Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[F:9].[Br:10]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:10])=[CH:4][C:3]=1[F:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(Br)c(F)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CC#N
Product: Fc1cc(CBr)ccc1Br
Temperature: 25 °C
Yield: 90 %

Procedure:
A solution of 4-bromo-3-fluorotoluene (21.5 g, 0.114 moles) in acetonitrile (200 ml) is added with N-bromosuccinimide, (NBS; 21.2 g, 0.119 moles). The mixture is refluxed, added with dibenzoyl peroxide (1.4 g, 0.004 moles), refluxed for 3 hour, then cooled at room temperature, and extracted with water. The aqueous phase is discarded, and the organic phase is washed with brine, dried over sodium sulphate, and concentrated under vacuum to give an oil (27.1 g, 90% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]2[N:9]=[C:10]([NH2:12])[N:11]=[C:7]2[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][CH:4]=1.C[Al](C)C.C[O:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][CH:28]=1)=O.Cl>O1CCOCC1.C1(C)C=CC=CC=1>[Br:33][C:30]1[CH:31]=[CH:32][C:27]([C:25]([NH:12][C:10]2[N:11]=[C:7]3[C:6]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]3[N:9]=2)=[O:24])=[CH:28][CH:29]=1
Reactant: COC(=O)c1ccc(Br)cc1
Reactant: COc1ccc(-c2ccccc2)c2nc(N)nn12
Agent: C[Al](C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccccc2)c2nc(NC(=O)c3ccc(Br)cc3)nn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.2 %

Procedure:
To a solution of 24 mg (0.1 mmol) 5-methoxy-8-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl-amine in 1 ml dioxane was added 0.4 ml (0.4 mmol) of a 1 M solution of AlMe3 in toluene and allowed to stir for 1 h at room temperature. 86 mg (0.4 mmol) 4-bromo-phenyl carboxylic acid methyl ester in I ml dioxane was added and the mixture was stirred for 48 h at 90° C. 0.5 ml 1N HCl aq. was added and the mixture was evaporated to dryness. The residue was taken up in 1.5 ml formic acid and 0.5 ml methanol and subjected to reversed phase HPLC chromatography eluting with a water/acetonitrile gradient. Evaporation of the eluents yielded 6 mg (15%) of the title compound. MS m/e (%): 423.3 (M+H+, 100).
Reaction SMILES: [OH:1][CH:2]([CH:14]=[CH2:15])[CH2:3][CH2:4][N:5]([CH3:13])[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[Cl:16][C:17]1[C:24]([F:25])=[CH:23][C:20]([C:21]#[N:22])=[C:19](F)[CH:18]=1>CN(C)C=O>[Cl:16][C:17]1[C:24]([F:25])=[CH:23][C:20]([C:21]#[N:22])=[C:19]([CH:18]=1)[O:1][CH:2]([CH:14]=[CH2:15])[CH2:3][CH2:4][N:5]([CH3:13])[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:9])[CH3:10]
Reactant: N#Cc1cc(F)c(Cl)cc1F
Reactant: C=CC(O)CCN(C)C(=O)OC(C)(C)C
Solvent: CN(C)C=O
Product: C=CC(CCN(C)C(=O)OC(C)(C)C)Oc1cc(Cl)c(F)cc1C#N

Procedure:
The subtitle compound was prepared according to the method of Example 3 step (b) using (3-hydroxy-4-pentenyl)methylcarbamic acid, 1,1-dimethylethyl ester and 4-chloro-2,5-difluorobenzonitrile in N,N-dimethylformamide.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][CH:7]=[C:6]3[C:12](=[O:21])[N:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:14]=[C:5]3[C:4]=2[CH:3]=1.C(OC(C1C=NC2C(C=1[Cl:37])=CC(F)=C(Cl)C=2)=O)C>>[Cl:37][C:11]1[C:2]([F:1])=[CH:3][C:4]2[C:5]3[C:6]([C:12](=[O:21])[N:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:14]=3)=[CH:7][NH:8][C:9]=2[CH:10]=1
Reactant: O=c1c2c[nH]c3ccc(F)cc3c-2nn1-c1ccccc1
Reactant: CCOC(=O)c1cnc2cc(Cl)c(F)cc2c1Cl
Product: O=c1c2c[nH]c3cc(Cl)c(F)cc3c-2nn1-c1ccccc1

Procedure:
The title compound was prepared following procedure for 23a using ethyl-4,7-dichloro-6-fluoro-quinoline-3-carboxylate. 1H-NMR (DMSO-d6) δ (ppm): 7.20 (1H, t, J=7.41 Hz), 7.48 (3H, m), 8.19 (2H, m), 8.43 (1H, dd, J=8.79, 2.46 Hz), 8.54 (1H, d, J=2.20 Hz), 8.92 (1H, s). m/z 314.7 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[C:9]([F:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:16])=O>>[Cl:1][C:2]1[C:10]([CH3:11])=[C:9]([F:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: Cc1c(F)c(F)cc(C(=O)O)c1Cl
Reactant: O=S(Cl)Cl
Product: Cc1c(F)c(F)cc(C(=O)Cl)c1Cl
Reaction time: 1 h

Procedure:
To 2-chloro-4,5-difluoro-3-methylbenzoic acid (3.1 g) is added thionyl chloride (6 ml), and the mixture is reflexed for one hour. The mixture is concentrated under reduced pressure to give 2-chloro-4,5-difluoro-3-methylbenzoyl chloride (3.3 g).
Reaction SMILES: [CH3:1][C:2]([OH:6])([CH3:5])[CH2:3][NH2:4].[CH:7]1([CH:13]=O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>>[CH:7]1([CH:13]2[NH:4][CH2:3][C:2]([CH3:5])([CH3:1])[O:6]2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CC(C)(O)CN
Reactant: O=CC1CCCCC1
Product: CC1(C)CNC(C2CCCCC2)O1

Procedure:
2-Methyl-2-hydroxypropylamine was reacted with cyclohexanecarboxaldehyde according to Method B4c, Step 1 to give 2-cyclohexyl-5,5-dimethyl-1,3-oxazolidine. The oxazolidine was reduced according to Method B4c, Step 2 to give N-cyclohexyl-2-methyl-2-hydroxypropylamine. The propanolamine was reacted with SOCl2 followed by 2,6-dichlorophenyl isothiocyanate according to Method C2f to afford 2-(2,6-dichlorophenylimino)-3-cyclohexyl-5,5-dimethyl-1,3-thiazolidine.
Reaction SMILES: Cl[C:2](=[O:9])[CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].[CH3:10][O:11][CH:12]([O:32][CH3:33])[CH:13]1[CH2:18][CH2:17][N:16]([S:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28](=[NH:31])[NH:29]O)=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH2:15][CH2:14]1.N1C=CC=CC=1>>[CH3:8][O:7][C:5](=[O:6])[CH2:4][CH2:3][C:2]1[O:9][N:31]=[C:28]([C:25]2[CH:26]=[CH:27][C:22]([S:19]([N:16]3[CH2:17][CH2:18][CH:13]([CH:12]([O:11][CH3:10])[O:32][CH3:33])[CH2:14][CH2:15]3)(=[O:21])=[O:20])=[CH:23][CH:24]=2)[N:29]=1
Reactant: COC(=O)CCC(=O)Cl
Reactant: COC(OC)C1CCN(S(=O)(=O)c2ccc(C(=N)NO)cc2)CC1
Solvent: c1ccncc1
Product: COC(=O)CCc1nc(-c2ccc(S(=O)(=O)N3CCC(C(OC)OC)CC3)cc2)no1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
Methyl 4-chloro-4-oxobutanoate (0.391 g, 2.6 mmol), 4-{[4-(dimethoxy-methyl)-1-piperidinyl]sulfonyl}-N-hydroxybenzenecarboximidamide (0.480 g, 1.3 mmol) was dissolved in 4 mL (49.5 mmol) of pyridine and stirred at 85° C. overnight. The solvent was evaporated with toluene, and the reaction mixture was partitioned between chloroform and water. The organic layer was washed with brine and dried with sodium sulfate. The final product was purified my flash chromatography (chloroform-methanol, 50:1) to give 0.130 g (0.22 mmol).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:24])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH2:32][CH2:31]1)=[O:29])[CH3:26]>>[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([CH3:24])[CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:4][CH:3]=3)=[CH:35][CH:34]=2)[CH2:31][CH2:32]1)=[O:29])[CH3:26]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCc1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)CCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-(1-methyl-3-phenyl-propyl)-amine (Enantiomer B) and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][C:10](=[O:18])[C:11]3[C:12]([O:17][C:7]=2[CH:6]=[CH:5][CH:4]=1)=[N:13][CH:14]=[CH:15][CH:16]=3.[Cl-].[NH4+].C(OCC)(=O)C.[CH2:27]1[CH2:31]OC[CH2:28]1>>[CH:28]1([C:10]2([OH:18])[C:11]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[O:17][C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=3[CH2:9]2)[CH2:27][CH2:31]1
Reactant: COc1cccc2c1CC(=O)c1cccnc1O2
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: COc1cccc2c1CC(O)(C1CC1)c1cccnc1O2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5,11-dihydro-7-methoxy [1]benzoxepino[2,3-b]pyridin-5-one (5.0 g) in THF (50 ml) was added 1.1M cyclopropylmagnesium bromide THF solution (25 ml) at 0° C. The reaction mixture was warmed to room temperature, and stirred for 30 minutes. Aqueous ammonium chloride and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was filtered and washed with ethyl acetate-hexane (1:2) to give 5-cyclopropyl-5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ol (5.0 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]([O:13][CH2:14][C:15]3([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)[CH3:12])[CH:10]=1)[NH:7][N:6]=[CH:5]2.FC(F)(F)C(O)=O.C(Cl)Cl>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]([O:13][CH2:14][C:15]3([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]3)[CH3:12])[CH:10]=1)[NH:7][N:6]=[CH:5]2
Reactant: CC(OCC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2cn[nH]c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(OCC1(c2ccccc2)CCNCC1)c1cc(Cl)cc2cn[nH]c12

Procedure:
(±)-tert-Butyl 4-((1-(5-chloro-1H-indazol-7-yl)ethoxy)methyl)-4-phenylpiperidine-1-carboxylate (80 mg, 0.17 mmol) was treated with a trifluoroacetic acid/methylene chloride mixture (1:1, 2 mL) for 1 h. The solvent was removed in vacuo and the resulting crude mixture passed through a strong cation exchange column. After washing the column with several volumes of methanol, the product was eluted by washing the column with 2 M ammonia in methanol. The solvent was evaporated to afford 50 mg (79%) as a clear oil. 1H-NMR (CDCl3, 500 MHz) δ 7.89 (s, 1H), 7.54 (d, J=1.8 Hz, 1H), 7.37-7.40 (m, 2H), 7.30-7.32 (m, 3H), 7.69 (m, 1H), 4.49 (q, J=6.7 Hz, 1H), 3.40 (d, J=9.2 Hz, 1H), 3.29 (d, J=9.2 Hz, 1H), 2.87-2.93 (m, 2H), 2.67-2.77 (m, 2H), 2.07-2.26 (m, 2H), 1.78-1.93 (m, 2H), 1.41 (m, 3H); 13C-NMR (126 MHz, CDCl3) δ ppm 143.7, 135.7, 133.6, 128.8, 127.9, 127.1, 126.7, 126.0, 124.8, 124.1, 118.9, 78.0, 50.4, 42.6, 41.9, 33.5, 22.1. Mass spec.: 370.17 (MH)+.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[N+:4]([O-])[CH:3]=1.C(N(CC)CC)C.O=P(Cl)(Cl)[Cl:20]>>[Cl:20][C:3]1[N:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:1]([OH:10])=[O:9]
Reactant: O=C(O)c1ccc[n+]([O-])c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(O)c1cccnc1Cl
Temperature: 100 °C

Procedure:
70 gm. of nicotinic acid-N-oxide was suspended in 300 ml of POCl3. Then 50 gm. of triethyl amine was added drop by drop at room temperature, whereby the nicotinic acid-N-oxide dissolved at about 50° C. (the temperature rise occured due to an exothermic reaction). Then the solution was heated in a water bath at 100° C. for another 4 hours. The main quantity of excess phosphorus oxychloride was distilled off under vacuum. The residue was allowed to flow into water at a temperature below 40° C. After addition of diluted caustic soda solution, the 2-chloronicotnic acid precipitated at a pH value of 2.0 to 2.5. The product had a melting point of 173° to 175° C. (Kofler). The product (2-chloronicotinic acid) yield amounted to 65 to 70 percent of theory.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:11][N:12]([CH2:23][C:24]2[CH:29]=[C:28]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:27]=[CH:26][N:25]=2)[CH:13]2[C:22]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:16][CH2:15][CH2:14]2)=[C:7]([CH2:9][OH:10])[CH:8]=1.Cl.[CH2:35]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:38][CH:37]([C:45](O)=[O:46])[NH:36]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:30]([C:28]1[CH:27]=[CH:26][N:25]=[C:24]([CH2:23][N:12]([CH2:11][C:6]2[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:45]([CH:37]3[CH2:38][C:39]4[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH2:35][NH:36]3)=[O:46])=[CH:8][C:7]=2[CH2:9][OH:10])[CH:13]2[C:22]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:16][CH2:15][CH2:14]2)[CH:29]=1)([CH3:33])([CH3:32])[CH3:31]
Reactant: O=C(O)C1Cc2ccccc2CN1
Reactant: CC(C)(C)c1ccnc(CN(Cc2ccc(CN)cc2CO)C2CCCc3cccnc32)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccnc(CN(Cc2ccc(CNC(=O)C3Cc4ccccc4CN3)cc2CO)C2CCCc3cccnc32)c1
Yield: 27.1 %

Procedure:
(5-Aminomethyl-2-{[(4-tert-butyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-phenyl)-methanol (0.047 g, 0.11 mmol), (±)-1,2,3,4-tetrahydro-3-isoquinoline carboxylic acid hydrochloride (0.027 g, 0.13 mmol), HOBT (0.017 g, 0.13 mmol), EDCI (0.024 g, 0.13 mmol) and DIPEA (40 μL, 0.26 mmol) in CH2Cl2 (8 mL) were reacted according to General Procedure G. Purification by column chromatography on silica gel (CH2Cl2:MeOH:NH4OH, 94:5:1, v/v/v) afforded 1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid 4-{[(4-tert-butyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-3-hydroxymethyl-benzylamide as a white solid (0.018 g, 28%). 1H NMR (CDCl3) δ 1.40 (s, 9H), 1.59 (m, 1H), 1.89-2.02 (m, 2H), 2.22 (m, 1H), 2.69 (m, 1H), 2.79 (m, 1H), 3.22 (dt, 1H, J=12.0, 3.0 Hz), 3.55-3.66 (m, 4H), 3.87 (m, 1H), 3.94 (d, 2H, J=4.5 Hz), 4.06 (d, 2H, J=12.0 Hz), 4.40 (m, 3H), 7.04-7.24 (m, 9H), 7.36 (d, 1H, J=7.5 Hz), 7.52 (br t, 1H), 7.89 (s, 1H), 8.36 (d, 1H, J=6.0 Hz), 8.51 (d, 1H, J=3.0 Hz). HPLC: 89%. ES-MS m/z 604 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[S:17]([N:20]=CN(C)C)(=[O:19])=[O:18].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:32][CH2:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[S:17]([NH2:20])(=[O:19])=[O:18]
Reactant: BrCCCc1ccccc1
Reactant: CN(C)C=NS(=O)(=O)c1cc(C(=O)c2ccc(O)cc2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: NS(=O)(=O)c1cc(C(=O)c2ccc(OCCCc3ccccc3)cc2)ccc1Cl
Temperature: 65 °C
Yield: 3.4 %

Procedure:
2-Chloro-N-dimethylaminomethylene-5-(4-hydroxy-benzoyl)-benzenesulfonamide (250 mg, 0.68 mmol) is dissolved in N,N,-dimethylformamide (5 mL). Potassium carbonate (235 mg, 1.7 mmol) is then added followed by (3-bromo-propyl)-benzene (135 mg, 0.68 mmol). The reaction is heated to 65° C. for 18 hours. The reaction mixture is diluted with water and extracted with ethyl acetate, the organic layer is separated and concentrated in vacuo. The crude ether is purified by column chromatography (gradient of ethyl acetate in hexanes 25-75%). The residue is dissolved in ethanol (3 mL), treated with concentrated HCl (400 μl) and heated to reflux for 2.5 hours after which the reaction is allowed to cool to ambient temperature overnight. The volatiles were removed in vacuo and the crude sulfonamide is purified by column chromatography (gradient of ethyl acetate in hexanes 20-70%) affording 10 mg of the title compound. 1H NMR (DMSO) δ 2.02-2.11 (m, 2H), 2.76 (t, 2H, J=7.16 Hz), 4.10 (t, 2H, J=6.41 Hz), 7.10 (d, 2H, J=8.67 Hz), 7.17-7.32 (m, 5H), 7.75-7.91 (m, 6H), 8.24 (d, 1H, J=1.88 Hz). MS (m/z): 430 (M+1).
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH2:13])=[CH:8][CH:7]=1)=O.[N+](=[CH:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N-].C(=O)([O-])[O-].[K+].[K+].O>C(Cl)(Cl)Cl>[CH2:22]([O:21][C:19]([C@@H:18]1[CH2:13][C@H:12]1[C:9]1[CH:8]=[CH:7][C:6]([NH2:5])=[CH:11][CH:10]=1)=[O:20])[CH3:23]
Reactant: C=Cc1ccc(NC(=O)C(F)(F)F)cc1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)[C@@H]1C[C@H]1c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.9 %

Procedure:
Trifluoroacetic anhydride (10.3 mL, 73.9 mmol) was added to a solution of 4-aminostyrene (8.00 g, 67.2 mmol) and pyridine (8.1 mL, 100.8 mmol) in 100 mL of dichloromethane at 0° C. The reaction mixture was diluted with dichloromethane and washed with 1N aqueous hydrochloric acid, dried over anhydrous sodium sulfate, concentrated under vacuum and purified by chromatography (silica gel, hexane:ethyl acetate) to give 10.89 g (75%) of 2,2,2-trifluoro-N-(4-vinylphenyl)acetamide (VIII-3) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.85 (br s, 1H), 7.52 (d, J=8.61 Hz, 2H), 7.42 (d, J=8.61 Hz, 2H), 6.67 (dd, J=10.99 Hz, 17.58 Hz, 1H), 5.73 (d, J=17.58 Hz, 1H), 5.27 (d, J=10.80 Hz, 1H). (2R)-4-tert-Butyl-2-{1-[(4R)-4-tert-butyl-4,5-dihydro-1,3-oxazol-2-yl]-1-methylethyl}-4,5-dihydro-1,3-oxazole (VIII-A) (0.147 g, 0.501 mmol) prepared as described by Evans et al., J. Am. Chem. Soc. 1991, 113, 726-728, was added to a suspension of copper (I) trifluormethanesulfonate-toluene complex (2:1) in 15 mL of chloroform at room temperature. After 1.5 hours the mixture was added to a solution of 2,2,2-trifluoro-N-(4-vinylphenyl)acetamide (10.77 g, 50.1 mmol) in 200 mL of chloroform. A small amount (2-3 mL) of a solution of ethyl diazoacetate (7.8 mL, 74.1 mmol) in 100 mL of chloroform was added. The mixture was carefully warmed with a heat gun until gas evolution and a color change from green to yellow occurred. The remaining ethyl diazoacetate solution was added dropwise over two hours. The solvent was evaporated. The crude product (˜3:1 trans VIII-4/cis VIII-5) was dissolved in 150 mL of methanol and potassium carbonate (13.8 g, 100.2 mmol) and 50 mL of water were added. The mixture was stirred at room temperature overnight. Methanol was evaporated and the residue was extracted between dichloromethane and water. The organic phase was evaporated and the residue was purified by chromatography on silica gel with an ethyl acetate gradient (5 to 30%) in hexanes to give 1.02 g (10% yield) of the title compound as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 6.89 (d, J=8.24 Hz, 2H), 6.59 (d, J=8.42 Hz, 2H), 4.14 (quartet, J=7.14 Hz, 2H), 3.59 (br s, 2H), 2.41 (m, 1H), 1.75 (m, 1H), 1.50 (m, 1H), 1.26 (t, J=7.14 Hz, 3H), 1.21 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[C:16]([C:18]2[NH:19][C:20]([C:23]3[S:24][CH:25]=[CH:26][N:27]=3)=[CH:21][CH:22]=2)[CH:15]=[C:14]([O:28][C@@H:29]([CH3:33])[CH2:30][O:31][CH3:32])[CH:13]=1)[C:5]([OH:7])=O.N.CC[N:37]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.O>ClCCl.O>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[C:16]([C:18]2[NH:19][C:20]([C:23]3[S:24][CH:25]=[CH:26][N:27]=3)=[CH:21][CH:22]=2)[CH:15]=[C:14]([O:28][C@@H:29]([CH3:33])[CH2:30][O:31][CH3:32])[CH:13]=1)[C:5]([NH2:37])=[O:7]
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)O)cc2F)cc(-c2ccc(-c3nccs3)[nH]2)c1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: COC[C@H](C)Oc1cc(Oc2ccc(C(N)=O)cc2F)cc(-c2ccc(-c3nccs3)[nH]2)c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 23.7 %

Procedure:
3-Fluoro-4-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxyl}benzoic acid (40.0 mg, 0.163 mmol) synthesized in Example (44a) was dissolved in dichloromethane (5 mL), and 28% aqueous ammonia solution (0.50 mL), WSCI•HCl (19.6 mg, 0.102 mmol) and HOBt•H2O (13.1 mg, 0.086 mmol) were added, followed by stirring at room temperature for 7 hours under nitrogen atmosphere. To the reaction solution, water (10 mL) was added, and extraction was carried out with ethyl acetate (20 mL). The organic layer was washed with saturated brine, and subsequently dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=0%-75%) to afford the desired compound (11.3 mg, yield 28%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[N:15]4[CH2:16][CH2:17][S:18][C@:19]([CH2:22][O:23][Si](C(C)(C)C)(C)C)([CH3:21])[CH2:20][C:14]4=[N:13][N:12]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:39]2[CH:40]=[N:41][NH:42][CH:43]=2)O1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.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>[CH3:21][C@@:19]1([CH2:22][OH:23])[S:18][CH2:17][CH2:16][N:15]2[C:11]([C:8]3([C:5]4[CH:4]=[CH:3][C:2]([C:39]5[CH:40]=[N:41][NH:42][CH:43]=5)=[CH:7][CH:6]=4)[CH2:9][CH2:10]3)=[N:12][N:13]=[C:14]2[CH2:20]1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@]1(C)Cc2nnc(C3(c4ccc(Br)cc4)CC3)n2CCS1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: C[C@]1(CO)Cc2nnc(C3(c4ccc(-c5cn[nH]c5)cc4)CC3)n2CCS1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.3 %

Procedure:
A solution of the compound (500 mg, 0.98 mmol) obtained in Example 52-1), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (210 mg, 1.08 mmol), tetrakis(triphenylphosphine)palladium(0) (114 mg, 0.10 mmol), and potassium carbonate (272 mg, 1.97 mmol) in 1,2-dimethoxyethane (6 mL) and water (3 mL) was stirred at 120° C. for 1 h under microwave irradiation. The reaction mixture was cooled to room temperature, water (10 mL) was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After concentration under reduced pressure, the residue was partially purified by silica gel chromatography (ethyl acetate:methanol=40:60). A solution of the residue and 4 M hydrochloric acid (1,4-dioxane solution, 3 mL) in methanol (6 mL) was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, a 5 N aqueous sodium hydroxide solution (10 mL) was added to the residue, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After concentration under reduced pressure, the residue was partially purified by silica gel chromatography (ethyl acetate/methanol=40:60). The residue was dissolved in a solution (8 mL) of ethyl acetate/methanol=3:1, and diisopropyl ether (20 mL) was gradually added to the mixture with stirring at room temperature to prepare a suspension. The suspension was stirred at 60° C. for 1 h and stirred for 1 h with cooling to room temperature. The colorless precipitate was collected by filtration and washed with diisopropyl ether. The solid was dried under reduced pressure to obtain the title compound (46 mg, 12%) as a colorless solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[C:4]([O:10][C:11]([F:14])([F:13])[F:12])[CH:3]=1.[B:15](OC(C)C)([O:20]C(C)C)[O:16]C(C)C.Cl>O1CCCC1>[CH3:9][S:8][C:5]1[CH:6]=[CH:7][C:2]([B:15]([OH:20])[OH:16])=[CH:3][C:4]=1[O:10][C:11]([F:14])([F:13])[F:12]
Reactant: CSc1ccc(Br)cc1OC(F)(F)F
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CSc1ccc(B(O)O)cc1OC(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.9 %

Procedure:
To a solution of 4-bromo-1-(methylthio)-2-(trifluoromethoxy)benzene (6.63 g, 23.1 mmol) and triisopropyl borate (6.92 mL, 30.0 mmol) in tetrahydrofuran (50 mL) was added dropwise 1.6 M n-butyllithium-hexane solution (25.0 mL, 40.0 mmol) at −78° C., and the resulting mixture was stirred for 30 min. The reaction mixture was warmed to 0° C., 2 M hydrochloric acid (150 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was washed with hexane/ethyl acetate (5/1) and recrystallized from hexane/tetrahydrofuran to give the title compound (4.13 g, yield 71%) as colorless crystals.