Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([O:18][CH:19]([CH3:21])[CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[C:25]([F:32])[CH:24]=1>>[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:1][CH2:2][C:3]2[CH:4]=[C:5]([CH2:11][CH:12]([O:18][CH:19]([CH3:20])[CH3:21])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:6]=[CH:7][C:8]=2[O:9][CH3:10])=[O:28])=[C:25]([F:32])[CH:24]=1
Reactant: O=C(O)c1ccc(Cl)cc1F
Reactant: CCOC(=O)C(Cc1ccc(OC)c(CN)c1)OC(C)C
Product: CCOC(=O)C(Cc1ccc(OC)c(CNC(=O)c2ccc(Cl)cc2F)c1)OC(C)C

Procedure:
Ethyl 3-[3-(aminomethyl)-4-methoxyphenyl]-2-isopropoxypropanoate and 4-chloro-2-fluorobenzoic acid were treated in the same manner as in Example 19d), to give ethyl 3-(3-{[(4-chloro-2-fluorobenzoyl)amino]methyl}-4-methoxyphenyl)-2-isopropoxypropanoate.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[OH-].[Na+].[CH3:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH:14]1[O:16][CH2:15]1.Cl>CC(C)=O>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:15][CH:14]([OH:16])[CH2:13][O:12][CH2:11][CH2:10][O:9][CH3:8]
Reactant: COCCO
Reactant: COCCOCC1CO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: COCCOCC(O)COCCOC
Temperature: 80 °C
Reaction time: 2 h
Yield: 42.3 %

Procedure:
To ethylene glycol monomethyl ether (86.4 g, 2.27 moles), ground caustic soda (16.7 g, 0.83 moles) was added by several portions and caustic soda was dissolved by heating to 80° C. Ethylene glycol glycidyl methyl ether (50 g, 0.76 moles) was then added dropwise. After the completion of the dropwise addition, the solution was stirred for 2 hours and then air-cooled at room temperature. The solution was neutralized with hydrochloric acid and a salt was deposited by adding acetone, followed by filtration. Low-boiling materials were removed under reduced pressure to obtain 67 g (yield 85%) of 1,3-bis(2-methoxyethoxy)-2-propanol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:16])[CH:9]([OH:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.CO[C:19](OC)([CH3:21])[CH3:20].CC1C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:16][C:19]([CH3:21])([CH3:20])[O:15][CH:9]2[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(O)C(O)c1ccc(Br)cc1
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CCOC(=O)C1OC(C)(C)OC1c1ccc(Br)cc1

Procedure:
A solution of diol from step 1 (1 eq) in acetone (0.2M), dimethoxypropane (8 eq) and pTsOH (0.05 eq) was stirred at rt for 4 h. The solvent was evaporated, the residue dissolved in EtOAc and washed with aqueous NaHCO3 sol. The organic extract was washed with brine, dried over Na2SO4, filtered and concentrated. Flash chromatography (hexane:EtOAc, 95:5 to 85:15) afforded the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1.C([Li])CCC.CCCCCC.[CH3:34][C:35](=[O:38])[CH2:36][CH3:37]>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:35]([OH:38])([CH2:36][CH3:37])[CH3:34])[N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1
Reactant: CCC(C)=O
Reactant: Clc1nc(N2CCOCC2)c2ncn(C3CCCCO3)c2n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCC(C)(O)c1nc2c(N3CCOCC3)nc(Cl)nc2n1C1CCCCO1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 4-(2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)morpholine (5.0 g, 15 mmol) in THF (100 mL) was cooled to −42° C. and treated with a solution of 2.5M n-Butyllithium (n-BuLi) in hexane (12.35 mL, 31 mmol) dropwise over 5 minutes. After 15 min at −42° C., 2-butanone (3.1 mL, 34 mmol) was added and the reaction mixture was slowly warmed to 0° C. over 2 hr. The mixture was quenched with water, and diluted with ethyl acetate. The aqueous layer was extracted into ethyl acetate (3×), and the combined organics were dried over sodium sulfate, filtered, and concentrated in vacuo to provide 2-(2-chloro-6-morpholino-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-8-yl)butan-2-ol as a yellow-orange foam (quant). LC/MS (ESI+): m/z 396 (M+H)
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:11]3=[CH:20][C:21]([C:23]([N:25]([CH3:27])[CH3:26])=[O:24])=[CH:22][N:10]3[N:9]=2)=[CH:4][CH:3]=1.[OH:28][CH2:29]C1C=C(C2N=C(N3CCOCC3)C3=CC(C(O)=O)=CN3N=2)C=CC=1>>[OH:28][CH2:29][C:7]1[CH:6]=[C:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[C:11]3=[CH:20][C:21]([C:23]([N:25]([CH3:26])[CH3:27])=[O:24])=[CH:22][N:10]3[N:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1cc2c(N3CCOCC3)nc(-c3cccc(CO)c3)nn2c1
Reactant: CN(C)C(=O)c1cc2c(N3CCOCC3)nc(-c3ccc(N)cc3)nn2c1
Product: CN(C)C(=O)c1cc2c(N3CCOCC3)nc(-c3cccc(CO)c3)nn2c1

Procedure:
Compound 18 was prepared by the method which was identical with that for preparing compound 12a, wherein compound 17 (92 mg, 0.26 mmol) was used as the starting material. White solid (80 mg, 80.8%). m.p. 170-171° C. 1H NMR (300 MHz, CDCl3): δ 8.22 (s, 1H), 8.20-8.17 (m, 1H), 7.84 (d, J=1.5 Hz, 1H), 7.46-7.43 (m, 2H), 7.04 (d, J=1.5 Hz, 1H), 4.77 (s, 2H), 4.11 (t, J=4.7 Hz, 4H), 3.87 (t, J=4.7 Hz, 4H), 3.20 (br, s, 6H). LC-MS: 382 (M+1).
Reaction SMILES: [CH3:1][S:2][CH:3]([C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)[C:4]([O:6][CH3:7])=[O:5].[C:15]1(=O)[O:20][C:18](=[O:19])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12>C(O)(=O)C>[CH3:1][S:2][CH:3]([C:8]1[CH:9]=[CH:10][C:11]([N:14]2[C:18](=[O:19])[C:17]3=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]3[C:15]2=[O:20])=[CH:12][CH:13]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: COC(=O)C(SC)c1ccc(N)cc1
Solvent: CC(=O)O
Product: COC(=O)C(SC)c1ccc(N2C(=O)c3ccccc3C2=O)cc1
Yield: 99.5 %

Procedure:
Methyl α-methylthio(p-aminophenyl)acetate (760 mg) and 533 mg of phthalic anhydride were dissolved in 8 ml of acetic acid, and the solution was heated under reflux for 4 hours. The reaction mixture was concentrated under reduced pressure, and 100 ml of an aqueous solution of sodium bicarbonate was added. The mixture was extracted once with 20 ml of methylene chloride, and then twice with 10 ml of methylene chloride. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford 1.222 g of methyl α-methylthio(p-phthalimidophenyl)acetate as colorless crystals in a yield of 99.5%.
Reaction SMILES: [CH:1]1[S:2][CH:3]=[C:4]2[C:10]=1[C:9](=[O:11])[NH:8][C:7]1[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=1[NH:5]2.[H-].[Na+].[CH2:18](I)[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>CN(C)C=O>[CH2:18]([N:8]1[C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=2[NH:5][C:4]2=[CH:3][S:2][CH:1]=[C:10]2[C:9]1=[O:11])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: O=C1Nc2ccccc2Nc2cscc21
Reactant: CCCCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCN1C(=O)c2cscc2Nc2ccccc21
Temperature: 0 °C
Reaction time: 8 h

Procedure:
An 11.8 g. portion of 4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one is combined with 2.8 g. of 50% sodium hydride in mineral oil and 175 ml. of dimethylformamide and stirred for 2 hours. A 15.7 g. (11 ml.) portion of n-hexyl iodide is added and the mixture is stirred overnight. The reaction mixture is poured into ice water and the brown oil is separated and dissolved in methylene chloride. The dimethylformamide-water mixture is extracted twice with methylene chloride. All methylene chloride portions are combined, washed with water, dried over sodium sulfate, filtered and concentrated to a dark brown oil. This oil is dissolved in 10 ml. of methylene chloride and chromatographed on an alumina column. The column is eluted with 500 ml. of hexane followed by 30% methylene chloride in hexane for fractions 5-13 and methylene chloride:hexane (50:50) for fractions 14-19. Fraction 6 is concentrated to a dark brown viscous oil (A). Fractions 7-19 are combined and concentrated to dryness (B). (A) and (B) both crystallize in hexane and are combined, filtered, washed with hexane and dried. The product is dissolved with warming in 50 ml. of benzene and filtered. To the filtrate is added 100 ml. of hexane and the mixture is cooled overnight. The solid is collected, washed with ether and dried, giving the desired product, mp. 100°-102° C.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:18]([CH:19]=O)=[C:17]([CH:21]([CH3:23])[CH3:22])[CH:16]=[C:15]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:14]=2)=[CH:9][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCl.C(Cl)Cl>[Br:2][C:1]([Br:5])=[CH:19][C:18]1[C:13]([C:10]2[CH:9]=[CH:8][C:7]([F:6])=[CH:12][CH:11]=2)=[N:14][C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:16][C:17]=1[CH:21]([CH3:23])[CH3:22]
Reactant: CC(C)c1cc(-c2ccccc2)nc(-c2ccc(F)cc2)c1C=O
Reactant: BrC(Br)(Br)Br
Agent: ClCl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)c1cc(-c2ccccc2)nc(-c2ccc(F)cc2)c1C=C(Br)Br
Reaction time: 0.33 h
Yield: 98.7 %

Procedure:
A solution of carbon tetrabromide (2.866 gm, 8.64 mmol) in CH2 Cl2 (8 ml) was added over a 10 minute period to a cold (-10° C.) solution of 2-(4-Fluorophenyl)-4-(1-methylethyl)-6-phenyl-3-pyridinecarboxaldehyde (1.840 gm, 5.76 mmol) (the preparation of which is described in Example 3) and triphenylphosphine (4.590 gm, 17.5 mmol) in CH2Cl2 (30 ml). After the addition was complete, the cooling bath was removed and the mixture was stirred for 20 minutes. The solution was quenched with saturated NaHCO3 and extracted 2X with CH2Cl2. The combined organic layers were washed with saturated NaHCO3, dried (Na2SO4), filtered and concentrated. The concentrate was chromatographed (flash, Merck, SiO2, 1:1 CH2Cl2 :hexane) to give 3-(2,2-Dibromoethenyl)-2-(4-fluorophenyl)-4-(1-methylethyl)-6-phenylpyridine as a white solid (2.701 gm, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2(O)[CH2:15][CH:14]3[N:16]([CH3:17])[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:10][CH:11]3[N:16]([CH3:17])[CH:14]([CH2:13][CH2:12]3)[CH:15]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN1C2CCC1CC(O)(c1ccc(Cl)c(Cl)c1)C2
Agent: Cl
Solvent: CC(=O)O
Product: CN1C2C=C(c3ccc(Cl)c(Cl)c3)CC1CC2

Procedure:
To a stirred solution of 3-(3,4-dichlorophenyl)-8-methyl-8-azabicyclo[3.2.1]octan-3-ol (50 g, 0.17 mol) in glacial acetic acid (160 mL) at room temperature was added concentrated hydrochloric acid (50 mL). The reaction mixture was heated at reflux. The starting material was consumed after 20 minutes and the reaction mixture was poured into approximately 1.5 L of crushed ice. The resulting aqueous solution was added concentrated NH4OH (approximately 325 mL) to pH=9-10 resulting in precipitation of a sticky solid. The mixture was decanted and the reminiscence was triturated in water (1.5 L) resulting in a crystalline crude product. The crude product was washed a last time with water (300 mL) and was dried in a fume hood yielding the title compound as an off-white solid, m.p. 44-52° C.
Reaction SMILES: [C:1]1(=[O:8])[O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-:9].[Na+:10]>O>[OH:9][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O-:7])=[O:8].[Na+:10]
Reactant: [OH-]
Reactant: O=C1CCCCCO1
Agent: [Na+]
Solvent: O
Product: O=C([O-])CCCCCO
Reaction time: 0.5 h
Yield: 68 %

Procedure:
To a well-stirred reaction vessel equipped with a thermometer and a pH electrode were added 34.3 g of 6-hexanolactone, 20 g of water, and 48 g of a 25 wt % aqueous NaOH solution. The reaction mixture was stirred for 30 min while cooling down slowly. The sodium 6-hydroxyhexanoate solution formed was cooled to 4° C. and to this solution 130 mg of N-methylmorpholine was added. Then, 34 g of isopropyl chloroformate was added in 2 min. The reaction mixture was stirred for 90 min at 10° C. Chloroformate level in the organic layer was low and mixed anhydride was formed according to analysis by FT-IR. To this reaction mixture, 6.5 g of a 70 wt % aqueous H2O2 Solution was added with stirring and the temperature was kept at 10° C. for 120 min. The pH was kept at 6-7 by addition of 3 g of a 25 wt % aqueous NaOH solution. The white solid formed was filtered and washed with 300 g of cold water. Vacuum drying of the solid resulted in 29 g of di(6-hydroxyhexanoyl)peroxide with an active content of 86% in a yield of 68%.
Reaction SMILES: [CH2:1]([C@@:4]1([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].C1C[O:30]CC1>>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([C@@H:11]([N:7]2[CH2:6][CH2:5][C@@:4]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)([CH2:1][CH2:2][CH2:3][OH:30])[O:9][C:8]2=[O:10])[CH3:12])=[CH:14][CH:15]=1
Reactant: C1CCOC1
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Reaction time: 2 h
Yield: 92 %

Procedure:
To a solution of (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (1.19 g, 2.8 mmol) in THF (30 mL) was added BH3 THF (8.5 mL, I mol/L, 8.5 mmol) at 0° C. under nitrogen atmosphere. The formed mixture was stirred for 2 h. The reaction was quenched with water. Then NaOH (1 mol/L, 6 mL) and H2O2 (5 mL) were added to the above mixture. When the reaction was over, the mixture was extracted with EtOAc. The combined organic phase was concentrated to give the crude product, which was purified by preparative TLC to give (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one (1.13 g, 92%).
Reaction SMILES: C([O:3][C:4](=[O:18])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](Cl)(=O)=O)=[CH:9][C:8]=1[Cl:17])C.C(C1C=C(S[CH2:33][C:34]2[CH:38]=[C:37]([C:39]3[CH:44]=[CH:43][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:41][CH:40]=3)[O:36][C:35]=2[CH3:49])C=CC=1OCC(O)=O)C>>[Cl:17][C:8]1[CH:9]=[C:10]([S:13][CH2:33][C:34]2[CH:38]=[C:37]([C:39]3[CH:40]=[CH:41][C:42]([C:45]([F:48])([F:46])[F:47])=[CH:43][CH:44]=3)[O:36][C:35]=2[CH3:49])[CH:11]=[CH:12][C:7]=1[O:6][CH2:5][C:4]([OH:3])=[O:18]
Reactant: CCc1cc(SCc2cc(-c3ccc(C(F)(F)F)cc3)oc2C)ccc1OCC(=O)O
Reactant: CCOC(=O)COc1ccc(S(=O)(=O)Cl)cc1Cl
Product: Cc1oc(-c2ccc(C(F)(F)F)cc2)cc1CSc1ccc(OCC(=O)O)c(Cl)c1

Procedure:
The title compound was prepared from ethyl[4-(chlorosulfonyl)-2-chlorophenoxy]acetate (intermediate 113) by a method analogous to that used for the preparation of {2-ethyl-4-[({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}acetic acid (example 145).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:19]=[C:18]([CH2:20][C:21]([NH:23][CH:24]([CH2:37][O:38][C:39](=[O:41])[CH3:40])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[O:22])[CH:17]=[CH:16][C:5]=1[C:6]([O:8]CC1C=CC=CC=1)=[O:7])[CH3:2]>C(O)C>[CH2:1]([O:3][C:4]1[CH:19]=[C:18]([CH2:20][C:21]([NH:23][CH:24]([CH2:37][O:38][C:39](=[O:41])[CH3:40])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[O:22])[CH:17]=[CH:16][C:5]=1[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCOc1cc(CC(=O)NC(COC(C)=O)c2ccccc2N2CCCCC2)ccc1C(=O)OCc1ccccc1
Solvent: CCO
Product: CCOc1cc(CC(=O)NC(COC(C)=O)c2ccccc2N2CCCCC2)ccc1C(=O)O

Procedure:
Prepared analogously to Example 68 by catalytic hydrogenation of benzyl 2-ethoxy-4-[N-(α-acetoxymethyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate in ethanol.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:17]2[C:25]3[C:20](=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:22]=[CH:23][CH:24]=3)[NH:19][N:18]=2)=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH:32]1(Br)[CH2:36][CH2:35][CH2:34][CH2:33]1>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([C:17]2[C:25]3[C:20](=[C:21]([C:26]([F:29])([F:27])[F:28])[CH:22]=[CH:23][CH:24]=3)[N:19]([CH:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)[N:18]=2)=[O:16])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(OCc2ccccc2)cc1)c1n[nH]c2c(C(F)(F)F)cccc12
Reactant: BrC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccc(OCc2ccccc2)cc1)c1nn(C2CCCC2)c2c(C(F)(F)F)cccc12
Temperature: 50 °C
Reaction time: 24 h
Yield: 73.3 %

Procedure:
To a solution of [4-(benzyloxy)phenyl](7-trifluoromethyl-1H-indazol-3-yl)methanone (0.372 g, 0.94 mmol) in 3 mL DMF was added in one portion sodium hydride (0.044 g, 1.1 mmol, 60% in oil). After the gas evolution ceased, cyclopentyl bromide (0.118 mL, 1.1 mmol) was added and the reaction was stirred at ambient to 50° C. for 24 hours. The cool reaction mixture was partitioned with EtOAc and 1 N HCl. The organic phase was washed with brine and dried (Na2SO4). The solvent was removed in vacuo. The resulting residue was purified by flash chromatography (silica gel, hexane-EtOAc, 9:1) to give 0.320 g of the title compound as a yellow solid.
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[CH:19]=[C:18]([F:20])[C:17]([N:21]2[C:26](=[O:27])[CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[NH:23][C:22]2=O)=[CH:16][C:9]=1[C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11].P(Cl)(Cl)([Cl:35])=O>C1(C)C=CC=CC=1>[Cl:7][C:8]1[CH:19]=[C:18]([F:20])[C:17]([N:21]2[C:26](=[O:27])[CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[N:23]=[C:22]2[Cl:35])=[CH:16][C:9]=1[C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11]
Reactant: CC(C)OC(=O)c1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Reactant: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)c1cc(-n2c(Cl)nc(C(F)(F)F)cc2=O)c(F)cc1Cl

Procedure:
23.3 g of pyridine are added at room temperature while stirring and cooling to a suspension of 38.8 g of isopropyl 2-chloro-5-[3,6-dihydro-2,6-dioxo-4-trifluoromethyl-1(2H)-pyrimidinyl]-4-fluorobenzoate in 45.2 g of phosphorus oxychloride and 40 ml of toluene. A solution forms rapidly. The temperature is maintained between 30° to 35° C. and, after 15 minutes, a colourless precipitate begins to separate. The reaction mixture is stirred at 30°-35° C. for 45 minutes and is then poured onto 300 g of ice. The mixture is subsequently extracted with 200 ml of ethyl acetate and the organic phase is washed three times with 50 ml of water each time, dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. The residue is recrystallized from n-hexane. There is obtained isopropyl 2-chloro-5-[2-chloro-6-oxo-4-trifluoromethyl-1(6H)-pyrimidinyl]-4-fluorobenzoate, m.p. 72°-75° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][NH:23][C@H:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26][C@H:25]2[OH:33])[C:8]([F:11])=[CH:9][CH:10]=1.[C:35](Cl)(Cl)=[O:36]>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:21])[F:19])=[CH:14][C:13]=2[CH2:22][N:23]2[C@H:24]3[C:32]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[CH2:26][C@H:25]3[O:33][C:35]2=[O:36])[C:8]([F:11])=[CH:9][CH:10]=1
Reactant: O=C(Cl)Cl
Reactant: COC(=O)Cc1ccc(F)c(-c2ccc(C(F)(F)F)cc2CN[C@H]2c3ccccc3C[C@H]2O)c1
Product: COC(=O)Cc1ccc(F)c(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@@H]3Cc4ccccc4[C@@H]32)c1

Procedure:
Prepared according to the procedure described in Example 25, Step 5, using the following starting materials: {6-fluoro-2′-[((1S,2R)-2-hydroxy-indan-1-ylamino)-methyl]-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid methyl ester and phosgene (1.9M in toluene).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]#[C:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[C:14]([O:18][C:19]([N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([CH2:31][CH2:32][O:33][C:34]3[CH:35]=[C:36]4[C:40](=[CH:41][CH:42]=3)[NH:39][CH:38]=[CH:37]4)[N:29]=2)[CH2:24][CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19]([N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([CH2:31][CH2:32][O:33][C:34]3[CH:35]=[C:36]4[C:40](=[CH:41][CH:42]=3)[N:39]([C:5]([C:6]3[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=3)=[CH:4][C:3]([O:2][CH3:1])=[O:13])[CH:38]=[CH:37]4)[N:29]=2)[CH2:24][CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: COC(=O)C#Cc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCCc2ccc(CCOc3ccc4[nH]ccc4c3)nc21
Product: COC(=O)C=C(c1ccc(F)cc1)n1ccc2cc(OCCc3ccc4c(n3)N(C(=O)OC(C)(C)C)CCC4)ccc21
Yield: 73 %

Procedure:
The title compound was synthesized from (4-fluoro-phenyl)-propynoic acid methyl ester and 7-[2-(1H-Indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester using the procedure described in Example 17, step (a), in 73% yield as an E/Z isomeric mixture. 1H NMR (CDCl3) [E/Z mixture] δ 7.43 (m, 1H), 7.30 (m, 2H), 7.00-7.20 (m, 3), 6.94 (m, 1H), 6.50-6.90 (m, 3H), 6.12 (s, 1H), 4.36 (m, 2H), 3.75 (m, 2H), 3.7 and 3.6 (s, 3H), 3.20 (m, 2H), 2.75 (m, 2H), 1.90 (m, 2H), 1.50 (s, 9H). Mass Spectrum (LCMS, ESI) calculated for C33H35FN3O5 572.3 (M+H); found 472.3 (M-Boc+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][C:15]1[C:19]([C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][NH:26][CH:27]3[CH3:30])=[CH:22][CH:21]=2)=[C:18]([CH3:31])[O:17][N:16]=1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:26]3[CH2:25][CH2:24][C:23]4[C:28](=[CH:29][C:20]([C:19]5[C:15]([CH3:14])=[N:16][O:17][C:18]=5[CH3:31])=[CH:21][CH:22]=4)[CH:27]3[CH3:30])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: Cc1noc(C)c1-c1ccc2c(c1)C(C)NCC2
Product: Cc1noc(C)c1-c1ccc2c(c1)C(C)N(C(=O)c1cc3ncc(Br)cn3n1)CC2

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-(3,5-Dimethyl-isoxazol-4-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: Cl[CH2:2][O:3][C:4](=[O:10])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[SH:11][C:12]1[N:13]=[N:14][NH:15][CH:16]=1.[Na]>CN(C)C=O.C(OCC)(=O)C>[CH2:5]([C:4]([O:3][CH2:2][S:11][C:12]1[N:13]=[N:14][NH:15][CH:16]=1)=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: Sc1c[nH]nn1
Reactant: CCCCCC(=O)OCCl
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCC(=O)OCSc1c[nH]nn1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
23.1 g hexanoic acid chloromethyl ester are added over a period of 30 minutes with stirring to 17.2 g 4-mercapto-1,2,3-triazole, sodium salt, in 100 ml dimethyl formamide. After 2 h, the mixture is added to 600 ml ice water and the oil formed is taken up in ethyl acetate.
Reaction SMILES: [OH:1]OS(O)(=O)=O.[C:7]1([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[C:14]1([S:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:1])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc(Sc2ccccc2)cc1
Reactant: O=S(=O)(O)OO
Product: O=S(c1ccccc1)c1ccccc1
Yield: 39 %

Procedure:
The effectiveness of Caro's acid as an oxidizing agent is unexpected. More explicitly, diphenyl sulfide has been oxidized by Caro's acid to give diphenyl sulfoxide in 39% yield by I. P. Gragerov and A. F. Levit, Zh. Obshch. Khim., 33, 543 (1963). Diphenyl sulfide is a typical aromatic sulfide. The starting material used in this invention also is an aromatic sulfide and would be expected to behave as a typical aromatic sulfide; however, it does not. Most aromatic sulfides can be oxidized in 70% dioxane in water to the corresponding sulfoxide with an equivalent amount of N-bromosuccinimide. On the other hand, the reaction of N-bromosuccinimide with alkyl sulfides gives no sulfoxides, W. Tagaki et al., Chemistry and Industry (London), September 19, 1964, p 1624. The starting sulfide used in this invention failed to be oxidized to the sulfinyl compound under similar conditions using N-bromosuccinimide. Thus, the lack of reactivity of 1,2-diphenyl-4-[2-(phenylthio)ethyl]-3,5-pyrazolidinedione, when compared to typical aromatic sulfides, would predict that oxidation of the starting sulfide used in this invention with Caro's acid should give very low yields of the corresponding sulfinyl compound. However, the reverse was discovered, Caro's acid is an effective and safe oxidizing agent for selectivity converting 1,2-diphenyl-4-[2-(phenylthio)ethyl]-3,5-pyrazolidinedione to the corresponding sulfinyl compound.