Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]=[C:7]([CH:9]3[CH2:12][C:11](=O)[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:16][C@@H:17]1[CH2:21][CH2:20][CH2:19][NH:18]1.N1C=CC=CC=1.B>ClCCl.C(O)C>[Br:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@@H:11]([N:18]4[CH2:19][CH2:20][CH2:21][C@H:17]4[CH3:16])[CH2:10]3)[S:8][C:4]=2[CH:3]=1
Reactant: C[C@@H]1CCCN1
Reactant: O=C1CC(c2nc3ccc(Br)cc3s2)C1
Agent: B
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCO
Product: C[C@@H]1CCCN1[C@H]1C[C@@H](c2nc3ccc(Br)cc3s2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 7.2 %

Procedure:
The product of Example 1C (500 mg, 1.77 mmole) was dissolved in 6 ml dichloromethane and 4 ml ethanol. 2-(R)-methylpyrrolidine (1.04 g, 4.43 mmole, toluene extract from 50% sodium hydroxide) was added and stirred at room temperature for 30 minutes. Then borane-pyridine (358 μl, 3.54 mmole) was added. The mixture was stirred at room temperature overnight. The reaction was quenched with saturated sodium bicarbonate and extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product which was purified by column chromatography (0.4% ammonium hydroxide and 4% methanol in dichloromethane) to give 45 mg (9% yield) of the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 7.98 (d, J=1.83 Hz, 1H) 7.80 (d, J=8.85 Hz, 1H) 7.54 (dd, J=8.54, 1.83 Hz, 1H) 3.54-3.65 (m, 1H) 3.15-3.29 (m, 1H) 3.00-3.13 (m, 1H) 2.73-2.86 (m, 1H) 2.56-2.69 (m, 2H) 2.32-2.57 (m, 3H) 1.92-2.05 (m, 1H) 1.79-1.90 (m, 1H) 1.67-1.78 (m, 1H) 1.46-1.57 (m, 1H) 1.17 (s, 3H). MS: (M+H)+=351/353.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([O:21][CH3:22])[CH:15]=2)=[O:13])[N:3]=1.[CH3:23][C:24]1[NH:28][N:27]=[C:26]([NH2:29])[CH:25]=1.[I-].[K+].CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]([C:4]2[N:3]=[C:2]([NH:29][C:26]3[CH:25]=[C:24]([CH3:23])[NH:28][N:27]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)=[O:13])=[CH:15][C:16]=1[O:21][CH3:22]
Reactant: Cc1cc(N)n[nH]1
Reactant: COc1cc(C(=O)c2nc(Cl)c3ccccc3n2)ccc1F
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)c2nc(Nc3cc(C)[nH]n3)c3ccccc3n2)ccc1F
Temperature: 25 °C
Reaction time: 20 h
Yield: 75 %

Procedure:
A mixture of (4-chloroquinazolin-2-yl)(4-fluoro-3-methoxyphenyl)methanone (337 mg, 1.06 mmol), 5-methyl-1H-pyrazol-3-amine (206 mg, 2.12 mmol), potassium iodide (528 mg, 3.18 mmol) and DIEA (0.37 mL, 2.13 mmol) in DMF (10 mL) was stirred at rt for 20 h. To the mixture was added water (80 mL) and the resulting solid was collected by filtration and washed with water and then diethyl ether. The solid was dried to afford (4-fluoro-3-methoxyphenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanone as a yellow solid (300 mg, 75%). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.19 (s, 3H), 3.90 (s, 3H), 6.55 (s, 1H), 7.38 (dd, J=11.1, 8.4 Hz, 1H), 7.59 (m, 1H), 7.68 (dd, J=7.8, 7.8 Hz, 1H), 7.77-7.94 (m, 3H), 8.75 (d, J=7.8 Hz, 1H), 10.69 (br s, 1H), 12.23 (br s, 1H); LC-MS (ESI) m/z 378 (M+H)+.
Reaction SMILES: Cl.[C:2]([C:6]1[N:10]=[CH:9][N:8]([CH2:11]Cl)[N:7]=1)([CH3:5])([CH3:4])[CH3:3].[F:13][C:14]([F:23])([F:22])[CH2:15][CH2:16][CH:17]([C:20]#[N:21])[C:18]#[N:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:2]([C:6]1[N:10]=[CH:9][N:8]([CH2:11][C:17]([CH2:16][CH2:15][C:14]([F:13])([F:22])[F:23])([C:18]#[N:19])[C:20]#[N:21])[N:7]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)c1ncn(CCl)n1
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1ncn(CC(C#N)(C#N)CCC(F)(F)F)n1
Yield: 33.6 %

Procedure:
1.61 g of 3-t-butyl-1-(chloromethyl)-1H-1,2,4-triazole hydrochloride and 1.24 g of (3,3,3-trifluoropropyl) malononitrile were dissolved in 22 ml of N,N-dimethylformamide. 2.13 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for 4 hours. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from hexane-MTBE to obtain 0.77 g of [(3-t-butyl-1H-1,2,4-triazole-1-yl)methyl](3,3,3-trifluoropropyl) malononitrile (referred as the compound of the present invention (29), hereinafter) shown by below formula.
Reaction SMILES: [C:1]([NH:9][C:10]1[N:18]=[CH:17][N:16]=[C:15]2[C:11]=1[N:12]=[CH:13][N:14]2[C@@H:19]1[O:24][C@H:23]([C:25]([OH:27])=[O:26])[C@@H:22]([NH:28][C:29](=[O:51])[C@H:30]([CH2:42][C:43]2[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=2)[NH:31][C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[C@H:20]1[OH:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH2:54])=[N-]>C(OCC)(=O)C>[C:1]([NH:9][C:10]1[N:18]=[CH:17][N:16]=[C:15]2[C:11]=1[N:12]=[CH:13][N:14]2[C@@H:19]1[O:24][C@H:23]([C:25]([O:27][CH3:54])=[O:26])[C@@H:22]([NH:28][C:29](=[O:51])[C@H:30]([CH2:42][C:43]2[CH:44]=[CH:45][C:46]([O:49][CH3:50])=[CH:47][CH:48]=2)[NH:31][C:32]([O:34][CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)=[O:33])[C@H:20]1[OH:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)N[C@H]2[C@@H](O)[C@H](n3cnc4c(NC(=O)c5ccccc5)ncnc43)O[C@@H]2C(=O)O)cc1
Reactant: C=[N+]=[N-]
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1O[C@@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)[C@H](O)[C@@H]1NC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 1-(6-benzoylamino-9H-purin-9-yl)-1,3-dideoxy-3-(N-benzyloxycarbonyl-O-methyl-L-tyrosylamino)-β-D-ribofuranuronic acid (695 mg) prepared in Example 2 in ethyl acetate (200 ml) was added excess ethereal solution of diazomethane and the mixture was stirred for 30 minutes at room temperature. The resulting solution was evaporated to dryness and the residue was triturated in diethyl ether to give methyl 1-(6-benzoylamino-9H-purin-9-yl)-1,3-dideoxy-3-(N-benzyloxycarbonyl-O-methyl-L-tyrosylamino)-β-D-ribofuranuronate (700 mg), mp. 124°-128° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:8]=2[C:9]#[N:10])=[CH:4][C:3]=1[CH3:18].Cl.[N:20]([O-])=O.[Na+].CC([O-])=O.[K+]>CC(O)=O.O.CCOC(C)=O>[F:15][C:12]1[CH:13]=[CH:14][C:7]([O:6][C:5]2[CH:4]=[C:3]3[C:2](=[CH:17][CH:16]=2)[NH:1][N:20]=[CH:18]3)=[C:8]([CH:11]=1)[C:9]#[N:10]
Reactant: O=N[O-]
Reactant: Cc1cc(Oc2ccc(F)cc2C#N)ccc1N
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1cc(F)ccc1Oc1ccc2[nH]ncc2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.6 %

Procedure:
Intermediate (25t) (13.2 g, 54.5 mmol) and NH4BF4 were dissolved in 550 mL of mixed solvent of AcOH and water (2:1) and cooled to 0° C. Added concentrated HCl (12N, 23 mL, 272 mmol) and NaNO2 (4.14 g, 59.9 mmol) to the solution at 0° C., then the mixture was allowed to warm to room temperature and stirred. After 3 hours of stirring, the solution was concentrated under reduced pressure and azeotroped with toluene 4 times to dryness to obtain a pale yellow crude solid. The solid was dissolved in 600 mL of EtOAc and KOAc was added to the solution then the mixture was stirred under room temperature. In 30 minutes, the yellow solution became orange and was stirred further. After overnight stirring, the orange suspension was filtered and washed with EtOAc a few times to 1000 mL total volume. The organic solution was transferred to a separatory funnel and washed with saturated NaHCO3 and brine, dried with MgSO4, filtered and evaporated. The obtained crude orange solid was purified on silica gel with EtOAc/hexane (1:2-1:1) to afford an orange solid (13.2 g), which was washed with toluene. The orange colored toluene solution was concentrated and washed with toluene again. Repeating the same toluene washing afforded compound (26t) as a slightly orange colored solid (11.7 g, 84% yield over 2 steps). 1HNMR (400 MHz, CDCl3) δ 12.12 (s, 1H), 8.03 (s, 1H), 7.58 (d, J=9.4 Hz, 1H), 7.40 (d, J=2.3 Hz, 1H), 7.37 (dd, J=7.9, 3.1 Hz, 1H), 7.18 (ddd, J=9.4, 7.9, 3.1 Hz, 1H), 7.13 (dd, J=8.5, 2.3 Hz, 1H), 6.80 (dd, J=9.3, 3.9 Hz, 1H) ppm.
Reaction SMILES: C(OC[N:9]1[CH:13]=[C:12]([C:14]2[S:15][C:16]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[N:24]=3)=[C:17]([C:19]([NH2:21])=[O:20])[CH:18]=2)[N:11]=[N:10]1)(=O)C(C)(C)C.[OH-].[Na+].Cl>CO.O>[N:30]1([CH2:29][C:25]2[N:24]=[C:23]([NH:22][C:16]3[S:15][C:14]([C:12]4[N:11]=[N:10][NH:9][CH:13]=4)=[CH:18][C:17]=3[C:19]([NH2:21])=[O:20])[CH:28]=[CH:27][CH:26]=2)[CH2:31][CH2:32][O:33][CH2:34][CH2:35]1
Reactant: CC(C)(C)C(=O)OCn1cc(-c2cc(C(N)=O)c(Nc3cccc(CN4CCOCC4)n3)s2)nn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: NC(=O)c1cc(-c2c[nH]nn2)sc1Nc1cccc(CN2CCOCC2)n1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a suspension of [4-(4-(aminocarbonyl)-5-{[6-(morpholin-4-ylmethyl)pyridin-2-yl]amino}-2-thienyl)-1H-1,2,3-triazol-1-yl]methyl pivalate (70 mg, 0.14 mmol) in MeOH (1.5 mL) and water (1.0 mL) was added NaOH (1.0 M, 0.310 ml, 0.31 mmol). The mixture was stirred at room temperature for 45 min (the suspension became a clear orange solution). The reaction was neutralized with 2 N HCl (0.150 ml), diluted with water, and extracted with 5:1 CH2Cl2:MeOH (3×). The combined organic extracts were dried (MgSO4), filtered, combined with silica gel, and evaporated to dryness. Flash chromatography (dry load, 0-10% MeOH/CH2Cl2) yielded the title compound as a colorless solid.
Reaction SMILES: C([Li])CCC.[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22](Br)=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1.[CH3:32][O:33][C:34]1[N:39]=[CH:38][C:37]([C:40]([C:42]2[S:46][CH:45]=[N:44][CH:43]=2)=[O:41])=[CH:36][CH:35]=1>C1COCC1>[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22]([C:40]([C:37]3[CH:38]=[N:39][C:34]([O:33][CH3:32])=[CH:35][CH:36]=3)([C:42]3[S:46][CH:45]=[N:44][CH:43]=3)[OH:41])=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1
Reactant: COc1ccc(C(=O)c2cncs2)cn1
Reactant: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C(O)(c2ccc3nc(OC)c(Cc4ccc(-n5cccn5)cc4)c(Cl)c3c2)c2cncs2)cn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (0.154 mL, 0.246 mmol; 1.6 M in hexane) was added dropwise to a solution of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-4-chloro-2-methoxyquinoline (0.081 g, 0.189 mmol, Intermediate 16) in dry THF (4 mL) at −78° C. over a 5 minute period. After complete addition stirring was continued at −78° C. for 30 minutes then (6-methoxypyridin-3-yl)(thiazol-5-yl)methanone (0.046 g, 0.189 mmol, Intermediate 15) dissolved in THF (1.9 mL) was slowly added and the reaction warmed in an ice bath to 0° C. The mixture was stirred for 30 minutes, quenched with saturated aqueous NH4Cl then warmed to room temperature. After stirring for 10 minutes layers were separated and the aqueous layer extracted with EtOAc. The combined organic extracts were dried over Na2SO4, filtered, evaporated in vacuo and chromatographed (0-100% EtOAc in DCM) to provide the title compound. 1H NMR (400 MHz, MeOH-d4) δ ppm 3.94 (s, 3H) 4.08 (s, 3H) 4.35 (s, 2H) 6.43-6.52 (m, 1H) 6.88 (d, J=9.09 Hz, 1H) 7.37 (d, J=8.08 Hz, 2H) 7.54-7.63 (m, 3H) 7.66-7.72 (m, 2H) 7.77 (dd, J=8.59, 2.53 Hz, 1H) 7.85 (d, J=8.59 Hz, 1H) 8.12 (dd, J=13.14, 2.53 Hz, 2H) 8.20 (s, 1H) 9.08 (s, 1H); MS (ESI) 570.
Reaction SMILES: [CH3:1][C@@:2]12[C@@:10]([OH:15])([C:11]([CH2:13][OH:14])=[O:12])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:16][CH2:17][C:18]3[C@@:24]([CH3:25])([C@H:5]1[C@@H:4]([OH:26])[CH2:3]2)[CH:23]=[CH:22][C:20](=[O:21])[CH:19]=3.[CH:27]1[C:32]([CH2:33][CH2:34][CH2:35][C:36](O)=[O:37])=[CH:31][CH:30]=[C:29]([N:39]([CH2:43][CH2:44][Cl:45])[CH2:40][CH2:41][Cl:42])[CH:28]=1.CC1C=CC(S(O)(=O)=O)=CC=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl.C(O)(=O)C>[CH3:1][C@@:2]12[C@@:10]([OH:15])([C:11]([CH2:13][O:14][C:36]([CH2:35][CH2:34][CH2:33][C:32]3[CH:27]=[CH:28][C:29]([N:39]([CH2:40][CH2:41][Cl:42])[CH2:43][CH2:44][Cl:45])=[CH:30][CH:31]=3)=[O:37])=[O:12])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:16][CH2:17][C:18]3[C@@:24]([CH3:25])([C@H:5]1[C@@H:4]([OH:26])[CH2:3]2)[CH:23]=[CH:22][C:20](=[O:21])[CH:19]=3
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CO
Reactant: O=C(O)CCCc1ccc(N(CCCl)CCCl)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)COC(=O)CCCc1ccc(N(CCCl)CCCl)cc1
Temperature: 0 °C
Reaction time: 20 h
Yield: 91 %

Procedure:
To 250 ml CH2Cl2 is added with stirring 36 g prednisolone (0.10 mol), 31.3 g chlorambucil (0,103 mol), 1.2 g DMAP (0,01 mol) and 1.1 g pTSA (0,06 mol). The reaction mixture is cooled to 0° C. and with continued stirring at this temperature a solution of 22.7 g DCC (0,11 mol) in 50 ml CH2Cl2 is slowly added. The reaction mixture is then kept at 0° C. with stirring for 20 h. 3 ml acetic acid is added and precipitated urea filtered off. The filtrate is evaporated in vacuo and the residue recrystallized from ethanol to give 58.9 g of TLC pure prednimustine (91% yield) without any discolouration. M.P. 165°-166° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:7].[H-].[Na+].Br[CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].C(OCC)(=O)C>CN(C)C=O.O>[O:7]=[C:2]1[CH2:3][CH2:4][CH2:5][CH2:6][N:1]1[CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: O=C1CCCCN1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(CN1CCCCC1=O)OCc1ccccc1
Reaction time: 1 h
Yield: 24.5 %

Procedure:
Under a nitrogen atmosphere, to a solution of piperidin-2-one (9.8 g, 99 mmol) in N,N-dimethylformamide (100 ml) was added sodium hydride (4.4 g, 110 mmol) under ice-cooling, and the mixture was stirred for 1 hr. Then, benzyl bromoacetate (19 ml, 120 mmol) was added, and the mixture was further stirred for 2 hr. To the reaction mixture were added ethyl acetate and water, and the organic layer was separated, washed successively with water and saturated brine, and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (6.0 g, yield 24%).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH2:12]1CC2C(CC(CC2)=O)CC1>>[C:1]([CH:5]1[CH2:10][CH2:9][C:8](=[CH2:12])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C1CCC(=O)CC1
Reactant: O=C1CCC2CCCCC2C1
Product: C=C1CCC(C(C)(C)C)CC1

Procedure:
The title compound was prepared as described in Example 45A substituting 4-tert-Butyl cyclohexanone, commercially available from Aldrich, for 2-decalone.
Reaction SMILES: [C:1]([C:5]1[CH:42]=[CH:41][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2/[CH:17]=[CH:18]/[CH:19]([CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][CH:34]=2)[CH2:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].Cl>C1COCC1.O>[C:1]([C:5]1[CH:42]=[CH:41][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2/[CH:17]=[CH:18]/[CH:19]([CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][CH:34]=2)[CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:29][CH:30]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(CC(/C=C/c2ccccc2OCc2ccc(C(C)(C)C)cc2)CCc2ccc(C#N)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(COc2ccccc2/C=C/C(CCc2ccc(C#N)cc2)Cc2ccc(C(=O)O)cc2)cc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 90 %

Procedure:
A solution of 1.1 g (1.97 mmol) of methyl-4-{(3E)-4-{2-[(4-tert-butylbenzyl)oxy]phenyl}-2-[2-(4-cyanophenyl)ethyl]but-3-en-1-yl}benzoate from Example 102A in 7.20 ml of THF and 3.60 ml of water is mixed with 189 mg (7.89 mmol) of lithium hydroxide and stirred at 60° C. for 12 h. The reaction mixture is adjusted to pH 34 with 1 M hydrochloric acid and concentrated. The residue is taken up on silica gel and purified by chromatography (mobile phase: cyclohexane/ethyl acetate 1:1, with 0.1% formic acid). 990 mg (1.77 mmol, 97% purity, 90% yield) of a solid are isolated.
Reaction SMILES: O[C:2]1([C:27]([F:30])([F:29])[F:28])[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)=[N:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:16][S:13]([C:10]1[CH:11]=[CH:12][C:7]([N:5]2[CH:6]=[C:2]([C:27]([F:28])([F:29])[F:30])[N:3]=[C:4]2[C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][CH:18]=2)=[CH:8][CH:9]=1)(=[O:14])=[O:15]
Reactant: CS(=O)(=O)c1ccc(N2CC(O)(C(F)(F)F)N=C2c2ccc(C(F)(F)F)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(-n2cc(C(F)(F)F)nc2-c2ccc(C(F)(F)F)cc2)cc1

Procedure:
A mixture of 4-hydroxy-1-[4-(methylsulfonyl)phenyl]-2-(4-trifluoromethylphenyl)-4-trifluoromethyl-4,5-dihydro-1H-imidazole (10 mmol) and p-toluenesulfonic acid monohydrate (1 mmol) in toluene (100 mL) is heated to reflux for 72 hours. The reaction mixture is cooled and the solvent removed under reduced pressure. The crude residue is redissolved in methylene chloride and washed with water, aqueous sodium bicarbonate and brine. After drying (Na2SO4), filtration and concentration in vacuo, the crude mixture is purified by chromatography on silica gel using toluene/ethyl acetate to give pure 1-[4-(methylsulfonyl)phenyl]-2-(4-trifluoromethylphenyl)-4-trifluoromethyl-1H-imidazole.
Reaction SMILES: N[C@H](CO)C(O)=O.CC1N=C([C@H]2CSCN2)SC=1.[CH3:19][C:20]1[N:21]=[C:22]([C@H:25]2[CH2:29][O:28][CH2:27][N:26]2C(OC(C)(C)C)=O)[S:23][CH:24]=1.Cl>O1CCOCC1>[CH3:19][C:20]1[N:21]=[C:22]([C@H:25]2[CH2:29][O:28][CH2:27][NH:26]2)[S:23][CH:24]=1
Reactant: Cc1csc([C@H]2COCN2C(=O)OC(C)(C)C)n1
Agent: Cc1csc([C@H]2CSCN2)n1
Agent: Cl
Agent: N[C@H](CO)C(=O)O
Solvent: C1COCCO1
Product: Cc1csc([C@H]2COCN2)n1

Procedure:
Methyl thiazole-D-oxaproline (R)-4-(4-methylthiazol-2-yl)oxazolidine was made from (R)-2-amino-3-hydroxypropanoic acid (Aldrich), following similar procedure described for the synthesis of (R)-4-methyl-2-(thiazolidin-4-yl)thiazole. The intermediate (R)-tert-butyl 4-(4-methylthiazol-2-yl)oxazolidine-3-carboxylate was deprotected using 4N HCl in 1,4-dioxane (20 min) and the desired product was used for the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[O:12][CH2:13][C:14]([CH3:17])([CH3:16])[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C([Li])CCC.[C:23]1([CH2:29]Br)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1>[CH3:1][O:2][C:3]1[C:4]([CH2:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:5]([C:11]2[O:12][CH2:13][C:14]([CH3:17])([CH3:16])[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: BrCc1ccccc1
Reactant: COc1ccc(C2=NC(C)(C)CO2)cc1OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C2=NC(C)(C)CO2)c(Cc2ccccc2)c1OC
Reaction time: 2 h

Procedure:
A solution of 2-[3,4-Dimethoxyphenyl]-4,5-dihydro 4,4-dimethyloxazole (15 g) in dry tetrahydrofuran (100 ml) under a nitrogen atmosphere was cooled to -45° in a chlorobenzene/dry ice bath. Butyl lithium (45.9 ml 1.6 M solution) was added dropwise and the mixture stirred at -45° for 2 hours. Phenylmethyl bromide (38 ml) was then added dropwise and the mixture allowed to stir at 20° for 16 hours. The mixture was quenched with brine and the aqueous phase extracted with ether. The organic phase was separated, dried over magnesium sulphate, filtered and evaporated to leave a solid. Purification by flash chromatography (30% ether/40/60 petrol) gave the title compound as a colourless solid (10.58 g); mp 81°-82°.
Reaction SMILES: O1CCCC1.CN(OC)[C:8](=[O:17])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[NH2:16].[C:20]([NH:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43](Br)[CH:42]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([Li])CCC>C(OC(=O)C)C.O.CCCCCC>[NH2:16][C:10]1[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:9]=1[C:8]([C:45]1[CH:44]=[CH:43][CH:42]=[C:41]([CH2:40][NH:39][C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:46]=1)=[O:17]
Reactant: Brc1cccc(CNC(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: CON(C)C(=O)c1cc(Cl)ccc1N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Nc1ccc(Cl)cc1C(=O)c1cccc(CNC(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Yield: 43.8 %

Procedure:
A tetrahydrofuran (30 ml) solution of N-methyl-N-methyloxy-2-amino-5-chlorobenzamide (3.22 g) and N-trityl-3-bromobenzylamine (4.28 g) was cooled to −78° C. To the solution was gradually added dropwise a hexane solution of n-butyl lithium (1.6 mol/L) (31 ml). To the mixture were then added water (70 ml) and acetic acid ethyl ester (100 ml). The organic layer was washed with water and dried over anhydrous MgSO4. The solvent was distilled off, and the residual yellow oily compound was purified by a silica gel column chromatography to give 2-amino-3′-tritylaminomethyl-5-chlorobenzophenone (2.2 g) as a yellow oily product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.C[OH:11]>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:1]=[O:11])=[CH:3][CH:4]=1
Reactant: COc1ccc(C)cc1
Reactant: CO
Product: COc1ccc(C=O)cc1
Yield: 97.3 %

Procedure:
In the same manner as in Example 1, p-methyl anisole is oxidized with use of an 80% by weight aqueous solution of methanol in place of methanol, affording anisaldehyde in a yield of 97.3%. With use of cerium salt regenerated in the same manner as in Example 1 (and using an 80% by weight methanol aqueous solution in place of methanol) for the second oxidation, anisaldehyde is obtained in a yield of 94.3%.
Reaction SMILES: [CH3:1][C@H:2]([O:6][C:7]1[CH:8]=[C:9]([CH:20]=[C:21]([O:23]CC2C=CC=CC=2)[CH:22]=1)[C:10]([NH:12][C:13]1[CH:18]=[N:17][C:16]([CH3:19])=[CH:15][N:14]=1)=[O:11])[CH2:3][O:4][CH3:5]>[Pd].C(O)C>[OH:23][C:21]1[CH:20]=[C:9]([CH:8]=[C:7]([O:6][C@@H:2]([CH3:1])[CH2:3][O:4][CH3:5])[CH:22]=1)[C:10]([NH:12][C:13]1[CH:18]=[N:17][C:16]([CH3:19])=[CH:15][N:14]=1)=[O:11]
Reactant: COC[C@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)Nc2cnc(C)cn2)c1
Agent: [Pd]
Solvent: CCO
Product: COC[C@H](C)Oc1cc(O)cc(C(=O)Nc2cnc(C)cn2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.3 %

Procedure:
10% Palladium on charcoal (700 mg) was added to a solution of 3-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)-5-[(phenylmethyl)oxy]benzamide (7.0 g, 17.2 mmol) in ethanol (125 mL) and the mixture stirred at RT under a hydrogen atmosphere for 4 hours. The catalyst was removed by filtration and the ethanol evaporated in vacuo. The residue was crystallised from ethyl acetate to give the desired compound (4.22 g). 1H NMR δ (CDCl3): 1.25 (d, 3H), 2.5 (s, 3H), 3.3 (s, 3H), 3.4-3.5 (m, 2H), 4.5 (m, 1H), 6.3 (br, 1H), 6.55 (s, 1H), 6.9 (s, 1H), 6.95 (s, 1H), 8.05 (s, 1H), 8.45 (s, 1H) and 9.5 (s, 1H). m/z 318 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[S:9]1[CH2:14][CH2:13][CH:12]([CH:15]=[O:16])[CH2:11][CH2:10]1>>[Br:8][C:4]1[N:3]=[C:2]([CH:15]([CH:12]2[CH2:13][CH2:14][S:9][CH2:10][CH2:11]2)[OH:16])[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)n1
Reactant: O=CC1CCSCC1
Product: OC(c1cccc(Br)n1)C1CCSCC1

Procedure:
The title compound was prepared as described in Example 162, Step 1 with 2,6-dibromopyridine (3.64 g, 15.36 mmol) and tetrahydro-2H-thiopyran-4-carbaldehyde (2.00 g, 15.36 mmol) as the starting materials.