Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(CC1SC(S)=NC=1)(O)=O.[C:11]1([O:19][CH3:20])[C:12](=[CH:15][CH:16]=[CH:17][CH:18]=1)[O:13][CH3:14].[C:21]1(=[O:27])[O:26][C:24](=[O:25])[CH2:23][CH2:22]1.[Cl-].[Al+3].[Cl-].[Cl-]>>[CH3:14][O:13][C:12]1[CH:15]=[C:16]([CH:17]=[CH:18][C:11]=1[O:19][CH3:20])[C:21]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[O:27]
Reactant: O=C1CCC(=O)O1
Reactant: COc1ccccc1OC
Agent: O=C(O)Cc1cnc(S)s1
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(=O)CCC(=O)O)cc1OC

Procedure:
A 5-carboxymethyl-2-mercaptothiazole derivative can be prepared by reacting veratrole with succinic anhydride in the presence of anhydrous aluminum chloride to obtain 3-(3,4-dimethoxybenzoyl)propionic acid, subjecting the compound to demethylation with hydrobromic acid to obtain 3-(3,4-dihydroxybenzoyl)propionic acid, subjecting the compound to enol-lactonation in the presence of acetic anhydride and sodium acetate, reacting the resulting compound sequentially with N-bromosuccinimide and with diphenyldiazomethane to obtain 3-(3,4-diacetoxybenzoyl)-3-bromopropionate, and further reacting the compound with ammonium dithiocarbamate.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH2:14][CH3:15])=[N:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].Br[CH:17]1[CH2:22][CH2:21][CH2:20][CH:19]=[CH:18]1>>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH2:14][CH3:15])=[N:10][N:11]2[CH:22]2[CH2:21][CH2:20][CH2:19][CH:18]=[CH:17]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: CCc1n[nH]c2cc(C(=O)OC)ccc12
Reactant: BrC1C=CCCC1
Product: CCc1nn(C2C=CCCC2)c2cc(C(=O)OC)ccc12
Yield: 44.8 %

Procedure:
This compound was prepared according to the method of Preparation 1, using 750 mg (3.67 mmol, 1.0 equiv) 3-ethyl-1H-indazole-6-carboxylic acid methyl ester and 0.46 mL (4.04 mmol, 1.1 equiv) 3-bromocyclohexene as starting materials to give 467 mg (45%) of a clear oil: HRMS calcd for C27H20N2O2: 284.1525. Found: 284.1512.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([NH2:12])[CH:9]=[CH:10][CH:11]=1.[CH3:13][NH2:14]>CO>[NH2:12][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[O:5][CH2:4][CH2:3][CH2:2][NH:14][CH3:13]
Reactant: Nc1cccc(OCCCCl)c1
Reactant: CN
Solvent: CO
Product: CNCCCOc1cccc(N)c1
Temperature: 100 °C

Procedure:
The 3-(3-chloropropoxy)phenylamine was dissolved in methanol (25 mL) and added to a 40 wt % aqueous solution of methylamine (50 mL) in a heavy-walled glass pressure-tube apparatus. The tube was sealed and the mixture was stirred and heated at 100° C. (oil bath temperature) for 4 h. After cooling, the mixture was concentrated by rotary evaporation. Saturated NaCl solution (25 mL) was added to the residue. The pH of the solution was adjusted to 6, and impurities were extracted with ether (4×30 mL). The aqueous layer was basified to pH 11 with 10% NaOH solution and extracted with chloroform (4×50 mL). The combined chloroform extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation to a residue that was dried briefly under high vacuum to give 2.77 g of an oil.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([C:24]([OH:26])=[O:25])[CH2:10][CH2:11][CH2:12][NH:13]C(OCC1C=CC=CC=1)=O)=[O:7])([CH3:4])[CH3:3].[H-].[Na+].[CH3:29]I.O>C1COCC1>[N:8]([C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])([CH3:29])[C@H:9]([C:24]([OH:26])=[O:25])[CH2:10][CH2:11][CH2:12][NH2:13]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C(=O)OC(C)(C)C)[C@@H](CCCN)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 159.6 %

Procedure:
To a solution of 3.00 g (8.19 mmol) of Boc-Orn (Z)-OH in 82 ml of THF were added 1.31 g (32.8 mmol) of 60% sodium hydride and 4.08 ml (65.5 mmol) of methyl iodide with ice cooling, and the mixture was stirred at room temperature for 16 hours. The reaction solution was combined with water with ice cooling, and washed with hexane. The aqueous layer was combined with 10% aqueous citric acid solution, extracted with ethyl acetate and the extract was washed with saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure to give 3.22 g (100%) of Boc-N-Me-Orn (Me) (Z)-OH.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:31]1[CH2:30][CH2:29][N:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([O:21][CH3:20])[CH:23]=3)[CH2:33][CH2:32]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: COc1cccc(N2CCNCC2)c1
Reactant: CCOC(=O)Nc1nc2ccc(F)cc2nc1OC
Product: COc1cccc(N2CCN(C(=O)Nc3nc4ccc(F)cc4nc3OC)CC2)c1
Yield: 77 %

Procedure:
Ethyl N-(6-fluoro-3-methoxyquinoxalin-2-yl)carbamate and 1-(3-methoxyphenyl)piperazine were reacted by the same way with the example 85 to obtain the titled compound (yield, 77%). 1H NMR (300 MHz, CDCl3): δ 3.28-3.31 (m, 4H), 3.74-3.77 (m, 4H), 3.80 (s, 3H), 4.15 (s, 3H), 6.46-6.58 (m, 2H), 7.18-7.28 (m, 4H), 7.40 (dd, J=9.3 and 2.7 Hz, 1H), 7.78-7.81 (m, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[NH:8][C:7]=1[NH2:17])=O)C.C[O-].[Na+].[CH:21]([NH2:23])=O>>[CH3:16][O:15][C:12]1[CH:11]=[CH:10][C:9]2=[N:8][C:7]3[C:6]([C:4](=[O:3])[NH:23][CH2:21][N:17]=3)=[C:14]2[CH:13]=1
Reactant: NC=O
Reactant: CCOC(=O)c1c(N)[nH]c2ccc(OC)cc12
Agent: C[O-]
Agent: [Na+]
Product: COc1ccc2c(c1)=C1C(=O)NCN=C1N=2
Temperature: 25 °C
Reaction time: 60 h
Yield: 72 %

Procedure:
A solution of 2-amino-5-methoxy-1H-indole-3-carboxylic acid ethyl ester (2.15 g (9.2 mmol), sodium methoxide (0.5 g (9.3 mmol), and formamide (200 mL), is heated under N2 at 220° C. for 1.5 h. The solution is cooled to room temperature, stored for 2.5 days, and filtered. The solvent is evaporated by Kugelrohr distillation at 95° C./0.8 mm. The residual solids are washed with H2O, then heated in 35 mL of boiling N,N-dimethylformamide. The hot suspension is filtered hot over a pad of flash silica gel. The cooled filtrate is concentrated in vacuo to a solid that is sonicated in about 30 mL of MeOH. The solids are filtered, washed with MeOH, and dried to leave 6-methoxy-3H-indolo[2,3-d]pyrimidine-4-one (1.71 g,72%) that is about 83% pure. 1H NMR (DMSO): δ12.16 (1H, br s, exchanges with D2O), 12.04 (1H, br s, exchanges with D2O), 8.08 (1H, d, J=3.4 Hz, exchanges to s with D2O), 7.46 (1H, d, J=1.9 Hz), 7.37 (1H, d, J=8.7 Hz), 6.95 (1H, dd, J=8.8, 2.5 Hz), 3.81 (3 H, s).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](/[C:11](/[Sn](CCCC)(CCCC)CCCC)=[CH:12]\[C@@H:13]2[N:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=3[O:27][CH3:28])[C:16](=[O:29])[CH2:15][CH2:14]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].I[C:44]1[N:49]=[C:48]([O:50][CH3:51])[C:47]([NH2:52])=[CH:46][CH:45]=1.[F-].[Cs+].O>CN(C)C=O.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.[Cu](I)I.C(OCC)(=O)C>[NH2:52][C:47]1[CH:46]=[CH:45][C:44](/[C:11](/[C:8]2[CH:9]=[CH:10][C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:6][CH:7]=2)=[CH:12]/[C@@H:13]2[N:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=3[O:27][CH3:28])[C:16](=[O:29])[CH2:15][CH2:14]2)=[N:49][C:48]=1[O:50][CH3:51]
Reactant: COc1nc(I)ccc1N
Reactant: CCCC[Sn](CCCC)(CCCC)/C(=C/[C@H]1CCC(=O)N1Cc1ccc(OC)cc1OC)c1ccc(C(C)(C)C)cc1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(N)c(OC)n2)c(OC)c1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (50 mg) was added to a solution of (5R)-5-[(E)-2-(4-tert-butylphenyl)-2-(tributylstannyl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one obtained in Reference Example 4-26 (296 mg), 6-iodo-2-methoxypyridin-3-amine obtained in Reference Example 4-31(1) (220 mg), cesium fluoride (135 mg) and copper iodide (93 mg) in N,N-dimethylformamide (1.5 mL) in a nitrogen atmosphere, and the mixture was stirred at 65° C. for three hours. The reaction solution was left to cool, and then water and ethyl acetate were added, followed by filtration through celite. The filtrate was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→1:4) to give (5R)-5-[(E)-2-(5-amino-6-methoxypyridin-2-yl)-2-(4-tert-butylphenyl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one as a light brown amorphous (152 mg, 68%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=O)=[CH:4][CH:3]=1.[CH3:13][C:14]([S:17]([NH2:19])=[O:18])([CH3:16])[CH3:15].CCOC(C)=O.C([O-])(O)=O.[Na+]>[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC.O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[N:19][S:17]([C:14]([CH3:16])([CH3:15])[CH3:13])=[O:18])=[CH:4][CH:3]=1
Reactant: O=C1CCCc2ccc(Br)cc21
Reactant: CC(C)(C)S(N)=O
Agent: [Ti+4]
Agent: CC[O-]
Agent: O=C([O-])O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)S(=O)N=C1CCCc2ccc(Br)cc21
Temperature: 25 °C
Yield: 100 %

Procedure:
7-Bromo-3,4-dihydronaphthalen-1(2H)-one (5 g, 22.21 mmol), 2-methylpropane-2-sulfinamide (4.04 g, 33.32 mmol) and titanium ethoxide (9.15 mL, 44.43 mmol) were dissolved in 2-Me THF (50 mL) and heated to reflux for 22 h. The reaction was left to cool down to r.t. EtOAc (20 mL), NaHCO3 (sat, 5 mL) and water was added under stirring. The mixture was left to stand without stirring for 1 h. The organic phase was collected by filtration, dried over MgSO4 and concentrated in vacuo to give the title compound (7.29 g) that was used without purification in the next step: 1 H NMR (500 MHz, CDCl3) δ ppm 1.34 (s, 9 H), 2.00-2.10 (m, 2 H), 2.77-2.86 (m, 2 H), 3.01-3.12 (m, 1 H), 3.28 (ddd, 1 H), 7.09 (d, 1 H), 7.50 (dd, 1 H), 8.25 (d, 1 H), MS (ES+) m/z 328[M+H]+.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17](Br)[CH:18]=[C:13]3[CH:12]=[C:11]2[CH3:20])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=2)[CH2:24][CH2:23]1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH3:20][C:11]1[N:10]([S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[C:14]2=[N:15][CH:16]=[C:17]([C:32]3[CH:31]=[CH:30][C:29]([CH2:28][N:25]4[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]4)=[CH:34][CH:33]=3)[CH:18]=[C:13]2[CH:12]=1
Reactant: CN1CCN(Cc2ccc(B(O)O)cc2)CC1
Reactant: Cc1cc2cc(Br)cnc2n1S(=O)(=O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cc1cc2cc(-c3ccc(CN4CCN(C)CC4)cc3)cnc2n1S(=O)(=O)c1ccccc1
Yield: 74.1 %

Procedure:
1-Benzenesulfonyl-5-bromo-2-methyl-1H-pyrrolo[2,3-b]pyridine (378 mg, 1.076 mmole) and 4-((4-methylpiperazin-1-yl)methyl)phenylboronic acid (303 mg, 1.29 mmole) are dissolved in acetonitrile (10 mL) and treated with 10 mL 1 M sodium carbonate solution. To this is added 40 mg of PdCl2(PPh3)2 catalyst, and the mixture is irradiated for 5 minutes at 150 degrees in a Biotage microwave reactor. After cooling, the reaction mixture is diluted with water and extracted with ethyl acetate, dried, and concentrated. MPLC silica gel chromotagraphy 5-20% MeOH in dichloromethane gradient elution, provided 367 mg of the title compound as a solid.
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][C:19]([CH3:22])(C)[CH3:20])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:26]1(O)[CH2:31]CCC[CH2:27]1.Cl>CCO.CCO.CCO.CCO.[Ti].O>[Br:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH:19]3[CH2:20][CH2:31][CH2:26][CH2:27][CH2:22]3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1c(Br)cccc1-2
Reactant: OC1CCCCC1
Agent: [Ti]
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C(OC1CCCCC1)c1ncn2c1[C@@H]1CCN1C(=O)c1c(Br)cccc1-2

Procedure:
8 g (20 mmol) of tert.butyl (S)-8-bromo-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylate, 25 g (250 mmol) of cyclohexanol and 1.8 g (8 mmol) of tetraethyl orthotitanate are stirred at 120° overnight, the excess cyclohexanol is removed in a water-jet vacuum and the residue is taken up in chloroform. The solution obtained is stirred for 0.5 hour with 40 ml of a 1:1 mixture of concentrated hydrochloric acid and water, the organic phase is separated, washed once with 1N hydrochloric acid and once with saturated sodium bicarbonate solution, dried over magnesium sulphate and evaporated. By recrystallization from ethanol there is obtained cyclohexyl (S)-8-bromo-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylate of melting point 203°-204°.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[C:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:19]2[CH2:24][CH2:23][S:22][C:21]([CH3:26])([CH3:25])[C@@H:20]2[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])(=[O:18])=[O:17])=[CH:12][CH:11]=1.[C:34](OC(=O)C)(=[O:36])[CH3:35].N1C=CC=CC=1>>[C:34]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[C:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:19]2[CH2:24][CH2:23][S:22][C:21]([CH3:26])([CH3:25])[C@@H:20]2[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])(=[O:18])=[O:17])=[CH:12][CH:11]=1)(=[O:36])[CH3:35]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)[C@@H]1N(S(=O)(=O)c2ccc(OCC#CCCCCO)cc2)CCSC1(C)C
Solvent: c1ccncc1
Product: CC(=O)OCCCCC#CCOc1ccc(S(=O)(=O)N2CCSC(C)(C)[C@@H]2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 97.1 %

Procedure:
A mixture of 0.452 g (0.908 mmol) of tert-butyl (3S)-4-({4-[(7-hydroxy-2-heptynyl)oxy]phenyl}sulfonyl)-2,2-dimethyl-3-thiomorpholinecarboxylate, 2.6 mL (27 mmol) of acetic anhydride and 0.22 mL (2.7 mmol) of pyridine was stirred at room temperature for 6 h and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate:hexanes (1:5) to provide 0.476 g (97%) of tert-butyl (3S)-4-[(4-{[7-(acetyloxy)-2-heptynyl]oxy) phenyl)sulfonyl]-2,2-dimethyl-3-thiomorpholinecarboxylate as a colorless oil. Electrospray Mass Spec: 540.0 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[N:5]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[CH:25][CH:24]=2)[C:6](=[O:21])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:11][C:10]([Br:20])=[CH:9][CH:8]=2)(=[O:3])[CH3:2].[CH3:32][Mg]Br.[Cl-].[NH4+]>C1COCC1>[C:1]([C:4]1[N:5]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]([OH:31])([CH3:32])[CH3:30])=[CH:27][CH:28]=2)[C:6](=[O:21])[C:7]2[C:12]([C:13]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[CH:11][C:10]([Br:20])=[CH:9][CH:8]=2)(=[O:3])[CH3:2]
Reactant: C[Mg]Br
Reactant: CC(=O)c1ccc(Cn2c(C(C)=O)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(C(C)(C)O)cc1
Yield: 83 %

Procedure:
To a solution of 3-acetyl-2-(4-acetylbenzyl)-6-bromo-4-phenyl-2H-isoquinolin-1-one (297 mg) in THF (10 ml) was added methyl magnesium bromide (1M tetrahydrofuran solution, 1.89 ml) under ice-cooling and the mixture was stirred under ice-cooling for 1 hr. The reaction solution was poured into saturated aqueous ammonium chloride solution, extracted with ethyl acetate, washed with brine and dried by adding sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=9/1→3/2) to give the title compound (258 mg, 83%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([NH:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1)=[O:4].N1C=CC=CC=1.Cl[C:22]([O:24][CH2:25][C:26]([Cl:29])([Cl:28])[Cl:27])=[O:23]>CN(C)C(=O)C>[F:1][C:2]([F:13])([F:14])[C:3]([NH:5][C:6]1[CH:12]=[CH:11][C:9]([NH:10][C:22](=[O:23])[O:24][CH2:25][C:26]([Cl:29])([Cl:28])[Cl:27])=[CH:8][CH:7]=1)=[O:4]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Nc1ccc(NC(=O)C(F)(F)F)cc1
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Product: O=C(Nc1ccc(NC(=O)C(F)(F)F)cc1)OCC(Cl)(Cl)Cl
Temperature: 0 °C
Yield: 96.8 %

Procedure:
To a solution of 4-trifluoroacetylaminoaniline (1.00 g, 4.90 mmol) and pyridine (1.20 ml, 15.0 mmol) in N,N-dimethylacetamide (20 ml) was added 2,2,2-trichloroethyl chloroformate (1.01 ml, 7.35 mmol) under ice-cooling, and the mixture was stirred under ice-cooling for 2 hours. The reaction mixture was poured into ice-water, and a solid was collected by filtration to give 1.80 g (96.8%) of the desired product as a solid.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:42]([O:46][CH2:47][CH3:48])(=[O:45])[CH:43]=[CH2:44]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:4][C:3]1[CH:5]=[CH:6][C:7]([C:9]([F:12])([F:11])[F:10])=[CH:8][C:2]=1/[CH:44]=[CH:43]/[C:42]([O:46][CH2:47][CH3:48])=[O:45]
Reactant: C=CC(=O)OCC
Reactant: Nc1ccc(C(F)(F)F)cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1cc(C(F)(F)F)ccc1N
Temperature: 120 °C

Procedure:
To a mixture of 2-bromo-4-(trifluoromethyl)aniline (5 g, 20.83 mmol), triethylamine (4.4 mL, 31.2 mmol) and P(o-tol)3 (2.5 g, 8.33 mmol) in DMF (42 mL, 0.5 M) in a glass pressure tube under nitrogen gas were added ethyl acrylate (2.3 g, 23 mmol) and palladium acetate (940 mg, 4.167 mmol). The tube was sealed and heated to 120° C. for 18 h. The resulting solution was concentrated under vacuum and purified by column chromatography. Retention time(min)=2.532, method [1], MS(ESI) 260.1 (M+H).
Reaction SMILES: [F:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([N:6]=[CH:7][C:8](=O)[NH:9]2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:8]1[CH:7]=[N:6][C:5]2[C:10](=[C:11]([CH3:12])[C:2]([F:1])=[CH:3][CH:4]=2)[N:9]=1
Reactant: Cc1c(F)ccc2ncc(=O)[nH]c12
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1c(F)ccc2ncc(Cl)nc12
Yield: 65 %

Procedure:
7-Fluoro-8-methyl-2(1H)-quinoxalinone (5.75 g, 32.3 mmol) in phosphorus oxychloride (30 ml) was heated under reflux for 2 h. Phosphorus oxychloride was removed by evaporation, and the residue was basified with aqueous sodium bicarbonate and extracted several times with ethyl acetate. The extracts were dried and evaporated, and the residue was dissolved in dichloromethane and passed quickly through a short column of silica (20 g), washing through with more dichloromethane. Removal of solvent gave product (4.13 g, 65%).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][CH:9]([C:16](=[O:21])[CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=O)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>CN(C)C=O>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]2[O:21][C:16]([CH2:17][CH:18]([CH3:20])[CH3:19])=[C:9]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(NC(=O)c1ccc(Cl)cc1)C(=O)CC(C)C
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)Cc1nc(-c2ccc(Cl)cc2)oc1CC(C)C
Yield: 63.4 %

Procedure:
2.5 g of ethyl 3-(4-chlorobenzoylamino)-3-isovalerylpropionate, 10 ml of dimethylformamide and 2.3 g of phosphorus oxychloride are treated in the same manner as described in Example 1. 1.5 g of ethyl 2-[2-(4-chlorophenyl)-5-isobutyl-4-oxazolyl]acetate are thereby obtained. Yield: 63.3%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[C:25]1([CH3:34])[C:26]([N:31]=[C:32]=[S:33])=[CH:27][CH:28]=[CH:29][CH:30]=1>>[O:16]=[C:12]1[NH:11][C:10]2[C:17]3[C:22]([CH:23]=[CH:24][C:9]=2[N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:32]([NH:31][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[CH3:34])=[S:33])=[CH:3][CH:4]=2)[C:14](=[O:15])[CH2:13]1)=[CH:21][CH:20]=[CH:19][CH:18]=3
Reactant: Cc1ccccc1N=C=S
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Product: Cc1ccccc1NC(=S)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Yield: 29.9 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (150 mg, 0.473 mmol), and o-tolyl isothiocyanate (159 μL, 1.183 mmol), the title compound (66 mg, yield 30%) was obtained in the same manner as that of Example 24.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[O:15][CH:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:13][CH2:12]3)=[N:6][CH:7]=1.ClC1N=CC([CH2:32][N:33]([CH3:35])[CH3:34])=CC=1>>[CH3:32][N:33]([CH3:35])[CH2:34][C:2]1[CH:7]=[N:6][C:5]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[O:15][CH:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:13][CH2:12]3)=[CH:4][CH:3]=1
Reactant: CN(C)Cc1ccc(Cl)nc1
Reactant: Clc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Product: CN(C)Cc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1

Procedure:
Dimethyl-[6-(2-phenylchroman-6-yloxy)pyridin-3-ylmethyl]amine was prepared as described for 5-Chloro-2-(2-phenylchroman-6-yloxy)pyridine in Example 61, but replacing 2,5-dichloropyridine with (6-chloropyridin-3-ylmethyl)dimethylamine. 1H NMR (400 MHz, CDCl3) δ: 8.03 (d, 1H, J 2.3 Hz), 7.65 (dd, 1H, J 8.4, 2.3 Hz), 7.44-7.32 (m, 5H), 6.92-6.88 (m, 3H), 6.84 (d, 1H, J 8.4 Hz), 5.05 (dd, 1H, J 10.2, 2.3 Hz), 3.36 (s, 2H), 3.02 (m, 1H), 2.80 (m, 1H), 2.23 (s, 1H), 2.19 (m, 1H), 2.10 (m, 1H).
Reaction SMILES: IC(CC)CCC[N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16].NC1C=CC=C2C=1N=CC=C2.[ClH:30].CC(O)C>C(O)(C)C>[ClH:30].[C:10]1(=[O:11])[NH:6][C:7](=[O:16])[C:8]2=[CH:15][CH:14]=[CH:13][CH:12]=[C:9]12
Reactant: CCC(I)CCCN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: Nc1cccc2cccnc12
Solvent: CC(C)O
Product: O=C1NC(=O)c2ccccc21

Procedure:
A solution of 8-amino-6-methoxy-4-methyl-5-(3-trifluoromethylphenoxy)-quinoline (10 g, 29 mmol), prepared as in Example 1, 4-iodo-1-phthalimidohexane (IPH, 10 g, 28 mmol), triethylamine (TEA, 4.5 mL) and 2-ethoxyethanol (10 mL) were heated at 115° for 21/2 hours. One equivalent of IPA and TEA was added and the solution was heated at 115° an additional 2.5 hours. Then one-half equivalent each of IPH and TEA was added and the reaction mixture was heated 5 hours longer. The reaction mixture was diluted with chloroform and washed with water (×3). The organic layer was dried (K2CO3) and concentrated to dryness in vacuo. The oily residue was combined with that obtained from another 8.5 g run and chromatographed over a silica gel column (EM Labs.). Elution with CHCl3 and collection of the fast-moving yellow band afforded the desired phthalimide intermediate (ca. 12 g) contaminated with some IPH. The slower moving material, ca. a 1/1 mixture of product and starting 8-aminoquinoline, was then collected and recycled with IPH and TEA as described above. An additional 7 g of crude product was obtained. The crude material from both runs was combined, dissolved in hot isopropyl alcohol and acidified with 2.7 N HCl-i-PrOH. Pure phthalimide hydrochloride was obtained, 13.2 g (40%), mp 185°-7°.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:6](=[S:7])[C:5]2[CH:8]=[CH:9][CH:10]=[C:11]([N+:12]([O-])=O)[C:4]=2[O:3]1>C(O)(=O)C.O.[Fe]>[NH2:12][C:11]1[C:4]2[O:3][C:2]([CH3:1])([CH3:15])[C:6](=[S:7])[C:5]=2[CH:8]=[CH:9][CH:10]=1
Reactant: CC1(C)Oc2c(cccc2[N+](=O)[O-])C1=S
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: CC1(C)Oc2c(N)cccc2C1=S

Procedure:
By the method of Example 1, Step E, 3.35 g (0.015 mole) of 2,3-dihydro-2,2-dimethyl-7-nitrobenzofuran-3-thione is reacted with 3.35 g (0.060 mole) of powdered iron in 50 mL of glacial acetic acid and 8 mL of water, yielding 7-amino-2,3-dihydro-2,2-dimethylbenzofuran-3-thione.