Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][C@H:4]([CH2:7][C@H:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:9]([OH:11])=O)[CH2:3]1.C(Cl)(=O)C(Cl)=O.[CH3:28][O:29][CH2:30][CH2:31][N:32]1[CH:36]=[CH:35][C:34]([NH2:37])=[N:33]1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O>[CH3:28][O:29][CH2:30][CH2:31][N:32]1[CH:36]=[CH:35][C:34]([NH:37][C:9](=[O:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[CH2:7][C@H:4]2[CH2:5][CH2:6][C:2](=[O:1])[CH2:3]2)=[N:33]1
Reactant: COCCn1ccc(N)n1
Reactant: O=C1CC[C@H](C[C@@H](C(=O)O)c2cccc(C(F)(F)F)c2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COCCn1ccc(NC(=O)[C@H](C[C@H]2CCC(=O)C2)c2cccc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.3 %

Procedure:
(R)-3-((R)-3-Oxo-cyclopentyl)-2-(3-trifluoromethyl-phenyl)-propionic acid (prepared in Example 118, 90 mg, 0.30 mmol) was dissolved in methylene chloride (3 mL) and N,N-dimethylformamide (three drops) at 25° C. under argon. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 160 μL, 0.32 mmol) which produced gas evolution and it was then stirred at 25° C. for 30 minutes after which time it was concentrated in vacuo. The residue was then dissolved in methylene chloride (3 mL) and added dropwise into a solution of 1-(2-methoxy-ethyl)-1H-pyrazol-3-ylamine (prepared in Example 72, 42 mg, 0.20 mmol), 2,6-lutidine (70 μL, 0.60 mmol) and methylene chloride (3 mL) at 0° C. It was then allowed to warm to 25° C. and stirred for 1 h. After this time, the reaction was quenched with a small amount of methanol and diluted with methylene chloride and then concentrated with silica gel (2 g) in vacuo and purified on Biotage Flash chromatography system (40S column, silica gel, 50% ethyl acetate/hexanes to 100% ethyl acetate) to afford (R)—N-[1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-3-((R)-3-oxo-cyclopentyl)-2-(3-trifluoromethyl-phenyl)-propionamide (79 mg, 62%) as a pale yellow gum: [α]29589=−79.3° (c=0.14, methanol); ES-HRMS m/e calcd for C21H24N3O3F3 (M+H)+ 424.1843, observed 424.1841; 1H NMR (300 MHz, DMSO-d6) δ 1.51 (m, 1H, CH), 1.74-2.29 (m, 8H, 4×CH2), 3.19 (s, 3H, OCH3), 3.61 (t, J=5.3 Hz, 2H, OCH2), 3.94 (m, 1H, ArCHCO), 4.12 (t, J=5.3 Hz, 2H, NCH2), 6.42 (d, J=2.2 Hz, 1H, Ar), 7.54 (d, J=2.2 Hz, 1H, Ar), 7.60 (m, 2H, Ar), 7.69 (brd, 1H, Ar), 7.73 (brs, 1H, Ar), 10.80 (s, 1H, NH).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[OH:32][C:33]1[CH:43]=[CH:42][C:36]([C:37]([O:39][CH2:40]C)=[O:38])=[CH:35][CH:34]=1.[CH2:44]([C:48]1[CH:55]=[CH:54][C:51]([CH2:52]O)=[CH:50][CH:49]=1)[CH2:45][CH2:46][CH3:47]>C1COCC1>[CH2:44]([C:48]1[CH:49]=[CH:50][C:51]([CH2:52][O:32][C:33]2[CH:43]=[CH:42][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=2)=[CH:54][CH:55]=1)[CH2:45][CH2:46][CH3:47]
Reactant: CCCCc1ccc(CO)cc1
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCc1ccc(COc2ccc(C(=O)OC)cc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of triphenylphosphine (656 mg, 2.50 mmol) in THF (12 mL) at 0° C. was treated with diethyl azodicarboxylate (442 mg, 2.54 mmol), stirred for 20 minutes, treated with ethyl 4-hydroxybenzoate (350 mg, 2.30 mmol) and 4-butylbenzyl alcohol (414 mg, 2.52 mmol), warmed to room temperature, stirred for 16 hours, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 30% ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>>[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[NH2:8][CH2:9][CH2:10][NH+:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: O=C(O)C(F)(F)F
Reactant: NCCN1CCNCC1
Product: NCC[NH+]1CCNCC1
Product: O=C([O-])C(F)(F)F

Procedure:
1-(2-aminoethyl)piperazinium trifluoroacetate was prepared in the same manner as Synthesis Example 1, except that 22.8 g (0.2 mol) of trifluoroacetic acid was added such that the molar ratio of 1-(2-aminoethyl)piperazine to trifluoroacetic acid was 1:2.
Reaction SMILES: C([O:5][C:6](=[O:27])[CH:7]=[C:8]([CH3:26])[CH:9]=[CH:10][CH:11]=[C:12]([CH3:25])[CH:13]=[CH:14][C:15]1[C:20]([CH3:21])=[CH:19][C:18]([O:22][CH3:23])=[CH:17][C:16]=1[CH3:24])CCC.[Cl-].COC1C=C(C)C(C[P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=C(C)C=1.C(OC(=O)C=C(C)C=CC=C(C=O)C)CCC>>[CH3:23][O:22][C:18]1[CH:17]=[C:16]([CH3:24])[C:15]([CH:14]=[CH:13][C:12]([CH3:25])=[CH:11][CH:10]=[CH:9][C:8]([CH3:26])=[CH:7][C:6]([OH:27])=[O:5])=[C:20]([CH3:21])[CH:19]=1
Reactant: CCCCOC(=O)C=C(C)C=CC=C(C)C=Cc1c(C)cc(OC)cc1C
Agent: CCCCOC(=O)C=C(C)C=CC=C(C)C=O
Agent: COc1cc(C)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(C)c1
Agent: [Cl-]
Product: COc1cc(C)c(C=CC(C)=CC=CC(C)=CC(=O)O)c(C)c1

Procedure:
By the procedure described in Example 14, 9-(4-methoxy-2,6-dimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid butyl ester is manufactured from 4-methoxy-2,6-dimethyl-benzyl-triphenylphosphonium chloride by reaction with 7-formyl-3-methyl-octa-2,4,6-trien-1-oic acid butyl ester. From this product, there is produced by the procedure of Example 15, 9-(4-methoxy-2,6-dimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid of melting point 207°-208° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][C:3](=O)[CH2:2]1.[C:8]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:11])[NH:9][NH2:10].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O>[O:1]1[CH2:6][CH2:5][CH2:4][CH:3]([NH:10][NH:9][C:8]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:2]1
Reactant: O=C1CCCOC1
Reactant: CC(C)(C)OC(=O)NN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: O
Product: CC(C)(C)OC(=O)NNC1CCCOC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Dihydro-2H-pyran-3(4H)-one (100 mg, 1.00 mmol), tert-butyl carbazate (145 mg, 1.10 mmol, 1.1 equiv) and acetic acid (0.280 mL, 4.99 mmol, 5 equiv) were combined in 1,2-dichloroethane (3 mL), stirred at ambient temperature for 10 minutes and treated with sodium triacetoxyborohydride (296 mg, 1.34 mmol, 1.4 equiv). After stirring for 1 hour, the mixture was poured into water and extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo to provide the titled compound.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][C:14]3=O)=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl-].[OH:19][NH3+:20].C([O-])(=O)C.[Na+].O>C(O)C.C(OCC)(=O)C>[N:1]1([C:7]2[CH:16]=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][C:14]3=[N:20][OH:19])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C1CCCc2ccc(N3CCOCC3)cc21
Reactant: [NH3+]O
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: ON=C1CCCc2ccc(N3CCOCC3)cc21
Yield: 100.2 %

Procedure:
A solution of 7-morpholin-4-yl-3,4-dihydro-2H-naphthalen-1-one (360 mg), hydroxylammonium chloride (163 mg) and sodium acetate (384 mg) in ethanol (5.0 mL) was heated to reflux for 1 hour and 50 minutes. Water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was washed with brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 384 mg of the title compound as a crude product. The physical properties of the compound are as follows.
Reaction SMILES: Cl[C:2]1C=C(C=C[CH:11]=1)C(OO)=O.C(S[C:15]1[CH:20]=[C:19]([S:21][C:22]([F:25])([F:24])[F:23])[CH:18]=[CH:17][C:16]=1[C:26]1[N:39]([CH3:40])[C:29]2=[N:30][CH:31]=[C:32]([S:34][C:35]([F:38])([F:37])[F:36])[CH:33]=[C:28]2[N:27]=1)C.C(=O)(O)[O-].[Na+].[S:46]([O-:50])([O-])(=[O:48])=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:2]([S:46]([C:15]1[CH:20]=[C:19]([S:21][C:22]([F:23])([F:24])[F:25])[CH:18]=[CH:17][C:16]=1[C:26]1[N:39]([CH3:40])[C:29]2=[N:30][CH:31]=[C:32]([S:34][C:35]([F:38])([F:36])[F:37])[CH:33]=[C:28]2[N:27]=1)(=[O:50])=[O:48])[CH3:11]
Reactant: CCSc1cc(SC(F)(F)F)ccc1-c1nc2cc(SC(F)(F)F)cnc2n1C
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])([O-])=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCS(=O)(=O)c1cc(SC(F)(F)F)ccc1-c1nc2cc(SC(F)(F)F)cnc2n1C
Reaction time: 2 h

Procedure:
0.20 g of 3-chloroperoxybenzoic acid (purity of 65% or more) was added to a mixture of 0.20 g of 2-(2-ethylsulfanyl-4-trifluoromethylsulfanylphenyl)3-methyl-6-trifluoromethylsulfanyl-3H-imidazo[4,5-b]pyridine and 3 ml of chloroform under ice cooling, and then the mixture was stirred under ice cooling for 2 hours. A saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium thiosulfate solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 0.22 g of 2-(2-ethylsulfonyl-4-trifluoromethylsulfanylphenyl)3-methyl-6-trifluoromethylsulfanyl-3H-imidazo[4,5-b]pyridine (hereinafter, referred to as Compound 9).
Reaction SMILES: [CH3:1][CH2:2][CH:3](P(OCC)(OCC)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:17][C:18](C)([O-])[CH3:19].[K+].[CH3:23][S:24][CH:25]([C:36]1[CH:41]=[C:40](C=O)[CH:39]=[CH:38][C:37]=1[O:44][CH3:45])[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>O1CCCC1>[CH3:23][S:24][CH:25]([C:36]1[CH:41]=[C:40]([C:3]2([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:2]=[CH:1][CH:17]=[CH:18][CH2:19]2)[CH:39]=[CH:38][C:37]=1[O:44][CH3:45])[C:26]([O:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:27]
Reactant: CC(C)(C)[O-]
Reactant: COc1ccc(C=O)cc1C(SC)C(=O)OCc1ccccc1
Reactant: CCOC(=O)C(CC)P(=O)(OCC)OCC
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(c2ccc(OC)c(C(SC)C(=O)OCc3ccccc3)c2)C=CC=CC1
Yield: 73.9 %

Procedure:
Under an argon atmosphere, triethyl 2-phosphonobutyrate (3.77 g, 14.9 mmol) was dissolved in dehydrated tetrahydrofuran (40 mL) and potassium tert-butoxide (1.68 g, 15.0 mmol) was added under stirring and cooling with ice. After completion of the addition, the mixture was stirred for 1 hour. Following this, benzyl 2-methylthio-2-(5-formyl-2-methoxyphenyl)acetate (4.49 g, 13.6 mmol) dissolved in dehydrated tetrahydrofuran (30 mL) was added and the mixture was stirred for 6 hours at room temperature. The reaction mixture was concentrated and ice water was added, which was made acidic with 1 mol/L hydrochloric acid. The reaction mixture was extracted with ethyl acetate. The extracte was washed with water and brine, dried over anhydrous sodium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (eluent n-hexane:ethyl acetate=9:1 v/v) to afford 4.55 g (78%) of the title compound as a colorless oil.
Reaction SMILES: CCOCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Li]CCCC.[CH3:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1>[Cl-].[Na+].O>[CH3:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:20]=1
Reactant: Cc1ccncc1
Reactant: Brc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: Cc1ccnc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 36 %

Procedure:
A two necked round-bottom flask (250 mL) containing a stir bar fitted with a reflux condenser was evacuated and purged with nitrogen gas. Dry ether (50 mL) and bromobenzene (0.0191 mol, 3.0 g) were added to the flask followed by the slow addition of n-BuLi (0.0229 mol, 9.17 mL) via a syringe pump. The reaction mixture was stirred at room temperature for 30-40 min and then 4-methyl pyridine (0.0191 mol, 1.779 g) was slowly added. The reaction mixture was then refluxed for 2 to 3 hr. The reaction mixture was then cooled to room temperature, diluted with an aqueous brine solution and extracted with ether (3×30 mL). The combined extracts were dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography using hexanes/EA as eluent. The desired 4-methyl-2-phenylpyridine was obtained. (1.15 g; 36% yield).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([CH3:12])[N:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=1.C(N(CC)CC)C>C1COCC1>[Cl:11][C:6]1[N:5]=[C:4]([CH3:12])[N:3]=[C:2]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=2)[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Nc1ccc(CCO)cc1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nc(Cl)c([N+](=O)[O-])c(Nc2ccc(CCO)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
To a stirred solution of 4,6-dichloro-2-methyl-5-nitro-pyrimidine (Albert et al., J. Chem. Soc., 1954, 3832, 7.5 g, 36.1 mmol) in THF (150 ml) was added 4-aminophenylethyl alcohol (2.47 g, 18.0 mmol), triethylamine (3.65 g, 36.1 mmol), and the mixture was stirred at room temperature for 1 h. The reaction was quenched with water (10 ml), and the mixture was extracted with ethyl acetate (100 ml×3). The organic layer was washed with brine (50 ml), dried (MgSO4), and concentrated. Purification by flash column chromatography eluting with hexane/ethyl acetate (gradient elution from 1:1 to 1:2) to afford 4.0 g (72%) of the title compound as a yellow solid.
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=1.[F:26][C:27]1[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O.C(=O)([O-])O.[Na+].COCCOC>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.O>[F:26][C:27]1[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[CH:29][C:28]=1[C:2]1[N:6]([S:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=1
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Reactant: COc1cccc(B(O)O)c1F
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cccc(-c2cc(CN(C)C(=O)OC(C)(C)C)cn2S(=O)(=O)c2cccnc2)c1F
Temperature: 100 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
tert-Butyl {[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (431 mg), (2-fluoro-3-methoxyphenyl)boronic acid (256 mg), sodium hydrogencarbonate (253 mg) and tetrakis(triphenylphosphine)palladium (88 mg) were added to a mixture of 1,2-dimethoxyethane (8 mL) and water (2 mL), and the mixture was stirred under a nitrogen atmosphere 100° C. for 2 hr. The reaction mixture was allowed to cool, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=1:1) to give the title compound as a colorless oil (yield 475 mg, about 100%).
Reaction SMILES: [H-].[Na+].[CH:3]1([N:9]2[C:13]3[CH:14]=[C:15]([O:18][CH:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)[CH:16]=[CH:17][C:12]=3[NH:11][C:10]2=[O:24])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.CN(C=O)C.[CH3:30][O:31][C:32]([C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[C:36]([O:44][CH3:45])[CH:35]=1)=[O:33]>O.C1COCC1>[CH:3]1([N:9]2[C:13]3[CH:14]=[C:15]([O:18][CH:19]4[CH2:20][CH2:21][CH2:22][CH2:23]4)[CH:16]=[CH:17][C:12]=3[N:11]([S:40]([C:37]3[CH:38]=[CH:39][C:34]([C:32]([O:31][CH3:30])=[O:33])=[CH:35][C:36]=3[O:44][CH3:45])(=[O:42])=[O:41])[C:10]2=[O:24])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: O=c1[nH]c2ccc(OC3CCCC3)cc2n1C1CCCCC1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(S(=O)(=O)n2c(=O)n(C3CCCCC3)c3cc(OC4CCCC4)ccc32)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.5 %

Procedure:
0.095 g of sodium hydride as a 60% dispersion in oil is added in portions to a mixture of 0.7 g of 3- cyclohexyl-5-cyclopentoxy-1,3-dihydro-2H-benzimidazol-2-one, 50 ml of DMF and 50 ml of THF and the mixture is stirred for 30 minutes at RT. 0.6 g of 4-methoxycarbonyl-2-methoxybenzenesulfonyl chloride is then added and the mixture is stirred for 18 hours at RT. The reaction mixture is poured into a mixture of water and ice and the precipitate formed is filtered off and washed with water and then with heptane to give 1 g of the expected product, which is used as such in the next step.
Reaction SMILES: [O:1]=[C:2]1[C:10](=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:12][C:13]([NH2:15])=[O:14].O.Cl>CS(C)=O.CCOC(C)=O>[O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:12][C:13]([NH2:15])=[O:14]
Reactant: NC(=O)CN1C(=O)C(=O)c2ccccc21
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)CN1C(=O)Cc2ccccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 44.2 %

Procedure:
The above 2-(2,3-dioxoindolin-1-yl)acetamide (4.32 g) was redissolved in DMSO (20 mL) and N2H4-xH2O (2.5 mL) was added dropwise over 10 min. After addition, the resulting mixture was stirred for 5 min at rt, then 2 h at 140° C. before cooling to rt. The reaction was quenched with ice (20 mL) and 6 M HCl (8 mL), then stirred for 30 min at rt. Suction filtration gave crude title compound (2.92 g) as a light yellow solid. The product was suspended in EtOAc (120 mL) and H2O (60 mL) was added, followed by 2 M HCl (30 mL). The mixture was separated and suction filtration of aqueous layer afforded the title compound as a light beige solid (1.78 g, 27% over 2 steps) after drying. 1H NMR (400 MHz, DMSO-d6) δ 7.59 (s, 1H, NH), 7.28-7.08 (m, 4H), 6.99 (t, J=7.4 Hz, 1H), 6.81 (d, J=8.0 Hz, 1H), 4.22 (s, 2H), 3.56 (s, 2H); MS ESI 191.0 [M+H]+, calcd for [C10H10N2O2+H]+ 191.1; MS ESI 174.0 [M−NH2]+, calcd for [C10H10N2O2−NH2]+ 174.1; MS ESI 146.0 [M−CONH2]+, calcd for [C10H10N2O2—CONH2]+ 146.1.
Reaction SMILES: [CH3:1][C:2]1([NH2:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.CCN(CC)CC.[Cl:16][CH2:17][CH2:18][CH2:19][C:20](Cl)=[O:21].O>C1COCC1>[Cl:16][CH2:17][CH2:18][CH2:19][C:20]([NH:8][C:2]1([CH3:1])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)=[O:21]
Reactant: O=C(Cl)CCCCl
Reactant: CC1(N)CCCCC1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC1(NC(=O)CCCCl)CCCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
Dissolve 1-methylcyclohexanamine (0.78 g, 6.89 mmol) in anhydrous THF (100 mL) and cool to 0° C. Add Et3N (3.49 g, 34.45 mmol) and 4-chlorobutanoyl chloride (1.94 g, 13.78 mmol) with stirring under N2. Stir the reaction mixture for 2 hours at room temperature and add water (100 mL). Extract the aqueous with EtOAc (3×200 mL) and then combine the organic layers and dry with Na2SO4, filter, concentrate and purify by flash column chromatography (silica gel, 30-80% of EtOAc-Hexane) to give 1.35 g (90%) of 4-chloro-N-(1-methylcyclohexyl)butanamide as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]2[NH:6][C:7](=[O:12])[O:8][C:9]([CH3:11])([CH3:10])[C:4]=2[CH:3]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1>>[CH3:15][O:16][C:17]1[CH:22]=[C:21]([C:2]2[CH:14]=[CH:13][C:5]3[NH:6][C:7](=[O:12])[O:8][C:9]([CH3:11])([CH3:10])[C:4]=3[CH:3]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: CC1(C)OC(=O)Nc2ccc(Br)cc21
Product: COc1cccc(-c2ccc3c(c2)C(C)(C)OC(=O)N3)c1

Procedure:
Prepared according to Procedure A from 6-bromo-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one and 3-methoxyphenyl boronic acid. Yellow solid: mp 164-165° C.; 1H-NMR (DMSO-d6) δ 10.3 (s, 1H), 7.56 (m, 2H), 7.36 (t, 1 H, J=7.89 Hz), 7.20 (m, 2H), 6.96 (d, 1H, J=8.88 Hz), 6.91 (dd, 1H, J=8.13, 2.35 Hz), 3.8 (s, 3H), 1.7 (s, 6H); MS (ESI) m/z 284 ([M+H]+, 30%); Anal. Calc. For C17H17NO3: C, 72.07; H, 6.05; N, 4.94. Found: C, 70.58, H, 5.73; N, 4.67.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:12])[CH3:11])=[CH:5][C:4]=1[C:13]1[N:14]([CH3:18])[N:15]=[CH:16][CH:17]=1.B(Br)(Br)Br>ClCCCl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:12])[CH3:11])=[CH:5][C:4]=1[C:13]1[N:14]([CH3:18])[N:15]=[CH:16][CH:17]=1
Reactant: COc1ccc(NC(C)=O)cc1-c1ccnn1C
Agent: BrB(Br)Br
Solvent: ClCCCl
Product: CC(=O)Nc1ccc(O)c(-c2ccnn2C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 21 %

Procedure:
To a suspension of N-[4-methoxy-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide (2.57 g, 10.48 mmol) in 1,2-dichloroethane (75 mL) was added BBr3 (10 mL, 106 mmol) and stirred for three hours. The nonhomogeneous suspension was heated to reflux for 15 minutes and then cooled to room temperature. The reaction was quenched by slow addition of methanol. The resulting material was purified by HPLC. The product was dried in vacuo to afford N-[4-hydroxy-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]acetamide as a white solid (508 mg, 21%). LCMS m/z (%)=232 (M+H, 100), 1H NMR (400 MHz, DMSO-d6) δ: 9.77 (bs, 1H), 9.66 (bs, 1H), 7.44-7.40 (m, 3H), 6.89 (d, J=8.85 Hz, 1H), 6.37 (d, J=1.81 Hz, 1H), 3.66 (s, 3H), 1.99 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@@H:16]2[C@@H:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:19][N:18]([C:27]([CH:29]3[CH2:33][O:32]C(C)(C)[N:30]3C(OC(C)(C)C)=O)=[O:28])[CH2:17]2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:30][CH:29]([C:27]([N:18]1[CH2:19][C@H:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C@@H:16]([O:15][C@@H:13]([C:5]2[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:3]([C:2]([F:44])([F:1])[F:43])[CH:4]=2)[CH3:14])[CH2:17]1)=[O:28])[CH2:33][OH:32]
Reactant: C[C@@H](O[C@H]1CN(C(=O)C2COC(C)(C)N2C(=O)OC(C)(C)C)C[C@@H]1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](O[C@H]1CN(C(=O)C(N)CO)C[C@@H]1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 48 mg tert-butyl 4-{[(3R,4S)-3-({(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}oxy)-4-phenylpyrrolidin-1-yl]carbonyl}-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (Example 4) in 3 mL methylene chloride was added 0.5 mL anisole and 3 mL TFA. The reaction mixture was stirred at RT for 2 hr and then the volatiles were removed under vacuum. The residue was partitioned between methylene chloride (5 mL) and sat. aq. sodium carbonate (5 mL). The organic layer was dried over sodium sulfate, filtered and the solvent removed under vacuum. The residue was purified by prep TLC eluting with methylene chloride/methanol (9/1) to afford the title compound. 1H-NMR (CDCl3): δ: 1.43 (d, 3H, 6.5 Hz), 2.0 (br. s, 3H), 3.30-4.18 (m, 9H), 4.54 (m, 1H), 7.00-7.08 (m, 2H), 7.22-7.31 (m, 3H), 7.56 (s, 2H), 7.75 (s, 1H)ppm. MS: 491.2 (MH+) observed.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[O:12]1[CH2:17][CH2:16][CH:15]([CH:18]([C:21]2[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[N:25][CH:26]=2)[CH2:19][NH2:20])[CH2:14][CH2:13]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([CH:15]1[CH2:16][CH2:17][O:12][CH2:13][CH2:14]1)[C:21]1[CH:22]=[N:23][C:24]([C:27]([F:29])([F:30])[F:28])=[N:25][CH:26]=1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: NCC(c1cnc(C(F)(F)F)nc1)C1CCOCC1
Product: O=C(NCC(c1cnc(C(F)(F)F)nc1)C1CCOCC1)c1cccc(Cl)c1Cl

Procedure:
The racemic mixture which was prepared in a similar manner to example 3a from 2,3-dichlorobenzoic acid and 2-(tetrahydro-2H-pyran-4-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine was separated into the two enantiomers by preparative SFC to yield the title compound. LCMS (M+): m/z=448.0, tR (minutes, Method F)=2.72. [α]D20=+42.52 (c=3.8 mg/mL,CHCl3)