Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[CH3:23][O:24][CH2:25][CH2:26][O:27][C:28]1[CH:29]=[C:30]([NH:38][C:39](=O)[O:40]C2C=CC=CC=2)[CH:31]=[CH:32][C:33]=1[C:34]([F:37])([F:36])[F:35]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([NH:19][C:39]([NH:38][C:30]2[CH:31]=[CH:32][C:33]([C:34]([F:36])([F:37])[F:35])=[C:28]([O:27][CH2:26][CH2:25][O:24][CH3:23])[CH:29]=2)=[O:40])[CH:20]=[CH:21][CH:22]=1
Reactant: COCCOc1cc(NC(=O)Oc2ccccc2)ccc1C(F)(F)F
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Product: COCCOc1cc(NC(=O)Nc2cccc(Sc3ncnc4cc(OC)c(OC)cc34)c2)ccc1C(F)(F)F
Temperature: 50 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
The title compound was prepared according to the procedure described in Example 147B by using 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from Example 115B (95 mg, 0.3 mmol) and phenyl 3-(2-methoxyethoxy)-4-(trifluoromethyl)phenylcarbamate described in Example 147A (161 mg, 0.45 mmol). The reaction was stirred at 50° C. overnight. After removal of the solvent, dichloromethane was added and the precipitating solid filtered off, washed with DCM and dried to give 1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(3-(2-methoxyethoxy)-4-(trifluoromethyl)phenyl)urea (78 mg, 45%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 9.15 (s, 1H), 9.03 (s, 1H), 8.70 (s, 1H), 7.86 (s, 1H), 7.55-7.42 (m, 4H), 7.35 (d, 2H), 7.28 (d, 1H), 7.05 (d, 1H), 4.18-4.15 (m, 2H), 4.00 (s, 6H), 3.69-3.68 (m, 2H), 3.31 (s, 3H); LC-MS (ESI) m/z 575 (M+H)+.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][C:4]=1[O:11][CH3:12].C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[C:25](Cl)(=[O:34])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>O>[CH3:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][C:25]([NH:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([OH:2])=[C:4]([O:11][CH3:12])[CH:5]=1)=[O:34]
Reactant: COc1cc(CN)ccc1O
Reactant: CCCCCCCCC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: O
Product: CCCCCCCCC(=O)NCc1ccc(O)c(OC)c1
Reaction time: 0.5 h

Procedure:
58.5 parts of 4-hydroxy-3-methoxybenzylamine hydrochloride, 200 parts of benzene and 200 parts of water were charged into a reaction vessel equipped with a three-one motor the rotational frequency of which is variable and an outlet having a stopper at the bottom portion and stirred. 58 parts of potassium carbonate was added to the mixture and further 54 parts of pelargonoyl chloride was added dropwise to the resultant mixture at room temperature. In this state, the mixture was stirred for 3 hours until the end of the reaction. After the stirring was stopped and the mixture was allowed to stand for 30 minutes, the water layer in the lower layer was discharged from the bottom portion. The residue was distilled under a reduced pressure to remove the solvent almost completely, thereby obtaining crude nonylic acid vanillylamide. As a result of quantitative analysis of a slight amount of product by high pressure liquid chromatography (hereinunder referred to as "HPLC"), the purity of nonylic acid vanillylamide was determined to be 91.7%. The irritant nature thereof to skin, especially, to mucosae was strong.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH3:9])=[C:4]([O:10][CH3:11])[N:3]=1.[N:12]([S:15]([C:18]1[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21])(=[O:17])=[O:16])=[C:13]=[O:14]>C(#N)C>[Cl:8][C:6]1[C:5]([CH3:9])=[C:4]([O:10][CH3:11])[N:3]=[C:2]([NH:1][C:13]([NH:12][S:15]([C:18]2[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=2[C:20]([O:22][CH3:23])=[O:21])(=[O:17])=[O:16])=[O:14])[N:7]=1
Reactant: COc1nc(N)nc(Cl)c1C
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Solvent: CC#N
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(Cl)c(C)c(OC)n1
Reaction time: 3 h

Procedure:
To 1.0 g of 2-amino-4-chloro-6-methoxy-5-methylpyrimidine in 35 ml of anhydrous acetonitrile, with stirring at ambient temperature, was added 1.5 g of methyl 2-(isocyanatosulfonyl)benzoate. The mixture was stirred for 3 hours, heated to 50° and allowed to cool. The solid precipitate thus obtained was filtered off and washed with 1-chlorobutane. It melted at 204°-205° and showed infrared absorption peaks at 1740, 1710, 1650 and 1510 cm-1, consistent for the above-named product.
Reaction SMILES: [ClH:1].C([N:5]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:6][CH2:7][SH:8])(=O)C>C(O)(=O)C>[ClH:1].[SH:8][CH2:7][CH2:6][NH:5][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)N(CCS)CCc1ccccc1
Agent: Cl
Solvent: CC(=O)O
Product: SCCNCCc1ccccc1
Yield: 50 %

Procedure:
Concentrated hydrochloric acid (5 ml) is added to a solution of N-acetyl-N-(2-mercaptoethyl)phenethylamine (500 mg) in acetic acid (5 ml) under a nitrogen atmosphere, and the mixture is refluxed for 24 hours. The reaction mixture is concentrated under reduced pressure, and then a 10% aqueous sodium carbonate solution is added to the concentrate. Weak basicity of the liquid is confirmed, and the whole is extracted with ethyl acetate. The organic layer is washed with saturated brine and dried over anhydrous sodium sulfate. A 4 N solution of hydrogen chloride in ethyl acetate is added to the organic layer, and the mixture is concentrated under reduced pressure. Ether is added to the concentrate, and the resulting precipitate is filtered off to give 244 mg (50%) of the titled compound (Reference compound No. 17-1) as crystals.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:17])[C:12](=[O:15])[NH:13][N:14]=2)=[CH:5][CH:4]=1)#[N:2].[CH2:26](Cl)Cl.CO>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[C:11]([C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:17])[C:12](=[O:15])[N:13]([CH3:26])[N:14]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: ClCCl
Reactant: N#Cc1ccc(-c2cc(C(=O)NCCCCC(=O)O)c(=O)[nH]n2)cc1
Solvent: CO
Product: Cn1nc(-c2ccc(C#N)cc2)cc(C(=O)NCCCCC(=O)O)c1=O

Procedure:
6-(4-cyanophenyl)-4-[(4-carboxybutyl )-aminocarbonyl]-(2H)-pyridazin-3-one Rf value: 0.30 (silica gel; methylene chloride/methanol=9:1)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[CH2:9][CH:10]=[O:11])=[CH:4][CH:3]=1.[F:14][C:15](C[SiH](C1C=CC=CC=1)C1C=CC=CC=1)=[CH2:16].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[F:14][C:15]([CH:10]([OH:11])[CH2:9][C:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)([CH3:13])[CH3:12])=[CH2:16]
Reactant: CC(C)(CC=O)c1ccc(F)cc1
Reactant: C=C(F)C[SiH](c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=C(F)C(O)CC(C)(C)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-(4-fluorophenyl)-3-methylbutyraldehyde (1.2 g, 6.6 mmol) and (1-fluorovinyl)methyldiphenylsilane in 5 mL of THF cooled on ice under nitrogen gas was added 1 mL of TBAF (1 M in THF). The mixture was allowed to warm to room temperature and left overnight. The solvent was evaporated and the residue was taken up in hexanes. The hexane soluble material was fractionated over silica gel (eluent: hexanes to hexanes-ethyl acetate (98:2)) to give a fraction (3.1 g) containing silylated product along with other silanes. This fraction was dissolved in 5 mL of THF and 10 mL of TBAF solution (1 M in THF) was added. The mixture was left at room temperature for 20 minutes, diluted with hexanes-ethyl acetate, and washed with water, dried, filtered, and concentrated in vacuo. Fractionation of the residue over silica gel (eluent: hexanes-ethyl acetate (99:1 to 9:1 gradient)) gave 1.73 g of the crude 2-fluoro-5-(4-fluorophenyl)-5-methylhex-1-en-3-ol as an oil which was used without additional purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([N:9]2[CH:14]([C:15]([O:17]CC)=[O:16])[CH:13]3[CH2:20][CH:10]2[CH2:11][CH2:12]3)=[O:8])=[CH:5][CH:4]=1.CO.[OH-].[Na+].Cl>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:9]2[CH:14]([C:15]([OH:17])=[O:16])[CH:13]3[CH2:20][CH:10]2[CH2:11][CH2:12]3)=[O:8])=[CH:21][CH:22]=1
Reactant: CCOC(=O)C1C2CCC(C2)N1C(=O)c1ccc(OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(C(=O)N2C3CCC(C3)C2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of ethyl 2-(4-methoxybenzoyl)-2-azabicyclo[2.2.1]heptane-3-carboxylate (239 mg, 0.787 mmol) in tetrahydrofuran (5 ml)-methanol (4 ml) was added 1N sodium hydroxide (5 ml), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated, to give 2-(4-methoxybenzoyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:14]2[NH:13][C:12](=[O:15])[N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH2:4][CH3:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>CN(C)C=O>[CH2:36]([O:35][C:33](=[O:34])[CH2:32][CH2:31][CH2:30][N:13]1[C:14]2[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:7][CH:8]=[CH:9][C:10]=2[N:11]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[C:12]1=[O:15])[CH3:37]
Reactant: CCOC(=O)CCCBr
Reactant: CCC(CC)c1cccc2c1[nH]c(=O)n2C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCn1c(=O)n(C(=O)OC(C)(C)C)c2cccc(C(CC)CC)c21
Temperature: 85 °C
Reaction time: 8 h
Yield: 135.2 %

Procedure:
To a solution of tert-butyl 4-(1-ethylpropyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxylate (Reference Example 7; 10.37 g, 34.11 mmol) in N,N-dimethylformamide (100 mL) was added potassium carbonate (5.18 g, 37.52 mmol) and ethyl 4-bromobutyrate (8.55 g, 37.52 mmol), and the mixture was stirred at 80-90° C. overnight. The reaction solution was concentrated to dryness and diluted with water (150 mL). The resulting mixture was extracted with ethyl acetate (100 mL×2). The combined extracts were washed with water (80 mL×2), brine (100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to give 19.3 g of crude tert-butyl 3-(4-ethoxy-4-oxobutyl)-4-(1-ethylpropyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxylate, which was used for the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([Cl:8])=[N:6][CH:7]=1.[NH3:13]>O1CCOCC1>[Br:1][C:2]1[C:3]([NH2:13])=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: N
Reactant: O=[N+]([O-])c1c(Cl)ncc(Br)c1Cl
Solvent: C1COCCO1
Product: Nc1c(Br)cnc(Cl)c1[N+](=O)[O-]
Temperature: 30 °C
Yield: 46 %

Procedure:
A 250 mL round bottom flask was charged with 5-bromo-2,4-dichloro-3-nitropyridine (3.5 g, 12.6 mmol) and a solution of ammonia in 1,4-dioxane (150 mL). The mixture was heated at 30° C. for 4 h. Work-up: the reaction mixture was concentrated in vacuo. The residue was poured into saturated aqueous NaHCO3 and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was further purified by flash column chromatography on silica gel with 20% EtOAc in petroleum ether, to afford 1.5 g (46%) of the product as a white solid. MS m/z: 252 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[C:4]([Cl:19])[N:3]=1>C(O)C.O.[Fe]>[NH2:8][C:7]1[C:2]([Cl:1])=[N:3][C:4]([Cl:19])=[CH:5][C:6]=1[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)nc(Cl)c1[N+](=O)[O-]
Agent: [Fe]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1cc(Cl)nc(Cl)c1N
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of tert-butyl (2,6-dichloro-3-nitropyridin-4-yl)carbamate (700 g, 2.27 mol) and iron (1272.7 g, 22.7 mol) in ethanol (5 L) and water (1 L) was stirred at room temperature for 10 h. The mixture was filtered, the filtrate was concentrated in vacuo, and the crude product was crystallized using EtOAc to give tert-butyl (3-amino-2,6-dichloropyridin-4-yl)carbamate. Preparative Example 2.3 4,6-dichloro-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH3:14])[O:13][CH2:12][CH2:11][O:10]2)=[CH:5][CH:4]=1)=[O:2].S([CH2:25][N+:26]#[C-:27])(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CO.O>[O:2]1[C:1]([C:3]2[CH:4]=[CH:5][C:6]([C:9]3([CH3:14])[O:10][CH2:11][CH2:12][O:13]3)=[CH:7][CH:8]=2)=[CH:27][N:26]=[CH:25]1
Reactant: CC1(c2ccc(C=O)cc2)OCCO1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC1(c2ccc(-c3cnco3)cc2)OCCO1
Yield: 37.4 %

Procedure:
To a stirred solution of 2-(4-formylphenyl)-2-methyl-1,3-dioxolane (1.58 g, 8.23 mmol) in methanol (10 ml) was added tosylmethyl isocyanide (2.0 g, 10.3 mmol), potassium carbonate (1.42 g, 10.3 mmol), and the mixture was heated at reflux temperature for 2 hours. The reaction mixture was diluted with water and the whole was extracted with CH2Cl2. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate-hexane (1:4) to give the title compound (711 mg, 37% yield).
Reaction SMILES: [Si:1]([O:8][C:9]([CH3:14])([CH3:13])[C@@H:10]([NH2:12])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl[CH2:16][CH2:17][C:18]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([OH:22])[CH2:19][CH:20]=[CH2:21].C([O-])([O-])=O.[K+].[K+]>CC#N>[Si:1]([O:8][C:9]([CH3:13])([CH3:14])[C@@H:10]([NH:12][CH2:16][CH2:17][C:18]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([OH:22])[CH2:19][CH:20]=[CH2:21])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C=CCC(O)(CCCl)c1ccccc1
Reactant: C[C@H](N)C(C)(C)O[Si](C)(C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCC(O)(CCN[C@@H](C)C(C)(C)O[Si](C)(C)C(C)(C)C)c1ccccc1
Yield: 3.3 %

Procedure:
A mixture of (S)-3-(tert-butyldimethylsilyloxy)-3-methylbutan-2-amine (6 g, 27.6 mmol), 1-chloro-3-phenylhex-5-en-3-ol (4.83 g, 23 mmol) and K2CO3 (15 g, 100 mmol) in CH3CN (100 mL) was stirred and heated to reflux overnight. The solid was filtered, and the filtrate was concentrated to give the crude product which was purified by column chromatography to afford 1-((S)-3-(tert-butyldimethylsilyloxy)-3-methylbutan-2-ylamino)-3-phenylhex-5-en-3-ol (300 mg, 3%). 1H NMR (CDCl3): 0.00 (s, 6H), 0.73 (s, 9H), 1.02 (s, 3H), 1.12 (d, 3H), 1.21 (s, 3H), 1.92 (m, 2H), 2.30 (m, 4H), 2.49 (m, 3H), 2.96 (m, 2H), 4.92 (m, 3H), 5.45 (m, 2H), 7.11 (m, 1H), 7.21 (m, 2H), 7.26 (m, 2H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:18]=[CH:17][C:16]2[S:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8](C(=O)CCl)[C:7]=2[CH:6]=1)=[O:4].[ClH:23]>C(O)(=O)C>[Cl:23][CH2:2][C:3]([C:5]1[CH:18]=[CH:17][C:16]2[S:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]=2[CH:6]=1)=[O:4]
Reactant: Cl
Reactant: O=C(CBr)c1ccc2c(c1)N(C(=O)CCl)c1ccccc1S2
Solvent: CC(=O)O
Product: O=C(CCl)c1ccc2c(c1)Nc1ccccc1S2
Yield: 82 %

Procedure:
2-bromo-1-[10-(chloroacetyl)-10H-phenothiazin-2-yl)ethanone (2.2 g; 5.55 mmol; prepared according to a protocol described in J. Heterocyclic. Chem.(1978), 15, 175, followed by a Friedel-Crafts reaction) is dissolved hot in a mixture of acetic acid (20 ml) and 20% HCl (5.5 ml) and the mixture obtained is heated under reflux for 30 minutes. The reaction mixture is allowed to cool down, the precipitate is filtered, the mixture rinsed with acetic acid (5 ml) and dried under Vacuum, the solid obtained is purified by crystallization from toluene in order to produce a brown product with a yield of 82%. Melting point: 190-191° C. (value in the literature: 197-198° C.).
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:4]=2[CH2:3]1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.[OH-].[Na+].Cl>C1C=CC=CC=1>[F:13][C:10]1[CH:11]=[CH:12][C:7]2[S:6][C:5]3[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:4]=3[CH2:3][CH:2]([N:23]3[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]3)[C:8]=2[CH:9]=1
Reactant: Cc1ccc2c(c1)CC(Cl)c1cc(F)ccc1S2
Reactant: CN1CCNCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: Cc1ccc2c(c1)CC(N1CCN(C)CC1)c1cc(F)ccc1S2

Procedure:
75 G. of 10-chloro-8-fluoro-10,11-dihydro-2-methyl-dibenzo[b,f]-thiepin are heated together with 150 ml. of N-methyl-piperazine at 130° for 10 minutes. Thereafter, the mixture is cooled to 40°, mixed with ice, benzene and aqueous sodium hydroxide solution and again mixed well. The benzene phase is acidified with 6N hydrochloric acid and maintained in an ice bath for 30 minutes. The precipitate is filtered, made alkaline with aqueous sodium hydroxide solution and taken up in benzene. The benzene phase is dried over sodium sulfate and evaporated, whereby 1-(8-fluoro-10,11-dihydro-2-methyl-dibenzo[b,f]-thiepin-10-yl)-4-methyl-piperazine is formed and is treated with maleic acid and the corresponding maleate is formed. The maleate has a melting point of 173°-174°.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[C:17]([O:18]C)=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:20])[N:3]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:20][C:13]1[C:12]([C:4]2[N:3]=[C:2]([Cl:1])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)=[C:17]([OH:18])[CH:16]=[CH:15][CH:14]=1
Reactant: COc1cccc(Cl)c1-c1nc(Cl)c2ccccc2n1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cccc(Cl)c1-c1nc(Cl)c2ccccc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.6 %

Procedure:
To a solution of 4-chloro-2-(2-chloro-6-methoxyphenyl)quinazoline (0.3 g, 0.98 mmol) in CH2Cl2 at −78° C. was added 5 equivalents of 1 M BBr3 solution (4.9 mL, 4.9 mmol) in CH2Cl2. The reaction was complete after 30 minutes After allowing it to warm to room temperature, the reaction mixture was quenched with aqueous NaHCO3 to pH 7, the layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organic extracts were dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 2:1 CH2Cl2:hexanes yielded 3-chloro-2-(4-chloroquinazolin-2-yl)phenol (0.17 g, 60%). LC/MS: m/z 291.1 (M+H)+ at 3.16 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA))
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[C:30]4[C:29]5[CH:28]=[C:27]([C:31]6[CH:32]=[N:33][C:34]7[C:39]([CH:40]=6)=[CH:38][CH:37]=[CH:36][CH:35]=7)[CH:26]=[CH:25][C:24]=5[N:23]=[CH:22][C:21]=4[C:20](=[O:41])[O:19][C:18]3=O)=[CH:13][C:12]=2[C:43]([F:46])([F:45])[F:44])[CH2:7][CH2:6]1)(=[O:4])[CH2:2][CH3:3].[CH3:47][NH2:48]>C1COCC1.C(Cl)Cl>[CH3:47][N:48]1[C:20](=[O:41])[C:21]2[CH:22]=[N:23][C:24]3[CH:25]=[CH:26][C:27]([C:31]4[CH:32]=[N:33][C:34]5[C:39]([CH:40]=4)=[CH:38][CH:37]=[CH:36][CH:35]=5)=[CH:28][C:29]=3[C:30]=2[N:17]([C:14]2[CH:15]=[CH:16][C:11]([N:8]3[CH2:7][CH2:6][N:5]([C:1](=[O:4])[CH2:2][CH3:3])[CH2:10][CH2:9]3)=[C:12]([C:43]([F:46])([F:44])[F:45])[CH:13]=2)[C:18]1=[O:19]
Reactant: CN
Reactant: CCC(=O)N1CCN(c2ccc(-n3c(=O)oc(=O)c4cnc5ccc(-c6cnc7ccccc7c6)cc5c43)cc2C(F)(F)F)CC1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCC(=O)N1CCN(c2ccc(-n3c(=O)n(C)c(=O)c4cnc5ccc(-c6cnc7ccccc7c6)cc5c43)cc2C(F)(F)F)CC1
Temperature: 40 °C
Reaction time: 2 h
Yield: 14.7 %

Procedure:
To a solution of compound 5.6 1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)-1H-[1,3]oxazino[5,4-c]quinoline-2,4-dione (20 mg, 0.032 mmol, 1 equiv.) in THF/CH2Cl2 (5 mL, 1:1) at room temperature was added MeNH2 (5 mg, 0.16 mmol, 5 equiv.). The resulting solution was heated to 40° C. and stirred for 2 h. Upon concentration, the mixture was purified via preparative LC-MS (CH3CN:H2O) to furnish the desired compound 5.7 3-methyl-1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)pyrimido[5,4-c]quinoline-2,4(1H,3H)-dione (3 mg). LC-MS (M+H): 639.49
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([CH3:17])=[N:7][O:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1)=[O:4].[CH3:18][C:19]([SH:22])([CH3:21])[CH3:20]>>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]2[O:8][N:7]=[C:6]([CH3:17])[C:5]=2[C:3](=[O:4])[CH2:2][S:22][C:19]([CH3:21])([CH3:20])[CH3:18])=[CH:11][CH:12]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(=O)CBr
Reactant: CC(C)(C)S
Product: Cc1noc(-c2ccc(Br)cc2)c1C(=O)CSC(C)(C)C

Procedure:
Prepared according to the procedure described in Example 3, Step 7, using 2-bromo-1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-ethanone and 2-methyl-propane-2-thiol.
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].C(N(CC)CC)C.[CH:12]1([N:22]=[C:23]=[S:24])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][CH2:13]1>C(Cl)Cl>[CH3:2][O:3][NH:4][C:23]([NH:22][CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][CH2:13]1)=[S:24]
Reactant: CON
Reactant: S=C=NC1CCCc2ccccc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CONC(=S)NC1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice-cold, stirred mixture of 0.02 mole of methoxyamine hydrochloride and methylene chloride is added 0.02 mole of triethylamine. The mixture is then allowed to warm to about 15° to 25° C. while a solution of 0.01 mole of 1,2,3,4-tetrahydro-1-naphthyl isothiocyanate in methylene chloride is added dropwise. The mixture is stirred overnight at room temperature and then filtered. The filtrate is washed with water, dried (sodium sulfate), and the solvent evaporated at reduced pressure to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=O)=[CH:5][CH:4]=1.[O:17]1[C:26]2[CH:25]=[C:24]([CH2:27][N:28]([CH:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[N:23]=[CH:22][C:21]=2[O:20][CH2:19][CH2:18]1.CO.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)(Cl)Cl>[O:17]1[C:26]2[CH:25]=[C:24]([CH2:27][N:28]([CH:36]3[CH2:41][CH2:40][N:39]([CH2:14][CH2:13][N:10]4[C:11]5[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=5)[CH:7]=[CH:8][C:9]4=[O:16])[CH2:38][CH2:37]3)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[N:23]=[CH:22][C:21]=2[O:20][CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCNCC1
Reactant: COc1ccc2ccc(=O)n(CC=O)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc2ccc(=O)n(CCN3CCC(N(Cc4cc5c(cn4)OCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
A solution of [7-(methyloxy)-2-oxo-1(2H)-quinolinyl]acetaldehyde (65 mg, 0.3 mmol) and 1,1-dimethylethyl (2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-4-piperidinylcarbamate (for a synthesis see WO2004/058144 Example 99(h)) (105 mg, 0.3 mmol) in chloroform (3 ml) and MeOH (3 ml) was stirred at rt for 1 h. The mixture was then treated with NaBH(OAc)3 (190.8 mg, 0.9 mmol), stirred at rt for 0.5 h. 1,1-dimethylethyl (2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-4-piperidinylcarbamate (52 mg, 0.15 mmol) and NaBH(OAc)3 (127 mg, 0.6 mmol) were added and the reaction stirred at rt for 1 hour. The solvents were then removed and the residue was subjected to column chromatography on silica gel eluting with 0-10% methanol-DCM to afford the desired compound (92 mg, 56%).