Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([NH:17][S:18]([C:21]4[CH:42]=[CH:41][C:24]([C:25]([NH:27][C@H:28]([C:36]([O:38]CC)=[O:37])[CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])=[O:26])=[CH:23][CH:22]=4)(=[O:20])=[O:19])[CH:15]=[CH:16][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1.Cl>[OH-].[Na+]>[NH2:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([NH:17][S:18]([C:21]4[CH:22]=[CH:23][C:24]([C:25]([NH:27][C@H:28]([C:36]([OH:38])=[O:37])[CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:26])=[CH:41][CH:42]=4)(=[O:20])=[O:19])[CH:15]=[CH:16][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(S(=O)(=O)Nc2ccc3ccc4nc(N)[nH]c(=O)c4c3c2)cc1)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1nc2ccc3ccc(NS(=O)(=O)c4ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc4)cc3c2c(=O)[nH]1
Temperature: 50 °C

Procedure:
A solution of diethyl N-(4-(((3-amino-1,2-dihydro-1-oxobenzo[f]quinazolin-9-yl)amino)sulfonyl)benzoyl)-L-glutamate (0.175 g, 0.3 mmoles) in 1N NaOH (12 ml) was stirred and heated to 50° C. under a nitrogen atmosphere for 24 hrs. After cooling, the solution was acidified (pH 3) with concentrated HCl to cause precipitation of the product which was filtered, washed with water and dried to give N-(4-(((3-amino-1,2 -dihydro-1-oxobenzo[f]quinazolin-9-yl)-amino)sulfonyl)benzoyl)-L-glutamic acid as an off-white solid. (0.18 g, 99%) 1HNMR (DMSO-d6, 300 MHz) δ: 1.81-2.13(m, 2H, glu-CH2); 2.32(t, J=7.6 Hz, 2H, glu-CH2); 4.34(m, 1H, glu-CH); 6.58(br s, 2H, NH2); 7.16(d, J =Hz, 1H, Ar); 7.22(dd, J=8.6, 2 Hz, 1H, Ar); 7.74(d, J=8.7 Hz, 1H, Ar); 7.89(d, J=9.0 Hz, 1H, Ar); 7.96(m, 4H, Ar); 8.78(d, J=7.16 Hz, 1H, glu-NH); g.4 g(d, J=2 Hz, 1H, Ar); 10.68(s, 1H, 11.1(br s, 1H, NH); 12.3(br s, 2H, (CO2H)2). Anal. Calculated for C24H21N5O8S.3H2O; C, 48.56; H, 4.58; N, 11.80; S, 5.40. Found: C, 48.38; H, 4.30; N, 11.69; S, 5.34.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[C:24]2[CH2:25][CH2:26][N:27]([CH2:29][C:30]#[CH:31])[CH2:28][C:23]=2[C:5]2[C:6]([OH:22])=[CH:7][C:8]([C:10]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)([CH3:14])[CH2:11][CH2:12][CH3:13])=[CH:9][C:4]=2[O:3]1.[ClH:33].[N:34]1([CH2:40][CH2:41][CH2:42][CH2:43][C:44](O)=[O:45])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[ClH:33].[CH3:32][C:2]1([CH3:1])[C:24]2[CH2:25][CH2:26][N:27]([CH2:29][C:30]#[CH:31])[CH2:28][C:23]=2[C:5]2[C:6]([O:22][C:44](=[O:45])[CH2:43][CH2:42][CH2:41][CH2:40][N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[CH:7][C:8]([C:10]([C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)([CH3:14])[CH2:11][CH2:12][CH3:13])=[CH:9][C:4]=2[O:3]1
Reactant: O=C(O)CCCCN1CCCCC1
Reactant: C#CCN1CCC2=C(C1)c1c(O)cc(C(C)(CCC)c3ccc(F)cc3)cc1OC2(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: C#CCN1CCC2=C(C1)c1c(OC(=O)CCCCN3CCCCC3)cc(C(C)(CCC)c3ccc(F)cc3)cc1OC2(C)C

Procedure:
A mixture of 2.4 g. (6.06 mm.) of 5,5-dimethyl-10-hydroxy-8-(4-fluorophenyl-1-methylbutyl)-2-(2-propynyl)-1,2,3,4-tetrahydro-5H[1]benzopyrano[3,4-d]pyridine, 1.35 g. (6.06 mm.) of δ-piperidinovaleric acid hydrochloride and 1.30 g. (6.30 mm.) of dicyclohexylcarbodiimide in 100 ml. of methylene chloride are stirred at room temperature for 5 hours. The reaction mixture is cooled overnight in the refrigerator and the by-product of dicyclohexylurea removed by suction filtration. The mother liquor is evaporated and the residue dissolved in a mixture of methylene chloride/cyclohexane and allowed to stand in the cold for 2 hours. Gravity filtration separates the small amount of solid which appears, and the solvents are removed using a rotary evaporator. Crystallization from methylene chloride/diethyl ether yields the desired product.
Reaction SMILES: [CH2:1]([C:4]1([CH3:47])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][N:18]=2)[N:6]([C@@H:24]([CH2:44][CH3:45])[CH2:25][O:26][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[C:5]1=[O:46])[CH:2]=[CH2:3].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH2:1]([C:4]1([CH3:47])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][N:18]=2)[N:6]([C@@H:24]([CH2:44][CH3:45])[CH2:25][OH:26])[C:5]1=[O:46])[CH:2]=[CH2:3]
Reactant: C=CCC1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cn2)N([C@@H](CC)CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=CCC1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cn2)N([C@@H](CC)CO)C1=O
Temperature: 25 °C
Reaction time: 3.75 h

Procedure:
To an ice-cooled solution of 1.30 g (1.90 mmol) of (5R,6S)-3-allyl-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methylpiperidin-2-one (Example 121, Step K) in THF (55 mL) was added 11.37 mL (11.37 mmol) of a 1 M solution of TBAF in THF. The orange solution was warmed to room temperature and stirred for 3.75 h. The reaction was partitioned between 1 M HCl and EtOAc (2×), and then the combined organic layers were washed with water (2×). The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated. Purification of the residue by flash chromatography on silica gel (0 to 10% MeOH/DCM, gradient elution) provided the title compound as a light yellow solid.
Reaction SMILES: C(O[NH:9][CH2:10][C@@H:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:12]([OH:14])=[O:13])C1C=CC=CC=1.[C:20]([O:23][C:24](=O)[CH3:25])(=[O:22])C>C(O)=O.ClCCl>[CH2:24]([O:23][C:20]([NH:9][CH2:10][C@@H:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:12]([OH:14])=[O:13])=[O:22])[C:25]1[CH:17]=[CH:16][CH:15]=[CH:11][CH:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: CCCCC[C@H](CNOCc1ccccc1)C(=O)O
Solvent: O=CO
Solvent: ClCCl
Product: CCCCC[C@H](CNC(=O)OCc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 3 h
Yield: 189.3 %

Procedure:
To a cold solution of (R)-3-benzyloxyamino-2-pentylpropionic acid (1.03 g, 3.89 mmol) in HCO2H (19 mL) and dichloromethane (19 mL) at 0° C. was added acetic anhydride (3.9 mL, 41.2 mmol). The mixture was stirred at 0° C. for 3 hours. The volatiles were removed by evaporation under vacuum. Dichloromethane (50 mL) was added. The organic solution was washed with brine (50 mL×2), and dried over MgSO4. Filtration and evaporation under vacuum provided the title compound (1.08 g, 95%). 1H NMR (400 MHz, CHCl3) δ 8.07 (br s, 1H), 7.29 (m, 5H), 4.91-4.71 (m, 2H), 3.76 (m, 2H), 2.67 (m, 1H), 1.54 (m, 1H), 1.41(m, 1H), 1.20 (m, 6H), 0.80 (t, J=7.0 Hz, 3H). MH+294.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1[NH:7][N:6]=[C:5]([NH2:8])[CH:4]=1.[Cl:11][C:12]1[N:17]=[C:16](Cl)[C:15]([Cl:19])=[CH:14][N:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>CCO>[Cl:11][C:12]1[N:17]=[C:16]([NH:8][C:5]2[CH:4]=[C:3]([C:2]([F:10])([F:9])[F:1])[NH:7][N:6]=2)[C:15]([Cl:19])=[CH:14][N:13]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: Nc1cc(C(F)(F)F)[nH]n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: FC(F)(F)c1cc(Nc2nc(Cl)ncc2Cl)n[nH]1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 5-(trifluoromethyl)-1H-pyrazol-3-amine (500 mg, 3.3 mmol), 2,4,5-trichloropyrimidine (607 mg, 3.3 mmol) and sodium carbonate (525 mg, 5 mmol) in anhydrous EtOH (10 mL) was stirred at rt. After one day, LCMS showed the reaction was not complete. Additional 2,4,5-trichloropyrimidine (0.15 mL) and sodium carbonate (525 mg) were added and the reaction continued for two more days. The solvent was evaporated, and the residue was extracted with DCM (3×20 mL). The combined DCM layers were washed with brine (10 mL), dried over Na2SO4 and evaporated. The crude product was purified by silica chromatography (0-50% EtOAc in hexanes gradient) to give 2,5-Dichloro-N-(5-(trifluoromethyl)-1H-pyrazol-3-yl)pyrimidin-4-amine as a light tan colored solid; ESMS m/z 297.9 (MAI).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([O:12][CH3:13])=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].Br[CH:15]([CH2:22][CH:23]1[CH2:28][CH2:27][C:26]([F:30])([F:29])[CH2:25][CH2:24]1)[C:16](=O)[C:17]([F:20])([F:19])[F:18]>C(O)CCC>[F:29][C:26]1([F:30])[CH2:27][CH2:28][CH:23]([CH2:22][C:15]2[N:11]3[CH:10]=[C:9]([O:12][CH3:13])[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]3=[N:1][C:16]=2[C:17]([F:18])([F:19])[F:20])[CH2:24][CH2:25]1
Reactant: O=C(C(Br)CC1CCC(F)(F)CC1)C(F)(F)F
Reactant: COC(=O)c1cc(N)ncc1OC
Solvent: CCCCO
Product: COC(=O)c1cc2nc(C(F)(F)F)c(CC3CCC(F)(F)CC3)n2cc1OC
Temperature: 130 °C
Reaction time: 8 h
Yield: 51.5 %

Procedure:
Methyl 2-amino-5-methoxyisonicotinate (20 mg, 0.110 mmol) obtained in step 3 was suspended in n-butanol (1.10 mL), and the suspension was stirred overnight at 130° C. after adding 3-bromo-4-(4,4-difluorocyclohexyl)-1,1,1-trifluorobutan-2-one (53 mg, 0.165 mmol) obtained in step 2 of Example 36, and molecular sieve 4A (20 mg). The reaction mixture was allowed to cool to room temperature, filtered through Celite (registered trademark) after adding a sodium hydrogen carbonate aqueous solution, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was then evaporated under reduced pressure. The residue was purified by preparative thin-layer chromatography (chloroform/methanol=15/1) to give methyl 3-(4,4-difluorocyclohexylmethyl)-6-methoxy-2-(trifluoromethyl)imidazo[1,2-a]pyridine-7-carboxylate (23.0 mg, yield 52%).
Reaction SMILES: C(N(CC)CC)C.[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][N:19]=[CH:18]3)[CH2:10][CH2:9]1.[CH3:24][S:25](Cl)(=[O:27])=[O:26].[OH-].[Na+]>O1CCCC1>[CH3:24][S:25]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][N:19]=[CH:18]3)[CH2:12][CH2:13]1)(=[O:27])=[O:26]
Reactant: c1cc2[nH]ncc2cc1NC1CCNCC1
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)N1CCC(Nc2ccc3[nH]ncc3c2)CC1
Yield: 21.5 %

Procedure:
Triethylamine (0.39 ml, 2.80 mmol) was added to a solution of the N-(4-piperidinyl)-1H-indazol-5-amine (0.300 g, 1.39 mmol) obtained in Example 15, (a) in tetrahydrofuran (5 ml) at room temperature, followed by adding thereto a solution of methanesulfonyl chloride (0.175 g, 1.53 mmol) in tetrahydrofuran (2 ml) at 0° C., and the resulting mixture was stirred at room temperature for 1 hour. Then, the reaction solution was poured into a 1N-aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol=30/1) to obtain N-[1-(methylsulfonyl)-4-piperidinyl]-1H-indazol-5-amine (0.088 g, 22%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[N:25][CH:24]=[CH:23][N:22]=3)=[CH:17][CH:16]=2)[CH:7]=1.[C:28]1([S:34](Cl)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:34]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:36])=[O:35])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[N:25][CH:24]=[CH:23][N:22]=3)=[CH:17][CH:16]=2)[CH:7]=1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(-c3cnccn3)cc2)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc(-c3cnccn3)cc2)S(=O)(=O)c2ccccc2)c1

Procedure:
The title compound of Step B was prepared from 3-{3-[(4-pyrazin-2-yl-benzylamino)-methyl]-phenyl}-propionic acid methyl ester, of Step A, and benzenesulfonyl chloride following the method described in Example 1, Step B using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 8.98 (s, 1H), 8.60 (m, 1H), 8.50 (d, 1H), 7.87 (m, 4H), 7.63 (m, 1H), 7.56 (m, 2H), 7.17 (d, 2H), 7.12 (m, 1H), 7.02 (d, 1H), 6.87 (d, 1H), 6.78 (s, 1H), 4.37 (s, 2H), 4.32 (s, 2H), 3.64 (s, 3H), 2.78 (t, 2H), 2.47 (t, 2H); MS 502 (M+1).
Reaction SMILES: [BH4-].[Na+].[C:3]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[N:14]=[CH:15][S:16][C:17]=1/[CH:18]=[CH:19]/[C:20](=[O:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])([O:5][CH3:6])=[O:4]>O.C(O)(C)C>[C:3]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[N:14]=[CH:15][S:16][C:17]=1/[CH:18]=[CH:19]/[CH:20]([OH:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])([O:5][CH3:6])=[O:4]
Reactant: CCCCCC(=O)/C=C/c1scnc1CCCCCCC(=O)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CCCCCC(O)/C=C/c1scnc1CCCCCCC(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.5 %

Procedure:
The solution of 143 mg of sodium borohydride in 30 ml of water was added to the solution of 2.65 g of 4-(6-carbomethoxyhexyl)-5-(3-keto-1-trans-octenyl)-thiazole (Ia, R1 = H) in 30 ml of isopropanol. The obtained reaction mixture was stirred for 2 hours at room temperature, then poured onto 150 ml of water, and extracted with 3 × 75 ml of ethyl acetate. The ethyl acetate extract was washed with water to neutral and evaporated in vacuo. The obtained 2.5 g of evaporation residue was subjected to chromatography on a column prepared with 100 g of silicic acid, the elution was carried out with mixtures of n-heptane and ethyl acetate of gradually increasing ethyl acetate content. The desired 4-(6-carbomethoxyhexyl)-5-(3-hydroxy-1-trans-octenyl-thiazole, (Ic, R1 = H) was eluted from the column with a mixture consisting of 70 % n-heptane and 30 % ethyl acetate, affording 2.2 g of a product of chromatographic purity.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][CH2:34][C:35]([C:38]([O:40]C)=[O:39])([CH3:37])[CH3:36])=[C:6]([C@@H:8]2[C@:13]3([C:21]4[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=4)[NH:15][C:14]3=[O:23])[C@H:12]([C:24]3[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=3[CH3:31])[CH2:11][C:10](=[O:32])[NH:9]2)[CH:7]=1.[OH-].[Na+].O>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][CH2:34][C:35]([C:38]([OH:40])=[O:39])([CH3:37])[CH3:36])=[C:6]([CH:8]2[C:13]3([C:21]4[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=4)[NH:15][C:14]3=[O:23])[CH:12]([C:24]3[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=3[CH3:31])[CH2:11][C:10](=[O:32])[NH:9]2)[CH:7]=1
Reactant: COC(=O)C(C)(C)COc1ccc(Br)cc1[C@H]1NC(=O)C[C@@H](c2cc(Cl)ccc2C)[C@]12C(=O)Nc1cc(Cl)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(Cl)cc1C1CC(=O)NC(c2cc(Br)ccc2OCC(C)(C)C(=O)O)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 80 °C
Yield: 40.9 %

Procedure:
A mixture of (2′R,3R,4′S)-2′-[5-bromo-2-(2-methoxycarbonyl-2-methyl-propoxy)-phenyl]-6-chloro-4′-(5-chloro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (50 mg), NaOH (40 mg), H2O (5 mL) and THF (2 mL) was heated at 80° C. for 2 h. Then the mixture was concentrated. The remaining aqueous solution was acidified to “pH” 2 by concentrated aqueous HCl (1.5 mL). The white precipitate was collected by filtration to give the title compound as a white solid (Yield: 20 mg).
Reaction SMILES: Cl.[OH:2][C:3]1[C:12]([OH:13])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.C[CH2:15][O:16]CC>[C-]#N.[Zn+2].[C-]#N>[OH:2][C:3]1[C:12]([OH:13])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[CH:15]=[O:16]
Reactant: CCOCC
Reactant: Oc1cc2ccccc2cc1O
Agent: Cl
Agent: [C-]#N
Agent: [Zn+2]
Product: O=Cc1c(O)c(O)cc2ccccc12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A stream of HCl gas was passed through a stirred, cooled (0° C.) mixture of 2,3-dihydroxynaphthalene (6 g, 37.4 mmol) and zinc cyanide (6.6 g, 56.1 mmol) in dry Et2O (28 mL) for 20 min. An insoluble yellow oil was generated. Stirring was continued for 1 h at 0° C., then at room temperature for 1 h. The yellow brown oil was separated and washed with Et2O. Water (120 mL) was added and the mixture was heated at 60° C. for 10 min. The yellow solid generated was filtered and washed with water to give product (5.48 g, containing 20% starting material). MS (APCI) m/z 187 (M−H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[OH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]2[C@H:15]3[C@H:25]([CH2:26][CH2:27][C@:10]12[CH3:11])[C@:23]1([CH3:24])[C@H:18]([CH2:19][C:20](=[O:28])[CH2:21][CH2:22]1)[CH2:17][CH2:16]3.[CH2:29]([O:31][CH:32](OCC)[O:33][CH2:34][CH3:35])[CH3:30]>B(F)(F)F.CCOCC>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:29]([O:31][CH:32]([O:33][CH2:34][CH3:35])[C@@H:21]1[CH2:22][C@@:23]2([CH3:24])[C@@H:18]([CH2:17][CH2:16][C@@H:15]3[C@@H:25]2[CH2:26][CH2:27][C@@:10]2([CH3:11])[C@H:12]3[CH2:13][CH2:14][C@@H:9]2[OH:8])[CH2:19][C:20]1=[O:28])[CH3:30]
Reactant: CCOC(OCC)OCC
Reactant: C[C@]12CCC(=O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Agent: FB(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: CCOC(OCC)[C@@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]32)CC1=O
Yield: 71 %

Procedure:
By the method of part A of Example 20 (5α,17β)-17-hydroxyandrostan-3-one trifluoroacetate (ester) (0.344 mole) was diethoxymethylated using triethylorthoformate (126 ml.) and boron trifluoride etherate (140 ml.). The product was crystallized from methanol, affording (2α,5α,17β)-2-(diethoxymethyl)-17-hydroxyandrostan-3-one trifluoroacetate (ester) (118.7 g., 71% yield, m.r. 122°-123° C.).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([CH3:11])[CH:3]=1>O1CCCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Solvent: C1CCOC1
Product: Cc1cc(Br)ccc1CO
Reaction time: 18 h
Yield: 88.9 %

Procedure:
Add borane-tetrahydrofuran complex (0.2 mol, 200 mL, 1.0 M solution) to a solution of 4-bromo-2-methylbenzoic acid (39 g, 0.18 mol) in tetrahydrofuran (200 mL). After 18 hours at room temperature, remove the solvent under the reduced pressure to give a solid. Purify by flash chromatography to yield the title compound as a white solid (32.9 g, 0.16 mol). 1H NMR (CDCl3): δ 1.55 (s, 1H), 2.28 (s, 3H), 4.61 (s, 2H), 7.18-7.29 (m, 3H).
Reaction SMILES: [CH2:1]([C:3]1([OH:13])[CH2:8][CH2:7][CH:6]([C:9]([F:12])([F:11])[F:10])[CH2:5][CH2:4]1)[CH3:2].C(N(CC)CC)C.[C:21](Cl)(=[O:25])[C:22]([CH3:24])=[CH2:23]>CN(C)C1C=CN=CC=1.CC(C)=O>[C:21]([O:13][C:3]1([CH2:1][CH3:2])[CH2:4][CH2:5][CH:6]([C:9]([F:10])([F:12])[F:11])[CH2:7][CH2:8]1)(=[O:25])[C:22]([CH3:24])=[CH2:23]
Reactant: CCC1(O)CCC(C(F)(F)F)CC1
Reactant: C=C(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: C=C(C)C(=O)OC1(CC)CCC(C(F)(F)F)CC1
Yield: 75.7 %

Procedure:
A four-necked flask equipped with a stirrer, a thermometer, and a dropping funnel was charged with 7.9 g (0.04 mol) of 1-ethyl-4-trifluoromethylcyclohexanol, 0.2 g of 4-dimethylaminopyridine, 4.9 g of triethylamine, and 20 g of acetone. The mixture was stirred to obtain a solution. A solution prepared by dissolving 4.6 g (0.044 mol) of methacrylic acid chloride in 5 g of acetone was added to the solution at 4° C. over 30 minutes. The mixture was stirred at 4° C. for 3 hours to obtain a reaction mixture. The reaction mixture was washed with water to obtain 8.0 g of 1-ethyl-4-(trifluoromethyl)cyclohexyl methacrylate (hereinafter may be referred to as “compound (M-3)” ((M-3) in Table 1)). The yield of 1-ethyl-4-(trifluoromethyl)cyclohexyl methacrylate with respect to 1-ethyl-4-trifluoromethylcyclohexanol was 76%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[O:7][CH:8]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)[CH3:9].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[NH2:38][CH2:39][C:40]1[C:41]([OH:48])=[N:42][C:43]([CH3:47])=[CH:44][C:45]=1[CH3:46]>ClCCl>[OH:48][C:41]1[C:40]([CH2:39][NH:38][C:14](=[O:16])[C:13]2[CH:12]=[CH:11][C:10]([CH:8]([O:7][C:2]3[N:1]=[CH:6][CH:5]=[CH:4][N:3]=3)[CH3:9])=[CH:18][CH:17]=2)=[C:45]([CH3:46])[CH:44]=[C:43]([CH3:47])[N:42]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: CC(Oc1ncccn1)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)Oc3ncccn3)cc2)c(O)n1
Temperature: 20 °C
Reaction time: 13 h
Yield: 32.2 %

Procedure:
To a solution of 4-(1-(pyrimidin-2-yloxy)ethyl)benzoic acid (100 mg, 0.41 mmol), 1-hydroxybenzotriozole (83 mg, 0.61 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (118 mg, 0.61 mmol), triethylamine (0.2 mL) in dichloromethane (15 mL) was added 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (62 mg, 0.41 mmol). The reaction mixture was stirred at 20° C. for 13 hours. The mixture was washed with water (20 mL×2). The organic phase was dried over sodium sulfate and filtered. The filtrate was concentrated. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(1-(pyrimidin-2-yloxy)ethyl)benzamide as a white solid (50 mg, 32%). LRMS (M+H+) m/z: 378.17. found 378. HPLC Purity (214 nm): 100%. 1H NMR (300 MHz, d6-DMSO): δ 11.46 (s, 1H), 8.30 (d, J=4.8 Hz, 1H), 8.06-8.04 (m, 1H), 7.80-7.68 (m, 2H), 7.44-7.42 (m, 2H), 6.93-6.84 (m, 2H), 6.17 (q, J=6.6 Hz, 1H), 5.84 (s, 1H), 4.27 (d, J=4.8, 2H), 2.15 (s, 3H), 2.11 (s, 3H), 1.55 (d, J=6.6 Hz, 3H).
Reaction SMILES: [NH2:1][C:2](=[O:20])[CH2:3][CH2:4][NH:5][C:6](=[O:19])[C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:17][CH2:16][C:15](=O)[CH2:14]2)=[CH:9][CH:8]=1.Cl.[O:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[C:30]([C@H:31]([NH2:33])[CH3:32])[C:25]=2[O:24][CH2:23]1>>[NH2:1][C:2](=[O:20])[CH2:3][CH2:4][NH:5][C:6](=[O:19])[C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:17][CH2:16][CH:15]([NH:33][C@@H:31]([C:30]3[C:25]4[O:24][CH2:23][O:22][C:26]=4[CH:27]=[CH:28][CH:29]=3)[CH3:32])[CH2:14]2)=[CH:9][CH:8]=1
Reactant: C[C@@H](N)c1cccc2c1OCO2
Reactant: NC(=O)CCNC(=O)c1ccc([C@H]2CCC(=O)C2)cc1
Agent: Cl
Product: C[C@@H](NC1CC[C@H](c2ccc(C(=O)NCCC(N)=O)cc2)C1)c1cccc2c1OCO2

Procedure:
General procedure B was followed using N-(3-amino-3-oxo-propyl)-4-[(1S)-3-oxocyclopentyl]benzamide as the ketone and (1R)-1-(1,3-benzodioxol-4-yl)ethanamine hydrochloride as the amine. 1H NMR (600 MHz, DMSO) δ 8.39 (t, 1H), 7.74 (d, J=8.2 Hz, 2H), 7.36-7.31 (m, 3H), 6.92 (d, J=7.8 Hz, 1H), 6.84-6.79 (m, 2H), 6.78-6.75 (m, 1H), 5.97 (s, 2H), 3.91 (q, J=6.7 Hz, 1H), 3.46-3.31 (m, 2H), 3.01-2.93 (m, 2H), 2.33 (t, 2H), 2.24-2.17 (m, 1H), 1.96-1.86 (m, 1H), 1.80-1.59 (m, 2H), 1.54-1.46 (m, 1H), 1.42-1.34 (m, 1H), 1.26 (d, J=6.7 Hz, 3H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N2CCOCC2)cc1
Temperature: 60 °C
Reaction time: 48 h
Yield: 88.1 %

Procedure:
To a stirred solution of 4-fluoronitrobenzene (5.0 g, 35.43 mmol) in DMF (40 mL) were added morpholine (4.7 mL, 53.15 mmol) and cesium carbonate (17.3 g, 53.15 mmol). The reaction mixture was stirred at 60° C. for 48 h, then water (50 mL) was added. The solid formed was filtered and washed with water (5×100 mL), then Et2O (3×50 mL) to give the title compound (6.5 g, 88%) as a yellow solid that was used without further purification. δH (DMSO-d6) 8.12-8.02 (2H, m), 7.09-7.00 (2H, m), 3.79-3.68 (4H, m), 4.46-3.37 (4H, m). LCMS (ES+) 208.9 (M+H)+, RT 2.49 minutes (Method 3).