Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:32]=[CH:31][C:21]([CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:20][CH:19]=1.[Cl:33][C:34]1[CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:37]=[C:36]([F:49])[C:35]=1[OH:50]>>[Cl:33][C:34]1[CH:39]=[C:38]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[C:5]3[NH:17][C:18]2[CH:32]=[CH:31][C:21]([CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[CH:20][CH:19]=2)[CH:37]=[C:36]([F:49])[C:35]=1[OH:50]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)cc1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Product: CC(C)(C)OC(=O)NCc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(F)c(O)c(Cl)c4)cc23)cc1
Yield: 98.1 %

Procedure:
Following general procedure F, tert-butyl 4-[6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino]benzylcarbamate (63 mg, 0.127 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (52 mg, 0.191 mmol) to afford the crude product (70 mg) as a yellow solid: ESI MS m/z 562 [C31H29ClFN3O4+H]+.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:13][C:12](=[O:14])[C:11]([CH2:15][CH3:16])=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O1CCC[CH2:18]1.C[Li].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(OCC)C>[Si:1]([O:8][CH:9]1[CH2:13][C:12]([CH3:18])([OH:14])[C:11]([CH2:15][CH3:16])=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: C1CCOC1
Reactant: CCC1=CC(O[Si](C)(C)C(C)(C)C)CC1=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]C
Solvent: CCOCC
Product: CCC1=CC(O[Si](C)(C)C(C)(C)C)CC1(C)O
Reaction time: 2 h
Yield: 98 %

Procedure:
To a liquid mixture of 2 g of (RS)-3-ethyl-4-oxo-2-cyclopenten-1-yl (t-butyldimethylsilyl) ether and 20 ml of tetrahydrofuran was added under nitrogen stream 10 ml of 1.07 M diethyl ether solution of methyllithium at -78° C. and the resulting mixture was stirred at the same temperature for 2 hours. Then the reaction liquid was poured into ice-cooled 5% aqueous solution of citric acid and extracted two times with diethyl ether. The combined ether layer was washed successively with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography to obtain 2.1 g of (1RS,4RS)-3-ethyl-4-methyl-4-hydroxy-2-cyclopenten-1-yl (t-butyldimethylsilyl) ether. Yield 98%
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:10])[CH2:6][C:7]([CH3:9])=[O:8].[Li]CCCC.Cl[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23][CH3:24]>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C.C1COCC1>[C:18]1([S:23][CH2:24][CH2:9][C:7](=[O:8])[CH2:6][C:5]([O:4][CH3:3])=[O:10])[CH:19]=[CH:20][CH:21]=[CH:22][CH:17]=1
Reactant: COC(=O)CC(C)=O
Reactant: CSc1ccccc1Cl
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)CC(=O)CCSc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 22.7 %

Procedure:
To a suspension of NaH (60%) (815 mg, 20.39 mmol) in THF-HMPA (20 ml, 5 ml) was added methylacetoacetate (2.0 g, 18.5 mmol) in THF (5 ml) at 0° C. The mixture was stirred for 10 min. at 0° C. under nitrogen atmosphere. BuLi (12.3 ml, 20.39 mmol) was dropwise added and the red mixture was stirred for 15 min. at 0° C. Then a solution of chlorothioanisole (2.7 ml, 20.39 mmol) in THF (5 ml) was added to the mixture at 0° C. The mixture was stirred for 1 h at -5° C. The mixture was quenched with H2O, then extracted with AcOEt (100 ml×2). AcOEt layer was washed with H2O (10 ml×2) and brine (10 ml), then dried over MgSO4 and evaporated. The residue was purified by a silica gel column chromatography (150 g, hexane :AcOEt=6:1) to give a colorless oil (1.0 g, 22.7%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH3:20][O:21][CH2:22][CH:23]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:23][CH2:22][O:21][CH3:20])[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Br)cc(NC2CCOCC2)c1C
Reactant: COCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COCCN(c1cc(Br)cc(C(=O)OC)c1C)C1CCOCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 55.2 %

Procedure:
To a stirred solution of methyl 5-bromo-2-methyl-3-((tetrahydro-2H-pyran-4-yl)amino)benzoate (400 mg, 1.22 mmol) and 2-methoxyacetaldehyde (1.3 mg, 17.56 mmol) in 7 ml of dichloroethane, acetic acid (0.42 mL, 7.33 mmol) was added and stirred at room temperature for 20 minutes. The reaction mixture was cooled to 0° C. and sodium triacetoxyborohydride (777 mg, 3.66 mmol) was added and stirred at room temperature for 2 h. The reaction mixture was then neutralized with sat. NaHCO3 and extracted with DCM, and the organic layer was dried over Na2SO4, concentrated under reduced pressure to get 260 mg of crude product.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[N:14][O:15][CH3:16])[C:10]([NH:12][CH3:13])=[O:11].[H-].[Na+].Cl[C:20]1[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][C:23]([Cl:30])=[CH:22][N:21]=1.Cl>C1COCC1>[Cl:30][C:23]1[CH:24]=[C:25]([C:26]([F:29])([F:27])[F:28])[C:20]([O:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2/[C:9](=[N:14]\[O:15][CH3:16])/[C:10]([NH:12][CH3:13])=[O:11])=[N:21][CH:22]=1
Reactant: CNC(=O)C(=NOC)c1ccccc1CO
Reactant: FC(F)(F)c1cc(Cl)cnc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CNC(=O)/C(=N/OC)c1ccccc1COc1ncc(Cl)cc1C(F)(F)F
Reaction time: 0.17 h
Yield: 73.4 %

Procedure:
2-(2-Hydroxymethylphenyl)-2-methoxyimino-N-methylacetamide (300 mg) was dissolved in THF (5 ml). 40% sodium hydride (65 mg) was added, and the mixture was stirred for 10 minutes. 2,5-Dichloro-3-trifluoromethylpyridine (350 mg) was added, and the mixture was stirred at room temperature for 12 hours. The mixture was neutralized with 1N-hydrochloric acid and extracted with ethyl acetate. The resulting organic layer was dried over MgSO4, and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to obtain the title compound (398 mg, Yield: 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)/[CH:5]=[C:6]1\[C:7](=[O:15])[NH:8][C:9]2[C:14]\1=[CH:13][CH:12]=[CH:11][CH:10]=2.[F:19][C:20]1[CH:21]=[CH:22][C:23]([CH3:35])=[C:24]([CH:26]=[N:27][C:28]([O:30][Si](C)(C)C)=[CH2:29])[CH:25]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]2[CH2:29][C:28](=[O:30])[NH:27][CH:26]([C:24]3[CH:25]=[C:20]([F:19])[CH:21]=[CH:22][C:23]=3[CH3:35])[C:6]32[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]3=[O:15])[CH:16]=[CH:17][CH:18]=1
Reactant: O=C1Nc2ccccc2/C1=C/c1cccc(Cl)c1
Reactant: C=C(N=Cc1cc(F)ccc1C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1ccccc12
Yield: 15 %

Procedure:
In a manner similar to the method described in example 1c, E/Z-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole (0.4 g, 1.10 mmol) prepared in example 169a was reacted with 1-(5-fluoro-2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 36a, in toluene to give racemic (2′R,3R,4′S)-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.08 g, 15%).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:36](=[O:37])[N:13]3[C:14]([C:20]([O:22][CH:23]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:21])=[C:15]([OH:19])[CH2:16][S:17](=[O:18])[C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:38](Cl)([CH3:41])(=[O:40])=[O:39].O>N1C=CC=CC=1>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:36](=[O:37])[N:13]3[C:14]([C:20]([O:22][CH:23]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:21])=[C:15]([O:19][S:38]([CH3:41])(=[O:40])=[O:39])[CH2:16][S:17](=[O:18])[C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(O)CS(=O)[C@H]12
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)OC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S(=O)C1
Temperature: 25 °C
Yield: 80.4 %

Procedure:
To a solution of benzhydryl 7-phenylacetamido-3-hydroxy-3-cephem-4-carboxylate-1-oxide (40 g) in pyridine (120 ml) was added mesyl chloride (13 g) under ice-cooling. The reaction mixture was stirred at ambient temperature for an hour. The resulting suspension was poured into water (1 l). The precipitates were collected by filtration, washed with water and methanol, dried under reduced pressure to give benzhydryl 7-phenylacetamido-3-mesyloxy-3-cephem-4-carboxylate-1-oxide (37.0 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:26])[NH:15][C:16]2[S:17][C:18]3[CH:24]=[C:23]([OH:25])[CH:22]=[CH:21][C:19]=3[N:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1.C(N(CC)CC)C>CC(C)=O>[NH:8]1[CH2:9][CH2:10][CH:11]([C:14]([NH:15][C:16]2[S:17][C:18]3[CH:24]=[C:23]([O:25][S:34]([C:31]4[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=4)(=[O:36])=[O:35])[CH:22]=[CH:21][C:19]=3[N:20]=2)=[O:26])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2nc3ccc(O)cc3s2)CC1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: O=C(Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1)C1CCNCC1
Yield: 76.5 %

Procedure:
A solution of 4-(6-hydroxybenzothiazol-2-ylcarbamoyl)piperidine-1-carboxylic acid tert-butyl ester (intermediate 2) (454 mg, 1.20 mmol), of 4-fluoro-benzenesulfonyl chloride (234 mg, 1.20 mmol) and of triethylamine (320 μl) in 10 ml of acetone is stirred at room temperature for 1 hour. The triethylamine hydrochloride is filtered off and the filtrate is evaporated. The crude reaction product is purified by column chromatography (eluent: EtOAc/heptane (7/3)) to give 400 mg of 4-fluorobenzenesulfonic 2-[(piperidine-4-carbonyl)amino]-benzothiazol-6-yl ester (white solid).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:17][C:16]3[CH:18]=[C:19](Br)[CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[CH3:23][S:24]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)(=[O:26])=[O:25].C([O-])([O-])=O.[Na+].[Na+]>CN(C)C=O>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:30]4[CH:31]=[CH:32][C:27]([S:24]([CH3:23])(=[O:26])=[O:25])=[CH:28][CH:29]=4)[CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCC(C2Cc3cc(Br)ccc3O2)CC1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)OC(=O)N1CCC(C2Cc3cc(-c4ccc(S(C)(=O)=O)cc4)ccc3O2)CC1
Temperature: 90 °C

Procedure:
To a mixture of 4-(5-bromo-2,3-dihydro-benzofuran-2-yl)-piperidine-1-carboxylic acid isopropyl ester (200 mg) and 4-(methanesulfonyl)phenylboronic acid (119 mg) in N,N-dimethylformamide (2 mL) a 2 M aqueous Na2CO3 solution (0.68 mL) is added. The mixture is sparged with argon for 10 min and PdCl2[1,1′-bis(diphenylphosphino)-ferrocene]*CH2Cl2 complex (44 mg) is added. The resulting mixture is stirred over night at 90° C. After cooling to room temperature, water (20 mL) is added and the mixture is extracted three times with ethyl acetate. The organic phase is dried (Na2SO4) and the solvent is evaporated. The residue is chromatographed on silica gel (ethyl acetate/cyclohexane 1:22:1) to give the title compound. Yield: 149 mg (62% of theory); LC (method 1): tR=1.29 min; Mass spectrum (ESI+): m/z=444 [M+H]+.
Reaction SMILES: [CH3:1][C@H:2]1[C:18]23[CH:21]=[C:22]([CH3:25])[C@H:23]([OH:24])[C@@:17]2([OH:26])[C@H:16]2[C:11]([CH2:12][O:13]C(C)(C)[O:15]2)=[CH:10][CH:9]([C:19]3=[O:20])[CH:5]2[C:6]([CH3:8])([CH3:7])[CH:4]2[CH2:3]1.[C:29](O)(=[O:34])/[C:30](=[CH:32]\[CH3:33])/[CH3:31]>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1>[CH3:33]/[CH:32]=[C:30](\[C:29]([O:24][C@@H:23]1[C@@:17]2([OH:26])[C@H:16]([OH:15])[C:11]([CH2:12][OH:13])=[CH:10][C@H:9]3[C@@H:5]4[C:6]([CH3:7])([CH3:8])[C@@H:4]4[CH2:3][C@@H:2]([CH3:1])[C@:18]2([C:19]3=[O:20])[CH:21]=[C:22]1[CH3:25])=[O:34])/[CH3:31]
Reactant: CC1=CC23C(=O)C(C=C4COC(C)(C)O[C@H]4[C@]2(O)[C@H]1O)C1C(C[C@H]3C)C1(C)C
Reactant: C/C=C(/C)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: C/C=C(/C)C(=O)O[C@H]1C(C)=C[C@]23C(=O)[C@@H](C=C(CO)[C@@H](O)[C@]12O)[C@H]1[C@@H](C[C@H]3C)C1(C)C
Yield: 71.5 %

Procedure:
A solution of ingenol-5,20-acetonide (100 mg, 0.26 mmol), angelic acid (39 mg, 0.39 mmol, 1.5 mol. equiv.) and DMAP (48 mg, 0.39 mmol, 1.5 mol. equiv.) in toluene (4 ml), was stirred at room temperature for 2 hours and was then filtered through a bed of celite and evaporated. The resulting material was filtered in silica gel (ca. 5 g) and evaporated. The residue was purified by means of silica gel gravity column chromatography (5 g, petroleum ether:EtOAc 85:15) until obtaining over 80 mg of ingenol-3-angelate with a purity>99%. For physical and spectroscopic data, see Hohmann J et al. Planta Medica 2000, 66, 291-294.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:21][CH2:22][N:23]([CH3:25])[CH3:24]>CN(C)C=O.C(OC(C)C)(C)C>[CH3:24][N:23]([CH3:25])[CH2:22][CH2:21][O:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: CN(C)CCCl
Reactant: O=Cc1cc(O)ccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)OC(C)C
Product: CN(C)CCOc1ccc([N+](=O)[O-])c(C=O)c1

Procedure:
10 mmol of 5-hydroxy-2-nitrobenzaldehyde dissolved in dimethylformamide are added dropwise to 20 mmol of potassium carbonate suspended in a mixture of dimethyl-formamide and isopropyl ether, and then the reaction mixture is heated at reflux for 2 hours. After the mixture has returned to ambient temperature, 10 mmol of 2-chloro-N,N-dimethylethanamine hydrochloride are added dropwise, and then the reaction mixture is heated at reflux again for one night. After returning to ambient temperature, the mixture is filtered and the solvents of the filtrate are evaporated off to yield the expected product in the form of an oil.
Reaction SMILES: [CH:1]([O:3][C:4]([N:6]1[CH2:30][C@:29]2([C:31](=[O:37])[CH2:32][O:33]C(=O)C)[C@@H:8]([CH2:9][C@H:10]3[C@H:23]4[C@@:14]([F:27])([C@:15]5([CH3:26])[C:20]([C@@H:21]([F:24])[CH2:22]4)=[CH:19][C:18](=[O:25])[CH:17]=[CH:16]5)[C@@H:13]([OH:28])[CH2:12][C@@:11]32[CH3:38])[CH2:7]1)=[O:5])=[CH2:2].C([O-])([O-])=O.[K+].[K+]>CO>[CH:1]([O:3][C:4]([N:6]1[CH2:30][C@:29]2([C:31](=[O:37])[CH2:32][OH:33])[C@@H:8]([CH2:9][C@H:10]3[C@H:23]4[C@@:14]([F:27])([C@:15]5([CH3:26])[C:20]([C@@H:21]([F:24])[CH2:22]4)=[CH:19][C:18](=[O:25])[CH:17]=[CH:16]5)[C@@H:13]([OH:28])[CH2:12][C@@:11]32[CH3:38])[CH2:7]1)=[O:5])=[CH2:2]
Reactant: C=COC(=O)N1C[C@@H]2C[C@H]3[C@@H]4C[C@H](F)C5=CC(=O)C=C[C@]5(C)[C@@]4(F)[C@@H](O)C[C@]3(C)[C@]2(C(=O)COC(C)=O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C=COC(=O)N1C[C@@H]2C[C@H]3[C@@H]4C[C@H](F)C5=CC(=O)C=C[C@]5(C)[C@@]4(F)[C@@H](O)C[C@]3(C)[C@]2(C(=O)CO)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
A solution of compound 19 (1.175 g, 2.202 mmol) in MeOH is degassed with nitrogen at 0° C. for 15 minutes, then K2CO3 (0.152 g, 1.101 mmol) is added and the mixture is stirred at 0° C. for 1 hour, then the mixture is partitioned between AcOEt and water. The aqueous phase is extracted with AcOEt and the combined organic layers are washed with brine, dried over Na2SO4 and filtered. The solvent is evaporated to give a solid which is triturated with petroleum ether to give the title compound (1.08 g, 100%).
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[CH2:8][CH2:9][N:10]2[C:14](=[CH:15][C:16](SC3C=CC=CC=3)=[O:17])[CH2:13][S:12][C:11]=12)=[O:6])([CH3:3])[CH3:2].[CH3:25][NH:26][CH3:27]>>[CH3:25][N:26]([CH3:27])[C:16](=[O:17])[CH:15]=[C:14]1[CH2:13][S:12][C:11]2=[C:7]([C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[O:6])[CH2:8][CH2:9][N:10]12
Reactant: CNC
Reactant: CC(C)OC(=O)C1=C2SCC(=CC(=O)Sc3ccccc3)N2CC1
Product: CC(C)OC(=O)C1=C2SCC(=CC(=O)N(C)C)N2CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.0 g of S-phenyl (7-isopropoxycarbonyl-2,3,5,6-tetrahydropyrrolo[2,1-b]thiazol-3-ylidene)thioacetate was suspended in 10 ml of a 40% aqueous solution of dimethylamine and stirred at room temperature for 1 hour. After distilling off the excessive dimethylamine, the obtained crude crystals were recrystallized from isopropyl alcohol. Thus 0.7 g of the title compound was obtained as crystals.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([NH:13][C:14]([CH:16]2[CH2:19][CH2:18][CH2:17]2)=[O:15])[CH:10]=[CH:11][CH:12]=1)=[O:6].[CH3:21]I>>[CH3:20][N:2]([CH3:1])[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([N:13]([CH3:21])[C:14]([CH:16]2[CH2:19][CH2:18][CH2:17]2)=[O:15])[CH:10]=[CH:11][CH:12]=1)=[O:6]
Reactant: CI
Reactant: CN(C)C=CC(=O)c1cccc(NC(=O)C2CCC2)c1
Product: CN(C)C=CC(=O)c1cccc(N(C)C(=O)C2CCC2)c1

Procedure:
This compound was then converted to N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]cyclobutanecarboxamide, mp 155°-157° C., by the procedure of Example 1 and further alkylated by the procedure of Example 6, using methyl iodide to give 8.32 g of N-[3-[3-(dimethylamino)1-oxo-2-propenyl]phenyl]-N-methylcyclobutanecarboxamide, mp 117°-119° C.
Reaction SMILES: C([O:3][C:4](=[O:40])[C:5]([CH3:39])([O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[C:18](=[O:30])[N:17]2[CH3:31])=[CH:9][CH:8]=1)C.[OH-].[Na+].Cl>C(O)C>[Cl:29][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][C:25]=1[Cl:28])[CH2:21][N:19]1[CH2:20][CH:16]([CH2:15][CH2:14][O:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C:5]([CH3:39])([O:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:4]([OH:40])=[O:3])=[CH:12][CH:11]=2)[N:17]([CH3:31])[C:18]1=[O:30]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCC2CN(Cc3ccc(Cl)c(Cl)c3)C(=O)N2C)cc1)Oc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN1C(=O)N(Cc2ccc(Cl)c(Cl)c2)CC1CCOc1ccc(CC(C)(Oc2ccccc2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of the esters obtained from Step A (320 mg) in absolute ethanol (5.5 ml) is added 5N NaOH (2.2 ml, 10.9 mmol), and the mixture stirred for 20 hours at ambient temperature. The mixture is poured into 1N HCl, then extracted with ethyl acetate (2×20 ml). The combined ethyl acetate extracts were washed with water, brine, dried (Na2SO4), and concentrated to an oil which is purified is purified by flash chromatography on a Biotage silica cartridge (gradient elution, 3:1 hexanes:ethyl acetate to 1:2 hexanes:ethyl acetate to yield a foam (180 mg.)
Reaction SMILES: [CH2:1]([N:5]([CH2:10][CH2:11][CH2:12][CH3:13])[C:6](=[O:9])[CH2:7]Cl)[CH2:2][CH2:3][CH3:4].[CH2:14]([PH:18](=[O:23])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH3:17]>>[CH2:14]([P:18](=[O:23])([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:7][C:6](=[O:9])[N:5]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:1][CH2:2][CH2:3][CH3:4])[CH2:15][CH2:16][CH3:17]
Reactant: CCCC[PH](=O)CCCC
Reactant: CCCCN(CCCC)C(=O)CCl
Product: CCCCN(CCCC)C(=O)CP(=O)(CCCC)CCCC
Yield: 104.1 %

Procedure:
The reaction was conducted as described in example I with the substitution of 22.6 g (0.11 mole) of N,N-di(n-butyl)chloroacetamide and 18.0 g (0.10 mole) of di(n-butyl)phosphine oxide as starting materials. After a reaction period of 5 hours, workup yielded 34.5 g of an amber oil which was 84% pure by GLC. Flash distillation in a Kugelrohr apparatus (10-3 mm Hg) produced a colorless oil which was 91% pure by GLC. Analytical data for this product is summarized in Table I.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[O:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH:6]=[CH:7][C:8]=1[CH2:9][N:10]1[CH:14]=[CH:13]N=[N:11]1.Br[CH2:25]C1C=CC(C2OC3C=CC=CC=3N=2)=CC=1OC.N1C=CC=N1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[O:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH:6]=[CH:7][C:8]=1[CH2:9][N:10]1[CH:14]=[CH:13][CH:25]=[N:11]1
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1Cn1ccnn1
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1CBr
Agent: c1cn[nH]c1
Product: COc1cc(-c2nc3ccccc3o2)ccc1Cn1cccn1

Procedure:
Utilizing the general procedure outlined for 2-[3-methoxy-4-(1H-1,2,3-triazol-1-ylmethyl)phenyl]-1,3-benzoxazole, reaction of 2-[4-(bromomethyl)-3-methoxyphenyl]-1,3-benzoxazole (300 mg, 1.0 mmol) and pyrazole (70 mg, 1.0 mmol) afforded the desired 2-[3-methoxy-4-(1H-pyrazol-1-ylmethyl)phenyl]-1,3-benzoxazole as a colorless solid: 1H NMR (CDCl3, 300 MHz) δ 7.60–7.91 (m, 7H), 7.38–7.41 (m, 2H), 6.54 (m, 1H), 5.81 (s, 2H), 4.11 (s, 3H). MS (ESI) 306 (M+H)+.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH:9]1([C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]3[CH:25]=[C:24]([C:26]4[S:30][CH:29]=[N:28][CH:27]=4)[CH:23]=[C:22]([F:31])[CH:21]=3)[N:13]=2)[CH2:11][CH2:10]1.[C:32]([Si:36]([CH3:43])([CH3:42])[O:37][CH2:38][C:39]([CH3:41])=[O:40])([CH3:35])([CH3:34])[CH3:33]>O1CCCC1>[Si:36]([O:37][CH2:38][C:39]([C:29]1[S:30][C:26]([C:24]2[CH:23]=[C:22]([F:31])[CH:21]=[C:20]([NH:19][C:14]3[N:13]=[C:12]([CH:9]4[CH2:11][CH2:10]4)[C:17]([F:18])=[CH:16][N:15]=3)[CH:25]=2)=[CH:27][N:28]=1)([OH:40])[CH3:41])([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:43])[CH3:42]
Reactant: CC(=O)CO[Si](C)(C)C(C)(C)C
Reactant: Fc1cc(Nc2ncc(F)c(C3CC3)n2)cc(-c2cncs2)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(O)(CO[Si](C)(C)C(C)(C)C)c1ncc(-c2cc(F)cc(Nc3ncc(F)c(C4CC4)n3)c2)s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63.9 %

Procedure:
LDA (0.757 mL, 1.362 mmol) was added to tetrahydrofuran (4 mL) at −78° C. After 15 minutes at −78° C., a solution of the product of Step 4 (150 mg, 0.454 mmol) in tetrahydrofuran (4 mL) was added dropwise. After 30 minutes at −78° C., a solution of 1-{[tert-butyl(dimethyl)-silyl]oxy}acetone (0.110 mL, 0.568 mmol) in tetrahydrofuran (4 mL) was added dropwise at −78° C. The reaction mixture was allowed to warm to ambient temperature. After 1 hour, the reaction mixture was quenched with saturated ammonium chloride, diluted with ethyl acetate, washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate and hexanes to afford 1-{[tert-butyl(dimethyl)silyl]oxy}-2-(5-{3-[(4-cyclopropyl-5-fluoropyrimidin-2-yl)amino]-5-fluorophenyl}-1,3-thiazol-2-yl)propan-2-ol (150 mg, 0.29 mmol, 64%). MS ESI: [M+H]+ m/z 519.2.
Reaction SMILES: CN(OC)[C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[CH2:13]([Mg]Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(OCC)C.O>O1CCCC1>[CH2:13]([C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: CON(C)C(=O)C1CCCCC1
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)C1CCCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
To a stirred solution of N-methyl-N-methoxy cyclohexanecarboxamide (7.42 mmol) in 30 mL of tetrahydrofuran at 0° C. under nitrogen was added a solution of benzyl magnesium chloride (2.0 M in tetrahydrofuran, 4.5 mL, 9.0 mmol). The mixture was stirred at 0° C. for 30 minutes and at room temperature for 1 hour. Diethyl ether (50 mL) and water (20 mL) were added. The organic layer was separated, dried, filtered, and concentrated. Purification of the residue by flash chromatography using hexanes and ethyl acetate gave cyclohexyl benzyl ketone (1.05 g) in 70% yield as oil.