Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCl.C[O:4][C:5](=[O:17])[C:6]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)([CH3:9])[CH2:7][OH:8].C(N(C(C)C)CC)(C)C.[CH3:27][O:28][CH2:29]Cl.Cl>C(OCC)(=O)C.C1COCC1>[F:16][C:13]1[CH:14]=[CH:15][C:10]([C:6]([CH3:9])([CH2:7][O:8][CH2:27][O:28][CH3:29])[C:5]([OH:4])=[O:17])=[CH:11][CH:12]=1
Reactant: COC(=O)C(C)(CO)c1ccc(F)cc1
Reactant: COCCl
Agent: CCl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCOCC(C)(C(=O)O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a methyl chloride (10 mL)-and-THF (5 mL) solution of 2-(4-fluorophenyl)-3-hydroxy-2-methylpropionic acid methyl ester (825 mg) synthesized according to the method described in Tetrahedron Letters, 1999, vol. 40, p. 5467, IPEA (2 mL) and chloromethyl methyl ether (0.74 mL) were added at 0° C. The reaction solution was agitated at 0° C. for 1 hour, and then at room temperature for 10 hours. 1N hydrochloric acid and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. The organic layer obtained was washed with saturated sodium bicarbonate water, dried over magnesium sulfate, and then concentrated under reduced pressure. To a methanol (5 mL) solution of the obtained residue, 5N sodium hydroxide aqueous solution (4 mL) was added, and the reaction solution was agitated at room temperature for 10 hours. 5N hydrochloric acid (4 mL) and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. The organic layer obtained was dried over magnesium sulfate and concentrated under reduced pressure to obtain 850 mg of the title compound. The physical properties of the compound are as follows.
Reaction SMILES: C[S:2]([NH:5][C:6]([C:8]1[CH:47]=[CH:46][C:11]([C:12]([N:14]2[CH2:18][C@H:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C@@H:16]([CH2:25][N:26]([C@@H:34]([C:36]3C4C(=CC=CC=4)[CH:39]=[CH:38][CH:37]=3)[CH3:35])C(=O)OC(C)(C)C)[CH2:15]2)=[O:13])=[CH:10][CH:9]=1)=[O:7])(=[O:4])=[O:3].Cl.[O:49]1[CH2:54]COCC1>O1CCOCC1>[CH3:54][O:49][S:2]([NH:5][C:6](=[O:7])[C:8]1[CH:47]=[CH:46][C:11]([C:12]([N:14]2[CH2:18][C@H:17]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C@@H:16]([CH2:25][NH:26][C@@H:34]([C:36]3[C:47]4[C:8](=[CH:9][CH:10]=[CH:11][CH:46]=4)[CH:39]=[CH:38][CH:37]=3)[CH3:35])[CH2:15]2)=[O:13])=[CH:10][CH:9]=1)(=[O:3])=[O:4]
Reactant: C1COCCO1
Reactant: C[C@H](c1cccc2ccccc12)N(C[C@H]1CN(C(=O)c2ccc(C(=O)NS(C)(=O)=O)cc2)C[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Agent: Cl
Product: COS(=O)(=O)NC(=O)c1ccc(C(=O)N2C[C@H](CN[C@H](C)c3cccc4ccccc34)[C@@H](c3ccccc3)C2)cc1
Temperature: 25 °C

Procedure:
A 1.6 ml 1,4-dioxane solution of 160 mg of tert-butyl {[(3R,4S)-1-(4-{[(methylsulfonyl)amino]carbonyl}benzoyl)-4-phenylpyrrolidin-3-yl]methyl}[(1R)-1-(1-naphthyl)ethyl]carbamate was mixed with 1.5 ml of 4 M hydrogen chloride/1,4-dioxane and stirred at room temperature for 4Hours. The reaction solution was concentrated under a reduced pressure and dissolved in water. This was neutralized with saturated sodium bicarbonate solution and extracted with chloroform. The organic layer was dried with anhydrous sodium sulfate and then concentrated under a reduced pressure. The thus obtained residue was crystallized with ethyl acetate to obtain 85 mg of N-(methoxysulfonyl)-4-{[(3S,4S)-3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]carbonyl}benzamide as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[C:4]([OH:12])[CH:3]=1.[CH2:13](OC(OCC)OCC)C>>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[O:7][CH:13]=[N:9][N:8]=2)=[C:4]([OH:12])[CH:3]=1
Reactant: NNC(=O)c1ccc(Cl)cc1O
Reactant: CCOC(OCC)OCC
Product: Oc1cc(Cl)ccc1-c1nnco1
Temperature: 130 °C
Yield: 35 %

Procedure:
A mixture of 4-chloro-2-hydroxybenzoic acid hydrazide (Chemical Abstracts, 93:7808, 475 mg, 2.55 mmol) and triethylorthoformate. (3.6 ml) is heated at 130° C. for 3.5 hours. After cooling, a precipitate formed and is collected by filtration. The filter cake is recrystallized from methanol to give 173 mg (35%) of 5-chloro-2-(1,3,4-oxadiazol-2-yl)phenol. This phenolic product is reacted with (2S)-glycidyl 3-nitrobenzenesulfonate substantially as described for Epoxide 1 to yield 170 mg (69%) of the title epoxide.
Reaction SMILES: [CH3:1][C:2]([NH:14][C@@H:15]1[CH2:19][C@H:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=2)[N:17]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[C:16]1=[O:37])([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[N:5]=1)[CH3:3].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:45][CH2:46][CH2:47][F:48]>CN(C=O)C.CCOC(C)=O>[CH3:3][C:2]([NH:14][C@@H:15]1[CH2:19][C@H:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:45][CH2:46][CH2:47][F:48])[CH:21]=2)[N:17]([C:27]2[CH:28]=[CH:29][C:30]([C:33]([F:35])([F:34])[F:36])=[CH:31][CH:32]=2)[C:16]1=[O:37])([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[N:5]=1)[CH3:1]
Reactant: CC(C)(N[C@@H]1C[C@H](c2cccc(O)c2)N(c2ccc(C(F)(F)F)cc2)C1=O)c1cccc(C(F)(F)F)n1
Reactant: FCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(N[C@@H]1C[C@H](c2cccc(OCCCF)c2)N(c2ccc(C(F)(F)F)cc2)C1=O)c1cccc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 19.5 h
Yield: 77.4 %

Procedure:
Dissolve (3R,5R)-3-[1-methyl-1-(6-trifluoromethyl-pyridin-2-yl)-ethylamino]-5-(3-hydroxy-phenyl)-1-(4-trifluoromethyl-phenyl)-pyrrolidin-2-one (520 mg, 0.99 mmol) in DMF (9 mL) and add cesium carbonate (1.9 g, 5.9 mmol) and 1-bromo-3-fluoro-propane (170 mg, 1.19 mmol). Stir the mixture at ambient temperature for 19.5 hours and dilute with EtOAc. Wash with brine, dry over sodium sulfate, filter, and concentrate the organic to residue. Purify the residue by silica gel chromatography (30% EtOAc-hexane) to obtain (3R,5R)-3-[1-methyl-1-(6-trifluoromethyl-pyridin-2-yl)-ethylamino]-5-[3-(3-fluoro-propoxy)-phenyl]-1-(4-trifluoromethyl-phenyl)-pyrrolidin-2-one (447 mg, 77%) as a colorless oil. 1H NMR (400 MHz, DMSO-d6): δ 8.08 (d, J=7.9 Hz, 1H), 8.01 (dd, J=7.7, 7.7 Hz, 1H), 7.70 (d, J=7.5 Hz, 1H), 7.58 (d, J=8.8 Hz, 2H), 7.51 (d, J=8.8 Hz, 2H), 7.13 (dd, J=7.9, 7.9 Hz, 1H), 6.82-6.70 (m, 3H), 5.18 (dd, J=9.7, 6.6 Hz, 1H), 4.58 (t, J=5.9 Hz, 1H), 4.46 (t, J=5.9 Hz, 1H), 4.02-3.88 (m, 2H), 3.47-3.39 (m, 1H), 2.96 (d, J=3.5 Hz, 1H), 2.73-2.63 (m, 1H), 2.06-1.92 (m, 2H), 1.63 (dd, J=22.0, 10.5 Hz, 1H), 1.47 (s, 3H), 1.42 (s, 3H). LC-MS ESI m/z: 584.0 (M+H)+, Tr=3.61 min., method 1.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]([C:8]2[CH:31]=[CH:30][C:11]([CH2:12][N:13]3[C:17]([CH:18](OCC)[O:19]CC)=[C:16]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:15]=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1>C(O)(=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:31]=[CH:30][C:11]([CH2:12][N:13]3[C:17]([CH:18]=[O:19])=[C:16]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:15]=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:32][CH:33]=1
Reactant: CCOC(=O)c1ncn(Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c1C(OCC)OCC
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1ncn(Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c1C=O
Temperature: 25 °C
Reaction time: 23 h
Yield: 95.6 %

Procedure:
In 20% aqueous acetic acid (15 ml) was dissolved ethyl 1-[4-(4-chlorobenzoyl)benzyl]-5-(diethoxymethyl)-imidazole-4-carboxylate (1.70 g) and the solution was stirred at room temperature for 23 hours. This solution was diluted with water and extracted with ethyl acetate. The extract was washed serially with water, saturated aqueous NaHCO3 solution, and water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to provide the title compound as white powder (1.37g; yield 95%). 1H-NMR (CDCl3) δ: 1.45(3H,t,J=7.2Hz), 4.47(2H,q,J=7.2Hz), 5.65(2H,s), 7.28(2H,d,J=8.4Hz), 7.46(2H,d,J=8.4Hz), 7.69-7.77(5H,m), 10.51(1H,s).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C@@H:21]([CH3:35])[C@@H:22]([CH3:34])[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=2)=[CH:16][C:15]=1[O:36][CH3:37].C(=O)([O-])[O-].[K+].[K+].[N+:44]([C:47]1[N:48]=[CH:49][NH:50][CH:51]=1)([O-:46])=[O:45]>>[CH3:33][O:32][C:26]1[CH:25]=[C:24]([CH2:23][C@H:22]([CH3:34])[C@H:21]([CH3:35])[CH2:20][C:17]2[CH:18]=[CH:19][C:14]([O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][N:50]3[CH:51]=[C:47]([N+:44]([O-:46])=[O:45])[N:48]=[CH:49]3)=[C:15]([O:36][CH3:37])[CH:16]=2)[CH:29]=[CH:28][C:27]=1[O:30][CH3:31]
Reactant: COc1ccc(C[C@H](C)[C@H](C)Cc2ccc(OCCOCCOCCOCCBr)c(OC)c2)cc1OC
Reactant: O=[N+]([O-])c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(C[C@H](C)[C@H](C)Cc2ccc(OCCOCCOCCOCCn3cnc([N+](=O)[O-])c3)c(OC)c2)cc1OC
Yield: 57.3 %

Procedure:
The Standard Procedure 2 was followed by use of 9b (146.6 mg, 0.2512 mmol, 1.0 equiv), potassium carbonate (74.4 mg, 0.538 mmol, 2.1 equiv), and 4-nitroimidazole (6a, 56.3 mg, 0.498 mmol, 2.0 equiv). After workup and purification with column chromatography (100% EtOAc as eluant), 10c (88.4 mg, 0.144 mmol) was obtained in 57% yield as a yellow gummy oil: 1H NMR (CDCl3, 400 MHz) δ 0.81 (d, J=6.4 Hz, 3H, CH3), 0.82 (d, J=6.4 Hz, 3H, CH3), 1.73 (m, 2H, 2×CH), 2.23-2.31 (m, 2H, 2×ArCH), 2.70-2.75 (m, 2H, 2×ArCH), 3.62-3.86 (m, 21H, 3×OCH3+6×OCH2), 4.09-4.14 (m, 4H, CH2N+CH2O), 6.62-6.68 (m, 4H, 4×ArH), 6.76-6.80 (m, 2H, 2×ArH), 7.47 (s, 1H, nitroimidazole C5-H), 7.88 (s, 1H, nitroimidazole C2-H); 13C NMR (CDCl3, 100 MHz) δ 16.12, 16.18, 38.74, 38.84, 39.12, 39.21, 48.24, 55.76, 55.78, 55.85, 68.60, 69.49, 69.69, 70.54 70.57, 70.65, 110.97, 112.21, 112.81, 113.66, 120.17, 120.89, 121.04, 134.41, 135.24, 136.48, 146.18, 146.98, 147.95, 148.63, 149.22; IR (neat) 2924 (s), 2854 (s), 1634 (w), 1589 (w), 1515 (s), 1456 (m), 1417 (m), 1334 (s), 1260 (s), 1028 (s) cm−1; HRMS (FAB) m/z calcd for C32H46N3O9 (M+H)+: 616.3234. found: 616.3232.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10](I)=[C:9]([O:14][CH3:15])[C:8](=[O:16])[NH:7][C:6]=2[CH:17]=1.C([Sn](CCCC)(CCCC)[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)CCC>C1(C)C=CC=CC=1.[CH2-]C1C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=3)=[C:9]([O:14][CH3:15])[C:8](=[O:16])[NH:7][C:6]=2[CH:17]=1
Reactant: COc1c(I)c(=O)c2ccc(Cl)cc2[nH]c1=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc([N+](=O)[O-])cc1
Agent: Cl[Pd+]
Agent: [CH2-]c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1c(-c2ccc([N+](=O)[O-])cc2)c(=O)c2ccc(Cl)cc2[nH]c1=O
Temperature: 25 °C
Yield: 60.8 %

Procedure:
8-Chloro-4-iodo-3-methoxy-2,5-dioxo-2,5-dihydro-1H-benz[b]azepine (0.50 g) was dissolved in toluene (12 mL). To this stirred suspension was added trans-benzyl(chloro)bis(triphenylphosphine)palladium(II) (0.050 g) and tributyl(4-nitrophenyl)tin (0.70 g). The resulting suspension was stirred at reflux for 48 hours, then cooled to room temperature, applied directly to a silica column (1.5 cm by 15 cm), and eluted with dichloromethane (250 mL), (ether:dichloromethane (20:80)(250 mL), and methanol:dichloromethane (5:95)(250 mL) to afford the title product (0.30 g, 61%) as a light green solid; mp 250°-251° C. (dec); NMR: 8.24 (d,2, J=9.0), 7.68 (d,1, J=8.6), 7.54 (d,2, J=8.9), 7.42 (d,1, J=2.0), 7.32 (dd,1, J=9.0, 2.1), 3.72 (s,3); MS: m/z=359(M+1).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH2:9]([C:11]1[N:16]=[C:15]([Cl:17])[N:14]=[C:13]([N:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19]2)[CH:12]=1)[CH3:10]>CN(C)C=O>[ClH:17].[CH2:9]([C:11]1[N:16]=[C:15]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=2)[N:14]=[C:13]([N:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19]2)[CH:12]=1)[CH3:10]
Reactant: CCc1cc(N2CCc3ccccc3C2)nc(Cl)n1
Reactant: Nc1ccc(F)cc1
Solvent: CN(C)C=O
Product: CCc1cc(N2CCc3ccccc3C2)nc(Nc2ccc(F)cc2)n1
Product: Cl
Yield: 41.6 %

Procedure:
After 4-fluoroaniline(0.50 ml, 5.28 mmol) was added to a mixture solution of 6-ethyl-4-(1,2,3,4-tetrahydroisoquinoline-2-yl)-2-chloropyrimidine(0.7 g, 2.56 mmol) and dimethylformamide(5 ml), 0.41 g of the titled compound was obtained in accordance with the same procedure as in Step 2 of Example 1.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:16][C:15]2[CH:17]=[C:18]([CH:21]=O)[CH:19]=[CH:20][C:14]=2[O:13][CH2:12][CH2:11]1.[S:23]1[CH2:27][C:26](=[O:28])[NH:25][C:24]1=[O:29].C([O-])(=O)C.[NH2+]1CCCCC1>C1(C)C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:16][C:15]2[CH:17]=[C:18]([CH:21]=[C:27]3[S:23][C:24](=[O:29])[NH:25][C:26]3=[O:28])[CH:19]=[CH:20][C:14]=2[O:13][CH2:12][CH2:11]1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1ccc2c(c1)CN(c1nc3ccccc3o1)CCO2
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: O=C1NC(=O)C(=Cc2ccc3c(c2)CN(c2nc4ccccc4o2)CCO3)S1

Procedure:
To 4-benzooxazol-2-yl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepine-7-carbaldehyde [compound of Step VI] (0.176 g, 0.6 mmol) taken in toluene (25 mL) were added 2,4-thiazolidine dione (0.105 g, 0.9 mmol) and catalytic amount of piperidinium acetate (0.025 g). The resulting mixture was refluxed under Dean Stark conditions for 1.5 hours and then cooled in an ice-bath. The precipitate was filtered and washed with toluene and petroleum ether to give 5-(4-benzooxazol-2-yl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-7-ylmethylene)-thiazolidine-2,4-dione.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]([CH2:9][CH2:10][CH2:11][N:12]3[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([Mg]Br)[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1.[Cl-:32].[NH4+]>O1CCCC1.CCOCC>[ClH:32].[F:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]([CH2:9][CH2:10][CH2:11][N:12]3[CH2:13][CH2:14][C:15]([OH:18])([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)[CH2:16][CH2:17]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C1CCN(CCCc2noc3cc(F)ccc23)CC1
Reactant: [Cl-]
Reactant: COc1ccc(C[Mg]Br)cc1
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(C2(O)CCN(CCCc3noc4cc(F)ccc34)CC2)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 6.3 g of 1-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-4-piperidone in 35 ml of tetrahydrofuran was slowly added to a solution of 49 ml of p-anisylmagnesium bromide (1.4 M in tetrahydrofuran). After the addition was complete, the reaction mixture was stirred at ambient temperature for one hr, diluted with ether, poured into 400 of ml saturated ammonium chloride solution and extracted with ether. The organic extracts were washed with water (2×), saturated sodium chloride solution and dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was converted to 8.5 g (89%) of product, mp 100°-105° C., by treatment with ethereal hydrogen chloride. An analytical sample was obtained by recrystallization from ethyl acetate/methanol and had mp 181°-182° C. (dec).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=O)[CH2:8]2.[CH3:14][NH:15][CH3:16].CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH:7]([N:15]([CH3:16])[CH3:14])[CH2:8]2
Reactant: COc1cccc2c1CCC(=O)C2
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cccc2c1CCC(N(C)C)C2
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.6 %

Procedure:
To a solution of 5-methoxy-2-tetralone (10.33 g, 58.62 mmol) dissolved in CH2Cl2 (400 mL) were added dimethylamine (5.6 M in EtOH, 14 mL, 76.206 mmol) and AcOH (0.46 mL, 5.862 mmol), and the mixture was stirred for 4 h at room temperature. It was then cooled to 0° C. and NaB(OAc)3H (0.45 eq, 5.59 g, 26.379 mmol) was added over a period of 20 min. After 1 h stirring at 0° C., NaB(OAc)3H (1.0 eq, 12.42 g, 58.62 mmol) was added over a period of 30 min. The reaction mixture was warmed to room temperature and stirred for 16 h. The mixture was cooled again to 0° C., and H2O (250 mL) was added slowly. The pH of the solution was adjusted to 8.0 by adding NaHCO3 saturated aqueous solution, and the mixture was stirred at 0° C. for 15 min. The layers were separated, and the aqueous phase was extracted with CH2Cl2 (4×100 mL). All organic phases were combined, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue (12.51 g) was purified by flash chromatography on silica gel (1:100:1-100:0:1 AcOEt/Hexane/Et3N) affording 8.86 g of the title compound (Rf=0.5 (AcOEt/Hexane/Et3N 10:10:2), brown colored oil, 74% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[CH2:6][CH2:5]2.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][C:13]1=[O:21].N1CCCCC1.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[C:14]1[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[NH:12][C:13]1=[O:21])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Cl)ccc21
Reactant: O=C1Cc2ccccc2N1
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCNCC1
Product: O=C1Nc2ccccc2C1=C1CCc2cc(Cl)ccc21
Temperature: 95 °C
Yield: 20.3 %

Procedure:
A mixture of 500 mg 5-chloro-1-indanone, 1.33 g oxindole and 0.5 ml piperidine in 3 ml dimethylforamide was heated in a sealed tube at 95° C. overnight. Water was added to the reaction mixture to yield an oily solid. The mixture was sonicated for a few minutes then decanted. This washing procedure was repeated several times. The solid was then filtered and washed with ethyl acetate/hexanes (1:3) to yield 172 mg of 3-(5-chloroindan-1-ylidene)-1,3-dihydroindol-2-one as a mustard colored solid.
Reaction SMILES: B(Cl)(Cl)Cl.[C:5](Cl)(=[O:12])C1C=CC=CC=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([OH:24])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23].[OH-].[Na+]>ClCCl.C1C=CC=CC=1>[OH:24][C:18]1[CH:17]=[C:16]([O:15][CH3:14])[C:21]([O:22][CH3:23])=[CH:20][C:19]=1[CH:5]=[O:12]
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc(O)cc1OC
Agent: ClB(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: ClCCl
Product: COc1cc(O)c(C=O)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
A 1.0M solution of boron trichloride (210 ml, Aldrich) in dichloromethane was added to benzoyl chloride (130 g. Aldrich) in benzene (350 ml). Next, 3,4-dimethoxyphenol (30.0 g, Aldrich) in benzene (130 ml) was added and the reaction mixture was stirred at room temperature for 21/2 hours. 50% NaOH (55 ml) was then added and the mixture was stirred for 15 minutes. The organic layers were separated, dried and concentrated in vacuo. The resulting residue was triturated with 1N NaOH for 40 minutes then filtered. The aqueous basic filtrate was acidified with conc. HCl to give the title product as a yellow solid (25.9 g), mp 104-105° C. 1H NMR was consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[CH2:12][C:13]([OH:15])=O.C(Cl)CCl.C[CH2:21][N:22](CC)[CH2:23]C.Cl.CNC>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[CH2:12][C:13]([N:22]([CH3:23])[CH3:21])=[O:15]
Reactant: COc1ccc([N+](=O)[O-])cc1CC(=O)O
Reactant: CCN(CC)CC
Agent: CNC
Agent: Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1ccc([N+](=O)[O-])cc1CC(=O)N(C)C

Procedure:
2-(2-Methoxy-5-nitrophenyl)acetic acid (17.1 g, 1 eq, Step B), EDC (18.6 g, 1.2 eq.), Et3N (9.8 g, 13.6 mL, 1.2 eq) and dimethylamine hydrochloride (7.9 g, 1.2 eq.) in 150 mL of CH2Cl2 were stirred together with exclusion of air overnight. CH2Cl2 (150 mL) was added and the mixture was washed twice with 1M HCl, twice with 1M NaOH, H2O and brine. Removal of the solvent under reduced pressure followed by silica gel chromatography (90:10 CH2Cl2:EtOAc) afforded pure 2-(2-methoxy-5-nitrophenyl)-N,N-dimethyl-acetamide as a white solid.
Reaction SMILES: [F:1][C:2]1[C:8]([N:9]2[C:16]3[N:12]([N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[CH:11]=[CH:10]2)=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:23]([C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([S:34]([F:39])([F:38])([F:37])([F:36])[F:35])[CH:33]=1)[C:28](O)=[O:29])#[N:24]>>[C:23]([C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([S:34]([F:38])([F:39])([F:35])([F:36])[F:37])[CH:33]=1)[C:28]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[C:8]([N:9]2[C:16]3[N:12]([N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[CH:11]=[CH:10]2)[C:2]=1[F:1])=[O:29])#[N:24]
Reactant: Nc1cccc(-n2ccn3nc(-c4cccnc4)cc23)c1F
Reactant: N#Cc1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Product: N#Cc1cc(C(=O)Nc2cccc(-n3ccn4nc(-c5cccnc5)cc34)c2F)cc(S(F)(F)(F)(F)F)c1

Procedure:
Analogously to the process described in Example 96, 100 mg (0.341 mmol) of the compound of Example 70A and 110 mg (0.341 mmol, 85% pure) of the compound from Example 23A gave 52 mg (28% of theory) of the title compound. Here, purification was by preparative HPLC according to Method 33, and final trituration of the product could be dispensed with.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[N:12]([O-])=O.[Na+].[C:16]([O:22][CH3:23])(=[O:21])[CH2:17][C:18]([CH3:20])=[O:19].C([O-])(=O)C.[Na+]>Cl.O.C(O)C>[O:19]=[C:18]([CH3:20])[C:17](=[N:12][NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=1)[C:16]([O:22][CH3:23])=[O:21]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: COC(=O)CC(C)=O
Reactant: O=N[O-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COC(=O)C(=NNc1cccc(C(F)(F)F)c1)C(C)=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 69.4 %

Procedure:
A slurry of 3-(trifluoromethyl)aniline (16.12 g, 100 mmol) in 6 N HCl (100 mL) was cooled to 0° C. and treated dropwise with a solution of sodium nitrite (8.33 g, 121 mmol) in water (20 mL). The resulting pale yellow solution was poured into a slurry of methyl acetoacetate (11.62 g, 100 mmol) and sodium acetate (150 g) in ethanol (170 mL), pre-cooled to 0° C. The resulting orange slurry was stirred for 10 min. After that time, the product was collected by filtration and washed with water (500 mL). The crude material was dissolved in ethyl acetate (250 mL) and dried (MgSO4). The product crystallized upon concentration of the ethyl acetate to give 19.997 g (69%) of methyl 3-oxo-2-{[3-(trifluoromethyl)phenyl]hydrazono}butanoate as light yellow crystals.
Reaction SMILES: [I:1][C:2]1[CH:19]=[CH:18][C:5]([NH:6][C:7]2[S:8][C:9]3[N:17]=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[N:12]=2)=[CH:4][CH:3]=1.[H-].[Li+].[CH3:22]I>>[I:1][C:2]1[CH:19]=[CH:18][C:5]([N:6]=[C:7]2[N:12]([CH3:22])[C:11](=[O:13])[C:10]3[CH:14]=[CH:15][CH:16]=[N:17][C:9]=3[S:8]2)=[CH:4][CH:3]=1
Reactant: O=c1nc(Nc2ccc(I)cc2)sc2ncccc12
Reactant: CI
Agent: [H-]
Agent: [Li+]
Product: Cn1c(=Nc2ccc(I)cc2)sc2ncccc2c1=O
Yield: 62.2 %

Procedure:
The reaction procedure of Example 11 was followed except that 900 mg (2.36 mmol) of 2-(4-iodoanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 23 mg of lithium hydride and 402 mg of methyl iodide were used. The resulting residue was then purified through silica gel column chromatography (eluant: chloroform) to obtain 580 mg of 2-[(4-iodophenyl)imino]-2,3-dihydro-3-methyl-4H-pyrido[3,2-e]-1,3-thiazin-4-one (62%, recrystallized from a mixture of ether and hexane).