Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.[N:3]1([C:9]2[C:10]3[CH:17]=[CH:16][NH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[Br:18][C:19]1[CH:38]=[CH:37][C:22]([CH2:23][CH:24]([CH2:28][NH:29]C(OC(C)(C)C)=O)[C:25](O)=[O:26])=[C:21]([F:39])[CH:20]=1>>[ClH:1].[ClH:1].[NH2:29][CH2:28][CH:24]([CH2:23][C:22]1[CH:37]=[CH:38][C:19]([Br:18])=[CH:20][C:21]=1[F:39])[C:25]([N:6]1[CH2:5][CH2:4][N:3]([C:9]2[C:10]3[CH:17]=[CH:16][NH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH2:8][CH2:7]1)=[O:26]
Reactant: CC(C)(C)OC(=O)NCC(Cc1ccc(Br)cc1F)C(=O)O
Reactant: c1nc(N2CCNCC2)c2cc[nH]c2n1
Agent: Cl
Product: NCC(Cc1ccc(Br)cc1F)C(=O)N1CCN(c2ncnc3[nH]ccc23)CC1

Procedure:
3-Amino-2-(4-bromo-2-fluoro-benzyl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperazin-1-yl]-propan-1-one dihydrochloride was prepared by substituting 5-piperazin-1-yl-1H-indazole with 4-Piperazin-1-yl-7H-pyrrolo[2,3-d]pyrimidine dihydrochloride and substituting (D)-Boc-4-chlorophenylalanine with 2-(4-Bromo-2-fluoro-benzyl)-3-tert-butoxycarbonylamino-propionic acid in Example 34, Step 2, then removing the Boc protecting group as described in Example 34, Step 3. 1H NMR (CD3OD, 400 MHz) δ 8.37 (s, 1H), 7.40 (d, J=3.6 Hz, 1H), 7.36 (m, 1H), 7.31 (m, 1H), 7.24 (t, J=8.0 Hz, 1H), 6.95 (d, J=3.6 Hz, 1H), 4.14 (m, 2H), 4.02 (m, 1H), 3.87 (m, 4H), 3.55 (m, 2H), 3.34 (m, 1H), 3.11 (m, 1H), 2.98 (m, 2H). LCMS (APCI+) m/z 461, 463 [M+H]+; Rt=1.79 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:16]3[CH2:15][CH2:14][NH:13][CH2:12][C:11]=3[C:10](=[O:17])[O:9][C:7]=2[CH:8]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH:23]=O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:16]3[CH2:15][CH2:14][N:13]([CH2:23][C:22]4[CH:25]=[C:26]([O:30][CH3:31])[C:27]([O:28][CH3:29])=[C:20]([O:19][CH3:18])[CH:21]=4)[CH2:12][C:11]=3[C:10](=[O:17])[O:9][C:7]=2[CH:8]=1
Reactant: COc1ccc2c3c(c(=O)oc2c1)CNCC3
Reactant: COc1cc(C=O)cc(OC)c1OC
Product: COc1ccc2c3c(c(=O)oc2c1)CN(Cc1cc(OC)c(OC)c(OC)c1)CC3
Yield: 72 %

Procedure:
Prepared by the procedure of Example 3 from 8-methoxy-1,2,3,4-tetrahydro-chromeno[3,4-c]pyridin-5-one and 3,4,5-trimethoxybenzaldehyde. Yield 72%; mp 171°-173° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]([C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1)#[N:9]>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:13]1[CH:14]=[CH:15][C:10]([C:8]#[N:9])=[CH:11][CH:12]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: Brc1ccccn1
Product: N#Cc1ccc(-c2ccccn2)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 11 using 2-bromopyridine instead of 1-bromo-3-pentyloxybenzene and 4-cyanophenylboronic acid instead of tert-butyl N-[ 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-benzyl]carbamate.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].I[C:10]1[CH:27]=[CH:26][C:13]([CH2:14][O:15][Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])=[CH:12][CH:11]=1.C([O-])([O-])=O.[Cs+].[Cs+].N1C=CC=CC=1C(O)=O>O1CCOCC1.[Cu]I>[C:1]([CH:3]([C:10]1[CH:27]=[CH:26][C:13]([CH2:14][O:15][Si:16]([CH:20]([CH3:22])[CH3:21])([CH:23]([CH3:25])[CH3:24])[CH:17]([CH3:18])[CH3:19])=[CH:12][CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: CC(C)[Si](OCc1ccc(I)cc1)(C(C)C)C(C)C
Reactant: CCOC(=O)CC#N
Agent: [Cu]I
Agent: O=C(O)c1ccccn1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCOC(=O)C(C#N)c1ccc(CO[Si](C(C)C)(C(C)C)C(C)C)cc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 2-cyanoacetate and (4-iodobenzyloxy)triisopropylsilane (E199) in dioxane were added Cs2CO3, CuI, and picolinic acid. The mixture was stirred overnight at 90° C. The solid was removed by filtration and the dioxane concentrated under reduced pressure. Column chromatography (SiO2, hexane:ethyl acetate 25:1) gave pure ethyl 2-cyano-2-(4-((triisopropylsilyloxy)methyl)phenyl)acetate (E200) as a yellow oil.
Reaction SMILES: [C:1]([OH:14])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(Cl)(=O)C(Cl)=O.[CH:21]1[CH:26]=[CH:25][CH:24]=CC=1>>[C:1]([O:14][CH2:24][CH:25]1[CH2:21][CH2:26]1)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: c1ccccc1
Reactant: CCCCCCCCCCCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Product: CCCCCCCCCCCC(=O)OCC1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 3.01 g. of lauric acid in benzene, under nitrogen, is added 5.8 g. of oxalyl chloride. The mixture is stirred at room temperature for 2 hours and then concentrated in vacuo at 40°. To the concentrate is added fresh benzene and 3.25 g. of cyclopropylmethyl alcohol. The solution is stirred overnight at room temperature and then diluted with water. The reaction mixture is worked up by washing with water and brine, drying over calcium sulfate, concentrating the organic phase under reduced pressure and purifying by distillation to yield cyclopropylmethyl laurate (cyclopropanemethyl-n-dodecanoate), b.p. (bath) 90° at 0.005 mm.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([N:9]2C(=O)C3C=CC=CC=3OC2(C)C)[CH:3]=1.C([O-])([O-])=O.[Na+].[Na+]>Cl>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([NH2:9])[CH:3]=1
Reactant: Cc1cnc(N2C(=O)c3ccccc3OC2(C)C)cc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1cnc(N)cc1C
Yield: 103.7 %

Procedure:
A solution of 3-(4,5-dimethylpyridin-2-yl)-2,2-dimethyl-2H-benzo[e][1,3]oxazin-4(3H)-one (9 g, 0.03 mol) in concentrated hydrochloric acid (100 mL) was heated at reflux overnight. The mixture was basified by saturated solution of Na2CO3 and extracted with CH2Cl2 (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated under vacuum to give 4,5-dimethylpyridin-2-amine (3.8 g, 97%), that was directly used in the next step without further purification.
Reaction SMILES: C([O:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([CH3:12])=[C:6]([O:13][CH3:14])[CH:5]=1)=O.C([O-])([O-])=O.[K+].[K+].Cl>CO.O>[CH3:14][O:13][C:6]1[CH:5]=[C:4]([OH:3])[CH:9]=[C:8]([O:10][CH3:11])[C:7]=1[CH3:12]
Reactant: COc1cc(OC=O)cc(OC)c1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1cc(O)cc(OC)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.5 %

Procedure:
To a solution of 3,5-dimethoxy-4-methylphenyl formate (2.9 g, 14.8 mmol) in wet MeOH (81 mL) was added K2CO3 (8.1 g, 58.6 mmol). The mixture was stirred for 2 hrs at room temperature then H2O (2-3 mL) was added. After stirring for 21 hrs, the mixture was diluted with H2O, acidified with 6M HCl to pH 3-4, and extracted with EtOAc. The combined organics were washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification by chromatography (0-35% EtOAc-hexanes) gave 3,5-dimethoxy-4-methylphenol as an impure yellow powder (0.71 g, 29% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]#[N:10])=[CH:4][CH:3]=1.[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.O>N1C=CC=CC=1>[S:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:17]([C:14]2[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=2)(=[O:19])=[O:18])=[CH:3][CH:4]=1)[C:9]#[N:10]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#CSc1ccc(N)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ccc(SC#N)cc2)cc1
Temperature: 25 °C
Yield: 95.7 %

Procedure:
To a solution of 4-Aminophenyl thiocyanate (10.0 g (66.6 mmol)) in pyridine (70 ml), p-toluenesulfonyl chloride (12.7 g (66.6 mmol)) was added with stirring at room temperature, and the mixture was stirred at room temperature for 16 hours. Then, water was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The extract was washed with dilute hydrochloric acid and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 19.4 g (98%) of 4′-thiocyano-p-toluenesulfonanilide as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C@H:14]([NH2:16])[CH3:15])=[CH:10][CH:9]=2)=[CH:6][C:5]([F:17])=[CH:4][N:3]=1.C(N(CC)CC)C.[F:25][C:26]1[CH:27]=[C:28]([S:33](Cl)(=[O:35])=[O:34])[CH:29]=[CH:30][C:31]=1[F:32]>ClCCl>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][C:11]([C@H:14]([NH:16][S:33]([C:28]3[CH:29]=[CH:30][C:31]([F:32])=[C:26]([F:25])[CH:27]=3)(=[O:35])=[O:34])[CH3:15])=[CH:12][CH:13]=2)=[CH:6][C:5]([F:17])=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)c1ccc(F)c(F)c1
Reactant: C[C@@H](N)c1ccc(-c2cc(F)cnc2Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](NS(=O)(=O)c1ccc(F)c(F)c1)c1ccc(-c2cc(F)cnc2Cl)cc1
Temperature: 25 °C
Reaction time: 64 h
Yield: 40 %

Procedure:
To a solution of (R)-2-[1-(4-bromo-phenyl)-ethyl]-isoindole-1,3-dione (1.19 g, 3.6 mmol) (Example 26) in 1,2-dimethoxyethane (3 ml) was added 2-chloro-5-fluoropyridine-3-boronic acid (0.95 g, 5.4 mmol), tetrakis(triphenylphosphine)palladium (0) (0.21 g, 0.2 mmol) and 2M aqueous sodium carbonate (3.2 ml, 6.4 mmol). The reaction mixture was heated in a microwave oven at 150° C. for 10 min and the solvent evaporated. The residue was partitioned between ethyl acetate and water. The organic phase washed with brine, dried over anhydrous magnesium sulfate and the solvent evaporated. The residue was purified over silica gel eluting with heptane/ethyl acetate to give (R)-2-{1-[4-(2-chloro-5-fluoro-pyridin-3-yl)-phenyl]-ethyl}-isoindole-1,3-dione (0.62 g, 1.6 mmol, 44%) as a clear glass. To a solution of (R)-2-[1-(4-bromo-phenyl)-ethyl]-isoindole-1,3-dione (0.16 g, 0:4 mmol) in methanol (4 ml) was added hydrazine hydrate (0.43 g, 8.6 mmol). The reaction mixture was stirred at room temperature for 18 h and then concentrated under reduced pressure. Dichloromethane was added and the resultant white precipitate filtered off. The solvent was evaporated to give 1-[4-(2-chloro-5-fluoro-pyridin-3-yl)-phenyl]-ethylamine (0.11 g, 0.4 mmol, 100%) as a yellow gum. To a solution of (R)-1-[4-(2-chloro-5-fluoro-pyridin-3-yl)-phenyl]-ethylamine (26 mg, 0.1 mmol) in dichloromethane (1 ml) was added triethylamine (31.6 mg, 0.31 mmol) followed by 3,4-difluorobenzenesulfonyl chloride (28.7 mg, 0.14 mmol). The reaction mixture was agitated for 64 h at room temperature and the solvent evaporated. The crude product was taken up in dimethyl sulfoxide (1 ml) and purified by preparatory LCMS. The solvent was evaporated under reduced pressure to give the title compound (6.7 mg, 0.04 mmol, 38%). 1H NMR (400 MHz, DMSO-d6): δ 8.48 (m, 2H), 7.78 (dd, 1H), 7.45-7.60 (m, 3H), 7.27-7.34 (m, 4H), 4.50 (q, 1H), 1.33 (d, 3H) ppm; MS (ESI) m/z: 427 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[I:24]I>S([O-])([O-])(=O)=O.[Ag+2].[O-]S([O-])(=O)=O.[Ag+].[Ag+].CO>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([I:24])=[CH:4][C:3]=1[C:10]1[N:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[C:12]([C:20]([F:23])([F:21])[F:22])[CH:11]=1
Reactant: COC(=O)c1cnc(-c2ccc(OC)cc2F)cc1C(F)(F)F
Reactant: II
Agent: [Ag+2]
Agent: [Ag+]
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: COC(=O)c1cnc(-c2cc(I)c(OC)cc2F)cc1C(F)(F)F

Procedure:
Methyl 6-(2-fluoro-4-methoxyphenyl)-4-(trifluoromethyl)pyridine-3-carboxylate (750 mg, 2.278 mmol), iodine (578 mg, 2.278 mmol), silver sulfate (710 mg, 2.278 mmol) and MeOH (20 mL) were stirred in a 70° C. oil bath and monitored by LCMS. The dark color disappeared and LCMS indicated >50% conversion when reaction time=1 hr. Additional I2 (280 mg, 0.788 mmol) and Ag2SO4 (355 mg, 1.074 mmol) were added and resumed stirring/heating for 30 min. The reaction was cooled and quenched by adding Na2S2O3 (sat.). Volatiles were removed under reduced pressure. The pot residue was worked up with brine, extracted with ethyl acetate, dried over Na2SO4, filtered and evaporated in vacuo. The resulting mixture was purified by flash chromatography (SiO2, Biotage SNAP Cartridge, silica gel, KP-Sil, 100 g cartridge). The column was eluted by an EtOAc/hexanes mixture (0% to 40%). Pure fractions were pooled and evaporated to afford a white solid as the titled compound. LCMS calc.=454.96. found=456.03 (M+H)+. 1H NMR (CDCl3, 600 MHz) δ 9.15 (s, 1H), 8.61 (d, J=9.0 Hz, 1H), 8.11 (s, 1H), 6.68 (d, J=11.0, 1H), 4.00 (s, 3H), 3.96 (s, 3H).
Reaction SMILES: ClC1C(Cl)=C(C(=O)C(=C)CC)C=CC=1OCC(O)=O.[Cl:20][C:21]1[C:34]([Cl:35])=[C:33]([C:36](=[O:41])[C:37](=[CH2:40])[CH2:38][CH3:39])[CH:32]=[CH:31][C:22]=1[O:23][C:24]1([C:28](O)=[O:29])[CH2:27][CH2:26][CH2:25]1.NCC(O)=O.[NH2:47][CH2:48][CH2:49][C:50]([OH:52])=[O:51]>>[Cl:20][C:21]1[C:34]([Cl:35])=[C:33]([C:36](=[O:41])[C:37](=[CH2:40])[CH2:38][CH3:39])[CH:32]=[CH:31][C:22]=1[O:23][C:24]1([C:28]([NH:47][CH2:48][CH2:49][C:50]([OH:52])=[O:51])=[O:29])[CH2:27][CH2:26][CH2:25]1
Reactant: NCCC(=O)O
Reactant: C=C(CC)C(=O)c1ccc(OC2(C(=O)O)CCC2)c(Cl)c1Cl
Agent: C=C(CC)C(=O)c1ccc(OCC(=O)O)c(Cl)c1Cl
Agent: NCC(=O)O
Product: C=C(CC)C(=O)c1ccc(OC2(C(=O)NCCC(=O)O)CCC2)c(Cl)c1Cl

Procedure:
By carrying out the reaction essentially as described in Example 9, except that the [2,3-dichloro-4-(2-methylenebutyryl)phenoxy]acetic acid is replaced by an equimolar quantity of 1-[2,3-dichloro-4-(2-methylenebutyryl)phenoxy]cyclobutane-1-carboxylic acid and the glycine is replaced by an equimolar quantity of β-alanine, there is obtained N-{1-[2,3-dichloro-4-(2-methylenebutyryl)phenoxy]cyclobutane-1-carbonyl}3-aminopropionic acid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[N:25]=1)[C:20]([OH:22])=O>>[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[N:25]=1)[C:20]([N:2]([CH3:1])[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])=[O:22]
Reactant: O=C(O)c1cc(Cl)nc(C(F)(F)F)c1
Reactant: CNc1cnccc1-c1ccccc1C
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1cc(Cl)nc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 90, from N-methyl-4-o-tolylpyridin-3-amine (example 1, intermediate a) and 2-chloro-6-trifluoromethyl-isonicotinic acid (prepared in analogy to F. Cottet, M. Schlosser, Eur. J. Org. Chem. 2004, 18, 3793-3798) after a reaction time of 66 hours. The compound was purified by two silica gel chromatographies (10 g column each, gradient of n-heptane:EtOAc (100:0 to 50:50) for the first and EtOAc for the second chromatography), followed by preparative HPLC (phenomenex gemini column, gradient of acetonitrile:water (containing 0.05% formic acid) (10:90 to 98:2)). Colorless foam (49%). MS (ESI): m/z=406.09 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:13][CH:14]1[CH2:16][CH:15]1[C:17]1[C:27]([F:28])=[CH:26][C:20]([C:21]([O:23]CC)=[O:22])=[C:19]([F:29])[C:18]=1[F:30])C(OC)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O.Cl>C(O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][CH2:13][CH:14]1[CH2:16][CH:15]1[C:17]1[C:27]([F:28])=[CH:26][C:20]([C:21]([OH:23])=[O:22])=[C:19]([F:29])[C:18]=1[F:30])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cc(F)c(C2CC2CN(C(=O)OC)C(=O)OC(C)(C)C)c(F)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NCC1CC1c1c(F)cc(C(=O)O)c(F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
In 60 ml of ethanol was dissolved 5.22 g of ethyl 4-[2-(N-tert-butoxycarbonyl-N-methoxycarbonylaminomethyl)cyclopropyl]-2,3,5-trifluorobenzoate. To the resulting solution was added 60 ml of a 1N aqueous sodium hydroxide solution. The resulting mixture was stirred at room temperature for 2 hours. To the reaction mixture was added 60 ml of water and the resulting mixture was adjusted to pH 8 with 6N hydrochloric acid. Then, 150 ml of ethyl acetate was added thereto. The aqueous layer was separated and 100 ml of ethyl acetate was added thereto. The resulting mixture was adjusted to pH 2 with 6N hydrochloric acid. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain 4.10 g (98.1%) of 4-(2-tert-butoxycarbonylaminomethylcyclopropyl)-2,3,5-trifluorobenzoic acid.
Reaction SMILES: C([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:13][C:12]([C:14]2[C:15]3[N:22]=[C:21]([NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])[S:20][C:16]=3[N:17]=[CH:18][N:19]=2)=[CH:11][C:10]=1[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[Cl:35])C=C.C(O)(=O)C.C1([SiH3])C=CC=CC=1.O>C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:24]([NH:23][C:21]1[S:20][C:16]2[N:17]=[CH:18][N:19]=[C:14]([C:12]3[S:13][C:9]([C:5]4[NH:6][CH:7]=[CH:8][N:4]=4)=[C:10]([C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=4[Cl:35])[CH:11]=3)[C:15]=2[N:22]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: C=CCn1ccnc1-c1sc(-c2ncnc3sc(NC(C)(C)C)nc23)cc1-c1ccc(Cl)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [SiH3]c1ccccc1
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)Nc1nc2c(-c3cc(-c4ccc(Cl)cc4Cl)c(-c4ncc[nH]4)s3)ncnc2s1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 49.6 %

Procedure:
A solution of 7-[5-(1-allyl-1H-imidazol-2-yl)-4-(2,4-dichlorophenyl)-2-thienyl]-N-(tert-butyl)[1,3]thiazolo[5,4-d]pyrimidin-2-amine (100 mg, 0.185 mmol) and acetic acid (2 mL, 40 mmol) in DCM (6 mL) was degassed with vacuum and then the atmosphere was replaced with nitrogen. To the mixture, tetrakis(triphenylphosphine)palladium(0) (10.7 mg, 0.00923 mmol) and phenylsilane (0.136 mL, 1.11 mmol) were added. The resulting mixture was stirred at 40° C. for 30 min. The solution was allowed to cool to rt, followed by adding water and DCM. After being stirred for 10 min, the organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Column chromatography was performed to yield the title compound (46.0 mg, 50%) as a pale yellow solid. LCMS: (AA) ES+ 501, 503. 1H NMR (400 MHz, d6-DMSO) δ: 11.84 (bs, 1H), 8.69 (bs, 1H), 8.63 (s, 1H), 8.43 (s, 1H), 7.73 (d, J=2.0 Hz, 1H), 7.46-7.43 (m, 1H), 7.34 (d, J=8.3 Hz, 1H), 7.14 (bs, 1H), 6.98 (bs, 1H), 1.47 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[NH2:25]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:12]([NH2:14])=[O:13])=[CH:7][C:8]=1[C:9]([NH:25][C:16]1[CH:17]=[CH:18][C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:15]=1)=[O:11]
Reactant: Nc1ccc2ccccc2c1
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1ccc2ccccc2c1

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 2-naphthaleneamine by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([O:9][CH2:10][C@@H:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:12]=[CH2:13])C=C)(=[O:3])[CH3:2]>C(=[Ru](Cl)(Cl)([C-]1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)P(C1CCCCC1)(C1CCCCC1)C1CCCCC1)C1C=CC=CC=1>[C:1]([O:4][CH2:5][CH:6]1[CH:13]=[CH:12][C@H:11]([NH:14][C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:10][O:9]1)(=[O:3])[CH3:2]
Reactant: C=CC(COC(C)=O)OC[C@H](C=C)NC(=O)OC(C)(C)C
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)[C-]2[Ru](Cl)(Cl)(=Cc2ccccc2)[PH](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Product: CC(=O)OCC1C=C[C@H](NC(=O)OC(C)(C)C)CO1
Temperature: 25 °C
Reaction time: 15 h
Yield: 85.4 %

Procedure:
To a 500 mL 2-neck round bottom flask, benzylidene(dichloro)(1,3-dimesitylimidazolidin-2-id-2-yl)(tricyclohexylphosphoranyl)ruthenium (38 mg, 0.044 mmol) was added. After purged with nitrogen for 3 times, dichloromethane (anhydrous, 8 mL) was added followed by 2-({(2S)-2-[(tert-butoxycarbonyl)amino]but-3-en-1-yl}oxy)but-3-en-1-yl acetate (265 mg, 0.885 mmol). The reaction mixture was stirred at room temperature for 15 h. The mixture was concentrated in vacuo. The residue was purified via flash chromatography (eluting with hexanes to 25% EtOAc in hexanes) to give the desired product as a brown oil (0.205 g, 85%). LCMS calculated for C9H14NO5 (M+H-Bu+H)+: m/z=216.1. Found: 216.1. 1H NMR (300 MHz, CDCl3) δ 5.94 (0.17H, m), 5.84 (0.83H, m), 5.69 (1H, m), 4.89 (0.13H, m), 4.70 (0.83H, m), 4.25 (1H, m), 4.05 (4H, m), 3.56 (0.13H, m), 3.38 (0.87H, m), 2.04 (2.49H, s), 2.03 (0.51H, m), 1.38 (9H, s) ppm (The product was a ˜5:1 mixture of trans- and cis-isomers).
Reaction SMILES: [H-].[Na+].[C:3]([CH:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])[C:12]=1[O:25][CH3:26])[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4].[CH3:27][CH2:28][CH2:29]Br>>[C:3]([C:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])[C:12]=1[O:25][CH3:26])([CH2:27][CH2:28][CH3:29])[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4]
Reactant: CCCBr
Reactant: CCOC(=O)C(C#N)c1cccc(Oc2ccccc2C)c1OC
Agent: [H-]
Agent: [Na+]
Product: CCCC(C#N)(C(=O)OCC)c1cccc(Oc2ccccc2C)c1OC
Yield: 104 %

Procedure:
50% Sodium hydride (650 mg), ethyl 2-cyano-2-[2-methoxy-3-(o-tolyloxy)phenyl]acetate (4 g) and n-propyl bromide (3.8 g) were treated in a similar manner to that of Example 14-(6) to give oily ethyl 2-cyano-2-[2-methoxy-3-(o-tolyloxy)phenyl]valerate (4.7 g).
Reaction SMILES: CC[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([CH2:10][CH2:11][C@@H:12]1[C@@H:16]([CH2:17]/[CH:18]=[CH:19]/[CH2:20][CH2:21][CH2:22][C:23]([O:25]C(C)C)=[O:24])[C@@H:15]([OH:29])[CH2:14][C@H:13]1[OH:30])=[O:9].O[C@@H]1C[C@H](O)[C@H](C/C=C\CCCC(OC(C)C)=O)[C@H]1CCC(=O)CCCCCCC>>[OH:30][C@@H:13]1[CH2:14][C@H:15]([OH:29])[C@H:16]([CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C@H:12]1/[CH:11]=[CH:10]/[C@@H:8]([OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH3:3]
Reactant: CCCCCCCC(=O)CC[C@@H]1[C@@H](C/C=C/CCCC(=O)OC(C)C)[C@@H](O)C[C@H]1O
Agent: CCCCCCCC(=O)CC[C@@H]1[C@@H](C/C=C\CCCC(=O)OC(C)C)[C@@H](O)C[C@H]1O
Product: CCCCC[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H](O)C[C@H]1O

Procedure:
13,14-dihydro-15-keto-20-ethyl-PGF2 α isopropyl ester is isopropyl(Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-{3-oxo-1-decyl}cyclopentyl]-hept-5-enoate;
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:7]([NH:9][C:10]1[C:11]([CH3:19])=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=[O:14])=[O:8])(=O)C.N1CCCC1.Cl>CO>[SH:4][CH2:5][CH:6]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:7]([NH:9][C:10]1[C:11]([CH3:19])=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=[O:14])=[O:8]
Reactant: CC(=O)SCC(CC(C)C)C(=O)Nc1cccc(C(=O)O)c1C
Agent: Cl
Solvent: C1CCNC1
Solvent: CO
Product: Cc1c(NC(=O)C(CS)CC(C)C)cccc1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
3-[(2-Acetylthiomethyl-4-methylpentanoyl)amino]-2-methylbenzoic acid (compound of Example 175) (3 g), 70% aqueous methanol (30 ml) and pyrrolidine (2.2 g) are mixed, and the mixture is stirred at room temperature for 30 minutes. The reaction mixture is adjusted to pH 3.0 with 10% hydrochloric acid, and methanol is distilled off under reduced pressure. The precipitated crystals are separated by filtration and dissolved in 50% aqueous acetonitrile and purified by a column chromatography using Diaion HP-20 (eluant, water-acetonitrile). The fractions containing the desired compound are collected and acetonitrile is distilled off under reduced pressure, and the precipitated crystals are separated by filtration to give the title compound (2 g). m.p.: 166°-168° C. (colorless needles) IR (KBr; cm-1): 1690, 1660