Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:18]=[C:17]([N:19]([CH3:21])[CH3:20])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.[Br:31][C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[C:34]([O:42][C:43]([F:46])([F:45])[F:44])[CH:33]=1>C(Cl)Cl>[Br:31][C:32]1[CH:37]=[CH:36][C:35]([S:38]([NH:1][C@H:2]2[CH2:3][CH2:4][C@@H:5]([NH:8][C:9]3[N:18]=[C:17]([N:19]([CH3:21])[CH3:20])[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)[CH2:6][CH2:7]2)(=[O:40])=[O:39])=[C:34]([O:42][C:43]([F:45])([F:44])[F:46])[CH:33]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1OC(F)(F)F
Reactant: CN(C)c1nc(N[C@H]2CC[C@@H](N)CC2)nc2ccccc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)c1nc(N[C@H]2CC[C@@H](NS(=O)(=O)c3ccc(Br)cc3OC(F)(F)F)CC2)nc2ccccc12
Reaction time: 6.5 h
Yield: 55.8 %

Procedure:
To a suspension of cis-N2-(4-amino-cyclohexyl)-N4,N4-dimethyl-quinazoline-2,4-diamine (680 mg, 2.38 mmol) in CH2Cl2 (7 mL) was added diisopropylethylamine (620 μL, 3.56 mmol). The mixture was cooled on an ice-bath and a solution of 4-bromo-2-trifluoromethoxy-benzenesulfonyl chloride (849 mg, 2.50 mmol) in CH2Cl2 (3 mL) was added dropwise. The reaction mixture was stirred on an ice-bath for 6.5 hr. The reaction was quenched with saturated aqueous NaHCO3 The aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography (NH-silica gel, 33% EtOAc in hexane) to give cis-4-bromo-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexyl]-2-trifluoromethoxy-benzenesulfonamide (782 mg, 56%) as a pale yellow solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[Cl:21][C:22]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:23]=1[C:24](O)=[O:25]>>[Cl:21][C:22]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:23]=1[C:24]([NH:2][CH2:3][C:4](=[O:5])[NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:25]
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Reactant: O=C(O)c1ccc(F)cc1Cl
Agent: Cl
Product: O=C(CNC(=O)c1ccc(F)cc1Cl)NC(c1ccccc1)c1ccc(Cl)cc1

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and 2-chloro-4-fluorobenzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][OH:12])[C:9]#[N:10])=[C:4]([CH3:13])[CH:3]=1.ClC1C=C[C:18]([O:21]C(F)F)=[CH:17]C=1C(CO)C#N>>[C:18]([O:12][CH2:11][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[CH3:13])[C:9]#[N:10])(=[O:21])[CH3:17]
Reactant: Cc1cc(Cl)ccc1C(C#N)CO
Reactant: N#CC(CO)c1cc(OC(F)F)ccc1Cl
Product: CC(=O)OCC(C#N)c1ccc(Cl)cc1C
Yield: 74 %

Procedure:
This ester was prepared using the procedure described in Example 5, except 2(-2-(4-chloro-2-methylphenyl)-3-hydroxypropanenitrile was used in place of 2-(2-chloro-5-(difluoromethoxy)phenyl-3-hydroxypropanenitrile. The preparation of 2(2-(4-chloro-2-methylphenyl)-3-hydroxypropanenitrile is described in Example 11. The recovered ester product was a white solid (74% yield in two crops), m. p. 61-63° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:14]=3)[C:11]([CH3:23])=[C:10]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:9]=2)=[CH:4][CH:3]=1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:27]([O:26][C:24]([C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[CH:3][CH:4]=2)[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:14]=2)[C:11]=1[CH3:23])=[O:25])[CH3:28]
Reactant: C1COCCN1
Reactant: CCOC(=O)c1cc(-c2ccc(Br)cc2)n(-c2cccc(S(C)(=O)=O)c2)c1C
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(-c2ccc(N3CCOCC3)cc2)n(-c2cccc(S(C)(=O)=O)c2)c1C
Reaction time: 18 h

Procedure:
A mixture of Example 2 (0.05 g, 0.108 mmol), morpholine (0.023 g, 0.24 mmol), Pd2(dba)3 (0.002 g), BINAP (0.0035 g) and sodium tert-butoxide (0.017 g) in 5 mL of toluene heated to 90° C. and stirred for 18 hours. After cooling, the mixture was filtered through diatomaceous earth, concentrated under reduced pressure and purified by flash chromatography using a gradient of ethyl acetate (0-50%) in DCM to provide the titled compound. 1H NMR (CDCl3) δ ppm 1.31 (3H), 2.20 (3H), 2.80 (3H), 3.1 (4H), 3.70 (4H), 4.25 (2H), 6.71 (2H), 6.80 (1H), 7.30-7.90 (6H); MS (ESI) m/z 469 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[CH3:10][C:11](O)([CH3:13])[CH3:12].S(=O)(=O)(O)O>ClCCl>[Br:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([OH:8])=[C:6]([C:11]([CH3:13])([CH3:12])[CH3:10])[CH:7]=1
Reactant: Cc1cc(O)ccc1Br
Reactant: CC(C)(C)O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: Cc1cc(O)c(C(C)(C)C)cc1Br
Temperature: 25 °C
Yield: 51 %

Procedure:
A solution of 4-bromo-3-methylphenol (Aldrich, 5.1 g, 27.3 mmol) in anhydrous dichloromethane (50 mL) was treated with 2-methyl-2-propanol (15 mL) and concentrated sulfuric acid (3 mL) and stirred at ambient temperature for 3 months. The volatiles were evaporated in vacuo, the residue was diluted with water and extracted with diethyl ether. The combined organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to an oil. Flash column chromatography using 3-5% ethyl acetate in hexane as the eluent afforded the title compound as a deep yellow oil (3.42 g, 51%). It was used as such for the next step.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2=[N:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:9]([CH:10]=O)[N:4]2[N:3]=1.C(O)(=O)[CH2:19][C:20]([OH:22])=[O:21].N1CCCCC1>N1C=CC=CC=1>[CH3:1][C:2]1[S:6][C:5]2=[N:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:9]([CH:10]=[CH:19][C:20]([OH:22])=[O:21])[N:4]2[N:3]=1
Reactant: O=C(O)CC(=O)O
Reactant: Cc1nn2c(C=O)c(-c3ccccc3)nc2s1
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: Cc1nn2c(C=CC(=O)O)c(-c3ccccc3)nc2s1
Temperature: 5 °C
Reaction time: 2 h
Yield: 87.2 %

Procedure:
90 g of 2-methyl-6-phenyl-imidazo[2,1-b]-1,3,4-thiadiazole-5-carbaldehyde, 60 g of malonic acid and 3 ml of piperidine in 95 ml of pyridine were boiled under reflux for 10 hours. The mixture was cooled to 5° C., stirred at this temperature for 2 hours and filtered. The residue was washed with water and dried. 92 g (84% of theory) of β-(2-methyl-6-phenyl-imidazo[2,1-b]-1,3,4-thiadiazol-5-yl)-propenoic acid of melting point 278°-280° C. (decomposition) were obtained.
Reaction SMILES: Cl[C:2]1[C:6]([F:8])([F:7])[C:5]([F:10])([F:9])[C:4]([F:12])([F:11])[C:3]=1Cl.[H][H]>[Pd].C(N(CC)CC)C>[F:7][C:6]1([F:8])[CH2:2][CH2:3][C:4]([F:12])([F:11])[C:5]1([F:9])[F:10]
Reactant: FC1(F)C(Cl)=C(Cl)C(F)(F)C1(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Product: FC1(F)CCC(F)(F)C1(F)F
Temperature: 40 °C
Yield: 115.5 %

Procedure:
A stainless steel reactor, the inner wall of which was lined with a fluoroplastic, was charged with 5.0 g of 1,2-dichlorohexafluorocyclopentene, 0.1 g of a 5%-palladium/carbon catalyst and 4.1 g of triethylamine, and hydrogen gas was introduced to a pressure of 5 kg/cm2. The mixture was heated to 40° C. while being stirred, and the reaction was conducted while the hyfrogen consumed was supplemented. After 7 hours' reaction, it was confirmed that the consumption of hydrogen ceased. Then the catalyst was removed from the reaction mixture and the reaction mixture was distilled to give 4.2 g of 1,1,2,2,3,3-hexafluorocyclopentane (b.p., 84.5-85° C. ).
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:12]([NH:14][CH2:15][C:16](N)=[O:17])=[O:13])[CH:5]=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32].Cl.N[CH2:35][C:36](N)=O>>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([C:12]([N:14]3[CH2:36][CH2:35][C@@H:16]([OH:17])[CH2:15]3)=[O:13])[CH:19]=[CH:20][C:21]=2[CH3:22])[CH:5]=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32]
Reactant: Cc1ccc(C(=O)NCC(N)=O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Cl)c1=O
Reactant: NCC(N)=O
Agent: Cl
Product: Cc1ccc(C(=O)N2CC[C@@H](O)C2)cc1-n1cnc(OCc2ccc(F)cc2F)c(Cl)c1=O

Procedure:
The title compound was prepared using a procedure similar to that used in Step 4 of the synthesis of 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-N-[1-(aminocarbonyl)methyl]-4-methylbenzamide by substituting (R)-(+)-3-pyrrolidinol for glycineamide HCl. 1H NMR (CD3OD/400 MHz) δ8.31 (d, 1H, J=7.6 Hz), 7.62 (m, 2H), 7.52 (m, 2H), 7.01 (m, 2H), 5.51 (m, 2H), 4.42 (m, 1H), 3.65 (m, 4H), 2.19 (s, 3H), 2.00 (m, 2H). ESHRMS m/z 476.1175 (M+H calculated for C23H21ClF2N3O4 requires 476.1183).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(#N)C.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl[CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>CCOC(C)=O.O>[O:34]1[CH2:35][CH2:36][N:31]([CH2:30][CH2:29][O:1][C:2]2[CH:9]=[C:8]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])[CH2:32][CH2:33]1
Reactant: O=Cc1ccc(OCc2ccccn2)cc1O
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: O=Cc1ccc(OCc2ccccn2)cc1OCCN1CCOCC1
Temperature: 90 °C
Reaction time: 2 h
Yield: 104.4 %

Procedure:
To 1.0 g of 2-hydroxy-4-(2-pyridylmethoxy)benzaldehyde were successively added 30 mL of acetonitrile, 4.26 g of cesium carbonate and 0.85 g of 4-(2-chloroethyl)morpholine hydrochloride. The mixture was stirred at 90° C. for 2 hours. To the reaction mixture, 50 mL of water and 150 mL of AcOEt were added, and the organic layer was separated. The obtained organic layer was dried over Na2SO4 and concentrated to give 1.56 g of the title compound in quantitative yield.
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[C@@H:7]([NH:37][C:38](=[O:40])[CH3:39])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][C:18](=[O:20])[N:17](CC[Si](C)(C)C)[S:16]2(=[O:28])=[O:27])=[C:11]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[F-].[Cs+].C(OCC)(=O)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:41])[C@@H:7]([NH:37][C:38](=[O:40])[CH3:39])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][C:18](=[O:20])[NH:17][S:16]2(=[O:28])=[O:27])=[C:11]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)N[C@@H](Cc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1)C(=O)OC(C)(C)C
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)N[C@@H](Cc1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1)C(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-2-acetylamino-3-{3-benzyloxy-4-[1,1,4-trioxo-5-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionic acid tert-butyl ester (137 mg, 0.23 mmol) in DMF (5 mL) is added CsF (175 mg, 1.15 mmol) and the mixture is stirred at 70° C. for 2 h. Ethyl acetate is added and the mixture is washed with 1N HCl and brine. The organic phase is dried over magnesium sulfate and the solvent removed under reduced pressure to give the title compound which is used directly in the next step.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:6]=1[C:7](O)=[O:8])(O)=[O:2]>C1COCC1>[OH:8][CH2:7][C:6]1[CH:10]=[CH:11][C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:5]=1[CH2:4][CH2:1][OH:2]
Reactant: O=C(O)Cc1cc([N+](=O)[O-])ccc1C(=O)O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(CO)c(CCO)c1
Reaction time: 18.5 h
Yield: 78.5 %

Procedure:
A THF (60 mL) solution of 2-carboxymethyl-4-nitro-benzoic acid (3.0 g , 13.3 mmol) was treated with borane-THF complex (53.3 mL, 53.3 mmol) over 15 min at 0° C. The reaction was stirred for 18.5 hrs, quenched with THF/water (1:1, 30 mL), water (20 mL) added and the layers separated. The aqueous layer was reextracted with THF (30 mL); the combined organic phase washed with brine, dried with magnesium sulfate, and solvent removed under vacuum to give the product as a white solid (2.06 g, 78%) mp=79-81° C.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([O-:13])=O)[C:6]([O:8]CC)=[O:7])C.[Cl:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH2:20][CH2:19][CH2:18]2.C(O)C.[OH-].[Na+]>O>[Cl:14][C:15]1[CH:24]=[C:23]2[C:22]3[N:21]([CH:4]=[C:5]([C:6]([OH:8])=[O:7])[C:11]2=[O:13])[CH2:20][CH2:19][CH2:18][C:17]=3[CH:16]=1
Reactant: CCOC=C(C(=O)[O-])C(=O)OCC
Reactant: Clc1ccc2c(c1)CCCN2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cn2c3c(cc(Cl)cc3c1=O)CCC2
Temperature: 140 °C
Yield: 111.3 %

Procedure:
4.9 g of ethyl ethoxymethylenemalonate was added to 4 g of 6-chloro-1,2,3,4-tetrahydroquinoline and the mixture was heated on an oil bath at 110° C. during which time distillation of ethanol was observed. After heating the mixture at the same temperature as above for 30 minutes, 30 g of polyphosphoric acid was added thereto followed by heating at 140° C. for 30 minutes. After completion of the reaction, the reaction mixture was poured into 200 ml of water and the resulting mixture was rendered neutral with a 40% aqueous sodium hydroxide solution to precipitate light brown crystals. Without further purification, the crystals were mixed with 100 ml of a 10% aqueous sodium hydroxide solution and the mixture was heat-refluxed for 40 minutes during which time the crystals were dissolved to form a uniform solution. The solution was treated with activated carbon while hot and filtered. The filtrate was allowed to cool and adjusted pH value to pH 2 to obtain 7.0 g of 9-chloro-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid as light yellow crystals having a melting point of 282° to 286° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[N:5]=1)[CH3:2].Cl.Cl[CH2:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]=3)=[CH:21][CH:22]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)nc1OCC
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1nn(Cc2ccc(OCc3ccc4ccccc4n3)cc2)cc1CCC(=O)O
Temperature: 80 °C
Reaction time: 5 h
Yield: 86.1 %

Procedure:
A mixture of ethyl 3-[3-ethoxy-1-(4-hydroxybenzyl)-1H-pyrazol-4-yl]propionate (360 mg), 2-chloromethylquinoline hydrochloride (270 mg), potassium carbonate (300 mg) and N,N-dimethylformamide (10 ml) was stirred at 80° C. for 5 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio). After a mixture of the resulting oily substance, 1N aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, 1N hydrochloric acid (5 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[3-ethoxy-1-[4-(2-quinolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid (420 mg, yield: 86%). This was recrystallized from acetone-hexane. Melting point: 140–141° C.
Reaction SMILES: [C:1]1([C:6]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]2=[O:17])=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:25]([N:33]=[C:34]=[O:35])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl>CS(C)=O.O>[C:25]([NH:33][C:34]([N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]([C:6](=[O:7])[C:1]2[S:5][CH:4]=[CH:3][CH:2]=2)[C:9]1=[O:17])=[O:35])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C1Nc2ccccc2C1C(=O)c1cccs1
Reactant: O=C=NC(=O)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: O=C(NC(=O)N1C(=O)C(C(=O)c2cccs2)c2ccccc21)c1ccccc1
Reaction time: 1 h
Yield: 24.3 %

Procedure:
To a stirred solution of 486 mg (2.0 mmole) of 3-(2-thenoyl)-2-oxindole and 445 mg (4.4 mmole) of triethylamine in 5 ml of dimethyl sulfoxide was added 324 mg (2.2 mmole) of benzoyl isocyanate. Stirring was continued for 1 hour, and then the mixture was poured into a mixture of 50 ml of water and 1.7 ml of 3N hydrochloric acid. The resulting mixture was cooled in an ice-bath and the solid was removed by filtration. The solid was recrystallized from ca. 30 ml of 2:1 ethanol:water to give 190 mg of the title compound as fluffy, yellow crystals, mp 165°-166° C. (dec).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[Br:32][C:33]1[C:34]([CH3:40])=[N:35][CH:36]=[C:37]([OH:39])[CH:38]=1.[C:41]([N:48]1[CH2:51][CH2:50][C@H:49]1[CH2:52]O)([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42]>C1COCC1>[C:41]([N:48]1[CH2:51][CH2:50][C@H:49]1[CH2:52][O:39][C:37]1[CH:36]=[N:35][C:34]([CH3:40])=[C:33]([Br:32])[CH:38]=1)([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42]
Reactant: Cc1ncc(O)cc1Br
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ncc(OC[C@@H]2CCN2C(=O)OC(C)(C)C)cc1Br
Temperature: 0 °C
Reaction time: 72 h
Yield: 70 %

Procedure:
Triphenylphosphine (6.3 g, 24 mmol) was dissolved in THF (100 mL), cooled to 0° C. and treated with diethylazodicarboxylate (3.8 mL, 24 mmol) for 15 min. Then the compound of 196d (3 g, 16 mmol) followed by 1-BOC-2-(S)-azetidinemethanol (3.4 g, 18 mmol) was added and the reaction was allowed to warm slowly to ambient temperature. After 3 days, the solvent was evaporated and the crude residue was chromatographed (silica gel; hexanes/EtOAc, 4:1) to provide an oil. The product was contaminated with a byproduct related to the DEAD reagent and was taken forward as is; the subsequent allowed isolation of the byproduct and revealed ~35 wt % contamination therefor the calculated yield was 70% (4.0 g, 11.2 mmol): TLC Rf 0.6 (1:1 hexanes/EtOAc); MS (CI/NH3) m/z 357 (M+H)+.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:26][O:25][C:16]3[CH:17]=[CH:18][C:19]4[N:20]=[C:21]([CH3:24])[O:22][C:23]=4[C:15]=3[O:14]2)(=O)=O)=CC=1.[O:27]=[C:28]1[N:32]([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[C:31]2[CH:39]=[CH:40][CH:41]=[CH:42][C:30]=2[NH:29]1>CS(C)=O>[CH3:24][C:21]1[O:22][C:23]2=[C:15]3[C:16](=[CH:17][CH:18]=[C:19]2[N:20]=1)[O:25][CH2:26][CH:13]([CH2:12][N:36]1[CH2:35][CH2:34][CH:33]([N:32]2[C:31]4[CH:39]=[CH:40][CH:41]=[CH:42][C:30]=4[NH:29][C:28]2=[O:27])[CH2:38][CH2:37]1)[O:14]3
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4nc(C)oc4c3O2)cc1
Solvent: CS(C)=O
Product: Cc1nc2ccc3c(c2o1)OC(CN1CCC(n2c(=O)[nH]c4ccccc42)CC1)CO3
Temperature: 82 °C

Procedure:
(8R)-2-Methyl-7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazol-8-ylmethyl 4-methylbenzenesulfonate (0.43 g, 1.14 mmole) and 4-(2-keto-1-benzimidazolinyl)-piperidine (0.77 g, 3.54 mmole) were combined in 10 mL of DMSO under nitrogen. This solution was heated to 82° C. under nitrogen for 4 hours. After completion, the reaction was allowed to cool to room temperature and was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was washed with brine, dried over sodium sulfate and concentrated in vacuum. The resulting crude oil was column chromatographed on silica gel using first methylene chloride to remove impurities and then 1% methanol/methylene chloride to elute 0.4 g of the (S)-enantiomer of the title compound, m.p. 218-220° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]=[CH:8][C:7](=[O:11])[C:6]=2[CH:12]=1.C[Si]([C:17]#[N:18])(C)C.CO>CCOCC.[I-].[Zn+2].[I-]>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:17]#[N:18])[CH2:8][C:7](=[O:11])[C:6]=2[CH:12]=1
Reactant: C[Si](C)(C)C#N
Reactant: O=c1ccoc2ccc(F)cc12
Agent: [I-]
Agent: [Zn+2]
Solvent: CO
Solvent: CCOCC
Product: N#CC1CC(=O)c2cc(F)ccc2O1
Yield: 94.8 %

Procedure:
To a mixture of 72.2 g (0.44 mol) of 6-fluoro-4H-1-benzopyran-4-one obtained through the process as described in said Item b and 1.39 g (4.4 mmol) of zinc iodide in 610 ml of dry ether, 101 g (1.0 mol) of trimethylsilylcyanide were added under stirring. The mixture was heated at reflux temperature for 24 hours. After cooling the reaction mixture, the solution was poured into 500 ml of methanol, stirred for one hour at room temperature and evaporated in vacuo to dryness. Resulting residue was chromatographed on silica gel, eluting with dichloromethane to give 79.7 g (94.9%) of the desired compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1)[CH3:2].C([Li])(CC)C.B(OC)(OC)[O:16]C.OO.S([O-])([O-])=O.[Na+].[Na+]>C1COCC1.C(OCC)C.C(O)(=O)C>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([F:9])=[C:7]([OH:16])[CH:8]=1)[CH3:2]
Reactant: CCc1ccc(F)cc1
Reactant: COB(OC)OC
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Li]C(C)CC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCc1ccc(F)c(O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 15.5 g of 4-ethylfluorobenzene and 14.6 g of N,N,N′N′-tetramethylethylenediamine in 500 ml of THF was cooled to −75° C. under a nitrogen atmosphere, and then 126 ml of s-butyllithium (0.99M, cyclohexane solution) was added and the mixture was stirred for 2 hours. After then adding 28 ml of trimethyl borate, the reaction mixture was warmed to room temperature and 14.4 ml of acetic acid was added. After stirring for 30 minutes, the reaction mixture was cooled to 0° C., and then 28.4 ml of 30% aqueous hydrogen peroxide was added and the mixture was stirred at room temperature for 18 hours. Next, 500 ml of saturated aqueous sodium sulfite was added to the reaction mixture and extraction was performed with 1 liter of diethyl ether. The organic layer was washed with 500 ml of water and 500 ml of saturated aqueous sodium chloride in that order and dried over anhydrous magnesium sulfate, the desiccating agent was filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to distillation to give the title compound (16.35 g) as a colorless liquid (boiling point: 76-80° C., 17 mmHg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:18])[CH:11]=[C:12]([CH:15]([F:17])[F:16])O[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[NH4+:20].C(Cl)Cl.CCOC(C)=O>C(O)C>[CH2:1]([O:8][C:9]1[C:10](=[O:18])[CH:11]=[C:12]([CH:15]([F:17])[F:16])[NH:20][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(C(F)F)occ1OCc1ccccc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=c1cc(C(F)F)[nH]cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 73.3 %

Procedure:
5-Benzyloxy-2-difluoromethyl-pyran-4-one (0.47 g, 1.9 mmol) was dissolved in ethanol (15 mL) to give a slightly yellow clear solution. Ammonium hydroxide (28-30% aqueous solution, 15 mL, 235 mmol) was added at room temperature. The resulting solution was stirred at ambient temperature for 24 hours. The progress of the reaction was monitored by TLC (CH2Cl2/EtOAc, 7/3, v/v) and HPLC Method 2. Volatiles were removed in vacuo and the residue was purified by column chromatography on silica (95/5 then 85/15 CH2Cl2/MeOH, v/v) to give the title compound as a light yellow solid (0.35 g, 74%) with a HPLC purity (peak percent area) of 98.2%. 1H NMR (300 MHz, DMSO-D6) δ (ppm): 10.99 (br. s, 1H), 8.22 (s, 1H), 7.32-7.32 (m, 5H), 7.06 (s, 1H), 6.75 (t, J=55.4 Hz, 1H), 5.23 (s, 2H); MS (m/z) 252 [M+1]+, 192.2, 91.3 (100%).