Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([CH2:5][CH2:6][CH:7]1[CH:13]=[CH:12][N:11]([C:14](=[O:31])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:17][CH:16]=2)[C:10]2[CH:32]=[CH:33][CH:34]=[CH:35][C:9]=2[S:8]1)(=O)=O.[CH3:36][NH2:37]>O1CCCC1>[CH3:36][NH:37][CH2:5][CH2:6][CH:7]1[CH:13]=[CH:12][N:11]([C:14](=[O:31])[C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:19][CH:20]=2)[C:10]2[CH:32]=[CH:33][CH:34]=[CH:35][C:9]=2[S:8]1
Reactant: CN
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2C=CC(CCS(C)(=O)=O)Sc3ccccc32)cc1
Solvent: C1CCOC1
Product: CNCCC1C=CN(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2)c2ccccc2S1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Compound 13 as prepared in Example 10 (0.045 g, 0.08 mM) and methylamine (40% solution in water; 1 ml) in tetrahydrofuran (4 ml) was heated in a sealed tube with stirring in an 80° C. oil bath for 16 hours. The mixture was cooled to room temperature, evaporated to dryness, diluted with water (30 ml) and extracted with ethyl acetate (2×35 ml). The combined ethyl acetate extracts were dried (MgSO4) and evaporated in vacuo to give a crude mixture. Purification by chromatography (EM silica Gel 60; 10% EtOAc in CH2Cl2) gave the product as a white solid. m/z (MH+)460.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C@H:23]([NH:60][C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[C:24](=[O:59])[NH:25][CH2:26][CH2:27][CH2:28][CH2:29][C@H:30]([NH:51][C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[C:31](=[O:50])[NH:32][CH2:33][CH2:34][CH2:35][CH2:36][C@H:37]([NH:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C:38]([O:40]C)=[O:39])=[N:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.C1COCC1.O>[C:13]([O:12][C:11]([NH:10][C:9]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C@H:23]([NH:60][C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[C:24](=[O:59])[NH:25][CH2:26][CH2:27][CH2:28][CH2:29][C@H:30]([NH:51][C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[C:31](=[O:50])[NH:32][CH2:33][CH2:34][CH2:35][CH2:36][C@H:37]([NH:42][C:43]([O:45][C:46]([CH3:47])([CH3:48])[CH3:49])=[O:44])[C:38]([OH:40])=[O:39])=[N:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:17])([CH3:14])([CH3:15])[CH3:16]
Reactant: COC(=O)[C@H](CCCCNC(=O)[C@H](CCCCNC(=O)[C@H](CCCCNC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N=C(NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
A solution of methyl ester 48 (1.40 g, 1.32 mmol) in MeOH/THF/H2O (45 mL/45 mL/15 mL) was charged with NaOH (265 mg, 6.61 mmol) and the reaction mixture was stirred at room temperature for 1 h. After completion of the reaction, the mixture was concentrated under reduced pressure and the pH of the solution was adjusted to 5 with aqueous 1 N HCl. The suspension was partitioned between CH2Cl2 (50 mL) and water (10 mL). The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (2×50 mL) The combined organic extracts were dried over Na2SO4 and concentrated to afford compound 49 (1.20 g, 87%) as a white solid, which was used directly in the next step: 1H NMR (400 MHz, CD3OD) δ 4.06-3.89 (m, 3H), 3.35 (t, J=7.6 Hz, 2H), 3.25-3.11 (m, 4H), 1.86-1.66 (m, 3H), 1.64-1.55 (m, 5H), 1.54-1.30 (m, 10H), 1.52 (s, 9H), 1.46 (s, 9H), 1.43 (s, 27H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:7]([OH:9])=O)[NH:5][N:6]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C([O:36][C:37](=[O:64])[C@H:38]([CH2:62][OH:63])[CH2:39][C@H:40]([NH:54]C(OC(C)(C)C)=O)[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[CH:44][CH:43]=1)C.Cl.O1CCOCC1>CN(C=O)C.CC#N>[C:45]1([C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:44]=[CH:43][C:42]([CH2:41][C@@H:40]([NH:54][C:7]([C:4]2[NH:5][N:6]=[C:2]([Cl:1])[N:3]=2)=[O:9])[CH2:39][C@@H:38]([CH2:62][OH:63])[C:37]([OH:64])=[O:36])=[CH:47][CH:46]=1
Reactant: O=C(O)c1nc(Cl)n[nH]1
Reactant: CCOC(=O)[C@H](CO)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: C1COCCO1
Product: O=C(N[C@H](Cc1ccc(-c2ccccc2)cc1)C[C@@H](CO)C(=O)O)c1nc(Cl)n[nH]1
Reaction time: 0.08 h
Yield: 60.8 %

Procedure:
5-Chloro-2H-1,2,4-triazole-3-carboxylic acid (51.8 mg, 351 μmol, 1.5 eq.) and HATU (133 mg, 351 μmol, 1.5 eq.) were dissolved in DMF (3.0 mL), and the resulting mixture was stirred for 5 minutes to yield the activated acid. (2S,4S)-5-Biphenyl-4-yl-4-t-butoxycarbonylamino-2-hydroxymethyl-pentanoic acid ethyl ester (100 mg, 234 μmol, 1.0 eq.) was dissolved in MeCN (2 mL) followed by the addition of 4 M of HCl in dioxane (0.5 mL, 2.0 mmol). The mixture was stirred at room temperature for 2 hours, then concentrated to dryness. The activated acid was added and the resulting mixture was stirred for 2 minutes, followed by the addition of DIPEA (81.5 μL). The mixture was stirred at room temperature for 1 hour. The reaction was quenched with water, and the solvent removed under vacuum. The dried solid was dissolved in EtOH (2.0 mL) followed by the addition of 1.0 M of LiOH in water (2.0 mL). The mixture was stirred at room temperature for 3 hours, and the reaction was quenched with AcOH. The solvent was removed under vacuum, the residue was dissolved in AcOH/MeCN and purified by preparative HPLC. The clean fractions were combined and lyophilized to yield the title compound (61 mg, 95% purity). MS m/z [M+H]+ calc'd for C21H21ClN4O4, 429.13. found 429.4.
Reaction SMILES: C([C@@H](O)[C@H](O)C([O-])=O)(O)=O.[Cl:11][C:12]1[CH:21]=[C:20]2[C:15]([C@H:16]([NH3+:26])[CH2:17][C:18]([CH2:24][F:25])([CH2:22][F:23])[O:19]2)=[CH:14][CH:13]=1.[N:27]([C:30]1[CH:39]=[C:38]2[C:33]([CH2:34][CH2:35][C:36](=[O:40])[NH:37]2)=[CH:32][CH:31]=1)=[C:28]=[S:29].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:11][C:12]1[CH:21]=[C:20]2[C:15]([C@H:16]([NH:26][C:28]([NH:27][C:30]3[CH:39]=[C:38]4[C:33]([CH2:34][CH2:35][C:36](=[O:40])[NH:37]4)=[CH:32][CH:31]=3)=[S:29])[CH2:17][C:18]([CH2:24][F:25])([CH2:22][F:23])[O:19]2)=[CH:14][CH:13]=1
Reactant: O=C1CCc2ccc(N=C=S)cc2N1
Reactant: [NH3+][C@@H]1CC(CF)(CF)Oc2cc(Cl)ccc21
Agent: O=C([O-])[C@@H](O)[C@H](O)C(=O)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCc2ccc(NC(=S)N[C@@H]3CC(CF)(CF)Oc4cc(Cl)ccc43)cc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.1 %

Procedure:
To a slurry of (R)-7-chloro-2,2-bis(fluoromethyl)chroman-4-aminium (2S,3S)-3-carboxy-2,3-dihydroxypropanoate (0.20 g, 0.51 mmol) in CH2Cl2 (1.3 mL) was added the product of Example 252A (0.10 g, 0.51 mmol) and diisopropylethyl amine (0.088 mL, 0.51 mmol). The mixture was stirred at ambient temperature overnight then placed directly onto a silica gel column. Elution with a 20-60% EtOAc/hexane gradient afforded the title compound (0.18 g, 76% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 10.12 (s, 1H), 9.63 (s, 1H), 7.98 (d, J=8.1 Hz, 1H), 7.28 (d, J=8.3 Hz, 1H), 7.11 (d, J=8.1 Hz, 1H), 7.03 (dd, J=8.3, 2.1 Hz, 1H), 6.99-6.92 (m, 2H), 6.90 (d, J=1.9 Hz, 1H), 5.84-5.73 (m, 1H), 4.77-4.62 (m, 2H), 4.58-4.50 (m, 2H), 2.83 (dd, J=8.4, 6.6 Hz, 2H), 2.43 (dd, J=8.4, 6.7 Hz, 2H), 2.34 (dd, J=13.5, 5.8 Hz, 1H), 2.12-2.00 (m, 1H); MS (ESI) m/z: 451.9 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6](Cl)=[O:7].[CH2:14]([N:16]([CH:22]1[CH2:31][CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([O:32][CH3:33])[CH:28]=2)[CH2:23]1)[CH2:17][CH2:18][CH2:19][CH2:20][OH:21])[CH3:15].C(N(CC)CC)C>C1C=CC=CC=1>[CH2:14]([N:16]([CH:22]1[CH2:31][CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([O:32][CH3:33])[CH:28]=2)[CH2:23]1)[CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:15]
Reactant: CCN(CCCCO)C1CCc2cc(OC)ccc2C1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCN(CCCCOC(=O)c1ccc(OC)c(OC)c1)C1CCc2cc(OC)ccc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.9 g of 3,4-dimethoxybenzoic acid and 4 ml of thionyl chloride were heated for 4 hours at reflux and concentrated under reduced pressure to obtain 3,4-dimethoxybenzoyl chloride. The 3,4-dimethoxybenzoyl chloride was dissolved in 10 ml of anhydrous benzene, and the resulting solution was added dropwise to a solution of 4.0 g of N-ethyl-N-(4-hydroxybutyl)-6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine and 2.2 g of triethylamine in 50 ml of anhydrous benzene. After the addition, the resulting solution was stirred for 30 minutes at room temperature (about 25° C.) and heated for 3.5 hours at reflux. The reaction solution was washed with water, a 2 N-NaOH aqueous solution and water in this order, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was purified through silica gel chromatography to obtain N-ethyl-N-[4-(3,4-dimethoxybenzoyloxy)butyl]-6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine as a colorless oily product. To this oily product was added an ethanolic solution of hydrogen chloride having a concentration of about 18% and the resulting solution was concentrated under reduced pressure to obtain a residue. The residue was dissolved in a mixed solvent of acetone and diethyl ether, and the solution was left at a temperature of about 2° to 3° C. to form crystals. By collecting the crystals through filtration and recrystallization from a mixed solvent of acetone and diethyl ether, 3.0 g of N-ethyl-N-[4-(3,4-dimethoxybenzoyloxy)butyl]-6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride was obtained as colorless crystals having a melting point of 139°-140° C. The melting point, the infrared spectra and other physical data of this product corresponded to the date of the compound obtained in Example 2 (ii).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=O)[CH2:21][CH2:22][C:23](=O)[CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:16][CH:15]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1.CCOC(C)=O>[CH2:29]([O:28][C:26](=[O:27])[CH2:25][CH2:24][C:23]1[N:1]([C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[CH3:11])[C:20]([C:17]2[CH:16]=[CH:15][C:14]([O:13][CH3:12])=[CH:19][CH:18]=2)=[CH:21][CH:22]=1)[CH3:30]
Reactant: Cc1cc(C(=O)O)ccc1N
Reactant: CCOC(=O)CCC(=O)CCC(=O)c1ccc(OC)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1ccc(-c2ccc(OC)cc2)n1-c1ccc(C(=O)O)cc1C
Temperature: 140 °C
Yield: 50.4 %

Procedure:
4-Amino-3-methylbenzoic acid (0.322 g) was mixed with ethyl 7-(4-methoxyphenyl)-4,7-dioxoheptanoate (25C, see scheme 25) (0.498 g) and p-toluensulfonic acid (49 mg) in dioxane (3 mL). The mixture was heated at 140° C. via microwave over 2 hours. The resultant solution was diluted with EtOAc (20 mL) and washed with 0.5 N HCl (8 mL), Brine (8 mL) and dried over anhydrous Na2SO4. After removal of solvents under reduced pressure, the residue was purified by flash silica gel column chromatography, eluted with 10% MeOH in DCM, to afford 4-(2-(3-ethoxy-3-oxopropyl)-5-(4-methoxyphenyl)-1H-pyrrol-1-yl)-3-methylbenzoic acid (0.35 g) as a light yellow solid.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:18]=[C:17]4[CH:29]=O)[CH:7]=2)[CH2:3][CH2:2]1.[CH3:32][C@@H:33]1[CH2:38][NH:37][CH2:36][C@H:35]([CH3:39])[NH:34]1>>[CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:27][CH2:28]3)[CH:18]=[C:17]4[CH2:29][N:37]3[CH2:36][C@@H:35]([CH3:39])[NH:34][C@@H:33]([CH3:32])[CH2:38]3)[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Reactant: C[C@@H]1CNC[C@H](C)N1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CN3C[C@@H](C)N[C@@H](C)C3)c2c1

Procedure:
The title compound was prepared as a solid according to the method of Example 75 step ii) using the product of Example 75 step i) and (2R,6S)-2,6-dimethyl-piperazine, and the product purified by SiO2 chromatography (eluting with 5% methanol in dichloromethane followed by 5% of 7M methanolic ammonia in dichloromethane).
Reaction SMILES: [C:1](Cl)(=[O:3])C.C([O-])=O.[Na+].[NH2:9][C@H:10]([C:23]([O:25][CH3:26])=[O:24])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=1.C([O-])(O)=O.[Na+]>C(OCC)C.C(Cl)Cl>[NH:9]([CH:1]=[O:3])[C@H:10]([C:23]([O:25][CH3:26])=[O:24])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([C:19]([CH3:22])([CH3:20])[CH3:21])[CH:13]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)c(C(C)(C)C)c1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: O=C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)[C@H](Cc1ccc(O)c(C(C)(C)C)c1)NC=O
Temperature: 25 °C
Reaction time: 23 h
Yield: 101.7 %

Procedure:
To a solution of acetyl chloride (22.6 ml, 299 mmol) in diethyl ether (11), sodium formate (30.6 g, 450 mmol) was added under cooling with ice and stirred at room temperature for 23 hours. The reaction mixture was filtered and evaporated to remove the solvent. The thus obtained residue was added dropwise to a solution of H-Tyr(3-tBu)-OMe (22.2 g, 83.8 mmol) in methylene chloride (500 ml) under cooling with ice, mixed with TEA (46.7 ml, 335 mmol) and stirred at room temperature for 2 hours. The reaction mixture was mixed with saturated aqueous NaHCO3 and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure. The thus obtained residue was subjected to silica gel column chromatography (developing solvent: n-hexane:ethyl acetate=1:1), giving N-formyl-Tyr(3-tBu)-OMe (23.8 g, 100%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.[CH3:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:16]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[C:8]1([C:6]2[CH:7]=[C:2]([C:16]3[C:15]([CH3:14])=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:21])[N:3]=[CH:4][N:5]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Clc1cc(-c2ccccc2)ncn1
Reactant: Cc1cccc(C)c1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(C)c1-c1cc(-c2ccccc2)ncn1
Yield: 23 %

Procedure:
Next, 1.6 g of 4-chloro-6-phenylpyrimidine synthesized in Step 1, 1.5 g of 2,6-dimethylphenylboronic acid, 1.8 g of sodium carbonate, 59 mg of PdCl2(PPh3)2, 20 mL of N,N-dimethylformamide (abbreviation: DMF), and 20 mL of water were put into a 100-mL round-bottom flask, and the air in the flask was replaced with argon. Then, heating was performed by irradiation with microwaves (2.45 GHz, 100 W) for 2 hours. An organic layer was extracted from the obtained mixture with the use of dichloromethane, and was washed with water and saturated brine. Magnesium sulfate was added and gravity filtration was performed. A solvent in the obtained filtrate was distilled off, and the given residue was purified by flash column chromatography using a mixed solvent of ethyl acetate and hexane (ethyl acetate: hexane=1:5) as a developing solvent, whereby 0.50 g of the objective substance, Hppm-dmp (abbreviation) was obtained (yield: 23%, a pale yellow oily substance). A synthesis scheme of Step 2 is shown in (a-2) below.
Reaction SMILES: C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C([S:43][CH:44]([CH:74]([O:77][CH3:78])[O:75][CH3:76])[CH2:45][NH:46][C:47]([C:49]1[NH:50][C:51]2[C:56]([CH:57]=1)=[CH:55][C:54]([O:58][CH2:59][CH2:60][O:61][CH3:62])=[CH:53][C:52]=2[N:63]([CH3:73])[S:64]([C:67]1[N:68]([CH3:72])[CH:69]=[CH:70][N:71]=1)(=[O:66])=[O:65])=O)C1C=CC=CC=1.C1(SC)C=CC=CC=1>ClCCl.O>[CH3:78][O:77][CH:74]([O:75][CH3:76])[CH:44]1[S:43][C:47]([C:49]2[NH:50][C:51]3[C:56]([CH:57]=2)=[CH:55][C:54]([O:58][CH2:59][CH2:60][O:61][CH3:62])=[CH:53][C:52]=3[N:63]([CH3:73])[S:64]([C:67]2[N:68]([CH3:72])[CH:69]=[CH:70][N:71]=2)(=[O:66])=[O:65])=[N:46][CH2:45]1
Reactant: COCCOc1cc(N(C)S(=O)(=O)c2nccn2C)c2[nH]c(C(=O)NCC(SCc3ccccc3)C(OC)OC)cc2c1
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CSc1ccccc1
Solvent: O
Product: COCCOc1cc(N(C)S(=O)(=O)c2nccn2C)c2[nH]c(C3=NCC(C(OC)OC)S3)cc2c1
Reaction time: 0.17 h
Yield: 39.4 %

Procedure:
Triphenylphosphine oxide (0.9 g) was dissolved in dichloromethane (10 mL), trifluoromethanesulfonic anhydride (0.55 mL) was added under ice-cooling, and the mixture was stirred for 10 min. A solution of N-[2-(benzylthio)-3,3-dimethoxypropyl]-5-(2-methoxyethoxy)-7-{methyl[(1-methyl-1H-imidazol-2-yl)sulfonyl]amino}-1H-indole-2-carboxamide (1.9 g) and thioanisole (0.7 mL) in dichloromethane (10 mL) was added dropwise under ice-cooling, and the mixture was stirred for 25 min, and then at room temperature for 1 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtrated, and the filtrate was concentrated under reduced pressure. The residue was silica gel column chromatography (ethyl acetate:hexane=10:90-80:20) to give the title compound (620 mg, yield 39%) as a colorless oil.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH:12]1([NH:15][C:16]([C:18]2[CH:19]=[C:20]([F:39])[C:21]([CH3:38])=[C:22]([C:24]3[N:29]=[CH:28][C:27]([C:30]([NH:32][C@H:33]([CH3:37])[CH:34]([CH3:36])[CH3:35])=[O:31])=[CH:26][CH:25]=3)[CH:23]=2)=[O:17])[CH2:14][CH2:13]1>C(Cl)(Cl)Cl.CO>[CH:12]1([NH:15][C:16]([C:18]2[CH:19]=[C:20]([F:39])[C:21]([CH3:38])=[C:22]([C:24]3[N+:29]([O-:9])=[CH:28][C:27]([C:30]([NH:32][C@H:33]([CH3:37])[CH:34]([CH3:35])[CH3:36])=[O:31])=[CH:26][CH:25]=3)[CH:23]=2)=[O:17])[CH2:14][CH2:13]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)N[C@H](C)C(C)C)cn1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)N[C@H](C)C(C)C)c[n+]1[O-]
Temperature: 60 °C

Procedure:
mCPBA (57-86%, 10 mg) dissolved in chloroform (0.1 ml) was added to a solution of 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-[(1R)-1,2-dimethylpropyl]-3-pyridinecarboxamide (Intermediate 17, 10 mg) in chloroform (2 ml) at 60° C. and the reaction maintained at 60° C. for 5 hrs. The reaction was allowed to cool, diluted with methanol, and passed through an aminopropyl SPE (1 g). The filtrate was reduced to dryness under vacuum and the residue triturated with ether to give 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-[(1R)-1,2-dimethylpropyl]-3-pyridinecarboxamide 1-oxide as a white solid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]([C:17]1[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=1)O)C1C=CC=CC=1.Cl>CO.[OH-].[Pd+2].[OH-]>[C:23]([C:20]1[CH:21]=[CH:22][C:17]([CH2:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[OH:8])=[CH:18][CH:19]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1ccc(C(O)c2ccccc2OCc2ccccc2)cc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)c1ccc(Cc2ccccc2O)cc1
Reaction time: 24 h
Yield: 86.4 %

Procedure:
To a solution of (2-benzyloxyphenyl)-(4-tert-butylphenyl)methanol (2.17 g, 6.26 mmol) in methanol (27 mL), a 20% palladium hydroxide catalyst (217 mg) was added and furthermore 2N—HCl (0.52 mL) was added thereto. The mixture was stirred under a hydrogen atmosphere for 24 hours, and then the catalyst was filtered off. The solvent was distilled and the obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:10)] to obtain the title compound (1.3 g, 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.[OH-:13].[Na+].Cl>C(Cl)(Cl)Cl.CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:4]([CH3:9])([CH3:3])[C:5]([OH:8])=[O:13])=[C:4]([C:9]([F:10])([F:11])[F:12])[CH:3]=1
Reactant: [OH-]
Reactant: Oc1ccc(Cl)cc1C(F)(F)F
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: CC(C)(Oc1ccc(Cl)cc1C(F)(F)F)C(=O)O
Reaction time: 0.67 h
Yield: 37 %

Procedure:
A three-neck round bottom flask affixed with an overhead stirrer was charged with 4-chloro-2-(trifluoromethyl)phenol (prepared according methods described in U.S. Pat. No. 4,262,152), (5.0 g, 127 mmol, 1.0 eq) and dissolved in chloroform (3.3 mL) and acetone (8.4 mL). NaOH pellets (4.2 g, 104 mmol, 3.75 eq) were added in 2 portions and the mixture was stirred vigorously for 40 min. The resulting slurry was acidified to pH 2 with 3N HCl and extracted with EtOAc. The organic extracts were treated with satd. aq. sodium bicarbonate, and the basic layer was acidified to pH 4 with conc. HCl and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford 2.7 g (37%) of 2-(4-chloro-2-(trifluoromethyl)phenoxy)-2-methylpropanoic acid as a light brown crystalline solid. 1H NMR (400 MHz, CDCl3): δ 7.57 (d, J=2.6 Hz, 1H), 7.40 (dd, J=8.9, 2.6 Hz, 1H), 6.91 (d, J=8.9 Hz, 1H), 1.67 (s, 6H). LCMS (0-99% MeCN/water, 5 min, negative ion), Tret=2.99 min, [M−H]−=281.3 observed.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]2[S:18][C:17](=[S:19])[NH:16][C:15]=2[CH:20]=1)(O)=[O:8].Cl>O1CCCC1.O>[OH:8][CH2:7][CH2:10][C:11]1[CH:12]=[CH:13][C:14]2[S:18][C:17](=[S:19])[NH:16][C:15]=2[CH:20]=1
Reactant: O=C(O)Cc1ccc2sc(=S)[nH]c2c1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: OCCc1ccc2sc(=S)[nH]c2c1
Yield: 81.2 %

Procedure:
A solution of lithium aluminum hydride (65 mL of a 1M tetrahydrofuran solution, 0.065 mol) was added dropwise over 15 min to a mechanically stirred and refluxing solution of 5-carboxymethyl-2-thioxo-2,3-dihydrobenzothiazole (11.27 g, 0.050 mol) in anhydrous tetrahydrofuran (150 mL). The resulting mixture was stirred at reflux for 90 min then cooled in an ice-bath and cautiously treated with 2N hydrochloric acid (250 mL). The resulting mixture was diluted with water (250 mL) and extracted three times with ethyl acetate (250, 250, and 150 mL). The combined extracts were washed with brine (2×200 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to approximately 140 mL volume. Some solid was present at this point. The mixture was diluted with ether (100 mL) and filtered. The filter cake was washed with ether and dried in vacuo to afford 5-(2-hydroxyethyl)-2-thioxo-2,3-dihydrobenzothiazole (8.58 g) as pale tan crystals.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C@@H:11]([NH2:13])[CH3:12].[C:14]([O:18][CH3:19])(=[O:17])[CH:15]=[CH2:16]>C(O)(=O)C>[CH3:19][O:18][C:14](=[O:17])[CH2:15][CH2:16][N:13]([CH2:16][CH2:15][C:14]([O:18][CH3:19])=[O:17])[C@H:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[CH3:12]
Reactant: C[C@H](N)c1ccc2ccccc2c1
Reactant: C=CC(=O)OC
Solvent: CC(=O)O
Product: COC(=O)CCN(CCC(=O)OC)[C@@H](C)c1ccc2ccccc2c1
Reaction time: 18 h
Yield: 80.6 %

Procedure:
(S)-(−)-1-(2-Naphthyl)ethylamine (2.28 g, 13 mmol) was added dropwise to a solution of methyl acrylate (5 mL, 55 mmol) and acetic acid (0.26 mL) with stirring in a sealed tube. A white crystalline solid precipitated out of solution. The temperature was then elevated to 80° C., at which time a clear solution was formed again. Stirring was continued for 18 hours. Excess methyl acrylate and acetic acid were removed under reduced pressure. The crude oil was purified by chromatography on silica gel with ethyl acetate/hexanes (1:4) to give the title compound (3.6 g, 77%) as a pale yellow oil. 1H NMR (300 MHz, CDCl3) δ 1.45 (3H, d, J=6.78 Hz), 2.45 (4H, t, J=7.35 Hz), 2.73-2.94 (4H, m), 3.62 (6H, s), 4.00 (1H, q, J=6.78 Hz), 7.41-7.53 (3H, m), 7.70-7.84 (4H, m).