Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[CH:9][CH:10]=1)=[O:5])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[Br:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][C:23](Cl)=[O:24]>ClC(Cl)C>[CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([C:23](=[O:24])[CH2:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[Br:15])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc[nH]1
Reactant: O=C(Cl)Cc1ccccc1Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1cc(C(=O)Cc2ccccc2Br)c[nH]1
Temperature: 0 °C
Yield: 54.9 %

Procedure:
Ethylpyrrole-2-carboxylate (1.9428 g, 13.96 mmol) in a minimal amount (5 mL) of dichloroethane was added to an ice cooled stirring mixture of aluminum chloride (4.0458 g, 30.34 mmol) and 2-bromophenylacetyl chloride (6.7116 g, 28.74 mmol) in dichloroethane (44 mL, 0.66 M) under N2. The ice bath was removed, and the reaction was stirred at room temperature for 2 h. 19.2977 g (2.6 mMol/g) Polyamine resin HL (200-400 mesh) and dichloroethane (20 mL) were added, and the reaction was stirred for ˜100 min. The reaction was then filtered through a glass-fritted funnel directly into ice water. The resin was rinsed with CH2Cl2, then the organic layers were removed, dried with Na2SO4, filtered, concentrated, and purified by silica gel chromatography (Combiflash column, 80:20 to 60:40 Hexanes:EtOAc) to obtain 2.5751 g (54.9%) 63 as a white solid. Note: A small amount of CH2Cl2 was required to solubilize the crude product before placement on the silica column. 1H (CDCl3, 400 MHz): δ 10.32 (1H, broad s), 7.57-7.53 (2H, m), 7.38-7.37 (1H, m), 7.29-7.21 (2H, m), 7.13-7.07 (1H, m), 4.35 (2H, q, J=7.2 Hz), 4.25 (2H, s), 1.36 (3H, t, J=7.2 Hz) ppm. 13C (CDCl3, 100 MHz): δ 191.78, 161.04, 134.91, 132.62, 131.66, 128.59, 127.40, 126.95, 126.25, 124.98, 124.17, 114.88, 60.92, 46.56, 14.26 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons: 14.26; CH2 carbons: 60.92, 46.56; CH carbons: 132.62, 131.66, 128.59, 127.40, 126.95, 114.88 ppm. HPLC: 10.078 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6](Cl)=[O:7].[CH2:14]([N:16]([CH:22]1[CH2:31][CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([O:32][CH3:33])[CH:28]=2)[CH2:23]1)[CH2:17][CH2:18][CH2:19][CH2:20][OH:21])[CH3:15].C(N(CC)CC)C>C1C=CC=CC=1>[CH2:14]([N:16]([CH:22]1[CH2:31][CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([O:32][CH3:33])[CH:28]=2)[CH2:23]1)[CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:15]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: CCN(CCCCO)C1CCc2cc(OC)ccc2C1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCN(CCCCOC(=O)c1ccc(OC)c(OC)c1)C1CCc2cc(OC)ccc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.9 g of 3,4-dimethoxybenzoic acid and 4 ml of thionyl chloride were heated for 4 hours at reflux and concentrated under reduced pressure to obtain 3,4-dimethoxybenzoyl chloride. The 3,4-dimethoxybenzoyl chloride was dissolved in 10 ml of anhydrous benzene, and the resulting solution was added dropwise to a solution of 4.0 g of N-ethyl-N-(4-hydroxybutyl)-6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine and 2.2 g of triethylamine in 50 ml of anhydrous benzene. After the addition, the resulting solution was stirred for 30 minutes at room temperature (about 25° C.) and heated for 3.5 hours at reflux. The reaction solution was washed with water, a 2 N-NaOH aqueous solution and water in this order, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was purified through silica gel chromatography to obtain N-ethyl-N-[4-(3,4-dimethoxybenzoyloxy)butyl]-6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine as a colorless oily product. To this oily product was added an ethanolic solution of hydrogen chloride having a concentration of about 18% and the resulting solution was concentrated under reduced pressure to obtain a residue. The residue was dissolved in a mixed solvent of acetone and diethyl ether, and the solution was left at a temperature of about 2° to 3° C. to form crystals. By collecting the crystals through filtration and recrystallization from a mixed solvent of acetone and diethyl ether, 3.0 g of N-ethyl-N-[4-(3,4-dimethoxybenzoyloxy)butyl]-6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride was obtained as colorless crystals having a melting point of 139°-140° C. The melting point, the infrared spectra and other physical data of this product corresponded to the date of the compound obtained in Example 2 (ii).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([F:16])[CH:10]=2)=[CH:4][CH:3]=1.[C:23]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])(=[O:26])[CH:24]=[CH2:25].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(CC)CC>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[C:17]1(=[C:8]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([F:16])[CH:10]=2)[C:5]2[CH:6]=[CH:7][C:2](/[CH:25]=[CH:24]/[C:23]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:3][CH:4]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: Oc1ccc(C(=C2CCCCC2)c2ccc(Br)cc2)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)/C=C/c1ccc(C(=C2CCCCC2)c2ccc(O)c(F)c2)cc1
Temperature: 140 °C
Yield: 53 %

Procedure:
A mixture of 83 (317 mg, 0.877 mmol), tert-butyl acrylate (0.369 mL, 2.55 mmol), palladium acetate (15.0 mg, 0.067 mmol), P(o-tolyl)3 (40.0 mg, 0.131 mmol), and Et3N (0.520 mL, 3.73 mmol) were heated under microwave irradiation at 140° C. for 30 min. Water (30 mL) was added and the mixture was extracted with ether (3×20 mL). The combined ethereal extracts were washed with water (30 mL), brine (30 mL), and dried over MgSO4. Concentration followed by flash chromatography (20:1 to 5:1 hexanes:EtOAc) afforded 190 mg (54%) of 84. 1H NMR (400 MHz, CDCl3): δ 1.52 (s, 9H), 1.57-1.60 (m, 6H), 2.23 (m, 4H), 5.07 (d, 1H), 6.31 (d, J=16 Hz, 1H), 6.78 (m, 2H), 6.90 (t, J=8.6 Hz, 1H), 7.09 (d, J=8.1 Hz, 2H), 7.40 (d, J=8.1 Hz, 2H), 7.54 (d, J=16.0 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C@H:8]1[CH2:13][C@H:12]([CH3:14])[CH2:11][N:10](CC2C=CC=CC=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>[Pd].C(O)C>[C:1]([O:5][C:6](=[O:22])[NH:7][C@H:8]1[CH2:13][C@H:12]([CH3:14])[CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H]1C[C@H](NC(=O)OC(C)(C)C)CN(Cc2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Product: C[C@@H]1CNC[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 45 °C

Procedure:
A 40 L pressure vessel is charged with 0.6 Kg 50% wet, solid palladium on carbon (E101, 10 wt. %) under flow of nitrogen. A solution of 3.2 Kg intermediate (7) in 13.7 Kg of absolute ethanol is then charged to the reactor under nitrogen. The reactor is purged with nitrogen and is then pressurized with hydrogen at 45 psi. The reaction is then heated to 45° C. while maintaining a hydrogen pressure of 45 psi. The reaction is monitored by TLC or LC until complete. The reaction is cooled to ambient temperature, vented, and purged with nitrogen. The reactor contents are filtered through a bed of Celite and the solids are washed with 2.8 Kg of absolute ethanol. The filtrate is concentrated by rotary evaporation under vacuum until a waxy solid is obtained to afford intermediate (8): TLC Rf (Silica F254, 70:30 v/v ethyl acetate-hexanes, KMnO4 stain)=0.12; 1H NMR (300 MHz, CDCl3) δ5.31 (br s, 1H), 3.80-3.68 (m, 1H), 2.92 (d, J=11.4 Hz,1H), 2.77 (AB quart, JAB=12.0 Hz, Δv=50.2 Hz, 2H), 2.19 (t, J=10.7 Hz, 1H), 1.82-1.68 (m, 2H), 1.54 (br s, 1H), 1.43 (s, 9H), 1.25-1.15 (m, 1H), 0.83 (d, J=6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 155.3, 78.9, 54.3, 50.8, 45.3, 37.9, 28.4, 27.1, 19.2; MS (ESI+) m/z 215 (M+H), 429 (2M+H).
Reaction SMILES: COC(C1C=C(O[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)C=C2OC(C)CC=12)=O.[CH3:26][O:27][C:28]([C:30]1[CH:40]=[C:39]([OH:41])[C:33]2[CH2:34][C:35]([CH3:38])([CH3:37])[O:36][C:32]=2[C:31]=1[F:42])=[O:29]>>[CH3:26][O:27][C:28]([C:30]1[CH:40]=[C:39]([O:41][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[C:33]2[CH2:34][C:35]([CH3:38])([CH3:37])[O:36][C:32]=2[C:31]=1[F:42])=[O:29]
Reactant: COC(=O)c1cc(O)c2c(c1F)OC(C)(C)C2
Reactant: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2c1CC(C)O2
Product: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2c(c1F)OC(C)(C)C2

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 1f, from 7-fluoro-4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (190a). 1H NMR (400 MHz, CDCl3) δ 7.89-7.94 (m, 2 H) 7.10 (d, J=4.55 Hz, 1 H) 7.04-7.09 (m, 2 H) 3.92 (s, 3 H) 3.07 (s, 3 H) 2.92 (s, 2 H) 1.54 (s, 6 H); LCMS for C22H22FN3O5S m/z 395.00 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:11]([OH:12])=[N:10][C:9]2[C:8]3=[N:13]O[N:15]=[C:7]3[CH:6]=[CH:5][C:4]=2[N:3]=1.C(N(CC)CC)C>CN(C)C=O.[Pd]>[NH2:13][C:8]1[C:7]([NH2:15])=[CH:6][CH:5]=[C:4]2[C:9]=1[N:10]=[C:11]([OH:12])[C:2]([OH:1])=[N:3]2
Reactant: Oc1nc2ccc3nonc3c2nc1O
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ccc2nc(O)c(O)nc2c1N
Yield: 95.6 %

Procedure:
A solution of 5,0 g (24,5 mmol) 7,8-dihydroxy-1,2,5-oxadiazolo(3,4-f)quinoxaIine and 6,8 ml (49 mmol) triethylamine in 500 ml dimethylformamide was hydrogenated at atm. pressure using 5% Pd-C (0,5 g) as a catalyst. The reaction mixture was filtered and evaporated in vacuo. The residue was stirred with water, and the precipitate was filtered off to give 4,5 g (96%) 5,6-diamino-2,3-dihydroxyquinoxaline, m.p. >300° C. NMR (DMSO-d6) 11.0 (2H, broad m), 6.43 (1H,d), 6.23 (1H,d), 4.5 (4H, broad m).
Reaction SMILES: CS([C:4]1[N:5]=[CH:6][C:7]2[CH2:12][N:11]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([C:19]([NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=4)=[O:20])[CH:14]=3)[CH2:10][C:8]=2[N:9]=1)=O.CS(C1[N:37]=CC2CN(C3C=CN=C(C(NC4C=CC=C(C(F)(F)F)C=4)=O)C=3)CC=2N=1)(=O)=O.[OH-].[NH4+]>O1CCOCC1>[F:29][C:28]([F:31])([F:30])[C:24]1[CH:23]=[C:22]([NH:21][C:19]([C:15]2[CH:14]=[C:13]([N:11]3[CH2:12][C:7]4[CH:6]=[N:5][C:4]([NH2:37])=[N:9][C:8]=4[CH2:10]3)[CH:18]=[CH:17][N:16]=2)=[O:20])[CH:27]=[CH:26][CH:25]=1
Reactant: CS(=O)c1ncc2c(n1)CN(c1ccnc(C(=O)Nc3cccc(C(F)(F)F)c3)c1)C2
Reactant: CS(=O)(=O)c1ncc2c(n1)CN(c1ccnc(C(=O)Nc3cccc(C(F)(F)F)c3)c1)C2
Agent: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Nc1ncc2c(n1)CN(c1ccnc(C(=O)Nc3cccc(C(F)(F)F)c3)c1)C2
Temperature: 90 °C

Procedure:
A mixture of 4-(2-(Methylsulfinyl)-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-yl)-N-(3-(trifluoromethyl)phenyl)picolinamide and 4-(2-(methylsulfonyl)-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-yl)-N-(3-(trifluoromethyl)phenyl)picolinamide was suspended in 1,4-dioxane (7 mL). Ammonium hydroxide (30%, 1.5 mL) was added and the reaction was heated at 90° C. for 16 hours. TLC indicated only partial conversion to the desired amine. The solvent was reduced with a nitrogen stream and then additional ammonium hydroxide (1 mL) was added. The reaction was sealed in a tube and heated at 100° C. for 17 h. The solvent was evaporated in vacuo. The resulting solid was triturated with water and then methanol. The solid was chromatographed on silica gel (4 g) eluted with ethyl acetate:methanol (9:1) to give the title compound (10.6 mg, 0.026 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][C:11]([CH3:22])=[N:10][N:9]=2)=[CH:4][CH:3]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>C(O)C>[C:23]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][C:11]([CH3:22])=[N:10][N:9]=2)=[CH:4][CH:3]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: CC1=NN=C(c2ccc(N)cc2)c2cc3c(cc2C1)OCO3
Solvent: CCO
Product: CC(=O)Nc1ccc(C2=NN=C(C)Cc3cc4c(cc32)OCO4)cc1
Yield: 76.1 %

Procedure:
10 g (34 mmol) of 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine were stirred for 3 hours with 100 ml of acetic anhydride. The crystals formed were filtered, washed with 5×10 ml of anhydrous ethanol and dried, yielding 9.2 g of raw product, m.p. 252°-254° C. (decomp.). This product was treated with 45 ml of hot 99.5% ethanol. After cooling the crystals were filtered, washed with 3×10 ml of ethanol and dried to give 8.68 g (76.1%) of the aimed product, m.p.: 256°-258° C. (decomp.).
Reaction SMILES: [F:1][C:2]([F:22])([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[C:3]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([NH2:10])=[O:9])=O.Cl[Si](C)(C)C>ClCCCl>[F:1][C:2]([F:22])([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[C:3]1[N:10]=[C:8]([OH:9])[C:7]2[C:6](=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]=1
Reactant: NC(=O)c1ccccc1NC(=O)C(F)(F)c1ccc(F)cc1
Agent: C[Si](C)(C)Cl
Solvent: ClCCCl
Product: Oc1nc(C(F)(F)c2ccc(F)cc2)nc2ccccc12
Temperature: 85 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(2,2-difluoro-2-(4-fluorophenyl)acetamido)benzamide (0.95 g, 3.08 mmol) in DCE (25 mL), TEA (17.2 mL, 0.123 mol) and chlorotrimethylsilane (5.84 mL, 0.0462 mol) were added at rt. The reaction mixture was stirred at 85° C. overnight. After cooling to rt, the solid was filtered and the filtrate was concentrated to dryness. The residue was purified on a silica gel column, using DCM/MeOH as eluent. 2-(Difluoro(4-fluorophenyl)methyl)quinazolin-4-ol was obtained as an off white solid (0.668 g, 75%). 1H NMR (300 MHz, DMSO-d6) δ 7.39 (t, 2H), 7.62 (m, 1H), 7.78-7.71 (m, 3H), 7.84 (m, 1H), 8.16 (m, 1H), 13.11 (s, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH3:20])[CH:13]=2)[CH:8]=[C:7]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:6]=1[OH:25])([CH3:4])([CH3:3])[CH3:2].[C:26]1(=[O:32])[O:31][C:29](=[O:30])[CH2:28][CH2:27]1.[OH-].[Na+].Cl>O>[C:1]([C:5]1[CH:10]=[C:9]([N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH3:20])[CH:13]=2)[C:26]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:32])[CH:8]=[C:7]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:6]=1[OH:25])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOc1cccc(Nc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c1
Reactant: O=C1CCC(=O)O1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOc1cccc(N(C(=O)CCC(=O)O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c1
Temperature: 140 °C
Yield: 39.3 %

Procedure:
A mixture of 5 g (0.015 mole) of 2,6-di-tertiarybutyl-4-(3'-ethoxyanilino)phenol and 1.5 g (0.015 mole) of succinic anhydride was heated under a nitrogen atmosphere at 140° C. for two hours. The reaction was cooled to room temperature and the resulting glass was diluted with water. The addition of 100 ml of 10% sodium hydroxide failed to give a solution so the mixture was acidified with 10% hydrochloric acid. The resulting solid was collected and then recrystallized first from a mixture of ethanol and water and then from a mixture of diethyl ether and hexane to give 2.6 g of tan solid 3-[N-(3,5-di-tertiary-butyl-4-hydroxyphenyl)-N-(3-ethoxyphenyl)carbamoyl]propionic acid, m.p. 128°-130° C. Analysis: Calculated for C26H35NO5 : % C, 70.7; % H, 8.0; % N, 3.2; Found: % C, 70.5; % H, 7.8; % N, 3.4.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([C:12]([F:15])([F:14])[F:13])[CH:4]=1.[C:16]1(C)C=CC=CC=1.S(=O)(=O)(O)O>CO>[CH3:16][O:8][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([CH2:2][OH:1])=[CH:4][C:5]=1[C:12]([F:13])([F:14])[F:15]
Reactant: O=C(O)c1ccc(CO)cc1C(F)(F)F
Reactant: Cc1ccccc1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1ccc(CO)cc1C(F)(F)F
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of 4-hydroxymethyl-2-trifluoromethyl-benzoic acid (Example I8) (9.07 g) in methanol (250 ml) was added toluene (250 ml) and concentrated sulfuric acid (4.5 ml). The reaction mixture was stirred at 80° C. for 16 hours. The methanol was removed and the residue diluted with aqueous sodium hydrogen carbonate (saturated) (150 ml) and ethyl acetate (150 ml). The phases were separated and the aqueous layer was extracted with more ethyl acetate (2×150 ml). The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated to give 4-hydroxymethyl-2-trifluoromethyl-benzoic acid methyl ester (5.97 g) as a colorless oil. 1H-NMR (CDCl3, 400 MHz): 8.76-7.27 (m, 3H), 4.78 (s, 2H), 3.93 (s, 3H), 2.5 (br s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH2:11][CH:12]([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].F[C:22]1[C:27]([CH3:28])=[CH:26][C:25]([N+:29]([O-:31])=[O:30])=[CH:24][C:23]=1[CH3:32]>CS(C)=O>[CH3:28][C:27]1[CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=[C:23]([CH3:32])[C:22]=1[O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH2:11][CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)Cc1n[nH]c2ccc(O)cc12
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc([N+](=O)[O-])cc(C)c1Oc1ccc2[nH]nc(CC(C)C)c2c1
Yield: 37.9 %

Procedure:
In an analogous manner to the procedure of Example XVIII, 136 mg (0.715 mmol) of 5-hydroxy-3-isobutyl-1H-indazole are reacted with 99 mg (0.715 mmol) of potassium carbonate and 121 mg (0.715 mmol) of 4-fluoro-3,5-dimethylnitrobenzene in 5 ml of DMSO to give 92 mg (38%) of 5-(2,6-dimethyl-4-nitrophenoxy)-3-isobutyl-1H-indazole.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[S:4].Cl.[NH2:6][CH2:7][C:8]([C:10]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:13]([OH:20])=[C:12]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:11]=1)=O>N1C=CC=CC=1>[C:21]([C:12]1[CH:11]=[C:10]([C:8]2[N:2]([CH3:1])[C:3]([SH:4])=[N:6][CH:7]=2)[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:13]=1[OH:20])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)c1cc(C(=O)CN)cc(C(C)(C)C)c1O
Reactant: CN=C=S
Agent: Cl
Solvent: c1ccncc1
Product: Cn1c(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cnc1S
Yield: 18.8 %

Procedure:
After stirring a mixture of 100 ml of pyridine, 6 g of methyl isothiocyanate, and 3 g of 4-(2-aminoacetyl)-2,6-di-tert-butylphenol hydrochloride at room temperature for 2 hours, the resulted mixture was maintained at an inside temperature of 80°-90° C. for 1.5 hours. The reaction mixture was concentrated udner reduced pressure and then the residue was extracted with 100 ml of ethyl acetate. The extract was washed with diluted hydrochloric acid, dried, and concentrated under reduced pressure. The residue was recrystallized from ethanol to provide 0.6 g of 5-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-mercapto-1-methylimidazole.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Cl:19][C:20]1[C:25]([NH:26][C:27]2[N:32]=[C:31]([NH:33][CH:34]3[CH2:36][CH2:35]3)[C:30]3=[N:37][CH:38]=[C:39]([C:40]#[N:41])[N:29]3[N:28]=2)=[CH:24][C:23]([C:42]#[N:43])=[CH:22][C:21]=1[N:44]1[CH2:49][CH2:48][C@@H:47]([NH:50][S:51]([CH3:54])(=[O:53])=[O:52])[C@H:46]([O:55][Si](C(C)C)(C(C)C)C(C)C)[CH2:45]1>C1COCC1>[Cl:19][C:20]1[C:25]([NH:26][C:27]2[N:32]=[C:31]([NH:33][CH:34]3[CH2:35][CH2:36]3)[C:30]3=[N:37][CH:38]=[C:39]([C:40]#[N:41])[N:29]3[N:28]=2)=[CH:24][C:23]([C:42]#[N:43])=[CH:22][C:21]=1[N:44]1[CH2:49][CH2:48][C@@H:47]([NH:50][S:51]([CH3:54])(=[O:53])=[O:52])[C@H:46]([OH:55])[CH2:45]1
Reactant: CC(C)[Si](O[C@@H]1CN(c2cc(C#N)cc(Nc3nc(NC4CC4)c4ncc(C#N)n4n3)c2Cl)CC[C@H]1NS(C)(=O)=O)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CS(=O)(=O)N[C@@H]1CCN(c2cc(C#N)cc(Nc3nc(NC4CC4)c4ncc(C#N)n4n3)c2Cl)C[C@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
TBAF (1M in THF, 0.048 mL, 0.048 mmol) was added to a solution of N-((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-((triisopropylsilyl)oxy)piperidin-4-yl)methanesulfonamide (28 mg, 0.040 mmol) in THF (2 mL) and the reaction mixture was stirred at room temperature overnight. Solvent was evaporated and the crude product was purified by flash chromatography on silica gel using an automated ISCO system (12 g column, eluting with 0-6% methanol/dichloromethane). N-((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)methanesulfonamide (21 mg) was obtained as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[CH2:10][CH3:11])=[O:4].[OH-].[Na+].O1CCCC1>CO>[CH2:10]([C:9]1[CH:8]=[CH:7][S:6][C:5]=1[C:3]([OH:4])=[O:2])[CH3:11]
Reactant: CCc1ccsc1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1ccsc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
3-Acetyl-2-thiophenecarboxylic acid methyl ester (3.87 g) synthesized in this manner was dissolved in methanol (50 ml), and sodium borohydride (0.95 g) was added under ice-cooling. The mixture was stirred at room temperature for 1 hour, and 1N hydrochloric acid (50 ml) was added. The mixture was extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 3-(1-hydroxyethyl)-2-thiophenecarboxylic acid methyl ester (3.77 g). This product was dissolved in ethyl acetate (100 ml), and methanesulfonyl chloride (2.86 g), triethylamine (3.5 g) and dimethylaminopyridine (0.2 g) were added. The mixture was stirred at room temperature for 2 hours, and 1N hydrochloric acid (50 ml) was added. The mixture was extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in acetone (100 ml), and sodium iodide (10 g) was added. The mixture was stirred at room temperature for 2 hours, and insoluble substances were removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography. The desired fractions were concentrated under reduced pressure to give 3-(1-iodoethyl)-2-thiophenecarboxylic acid methyl ester (3.0 g). 3-(1-iodoethyl)-2-thiophenecarboxylic acid methyl ester was dissolved in dimethylsulfoxide (10 ml), and sodium borohydride (0.4 g) was added at room temperature. The mixture was stirred for 1 hour, and 1N hydrochloric acid was added. The mixture was extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-ethyl-2-thiophenecarboxylic acid methyl ester (1.0 g). A mixture of 3-ethyl-2-thiophenecarboxylic acid methyl ester (1.0 g), 1N aqueous sodium hydroxide (15 ml), tetrahydrofuran (30 ml) and methanol (10 ml) was stirred at room temperature for 1 hour. The mixture was washed with diethyl ether, and the aqueous layer was acidified with 1N hydrochloric acid and extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 3-ethyl-2-thiophenecarboxylic acid (0.9 g) as crystals.