Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8](Br)[CH:7]=[CH:6]2.[O:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH:16]=[C:15]1B(O)O.C(=O)([O-])[O-].[K+].[K+].ClCCl>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:15]1[O:14][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH:16]=1)[CH:7]=[CH:6]2
Reactant: OB(O)c1cc2ccccc2o1
Reactant: COc1ccc2cc(Br)ccc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc2cc(-c3cc4ccccc4o3)ccc2c1
Temperature: 70.5 °C
Yield: 81.4 %

Procedure:
A mixture of 6-methoxy-2-bromonaphthalene (10.1 g, 42.6 mmol), 2-benzofuranboronic acid (8.28 g, 51.1 mmol), potassium carbonate (11.7 g, 84.8 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (0.887g, 1.09 mmol) in dioxane (420 mL) and water (42 mL) was heated to 69-72° C. for 2 hours. It was allowed to cool to room temperature and solvent evaporated. The residue was paroom temperatureitioned, with heating (because the product is very insoluble) in chloroform/2N hydrochloric acid. The organic phase was washed with water and brine. It was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography using 15-75% chloroform in hexane and 100% chloroform as eluants. It was dried for 30 minutes at 60° C. to afford 2-(6-methoxy-2-naphthyl)-1-benzofuran as a light yellow-brown solid (9.51 g, 81%): mp 194-195° C.; mass spectrum (+EI, M+) m/z 274. 1HNMR (400 MHz, DMSO-d6): δ8.4 (s, 1H), 7.9-8.0 (m, 3H), 7.65-7.7 (m, 2H), 7.5 (s, 1H), 7.35 (d, 1H, J=2.5 Hz), 7.2-7.35 (m, 3H), and 3.9 ppm (s, 3H). Elemental Analysis for C19H14O2: Calculated: C, 83.19; H, 5.14; N, 0.00; Found: C, 82.96; H, 4.98; N, 0.01;
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[O:11][C:7]1([CH2:10][CH2:9][CH2:8]1)[CH2:6][CH2:5]2.C([Li])CCC.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:27]([C:30]2([OH:69])[C@H:35]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C@@H:34]([O:44][CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C@H:33]([O:52][CH2:53][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[C@@H:32]([CH2:60][O:61][CH2:62][C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)[O:31]2)=[CH:26][C:23]=1[CH:24]=[O:25]>C1COCC1.C1(C)C=CC=CC=1>[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:27]([C:30]2([OH:69])[C@H:35]([O:36][CH2:37][C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[C@@H:34]([O:44][CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C@H:33]([O:52][CH2:53][C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=3)[C@@H:32]([CH2:60][O:61][CH2:62][C:63]3[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=3)[O:31]2)=[CH:26][C:23]=1[C:24]([C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[O:11][C:7]1([CH2:10][CH2:9][CH2:8]1)[CH2:6][CH2:5]2)=[O:25]
Reactant: Brc1ccc2c(c1)CCC1(CCC1)O2
Reactant: COc1ccc(C2(O)O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1C=O
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(C2(O)O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1C(=O)c1ccc2c(c1)CCC1(CCC1)O2
Reaction time: 1 h
Yield: 65.6 %

Procedure:
To a stirred solution of 6-bromospiro[chromane-2,1′-cyclobutane] (0.563 g, 2.23 mmol) in THF (3 mL) at −78° C. was added n-butyl lithium (1.45 mL, 2.23 mmol) and stirred for 1 h. Compound obtained in step III (0.3 g, 0.45 mmol) in toluene (3 mL) was cooled to −78° C. and Ithium salt prepared above was added to this at −78° C. This reaction mixture was stirred for 1 h, quenched with sat. NH4Cl (10 mL) and extracted with ethyl acetate (2×20 mL). The ethyl acetate layer was washed with water, brine, dried over sodium sulphate, concentrated and purified by silica gel column chromatography to furnish [2-methoxy-5-[(3R,4S,5R,6R)-3,4,5-tribenzyloxy-6-(benzyloxymethyl)-2-hydroxytetrahydropyran-2-yl]phenyl]-spiro[chromane-2,1′-cyclobutane]-6-yl-methanone (0.250 g).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)=[C:12]2[CH2:17][C:16]([CH3:19])([CH3:18])[CH2:15][C:14]([CH3:21])([CH3:20])[CH2:13]2)=[CH:7][CH:6]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].CCOC(C)=O.Cl>C1COCC1>[OH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[C:12]2[CH2:13][C:14]([CH3:21])([CH3:20])[CH2:15][C:16]([CH3:19])([CH3:18])[CH2:17]2)[C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)Cc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(O)cc2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(CCO)cc2)CC(C)(C)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
To a solution of methyl {4-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}acetate (153) (0.22 g, 0.56 mmol) in THF (10 mL) at 0° C. was added LAH (1 M in THF, 1.40 mL, 1.40 mmol) dropwise. The reaction mixture was stirred at 0° C. for 1 h, EtOAc (5 mL) was added, and stirring continued for 10 min. The mixture was then acidified to pH=2 with an aqueous solution of 1 N HCl, extracted with EtOAc (2×50 mL). The combined organic extract washed with water, brine and dried (Na2SO4) filtered, and the filtrate was concentrated to give the crude product as colorless oil. The crude product was purified by flash chromatography on silica gel eluted with a gradient from hexanes to 40% EtOAc:hexanes to give a white residue, which upon trituration with hot hexanes containing 1% of MeOH yielded 0.185 g (91%) of the title compound 232 as a white solid. mp 159-160° C. 1H NMR (400 MHz, DMSO-d6): δ 0.87 (s, 12H), 1.23 (s, 2H), 1.87 (s, 2H), 1.89 (s, 2H), 2.65 (t, J=7.1 Hz, 2H), 3.50-3.60 (m, 2H), 4.58 (t, J=5.2 Hz, 1H), 6.64 (d, J=8.2 Hz, 2H), 6.90 (d, J=8.4 Hz, 2H), 7.00 (d, J=7.9 Hz, 2H), 7.10 (d, J=8.1 Hz, 2H), 9.22 (s, 1H). LCMS (ES): m/z 365 (M+H)+, 363 (M−H)−.
Reaction SMILES: [C:1]1([CH:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:16](=[O:23])C[CH2:18][CH2:19][C:20]=53)=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.[CH2:31]([Cl:33])[Cl:32]>C(OCC)(=O)C.C(#N)C>[Cl:32][C:31]1([Cl:33])[C:16](=[O:23])[C:15]2[C:14]3[C:22]4=[C:10]([O:9][CH2:8][CH:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[N:21]4[C:20]=2[CH2:19][CH2:18]1)[CH:11]=[CH:12][CH:13]=3
Reactant: O=C1CCCc2c1c1cccc3c1n2C(c1ccccc1)CO3
Reactant: ClCCl
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: O=C1c2c(n3c4c(cccc24)OCC3c2ccccc2)CCC1(Cl)Cl
Temperature: 95 °C
Reaction time: 5 h
Yield: 61 %

Procedure:
To a mixture of 1-phenyl-1,2,9,10-tetrahydro[1,4]oxazino[2,3,4-jk]carbazol-7(8H)-one (0.5681 g, 1.87 mmol) in ethyl acetate (10 mL) and acetonitrile (10 mL) is added trifluoroacetic acid (2 mL). Anhydrous cupric chloride (1.26 g, 9.36 mmol) is added and the mixture is heated to reflux at 95° C. for 2 h. After 5 h, additional anhydrous cupric chloride (0.63 g, 4.68 mmol) is added and the mixture is refluxed an additional hour. The mixture is then poured into CH2Cl2 (150 mL) and filtered. The filtrates are washed with aqueous potassium carbonate. The layers are separated and the organic layer is washed twice with water (200 mL), dried over magnesium sulfate and concentrated. Column chromatography (70 g silica gel) using ethyl acetate/CH2Cl2/hexane (5:45:50) gave 0.428 g (61%) of 8,8-dichloro-1-phenyl-1,2,9,10-tetrahydro[1,4]oxazino[2,3,4-jk]carbazol-7(8H)-one.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15].[N:16]1([C:22]2[N:23]=[C:24]3[NH:32][C@H:31]([C:33]([F:36])([F:35])[F:34])[CH2:30][CH2:29][N:25]3[C:26](=[O:28])[CH:27]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.O>CN(C)C=O>[Cl:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][N:32]1[C:24]2=[N:23][C:22]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:27][C:26](=[O:28])[N:25]2[CH2:29][CH2:30][C@H:31]1[C:33]([F:34])([F:35])[F:36]
Reactant: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2
Reactant: Clc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2Cc1ccccc1Cl
Reaction time: 16 h

Procedure:
214 mg of caesium carbonate and 74 mg of 1-(bromomethyl)-2-chlorobenzene are added to a solution of 100 mg of (8S)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one (Example 1e) in 2 ml of dimethylformamide. After 16 hours at a temperature in the region of 20° C., the reaction medium is run into water. The organic phase is separated and the aqueous phase is extracted with ethyl acetate. The combined organic phases are concentrated to dryness under reduced pressure. The residue is purified by preparative HPLC/MS (Method C). After evaporation of the acetonitrile and lyophilization, 94 mg of (8S)-9-(2-chloro-benzyl)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are obtained in the form of an oil, the characteristics of which are the following:
Reaction SMILES: ClCCl.[C:4]([O:8][C:9]([N:11]([CH2:35][C:36]1[CH:45]=[CH:44][C:39]2[O:40][CH2:41][CH2:42][O:43][C:38]=2[CH:37]=1)[CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][N:20]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([C:30]([OH:32])=O)[CH:28]=3)[C:23]([CH3:33])=[CH:22][C:21]2=[O:34])[CH2:14][CH2:13]1)=[O:10])([CH3:7])([CH3:6])[CH3:5].Cl.CN.F[P-](F)(F)(F)(F)F.[N:56]1(OC(N(C)C)=[N+](C)C)[C:60]2N=CC=CC=2N=N1>C(OCC)(=O)C.O.C(N(CC)CC)C>[C:4]([O:8][C:9](=[O:10])[N:11]([CH2:35][C:36]1[CH:45]=[CH:44][C:39]2[O:40][CH2:41][CH2:42][O:43][C:38]=2[CH:37]=1)[CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][N:20]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([C:30]([NH:56][CH3:60])=[O:32])[CH:28]=3)[C:23]([CH3:33])=[CH:22][C:21]2=[O:34])[CH2:14][CH2:13]1)([CH3:5])([CH3:6])[CH3:7]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1cc(=O)n(CCN2CCC(N(Cc3ccc4c(c3)OCCO4)C(=O)OC(C)(C)C)CC2)c2cc(C(=O)O)ccc12
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccc2c(C)cc(=O)n(CCN3CCC(N(Cc4ccc5c(c4)OCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Reaction time: 0.5 h
Yield: 56.7 %

Procedure:
To 1.7 mL of dichloromethane solution containing 0.10 g of 1-(2-(4-((tert-butoxycarbonyl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-4-methyl-2-oxo-1,2-dihydroquinoline-7-carboxylic acid, 13 mg of methylamine hydrochloride, 0.12 g of O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate and 89 μL of triethylamine were added at room temperature, stirred for 30 min, and allowed to stand for 12 hours. Further, 13 mg of methylamine hydrochloride, 0.12 g of O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, and 89 μL of triethylamine were added. Water and ethyl acetate were added, the insoluble material was filtered off, the organic layer was separated, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by basic silica gel column chromatography [eluent; chloroform:water=100:1], to give 58 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(4-methyl-7-((methylamino)carbonyl)-2-oxo-1,2-dihydroquinolin-1-yl)ethyl)piperidin-4-yl)carbamate as a brown oil.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.[Br:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25]([C:30]([OH:32])=[O:31])=[CH:24]2>C(#N)C>[Br:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25]([C:30]([O:32][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:31])=[CH:24]2
Reactant: O=C(O)c1cc2cc(Br)ccc2[nH]1
Reactant: BrCc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(OCc1ccccc1)c1cc2cc(Br)ccc2[nH]1
Reaction time: 22.5 h

Procedure:
Benzyl bromide (160 μl) and 1,8-diazabicyclo[5.4.0]undec-7-ene (201 μl) were added to a solution of 5-bromo-1H-indole-2-carboxylic acid (161 mg) in acetonitrile (3.5 ml) at room temperature, followed by stirring for 22.5 hours. The reaction solution was concentrated and separated by adding ethyl acetate and distilled water. The resulting organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting residue was solidified from dichloromethane-hexane, collected by filtration and washed with hexane. This was dried under reduced pressure to give the title compound (189 mg).
Reaction SMILES: CCCCCC.[H-].[Na+].[NH:9]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[C:24]([C:26]1[CH:27]=[C:28]([CH:33]=[CH:34][C:35]=1[CH2:36]Br)[C:29]([O:31][CH3:32])=[O:30])#[N:25]>CCOC(C)=O.CN(C=O)C>[C:24]([C:26]1[CH:27]=[C:28]([CH:33]=[CH:34][C:35]=1[CH2:36][N:9]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:29]([O:31][CH3:32])=[O:30])#[N:25]
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(CBr)c(C#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(C#N)c1
Reaction time: 3.5 h

Procedure:
To a mixture of hexane washed 60% disp. NaH (40 mg, 1 mmol) and DMF (8 mL) was added HN(BOC)2 (203 mg, 0.93 mmol) and stirred for 30 m. The reaction was added methyl 3-cyano-4-(bromomethyl)benzoate (202 mg, 0.80 mmol). After 3.5 h, the reaction was diluted with EtOAc (40 mL) and washed with H2O (6×5 mL). The organic layer was MgSO4 dried and concentrated. The crude material was chromatographed (30 g silica, 10% EtOAc/hexanes) to give the title compound (quant.). IR(CHCl3): 1125, 1370, 1723, 1791, 3020 cm−1; NMR(300 MHz, CDCl3): 1.46 (s, 18H); 3.96 (s, 3H); 5.08 (s, 2H); 7.42 (d, 1H, J=8.4 Hz); 8.23 (d, 1H, J=8.4 Hz); 8.32 (s, 1H); MS(FD): 391.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:10][C:6]=2[C:5](=[O:16])[N:4]([CH3:17])[N:3]=1.[H-].[Na+].Cl[CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26]>CN(C)C=O>[Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:6]=2[C:5](=[O:16])[N:4]([CH3:17])[N:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCOC(=O)c1cc2c(Cl)nn(C)c(=O)c2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(Cl)nn(C)c(=O)c2n1COCC[Si](C)(C)C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
A solution of Example 74d (0.41 g, 1.6 mmol) in dimethylformamide (15 mL) was treated with 60% sodium hydride (0.096 g, 2.4 mmol) at room temperature. The reaction mixture was stirred for 30 min, and then was treated with (2-(chloromethoxy)ethyl)trimethylsilane (0.40 g, 2.4 mmol). The reaction mixture was then stirred for 2 hours. It was partitioned between ethyl acetate and water. The aqueous layer was extracted with additional ethyl acetate twice. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel, eluting with 20% ethyl acetate to afford 0.50 g (81%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:12])[CH:8]=2)[N:3]=1.[Br:13]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]2
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2nc(C)ccc2c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1ccc2cc(CBr)ccc2n1
Yield: 27.4 %

Procedure:
In carbon tetrachloride (26 ml), 2,6-dimethylquinoline (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (1.0398 g), N-bromosuccinimide (1.2353 g), and azobisisobutyronitrile (98.5 mg) were dissolved and then the whole was subjected to thermal reflux for 2 hours under an argon atmosphere. After the reaction, a precipitate was removed through filtration and then washed with water, followed by drying with magnesium sulfate. The solvent was distilled off and the residue was then purified through silica gel column chromatography (hexane/ethyl acetate), thereby obtaining the subject compound (427.3 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][C:19]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[CH2:6][C:7](=[CH:10][N:11]1[CH2:16][CH2:15]OCC1)[C:8]#[N:9].Cl.N[C:32]1[CH:37]=CC=[CH:34][CH:33]=1.O>C(O)(C)C>[NH:11]([CH:10]=[C:7]([CH2:6][C:5]1[CH:17]=[CH:18][C:19]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)=[C:3]([O:2][CH3:1])[CH:4]=1)[C:8]#[N:9])[C:16]1[CH:34]=[CH:33][CH:32]=[CH:37][CH:15]=1
Reactant: Nc1ccccc1
Reactant: COc1ccc(COc2ccc(CC(C#N)=CN3CCOCC3)cc2OC)cc1
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: COc1ccc(COc2ccc(CC(C#N)=CNc3ccccc3)cc2OC)cc1
Yield: 71.4 %

Procedure:
To a homogeneous solution of 2-{3-methoxy-4-[(4-methoxybenzyl)oxy]benzyl}-3-morpholin-4-ylprop-2-enenitrile (14.5 g, 36.7 mmol) in isopropanol (050 mL) was added aniline hydrochloride (4.9 g, 37.5 mmol), and the mixture was stirred at reflux for 20 minutes, combined with 20 mL of water and cooled in an ice bath for 30 minutes. The resulting precipitate was filtered off, washed with water and air dried to give 13.7 g of crude product. This material was recrystalized from methanol/ethanol to afford pure product as a crystalline tan solid (10.5 g, 26.2 mmol). 1H NMR (300 MHz, d6-DMSO): δ 9.03 (d, J=12.8 Hz, 1H), 7.59 (d, J=12.8 Hz, 1H), 7.30 (d, J=8.6 Hz, 2H), 7.20 (d, J=7.4 Hz, 2H), 7.16 (m,2H), 6.93 (d, J=8.2 Hz, 1H), 6.88 (d, J=8.4, 1H), 6.86 (m, 1H), 6.83 (s, 1H), 4.90 (s, 2H), 3.69 (s, 3H), 3.68 (s, 3H), 3.50 (s, 2H), 3.28 (s, 2H). MS (ES-, m/z)=399 (M−H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:34]=[CH:33][C:6]([O:7][C:8]2[CH:32]=[CH:31][C:11]([CH2:12][NH:13][C:14]([C:16]3([NH:19][C:20]([C:22]4[CH:23]=[N:24][C:25]([S:28]([CH3:30])=[O:29])=[N:26][CH:27]=4)=[O:21])[CH2:18][CH2:17]3)=[O:15])=[CH:10][CH:9]=2)=[C:5]([C:35]([F:38])([F:37])[F:36])[CH:4]=1.ClC1C=CC=C(C(OO)=[O:47])C=1>>[CH3:1][O:2][C:3]1[CH:34]=[CH:33][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([CH2:12][NH:13][C:14]([C:16]3([NH:19][C:20]([C:22]4[CH:23]=[N:24][C:25]([S:28]([CH3:30])(=[O:47])=[O:29])=[N:26][CH:27]=4)=[O:21])[CH2:17][CH2:18]3)=[O:15])=[CH:31][CH:32]=2)=[C:5]([C:35]([F:36])([F:38])[F:37])[CH:4]=1
Reactant: COc1ccc(Oc2ccc(CNC(=O)C3(NC(=O)c4cnc(S(C)=O)nc4)CC3)cc2)c(C(F)(F)F)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: COc1ccc(Oc2ccc(CNC(=O)C3(NC(=O)c4cnc(S(C)(=O)=O)nc4)CC3)cc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Half the crude product mixture from Example 148 was combined with a further 186 mg 3-chloroperbenzoic acid and stirred for two hours at ambient temperature. After the solution had been evaporated down the crude product thus obtained was purified by chromatography (reversed phase HPLC).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7](=[O:14])[C:6]2=[CH:15]O.[O:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7](=[O:14])[C:6]2=[CH:15][N:27]1[CH2:28][CH2:29][N:24]([C:22]([C:18]2[O:17][CH:21]=[CH:20][CH:19]=2)=[O:23])[CH2:25][CH2:26]1
Reactant: O=C(c1ccco1)N1CCNCC1
Reactant: COc1cc2c(cc1OC)C(=CO)C(=O)N2
Product: COc1cc2c(cc1OC)C(=CN1CCN(C(=O)c3ccco3)CC1)C(=O)N2

Procedure:
3.0 g. of 5,6-Dimethoxy-3-hydroxymethylene oxindole was reacted with 4.0 g. N-furoyl piperazine as described in Example 2 except that 0.10 g. toluene sulfone acid was added as a catalyst. Yield 3.46 g. of product, m.p. 158°-160° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[Cl:18])[C:5]([C:7](=[C:10]([S:13][CH3:14])[S:11][CH3:12])[C:8]#[N:9])=O.[C:19]([O:23][CH2:24][CH3:25])(=[O:22])CS>CCO>[C:8]([C:7]1[C:5]([C:4]2[CH:15]=[CH:16][C:17]([Cl:18])=[C:2]([Cl:1])[CH:3]=2)=[C:12]([C:19]([O:23][CH2:24][CH3:25])=[O:22])[S:11][C:10]=1[S:13][CH3:14])#[N:9]
Reactant: CCOC(=O)CS
Reactant: CSC(SC)=C(C#N)C(=O)c1ccc(Cl)c(Cl)c1
Solvent: CCO
Product: CCOC(=O)c1sc(SC)c(C#N)c1-c1ccc(Cl)c(Cl)c1
Reaction time: 8 h
Yield: 89.3 %

Procedure:
To a stirred suspension of 2-(3,4-dichlorobenzoyl)-3,3-bis(methylsulfanyl)acrylonitrile (2.28 g, 7.16 mmol) in EtOH (31 mL) was added ethyl thioglycolate (0.864 mL, 7.88 mmol) and TEA (1.1 mL, 7.88 mmol). The reaction mixture was heated until reflux was achieved and was then allowed to cool. A solid formed. After sitting at rt overnight, the solid was filtered and washed with cold EtOH (100 mL) to give ethyl 4-cyano-3-(3,4-dichlorophenyl)-5-(methylsulfanyl)thiophene-2-carboxylate (2.38 g, 89%). 1H NMR (400 MHz, d6-DMSO) δ: 7.82 (d, 1H), 7.75 (d, 1H), 7.47 (dd, 1H), 4.14 (q, 2H), 2.82 (s, 3H) and 1.11 (t, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[C:11](Cl)(Cl)=[S:12]>C1C=CC=CC=1>[N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[N:6]=[C:11]=[S:12])([O-:3])=[O:2]
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: S=C(Cl)Cl
Solvent: c1ccccc1
Product: O=[N+]([O-])c1ccccc1N=C=S

Procedure:
To 200 ml of benzene were added 22 g of 2-nitroaniline and 6.6 ml of thiophosgene. The mixture was refluxed for 2 hours. After cooling, the resulting crystals were removed by filtration and the filtrate was concentrated. The resulting residue was purified by a silica gel column chromatography (eluant: ethyl acetate/n-hexane=0/1→1/10) to obtain 8.0 g of 2-nitrophenyl isothiocyanate.
Reaction SMILES: [Br-].[CH3:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:5][CH:4]=1.[H-].[Na+].[CH3:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1.O>C1(C)C=CC=CC=1>[CH3:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=[CH:7][C:6]2[CH:5]=[CH:4][C:3]([CH3:2])=[CH:28][CH:27]=2)=[CH:34][CH:33]=1
Reactant: Cc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1ccc(C=O)cc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(C=Cc2ccc(C)cc2)cc1
Yield: 71 %

Procedure:
2.4 g(5.37 mmol) of (4-methylbenzyl)triphenylphosphonium bromide and 0.98 g(60%, 24.4 mmol) of NaH were refluxed in toluene for 6 hours. After cooled down, 0.586 g(4.88 mmol) of 4-methylbenzaldehyde was introduced gradually to the solution to be refluxed again for 6 hours. The resulted product was treated with water to be extracted with ethyl acetate. The solvent was distilled off and the residue was recrystallized in ethanol. Yield; 71%.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]1[CH2:13][NH:12][C:11](=[O:14])[N:10]2[C:15]3[N:21]=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=[C:9]12.Cl[C:23](Cl)([O:25]C(=O)OC(Cl)(Cl)Cl)Cl.NCC(C1NC2C(C=1)=C(OC)C=CN=2)OC1CCCCO1.CCN(C(C)C)C(C)C>C(Cl)Cl>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]1[CH2:13][NH:12][C:11](=[O:14])[N:10]2[C:15]3[N:21]=[CH:20][CH:19]=[C:18]([O:25][CH3:23])[C:16]=3[CH:17]=[C:9]12
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: O=C1NCC(OC2CCCCO2)c2cc3cccnc3n21
Agent: COc1ccnc2[nH]c(C(CN)OC3CCCCO3)cc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccnc2c1cc1n2C(=O)NCC1OC1CCCCO1
Yield: 63 %

Procedure:
Following the same procedure as for 10a, from triphosgene (20 mg, 0.07 mmol) in CH2Cl2 (3 ml), 9b (58 mg, 0.20 mmol) and DIPEA (34 μl, 0.20 mmol) in CH2Cl2 (3 ml). Reaction time 30 min. at room temperature. The crude mixture was purified by flash column chromatography. Elution with CH2Cl2/MeOH (98/2) gave a diastereomeric mixture (1:1) of 10b (40 g, 63%).