Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[N:14]([C:15](=[O:36])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[Br:33])=[O:25])=[C:19]([O:34][CH3:35])[CH:18]=2)[C@H:13]([CH2:37][O:38][C:39]2[CH:48]=[CH:47][C:42]([C:43]([O:45]C)=[O:44])=[CH:41][CH:40]=2)[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.C1COCC1>[CH2:1]([O:8][CH2:9][C@@H:10]1[N:14]([C:15](=[O:36])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[Br:33])=[O:25])=[C:19]([O:34][CH3:35])[CH:18]=2)[C@H:13]([CH2:37][O:38][C:39]2[CH:40]=[CH:41][C:42]([C:43]([OH:45])=[O:44])=[CH:47][CH:48]=2)[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(OC[C@@H]2CC[C@H](COCc3ccccc3)N2C(=O)Cc2ccc(NC(=O)Nc3ccccc3Br)c(OC)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(CC(=O)N2[C@@H](COCc3ccccc3)CC[C@H]2COc2ccc(C(=O)O)cc2)ccc1NC(=O)Nc1ccccc1Br
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of methyl 4-[5-(R)-benzyloxymethyl-1-[4-[N′-(2-bromophenyl)ureido]-3-methoxyphenylacetyl]-2-(S)-pyrrolidinylmethoxy]benzoate (178 mg, 0.25 mmol) in MeOH-THF (2:5, 7 ml) was added 1.0M-NaOH (750 ml, 0.75 mmol) at rt, and the resulting mixture was heated at 80° C. with stirring for 1.5 h. The reaction mixture was poured into 1N-HCl, then extracted with CHCl3. The organic layer was washed with brine, drying over anhydrous Na2SO4, then concentrated in vacuo. The residue was chromatographed on silica gel with CHCl3-MeOH (15:1) as eluent to give 128 (159 mg, 91%) as a colorless amorphous solid MW 702.59 1H-NMR (CD3OD), mixture of rotamars δ1.88-2.35 (series of m, 4 H), 3.51-4.49 (series of m, 8 H), 3.64 and 3.72 (s, total 3 H), 4.87 (s, 2 H), 6.65-8.05 (series of m, 16 H); MS (ESI) m/z, 702 (M+), 704 (M++2); Anal. Calcd. for C36H36BrN3O7.H2O: C, 60.00; H, 5.32; N, 5.83. Found: C, 59.66; H, 5.04; N, 5.65.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([CH3:11])=[CH:9][C:6]([C:7]#[N:8])=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1.S(=O)(=O)(O)[OH:16]>O>[CH3:1][O:2][C:3]1[C:10]([CH3:11])=[CH:9][C:6]([C:7]([NH2:8])=[O:16])=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: COc1cc([N+](=O)[O-])c(C#N)cc1C
Reactant: O=S(=O)(O)O
Solvent: O
Product: COc1cc([N+](=O)[O-])c(C(N)=O)cc1C
Temperature: 105 °C
Reaction time: 2.5 h
Yield: 83 %

Procedure:
To a mixture of 4-methoxy-5-methyl-2-nitro-benzonitrile (8 g, 40 mmol) and water (50 ml) was added concentrated sulphuric acid (65 ml) and the mixture was stirred for 2.5 hours at 100-110° C. The mixture was allowed to stay overnight, filtered, washed with water and dried which gave the title compound (7 g, 83%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>COCCOC.O>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:10][OH:11])[CH2:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCOCC1
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N[C@H](CO)Cc1cc(F)cc(F)c1
Temperature: -20 °C
Yield: 79.9 %

Procedure:
Dissolve commercially available 2-(S)-tert-butoxycarbonylamino-3-(3,5-difluorophenyl)propionic acid (5.995 g, 19.9 mmol) in ethylene glycol dimethyl ether (20 mL) and cool −20° C. Add 4-methylmorpholine (2.4 mL, 21.89 mmol) and stir 5 min, then add isobutyl chloroformate (2.9 mL, 21.89 mmol) dropwise and stir 5 min. Filter into −15° C. cooled flask with course frit, rinse with cold ethylene glycol dimethyl ether. Add sodium borohydride (1.129 g, 29.85 mmol) in water (9 mL) followed by water (500 mL), then warm to room temperature. Filter and dissolve solid in dichloromethane. Wash with saturated aqueous sodium chloride, dry (magnesium sulfate) and concentrate to give the title compound as a solid (4.57 g, 80%).
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17]([OH:19])=O)=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[F:22][C:23]([F:34])([F:33])[C:24]1[N:28]2[CH2:29][CH2:30][NH:31][CH2:32][C:27]2=[N:26][N:25]=1>>[C:1]12([C:11]3[CH:12]=[CH:13][C:14]([O:15][CH2:16][C:17]([N:31]4[CH2:30][CH2:29][N:28]5[C:24]([C:23]([F:34])([F:22])[F:33])=[N:25][N:26]=[C:27]5[CH2:32]4)=[O:19])=[CH:20][CH:21]=3)[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: O=C(O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reactant: FC(F)(F)c1nnc2n1CCNC2
Product: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)N1CCn2c(nnc2C(F)(F)F)C1
Yield: 80.4 %

Procedure:
The title compound was prepared from 2-(4-(adamantan-1-yl)phenoxy)acetic acid (0.08 g, 0.27 mmol) and 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (0.053 g, 0.27 mmol) according to the example 1, which was given 2-(4-(adamantan-1-yl)phenoxy)-1-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)ethanone as a white solid (0.10 g, 78.1% yield).
Reaction SMILES: [CH3:1][S:2]([N:5]([CH2:11][CH2:12][Cl:13])[NH:6][S:7]([CH3:10])(=[O:9])=[O:8])(=[O:4])=[O:3].[Cl:14][CH2:15][CH2:16][N:17]=[C:18]=[O:19].C(N(CC)CC)C.C(O)C>C(#N)C>[CH3:1][S:2]([N:5]([CH2:11][CH2:12][Cl:13])[N:6]([S:7]([CH3:10])(=[O:9])=[O:8])[C:18]([NH:17][CH2:16][CH2:15][Cl:14])=[O:19])(=[O:3])=[O:4]
Reactant: CS(=O)(=O)NN(CCCl)S(C)(=O)=O
Reactant: O=C=NCCCl
Solvent: CCO
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N(CCCl)N(C(=O)NCCCl)S(C)(=O)=O
Reaction time: 0.17 h
Yield: 42.2 %

Procedure:
To a stirred solution of 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine (Shyam, et al.,J. Med. Chem., 1990, 33, 2259-2264) (2.5 g, 0.010 mol) and 2-chloroethyl isocyanate (1.2 g, 0.011 mol) in dry acetonitrile (100 mL) was added triethylamine (1.1 g, 0.011 mol) at room temperature. After an additional 10 min, the reaction mixture was evaporated to dryness in vacuo. The residue was triturated twice with 15 mL quantities of petroleum ether and the petroleum ether layer was discarded each time. The residue was then taken up in ethyl acetate (150 mL) and washed with dilute hydrochloric acid (3×15 mL). The ethyl acetate layer was dried over anhydrous magnesium sulfate and filtered. Upon evaporation of the solvent, a semi-solid residue was obtained which, upon trituration with absolute ethanol, gave a white solid. Recrystallization from ethanol afforded 1.5 g (42.2%) of the title compound: mp 96°-97.5° C.; 1H NMR (acetone-d6) δ 7.0 (br, 1 H, NH), 3.7-4.2 (m, 4 H, SO2NCH2CH2Cl ), 3.5-3.7 (m, 4H, CONHCH2CH2Cl), 3.5 and 3.3 (2s, 6 H, 2 CH3). Anal. (C7H15C12N3O5S2) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[N:14]([CH3:15])[C:13]2[C:16]3[CH2:17][C:18]([CH3:28])([CH3:27])[O:19][C:20]=3[C:21]([C:23]([O:25]C)=O)=[CH:22][C:12]=2[N:11]=1.[NH2:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]([F:39])([F:38])[F:37])=[N:34][CH:35]=1.C[Al](C)C>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[N:14]([CH3:15])[C:13]2[C:16]3[CH2:17][C:18]([CH3:27])([CH3:28])[O:19][C:20]=3[C:21]([C:23]([NH:29][C:30]3[CH:35]=[N:34][C:33]([C:36]([F:39])([F:37])[F:38])=[CH:32][CH:31]=3)=[O:25])=[CH:22][C:12]=2[N:11]=1
Reactant: Nc1ccc(C(F)(F)F)nc1
Reactant: COC(=O)c1cc2nc(Nc3c(F)cccc3Cl)n(C)c2c2c1OC(C)(C)C2
Agent: C[Al](C)C
Product: Cn1c(Nc2c(F)cccc2Cl)nc2cc(C(=O)Nc3ccc(C(F)(F)F)nc3)c3c(c21)CC(C)(C)O3
Yield: 19 %

Procedure:
The title compound was prepared by following the same procedure as described for Example-137 using methyl 2-((2-chloro-6-fluorophenyl)amino)-1,7,7-trimethyl-7,8-dihydro-1H-benzofuro[4,5-d]imidazole-5-carboxylate (step-7 of Intermediate-49, 0.100 g, 0.247 mmol), 5-amino-2-trifloromethylpyridine (0.162 g, 0.371 mmol), trimethyl aluminium (2M solution in toluene) (1 mL) to afford 0.025 g of the desired product. 1HNMR (DMSO-d6): δ 1.61 (s, 6H), 3.46 (s, 2H), 3.57 (s, 3H), 7.01 (m, 1H), 7.28 (s, 2H), 7.30 (d, 1H), 7.90 (d, J=8.7 Hz, 1H), 8.45 (d, J=7.8 Hz, 1H), 9.00 (s, 1H), 10.02 (s, 1H), 10.53 (s, 1H). MS [M−H]−: 532.19.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:6][CH2:7][OH:8])[CH2:4][OH:5].O.[C:10]1(C)[CH:15]=CC(S(O)(=O)=O)=C[CH:11]=1.C(N(CC)CC)C>CC(C)=O>[CH3:11][C:10]1([CH3:15])[O:5][CH2:4][CH:3]([CH2:6][CH2:7][OH:8])[CH2:2][O:1]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: OCCC(CO)CO
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC1(C)OCC(CCO)CO1
Reaction time: 15 h
Yield: 220.6 %

Procedure:
To an acetone (30 ml) solution of the 2-(hydroxymethyl)butane-1,4-diol (3.4 g, 28.3 mmol) obtained in accordance with the method described in J. Med. Chem., 30 (9), 1636-1642 (1987), p-toluenesulfonic acid monohydrate (244 mg, 2.83 mmol) was added at room temperature and the mixture was stirred for 15 hours. To the reaction mixture, triethylamine (394 μl, 2.83 mmol) was added and the mixture was concentrated. The residue was purified by silica gel column chromatography (elution solvent: heptane/ethyl acetate) to obtain the title compound (1.0 g, yield: 22%) as a light yellow oil.
Reaction SMILES: [C:1]([O:11][CH3:12])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=O.[NH2:13][C@H:14](CO)[CH:15]([CH3:17])[CH3:16]>ClC1C=CC=CC=1>[CH:15]([C@H:14]1[CH2:12][O:11][C:1]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]2[O:8][CH2:9][C@H:14]([CH:15]([CH3:17])[CH3:16])[N:13]=2)=[N:13]1)([CH3:17])[CH3:16]
Reactant: COC(=O)CCCCC(=O)OC
Reactant: CC(C)[C@H](N)CO
Solvent: Clc1ccccc1
Product: CC(C)[C@H]1COC(CCCCC2=N[C@@H](C(C)C)CO2)=N1
Yield: 64.8 %

Procedure:
Under an argon atmosphere, a mixture of dimethyl adipate (3 mmol), (L)-valinol (7.2 mmol), Zn4(OCOCF3)6O (0.3 mmol) and chlorobenzene (5 mL) was refluxed for 6 hours, then concentrated, and purified by silica gel column chromatography to give 1,4-bis((S)-4-isopropyl-1,3-oxazolin-2-yl) butane in 64.8% yield.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:17])[CH:10]([CH3:16])[CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:5][CH:4]=1.Br.C(O)(=O)C>O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9](=[O:17])[CH:10]([CH3:16])[CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:8]=1
Reactant: COC(=O)CC(C)C(=O)c1ccc(OC)cc1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)CC(C)C(=O)c1ccc(O)cc1

Procedure:
A mixture of the ester from Example 70, Step A (8.15 g), 48% HBr (40 ml) and acetic acid (80 ml) was refluxed for 4 days, then poured into water (250 ml) and extracted with ethyl acetate. The extracts were washed with water and dried (Na2SO4) and evaporated to an oil which was treated with 10% HCl in methanol (150 ml) for 18 hours. The volatiles were removed by evaporation and the residue was taken up in CH2Cl2, washed with water, brine, dried, evaporated to dryness then purified by chromatography on silica gel to provide the title compound, mp 89°-91° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7](#[N:24])[CH2:8][CH2:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH2:7]([NH2:24])[CH2:8][CH2:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCOCCCCCOCCCCC#N
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CCCCCOCCCCCOCCCCCN
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 29.5 %

Procedure:
0.15 g of lithium aluminum hydride was added to a solution of 1 g of 6,12-dioxaheptadecanenitrile prepared in the above-described step (2) in 20 ml of tetrahydrofuran and the mixture was stirred at room temperature for 1.5 h. A saturated aqueous solution of sodium sulfate was added thereto and the obtained mixture was filtered through a Celite filter (eluent: chloroform/methanol=9/1) to obtain 0.3 g of the intended product.
Reaction SMILES: C1C=CC=CC=1.[CH3:7][C:8]1[NH:9][C:10]([CH2:33][OH:34])=[C:11]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N+:25]([O-:27])=[O:26])[C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[C:35](Cl)(=[O:37])[CH3:36]>N1C=CC=CC=1.C(Cl)Cl>[CH3:7][C:8]1[NH:9][C:10]([CH2:33][O:34][C:35](=[O:37])[CH3:36])=[C:11]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N+:25]([O-:27])=[O:26])[C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)C1=C(C)NC(CO)=C(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: c1ccccc1
Product: CCOC(=O)C1=C(C)NC(COC(C)=O)=C(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]
Yield: 68.4 %

Procedure:
((5) To a mixture of diethyl 2-methyl-4-(2-nitrophenyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (2.35 g) in pyridine (30 ml), was dropwise added a solution of acetyl chloride (942 mg) in methylene chloride (5 ml) under stirring and ice-cooling over the period of 7 minutes. The mixture was further stirred for 70 minutes at room temperature. The pyridine was distilled off under reduced pressure and ethyl acetate was added to the residue. The resultant mixture was washed twice with water adjusted to pH 4 with hydrochloric acid and then an aqueous solution of sodium chloride, dried and concentrated under reduced pressure to give an oily substance. This oily substance was crystallized by treating with a mixture of diethyl ether and a small amaunt of n-hexane, and collected crude crystals (2.5 g) were washed with n-hexane and thus obtained crystals were recrystallized from diethyl ether to give pure crystals (1.78 g) of diethyl 2-methyl-4-(2-nitrophenyl)-6-acetoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate, m.p. 89° to 90° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C@H:9]1[C@@H:13]2[O:14][C:15]([CH3:18])([CH3:17])[O:16][C@@H:12]2[C@@H:11]([C:19]([OH:21])=[O:20])[O:10]1.O[N:23]=[C:24]([NH2:27])[CH2:25][CH3:26].C(N(C(C)C)C(C)C)C>ClCCl.C(OCC)(=O)C>[CH3:7][O:8][C@H:9]1[C@@H:13]2[O:14][C:15]([CH3:18])([CH3:17])[O:16][C@@H:12]2[C@@H:11]([C:19]([O:21][N:23]=[C:24]([NH2:27])[CH2:25][CH3:26])=[O:20])[O:10]1
Reactant: CCC(N)=NO
Reactant: CO[C@@H]1O[C@H](C(=O)O)[C@H]2OC(C)(C)O[C@@H]12
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(N)=NOC(=O)[C@H]1O[C@@H](OC)[C@@H]2OC(C)(C)O[C@@H]21
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.2 %

Procedure:
Oxalyl chloride (4 ml, 46 mmol) was added to a solution of (3aS,4S,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxylic acid (Justus Liebigs Ann. Chem., 1974, 11, 1856) (5 g, 23 mmol) in dichloromethane (100 ml). The solution was stirred at room temperature for two hours and then the solvent was evaporated under reduced pressure to yield a white solid. This was dissolved in ethyl acetate (80 ml) and N′-hydroxypropanimidamide (2.63 g, 30 mmol) was added followed by N-ethyldiisopropylamine (8.12 ml, 46 mmol). The reaction mixture was stirred at room temperature for 48 hours and then washed with saturated sodium hydrogencarbonate solution (50 ml) and brine (50 ml). The organic layer was separated, dried (anhydrous magnesium sulphate) and evaporated under reduced pressure to give the product as a dark yellow oil (5.85 g).
Reaction SMILES: [NH2:1][C:2]([CH:14]1[CH2:16][CH:15]1[OH:17])([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:7]=1[CH3:13])[CH:3]([F:5])[F:4].[C:18]([N:26]=[C:27]=S)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC>C1COCC1.ClCCl.O>[F:5][CH:3]([F:4])[C:2]1([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:7]=2[CH3:13])[CH:14]2[CH:15]([CH2:16]2)[O:17][C:27]([NH:26][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:1]1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Cc1c(F)cccc1C(N)(C(F)F)C1CC1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1c(F)cccc1C1(C(F)F)N=C(NC(=O)c2ccccc2)OC2CC21
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
To a solution of 2-(1-amino-2,2-difluoro-1-(3-fluoro-2-methylphenyl)ethyl)cyclopropanol (0.61 g, 2.487 mmol) in dry THF (10 mL) under nitrogen was added benzoyl isothiocyanate (0.7 ml, 5.20 mmol) dropwise and the reaction was stirred for 30 min. Diisopropylethylamine (1.731 ml, 9.95 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.954 g, 4.97 mmol) were added and the reaction stirred at room temperature for 1 hour and then warmed to 60° C. for another 12 hr. The reaction mixture was diluted with dichloromethane and water. The phases were mixed, separated, and the organic was evaporated to dryness under reduced pressure. The crude residue was purified via silica gel flash chromatography eluting with 0-30% ethyl acetate in hexane afforded the title compound N-(5-(difluoromethyl)-5-(3-fluoro-2-methylphenyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-yl)benzamide (0.8 g, 2.137 mmol, 86% yield). LC/MS (ESI+) m/z=375.0 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][C@H:20]2[CH2:22][O:21]2)=[C:13](C(=O)C)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=[C:26]([C:30]([O:32]O)=[O:31])C=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][C@H:20]2[CH2:22][O:21]2)=[C:13]([O:32][C:30](=[O:31])[CH3:26])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)c1cc(OCc2ccccc2)ccc1OC[C@H]1CO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)Oc1cc(OCc2ccccc2)ccc1OC[C@H]1CO1
Temperature: 25 °C
Reaction time: 72 h
Yield: 52.1 %

Procedure:
To a stirred solution of 1-[5-benzyloxy-2-((R)-1-oxiranylmethoxy)phenyl]ethanone (1.0 g, 3.36 mmol) in DCM (20 ml) was added m-chloroperbenzoic acid (1.24 g) and solid NaHCO3 (3.24 g). The mixture was stirred at RT for 3 d. The mixture was filtered and the filtrate washed once with 10% NaHSO4 solution and then twice with NaHCO3 solution. The organic layer was washed with water and brine and dried with Na2SO4. The solvent was removed under reduced pressure. The residue was triturated with ether to give the title compound (0.55 g) as a white solid, which was used without purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9]2[C:17]3[C:12](=[CH:13][C:14]([CH:18]=[C:19]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[NH:21][C:20]4=[O:28])=[CH:15][CH:16]=3)[N:11](COCC[Si](C)(C)C)[N:10]=2)=[CH:3][CH:2]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9]2[C:17]3[C:12](=[CH:13][C:14]([CH:18]=[C:19]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[NH:21][C:20]4=[O:28])=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCn1nc(CCc2ccncc2)c2ccc(C=C3C(=O)Nc4ccccc43)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2C1=Cc1ccc2c(CCc3ccncc3)n[nH]c2c1
Yield: 26.8 %

Procedure:
A solution of 3-((3-(2-(pyridin-4-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)-methyl)-1H-indazol-6-yl)methylene)indolin-2-one (57 mg, 0.115 mmol) in THF (3 mL) was treated with TBAF (0.58 mL of a 1.0 M solution in THF) and the reaction heated at reflux for 20 hours. The solvent was removed and the residue re-dissolved into EtOAc. The organics were washed with water (2×), brine (2×) and then dried (MgSO4). The solvent was removed and the residue purified by column chromatography (silica gel, 93:7 CH2Cl2/MeOH) to give a yellow solid which was impure by LC-MS. The mixture was further purified by prep-HPLC to give 11.3 mg, 27% of the title compound as a 76:24 mixture of (E)/(Z) geometric isomers. 1H NMR (400 MHz, CD3OD) δ 8.79, 7.87 (s, 1H), 8.69, 8.66 (d, J=6.52 Hz, 2H), 7.98-7.73 (m, 4H), 7.74, 7.62 (d, J=8.36 Hz, 1H), 7.66, 7.44 (d, J=8.44 Hz, 1H), 7.25, 7.05 (t, J=7.79 Hz, 1H), 6.95-6.84 (m, 2H), 3.53, 3.51 (s, 4H); MS ESI 367.2 [M+H]+, calcd for [C23H18N4O+H]+ 367.16.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:11]1[CH2:17][S:14](=[O:16])(=[O:15])[O:13][CH2:12]1>C(#N)C>[S:14]([CH2:17][CH2:11][CH2:12][N:1]1[C:10]2[CH:5]([CH2:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1)([OH:16])(=[O:15])=[O:13]
Reactant: O=S1(=O)CCCO1
Reactant: c1ccc2c(c1)CCCN2
Solvent: CC#N
Product: O=S(=O)(O)CCCN1CCCC2CC=CC=C21
Yield: 60 %

Procedure:
In a round bottom flask fitted with a stirrer and reflux condenser were placed 50.0 g of tetrahydroquinoline, 48.8 g of 1,3-propanesultone and 500 ml of reagent grade acetonitrile solvent. The mixture was heated at reflux under a nitrogen blanket overnight. The reaction mixture was cooled to ice-bath temperature and the resulting white solid precipitate filtered and washed with cold acetonitrile. A yield of 58 g (60%) of crude product was obtained with a melting point over 200° . Nuclear magnetic resonance (NMR) and mass spectrometry analyses showed the product to be consistent with the assigned structure.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4](=O)[CH:5]=[CH:6][C:7]1[S:8][C:9]([Br:12])=[CH:10][CH:11]=1.Cl.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][NH2:24]>C(O)(=O)C>[CH3:1][O:2][C:3]([C:4]1[CH2:5][CH:6]([C:7]2[S:8][C:9]([Br:12])=[CH:10][CH:11]=2)[N:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[Cl:16])[N:24]=1)=[O:14]
Reactant: NNc1ccccc1Cl
Reactant: COC(=O)C(=O)C=Cc1ccc(Br)s1
Agent: Cl
Solvent: CC(=O)O
Product: COC(=O)C1=NN(c2ccccc2Cl)C(c2ccc(Br)s2)C1
Temperature: 125 °C
Reaction time: 3 h
Yield: 65.5 %

Procedure:
4-(5-Bromo-thiophen-2-yl)-2-oxo-3-butenoic acid methyl ester (19.9 mg, 72.2 mmol) prepared in Step 2 and 2-chlorophenylhydrazine hydrochloride (14.2 g, 79.4 mmol) were added to acetic acid (250.0 mL). The reaction mixture was stirred at 125° C. for 3 hours, concentrated under reduced pressure, and then ethyl acetate was added thereto. The reaction mixture was washed with a saturated solution of sodium hydrogen carbonate, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/6) to give 18.9 g of the titled compound as a pale yellow liquid.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[Br:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](O)=[O:29])=[CH:23][CH:22]=1>>[Br:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([NH:1][N:2]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:19])=[O:29])=[CH:23][CH:22]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O
Product: O=C(Cc1ccc(Br)cc1)Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O

Procedure:
The product of Example 86A and 2-(4-bromophenyl)acetic acid were treated using a method similar to that described in Example 57 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.40-8.44 (m, 1H), 7.93-8.04 (m, 2H), 7.72-7.75 (m, 1H), 7.60-7.67 (m, 4H), 7.54-7.57 (m, 2H), 7.34-7.36 (m, 2H), 3.69 (s, 2H); MS (ESI−) M/Z 466 (M−H)−.
Reaction SMILES: [OH:1][CH2:2][P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].[H-].[Na+].[CH3:13][C:14]1[S:15][CH:16]=[C:17]([CH2:19]Cl)[N:18]=1>CN(C=O)C>[CH3:13][C:14]1[S:15][CH:16]=[C:17]([CH2:19][O:1][CH2:2][P:3]([O:7][CH2:8][CH3:9])([O:4][CH2:5][CH3:6])=[O:10])[N:18]=1
Reactant: Cc1nc(CCl)cs1
Reactant: CCOP(=O)(CO)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOP(=O)(COCc1csc(C)n1)OCC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of diethyl hydroxymethylphosphonate (1 mmole) in DMF was treated with sodium hydride (1.2 mmole) followed by 2-methyl-4-chloromethylthiazole (1 mmole) at 0° C. and stirred at 25° C. for 12 h. Extraction and chromatography gave 2-methyl-4-(diethylphosphonomethoxymethyl)thiazole.