Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:14]([O:16][C:17](=[O:36])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=1)[CH3:15]>>[CH2:14]([O:16][C:17](=[O:36])[CH2:18][C:19]1[CH:20]=[C:21]([C:2]2[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])[C:22]([O:25][CH3:26])=[CH:23][CH:24]=1)[CH3:15]
Reactant: CCOC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: O=Cc1ccc(C(F)(F)F)cc1Br
Product: CCOC(=O)Cc1ccc(OC)c(-c2cc(C(F)(F)F)ccc2C=O)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: 2-bromo-4-trifluoromethyl-benzaldehyde and [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[O:10][C:11](=[O:15])[N:12]([CH3:14])[CH3:13])#[N:2].[ClH:16].[H][H]>C(OCC)(=O)C.C(O)C.[Pd]>[ClH:16].[NH2:2][CH2:1][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[O:10][C:11](=[O:15])[N:12]([CH3:13])[CH3:14]
Reactant: CN(C)C(=O)Oc1cc(F)ccc1C#N
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN(C)C(=O)Oc1cc(F)ccc1CN
Yield: 38 %

Procedure:
To a solution of intermediate 132, dimethyl-carbamic acid 2-cyano-5-fluoro-phenyl ester, (340 mg, 1.63 mmol) in ethyl acetate (20 mL) and ethanol (20 mL), was added conc.HCl (0.4 mL) and 10% Pd—C (100 mg) and the mixture hydrogenated in a Parr Shaker at 55 psi of hydrogen for 20 hrs. The reaction mixture was filtered through Celite, and the filtrate concentrated in vacuo to give an oil which was partitioned between ethyl acetate (10 mL) and water (10 mL). After separation, the aqueous phase was washed with additional ethyl acetate (5 mL). The combined extracts were concentrated in vacuo to dryness. The residual oil was triturated with ether to provide 145 mg (Yield 38%) of the title compound, as a tan powder: 1H NMR (CD3OD, 500 MHz) δ ppm: 3.06 (3H, s, NMe), 3.21 (3H, s, NMe), 4.11 (2H, s, NCH2), 7.13 (2H, m, Ar-Hs), 7.60 (1H, m, Ar—H); 13C NMR (CD3OD, 125.77 Hz) δ ppm: 36.03, 36.25 37.58, 110.79, 110.99, 113.26, 113.43, 122.32, 132.18, 132.25, 151.55, 154.72, 162.69, 164.67. HRMS (ESI) calcd for C10H13N2O2F (M+H) 213.1039, found 213.1039.
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH2:25][CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[CH:18]1([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:25][CH:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:24])=[CH:5][N:6]=3)=[C:16]([CH3:17])[O:15][N:14]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: NC1CCOCC1
Reactant: COC(=O)c1ccc(OCc2c(C3CCCCC3)noc2C)nc1
Product: Cc1onc(C2CCCCC2)c1COc1ccc(C(=O)NC2CCOCC2)cn1
Yield: 39 %

Procedure:
As described for example 31e, 6-(3-cyclohexyl-5-methyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (472 mg, 1.0 mmol) was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (155 mg, 39%) which was obtained as a white solid after purification by chromatography (silica, 0 to 70% ethyl acetate in heptane). MS: m/e=400.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:19](=[O:21])[CH3:20])[CH:6]=[C:7]([O:17][CH3:18])[C:8]=1[O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].C([N-]C(C)C)(C)C.[Li+].[S:30]1[C:34]([C:35]2[C:36]([O:45][CH3:46])=[CH:37][C:38]([O:43][CH3:44])=[C:39]([CH:42]=2)[CH:40]=O)=[CH:33][C:32]2[CH:47]=[CH:48][CH:49]=[CH:50][C:31]1=2>O1CCCC1>[S:30]1[C:34]([C:35]2[C:36]([O:45][CH3:46])=[CH:37][C:38]([O:43][CH3:44])=[C:39]([CH:40]=[CH:20][C:19]([C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][Si:10]([C:13]([CH3:16])([CH3:14])[CH3:15])([CH3:11])[CH3:12])=[C:7]([O:17][CH3:18])[CH:6]=3)=[O:21])[CH:42]=2)=[CH:33][C:32]2[CH:47]=[CH:48][CH:49]=[CH:50][C:31]1=2
Reactant: COc1cc(OC)c(-c2cc3ccccc3s2)cc1C=O
Reactant: COc1cc(C(C)=O)cc(OC)c1O[Si](C)(C)C(C)(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(OC)c(-c2cc3ccccc3s2)cc1C=CC(=O)c1cc(OC)c(O[Si](C)(C)C(C)(C)C)c(OC)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 20 %

Procedure:
Ex-59B: To a solution of 3′,5′-dimethoxy-4′-(tert-butyldimethylsiloxy)acetophenone, from Ex-59A (0.5 g, 1.6 mmol) in tetrahydrofuran (10 mL) chilled with ice/water was added lithium diisopropylamide (2 M, 0.8 mL, 1.6 mmol). The mixture was stirred for 20 minutes while chilled. Then 5-(benzo[b]thien-2-yl)-2,4-dimethoxybenzaldehyde, from Ex-6A,(0.48 g, 1.6 mmol) in tetrahydrofuran (6 mL) was added, and the mixture was stirred at room temperature for 2 hours. Upon quenching with water, the mixture was extracted with dichloromethane. The organic phase was dried and evaporated. Crystallization from ethanol gave 0.19 g (20%) of the desired 3-[5-(benzo[b]thien-2-yl)2,4-dimethoxyphenyl]-1-(4-ter-butyldimethylsiloxy-3,5-dimethoxyphenyl)-2-propen-1-one as a yellow solid.
Reaction SMILES: C([O:8][C:9]1[C:14]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])=[CH2:26])[CH:20]=1)C1C=CC=CC=1>CO.C(OCC)(=O)C.[Pd]>[C:15]([C:14]1[CH:13]=[CH:12][CH:11]=[C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH3:34])[CH3:26])[CH:20]=2)[C:9]=1[OH:8])([CH3:16])([CH3:17])[CH3:18]
Reactant: C=C(c1cccc(-c2cccc(C(C)(C)C)c2OCc2ccccc2)c1)c1ccccc1OC
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccccc1C(C)c1cccc(-c2cccc(C(C)(C)C)c2O)c1
Reaction time: 4 h
Yield: 96 %

Procedure:
A solution of 38 (0.7 g, 1.56 mmol) in methanol (40 mL) and ethyl acetate (60 mL) was treated with 20% palladium on activated carbon (50% wet, 0.100 g) and was hydrogenated at 40 psi in a Parr shaker for 4 hr. The catalyst was filtered out and washed with ethyl acetate. The filtrate was stripped and the crude product was purified by chromatography on silica (40 g) hexane (3 L) to afford pure E2 (0.54 g, 96%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([C:13]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][C:15](Cl)=[O:16])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.FC(F)(F)C([NH:34][C:35]1[CH:40]=[CH:39][C:38]([N:41]2[CH2:46][CH2:45][N:44](C(=O)C(F)(F)F)[CH2:43][CH2:42]2)=[CH:37][CH:36]=1)=O>C(#N)C>[C:7]1([C:13]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][C:15]([NH:34][C:35]2[CH:36]=[CH:37][C:38]([N:41]3[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]3)=[CH:39][CH:40]=2)=[O:16])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(Cl)CC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(Nc1ccc(N2CCN(C(=O)C(F)(F)F)CC2)cc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(CC(c1ccccc1)(c1ccccc1)c1ccccc1)Nc1ccc(N2CCNCC2)cc1
Temperature: 80 °C
Reaction time: 48 h
Yield: 87 %

Procedure:
To an ice cooled and stirred solution of 4-(4-aminophenyl)piperazine (4.29 g, 24.2 mmol) in dichloromethane (100 mL) containing Et3N (7.42 mL, 52.5 mmol) was added trifluoroacetic anhydride (7.52 mL, 53.2 mmol) in dichloromethane (25 mL) over a 5 minute period. The mixture was allowed to warm to room temperature and stirred two days, then stirred with ice water. The pink solid that separated was isolated by filtration, washed with dichloromethane, aqueous sodium bicarbonate, and water, and dried to obtain 1-(4-(trifluoroacetamido)phenyl)-4-trifluoroacetylpiperazine (4.09 g, 46% , mp 193°-194° C.). To a mixture of this material (0.37 g, 1 mmol ) and anhydrous potassium carbonate (1.1 g, 8.0 mmol) in acetonitrile (50 mL) was added 3,3,3-triphenylpropionyl chloride (0.54 g) and the mixture stirred at 80° C. for two days. With tlc monitoring, four additional lots of the acid chloride (4×0.54 g) and potassium carbonate (4×1.1 g) were added at 3 hr intervals, with continued reflux until complete disappearance of the starting piperazine by tlc. The solvent was removed in vacuo, the residue triturated with methanol, the solids removed by filtration and the filtrate evaporated to dryness in vacuo. The residue was stirred with 20% KOH in methanol (15 mL) for 3 hr and then evaporated to dryness in vacuo. The residue was partitioned between water and ethyl acetate and the organic layer extracted with 2N HCl. The acid extract was basified with 2N NaOH to pH 9.5 and extracted with ethyl acetate. The organic layer was washed with brine, then dried over sodium sulfate and evaporated to dryness to give the title compound as a tan solid (0.40 g, 87%), mp 193°-195° C. 1H NMR (CDCl3) δ 7.33 (m,15H), 6.89 (d, J=8.9, 2H) 6.73 (d, J=8.9, 2H), 6.26 (s, 1H), 3.70 (s, 2H), 3.00 (d, J=10.0, 8H). IR 3056, 1665, 1598, 1515, 1447, 1239, 700 cm-1. MS 462 (MH+). Anal. calcd. for: C31H31N3O·0.5 H2O: C, 79.12; H, 6.85; N, 8.93. Found: C, 78.84; H, 6.66; N, 8.64.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1.[C:13]([O-:16])(=[S:15])[CH3:14].[K+].C(=O)(O)[O-].[Na+]>CN(C=O)C>[C:13]([S:15][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)(=[O:16])[CH3:14]
Reactant: CC([O-])=S
Reactant: Clc1ccc(OCCCBr)cc1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)SCCCOc1ccc(Cl)cc1
Yield: 93.5 %

Procedure:
A solution of Intermediate 2 (6.0 g) in DMF (50 ml) was treated with potassium thioacetate (5.7 g) at room temperature for 3 h, then the brown solution was added to 5% sodium bicarbonate solution and extracted with ether (3×200 ml). The solvent was washed with water (200 ml) and brine, dried over MgSO4 and evaporated to give the title compound (5.50 g) as a beige solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:12])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[C:13](O)(=[O:20])[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.CCN=C=NCCCN(C)C.N1C=CC=CC=1>O>[OH:12][C:3]1[C:2]([NH:1][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:7][C:6]([C:8]([F:11])([F:9])[F:10])=[CH:5][N:4]=1
Reactant: O=C(O)c1ccncc1
Reactant: Nc1cc(C(F)(F)F)cnc1O
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1cc(C(F)(F)F)cnc1O)c1ccncc1
Temperature: 80 °C
Yield: 76.9 %

Procedure:
A mixture of 1.0 g of 3-amino-2-hydroxy-5-trifluoromethylpyridine, 0.69 g of isonicotinic acid, 1.40 g of WSC and 7 ml of pyridine was stirred while heating at 80° C. for two hours. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate three times. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 1.22 g of N-[2-hydroxy-5-(trifluoromethyl)pyridin-3-yl]isonicotinamide.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15](Br)[N:14]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)#[N:2].[F:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1>>[C:1]([CH2:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:25]3[CH:24]=[CH:23][CH:22]=[C:21]([F:20])[CH:26]=3)[N:14]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)#[N:2]
Reactant: N#CCc1cccc(NC(=O)c2cccc(Br)n2)c1
Reactant: OB(O)c1cccc(F)c1
Product: N#CCc1cccc(NC(=O)c2cccc(-c3cccc(F)c3)n2)c1

Procedure:
The pyridyl bromide (91) (150 mg, 0.47 mmol) was coupled to 3-fluoro-phenylboronic acid (73 mg, 0.52 mmol) using Method E. The crude residue was purified by column chromatography eluting with 20% EtOAc in heptane to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][C:16]=1[N+:17]([O-])=O)[CH2:7][N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)([O-])=O>[Fe].O1CCOCC1.O>[N:8]1([CH2:7][C:6]2[CH:5]=[C:4]([NH2:1])[C:16]([NH2:17])=[CH:15][CH:14]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: O=[N+]([O-])c1ccc(CN2CCOCC2)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: C1COCCO1
Solvent: O
Product: Nc1ccc(CN2CCOCC2)cc1N
Yield: 72.6 %

Procedure:
To a mixture of 4-(3,4-dinitro-benzyl)-morpholine (2.5 g, 9.3 mmol), Fe powder (5.2 g, 93 mmol) and FeSO4.7H2O (1.3 g, 4.6 mmol) was added 1,4-dioxane:water (5:1, 60 ml). The mixture was refluxed for 3 h, filtered through celite, washing with MeOH, and reduced in vacuo azeotroping with toluene. EtOAc (100 ml) was added and insoluble material removed via filtration. The filtrate was reduced in vacuo to give 4-morpholin-4-ylmethyl-benzene-1,2-diamine as a dark brown solid (1.4 g, 73%). (LC/MS: Rt 0.40, no ionization).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][NH:16][CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:32]([BH3-])#N.[Na+]>CO.ClC(Cl)C>[CH3:32][N:16]([CH2:15][CH2:14][C:11]1[CH:10]=[CH:9][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:13][CH:12]=1)[CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCC(NCCc2ccc(Oc3ccccc3)cc2)CC1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CC(Cl)Cl
Product: CN(CCc1ccc(Oc2ccccc2)cc1)C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 17 h

Procedure:
A solution of 1,1-dimethylethyl 4-((2-(4-phenoxyphenyl)ethyl)amino)-1-piperidinecarboxylate (about 9.4 mmol) in a mixture of methanol and dichloroethane (30 mL) was treated with a formaldehyde (37% solution in water). After the addition of sodium cyanoborohydride (710 mg, 11.26 mmol), the reaction was stirred for 17 hours. The reaction was concentrated. Purification on silica gel using a gradient of ethyl acetate in hexane gave 1,1-dimethylethyl 4-(methyl(2-(4-phenoxyphenyl)ethyl)amino)-1-piperidinecarboxylate.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH2:9][NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][CH:12]=2)=[CH:4][N:3]=1.[N+](C1C=CC([O:28][C:29](=O)[NH:30][C@H:31]([CH3:41])[CH2:32][O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])=CC=1)([O-])=O.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:37]([Si:34]([CH3:36])([CH3:35])[O:33][CH2:32][C@H:31]([NH:30][C:29](=[O:28])[N:10]([CH2:9][C:5]1[C:6]([Cl:8])=[N:7][C:2]([Cl:1])=[N:3][CH:4]=1)[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][CH:12]=1)[CH3:41])([CH3:40])([CH3:39])[CH3:38]
Reactant: CCc1ccc(NCc2cnc(Cl)nc2Cl)cc1
Reactant: C[C@H](CO[Si](C)(C)C(C)(C)C)NC(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCc1ccc(N(Cc2cnc(Cl)nc2Cl)C(=O)N[C@H](C)CO[Si](C)(C)C(C)(C)C)cc1

Procedure:
A solution of (2,4-dichloro-pyrimidin-5-yl-methyl)-(4-ethyl-phenyl)amine (620 mg, 2.19 mmol) (from Example 38c supra), (R)-[2-(tert-butyl-dimethyl-silanyloxy)-1-methyl-ethyl]-carbamic acid 4-nitro-phenyl ester (778 mg, 2.19 mmol) (from Example 38b supra) and triethylamine (0.93 mL, 6.6 mmol) (Allied Signal) in toluene (20 mL) was heated at reflux for 48 hours. The reaction mixture was quenched at room temperature with 1 N aqueous hydrochloric acid then extracted with ethyl acetate. The combined organic layers were successively washed with 1 N aqueous sodium hydroxide solution and brine, then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (30% ethyl acetate in hexanes) to give (R)-3-[2-(tert-butyl-dimethyl-silanyloxy)-1-methyl-ethyl]-1-(2,4-dichloro-pyrimidin-5-yl-methyl)-1-(4-ethyl-phenyl)-urea. (Yield 383 mg, 36%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=[O:7].C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C=O)C>[CH2:16]([O:7][C:6]([C:2]1[NH:1][CH:5]=[CH:4][CH:3]=1)=[O:8])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)c1ccc[nH]1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1ccc[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 1H-pyrrole-2-carboxylic acid (1.11 g, 10 mmol) in DMF (15 mL) is added potassium carbonate (2.07 g, 15 mmol) and (bromomethyl)benzene (1.80 g, 10.50 mmol). After stirring the mixture at room temperature for 18 hours, water is added and the mixture is extracted three times with ethyl acetate. The combined organic layers are washed with water and brine then is dried over magnesium sulfate. The solvent is removed under reduced pressure and the residue is purified by flash chromatography (heptane/ethyl acetate=5:1) to give 1H-pyrrole-2-carboxylic acid benzylester.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([SH:15])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[C:17]([O:21][CH3:22])(=[O:20])[CH:18]=[CH2:19].C1(C)C=CC=CC=1>C(N(CC)CC)C>[CH3:22][O:21][C:17](=[O:20])[CH2:18][CH2:19][S:15][C:7]1[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:6]=1[OH:16]
Reactant: C=CC(=O)OC
Reactant: CC(C)(C)c1cc(S)c(O)c(C(C)(C)C)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)CCSc1cc(C(C)(C)C)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.5 %

Procedure:
In a 50 ml flask under nitrogen, a mixture of 5.00 grams of 2,4-di-tert-butyl-6-mercaptophenol, 1.80 grams of methyl acrylate and 20 mls toluene was treated with 0.50 mls of triethylamine. After stirring for three hours at ambient temperature, the solvent was removed in vacuo. The residue was purified by chromatography on silica gel using toluene/heptane eluent to give 3.90 g (57% yield) of a colorless oil.
Reaction SMILES: CC(OC([N:8]1[CH2:13][CH2:12][N:11]2[C:14](=[O:29])[O:15][C:16]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:10]2[CH2:9]1)=O)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:23]1([C:16]2([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:10]3[CH2:9][NH:8][CH2:13][CH2:12][N:11]3[C:14](=[O:29])[O:15]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)OC(c3ccccc3)(c3ccccc3)C2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1OC(c2ccccc2)(c2ccccc2)C2CNCCN12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (1,1-dimethylethyl)tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo[3,4-a]pyrazine-7(1H)-carboxylate (99 mg, 0.25 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.19 mL, 2.5 mmol), and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. This solution was washed with sodium hydrogen carbonate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain hexahydro-1,1-diphenyl-3H-oxazolo[3,4-a]pyrazin-3-one as a crude product. The product was dissolved in tetrahydrofuran (2 mL). Diisopropylethylamine (60 μL, 0.35 mmol) and phenyl chlorocarbonate (44 μL, 0.35 mmol) were added thereto, and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added ethyl acetate, and the resulting mixture was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-hexane to obtain the title compound (70 mg, yield 67%).
Reaction SMILES: [Na].[CH3:2][CH2:3][C@@H:4]([C:23]([C@H:25]([C@@H:27]([OH:43])[C@@H:28]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[C:34]([OH:39])[C:33]=1[C:40]([OH:42])=[O:41])[CH3:29])[CH3:26])=[O:24])[C@H:5]1[O:9][C@@:8]([C@@H:12]2[O:17][C@@H:16]([CH3:18])[C@@:15]([OH:21])([CH2:19][CH3:20])[CH2:14][CH2:13]2)([CH2:10][CH3:11])[CH2:7][C@@H:6]1[CH3:22].C(Cl)(Cl)[Cl:45].ClCl>C(Cl)(Cl)(Cl)Cl>[Cl:45][C:37]1[C:32]([CH2:31][CH2:30][CH:28]([CH3:29])[CH:27]([OH:43])[CH:25]([CH3:26])[C:23](=[O:24])[CH:4]([CH2:3][CH3:2])[CH:5]2[CH:6]([CH3:22])[CH2:7][C:8]([CH2:10][CH3:11])([CH:12]3[CH2:13][CH2:14][C:15]([CH2:19][CH3:20])([OH:21])[CH:16]([CH3:18])[O:17]3)[O:9]2)=[C:33]([C:40]([OH:42])=[O:41])[C:34]([OH:39])=[C:35]([CH3:38])[CH:36]=1
Reactant: CC[C@@H](C(=O)[C@@H](C)[C@@H](O)[C@H](C)CCc1ccc(C)c(O)c1C(=O)O)[C@H]1O[C@](CC)([C@H]2CC[C@](O)(CC)[C@H](C)O2)C[C@@H]1C
Reactant: ClC(Cl)Cl
Agent: ClCl
Agent: [Na]
Solvent: ClC(Cl)(Cl)Cl
Product: CCC(C(=O)C(C)C(O)C(C)CCc1c(Cl)cc(C)c(O)c1C(=O)O)C1OC(CC)(C2CCC(O)(CC)C(C)O2)CC1C

Procedure:
To a cold solution (~3°) of 6.12 g. of the sodium salt of antibiotic X-537A in 50 ml. of chloroform/3 ml. of carbon tetrachloride was slowly added 34 ml. of arbon tetrachloride saturated with 10 millimoles of chlorine gas. The reaction was continued for one-half hour after which the solution was filtered and the filtrate treated with a saturated aqueous solution of Na2CO3. The solvent layer was dried over Na2SO4 and concentrated to a small volume from which after addition of hexane the crystalline product was recovered. The crystalline material which had a tendency to incorporate the solvent of crystallization was twice recrystallized from methylene chloride/ether and acetone/-hexane, m.p. 183°-185°, [α]D25 -44.31° (C, 0.99 percent CHCl3).
Reaction SMILES: C([Mg]Cl)(C)C.[Si:6]([O:13][C@H:14]([CH3:21])[CH2:15][C:16]([O:18]CC)=O)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[CH3:22][NH:23][O:24][CH3:25].Cl>C1COCC1>[Si:6]([O:13][C@H:14]([CH3:21])[CH2:15][C:16]([N:23]([O:24][CH3:25])[CH3:22])=[O:18])([C:9]([CH3:10])([CH3:11])[CH3:12])([CH3:7])[CH3:8]
Reactant: CNOC
Reactant: CCOC(=O)C[C@@H](C)O[Si](C)(C)C(C)(C)C
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CON(C)C(=O)C[C@@H](C)O[Si](C)(C)C(C)(C)C
Reaction time: 3 h

Procedure:
A solution of 2M isopropylmagnesium chloride in THF (800 mL, 1.60 mol) was added dropwise via cannula over 60 min to a stirred solution of (R)-ethyl 3-(tert-butyldimethylsilyloxy)butanoate (131 g, 532 mmol) and N,O-dimethylhydroxylamine/HCl (80 g, 824 mmol) in dry THF (850 mL) while maintaining the internal temperature between −30° C. and −20° C. The suspension was allowed to stir for 3 h between −20 and −10° C., and quenched while cold with saturated aqueous ammonium chloride solution (400 mL). The reaction mixture was partitioned between water (200 mL) and diethyl ether (500 mL) and the aqueous phase was further extracted with diethyl ether (1 L). The combined organic phases were washed with brine, dried over MgSO4, filtered, concentrated and dried under high vacuum to yield (R)-3-(tert-butyldimethylsilyloxy)-N-methoxy-N-methylbutanamide. The reaction was repeated 6 times to yield a total of 717 g material. The analytical data complied with data reported in the literature. The material was used without additional purification.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[C:10]2[CH:15]=[C:14]([Cl:16])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)[C:10]3[CH:15]=[C:14]([Cl:16])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(Cl)cc23)cc1OC
Product: COc1ccc(CNc2nc(-n3ccnc3)nc3sc(Cl)cc23)cc1OC

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2,6-dichloro-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-chloro-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.