-difluorobenzonitrile (170 mg, 0.780 mmol), (R)-2-amino-2-cyclopropylacetamide hydrochloride (120 mg, 0.797 mmol) and DIEA (0.500 mL, 2.87 mmol) in DMSO (3 mL) was stirred at 120 C for 18 h. Water and EtOAc were added. The organic phase was separated, dried over Na2SO4, concentrated in vacuo to give (R)-2-(5-bromo-4-cyano-2-fluorophenylamino)-2-cyclopropylacetamide (197 mg)
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:7]=1[Br:15])(=O)C.O.[OH-].[Li+].N1C=CN=C1.[C:24]([Si:28]([CH3:31])([CH3:30])Cl)([CH3:27])([CH3:26])[CH3:25]>C1COCC1.O.C(O)C>[Br:15][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([N+:12]([O-:14])=[O:13])[C:6]=1[CH2:5][O:4][Si:28]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:31])[CH3:30]
Reactant: CC(=O)OCc1c(Br)cccc1[N+](=O)[O-]
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Li+]
Agent: [OH-]
Agent: c1c[nH]cn1
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1c(Br)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
A 150-mL single-neck round-bottomed flask equipped with a magnetic stirrer and nitrogen inlet was charged with a solution of 114b (11.6 g, 42.3 mmol) in a mixture of THF (20 mL), ethanol (20 mL) and water (20 mL). Lithium hydroxide monohydrate (7.00 g, 167.0 mmol) was added and the reaction was stirred at room temperature for 1 h. After this time, the reaction mixture was partitioned between water (200 mL) and ethyl acetate (400 mL). The layers were separated, and the aqueous phase was extracted with ethyl acetate (2×200 mL). The organic extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was dissolved in anhydrous methylene chloride (50 mL). Imidazole (14.4 g, 68.0 mmol) was added, followed by dropwise addition of tert-butyldimethylchlorosilane (16.0 g, 106 mmol). The mixture was stirred at room temperature for 14 h. After this time, water (200 mL) was added and the layers separated. The aqueous layer was extracted with methylene chloride (2×200 mL) and the combined organic layers were washed with brine, and dried over sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash chromatography to afford an 89% yield (13.1 g) of 114c as a white semi-solid: 1H NMR (500 MHz, CDCl3) δ 7.67 (d, 1H, J=8.5 Hz), 7.54 (d, 1H, J=8.5 Hz), 7.18 (t, 1H, J=8.0 Hz), 4.96 (s, 2H), 0.80 (s, 9H), 0.007 (s, 6H).
Reaction SMILES: [CH3:1][CH:2]([CH3:25])[CH2:3][CH2:4][N:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:13][CH:12]=2)=[CH:7][C:6]1=[O:24].[Cl:26]N1C(=O)CCC1=O.O>CN(C=O)C>[Cl:26][C:7]1[C:6](=[O:24])[N:5]([CH2:4][CH2:3][CH:2]([CH3:25])[CH3:1])[CH:10]=[CH:9][C:8]=1[C:11]1[CH:16]=[CH:15][C:14]([NH:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:13][CH:12]=1
Reactant: CC(C)CCn1ccc(-c2ccc(NC3CCOCC3)cc2)cc1=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CCn1ccc(-c2ccc(NC3CCOCC3)cc2)c(Cl)c1=O
Yield: 27.9 %

Procedure:
A solution of intermediate D8 (0.65 g, 1.91 mmol) and N-chlorosuccinimide (0.25 g, 1.91 mmol) in DMF (10 ml) was stirred at 45° C. for 16 hours. After cooling to room temperature water was added and the solution was extracted with EtOAc, The organic layer was separated and washed with brine, dried (Na2SO4) and the solvent evaporated in vacuo. The crude product was purified by column chromatography (silica gel; DCM/EtOAc 8:2 as eluent). The desired fractions were collected and evaporated in vacuo to yield E1 (0.20 g, 28%) as a pale pink solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2=O.O.NN>>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH2:7]2
Reactant: Cc1cccc2c1NC(=O)C2=O
Agent: NN
Solvent: O
Product: Cc1cccc2c1NC(=O)C2
Reaction time: 0.17 h

Procedure:
5.00 g (31.0 mmol) 7-methyl-1H-indol-2,3-dione in 18.1 mL (372 mmol) hydrazine hydrate were heated to 110° C. for 3 h. Then the reaction mixture was cooled, the precipitate formed was suction filtered and washed with water. The precipitate was suspended in water, acidified with conc. hydrochloric acid and stirred for 10 min. Then the reaction mixture was stirred for a further 30 min in the ice bath, the precipitate was suction filtered, washed with water and dried.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.FC(F)(F)S(O)(=O)=O.[C:17](Cl)(=[O:20])[CH2:18][CH3:19]>>[OH:8][C:4]1[CH:5]=[CH:6][C:7]([C:17](=[O:20])[CH2:18][CH3:19])=[C:2]([CH3:1])[CH:3]=1
Reactant: CCC(=O)Cl
Reactant: Cc1cccc(O)c1
Agent: O=S(=O)(O)C(F)(F)F
Product: CCC(=O)c1ccc(O)cc1C
Temperature: -10 °C
Reaction time: 3 h

Procedure:
3-Methylphenol (9.0 g, 83 mmol) was combined with trifluoromethanesulfonic acid (90 mL), cooled to −10° C., and treated in a drop-wise manner with propanoyl chloride (7.7 g, 83 mmol). The reaction mixture was stirred at −10° C. for 3 hours and then at room temperature for 18 hours, whereupon it was poured into ice water (600 mL). The resulting solid was collected via filtration and purified by silica gel chromatography (Gradient: 5% to 70% ethyl acetate in petroleum ether) to afford the product as an off-white solid. Yield: 6.7 g, 41 mmol, 49%. 1H NMR (400 MHz, CD3OD) δ 7.75 (d, J=8.5 Hz, 1H), 6.64-6.69 (m, 2H), 2.92 (q, J=7.3 Hz, 2H), 2.45 (s, 3H), 1.13 (t, J=7.3 Hz, 3H).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:2]2[N:3]=[CH:4][C:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:15][CH2:14]1
Reactant: Clc1cc2ccccc2cn1
Reactant: CN1CCNCC1
Product: CN1CCN(c2cc3ccccc3cn2)CC1

Procedure:
6.5 g of 3-chloroisoquinoline in 30 ml of N-methylpiperazine are boiled under reflux for 48 hours. The reaction mixture is cooled and partitioned between water and toluene, the toluene phase is washed thoroughly with water and, after drying, the solvent is removed in vacuo. The residue is recrystallized from diisopropyl ether, giving 3.8 g of 3-(4-methylpiperazin-1-yl)-isoquinoline, melting point 93°-94° C.; the dihydrochloride decomposes at 255°-257° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:24](=[O:40])[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[O:38][N:37]=[C:36]([CH3:39])[CH:35]=2)[CH:29]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:39][C:36]1[CH:35]=[C:34]([C:30]2[CH:29]=[C:28]([C:26]3[CH2:25][C:24](=[O:40])[NH:23][C:9]4[CH:10]=[C:11]([C:19]([F:20])([F:21])[F:22])[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])=[CH:13][C:8]=4[N:7]=3)[CH:33]=[CH:32][CH:31]=2)[O:38][N:37]=1
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(C)no3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cc(C)no3)c1)=N2

Procedure:
The title compound was prepared from [2-{3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionylamino}-5-(methyl-propyl-amino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M103) (0.26 g, 0.45 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (127 mg, 61%).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:6][C:5]([CH2:13][OH:14])=[C:4]([Cl:15])[CH:3]=1.CC(OO)(C)C.[I-].[K+].S([O-])([O-])(=O)=S.[Na+].[Na+].[CH3:31][OH:32]>>[CH3:31][O:32][C:13](=[O:14])[C:5]1[CH:6]=[C:7]([O:8][C:9]([F:10])([F:11])[F:12])[C:2]([Br:1])=[CH:3][C:4]=1[Cl:15]
Reactant: OCc1cc(OC(F)(F)F)c(Br)cc1Cl
Reactant: CO
Agent: CC(C)(C)OO
Agent: O=S([O-])([O-])=S
Agent: [I-]
Product: COC(=O)c1cc(OC(F)(F)F)c(Br)cc1Cl
Yield: 39 %

Procedure:
To a solution of (4-bromo-2-chloro-5-trifluoromethoxy-phenyl)-methanol (6.6 g, 21.61 mmol) in methanol (70 mL) was added 2-methyl-prop-2-yl-hydroperoxide (14.4 mL, 86.42 mmol), and potassium iodide (0.72 g, 4.32 mmol), The reaction mixture was stirred under reflux for 48 h and sat. sodium thiosulfate (20 mL) was added. The reaction mixture was concentrated and extracted with EtOAc (3×100 mL). The organic layers were combined, washed with brine, dried over sodium sulfate, concentrated, and purified by HPLC to provide the title intermediate (2.86 g, 39% yield). (m/z): [M+H]+ calcd for C9H5BrClF3O3 332.91; 334.91. found 332.9; 334.9. 1H NMR (400 MHz, CDCl3): δ(ppm) 7.79 (s, 1H), 7.77 (s, 1H), 3.94 (s, 3H).
Reaction SMILES: I[CH:2]1[C@H:19]([CH3:20])[C@@:18]2([CH3:21])[C:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C:12]2=[O:22])=[CH:4][C:3]1=[O:23].C(=O)([O-])[O-].[Li+].[Li+].O>CN1CCCC1=O>[CH3:20][C:19]1[C@@:18]2([CH3:21])[C:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C:12]2=[O:22])=[CH:4][C:3](=[O:23])[CH:2]=1
Reactant: C[C@H]1C(I)C(=O)C=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@]21C
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC1=CC(=O)C=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]12C

Procedure:
14.9 g of 2-iodo-1α-methyl-androst-4-ene-3,17-dione crude product of example 7 and 4.73 g (64 mmol) of anhydrous lithium carbonate are stirred in 95 ml of N-methyl-pyrrolidone for 1 hour at 130° C. under nitrogen atmosphere. After cooling of the reaction solution it is added to 0.6 1 of water and the product is extracted 3 times with 450 ml of ethyl acetate. The combined ethyl acetate phases are dried on sodium sulfate and then concentrated by evaporation. The residue is chromatographed on silica gel with ethyl acetate/hexane as mobile solvent. After concentration by evaporation of the fractions and recrystallization of the substance from ethyl acetate, 6.9 g of 1-methyl-androsta-1,4-diene-3,17-dione (69% of theory over 2 stages relative to 1α-methyl-androst-4-ene-3,17-dione in example 7) of melting point 168°-169° C. is obtained.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7](=O)[C:8]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[CH:14]=2)=[CH:9][N:10](C)C)=[CH:4][CH:3]=1.O.[NH2:22]N>C(O)C>[Cl:19][C:15]1[CH:14]=[C:13]([C:8]2[C:7]([C:5]3[S:6][C:2]([Cl:1])=[CH:3][CH:4]=3)=[N:22][NH:10][CH:9]=2)[CH:18]=[CH:17][N:16]=1
Reactant: NN
Reactant: CN(C)C=C(C(=O)c1ccc(Cl)s1)c1ccnc(Cl)c1
Solvent: CCO
Solvent: O
Product: Clc1cc(-c2c[nH]nc2-c2ccc(Cl)s2)ccn1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 101.3 %

Procedure:
A mixture of 1-(5-chloro-2-thienyl)-3-(dimethylamino)-2-(2-chloropyridin-4-yl)prop-2-en-1-one (10 mmol), hydrazine hydrate (20 mmol) in 90 mL ethanol was stirred at 80° C. for 1.5 h. The solvent was evaporated under reduced pressure to afford 3 g 2-chloro-4-[3-(5-chloro-2-thienyl)-1H-pyrazol-4-yl]pyridine (95% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[C:11]1(=O)[O:16][C:14](=[O:15])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12>C(O)(=O)C>[N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[N:6]1[C:14](=[O:15])[C:13]2[C:12](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]1=[O:16])([O-:3])=[O:2]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Nc1ccccc1[N+](=O)[O-]
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 121.2 %

Procedure:
To a mixture of 2-nitroaniline (1 g, 7.23 mmol) in acetic acid (5 mL) was added phthalic anhydride (1.29 g, 8.7 mmol) followed by stirring at ambient temperature for 16 h. The mixture was then heated at reflux for 20 h. Upon cooling, a yellow precipitate formed and was collected by filtration. The filtrate was washed with acetic acid and was dried under a under a stream of air to give 2.35 g (100%) of 2-(2-nitrophenyl)isoindole-1,3-dione: 1H NMR (300 MHz, DMSO-d6) δ 8.21 (m, 1H), 8.02–7.95 (m, 5H), 7.77 (m, 2H).
Reaction SMILES: C(O[C:4](=[O:19])[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1)C.O>C(Cl)Cl>[CH3:18][O:17][C:13]1[CH:12]=[C:11]2[C:16]([C:4](=[O:19])[CH2:5][CH:6]3[CH2:10][CH2:9][CH2:8][CH:7]32)=[CH:15][CH:14]=1
Reactant: CCOC(=O)CC1CCCC1c1cccc(OC)c1
Solvent: ClCCl
Solvent: O
Product: COc1ccc2c(c1)C1CCCC1CC2=O
Yield: 80.9 %

Procedure:
Heat a solution of [2-(3-methoxyphenyl)-cyclopentyl]-acetic acid ethyl ester (4.2 g, 16.0 mmoles) in polyphosphoric acid (27 g) at 100° C. for 3.5 hours. Cool the reaction to r.t. and add ice, water and methylene chloride cautiously. Extract the aqueous layer was 2× with additional methylene chloride, combine the organic layers and dry over anhydrous sodium sulfate. Concentrate in vacuo at 40° C. Chromatograph the crude product on silica with 11-17% ethyl acetate/hexanes to yield the titled compound (2.8 g, 81%) as a neat crystalline solid. 1H NMR (CDCl3): 7.95 (d, J=8.8 Hz, 1H), 6.8 (dd, J=2.8 Hz, 6.4 Hz, 1H), 6.73(m, 1H), 3.86 (s, 3H), 3.19 (m, 1H), 2.72 (m, 1H), 2.53 (m, 2H), 2.18 (m, 1H), 2.0-1.75 (m, 5H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH:14]([NH2:19])[C:13]=2[CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(NC(C)C)(C)C.[Br:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>>[C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH:14]([NH:19][S:35]([C:32]3[CH:33]=[CH:34][C:29]([Br:28])=[CH:30][CH:31]=3)(=[O:37])=[O:36])[C:13]=2[CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)COc1cccc2c1CCCC2N
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)COc1cccc2c1CCCC2NS(=O)(=O)c1ccc(Br)cc1
Yield: 59.3 %

Procedure:
Starting with (5-amino-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-acetic acid tert-butyl ester (example 1-1, method A, 3rd step) (0.500 g, 1.8 mmol), diisopropylamine (0.553 g, 2.1 mmol) and 4-bromobenzenesulfonyl chloride (0.465 g, 1.8 mmol), using the method analogous to the one described for example 1-1, method A, 4th step, [5-(4-bromo-benzenesulfonylamino)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid tert-butyl ester (0.53 g, 61%) was obtained. MS cald. for C22H26BrNO5S 495, obsd. 496 [(M+H)+].