Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[O:11][C:5]2[N:6]=[CH:7][NH:8][C:9](=O)[C:4]=2[C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:9]1[C:4]2[C:3]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:2]([I:1])[O:11][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2oc(I)c(-c3ccccc3)c12
Product: Clc1ncnc2oc(I)c(-c3ccccc3)c12
Yield: 68 %

Procedure:
163 (0.8 g, 2.35 mmol) was refluxed in phosphorous oxychloride (12 mL) for 90 minutes. The reaction mixture was concentrated and diluted with ice-cold water, extracted with dichloromethane. The organic layer was washed with water and dried over MgSO4. The organic solvent upon concentration provided a pale solid which on trituration with MeOH provided 164 as a pale solid (0.57 g, 68%).
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[C:8]([C:9]2[CH:10]=[CH:11][C:12]3[O:17][CH2:16][CH2:15][CH2:14][C:13]=3[CH:18]=2)=[C:7]([C:19](=[O:24])[C:20]([O:22][CH3:23])=[O:21])[N:6]([CH3:25])[N:5]=1.O>O1CCCC1>[Br:3][C:4]1[C:8]([C:9]2[CH:10]=[CH:11][C:12]3[O:17][CH2:16][CH2:15][CH2:14][C:13]=3[CH:18]=2)=[C:7]([CH:19]([OH:24])[C:20]([O:22][CH3:23])=[O:21])[N:6]([CH3:25])[N:5]=1
Reactant: COC(=O)C(=O)c1c(-c2ccc3c(c2)CCCO3)c(Br)nn1C
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(O)c1c(-c2ccc3c(c2)CCCO3)c(Br)nn1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.4 %

Procedure:
Under a nitrogen atmosphere, sodium borohydride (36 mg, 0.95 mmol) was added portionwise to a solution of methyl 2-[3-bromo-4-(3,4-dihydro-2H-1-benzopyran-6-yl)-1-methyl-1H-pyrazol-5-yl]-2-oxoacetate (11g) (300 mg, 0.79 mmol) in anhydrous tetrahydrofuran (8 mL) at 0° C. After 30 minutes stirring at 0° C., water was added (5 mL) and the mixture was concentrated in vacuo. The crude was dissolved in ethyl acetate (10 mL) then successively washed with water (10 mL), and brine (10 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC (dichloromethane/ethyl acetate 80/20) to provide methyl 2-[3-bromo-4-(3,4-dihydro-2H-1-benzopyran-6-yl)-1-methyl-1H-pyrazol-5-yl]-2-hydroxyacetate (11h) (204 mg, 0.54 mmol, 68%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:12]([N:19]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[CH:25]([CH2:32][CH3:33])[CH2:24][CH2:23][NH:22][CH2:21][C:20]1=[O:34])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(C)C=CC=C(N=C=O)C=1.C(OC(CN1C2C=CC=CC=2CCCNCC1=O)=O)(C)(C)C>>[CH2:12]([N:19]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[CH:25]([CH2:32][CH3:33])[CH2:24][CH2:23][N:22]([C:10](=[O:11])[NH:9][C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:21][C:20]1=[O:34])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCC1CCNCC(=O)N(Cc2ccccc2)c2ccccc21
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Agent: CC(C)(C)OC(=O)CN1C(=O)CNCCCc2ccccc21
Agent: Cc1cccc(N=C=O)c1
Product: CCC1CCN(C(=O)Nc2ccc(Cl)c(Cl)c2)CC(=O)N(Cc2ccccc2)c2ccccc21

Procedure:
The compound was prepared by a similar method to that used in the preparation of example 49 except that 3,4-dichlorophenylisocyanate and 1-benzyl-7-ethyl-2-oxo-2,3,4,5,6,7-hexahydro-1H-1,4-benzodiazonine were used in place of m-tolylisocyanate and 1-tert-butyloxycarbonylmethyl-2-oxo-2,3,4,5,6,7-hexahydro-1H-1,4-benzodiazonine respectively in step j.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:6]=[CH:5][C:4]=1[N:12]([CH2:21][CH3:22])[C:13]1[N:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[N:14]=1.C[OH:24]>O>[CH3:1][S:2]([C:3]1[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:6]=[CH:5][C:4]=1[N:12]([CH2:21][CH3:22])[C:13]1[N:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[N:14]=1)=[O:24]
Reactant: CCN(c1nc(C)cc(C)n1)c1ccc(C(C)C)cc1SC
Reactant: CO
Solvent: O
Product: CCN(c1nc(C)cc(C)n1)c1ccc(C(C)C)cc1S(C)=O
Yield: 70 %

Procedure:
The sulfide of Example 35, (300 mg, 0.95 mmoles), was reacted with 300 mg (1.41 mmoles) NaIO4 in 6 mL MeOH and 3 mL water at 25° C. for 24 h. The reaction mixture was partitioned between 100 mL EtOAc and 25 mL water and the EtOAc extract was washed with water, brine, dried and stripped in vacuo. The residue was purified by silica gel chromatography using 1:1 EtOAc/hexanes as eluent to give 220 mg product, (70% yield); mp 144-146° C. Elemental analysis for C18H25N3O5: Theory C, 65.22; H, 7.60; N, 12.68; S, 9.67. Found: C, 65.12; H, 7.63; N, 12.48; S, 9.71.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([CH:24]([CH3:26])[CH3:25])=[N:7][C:8]([CH:21]([CH3:23])[CH3:22])=[C:9]([CH2:18][CH:19]=O)[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=O.[Br-].[CH2:28]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[NH2-].[Na+]>C(OCC)(=O)C.CCCCCC>[CH:24]([C:6]1[C:5]([CH2:3][OH:2])=[C:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:9]([CH2:18][CH:19]=[CH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:8]([CH:21]([CH3:22])[CH3:23])[N:7]=1)([CH3:26])[CH3:25]
Reactant: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)c1c(C(C)C)nc(C(C)C)c(CC=O)c1-c1ccc(F)cc1
Agent: [Br-]
Agent: [NH2-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)c1nc(C(C)C)c(CC=Cc2ccccc2)c(-c2ccc(F)cc2)c1CO

Procedure:
The title compound was prepared from the intermediate obtained in Step A and benzyl triphenylphosphonium bromide/sodium amide according to the procedures described in Example 1, Steps F-G. The product was obtained as a 6:4 mixture of trans:cis isomers. 1H NMR (300 MHz, CDCl3): δ 7.19 (m, 8 H), 6.96 (m, 1 H), 6.32 (d, J=11 Hz, 0.4 H), 6.09 (dt, J=5.5, 16 Hz, 0.6 H), 5.96 (d, J=16 Hz, 0.6 H), 5.45 (dt, J=7, 11 Hz, 0.4 H), 4.37 (d, J=5 Hz, 1.25 H), 4.33 (d, J=5.5 Hz, 0.75 H), 3.41 (m, 1.6 H), 3.25 (m, 2 H), 3.08 (m, 0.4 H), 1.35 (m, 5 H), 1.30 (d, J=6.6 Hz, 5 H), 1.21 (m, 3 H). FAB-MS: calcd for (C27H30FNO) 403, found 404 (M+H). Anal. Calcd for C27H30FNO: C, 80.36; H, 7.49; N, 3.47. Found: C, 80.15; H, 7.44; N, 3.26. mp 72-73° C. Rf=0.3 (20% ethyl acetate/hexane).
Reaction SMILES: C1(=O)N([N:6]2[CH:14]=[CH:13][CH:12]=[C:8]([C:9]([O-:11])=O)[CH2:7]2)C(=O)CC1.[CH2:17]([CH2:19][NH2:20])[OH:18].C(N(C(C)C)CC)(C)C.C(N)C.CN(C=O)C.C([O-])(=O)C1C=CC=NC=1.ON1C(=O)CCC1=O>CN(C=O)C>[OH:18][CH2:17][CH2:19][NH:20][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][CH:14]=[N:6][CH:7]=1
Reactant: O=C([O-])C1=CC=CN(N2C(=O)CCC2=O)C1
Reactant: NCCO
Agent: CCN
Agent: O=C([O-])c1cccnc1
Agent: O=C1CCC(=O)N1O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCO)c1cccnc1
Reaction time: 0.25 h

Procedure:
The N-succinimidyl-nicotinate compound described in Example 1 was reacted with the hydrochloric salt of ethanolamine, available commercially in its radioactive form. The ethanolamine salt was dissolved in dried DMF and chilled in an ice bath. To the mixture was added an equimolar of diisopropylethylamine (DIEA) and stirred for 15 minutes. An equimolar solution of N-succinimidyl-nicotinate was added to the ethylamine-DMF mixture dropwise under a nitrogen atmosphere. As the nicotinate was added the mixture turned milky and was slurried for at least another half hour. The milky substance was the N-hydroxy-succinimide precipitating, which was filtered off. The DMF-mixture was washed with ether to remove any precipitant. The solvent mixture was removed under high vaccum. The oily mixture was triturated with ether to yield a precipitant, N-(2-hydroxyethyl)nicotinamide. The radioactive compound was isolated and identified by its TLC.
Reaction SMILES: [CH2:1]([C:5]1[CH:28]=[CH:27][C:8]([C:9]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[NH:19][C:18]3=[O:26])[CH2:13][CH2:12]2)=[O:10])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH2:29](Br)[CH:30]=[CH2:31].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>O>[CH2:31]([N:19]1[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:17]([CH:14]2[CH2:15][CH2:16][N:11]([C:9](=[O:10])[C:8]3[CH:7]=[CH:6][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[CH:28][CH:27]=3)[CH2:12][CH2:13]2)[C:18]1=[O:26])[CH:30]=[CH2:29]
Reactant: CCCCc1ccc(C(=O)N2CCC(n3c(=O)[nH]c4ccccc43)CC2)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCn1c(=O)n(C2CCN(C(=O)c3ccc(CCCC)cc3)CC2)c2ccccc21
Temperature: 120 °C
Reaction time: 72 h
Yield: 66.1 %

Procedure:
1-[1-(4-Butyl-benzoyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one (197.2 mg, 0.522 mmol), allyl bromide (260 μL, 3.0 mmol) and cesium carbonate (excess) were added to dimethyl formamide (3 mL) and the suspension was stirred at 120° C. in a sealed tube for 72 hours. The reaction was allowed to cool to room temperature and diluted with water (9 mL) then extracted with ethyl ether (2×10 mL). The combined organic phase was dried over sodium sulfate and purified by column chromatography on silica gel using ethyl ether as the eluent. The product fractions were combined and concentrated to give an oily residue. The residue was triturated with ethyl ether and the white crystals that formed were collected by filtration. Vacuum drying yielded 1-allyl-3-[1-(4-butyl-benzoyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one (144 mg, 66%) as a white crystalline solid.
Reaction SMILES: [CH3:1][CH:2]([CH2:7][F:8])[C:3]([F:6])([F:5])[F:4].S(=O)(=O)(O)[OH:10]>O>[CH3:1][C:2]([OH:10])([CH2:7][F:8])[C:3]([F:6])([F:5])[F:4]
Reactant: CC(CF)C(F)(F)F
Reactant: O=S(=O)(O)O
Solvent: O
Product: CC(O)(CF)C(F)(F)F

Procedure:
As another example, 2-methyl-1,1,1,3-tetrafluoro-2-propanol may be prepared by reacting commercially available methacrylic acid with hydrogen fluoride to form 2-methyl-3-fluoropropanoic acid which may then be fluorinated to form 2-methyl-1,1,1,3-tetrafluoropropane. The 2-methyl-1,1,1,3-tetrafluoropropane may then be dehydrogenated and reacted with sulfuric acid and then water to form 2-methyl-1,1,1,3-tetrafluoro-2-propanol.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.O>C(Cl)Cl>[CH3:14][O:13][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([CH2:2][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:12]=1
Reactant: C1COCCN1
Reactant: COC(=O)c1ccc(OC)cc1CBr
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc(OC)cc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.9 %

Procedure:
To a solution of methyl 2-(bromomethyl)-4-methoxybenzoate (960 mg, 3.7 mmol) in DCM (18.5 mL) was added morpholine (0.68 mL, 7.8 mmol). The reaction mixture was stirred at room temperature overnight and poured onto iced water. The aqueous mixture was extracted with DCM (3×), and the combined organics were dried over MgSO4, filtered, and concentrated in vacuo to provide a yellow oil. The crude material was purified by flash chromatography on silica using a gradient of EtOAc in hexane (0 to 50%) as eluant. The tittle product was obtained as a clear oil (490 mg, 50%)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:15])[CH:11]=2)[CH:6]=1)=[O:4].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:23][C:24]([O:26][CH3:27])=[O:25]>CC(C)=O.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:11]=2)[CH:6]=1)=[O:4]
Reactant: COC(=O)CBr
Reactant: COC(=O)c1ccc2cc(O)ccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)COc1ccc2cc(C(=O)OC)ccc2c1
Yield: 84.6 %

Procedure:
To a stirred solution of 6-hydroxy-2-naphthoic acid methyl ester (0.500 g, 2.47 mmol) in acetone (25 mL) at rt was added Cs2CO3 (0.886 g, 2.72 mmol) followed by methyl bromoacetate (0.257 mL, 2.72 mmol) dropwise. After 18 h at this temperature, it was diluted with EtOAc (200 mL). This layer was washed with 1 N HCl (20 mL), sat. aq. NaHCO3 (20 mL), and brine (20 mL) and then dried (MgSO4). After concentration, the residue was recrystallized from MeOH:H2O to afford the product (0.573 g, 85%) as a solid; 1H NMR (DMSO-d6) δ3.71 (s, 3H), 3.87 (s, 3H), 4.95 (s, 2H), 7.30 (dd, J=2.6, 8.9 Hz, 1H), 7.38 (d, J=2.4 Hz, 1H), 7.87 (d, J=8.7 Hz, 1H), 7.92 (dd, J=1.6, 8.6 Hz, 1H), 8.06 (d, J=9.1 Hz, 1H), 8.55 (s, 1H); mass spectrum [(+) ESI], m/z 275 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:12]=[C:11]3[N:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25]CC)=[O:24])[CH2:14][CH2:15][CH2:16][C:10]3=[N:9][C:8]=2[C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)=[CH:3][CH:2]=1.[Li+].[OH-]>C1COCC1.O>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:12]=[C:11]3[N:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[CH2:14][CH2:15][CH2:16][C:10]3=[N:9][C:8]=2[C:28]2[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=2)=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCCCCCN1CCCc2nc(-c3ccc(C)cc3)c(-c3ccncc3)nc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2nc3c(nc2-c2ccncc2)N(CCCCCCC(=O)O)CCC3)cc1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A solution of ethyl 7-(3-(pyridin-4-yl)-2-p-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoate (step 2) (15 mg, 0.033 mmol) in THF (2 ml) and water (1 ml) was treated with LiOH (7.83 mg, 0.327 mmol) and stirred at 70° C. for 4 hours. The mixture was cooled to room temperature and concentrated under vacuum. The residue was acidified (1N HCl, pH ˜5) and extracted with DCM (×3). The combined extracts were washed with brine, dried (MgSO4) and evaporated under vacuum to a yellow gum which was triturated with ether and dried under vacuum at 40° C. for 2.5 hours to afford the title compound;
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[OH:14])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH2:26](Br)[CH3:27]>O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[O:14][CH2:26][CH3:27])(=[O:3])[CH3:2]
Reactant: CCBr
Reactant: CC(=O)Nc1ccc([N+](=O)[O-])cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc([N+](=O)[O-])ccc1NC(C)=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To 400 g of 2-acetamido-5-nitrophenol in a 12-L, 4-necked flask equipped with a reflux condenser, nitrogen inlet, thermocouple, addition funnel, and mechanical stirrer was added 790 g of potassium carbonate and 2.0 L of dimethylformamide. The mixture was stirred at 60° C. as 294 g of ethyl bromide was added over 30 minutes. After 1 hour, an additional 27 g of ethyl bromide was added and the mixture was stirred at 60° C. for another hour. The mixture was cooled to room temperature and poured into 4 L of water. After 30 minutes, the product was collected by filtration and washed with water and heptane. The product was dried in a vacuum oven at 60° C. to give 457 g of the title compound.
Reaction SMILES: C([O:5][C:6](=[O:41])[C@@H:7]([NH:31][S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(=[O:34])=[O:33])[CH2:8][NH:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25]3[N:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[CH:19]=2)=[CH:14][CH:13]=1)=[O:11])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:26]1[CH2:27][CH2:28][CH2:29][NH:30][C:25]=1[NH:24][C:20]1[CH:19]=[C:18]([C:15]2[CH:14]=[CH:13][C:12]([C:10]([NH:9][CH2:8][C@H:7]([NH:31][S:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C:6]([OH:41])=[O:5])=[O:11])=[CH:17][CH:16]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(-c2cccc(Nc3ncccn3)c2)cc1)NS(=O)(=O)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC[C@H](NS(=O)(=O)c1ccccc1)C(=O)O)c1ccc(-c2cccc(NC3=NCCCN3)c2)cc1
Reaction time: 2 h

Procedure:
A solution of 1-9 (175 mg, 0.305 mmol), TFA (3 mL) and CH2Cl2 (3 mL) was stirred at ambient temperature for 3.0 hours. The reaction was concentrated and then azeotroped with toluene (3×10 mL). The residue was dissolved in 5:1 AcOH/HCl (36 mL). 10% Pd/C (150 mg) was added and the mixture was shaken under 62 psi of hydrogen gas for 2.0 hours. Following filtration and evaporative removal of the solvent, the residue was chromatographed (silica gel, 10:1:1 EtOH/ NH4OH/H2O) to give 1-10 as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][CH2:11][C:12]1[N:13]=[C:14]([CH:17]([CH3:19])[CH3:18])[S:15][CH:16]=1)=[O:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>CC(C)=O.O>[CH2:33]([O:32][C:30](=[O:31])[CH2:29][O:21][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:20][C:6]=1[C:7](=[O:8])[NH:9][CH2:10][CH2:11][C:12]1[N:13]=[C:14]([CH:17]([CH3:19])[CH3:18])[S:15][CH:16]=1)[CH3:34]
Reactant: CC(C)c1nc(CCNC(=O)c2cc(Cl)ccc2O)cs1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc(Cl)cc1C(=O)NCCc1csc(C(C)C)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 5-chloro-2-hydroxy-N-[2-(2-isopropyl-thiazol-4-yl)-ethyl]-benzamide (400 mg, 1.23 mmol, 1.00 eq.) and potassium carbonate anhydrous (340 mg, 2.46 mmol, 2.00 eq.) in acetone (20 mL), ethyl bromoacetate (0.14 mL, 1.29 mmol, 1.05 eq.) was added. The mixture was stirred at r.t. for 5 hours. The reaction mixture was poured in water (50 mL). The mixture was extracted with AcOEt (2×20 mL). The comb. org. phases were dried over MgSO4 and concentrated in vacuo. The residue was purified by flashmaster (column: 25 g, flow: 30 mL/min, 45 fractions of 15 mL, Heptane+20% AcOEt to Heptane+80% AcOEt) to yield the ester as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[C:14]1([CH:20]2[CH2:25][C:24](=[O:26])[CH2:23][C:22](=[O:27])[CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C.CC(C)(O)C#N>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([CH:23]2[C:22](=[O:27])[CH2:21][CH:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:25][C:24]2=[O:26])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: O=C1CC(=O)CC(c2ccccc2)C1
Agent: CC(C)(O)C#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CC(c2ccccc2)CC(=O)C1C(=O)c1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.5 %

Procedure:
A solution of 4-chloro-2-nitrobenzoyl chloride (4.4 g) in dry dichloromethane (5 ml) was added at 5°-10° C. to a stirred solution of 5-phenylcyclohexane-1,3-dione [3.7 g] and triethylamine (2.8 ml) in dry dichloromethane (50 ml), and the mixture was stirred at ambient temperature for 18 hours. Triethylamine (8.4 ml) and acetone cyanohydrin (0.4 ml) were added successively to the solution and the mixture was stirred at ambient temperature for 4 hours. The resulting solution was washed successively with 2N hydrochloric acid (25 ml) and water (3×25 ml), dried over sodium sulphate and evaporated under reduced pressure to give a brown solid which was recrystallised from acetonitrile to give 2-(4-chloro-2-nitrobenzoyl)-5-phenylcyclohexane-1,3-dione (4.2 g), mp 144°-145° C., as a light cream crystalline solid.
Reaction SMILES: C(Cl)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10](=[O:19])([O:15][CH2:16][CH:17]=[CH2:18])OCC=C>>[C:10]([O:15][CH2:16][CH:17]=[CH2:18])(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCOC(=O)OCC=C
Reactant: O=C(Cl)c1ccccc1
Product: C=CCOC(=O)c1ccccc1
Temperature: 170 °C
Yield: 90 %

Procedure:
The following example illustrates the use of basic amine catalysts. A mixture of benzoyl chloride (7.03 g, 0.05 mole), diallyl carbonate (7.10 g, 0.05 mole) and N,N-dimethylaminopyridine (0.06 g) were combined in a glass reaction vessel and heated to 170° C. for 4 hours. Distillation of the reaction mixture gave allyl benzoate, b.p. 110° C.-111° C. (13 mm Hg). Yield was 90 percent.
Reaction SMILES: Cl[CH2:2][Si:3]([CH3:13])([CH3:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1.[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.[K].O>CN(C)C=O>[CH3:12][Si:3]([CH2:2][N:18]1[C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]2[C:14]1=[O:24])([CH3:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1
Reactant: C[Si](C)(CCl)Cc1ccc(F)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(Cc1ccc(F)cc1)CN1C(=O)c2ccccc2C1=O
Yield: 94.9 %

Procedure:
Chloromethyl-dimethyl-4-fluorobenzylsilane (2.01 g, 9.33 mmol) and potassium phthalimide (1.90 g), 10.27 mmol) were heated in dry dimethylformamide (30 ml) at 70° C. for 5 hours and then the mixture was poured into water and extracted with ether. The ether solution was washed with water, brine, dried and evaporated. Chromatography (silica gel, ether/hexane-20/80) afforded N[(dimethyl-4-fluorobenzylsilyl)methyl]phthalimide as a white powder (2.90 g, 95% yield) 1H NMR (CDCl3, TMS) δ:0.20 (s,6H), 2.25 (s,2H), 3.27 (s,2H), 6.83-7.13 (m,4H), 7.67-7.97 (m,4H).
Reaction SMILES: [OH:1][NH:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:8](Cl)[CH:9]=[CH2:10].[OH-].[K+]>C(O)C>[CH2:10]([O:1][NH:2][C:3](=[O:4])[O:5][CH2:6][CH3:7])[CH:9]=[CH2:8]
Reactant: C=CCCl
Reactant: CCOC(=O)NO
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C=CCONC(=O)OCC
Temperature: 80 °C

Procedure:
100 g of N-hydroxyurethane and 80.3 g of allyl chloride were added, at 20° C., to a solution of 53.8 g of potassium hydroxide in 750 ml of ethanol. The mixture was stirred and refluxed (80° C.) for 4 hours, then was cooled to 25° C. and filtered. The solvent was evaporated from the filtrate and the residue, an oil, was distilled, 51°-55° C., 0.2 Torr., to give ethyl (2-propenyloxy)carbamate, 3A, as a colorless oil.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1>>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:1]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: CC(=O)c1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1

Procedure:
Entry 26: 4-Hydroxyacetophenone was reacted with 4-fluoronitrobenzene according to Method A13, Step 1 to give 4-(4-acetylphenoxy)nitrobenzene. The nitrobenzene was reduced according to Method A13, Step 4 to afford 4-(4-acetylphenoxy)aniline, which was converted to the 4-(4-(1-(N-methoxy)iminoethyl)phenoxyaniline HCl salt according to Method A16. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(4-(1-(N-methoxy)iminoethyl)phenoxyaniline HCl salt to Method C1a to afford the urea.
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][CH2:4][C@:5]1([CH3:22])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16](OCC)=O)[C:6]1=[O:21].[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:28][C:27]=1[S:40]([NH2:43])(=[O:42])=[O:41].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][CH2:4][C@:5]1([CH3:22])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16]2[NH:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:37])([CH3:38])[CH3:36])=[CH:28][C:27]=3[S:40](=[O:41])(=[O:42])[N:43]=2)[C:6]1=[O:21]
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)c(S(N)(=O)=O)c1
Reactant: CCOC(=O)C1=C(O)c2ccccc2[C@@](C)(CCC(C)(C)C)C1=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NC(=O)OC(C)(C)C)ccc3N2)=C(O)c2ccccc21
Temperature: 100 °C

Procedure:
To a solution of the product of Example 49-4 (330.1 g, 0.999 mol) in toluene (1500 mL) was added the product of Example 17A-4 (287.1 g, 0.999 mol). The solution was heated to 100° C. for 4 h then cooled to RT. The solution was transferred to a pressure bottle and triethylamine (505.4, 4.99 mol) was added and the solution was heated to 100° C. for 26 h. The solution was concentrated to ⅓ of the original volume and ethyl acetate (1500 mL) was added. The organic layer was washed with 10% KH2PO4 and 10% NaCl then concentrated to a thick oil then chased with dichloromethane. The crude title compound (assay for 375.8 g, 68%) was used directly in the next step.