Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15]C(NC3C=CC(CC)=CC=3)=O)=[CH:11][CH:10]=2)[CH:3]=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][C:29]=1[C:37]([F:40])([F:39])[F:38]>CN(C=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:35]([NH:34][C:31]3[CH:32]=[CH:33][C:28]([Cl:27])=[C:29]([C:37]([F:38])([F:39])[F:40])[CH:30]=3)=[O:36])=[CH:11][CH:10]=2)[CH:3]=1
Reactant: CCc1ccc(NC(=O)Nc2ccc(Cc3cc(N)ncn3)cc2)cc1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: CN(C)C=O
Product: Nc1cc(Cc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)ncn1
Reaction time: 2 h

Procedure:
The title compound is prepared as described in Example 102 but using 6-(4-aminobenzyl)-pyrimidin-4-ylamine (see Example 157), 4-chloro-3-(trifluoromethyl)-phenyl isocyanate, and DMF as the solvent. The reaction mixture is stirred for 2 h. The title compound is obtained as a white solid: ES-MS: 422.8 [M+H]+; single peak at tR=7.58 min (System 2).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH2:24]([C@@H:26]1[CH2:30][O:29][C:28](=[O:31])[NH:27]1)[CH3:25]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[N:6]=[N:7][C:2]([N:27]4[C@H:26]([CH2:24][CH3:25])[CH2:30][O:29][C:28]4=[O:31])=[CH:3][CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: CC[C@@H]1COC(=O)N1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)nn3)CC2)c(C)c1
Product: CC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C)cc3C)CC2)nn1
Yield: 31.9 %

Procedure:
Using (6-chloropyridazin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (152 mg) described in Preparation Example 230 and (R)-4-ethyloxazolidin-2-one (79 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (60 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[C:3]([S:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:4][C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])[C:6]=2[CH:17]=1.I([O-])(=O)(=O)=[O:24].[Na+].I([O-])(=O)=O.[Na+]>CO.O>[Br:1][C:2]1[C:3]([S:18]([CH2:19][C:20]([OH:22])=[O:21])=[O:24])=[CH:4][C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])[C:6]=2[CH:17]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: O=C(O)CSc1cc2onc(-c3ccccc3F)c2cc1Br
Agent: [Na+]
Agent: [O-][I+2]([O-])[O-]
Solvent: CO
Solvent: O
Product: O=C(O)CS(=O)c1cc2onc(-c3ccccc3F)c2cc1Br
Yield: 86 %

Procedure:
2.8 g (7.33 mmol) of [[5-bromo-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]thio]acetic acid was combined with 30 ml (2 eq.) of 0.5M sodium periodate solution in 300 ml of 4:1 methanol/water. The mixture was refluxed for 18 hours during which the insoluble sodium iodate precipitated. The reaction mixture was then poured into excess 3N HCl and extracted several times with ethyl acetate. The ethyl acetate extracts were combined, washed with water and a saturated salt solution, dried over magnesium sulfate, filtered and evaporated to yield a white solid. The solid was triturated with hexanes and dried under vacuum to yield 2.51 g (86%) of [[5-bromo-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]sulfinyl]acetic acid, m.p. 173°-174° C.
Reaction SMILES: [C:1]1([N:7]2[C:11]([NH:12][C:13](=[O:21])OC3C=CC=CC=3)=[CH:10][C:9]([C:22]([F:25])([F:24])[F:23])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][C:37]=1[O:38][CH2:39][CH2:40][O:41][CH3:42])[N:34]=[CH:33][N:32]=[C:31]2[O:43][C:44]1[CH:45]=[C:46]([CH:48]=[CH:49][CH:50]=1)[NH2:47].C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][C:37]=1[O:38][CH2:39][CH2:40][O:41][CH3:42])[N:34]=[CH:33][N:32]=[C:31]2[O:43][C:44]1[CH:45]=[C:46]([NH:47][C:13]([NH:12][C:11]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=[C:9]([C:22]([F:23])([F:24])[F:25])[CH:10]=2)=[O:21])[CH:48]=[CH:49][CH:50]=1
Reactant: COCCOc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: O=C(Nc1cc(C(F)(F)F)nn1-c1ccccc1)Oc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COCCOc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(F)(F)F)nn4-c4ccccc4)c3)c2cc1OC
Yield: 48.4 %

Procedure:
Using the procedure described in Example 159B, using phenyl 1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-ylcarbamate from Example 161C (0.139 g, 0.4 mmol), 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example 117B (0.137 g, 0.4 mmol), and N,N-diisopropylethylamine (0.3 mL) in THF (6 mL) at 50° C. for 6 hours, to afford 1-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy]phenyl}-3-[1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]urea as solid (0.115 g, 48%). 1H NMR (300 MHz, DMSO-d6) δ 9.32 (s, 1H), 8.81 (s, 1H), 8.54 (s, 1H), 7.49-7.62 (m, 7H), 7.38 (m, 2H), 7.20 (d, 1H), 6.95 (d, 1H), 6.87 (s, 1H), 4.38 (m, 2H), 3.98 (s, 3H), 3.78 (m, 2H), 3.35 (s, 3H); LC-MS (ESI) m/z 595 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:5])[CH2:3][OH:4].C(=O)(O)[O-].[Na+].[N+:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20](Cl)(=[O:22])=[O:21])([O-:13])=[O:12]>O.O1CCCC1>[OH:4][CH2:3][C@@H:2]([NH:1][S:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N+:11]([O-:13])=[O:12])(=[O:21])=[O:22])[CH3:5]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: C[C@H](N)CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](CO)NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 39 h
Yield: 87.3 %

Procedure:
To a solution of (S)-(+)-2-amino-1-propanol (2.6 kg, 35 mol) in purified water (10.5 L) was added sodium bicarbonate (4.4 kg, 52 mol). To the resulting mixture was added a solution of 2-nitrobenzenesulfonyl chloride (7.3 kg, 33 mol) in tetrahydrofuran (10.2 L) at an internal temperature of −8° C. to −6° C. Subsequently, the resulting reaction mixture was stirred at room temperature for 39 hours. After confirming the disappearance of 2-nitrobenzenesulfonyl chloride by TLC, the mixture was filtered. The filtrate was then extracted with ethyl acetate, and the resulting organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was then concentrated under reduced pressure. The residue thus obtained was crystallized from petroleum ether/ethyl acetate to give the target product as a white solid (7.5 kg, yield 82.4%).
Reaction SMILES: N.[OH:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][C@H:5]([C:9]#[N:10])[CH2:4]1>CO.[Ni]>[NH2:10][CH2:9][C@@H:5]1[CH2:6][CH2:7][CH2:8][C@H:3]([OH:2])[CH2:4]1
Reactant: N#C[C@H]1CCC[C@@H](O)C1
Agent: [Ni]
Agent: N
Solvent: CO
Product: NC[C@@H]1CCC[C@H](O)C1
Reaction time: 15 h
Yield: 77.4 %

Procedure:
To a 2 N solution of NH3 in MeOH (15 mL) in a high pressure Parr bottle was added cis-3-hydroxy-cyclohexanecarbonitrile (0.2 g, 1.6 mmol) and W-7 Raney Nickel (0.35 g, 6.0 mmol). The mixture was placed under 45 psi H2 and shaken for 15 h. The pressure was released and the reaction filtered through a pad of diatomaceous earth. The filter pad was washed with MeOH and the filtrate was concentrated under reduced pressure to provide 0.16 g (64%) of cis-3-aminomethyl-cyclohexanol as a white solid
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=[C:9]([C:11](=[S:13])[NH2:12])[CH:10]=1)=[O:4].[F:23][C:24]1[CH:25]=[C:26]([CH:31]=[CH:32][C:33]=1[F:34])[C:27](=O)[CH2:28]Br>>[F:23][C:24]1[CH:25]=[C:26]([C:27]2[N:12]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=3)[S:13][CH:28]=2)[CH:31]=[CH:32][C:33]=1[F:34]
Reactant: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Reactant: O=C(CBr)c1ccc(F)c(F)c1
Product: O=C(O)c1cc(-c2nc(-c3ccc(F)c(F)c3)cs2)ccc1-c1ccccc1[N+](=O)[O-]
Yield: 41 %

Procedure:
4-[4-(3,4-Difluoro-phenyl)-thiazol-2-yl]-2′-nitro-biphenyl-2-carboxylic acid (114 mg, 41%) was prepared from 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 4) and 3,4-difluorophenacyl bromide (available from Matrix Scientific) using the procedure described for the preparation of Example 18. 1H NMR (300 MHz, DMSO-d6) δ 8.56 (d, J=1.7 Hz, 1H), 8.36 (s, 1H), 8.10-8.24 (m, 3H), 7.95-7.99 (m, 1H), 7.75-7.80 (m, 1H), 7.53-7.67 (m, 2H), 7.40-7.43 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([OH:13])[CH2:7]2)([O-])=O>[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([OH:13])[CH2:7]2
Reactant: O=[N+]([O-])c1ccc2c(c1)CC(O)C2
Agent: [Pd]
Product: Nc1ccc2c(c1)CC(O)C2

Procedure:
5-nitro-indan-2-ol (450 mg, 2.5 mmol) was hydrogenated using Pd/C (10%, dry, 100 mg) and H2 balloon at 1 atm at room temperature. Pd/C was filtered off through a pad of celite and the mother liquid was concentrated to give the crude product, 5-Amino-indan-2-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][C:18]([OH:27])([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:34].[Na+]>CO.C(#N)C>[NH2:34][CH:12]([C:10]1[C:9]([N:15]2[CH2:20][CH2:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)([OH:27])[CH2:17][CH2:16]2)=[C:8]2[C:3]([CH:4]=[CH:5][CH:6]=[N:7]2)=[C:2]([Cl:1])[CH:11]=1)[CH3:13]
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCC(O)(c2ccccc2)CC1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: CC(N)c1cc(Cl)c2cccnc2c1N1CCC(O)(c2ccccc2)CC1
Temperature: 65 °C

Procedure:
A mixture of 1-[5-chloro-8-(4-hydroxy-4-phenylpiperidin-1-yl) quinolin-7-yl]ethanone (37 mg, 0.097 mmol) and ammonium acetate (74.9 mg, 0.971 mmol) in methanol (0.55 mL) and acetonitrile (0.55 mL) was heated at 65° C. in a sealed tube for 30 minutes. After cooling to room temperature, sodium cyanoborohydride (12.2 mg, 0.194 mmol). The reaction was heated at 65° C. for another 4 hours, then cooled to room temperature and quenched with sat. sodium bicarbonate, extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness (35 mg, 94%). LCMS calculated for C22H25ClN3O (M+H)+: m/z=382.2; Found: 382.1.
Reaction SMILES: [CH2:1]([C:8](=[O:12])[CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO>[CH2:1]([CH:8]([OH:12])[CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCO)Cc1ccccc1
Solvent: CO
Product: OCCC(O)Cc1ccccc1
Temperature: 35 °C
Reaction time: 20 h
Yield: 94.8 %

Procedure:
In a 500 ml stainless steel-made autoclave were charged 65.6 g (400 mmole) of 3-benzyl-3-oxopropanol and 550 mg (0.4 mmole) of [RuI(p-cymene)((R)-BINAP)]I3 synthesized in Example 1 in a nitrogen atmosphere, and 300 ml of methanol was added thereto, followed by stirring the mixture at 35° C. for 20 hours under a hydrogen pressure of 50 atm. The reaction mixture was concentrated by using rotary evaporator and then subjected to silica gel column chromatography (eluent: hexane/ethylacetate=8/2 by volume) to eliminate the complex to give 63 g of 3-benzyl-3-hydroxypropanol (96% yield). The thus obtained product was derived to the MTPA diester and subjected to high-performance liquid chromatography (column: Cosmosil-5SL, eluent: hexane/ether=8/2 by volume). As a result, it was found to have an optical purity of 97% ee.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([Br:9])=[C:7]([P:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[C:5]([O:23][CH3:24])[N:4]=1.[OH:25]O>CC(C)=O>[CH3:1][O:2][C:3]1[C:8]([Br:9])=[C:7]([P:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:25])[CH:6]=[C:5]([O:23][CH3:24])[N:4]=1
Reactant: OO
Reactant: COc1cc(P(c2ccccc2)c2ccccc2)c(Br)c(OC)n1
Solvent: CC(C)=O
Product: COc1cc(P(=O)(c2ccccc2)c2ccccc2)c(Br)c(OC)n1
Yield: 96 %

Procedure:
A round bottom flask with a magnetic stirring bar was charged with 2,6-dimethoxy-3-bromo-4-(diphenylphosphino)pyridine (4.96 g) and 50 mL acetone. To this solution was slowly added approximately 35% hydrogen peroxide (33.9 mL). The reaction was monitored by thin-layer chromatography. The product was extracted with 3×20 mL dichloromethane. The combined extract was dried with anhydrous magnesium sulfate and was concentrated in vaccuo to give a crude product which was purified by column chromatography (silica gel, CHCl3 : ethyl acetate=1:1 with 5% NEt3) to give 5.15 g pure product (96% of theoretical yield).
Reaction SMILES: [CH2:1]1[O:21][C:20]2[C:3](=[CH:4][CH2:5][C:6](OC)([CH:19]=2)[CH:7]=[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[O:2]1.[BH4-].[Na+].[CH2:26]([OH:28])C>>[CH2:1]1[O:21][C:20]2[C:3](=[CH:4][C:5]([O:28][CH3:26])=[C:6]([CH:19]=2)[CH2:7][CH:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:2]1
Reactant: CCOC(=O)C(=CC1(OC)C=C2OCOC2=CC1)C(=O)OCC
Reactant: CCO
Agent: [BH4-]
Agent: [Na+]
Product: CCOC(=O)C(Cc1cc2c(cc1OC)OCO2)C(=O)OCC
Temperature: 25 °C
Reaction time: 5 h
Yield: 86 %

Procedure:
To a solution of the diethyl 2-(4,5-methylenedioxy-1-methoxybenylidene)-malonate (23.40 g, 0.073 mol) in ethanol (100 mL) was added sodium borohydride (2.80 g, 0.073 mol) and the mixture was stirred at room temperature for 5 h. The reaction was quenched with water and extracted with ethyl acetate (3×200 mL). The combined organic extracts were dried (Na2SO4) and evaporated to afford the title compound as an oil (20.30 g, 86%): 1H NMR (250 MHz, CDCl3) δ 7.45 (d, J=10 Hz, 1H), 7.20 (d, J=15 Hz, 1H), 5.85 (s, 2H), 4.22 (m, 4H), 3.40 (s, 2H), 3.30 (s, 3H), 1.25 (m, 6H).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:19][C:20]1[CH:25]=[C:24]([S:26][Si](C(C)C)(C(C)C)C(C)C)[CH:23]=[CH:22][C:21]=1[NH:37][C:38](=[O:46])[C@:39]([OH:45])([CH3:44])[C:40]([F:43])([F:42])[F:41].Cl[CH2:48][C:49]([N:51]([CH3:53])[CH3:52])=[O:50].C(OCC)(=O)C>C1COCC1>[Cl:19][C:20]1[CH:25]=[C:24]([S:26][CH2:48][C:49](=[O:50])[N:51]([CH3:53])[CH3:52])[CH:23]=[CH:22][C:21]=1[NH:37][C:38](=[O:46])[C@:39]([OH:45])([CH3:44])[C:40]([F:41])([F:42])[F:43]
Reactant: CN(C)C(=O)CCl
Reactant: CC(C)[Si](Sc1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)C(=O)CSc1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Tetrabutylammonium fluoride (1.1 ml of a 1M solution in THF) was added to (R)-N-(2-chloro-4-(triisopropylsilylsulphanyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Method 28) (0.50 g) in anhydrous THF (5 ml) at −70° C. After 15 minutes 2-chlorodimethylacetamide (0.17 ml) was added and the mixture was allowed to warm up then was stirred at ambient temperature for 45 minutes. Ethyl acetate (80 ml) was added and the mixture was washed with brine (100 ml) then dried and volatile material was removed by evaporation. The residue was purified on a silica gel Mega Bond Elut column eluting with 10-50% ethyl acetate/hexane to give the title compound (0.30 g) as a solid. NMR (CDCl3) 1.72 (s, 3H), 2.97 (s, 3H), 3.08 (s, 3H), 3.71 (s, 2H), 4.76 (s, 1H), 7.32-7.36 (m, 1H), 7.53 (d, 1H), 8.32 (d, 1H), 9.05 (s, 1H); MS (ESP−): 383.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[NH:15][C:16](=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])C.[OH-].[Na+]>O1CCCC1.O>[CH3:24][O:23][C:20]1[CH:19]=[CH:18][C:17]([C:16]([NH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:4]([OH:5])=[O:3])=[O:25])=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1[nH]c2ccccc2c1NC(=O)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2c(C(=O)O)[nH]c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 68.1 %

Procedure:
To a solution of 3-(4-methoxybenzoyl)amino-2-indolecarboxylic acid ethyl ester (720 mg, 2.13 mmol) in tetrahydrofuran (7 mL) was added 5 N aqueous sodium hydroxide (2 mL). The resulting mixture was stirred for 10 h at room temperature. An additional portion of 5 N aqueous sodium hydroxide (5 mL) was added and the mixture heated at 60° C. for 5 h. The mixture was cooled to room temperature, stirred for 10 h, diluted with water, and extracted with diethyl ether. The aqueous layer was acidified with concentrated hydrochloric acid and extracted with three fresh portions of ethyl acetate. The combined ethyl acetate fractions were dried (sodium sulfate), filtered, and concentrated in vacuo to provide 450 mg (68%) of the title compound as a yellow solid.
Reaction SMILES: [Br:1]Br.[CH2:3]([O:5][C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=1[NH2:8])[CH3:4].[OH-].[K+]>C(O)(=O)C>[Br:1][C:11]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([O:5][CH2:3][CH3:4])[CH:12]=1
Reactant: BrBr
Reactant: CCOc1ccccc1N
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCOc1cc(Br)ccc1N
Reaction time: 1 h
Yield: 59.6 %

Procedure:
Over approximately 1 hour, 3 ml (58.4 mmol) of bromine dissolved in 20 ml of acetic acid is added dropwise to 7.8 ml (60 mmol, 1.03 eq) of 2-ethoxyaniline diluted in 20 ml of acetic acid. When all the bromine has been added, the precipitate formed is filtered on a Buchner funnel and rinsed with acetic acid. The hydrobromide is taken up in H2O, 5 g (90 mmol, 1.5 eq) of KOH pellets is added and extracted with CH2Cl2. The organic phase is dried on MgSO4 and the solvent is evaporated. The residue is purified by column chromatography (eluent CH2Cl2/pentane 9:1) to produce 7.52 g of the expected product as a brown oil (yield: 58%).
Reaction SMILES: [NH2:1][C:2]1[NH:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH:20](OCC)=[O:21]>>[CH:20]([NH:1][C:2]1[NH:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=2)=[N:4][C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:21]
Reactant: Nc1[nH]c(-c2ccc(F)cc2)nc1-c1ccccc1
Reactant: CCOC=O
Product: O=CNc1[nH]c(-c2ccc(F)cc2)nc1-c1ccccc1

Procedure:
A mixture of 5-amino-2-(4-fluorophenyl)-4-phenylimidazole (1.00 g) and ethyl formate (10 ml) was refluxed for 15 hours. After cooling, the reaction mixture was concentrated under reduced pressure and crystallized from diethyl ether to obtain 5-formylamino-2-(4-fluorophenyl)-4-phenylimidazole (1.17 g) as colorless crystal.
Reaction SMILES: C([NH:4][C:5]1[N:9]([C:10]2[C:15]([F:16])=[C:14]([F:17])[C:13]([C:18]([F:21])([F:20])[F:19])=[C:12]([F:22])[C:11]=2[F:23])[N:8]=[CH:7][C:6]=1[N+:24]([O-:26])=[O:25])(=O)C.Cl.C(O)C.[OH-].[Na+]>O>[NH2:4][C:5]1[N:9]([C:10]2[C:15]([F:16])=[C:14]([F:17])[C:13]([C:18]([F:20])([F:21])[F:19])=[C:12]([F:22])[C:11]=2[F:23])[N:8]=[CH:7][C:6]=1[N+:24]([O-:26])=[O:25]
Reactant: CC(=O)Nc1c([N+](=O)[O-])cnn1-c1c(F)c(F)c(C(F)(F)F)c(F)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1c([N+](=O)[O-])cnn1-c1c(F)c(F)c(C(F)(F)F)c(F)c1F
Yield: 91.2 %

Procedure:
19.3 g (0.05 mol) of 5-acetamido-4-nitro-1-(2,3,5,6-tetrafluoro-4-trifluoromethyl-phenyl)-pyrazole are heated under reflux in a mixture of 40 ml of 37 percent strength hydrochloric acid and 70 ml of ethanol for 7 hours. The reaction mixture is freed from the ethanol in vacuo. 35 ml of water are added to the residue and the mixture is neutralized with dilute sodium hydroxide solution. The precipitate is filtered off with suction, washed with water and dried in vacuo. 15.7 g (91.4% of theory) of 5-amino-4-nitro-1-(2,3,5,6-tetrafluoro-4-trifluoromethyl-phenyl)-pyrazole of melting point 123° C.-126° C. are obtained.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[C:8]([C:9]([OH:11])=[O:10])[C:7]([OH:13])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].Cl.CN(C)[CH2:17][CH2:18]CN=C=N.O.ON1C2C=CC=CC=2N=N1.C(O)C>CN(C)C=O.O>[C:1]([C:4]1[CH:12]=[C:8]([C:9]([O:11][CH2:17][CH3:18])=[O:10])[C:7]([OH:13])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CN(C)CCCN=C=N
Reactant: CC(=O)c1ccc(O)c(C(=O)O)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(C(C)=O)ccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
5-Acetylsalicylic acid (200 mg), 1-ethyl-3-(3-dimethylaminopropylcarbodiimide hydrochloride (382 mg), 1-hydroxybenzotriazole hydrate (306 mg), and ethanol (2 ml) were dissolved in N,N-dimethylformamide to prepare a solution which was then stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give ethyl 5-acetylsalicylate (211 mg, yield 92%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[C:9]([F:10])=[CH:8][C:7](F)=[CH:6][C:5]=1[F:12].Cl.[CH3:15][NH:16][CH3:17].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][O:2][C:3](=[O:13])[C:4]1[C:9]([F:10])=[CH:8][C:7]([N:16]([CH3:17])[CH3:15])=[CH:6][C:5]=1[F:12]
Reactant: CNC
Reactant: COC(=O)c1c(F)cc(F)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1c(F)cc(N(C)C)cc1F
Temperature: 55 °C
Reaction time: 5 h
Yield: 74 %

Procedure:
To a stirred solution of 4.28 g (22.5 mmol) 2,4,6-Trifluoro-benzoic acid methyl ester (Apollo) and 60.0 ml dimethylsulphoxid were added 2.23 g (27.0 mmol) dimethylamine hydrochloride and 6.54 g (47.3 mmol) potassium carbonate. The reaction mixture was stirred for 5 h at 55° C. in an autoclave and was reduced with high vacuum rotation evaporator at 65° C. The residue was diluted with dichloromethane, washed twice with water. The combined water phases were extracted with dichloromethane. The combined dichloromethane phases were washed with diluted sodium hydrogen carbonate solution, dried with sodium sulphate and concentrated. The oily crude was purified by column chromatography and the desired product 6a was obtained in 74% yield (3.59 g, 16.7 mmol).
Reaction SMILES: [Si:1]([C:8]1[N:9]([S:17]([N:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])[C:10]([CH:13]=[CH:14][C:15]#[N:16])=[CH:11][N:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(Cl)(Cl)Cl>C(O)C.C1COCC1.[Pt]=O>[Si:1]([C:8]1[N:9]([S:17]([N:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])[C:10]([CH2:13][CH2:14][CH2:15][NH2:16])=[CH:11][N:12]=1)([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: CN(C)S(=O)(=O)n1c(C=CC#N)cnc1[Si](C)(C)C(C)(C)C
Agent: O=[Pt]
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1c(CCCN)cnc1[Si](C)(C)C(C)(C)C

Procedure:
Compound 29 (2.1 mmol) is dissolved in absolute ethanol (75 mL) and THF (25 mL). Chloroform (1.5 mL) and platinum oxide (70 mg) are added and the mixture subjected to hydrogenation at 5 atmospheres in a Parr hydrogenation apparatus. After 4 hours the mixture is filtered through celite and the celite bed washed with absolute ethanol (2×20 mL). The filtrate and washings are evaporated in vacuo to give a product which is purified by column chromatography to provide the title compound 30.
Reaction SMILES: Cl.C([O:4][CH:5](OCC)[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[C:10]([F:17])[C:9]=1[F:18])C>O1CCOCC1.O>[F:18][C:9]1[C:10]([F:17])=[C:11]([CH2:14][CH2:15][OH:16])[CH:12]=[CH:13][C:8]=1[O:7][CH2:6][CH:5]=[O:4]
Reactant: CCOC(COc1ccc(CCO)c(F)c1F)OCC
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: O=CCOc1ccc(CCO)c(F)c1F
Reaction time: 1 h

Procedure:
Concentrated hydrochloric acid (5 mL) was added to a solution of 2-(4-(2,2-diethoxyethoxy)-2,3-difluorophenyl)ethanol (example 77, step c) (0.49 g) in 1,4-dioxane (10 mL) and the resulting mixture was stirred for 1 h. The mixture was carefully diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organics were washed with water (50 mL) and brine (50 mL), dried over sodium sulphate, filtered and evaporated to give the subtitled compound, which was used directly. Yield 0.31 g.