Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:7]([N+:9]([O-:11])=[O:10])[O:8][C:4]=2[CH:3]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>>[C:20]([NH:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:7]([N+:9]([O-:11])=[O:10])[O:8][C:4]=2[CH:3]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2c(-c3ccccc3)c([N+](=O)[O-])oc2c1
Product: CC(=O)Nc1ccc2c(-c3ccccc3)c([N+](=O)[O-])oc2c1

Procedure:
Using the method of Example 12, 6-amino-2-nitro-3-phenylbenzofuran is reacted with acetic anhydride to provide 6-acetamido-2-nitro-3-phenylbenzofuran, m.p. 212°-214° C.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]2[C:8]=1[CH:9]=[N:10][N:11]2[CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1.CN([CH:26]=[O:27])C>C1COCC1>[F:16][C:14]1[CH:15]=[C:7]([CH:26]=[O:27])[C:8]2[CH:9]=[N:10][N:11]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[C:12]=2[CH:13]=1
Reactant: Fc1cc(Br)c2cnn(C3CCCCO3)c2c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cc(F)cc2c1cnn2C1CCCCO1
Temperature: -40 °C
Reaction time: 2 h
Yield: 65.5 %

Procedure:
To a solution of n-butyllithium (13 mL, 21.4 mmol, 1.6 M in hexanes) in THF (60 mL) at −78° C. was added dropwise over 30 min a solution of 4-bromo-6-fluoro-1-tetrahydropyran-2-yl-indazole (4.00 g, 13.4 mmol) in THF (20 mL). The reaction was warmed to −40° C. for 5 min, re-cooled to −78° C., and DMF (4.2 mL, 53.5 mmol) was added. The reaction mixture was allowed to warm to RT and stirred for 2 h. The reaction was then quenched with a satd. aq. NH4Cl at 0° C. EtOAc was added and the layers were separated, and the aqueous layer was extracted once with EtOAc. The combined extracts were dried (Na2SO4), filtered and concentrated in vacuo. The crude mixture was purified by SiO2 chromatography to afford 6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-carbaldehyde (2.18 g, 66%), as a white solid. MS (ESI) m/z: 249.3 [M+1]+.
Reaction SMILES: [F:1][C:2]([F:16])([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[CH2:3][CH2:4][S:5]C(=O)C.[OH-].[Na+]>CCO>[F:16][C:2]([F:1])([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[CH2:3][CH2:4][SH:5]
Reactant: CC(=O)SCCC(F)(F)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Fc1ccc(C(F)(F)CCS)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
To a solution of ethanethioic acid S—[3,3-difluoro-3-(4-fluorophenyl)-propyl]ester (0.26 g, 1.05 mmol) in EtOH (3 ml) is added 35% aqueous sodium hydroxide (3 ml) at 0° C. and the reaction mixture is stirred at RT for 1 h. After completion of the reaction, the solvent is distilled off and the residue is diluted with water (10 ml) before acidification with 2N hydrochloric acid to pH 2. The aqueous layer is extracted with EtOAc (3×15 ml) and the combined organic layers are washed with water (20 ml), brine (20 ml), dried over anhydrous sodium sulfate and evaporated to get 3,3-difluoro-3-(4-fluorophenyl)-propane-1-thiol (0.20 g, 0.97 mmol, 92%), which is used in the next step without further purification.
Reaction SMILES: [CH:1]1([CH2:4][C:5]2[C:6]([OH:15])=[C:7]([CH:11]=[CH:12][C:13]=2[OH:14])[C:8]([NH2:10])=[O:9])[CH2:3][CH2:2]1.I[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:34]=[CH:33][C:24]2[CH2:25][CH2:26][CH:27]([C:29]([O:31][CH3:32])=[O:30])[O:28][C:23]=2[C:22]=1[CH2:35][CH2:36][CH3:37]>>[NH2:10][C:8]([C:7]1[CH:11]=[CH:12][C:13]([O:14][CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:34]=[CH:33][C:24]3[CH:25]=[CH:26][CH:27]([C:29]([O:31][CH3:32])=[O:30])[O:28][C:23]=3[C:22]=2[CH2:35][CH2:36][CH3:37])=[C:5]([CH2:4][CH:1]2[CH2:3][CH2:2]2)[C:6]=1[OH:15])=[O:9]
Reactant: NC(=O)c1ccc(O)c(CC2CC2)c1O
Reactant: CCCc1c(OCCCI)ccc2c1OC(C(=O)OC)CC2
Product: CCCc1c(OCCCOc2ccc(C(N)=O)c(O)c2CC2CC2)ccc2c1OC(C(=O)OC)C=C2

Procedure:
The compound of Example 66 and the compound of Example 23 are reacted together under the conditions described in Example 24. The crude product is purified by chromatography on silica gel using ethyl acetate/hexane (4:6) as eluant to afford the product.
Reaction SMILES: [ClH:1].Cl.[CH3:3][O:4][CH2:5][CH2:6][C@@H:7]1[NH:12][CH2:11][CH2:10][N:9]([C:13]2[C:22]3[CH:21]=[C:20]([CH3:23])[S:19][C:18]=3[NH:17][C:16]3[CH:24]=[CH:25][CH:26]=[CH:27][C:15]=3[N:14]=2)[CH2:8]1.[C:28]1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[ClH:1].[ClH:1].[CH3:3][O:4][CH2:5][CH2:6][C@@H:7]1[N:12]([CH3:28])[CH2:11][CH2:10][N:9]([C:13]2[C:22]3[CH:21]=[C:20]([CH3:23])[S:19][C:18]=3[NH:17][C:16]3[CH:24]=[CH:25][CH:26]=[CH:27][C:15]=3[N:14]=2)[CH2:8]1
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Reactant: COCC[C@H]1CN(C2=Nc3ccccc3Nc3sc(C)cc32)CCN1
Agent: Cl
Product: COCC[C@H]1CN(C2=Nc3ccccc3Nc3sc(C)cc32)CCN1C
Yield: 22 %

Procedure:
In a manner such as that described in Example 269, using (S)-10-[3-(2-methoxyethyl)-piperazin-1-yl]-2-methyl-4H-3-thia-4,9-diazabenzo[f]azulene dihydrochloride into the dihydrochloride salt of the title compound (102 mg, 22%): mass Spectrum (ES): m/z 371.2 (M+1 of free base).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[S:3]([O:6][C:7]1[C:8]2[CH:9]=[C:10](C#CC3C=CC(C(OCC)=O)=CC=3)[CH:11]=[CH:12][C:13]=2[C:14]([CH3:18])([CH3:17])[CH2:15][CH:16]=1)(=[O:5])=[O:4].CC1(C)C2C=C([C:45]#[C:46][C:47]3[CH:57]=[CH:56][C:50]([C:51]([O:53][CH2:54][CH3:55])=[O:52])=[CH:49][CH:48]=3)C=CC=2C(=O)CC1>C1COCC1>[F:33][C:2]([F:32])([F:1])[S:3]([O:6][C:7]1[C:8]2[CH:9]=[CH:10][C:11]([C:45]#[C:46][C:47]3[CH:57]=[CH:56][C:50]([C:51]([O:53][CH2:54][CH3:55])=[O:52])=[CH:49][CH:48]=3)=[CH:12][C:13]=2[C:14]([CH3:17])([CH3:18])[CH2:15][CH:16]=1)(=[O:5])=[O:4]
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(OS(=O)(=O)C(F)(F)F)=CCC3(C)C)cc1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3=O)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CC=C3OS(=O)(=O)C(F)(F)F)cc1

Procedure:
Employing the same general procedure as for the preparation of ethyl 4-[(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl]benzoate (Compound 66), 800 mg (2.31 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl benzoate (Compound 1) in 2 ml of THF was converted into the title compound (white solid) using 466 mg (2.5 ml, 2.54 mmol) of sodium bis(trimethylsilyl)amide (1.0M solution in THF) and a solution of 961 mg (2.54 mmol) of 2-(N,N-bis(trifluoromethylsulfonyloxy)amino]-5-chloropyridine in 2 ml of THF.
Reaction SMILES: [CH2:1]([NH:3][C@H:4]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH3:2].[C:18](OC(=O)C)(=[O:20])[CH3:19].N1C=CC=CC=1>>[CH2:1]([N:3]([C@H:4]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:9])[CH3:10])=[O:6])[C:18](=[O:20])[CH3:19])[CH3:2]
Reactant: CCN[C@@H](C(=O)OC(C)(C)C)c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCN(C(C)=O)[C@@H](C(=O)OC(C)(C)C)c1ccccc1
Yield: 26.4 %

Procedure:
A solution of product from Example 122A (0.267 g, 1.135 mmol) in acetic anhydride (1.073 mL, 11.35 mmol) and pyridine (0.918 mL, 11.35 mmol) was stirred at 98° C. for 2 hrs. The mixture was partitioned between CH2Cl2 and 1N HCl solution, and the organic extract was separated, dried over anhydrous sodium sulphate, filtered, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 1-35% ethyl acetate in hexane to give the title compound (0.083 g, 27%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[NH:15][CH2:16][CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])=[C:4]([O:22][CH3:23])[CH:3]=1.[F:24][C:25]([F:40])([F:39])[C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[N:34]=1)[C:29](O)=[O:30]>>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15]([CH2:16][CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])[C:29](=[O:30])[C:28]2[CH:32]=[C:33]([C:35]([F:36])([F:37])[F:38])[N:34]=[C:26]([C:25]([F:40])([F:24])[F:39])[CH:27]=2)=[C:4]([O:22][CH3:23])[CH:3]=1
Reactant: O=C(O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Reactant: COc1cc(F)c(F)cc1-c1ccncc1NCCS(C)(=O)=O
Product: COc1cc(F)c(F)cc1-c1ccncc1N(CCS(C)(=O)=O)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 90, from [4-(4,5-difluoro-2-methoxy-phenyl)-pyridin-3-yl]-(2-methanesulfonyl-ethyl)-amine and 2,6-bis(trifluoromethyl)isonicotinic acid (Key Organics Ltd.) after a reaction time of 15 hours. The compound was purified by silica gel chromatography on a 10 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Brown solid (42%). MS (ESI): m/z=584.09 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]2[N:7](C)[C:8](=O)[O:9][C:10](=O)[C:5]=2[CH:4]=1.[NH3:16]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([NH:7][CH3:8])=[C:5]([CH:4]=1)[C:10]([NH2:16])=[O:9]
Reactant: N
Reactant: COc1ccc2c(c1)c(=O)oc(=O)n2C
Solvent: C1CCOC1
Product: CNc1ccc(OC)cc1C(N)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1.50 g (7.24 mmol) 6-Methoxy-1-methyl-1H-benzo(d)(1,3)oxazine-2,4-dione were dissolved in 20 ml tetrahydrofuran and 10.0 ml ammonia (25%) added at 0° C. The solution was stirred for 30 min at 0° C. and for 30 min at room temperature. THF was distilled under vacuum and the remaining suspension was neutralized with diluted hydrogen chloride acid. The product was isolated by filtration.
Reaction SMILES: [C:1]([C:5]1([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:12][C:8]2=[CH:9][O:10][CH:11]=[C:7]2[CH2:6]1)([O:3]C)=[O:2].[OH-].[K+]>C(O)C.O.O1CCCC1>[C:1]([C:5]1([S:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[CH2:12][C:8]2=[CH:9][O:10][CH:11]=[C:7]2[CH2:6]1)([OH:3])=[O:2]
Reactant: COC(=O)C1(SCc2ccc(OC)cc2)Cc2cocc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CSC2(C(=O)O)Cc3cocc3C2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dissolve 5-(carbomethoxy)-5-(4-methoxybenzylthio)-2,4,5,6-tetrahydro-cyclopenta[c]furan (1.08 g, 3.55 mmol) in 95% ethanol (25 mL), water (12 mL) and tetrahydrofuran (15 mL). Treat with potassium hydroxide (1.3 g, 23 mmol) and stir at room temperature for 1 hour. Filter and evaporate the solvent in vacuo. Partition between water (125 mL) and ether (75 mL). Separate the aqueous phase and acidify with cold concentrated hydrochloric acid. Extract with methylene chloride (75 mL), dry (Na2SO4) and evaporate the solvent in vacuo. Purify by silica gel chromatography to give 5-(carboxy)-5-(4-methoxybenzylthio)-2,4,5,6-tetrahydrocyclopenta[c]furan.
Reaction SMILES: [CH:1]([CH:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([C:12]#[N:13])[C:6]=2[CH2:5][CH2:4]1)=O.[N:14]1(C(OC(C)(C)C)=O)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>C(#N)C1C=CC=CC=1>[N:14]1([CH2:1][CH:3]2[C:11]3[CH:10]=[CH:9][CH:8]=[C:7]([C:12]#[N:13])[C:6]=3[CH2:5][CH2:4]2)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: N#Cc1cccc2c1CCC2C=O
Solvent: N#Cc1ccccc1
Product: N#Cc1cccc2c1CCC2CN1CCNCC1

Procedure:
1-(Piperazin-1-ylmethyl)-2,3-dihydro-1H-indene-4-carbonitrile was prepared starting from 1-formyl-2,3-dihydro-1H-indene-4-carbonitrile and tert-butyl piperazine-1-carboxylate in two steps in an analogous fashion to that described for the synthesis of 2-methoxy-4-[2-piperazin-1-yl)ethyl]benzonitrile above. 1H-NMR (400 MHz, MeOD) δ ppm 7.68 (d, J=7.8 Hz, 1H), 7.58 (d, J=7.8 Hz, 1H), 7.40 (t, J=7.4 Hz, 1H), 3.64˜3.88 (m, 10H), 3.40˜3.46 (m, 1H), 3.20˜3.30 (m, 1H), 3.07˜3.16 (m, 1H), 2.55˜2.70 (m, 1H), 2.10˜2.25 (m, 1H).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)=[C:10]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:11]=2[F:13])[C:6](=[O:34])[C:5]([C:35](O)=[O:36])=[CH:4]1)[CH3:2].ClC(OCC(C)C)=O.CC(C[AlH]CC(C)C)C>O1CCCC1.C1(C)C=CC=CC=1>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([O:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=3)=[C:10]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[C:11]=2[F:13])[C:6](=[O:34])[C:5]([CH2:35][OH:36])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)c(F)c21
Agent: CC(C)COC(=O)Cl
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCn1cc(CO)c(=O)c2cc(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)c(F)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.4 %

Procedure:
To a suspension of 1-ethyl-8-fluoro-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (15 g, 29.6 mmol) in Tetrahydrofuran (THF) (100 mL) was added TEA (6.18 mL, 44.3 mmol) and isobutyl chloroformate (5.82 mL, 44.3 mmol). The resulting mixture was stirred at r.t. for 1 h. The mixture was then cooled down to −40° C. and a solution of DIBAL-H (49.3 mL, 73.9 mmol) in toluene (1.5 M) was added. The mixture was stirred at the same temperature for 1.5 h, when LCMS indicated completion of the reaction. The reaction was quenched with sat. NH4Cl (aq.), warmed up to r.t. and concentrated. The mixture was diluted with sat. NH4Cl and extracted with dichloromethane (2×30 mL). The combined organic solution was then dried over sodium sulfate, filtered and concentrated in vacuo to afford 1-ethyl-8-fluoro-3-(hydroxymethyl)-6,7-bis((4-methoxybenzyl)oxy)quinolin-4(1H)-one (10 g, 20.26 mmol, 68.6% yield) as a yellow solid, which was used in the next oxidation step without further purification.
Reaction SMILES: CC([Si](C)(C)[O:6][CH2:7][C@@H:8]([CH3:36])[C@@H:9]1[C@:26]2([CH3:27])[C:12]([C:13]3[CH2:14][CH2:15][C@@H:16]4[C@:21]([C:23]=3[CH2:24][CH2:25]2)([CH3:22])[CH2:20][CH2:19][C@H:18]([O:28][CH:29]([O:31][CH2:32][CH3:33])[CH3:30])[C:17]4([CH3:35])[CH3:34])=[CH:11][CH2:10]1)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[CH2:32]([O:31][CH:29]([O:28][C@H:18]1[CH2:19][CH2:20][C@@:21]2([CH3:22])[C@@H:16]([CH2:15][CH2:14][C:13]3[C:12]4[C@:26]([CH3:27])([CH2:25][CH2:24][C:23]=32)[C@@H:9]([C@H:8]([CH3:36])[CH2:7][OH:6])[CH2:10][CH:11]=4)[C:17]1([CH3:35])[CH3:34])[CH3:30])[CH3:33]
Reactant: CCOC(C)O[C@H]1CC[C@]2(C)C3=C(CC[C@H]2C1(C)C)C1=CC[C@H]([C@H](C)CO[Si](C)(C)C(C)(C)C)[C@@]1(C)CC3
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(C)O[C@H]1CC[C@]2(C)C3=C(CC[C@H]2C1(C)C)C1=CC[C@H]([C@H](C)CO)[C@@]1(C)CC3
Yield: 99.4 %

Procedure:
vi)—A solution of (3β,5α,20S)-21-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-3-[(1-ethoxyethyl)oxy]-4,4,20-trimethylpregna-8,14-diene (11.6 g) in a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (43 ml) was stirred at 50° C. for 1 h. The reaction mixture was poured into water and the product was extracted into ethyl acetate. The combined organic phases were washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, dried over sodium sulfate, and concentrated under reduced pressure. Column chromatography afforded (3β,5α,20S)-3-[(1 -ethoxyethyl)oxy]-4,4,20-trimethylpregna-8,14-dien-21-ol (9.11 g).
Reaction SMILES: [CH:1]([C:4]1[CH:21]=[CH:20][C:7]2[O:8][CH2:9][C:10]3[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=3[CH:12]([C:13](O)=[O:14])[C:6]=2[CH:5]=1)([CH3:3])[CH3:2].[CH2:22]([C:24]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][CH3:32])[C:25]=1[NH2:26])[CH3:23]>>[CH2:22]([C:24]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][CH3:32])[C:25]=1[NH:26][C:13]([CH:12]1[C:11]2[CH:16]=[CH:17][CH:18]=[CH:19][C:10]=2[CH2:9][O:8][C:7]2[CH:20]=[CH:21][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][C:6]1=2)=[O:14])[CH3:23]
Reactant: CC(C)c1ccc2c(c1)C(C(=O)O)c1ccccc1CO2
Reactant: CCc1cccc(CC)c1N
Product: CCc1cccc(CC)c1NC(=O)C1c2ccccc2COc2ccc(C(C)C)cc21
Yield: 50.5 %

Procedure:
The similar procedures as in Example 1 were repeated except using 2.34 g of Compound C in place of Compound A and 0.90 g of 2,6-diethylaniline in place of aniline to obtain 1.26 g of Compound 13.
Reaction SMILES: C([O:5][C:6](=[O:34])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:33])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:21][CH:20]=2)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:26]([NH:25][C:22]1[CH:21]=[CH:20][C:19]([O:18][CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:34])=[O:5])[S:12][CH:13]=2)=[CH:24][CH:23]=1)(=[O:33])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(NC(=O)c3ccccc3)cc2)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(Sc1nc(CCOc2ccc(NC(=O)c3ccccc3)cc2)cs1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 71.7 %

Procedure:
2-[(4-{2-[4-(Benzoylamino)phenoxy]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (550 mg) obtained in Example 54-1 was dissolved in dichloromethane (6 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=1:1 to 0:1) to give the title compound (350 mg) as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][C:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][CH2:15][C:16]3[CH:20]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=4)[O:18][N:17]=3)=[CH:13][C:8]=2[O:7][CH:6]=1.O.[OH-].[Li+].O.Cl>O1CCCC1>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C:19]2[O:18][N:17]=[C:16]([CH2:15][O:14][C:12]3[CH:11]=[CH:10][C:9]4[C:5]([CH2:4][C:3]([OH:28])=[O:2])=[CH:6][O:7][C:8]=4[CH:13]=3)[CH:20]=2)=[CH:22][CH:23]=1
Reactant: COC(=O)Cc1coc2cc(OCc3cc(-c4ccc(Cl)cc4)on3)ccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cc1coc2cc(OCc3cc(-c4ccc(Cl)cc4)on3)ccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of {6-[5-(4-chloro-phenyl)-isoxazol-3-ylmethoxy]-benzofuran-3-yl}-acetic acid methyl ester (0.20 g, 0.50 mmol) in 8.0 ml of tetrahydrofuran was treated with lithium hydroxide monohydrate (0.10 g, 2.4 mmol), followed by 2.5 ml of water. The mixture was stirred at room temperature for 16 hours and added to 75 ml of water. The solution was made strongly acidic by the addition of 4.0 N hydrochloric acid. The precipitated product was extracted with ethyl acetate (4×75 ml). The combined organic layers were washed with brine (2×150 ml), then dried over anhydrous sodium sulfate and evaporated to a white solid. The crude product was recrystallized from aqueous acetonitrile. mp 193–194° C.; IR (thin film) cm−1: 1716, 1611, 1434, 1288, 1224, 1146; 400 MHz 1H NMR (DMSO-d6) 12.39 (br s, 1H), 7.87 (d, 2H, J=8.8 Hz), 7.73 (s, 1H), 7.55 (d, 2H, J=8.8 Hz), 7.44 (d, 1H, J=8.6 Hz), 7.28 (d, 1H, J=2.0 Hz), 7.19 (s, 1H), 6.93–6.96 (m, 1H), 5.24 (2, 2H), 3.59 (s, 2H); MS m/z 382 (M−1). Anal. Calc'd for C20H14ClNO5: C, 62.59; H, 3.68; N, 3.65; found: C, 62.87; H, 3.67; N, 3.61.
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15](C(F)(F)F)=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:22]#[C:23][C:24]3[CH:34]=[CH:33][C:27]([C:28]([O:30]CC)=[O:29])=[CH:26][CH:25]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+].Cl.C[CH2:40][OH:41]>C1COCC1>[CH3:35][C:2]1([CH3:1])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:41][CH3:40])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:22]#[C:23][C:24]3[CH:34]=[CH:33][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C(F)(F)F)cc2)=CCC3(C)C)cc1
Reactant: CCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(C2=CCC(C)(C)c3ccc(C#Cc4ccc(C(=O)O)cc4)cc32)cc1
Temperature: 50 °C

Procedure:
To a solution of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(4-trifluoromethylphenyl)-2-naphthalenyl)ethynyl]benzoate (Compound 9) 70.0 mg (0.148 mmol) in 3 ml of EtOH and 2 ml of THF was added 60.0 mg (1.50 mmol, 1.50 ml) of NaOH (1.0M aqueous solution). The solution was heated to 50° C. for 2 hours, cooled to room temperature, and acidified with 10% HCl. Extraction with EtOAc, followed by drying over Na2SO4, and removal of the solvents under reduced pressure afforded the title compound as a colorless solid. 1H NMR (DMSO): δ 7.90 (2H, d, J=8.3 Hz), 7.80 (2H, d, J=8.1 Hz), 7.61-7.47 (6H, m), 6.97 (2H, s), 6.16 (1H, t, J=4.5 Hz), 2.37 (2H, d, J=4.6 Hz), 1.30 (6H, s).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][CH:7]=[CH:6][C:5]=1[F:19].Cl[C:22]1[N:27]=[CH:26][CH:25]=[CH:24][N:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.CC(OC)(C)C>[CH3:1][O:2][C:3](=[O:20])[C:4]1[C:9]([C:22]2[N:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[CH:8][CH:7]=[CH:6][C:5]=1[F:19]
Reactant: COC(=O)c1c(F)cccc1B1OC(C)(C)C(C)(C)O1
Reactant: Clc1ncccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)C
Product: COC(=O)c1c(F)cccc1-c1ncccn1
Temperature: 74 °C
Reaction time: 2.5 h
Yield: 38 %

Procedure:
To a 250 mL round-bottomed flask under nitrogen were added 2-fluoro-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (5.46 g, 19.5 mmol) in 2-methyl-THF (50 mL), 2-chloropyrimidine (2.68 g, 23.4 mmol), and sodium carbonate (6.2 g, 58.5 mmol) in water (17 mL). PdCl2(dppf)-dcm adduct (CAS#72287-26-4) (1.27 g, 1.56 mmol) was then added and the reaction mixture was warmed to 74° C. and stirred for 2.5 h. After cooling, the mixture was diluted with MTBE (50 mL) and water (80 mL). The layers were thoroughly mixed then separated. The aqueous layer was extracted with additional MTBE (100 mL). The combined organics were dried over magnesium sulfate, filtered, concentrated and then purified by flash chromatography (0-25% EA/hexanes) to provide the title compound (1.72 g, 72 wt %, 30% yield). 1H NMR (400 MHz, CDCl3): 8.79 (d, J=4.9 Hz, 2H), 8.15 (d, J=7.9 Hz, 1H), 7.51 (td, J=8.1, 5.6 Hz, 1H), 7.28-7.20 (m, 2H), 3.92 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19]O)[O:16][C:15]2=[O:21])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[N:11][C:10]([CH3:13])=[N:9]1.C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31].N1C=CC=CC=1>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][S:30]([CH3:29])(=[O:32])=[O:31])[O:16][C:15]2=[O:21])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[N:11][C:10]([CH3:13])=[N:9]1
Reactant: Cc1ncn(-c2ccc(N3C[C@H](CO)OC3=O)cc2F)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: Cc1ncn(-c2ccc(N3C[C@H](CS(C)(=O)=O)OC3=O)cc2F)n1
Temperature: 25 °C
Yield: 44.9 %

Procedure:
(5R)-3-[3-Fluoro-4-(3-methyl-1,2,4-triazol-1-yl)phenyl]-5-(hydroxymethyl)oxazolidin-2-one (Intermediate 25) (10.08 g, 34.5 mmol) in dichloromethane (100 ml) and triethylamine (6.0 ml, 43 mmol) was cooled to 0° C. and methanesulfonyl chloride (3.2 ml, 41 mmol) was added by syringe. The reaction mixture was allowed to warm to room temperature overnight. More pyridine (50 ml) was added and the reaction mixture was cooled to 0° C. before adding additional methanesulfonyl chloride (3.2 ml, 41 mmol). The reaction was allowed to warm to room temperature and the solid was collected by filtration and washed with ethyl acetate to afford the crude title compound (5.49 g).