Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@@H:9]([C@@H:35]1[NH:40][C@@H:39]([CH3:41])[CH:38]([OH:42])[O:37][CH2:36]1)[C@@H:10]([N:20]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:43](O)[C:44]([CH3:47])([CH3:46])[CH3:45].CS(O)(=O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:28]([N:20]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C@@H:10]([CH2:11][C:12]1[CH:13]=[C:14]([F:19])[CH:15]=[C:16]([F:18])[CH:17]=1)[C@@H:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@H:35]1[CH2:36][O:37][C@@H:38]([O:42][CH2:43][C:44]([CH3:47])([CH3:46])[CH3:45])[C@H:39]([CH3:41])[NH:40]1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC(C)(C)CO
Reactant: C[C@@H]1N[C@@H]([C@H](OCc2ccccc2)[C@H](Cc2cc(F)cc(F)c2)N(Cc2ccccc2)Cc2ccccc2)COC1O
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H]1N[C@@H]([C@H](OCc2ccccc2)[C@H](Cc2cc(F)cc(F)c2)N(Cc2ccccc2)Cc2ccccc2)CO[C@H]1OCC(C)(C)C
Temperature: 25 °C
Yield: 55.9 %

Procedure:
Mix (3S,5R)-5-[(1S,2S)-1-benzyloxy-2-dibenzylamino-3-(3,5-difluorophenyl)-propyl]-3-methylmorpholin-2-ol (1.06 g, 1.85 mmol) with neopentanol (1.63 g, 18.5 mmol,) in dichloromethane (0.2 mL). Add 4 Å molecular sieves (850 mg), then methanesulphonic acid (2.4 mL, 37 mmol) and heat at 50° C. for 4 hours. Cool to room temperature, dilute with dichloromethane and add slowly to a solution of saturated aqueous sodium bicarbonate. Extract the aqueous layer with dichloromethane, dry (sodium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 100:0 to 90:10 hexanes:ethyl acetate) to give the desired compound as a white solid (665 mg, 56% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH:9]1([C:12]2[CH:16]=[C:15]([NH2:17])[NH:14][N:13]=2)[CH2:11][CH2:10]1.CCN(C(C)C)C(C)C>CS(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([NH:17][C:15]2[NH:14][N:13]=[C:12]([CH:9]3[CH2:11][CH2:10]3)[CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cc(C2CC2)n[nH]1
Reactant: Clc1ccnc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Clc1nccc(Nc2cc(C3CC3)n[nH]2)n1
Temperature: 60 °C
Reaction time: 16 h
Yield: 80.8 %

Procedure:
A dried 5-L, three-necked round bottom flask fitted with an overhead stirrer and reflux condenser was charged with a solution of 2,4-dichloropyrimidine (250 g, 1.68 mol) in anhydrous DMSO (2300 mL). 3-Cyclopropyl-1H-pyrazol-5-amine (227.4 g, 1.85 mol) and DIPEA (438 mL, 2.52 mol) were added sequentially at RT. The resulting solution was stirred at 60° C. for 16 h, cooled to RT, and poured into ice water. The precipitated yellow solid was collected by vacuum filtration, washed with water, 1.5 N HCl (3×1 L), and finally with water (4×500 mL). The precipitate was dried by air suction overnight to give 320 g (81%) of 20 as yellow solid: 1H NMR (400 MHz, DMSO-d6): δ 12.19 (s, 1H), 10.29 (s, 1H), 8.15 (s, 1H), 7.0 (br s, 1H), 6.0 (br s, 1H), 1.85-1.92 (m, 1H), 0.91-0.95 (m, 2H), 0.7 (m, 2H); MS (ESI+) m/z: 236 [M+1]+.
Reaction SMILES: [CH3:1][Si:2]([CH3:26])([CH3:25])[O:3][CH2:4][C@@:5]12[C@@H:22]3[C@H:13]([C@H:14]4[C@@:18]([CH2:20][CH2:21]3)([CH3:19])[C:17](=[O:23])[CH2:16][CH2:15]4)[CH2:12][CH:11]=[C:10]1[CH2:9][C:8](=[O:24])[CH2:7][CH2:6]2.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>O1CCCC1>[CH3:25][Si:2]([CH3:1])([CH3:26])[O:3][CH2:4][C@@:5]12[C@@H:22]3[C@H:13]([C@H:14]4[C@@:18]([CH2:20][CH2:21]3)([CH3:19])[C@@H:17]([OH:23])[CH2:16][CH2:15]4)[CH2:12][CH:11]=[C:10]1[CH2:9][C@@H:8]([OH:24])[CH2:7][CH2:6]2
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4CC(=O)CC[C@@]43CO[Si](C)(C)C)[C@@H]1CCC2=O
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: C[C@]12CC[C@H]3[C@@H](CC=C4C[C@@H](O)CC[C@@]43CO[Si](C)(C)C)[C@@H]1CC[C@@H]2O

Procedure:
A tetrahydrofuran solution of 19-trimethylsiloxy-5-androstene-3,17-dione is added to lithium aluminum hydride in tetrahydrofuran and the resultant solution stirred overnight at room temperature. An aqueous solution of sodium potassium tartrate is added with stirring until a readily filterable precipitate forms. The filtrate is concentrated under reduced pressure and diluted with ether. The resulting solution is washed with water, dried over magnesium sulfate, and the ether removed under vacuum. The residual 19-trimethylsiloxy-5-androstene-3β,17β-diol so obtained is recrystallized from an acetone-hexane solution.
Reaction SMILES: [C:1]([C:5]1[N:9]=[C:8]([CH:10]([OH:35])[CH:11]([NH:14][C:15]([CH:17]([NH:26][C:27]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:28])[CH2:18][S:19]([CH2:22][CH:23]([CH3:25])[CH3:24])(=[O:21])=[O:20])=[O:16])[CH2:12][CH3:13])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[C:1]([C:5]1[N:9]=[C:8]([C:10]([CH:11]([NH:14][C:15]([CH:17]([NH:26][C:27]([N:29]2[CH2:30][CH2:31][O:32][CH2:33][CH2:34]2)=[O:28])[CH2:18][S:19]([CH2:22][CH:23]([CH3:24])[CH3:25])(=[O:21])=[O:20])=[O:16])[CH2:12][CH3:13])=[O:35])[O:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCC(NC(=O)C(CS(=O)(=O)CC(C)C)NC(=O)N1CCOCC1)C(O)c1nc(C(C)(C)C)no1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: CCC(NC(=O)C(CS(=O)(=O)CC(C)C)NC(=O)N1CCOCC1)C(=O)c1nc(C(C)(C)C)no1
Reaction time: 2 h

Procedure:
Morpholine-4-carboxylic acid [1-{1-[(3-tert-butyl-1,2,4-oxadiazol-5-yl)-hydroxy-methyl]-propylcarbamoyl}-2-(2-methyl-propane-1-sulfonyl)-ethyl]-amide (0.271 g) was dissolved in dichloromethane (10 mL) and the Dess-Martin periodinane (0.424 g, 1 mmol) was added. The reaction mixture was stirred for two hours and then poured into a mixture of saturated sodium bicarbonate and saturated sodium thiosulfate solution (1/1, 50 mL). The phases were separated and the aqueous phase extracted with dichloromethane. The combined organic phases were washed with sodium bicarbonate solution and brine. The solution was dried with magnesium sulfate and then concentrated under vacuum. The residue was subjected to flash chromatography (gradient from 5% ethyl acetate in heptane to 75% ethyl acetate in heptane) to give morpholine-4-carboxylic acid [1-[1-(3-tert-butyl-1,2,4-oxadiazole-5-carbonyl)-propylcarbamoyl]-2-(2-methyl-propane-1-sulfonyl)-ethyl]-amide, a mixture of diastereomers. 1H NMR (CDCl3, 300 MHz): [7.87 (d, J=6.5 Hz) 7.79 (d, J=7 Hz), 1H], [6.11 (d, J=6.5 Hz) 6.06 (d, J=6.5 Hz), 1H], 5.38-5.30 (m, 1H), 4.92-4.13 (m, 1H), 3.78-3.68 (m, 5H), 3.49-3.33 (m, 5H), 3.24-3.04 (m, 2H), 2.47-2.37 (m, 1H), 2.20-2.07 (m, 1H), 1.95-1.85 (m, 1H), 1.45 (s, 9H), 1.17 (d, J=6.5 Hz, 6H), [1.04 (t, J=7.5 Hz) 1.03 (t, J=7.5 Hz), 3H]. [LC/MS m/z=516(M+H+)]
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:47][CH2:48][CH2:49][CH2:50][CH2:51][NH2:52]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([CH2:40][C:41]([NH:52][CH2:51][CH2:50][CH2:49][CH2:48][CH3:47])=[O:43])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCCCCN
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCCCCNC(=O)CC1CCN(C(=O)N2C(c3cnc(C(C)(C)C)cc3OCC)=N[C@@](C)(c3ccc(Cl)cc3)[C@@]2(C)c2ccc(Cl)cc2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with n-amylamine (Fluka) to give the title product. LC-MS (ES+) 734 [(M+H)+].
Reaction SMILES: [C:1]([C@@H:4]1[CH2:8][S:7][C:6](=[O:9])[N:5]1[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)(=[O:3])[CH3:2].C[Mg]Cl.CON(C)C(C1CSC(=O)N1CC1C=CC(OC)=CC=1)=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O>[C:1]([CH:4]1[CH2:8][S:7][C:6](=[O:9])[N:5]1[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(CN2C(=O)SC[C@H]2C(C)=O)cc1
Agent: COc1ccc(CN2C(=O)SCC2C(=O)N(C)OC)cc1
Agent: C[Mg]Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)SCC2C(C)=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
Preparation of (R)-4-acetyl-3-(4-methoxy-benzyl)-thiazolidin-2-one (A compound of Formula I): A dry three-necked round bottom flask fitted with an internal temperature probe and a mechanical stirrer was charged with 0.805 L of a 3 M solution of methylmagnesium chloride in THF. The solution was purged with nitrogen and cooled to 0° C. In a separate flask, 3-(4-methoxy-benzyl)-2-oxo-thiazolidine-4-carboxylic acid methoxy-methyl-amide (250.0 g, 0.805 mol) was dissolved in 1.00 L of dry THF. The resulting solution was added to the solution of methyl magnesium chloride at a rate that maintained an internal reaction temperature less than 5° C. The reaction was monitored by HPLC and was considered complete upon the disappearance of starting material. The reaction mixture was slowly added to 1.00 L of a 10% citric acid solution at a rate that maintained a temperature of less than 25° C. The mixture was diluted with 0.90 L of water. The THF was removed by distillation at atmospheric pressure. The product was extracted with 2.5 L of ethyl acetate. The organic phase was separated, concentrated to a final volume of ˜800 mL and cooled to room temperature. A suspension was formed by the addition of 16 L of n-heptane. The suspension was stirred for 30 minutes. The resulting solid was isolated by filtration and was dried in a vacuum oven at 40° C. for 12 hours. Approximately 170 g of 4-acetyl-3-(4-methoxy-benzyl)-thiazolidin-2-one was obtained (80% yield). 1H NMR (300 MHz, DMSO) δ 7.14 (d, 8.9 Hz, 2H), 6.88 (d, 8.9 Hz, 2H), 4.48 (dd, J=9.4, 2.6 Hz, 1H), 4.27 (AB, JAB=15.2 Hz, ΔνAB=267.3 Hz, 2H), 3.72 (s, 3H), 3.62 (dd, J=11.9, 10.0 Hz, 1H), 3.37 (dd, J=11.8, 2.6 Hz, 1H), 2.19 (s, 3H). 13C NMR (75 MHz, DMSO) δ 26.9, 27.9, 47.2, 55.8, 66.0, 114.7, 129.1, 130.0, 159.4, 171.7, 205.1; [α]26.5D-56.0° (c=1.39, EtOH).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([F:8])[C:5]([OH:9])=[CH:4][CH:3]=1.[O:10]1[CH2:15][CH:14]=[C:13](B2OC(C)(C)C(C)(C)O2)[CH2:12][CH2:11]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(Cl)Cl>O1CCOCC1.O.CO.C(C1C(C(C)(C)C)=C([Pd]Cl)C=CC=1NC)(C)(C)C.[Pd]>[F:8][C:6]1[C:5]([OH:9])=[CH:4][CH:3]=[C:2]([CH:13]2[CH2:14][CH2:15][O:10][CH2:11][CH2:12]2)[N:7]=1
Reactant: Oc1ccc(Br)nc1F
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Agent: CNc1ccc([Pd]Cl)c(C(C)(C)C)c1C(C)(C)C
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: Oc1ccc(C2CCOCC2)nc1F
Temperature: 110 °C
Yield: 50.9 %

Procedure:
6-Bromo-2-fluoropyridin-3-ol (3.67 g, 19.12 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.02 g, 19.12 mmol), potassium phosphate (6.25 g, 29.4 mmol), and 1,1-bis[(di-t-butyl-p-methylaminophenyl]palladium(ii) chloride (0.23 g, 0.33 mmol) were suspended in a mixture of dioxane (5 mL) and water (0.5 mL) and heated in the microwave to 110° C. for 20 min. The phases were allowed to settle and the organic evaporated to dryness under reduced pressure. Purification using silica chromatography (hexane to EtOAc gradient) gave the desired coupled material. It was dissolved in MeOH (60 mL) and DCM (30 mL) and treated with palladium (10% wt on carbon, 0.26 g, 0.24 mmol) and hydrogenated at 60 psi overnight. The mixture was filtered through a pad of celite and the filtrate evaporated under reduced pressure to give the desired 2-fluoro-6-(tetrahydro-2H-pyran-4-yl)pyridin-3-ol (1.92 g, 9.74 mmol, 50.9% yield). It was used without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1Cl.[OH:13][C:14]1[CH:29]=[CH:28][C:17]([O:18][CH:19]([CH3:27])[C:20]([N:22]2[CH2:26][CH2:25][CH2:24][O:23]2)=[O:21])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>C1C=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:6][C:7]=1[O:13][C:14]1[CH:15]=[CH:16][C:17]([O:18][CH:19]([CH3:27])[C:20]([N:22]2[CH2:26][CH2:25][CH2:24][O:23]2)=[O:21])=[CH:28][CH:29]=1
Reactant: CC(Oc1ccc(O)cc1)C(=O)N1CCCO1
Reactant: FC(F)(F)c1cccc(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: c1ccccc1
Product: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1)C(=O)N1CCCO1
Temperature: 130 °C
Reaction time: 3 h
Yield: 96.1 %

Procedure:
A mixture of 1,2-dichloro-3-(trifluoromethyl)benzene (21.5 g), N-[(±)-2-(4-hydroxyphenoxy)propionyl]isoxazolidine (23.7 g) which was prepared as in Example 3, anhydrous potassium carbonate (14.5 g) and dimethylsulfoxide (200 ml) was stirred at 130° C. for 3 hours. After the mixture was cooled, water and benzene were added thereto to form two layers. The organic layer thus separated was washed with 1 N aqueous sodium hydroxide solution and then with water and dried over anhydrous sodium sulfate. Removal of the solvent by a distillation in vacuo gave N-[(±)-2-[4-(2-chloro-4-trifluoromethylphenoxy)phenoxy]propionyl]isoxazolidine (39.9 g) as a pale brown crystalline solid. Recrystallization from a mixture of n-hexane and ethyl acetate afforded a white crystalline solid. m.p. 66.5°-67.5° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[C:10]([O:13][CH3:14])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(O)(=O)C.[CH3:19][O:20][C:21](OC)(OC)OC>CO.[OH-].[Na+].O>[CH3:19][O:20][C:21]1[NH:1][C:2]2[C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[C:11]=2[N:12]=1
Reactant: COC(=O)c1ccc(OC)c(N)c1N
Reactant: COC(OC)(OC)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(OC)c2nc(OC)[nH]c12
Temperature: 80 °C
Reaction time: 0.67 h

Procedure:
A mixture of methyl 2,3-diamino-4-methoxybenzoate [0.5 g, Reference Example 8(a)] acetic acid (0.15 ml) and tetramethoxymethane (0.53 ml) was stirred at 80° C. for 40 minutes. After cooling to room temperature the reaction mixture was diluted with a mixture of methanol (3.6 ml), 1N sodium hydroxide (2.55 ml) and water (8 ml). The resulting precipitate was filtered and then passed through a short filtration silica gel column to give the title compound (0.49 g) as a tan coloured solid. M+236. NMR (CDCl3): δ 3.93(s, 3H), 4.05(s, 3H), 4.23(s, 3H), 6.69(d, J=8 Hz, 1H), 7.74(d, J=8 Hz, 1H), 9.48(bs, 1H)]
Reaction SMILES: C([O:8][C:9](=[O:30])[CH2:10][C:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[CH:16][CH:17]=2)[C:12]=1[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)C1C=CC=CC=1>CCO.[OH-].[OH-].[Pd+2]>[CH2:23]([CH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[C:15]([O:21][CH3:22])[CH:14]=2)[CH2:19][CH2:20][CH:11]1[CH2:10][C:9]([OH:30])=[O:8])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COc1ccc2c(c1)C(Cc1ccccc1)=C(CC(=O)OCc1ccccc1)CC2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2c(c1)C(Cc1ccccc1)C(CC(=O)O)CC2
Reaction time: 8 h
Yield: 74.3 %

Procedure:
The mixture of (1-benzyl-7-methoxy-3,4-dihydro-naphthalen-2-yl)-acetic acid benzyl ester (102 g, 0.26 mol) and Pd(OH)2/C (30 g) in EtOH (5 L) was stirred under H2 (30 psi) atmosphere overnight, then the solution was filtered to removed the solid and concentrated to give crude product, recrystallized from DCM to give (1-benzyl-7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-acetic acid (60 g, yield 74%) as white solid.
Reaction SMILES: CC(C(O)=O)C1C=CC2SC3C=CC=CC=3C(=O)CC=2C=1.N[C:23]1[CH:28]=[CH:27][C:26]([CH:29]([CH3:33])[C:30]([OH:32])=[O:31])=[CH:25][C:24]=1[CH2:34][C:35]([OH:37])=[O:36].[C:38]([OH:47])(=[O:46])[C:39]1[C:40](=[CH:42][CH:43]=[CH:44][CH:45]=1)[SH:41]>>[C:35]([CH2:34][C:24]1[CH:25]=[C:26]([CH:29]([CH3:33])[C:30]([OH:32])=[O:31])[CH:27]=[CH:28][C:23]=1[S:41][C:40]1[CH:42]=[CH:43][CH:44]=[CH:45][C:39]=1[C:38]([OH:47])=[O:46])([OH:37])=[O:36]
Reactant: CC(C(=O)O)c1ccc(N)c(CC(=O)O)c1
Reactant: O=C(O)c1ccccc1S
Agent: CC(C(=O)O)c1ccc2c(c1)CC(=O)c1ccccc1S2
Product: CC(C(=O)O)c1ccc(Sc2ccccc2C(=O)O)c(CC(=O)O)c1

Procedure:
Preparation-III of the invention for preparing Zaltoprofen is characterized in that 2-(4-amino-3-carboxymethylphenyl)propionic acid or its salt is diazotized and then reacted with thiosalicylic acid to give 2-[3-carboxymethyl-4-(2-carboxyphenylthio)phenyl]propionic acid or its salt; the resulting compound is esterified to give 2-[3-(lower)alkoxycarbonylmethyl-4-(2-(lower)alkoxycarbonylphenylthio)phenyl]propionic acid (lower)alkyl ester; the resulting ester is subjected to cyclization reaction, to give 2-(10,11-dihydro-11-(lower)alkoxycarbonyl-10-oxodibenzo[b,f]thiepin-2-yl)propionic acid (lower)alkyl ester; and the resulting ester is finally subjected to hydrolysis and decarboxylation. Preparation-III is illustrated in the following reaction scheme III: ##STR9## 1) Preparation of 2-[3-carboxymethyl-4-(2-carboxyphenylthio)phenyl]propionic acid or its salt
Reaction SMILES: [NH2:1][C:2]([CH3:40])([CH3:39])[CH:3]=[C:4]([C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[CH2:14][N:15]1[C:19]2=[N:20][CH:21]=[N:22][C:23]([NH2:24])=[C:18]2[C:17]([C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:27][C:26]=2[F:38])=[N:16]1)=[O:8])[C:5]#[N:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:48][CH2:49][O:50][CH3:51]>CC#N>[NH2:24][C:23]1[N:22]=[CH:21][N:20]=[C:19]2[N:15]([CH2:14][C@@H:10]3[CH2:11][CH2:12][CH2:13][N:9]3[C:7]([C:4](=[CH:3][C:2]([NH:1][CH2:48][CH2:49][O:50][CH3:51])([CH3:40])[CH3:39])[C:5]#[N:6])=[O:8])[N:16]=[C:17]([C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:27][C:26]=3[F:38])[C:18]=12
Reactant: COCCBr
Reactant: CC(C)(N)C=C(C#N)C(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCNC(C)(C)C=C(C#N)C(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Temperature: 50 °C
Reaction time: 8 h
Yield: 3.7 %

Procedure:
To a suspension of 4-amino-2-((S)-2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-methylpent-2-enenitrile (210 mg, 0.39 mmol, 1.0 equiv), KI (130 mg, 0.78 mmol, 2.0 equiv) and potassium carbonate (166 mg, 1.17 mmol, 3.0 equiv) in CH3CN (15 mL) was added 1-bromo-2-methoxyethane (160 mg, 1.17 mmol, 3.0 equiv). The resulting suspension was stirred at 50° C. overnight. The solvent was removed under reduced pressure and then water (20 mL) was added to the residue. The resulting mixture was extracted with ethyl acetate (30 mL*3). The organic layers were combined, washed with brine, dried over sodium sulfate and concentrated. The residue was purified on Prep-HPLC. Conditions: (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, WATER WITH 0.5% NH4OH and CH3CN (40% CH3CN up to 100% in 20 min); Detector, 254 nm. This resulted in 8.7 mg (3.7%) of the title compound as an off-white solid. MS (ESI, pos. ion) m/z: 599 (M+1) H-NMR (400 MHz, CDCl3, ppm): 8.38 (s, 1H), 7.54 (t, J=8.4, 7.2 Hz, 1H), 7.45 (t, J=7.6, 8.0 Hz, 2H), 7.28-7.25 (m, 1H), 7.13 (d, J=8.0 Hz, 2H), 6.95 (dd, J=8.4, 2.0 Hz, 1H), 6.87 (dd, J=11.2, 2.4 Hz, 1H), 6.77 (s, 1H), 5.42 (brs, 2H), 4.93-4.90 (m, 1H), 4.83-4.82 (m, 1H), 4.70-4.65 (m, 1H), 3.67-3.65 (m, 5H), 3.36 (s, 3H), 3.36-3.31 (m, 1H), 2.20-2.89 (m, 3H), 1.88-1.71 (m, 1H), 1.61-1.51 (m, 4H), 1.35 (s, 3H), 1.33 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]([CH3:18])[N:10]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.C(O)(=O)C.[Cl:23]Cl>CCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([C:9]2[C:13]([Cl:23])=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]([CH3:18])[N:10]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: ClCl
Reactant: Cn1nc(-c2ncc(Cl)cc2Cl)cc1C(F)(F)F
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cn1nc(-c2ncc(Cl)cc2Cl)c(Cl)c1C(F)(F)F
Yield: 90 %

Procedure:
2.0 g of 3-(3,5-dichloro-2-pyridyl)-5-trifluoromethyl-1-methyl-[1H]-pyrazole (Example P11) are introduced into glacial acetic acid at 40° C. and, with stirring, chlorine gas is slowly passed over the solution. The reaction can be monitored analytically by means of thin-layer chromatography (silica gel 60 F254, eluant: n-hexanelethyl acetate 4/1, UV). Once starting material can no longer be detected, glacial acetic acid is removed in vacuo and the residue is partitioned between dilute aqueous sodium hydroxide solution and ethyl acetate. After extraction by shaking, the separated organic phase is washed with brine, dried over sodium sulfate, filtered and concentrated. The yellow oil is purified by means of flash chromatography (silica gel; eluant: n-hexane/ethyl acetate 5/1). 1.6 g of of the desired compound are obtained in the form of a yellow oil (70% of the theoretical yield).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:26])[CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[Cl:25])=[CH:7][C:6]=1[Cl:27].ClC1C=C(N)C=CC=1OC[CH2:37][CH2:38][N:39]([CH2:42]C)[CH2:40][CH3:41]>>[Cl:27][C:6]1[CH:7]=[C:8]([NH:11][C:12](=[O:26])[CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[Cl:25])[CH:9]=[CH:10][C:5]=1[O:4][CH2:3][CH2:2][CH2:42][N:39]([CH2:40][CH3:41])[CH2:38][CH3:37]
Reactant: CCN(CC)CCCOc1ccc(N)cc1Cl
Reactant: O=C(COc1ccc(C(F)(F)F)cc1Cl)Nc1ccc(OCCBr)c(Cl)c1
Product: CCN(CC)CCCOc1ccc(NC(=O)COc2ccc(C(F)(F)F)cc2Cl)cc1Cl

Procedure:
Prepared analogously to Example 145 starting from N-[4-(2-bromo-ethoxy)-3-chloro-phenyl]-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide (Z28b) and 3-chloro-4-(3-diethylamino-propoxy)-phenylamine (Z29b).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N:15]([CH2:17][CH2:18][OH:19])[CH3:16])[CH:12]=[CH:11][C:10]=1[CH:20]=[CH:21][C:22]1[S:26][C:25]([CH:27]=O)=[CH:24][CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]([C:31]1[C:32](=[C:47]([C:50]#[N:51])[C:48]#[N:49])[O:33][C:34]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([C:37]([F:40])([F:39])[F:38])[C:35]=1[CH3:36])#[N:30]>C(O)C.C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N:15]([CH2:17][CH2:18][OH:19])[CH3:16])[CH:12]=[CH:11][C:10]=1[CH:20]=[CH:21][C:22]1[S:26][C:25]([CH:27]=[CH:36][C:35]2[C:34]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)([C:37]([F:40])([F:38])[F:39])[O:33][C:32](=[C:47]([C:50]#[N:51])[C:48]#[N:49])[C:31]=2[C:29]#[N:30])=[CH:24][CH:23]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(c1ccccc1)C(F)(F)F
Reactant: CN(CCO)c1ccc(C=Cc2ccc(C=O)s2)c(OCc2ccccc2)c1
Solvent: C1CCOC1
Solvent: CCO
Product: CN(CCO)c1ccc(C=Cc2ccc(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(c3ccccc3)C(F)(F)F)s2)c(OCc2ccccc2)c1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
In a mixed solvent of ethanol (40 ml) and THF (10 ml) were dissolved 5-(2-{2-benzyloxy-4-[(2-hydroxyethyl)-methylamino]-phenyl}-vinyl]-thiophene-2-carbaldehyde (2.16 g, 5.49 mmol) and 2-(3-cyano-4-methyl-5-phenyl-5-trifluoromethyl-5H-furan-2-ylidene)malononitrile (1.73 g, 5.49 mmol). The mixture was stirred at room temperature for 18 hours and further at 50° C. for 3 hours. The mixture was cooled and the solid was collected. The solid was washed with cold ethanol (40 ml) 3 times to give a reddish brown crystal (yield: 3.72 g (98.2%)).