Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[C:16]([O:24][CH3:25])[CH:15]=3)[CH:11]=[C:10]([CH3:26])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[C:27]([NH:31][S:32]([C:35]1[S:36][C:37](B2OC(C)(C)C(C)(C)O2)=[CH:38][CH:39]=1)(=[O:34])=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([NH:31][S:32]([C:35]1[S:36][C:37]([C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[C:16]([O:24][CH3:25])[CH:15]=4)[CH:11]=[C:10]([CH3:26])[N:9]=3)[CH:5]=[CH:4][N:3]=2)=[CH:38][CH:39]=1)(=[O:33])=[O:34])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: COc1cc(-c2cc(C)nc(-c3ccnc(Cl)c3)c2)ccc1C(F)(F)F
Product: COc1cc(-c2cc(C)nc(-c3ccnc(-c4ccc(S(=O)(=O)NC(C)(C)C)s4)c3)c2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 2′-chloro-4-(3-methoxy-4-trifluoromethyl-phenyl)-6-methyl-[2,4′]bipyridinyl (example E.99) (0.378 g, 1.0 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.380 g, 1.1 mmol) according to the general procedure VI. Obtained as a white solid (0.142 g, 25%). MS (ISP) 562.3 [(M+H)+]; mp 209° C. (dec.).
Reaction SMILES: C([O:4][C:5]1[C:6](=[O:16])[C:7]2[C:12]([C:13](=[O:15])[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)(=O)C.[F:17][C:18]([F:26])([F:25])[CH:19]([CH3:24])[CH2:20]C(O)=O>>[OH:4][C:5]1[C:6](=[O:16])[C:7]2[C:12]([C:13](=[O:15])[C:14]=1[CH2:20][CH:19]([C:18]([F:26])([F:25])[F:17])[CH3:24])=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: CC(=O)OC1=CC(=O)c2ccccc2C1=O
Reactant: CC(CC(=O)O)C(F)(F)F
Product: CC(CC1=C(O)C(=O)c2ccccc2C1=O)C(F)(F)F
Yield: 21.7 %

Procedure:
2-acetyloxynaphthalene-1,4-dione (1.24 g) and 3-trifluoromethylbutanoic acid (1.08 g) were reacted using the method as descibed in Example 3 yielding the title compound (353 mg) (mp 168° C.). This compound is listed as compound 11 in the Tables below.
Reaction SMILES: C[CH:2]([C:6]1[CH:11]=[CH:10][C:9]([S:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]3[CH:21]([C:29]([F:32])([F:31])[F:30])[N:22]([CH2:26][CH2:27][CH3:28])[O:23][C:24]=3[CH:25]=2)=[C:8]([Cl:33])[CH:7]=1)[C:3]([OH:5])=[O:4].[OH-].[Li+]>CO.O>[Cl:33][C:8]1[CH:7]=[C:6]([CH2:2][C:3]([OH:5])=[O:4])[CH:11]=[CH:10][C:9]=1[S:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]2[CH:21]([C:29]([F:31])([F:30])[F:32])[N:22]([CH2:26][CH2:27][CH3:28])[O:23][C:24]=2[CH:25]=1
Reactant: CCCN1Oc2cc(OCCCSc3ccc(C(C)C(=O)O)cc3Cl)ccc2C1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCN1Oc2cc(OCCCSc3ccc(CC(=O)O)cc3Cl)ccc2C1C(F)(F)F
Temperature: 0 °C

Procedure:
A solution of methyl 3-chloro-4-(3-(2-propyl-3-trifluoromethyl-6-benz-[4,5]-isoxazoloxy)propylthio)phenylacetic acid (0.113 grams) in methanol (1.5 mL) was treated with a solution of lithium hydroxide in water (1.01 M; 0.362 mL). The reaction was refluxed 1 hour. The reaction mixture was partitioned between isopropyl acetate and 0.1N HCl. The organic was dried over magnesium sulfate, filtered and concentrated to a solid. The solid was suspended in methylene chloride/cyclohexane (1:1; 2 mL). The mixture was refluxed briefly and cooled to 0° C. The title compound was isolated by filtration.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2([C:24]3[CH:29]=[CH:28][CH:27]=[C:26](Br)[CH:25]=3)[CH2:13][CH:14]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:15][CH:11]2[CH2:10][O:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:37][O:38][C:39]1[CH:40]=[C:41](B(O)O)[CH:42]=[CH:43][CH:44]=1>COCCOC.C(OCC)(=O)C>[CH2:1]([N:8]1[C:12]2([C:24]3[CH:25]=[C:26]([C:43]4[CH:42]=[CH:41][CH:40]=[C:39]([O:38][CH3:37])[CH:44]=4)[CH:27]=[CH:28][CH:29]=3)[CH2:13][CH:14]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:15][CH:11]2[CH2:10][O:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OC1CC2CON(Cc3ccccc3)C2(c2cccc(Br)c2)C1
Reactant: COc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1cccc(-c2cccc(C34CC(O[Si](C)(C)C(C)(C)C)CC3CON4Cc3ccccc3)c2)c1
Temperature: 110 °C
Reaction time: 0.33 h
Yield: 96.8 %

Procedure:
To a stirred solution of 1-benzyl-6a-(3-bromophenyl)-5-(tert-butyldimethylsilyloxy)hexahydro-1H-cyclopenta[c]isoxazole (7.42 g, 15.2 mmol) in 1,2-dimethoxyethane (30 mL) is added 2 M aqueous solution of sodium carbonate (22.8 mL, 45.6 mmol), 3-methoxyphenylboronic acid (2.77 g, 18.2 mmol) and (1,1′-bis(diphenylphosphino)ferrocene)palladium(II) chloride (0.759 g, 0.911 mmol). The reaction mixture is heated at 110° C. for 7 hours. The reaction is cooled, diluted with ethyl acetate, and filtered. The resulting filtrate is separated and the aqueous layer is extracted three times with ethyl acetate. The combined organic layers are washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product is purified by silica gel chromatography eluting with 10% to 20% ethyl acetate in hexanes gradient over 20 minutes to give the title compound (7.59 g, 92%). ES/MS m/e: 516 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:7])([CH3:6])[CH2:4][OH:5].S=[C:9]1[CH2:13][S:12][C:11](=[O:14])[NH:10]1>C(O)C>[OH:5][CH2:4][C:3]([CH3:7])([CH3:6])[CH2:2][NH:1][C:9]1[CH2:13][S:12][C:11](=[O:14])[N:10]=1
Reactant: O=C1NC(=S)CS1
Reactant: CC(C)(CN)CO
Solvent: CCO
Product: CC(C)(CO)CNC1=NC(=O)SC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.7 %

Procedure:
To a solution of 3-amino-2,2-dimethylpropan-1-ol (4.05 g) in ethanol (100 mL) was added 4-thioxo-1,3-thiazolidin-2-one (5.07 g). The reaction mixture was stirred at room temperature overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate) to give the title compound (4.52 g).
Reaction SMILES: N.F[C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH2:14][CH2:13][C@H:12]([N:15]3[CH:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18]([CH3:27])([CH3:26])[O:17][C:16]3=[O:28])[CH2:11][CH:10]=2)=[CH:5][C:4]=1[C:29]1[N:34]=[CH:33][CH:32]=[CH:31][N:30]=1.FC1[N:41]=CC(C2CC[C@@H](N3C(C4C=CC=CC=4)C(C)(C)OC3=O)CC=2)=CC=1C1N=CC=CN=1>CC(O)C.CS(C)=O>[NH2:41][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH2:14][CH2:13][CH:12]([N:15]3[CH:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18]([CH3:27])([CH3:26])[O:17][C:16]3=[O:28])[CH2:11][CH:10]=2)=[CH:5][C:4]=1[C:29]1[N:34]=[CH:33][CH:32]=[CH:31][N:30]=1
Reactant: CC1(C)OC(=O)N([C@H]2CC=C(c3cnc(F)c(-c4ncccn4)c3)CC2)C1c1ccccc1
Reactant: CC1(C)OC(=O)N([C@@H]2CC=C(c3cnc(F)c(-c4ncccn4)c3)CC2)C1c1ccccc1
Agent: N
Solvent: CC(C)O
Solvent: CS(C)=O
Product: CC1(C)OC(=O)N(C2CC=C(c3cnc(N)c(-c4ncccn4)c3)CC2)C1c1ccccc1
Temperature: 130 °C

Procedure:
A 2-mL glass microwave reaction vessel was charged with ammonia, (2 M solution in 2-propanol) (1.806 mL, 83 mmol, commercially available from Sigma-Aldrich, Milwaukee, Wis.) and a mixture of 3-((S)-4-(6-fluoro-5-(pyrimidin-2-yl)pyridin-3-yl)cyclohex-3-en-1-yl)-5,5-dimethyl-4-phenyloxazolidin-2-one and 3-((R)-4-(6-fluoro-5-(pyrimidin-2-yl)pyridin-3-yl)cyclohex-3-en-1-yl)-5,5-dimethyl-4-phenyloxazolidin-2-one (370 mg, 0.832 mmol) in DMSO (8.324 mL). The reaction mixture was stirred and heated at 130° C. for 3 days. LC-MS indicated clean and good conversion to the desired product with a small amount of starting material present. After cooling to room temperature, the reaction mixture was diluted with water and extracted with EtOAc (3×). The combined organic layers were washed with water and brine and dried over MgSO4. The solution was filtered and concentrated under reduced pressure. The material thus obtained was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 100% EtOAc in heptane, to provide Example 131 (3-(4-(6-amino-5-(pyrimidin-2-yl)pyridin-3-yl)cyclohex-3-en-1-yl)-5,5-dimethyl-4-phenyloxazolidin-2-one) (210 mg, 0.476 mmol, 57.1% yield) as yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 8.87-8.92 (m, 4H), 8.60-8.64 (m, 2H), 8.20 (d, J=2.56 Hz, 1H), 8.17 (d, J=2.46 Hz, 1H), 7.34-7.46 (m, 9H), 7.25-7.34 (m, 4H), 5.95-5.98 (m, 1H), 5.83-5.89 (m, 1H), 4.70 (s, 1H), 4.67 (s, 1H), 3.59-3.77 (m, 2H), 2.60-2.75 (m, 1H), 1.90-2.43 (m, 8H), 1.71-1.80 (m, 1H), 1.47-1.53 (m, 8H), 0.78-0.87 (m, 6H). m/z (ESI) 442.2 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]1(=[O:10])[NH:8][C:7](=[O:9])[CH2:6][CH2:5][CH2:4]1.Br[CH2:12][CH2:13][O:14][C:15]1[CH:24]=[C:23]2[C:18]([C:19]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=3[F:33])=[N:20][CH:21]=[N:22]2)=[CH:17][C:16]=1[O:34][CH3:35]>CN(C=O)C>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([NH:25][C:19]2[C:18]3[C:23](=[CH:24][C:15]([O:14][CH2:13][CH2:12][N:8]4[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][C:3]4=[O:10])=[C:16]([O:34][CH3:35])[CH:17]=3)[N:22]=[CH:21][N:20]=2)=[C:27]([F:33])[CH:28]=1
Reactant: O=C1CCCC(=O)N1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCN1C(=O)CCCC1=O
Reaction time: 0.5 h
Yield: 54.9 %

Procedure:
Sodium hydride (55 mg of a 60% dispersion in mineral oil. 1.1 mmol) was added to a solution of glutarimide (120 mg, 1.06 mmol) in DMF (5 ml) at ambient temperature under argon and the mixture stirred for 30 minutes. 7-(2-Bromoethoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline (428 mg, 1 mmol), (prepared as described for the starting material in Example 62), in DMF (2 ml) was added and the resulting pale green solution was stirred for 18 hours and then quenched with water. The volatiles were removed by evaporation, and the residue was partitioned between water and ethyl acetate. The organic phase was separated and washed with water and then dried (MgSO4). The solvent was removed by evaporation, and the residue was purified by column chromatography eluting with ethyl acetate then ethyl acetate/methanol (9/1). The purified product was recrystallised from ethyl acetate and hexane, collected by filtration and washed with ether to give 4-(4-chloro-2-fluoroanilino)-7-(2-(2,6-dioxopiperidino)ethoxy)-6-methoxyquinazoline (252 mg, 55%).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=[CH:8][C:7]=1[N:21]1[CH2:26][CH2:25][C:24]2[C:27]3[CH2:33][CH2:32][CH2:31][CH2:30][C:28]=3[S:29][C:23]=2[C:22]1=[O:34])(=[O:3])[CH3:2].Br[C:36]1[CH:37]=[C:38]([NH:44][C:45]2[CH:50]=[CH:49][C:48]([N:51]3[CH2:56][CH2:55][N:54]([CH:57]4[CH2:60][O:59][CH2:58]4)[CH2:53][CH2:52]3)=[CH:47][N:46]=2)[C:39](=[O:43])[N:40]([CH3:42])[CH:41]=1>>[C:1]([O:4][CH2:5][C:6]1[C:7]([N:21]2[C:22](=[O:34])[C:23]3[S:29][C:28]4[CH2:30][CH2:31][CH2:32][CH2:33][C:27]=4[C:24]=3[CH2:25][CH2:26]2)=[CH:8][CH:9]=[CH:10][C:11]=1[C:36]1[CH:37]=[C:38]([NH:44][C:45]2[CH:50]=[CH:49][C:48]([N:51]3[CH2:56][CH2:55][N:54]([CH:57]4[CH2:60][O:59][CH2:58]4)[CH2:53][CH2:52]3)=[CH:47][N:46]=2)[C:39](=[O:43])[N:40]([CH3:42])[CH:41]=1)(=[O:3])[CH3:2]
Reactant: Cn1cc(Br)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCc2c(sc3c2CCCC3)C1=O
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C5COC5)CC4)cn3)c(=O)n(C)c2)cccc1N1CCc2c(sc3c2CCCC3)C1=O
Yield: 50 %

Procedure:
Following Example 148c, 481 mg of 111a and 420 mg of 5-bromo-1-methyl-3-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridine-2-ylamino)pyridin-2(1H)-one 188e were reacted to give 209a as a yellow solid (347 mg, 50%). MS: [M+H]+ 695
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[NH:8][C:9](=O)[O:10][C:11]=2[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:23])=O>N1C=CC=CC=1>[Cl:23][C:9]1[O:10][C:11]([CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)CCCc1oc(=O)[nH]c1-c1ccc(Cl)s1
Solvent: c1ccncc1
Product: CCOC(=O)CCCc1oc(Cl)nc1-c1ccc(Cl)s1
Temperature: 125 °C
Reaction time: 0.75 h

Procedure:
A mixture of ethyl 4-[4-(5-chloro-2-thienyl)-2-oxo-4-oxazolin-5-yl]butanoate (12.5 g), phosphorus oxychloride (24.5 g) and pyridine (3.16 g) was heated to 120-130° C. and stirred for 45 minutes. The reaction mixture was poured into ice-water (200 ml) and extracted with ethyl acetate (150 ml×2). The organic layer was washed in sequence with a 10% aqueous solution of sodium hydrogen carbonate (100 ml) and a saturated aqueous solution of sodium chloride (100 ml) and dried over anhydrous magnesium sulfate. The organic layer was concentrated, the residue was subjected to silica gel column chromatography, and ethyl 2-chloro-4-(5-chloro-2-thienyl)-5-oxazolebutanoate was obtained as a yellow oil (5.79 g, 48%) from an ethyl acetate-hexane (1:4, v/v)-eluted fraction.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[NH:2][NH2:3].C(#N)C.[C:10]1([CH2:16][CH2:17][C:18](Cl)=[O:19])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([CH2:16][CH2:17][C:18]([NH:3][NH:2][C:1]([O:5][CH3:6])=[O:4])=[O:19])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)NN
Reactant: O=C(Cl)CCc1ccccc1
Solvent: CC#N
Product: COC(=O)NNC(=O)CCc1ccccc1
Reaction time: 15 h
Yield: 80.7 %

Procedure:
To a solution of 18 g. (0.2 moles) of methyl carbazate and 100 ml. of acetonitrile 33.7 g (0.2 moles) of β-phenylpropionyl chloride are added dropwise. The reaction mixture is heated to boiling for 15 hours, clarified and cooled. The crystals are filtered off. Thus 36.85 g of the desired compound are obtained, yield 80.7% m.p.: 118° C.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[C:3](=O)[CH2:4][S:5][CH3:6].Cl.[NH2:11][OH:12].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[CH3:1][C:2]([CH3:9])([CH3:8])[C:3](=[N:11][OH:12])[CH2:4][S:5][CH3:6]
Reactant: CSCC(=O)C(C)(C)C
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CSCC(=NO)C(C)(C)C

Procedure:
A solution of 20.4 g (0.14 mol) of 3,3-dimethyl-1-methylthio-2-butanone, 19.6 g (0.28 mol) of hydroxylamine hydrochloride and 14.8 g (0.14 mol) of anhydrous sodium carbonate in 140 ml of 95% ethanol and 80 ml of water was heated at reflux for 16 hr. The resulting nearly colorless solution was stripped of volatiles on a rotary evaporator to yield a two layered liquid residue. This residue was extracted with four portions of ethyl acetate. The organic extract was dried over magnesium sulfate, filtered from the drying agent and stripped of solvent. Distillation of the residue gave the desired product as a colorless liquid, b. 83° C./0.6 mm Hg, nD22 1.4989.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[CH3:27][O:28][C:29]1[C:30]([NH2:35])=[CH:31][CH:32]=[CH:33][CH:34]=1>C(#N)C.C(O)(=O)C>[Cl:1][C:2]1[C:3]([NH:35][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[O:28][CH3:27])=[C:4]2[NH:10][C:9]([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:15][CH:16]=3)=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccccc1N
Reactant: Clc1cnc2[nH]c(-c3ccc(OCCN4CCOCC4)cc3)nc2c1Cl
Solvent: CC#N
Solvent: CC(=O)O
Product: COc1ccccc1Nc1c(Cl)cnc2nc(-c3ccc(OCCN4CCOCC4)cc3)[nH]c12
Temperature: 180 °C
Yield: 27 %

Procedure:
6,7-Dichloro-2-[4-(2-morpholin-4-ylethoxy)phenyl]-3H-imidazo[4,5-b]pyridine (Example 206) (30 mg) was dissolved in o-anisidine (0.75 ml) and heated in a microwave oven (180° C., 20 min). The resulting mixture was diluted with acetonitrile (1 ml) and acetic acid (0.5 ml) and subjected to semi-preparative HPLC-C18. The fractions containing product (it co-elutes with o-anisidine) were pooled and evaporated in vacuo. The residue was dissolved in EtOAc (20 ml) and washed with 1% aqueous NaHCO3 (10 ml). The organic phase was treated with activated carbon and MgSO4, filtered and evaporated in vacuo. The oily residue was triturated with n-heptane (1 ml) and a few drops of EtOAc, which caused the product to crystallize. It was collected by filtration and washed with EtOAc to give the pure product as a white powder (10 mg, 27%). A second crop (2.9 mg) crystallized from the combined mother liquor and washing liquids.
Reaction SMILES: C1(C2C[C:9](=[O:11])C2)C=CC=CC=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:22][C:21](=O)[CH2:20]2)=[CH:15][CH:14]=1>>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C@H:19]2[CH2:22][C@H:21]([CH:9]=[O:11])[CH2:20]2)=[CH:15][CH:14]=1
Reactant: O=C1CC(c2ccccc2)C1
Reactant: O=C1CC(c2ccc(F)cc2)C1
Product: O=C[C@H]1C[C@H](c2ccc(F)cc2)C1

Procedure:
Instead of 3-phenylcyclobutanone, 3-(4-fluorophenyl)cyclobutanone (4.63 g) was used and treated by the same technique as in Reference Example 24-1 to give the titled compound as a colorless oil (720 mg).
Reaction SMILES: [CH2:1]([C@@H:7]1[CH2:10][N:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]1=[O:19])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[OH2:20].[OH-].[Li+].O.Cl>C1COCC1.O.CO>[CH2:12]([O:11][NH:9][CH2:10][C@@H:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6])[C:8]([OH:19])=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C=CCCCC[C@@H]1CN(OCc2ccccc2)C1=O
Reactant: O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C=CCCCC[C@H](CNOCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (3R)-3-(5-hexen-1-yl)-N-benzoxy-2-azetidinone (0.39 g, 1.52 mmol) in a mixture of THF—H2O-MeOH (15 mL, 3:1:1 v/v) was added lithium hydroxide monohydrate (1.64 g, 15.2 mmol). After stirring at room temperature overnight, water (15 mL) was added to the mixture. The solution was acidified to pH 4 with 3N aqueous HCl solution. It was extracted with EtOAc (30 mL×2). The combined organic layers were dried over MgSO4. Removal of the solvent under vacuum provided the title compound. MH+278.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[CH3:12][NH:13][CH3:14]>C(O)C>[CH3:12][N:13]([CH3:14])[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CNC
Solvent: CCO
Product: CN(C)c1ccc([N+](=O)[O-])c(N)c1
Temperature: 90 °C
Reaction time: 72 h
Yield: 95.7 %

Procedure:
To a solution of 5-chloro-2-nitroaniline (4.14 g, 24.0 mmol) in ethanol (62 ml) in a sealed thick-walled tube, was added aqueous 40% dimethylamine solution (22.5 ml, 178 mmol, 7.4 eq) and the mixture heated in a 90° C. oil-bath for 2 days (CAUTION: High pressure). After cooling, additional 40% dimethylamine solution (7.5 ml) was added and heating continued for a further 3 days. The reaction mixture was cooled to room temperature and the contents were tipped onto ice (250 ml). After stirring the suspension was filtered, washed with water (200 ml) and dried under vacuum to give 5-dimethylamino-2-nitroaniline as a bright yellow solid (4.16 g, 96%), mp 138.5-139.8° C. (lit. (8) mp 140° C.).
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[CH3:16][C:17]1[CH:21]=[C:20]([NH2:22])[N:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[N:18]=1>>[CH3:16][C:17]1[CH:21]=[C:20]([NH:22][CH:4]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[N:18]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Cc1cc(N)n(-c2ccccn2)n1
Product: CCOC(=O)C(=CNc1cc(C)nn1-c1ccccn1)C(=O)OCC
Temperature: 120 °C
Yield: 95.4 %

Procedure:
A mixture of diethyl ethoxymethylenemalonate (32.5 g, 0.15 mol) and 3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-amine (23.8 g, 0.137 mol) was heated under reflux at 120° C. for 1 hour. After the mixture was allowed to cool to room temperature, the reaction solvent was evaporated under reduced pressure. The crude crystals thus obtained were filtered and washed with diethylether to give the title compound (45 g, 96% yield).
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2.C(O)(=O)C.[Br-:21].[Li+]>C1COCC1>[Br:21][CH2:3][CH:2]([OH:1])[CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2
Reactant: O=C1CCc2cc(OCC3CO3)ccc2N1
Reactant: [Br-]
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C1CCc2cc(OCC(O)CBr)ccc2N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 10085.3 %

Procedure:
To a stirred solution of 6-(oxiran-2-ylmethoxy)-3,4-dihydroquinolin-2(1H)-one (0.2 g, 0.909 mmol) in dry THF (5 mL) was added acetic acid (0.162 g, 2.272 mmol) and lithium bromide (0.118 g, 1.363 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated to remove solvent and water was added (25 mL). The solid was filtered and dried to give crude 6-(3-bromo-2-hydroxypropoxy)-3,4-dihydroquinolin-2(1H)-one as an off-white solid (0.25 g, 91.675 mmol). LCMS: RT 0.65 min; LCMS (ES-API), m/z 300.0 (M+H).
Reaction SMILES: Cl[CH2:2][CH:3]1[CH2:7][CH2:6][O:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].[CH2:14]([NH2:17])[CH2:15][NH2:16]>C(O)C>[O:5]1[CH2:6][CH2:7][CH:3]([CH2:2][NH:16][CH2:15][CH2:14][NH2:17])[CH2:4]1
Reactant: NCCN
Reactant: ClCC1CCOC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: NCCNCC1CCOC1
Yield: 77 %

Procedure:
A mixture of 0.2 mol of 3-(chloromethyl)tetrahydrofuran, 200 ml of ethanol, 0.2 mol of potassium carbonate and 0.2 mol of ethylenediamine placed in a 500 ml of round-bottomed flask was refluxed for 24 hours, and then the solvent was removed. The obtained product was yellow oily liquid in 77% yield.
Reaction SMILES: Br[C:2]1[C:3](=[O:19])[C:4]([CH3:18])([CH3:17])[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:26]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)(=[O:28])[CH3:27]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:26]([C:29]1[CH:34]=[C:33]([C:2]2[C:3](=[O:19])[C:4]([CH3:18])([CH3:17])[O:5][C:6]=2[C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH:32]=[CH:31][CH:30]=1)(=[O:28])[CH3:27]
Reactant: CC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(Br)C1=O
Reactant: CC(=O)c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(=O)c1cccc(C2=C(c3ccc(S(C)(=O)=O)cc3)OC(C)(C)C2=O)c1
Temperature: 90 °C
Reaction time: 12 h
Yield: 52.8 %

Procedure:
To a stirred solution of 4-bromo-2,2-dimethyl-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone (170 mg) in 30 ml toluene and 10 ml ethanol, were added 25 mg of tetrakis(triphenylphosphine)palladium(0), 10 ml of saturated aqueous sodium carbonate, and 130 mg of 3-acetylbenzeneboronic acid. The reaction solution was stirred at 90° C. for 12 hours. Then the solvent was removed under reduced pressure. The resulting residue was extracted with water and dichloromethane. The organic layer was concentrated in vacuo and the resulting residue was separated by column chromatography (hexane/ethylacetate=2:1) to afford 100 mg of 4-(3-acetylphenyl)-2,2-dimethyl-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone as a solid. mp: 189-190° C. NMR: δ1.60 (s, 6H), 2.59 (s, 3H), 3.07 (s, 3H), 7.48 (m, 2H), 7.82 (d, J=8.7 Hz, 2H), 7.90 (m, 2H), 7.94 (d, J=8.4 Hz, 2H). IR (cm−1): 1690, 1620, 1589, 1149, 958, 770.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][N:10]([CH3:14])[CH2:11]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br:15]CC(C1N=CC2CCCCC=2C=1)=O>>[Br:15][CH2:2][C:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][N:10]([CH3:14])[CH2:11]2)=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccc2c(c1)CN(C)CC2
Reactant: O=C(CBr)c1cc2c(cn1)CCCC2
Product: CN1CCc2ccc(C(=O)CBr)cc2C1

Procedure:
*7-bromoacetyl-2-methyl-1,2,3,4-tetrahydroisoquinoline was prepared from 7-acetyl-2-methyl-1,2,3,4-tetrahydroisoquinoline (P.Charpentier et al., Tetrahedron, 1996, 52, 10441) according to the procedure for preparing 3-bromoacetyl-5,6,7,8-tetrahydroisoquinoline described in Example 1.