Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[CH:5]=[CH:4][C:3]=1[F:25].[CH3:26][NH2:27]>N1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15]([NH:27][CH3:26])[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[CH:5]=[CH:4][C:3]=1[F:25]
Reactant: CN
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)ccc1F
Solvent: c1ccncc1
Product: CNc1c(F)cc2c(=O)c(C(=O)O)cn(-c3ccc(F)c(N)n3)c2c1Cl
Temperature: 25 °C
Reaction time: 17 h
Yield: 103.2 %

Procedure:
1-(6-Amino-5-fluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (158 mg) and an aqueous solution (about 40%; 165 mg) of methylamine were added to pyridine (480 mg), and the mixture was stirred at room temperature for 17 hours. The reaction mixture was concentrated under reduced pressure, and ethanol (1 ml) was added to the residue. Deposits were collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain the title compound (168 mg) as a pale yellow powder.
Reaction SMILES: CS([CH2:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][N:15]=1)[C:9]([O:11][CH3:12])=[O:10])(=O)=O.[CH:16]1([NH:20][C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[O:31])=[CH:26][C:25]=2[F:38])=[O:22])[CH2:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:16]1([NH:20][C:21](=[O:22])[NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([N:32]3[CH2:37][CH2:36][N:35]([CH2:5][C:6]4[CH:7]=[C:8]([CH:13]=[CH:14][N:15]=4)[C:9]([O:11][CH3:12])=[O:10])[CH2:34][CH2:33]3)=[O:31])=[CH:26][C:25]=2[F:38])[CH2:17][CH2:18][CH2:19]1
Reactant: COC(=O)c1ccnc(CS(C)(=O)=O)c1
Reactant: O=C(Nc1ccc(C(=O)N2CCNCC2)cc1F)NC1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccnc(CN2CCN(C(=O)c3ccc(NC(=O)NC4CCC4)c(F)c3)CC2)c1
Yield: 58.6 %

Procedure:
Methyl 2-(methylsulfonylmethyl)isonicotinate (2.99 mmol, 0.686 g), 1-cyclobutyl-3-(2-fluoro-4-(piperazine-1-carbonyl)phenyl)urea (2.99 mmol, 0.959 g) and potassium carbonate (8.98 mmol, 1.241 g) were combined and heated to 40° C. in acetonitrile (20 mL) for 2 hours. The reaction mixture was concentrated at reduced pressure and the residue taken up in dichloromethane. The organic phase was dried over sodium sulfate and concentrated under vacuum. The residue was purified by silica chromatography (eluting with a solvent gradient from dichloromethane to 6% methanol/dichloromethane) to afford the title compound (822 mg). MS (ESI) m/z 470.5 [M+H]+
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[C:22]3[C:17](=[CH:18][C:19]([CH3:23])=[CH:20][CH:21]=3)[N:16]=[C:15]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[OH:30])[N:14]=2)[CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[C:22]3[C:17](=[CH:18][C:19]([CH3:23])=[CH:20][CH:21]=3)[N:16]=[C:15]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[OH:30])[N:14]=2)[CH2:9]1
Reactant: Cc1ccc2c(N3CC[C@H](NC(=O)OC(C)(C)C)C3)nc(-c3ccccc3O)nc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc2c(N3CC[C@H](N)C3)nc(-c3ccccc3O)nc2c1
Reaction time: 0.92 h

Procedure:
To (S)-{1-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (690 mg, 1.64 mmol) was added at room temperature 3 mL of 1:1 TFA:CH2Cl2. The reaction mixture was stirred for 55 min, diluted with 20 mL of CH2Cl2 and washed with 15 mL of satd. NaHCO3 solution. The organic layer was separated and dried over Na2SO4, and the solvent was removed under reduced pressure to give (S)-2-[4-(3-amino-pyrrolidin-1-yl)-7-methyl-quinazolin-2-yl]-phenol as an oil which was used without further purification.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][CH:6]=1>CO>[CH3:1][O:2][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][CH:6]=1
Reactant: C[O-]
Reactant: Clc1ccnc2ccccc12
Agent: [Na+]
Solvent: CO
Product: COc1ccnc2ccccc12
Yield: 76 %

Procedure:
To a solution of sodium methoxide (33 g) in methanol (130 ml), 4-chloroquinoline (10 g) was added under stirring. The mixture was heated under reflux for 6 hours. After cooling, the reaction mixture was concentrated, then dissolved in dichloromethane (250 ml) and washed with water (250 ml). The organic layer was dried over sodium sulfate. The solvent was evaporated to give a yellow oil (7.39 g, 76% yield) which was not purified.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:10])[CH2:6][C:7]([CH3:9])=[O:8].[Cl:11][C:12]1[CH:17]=[CH:16][C:15](F)=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=1.Cl>O.CN(C=O)C>[CH3:3][O:4][C:5](=[O:10])[C:6]([C:15]1[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][C:14]=1[N+:19]([O-:21])=[O:20])=[C:7]([OH:8])[CH3:9]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1F
Reactant: COC(=O)CC(C)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(=C(C)O)c1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 106.7 %

Procedure:
A mixture of sodium hydride (60% in mineral oil, 2.60 g, 65.0 mmol) and DMF (52 mL) is stirred in an ice bath and methylacetoacetate (6.46 mL, 59.9 mmol) is added via a syringe over 10 minutes. The mixture is stirred for an additional 10 minutes and the ice bath is removed. The solution is stirred at ambient temperature for 30 minutes and transferred via cannula into a flask containing 4-chloro-1-fluoro-2-nitrobenzene (5.00 g, 28.5 mmol) cooled to 0° C. via an ice bath. The reaction is allowed to warm slowly and is stirred for two days at room temperature. The black mixture is acidified with 2 N HCl, turning it yellow. The resulting solution is diluted with water and extracted with ether. The combined ether layers are washed with water and brine and dried over MgSO4 to give the crude title compound (8.26 g), which contains a small amount of mineral oil. The material is used without purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH2:13][O:14][C:15]3[C:16]([F:24])=[C:17]([C:20]([F:23])=[CH:21][CH:22]=3)[C:18]#[N:19])[S:10][N:9]=2)=[CH:4][CH:3]=1.Cl.[NH2:26][OH:27].[OH-].[Na+]>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH2:13][O:14][C:15]3[C:16]([F:24])=[C:17]([C:20]([F:23])=[CH:21][CH:22]=3)[C:18]([NH:26][OH:27])=[NH:19])[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1c(F)ccc(OCc2nc(-c3ccc(Cl)cc3)ns2)c1F
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N=C(NO)c1c(F)ccc(OCc2nc(-c3ccc(Cl)cc3)ns2)c1F
Yield: 68.7 %

Procedure:
To a solution of 3-[3-(4-chlorophenyl)-[1,2,4]thiadiazol-5-ylmethoxy]-2,6-difluorobenzonitrile (0.10 g, 2.75 mmol) in EtOH (3 ml) was added hydroxylamine hydrochloride (0.48 g, 6.87 mmol) and NaOH (0.27 g, 6.87 mmol). The resulting reaction mixture was refluxed overnight. After the completion of the reaction (TLC monitoring), the mixture was concentrated, added EtOH and filtered. The filtrate was evaporated in vacuum to get the desired product (0.75 g, 69%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5][NH2:6].C1(N=C=NC2CCCCC2)CCCCC1.[C:26](=S)=[S:27]>CCOCC>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5][N:6]=[C:26]=[S:27]
Reactant: NCc1cc(F)cc(F)c1
Reactant: S=C=S
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOCC
Product: Fc1cc(F)cc(CN=C=S)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of 3,5-difluorobenzylamine (11.6 g., 0.081 mole) in ether (20 ml.) was added dropwise to a solution of dicyclohexylcarbodiimide (16.7 g., 0.081 mole) and carbon disulfide (32.4 ml., 0.539 mole) in ether (100 ml.) at -5°to -10° C., and the mixture was stirred for 17 hours at 25° C. The mixture was filtered and the solvent was removed under vacuum. The resulting oil was dissolved in hexane-ether (19:1), filtered, and the solvent removed under vacuum. The oil was then dissolved in hexane and purified by flash chromatography (silica) to give 3,5-difluorobenzylisothiocyanate as an oil (5.40 g., 36%).
Reaction SMILES: O.[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([CH:37]=[CH:38][CH:39]=1)[O:13][C:14]1[CH:19]=[C:18]([N:20]2[C:25](=[O:26])[CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[N:22]([CH3:31])[C:21]2=[O:32])[C:17]([F:33])=[CH:16][C:15]=1[N+:34]([O-])=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(O)(=O)C.[Fe]>[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([CH:37]=[CH:38][CH:39]=1)[O:13][C:14]1[CH:19]=[C:18]([N:20]2[C:25](=[O:26])[CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[N:22]([CH3:31])[C:21]2=[O:32])[C:17]([F:33])=[CH:16][C:15]=1[NH2:34])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3cccc(OCc4ccccc4)c3)c([N+](=O)[O-])cc2F)c1=O
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3cccc(OCc4ccccc4)c3)c(N)cc2F)c1=O
Temperature: 35 °C
Reaction time: 2 h
Yield: 66.2 %

Procedure:
To a mixture of 2.5 g of an iron powder, 8 ml of acetic acid and 0.8 ml of water was added dropwise a solution of 2.4 g of 2-(3-benzyloxyphenoxy)-5-fluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]nitrobenzene in 6.0 ml of acetic acid, while maintaining the temperature of the reaction solution at 35° C. or lower. After completion of the addition, the mixture was stirred for 2 hours, then, the reaction solution was filtrated through Celite and diluted with ethyl acetate. The mixture was neutralized with saturated aqueous sodium bicarbonate, the organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated, then, the resulted residue was subjected to silica gel column chromatography to obtain 1.5 g of 2-(3-benzyloxyphenoxy)-5-fluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]aniline.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([NH2:13])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH:14](O)=[O:15]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[C:11]([NH:13][CH:14]=[O:15])[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Nc1cnn(-c2ccc(F)cc2)c1
Reactant: O=CO
Product: O=CNc1cnn(-c2ccc(F)cc2)c1
Temperature: 25 °C
Yield: 71 %

Procedure:
A solution of 1-(4-fluorophenyl)pyrazol-4-amine (0.59 g, 3.3 mmol) in formic acid (15 mL) was heated at 80° C. for 2 h. The reaction mixture was cooled to room temperature, concentrated in vacuo, and purified by flash chromatography (SiO2, 0-100% EtOAc/CH2Cl2 gradient elution) to give N-[1-(4-fluorophenyl)pyrazol-4-yl]formamide (0.490 g, 71%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([OH:22])[CH:21]=1)[C:5]([N:7]([C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1)[CH2:8][CH2:9][CH3:10])=[O:6].[H-].[Na+].[C:25]([O:29][C:30]([N:32]([C:46]1[CH:51]=[CH:50][N:49]=[CH:48][CH:47]=1)[CH2:33][CH2:34]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:31])([CH3:28])([CH3:27])[CH3:26]>CN(C=O)C>[C:25]([O:29][C:30](=[O:31])[N:32]([CH2:33][CH2:34][O:22][C:20]1[CH:19]=[C:4]([C:5](=[O:6])[N:7]([CH2:8][CH2:9][CH3:10])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=2)[CH:3]=[C:2]([Cl:1])[CH:21]=1)[C:46]1[CH:51]=[CH:50][N:49]=[CH:48][CH:47]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: Cc1ccc(S(=O)(=O)OCCN(C(=O)OC(C)(C)C)c2ccncc2)cc1
Reactant: CCCN(C(=O)c1cc(O)cc(Cl)c1)c1cc(F)cc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN(C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1)c1cc(F)cc(F)c1
Reaction time: 66 h
Yield: 34.7 %

Procedure:
To a solution of 3-chloro-N-(3,5-difluoro-phenyl)-5-hydroxy-N-propyl-benzamide (0.050 g) in DMF (0.5 ml) stirred at room temperature under nitrogen was added sodium hydride (60% dispersion in oil, 0.007 g) and after 10 min was added toluene-4-sulfonic acid 2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethyl ester (0.060 g). The reaction was stirred for 66 h, quenched with water and then concentrated in vacuo. and the residue subjected to preparative hplc. The title compound (0.029 g) was obtained as an colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:29])([CH2:23][N:24]1[CH:28]=[N:27][CH:26]=[N:25]1)[CH2:10][N:11]1[C:19]2[C:14](=[CH:15][C:16]([N+:20]([O-])=O)=[CH:17][CH:18]=2)[CH:13]=[N:12]1.[H][H]>CO.[Pd]>[NH2:20][C:16]1[CH:15]=[C:14]2[C:19](=[CH:18][CH:17]=1)[N:11]([CH2:10][C:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])([OH:29])[CH2:23][N:24]1[CH:28]=[N:27][CH:26]=[N:25]1)[NH:12][CH2:13]2
Reactant: O=[N+]([O-])c1ccc2c(cnn2CC(O)(Cn2cncn2)c2ccc(F)cc2F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(c1)CNN2CC(O)(Cn1cncn1)c1ccc(F)cc1F
Reaction time: 12 h
Yield: 87 %

Procedure:
To a solution of 2-(2,4-difluorophenyl)-1-(5-nitro-1H-indazol-1-yl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (3.57 g, 8.92 mmol) in methanol (50 ml) was added 5% palladium charcoal (Pd/C) (0.35 g) and hydrogen gas, followed by stirring for 12 hours. The reaction solution was filtered through celite. The filtrate was concentrated through vacuum evaporation to produce the title compound. (Yield 87%).
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].[Na].Cl[C:14]1[S:15][CH:16]=[C:17]([Cl:19])[N:18]=1>C(O)C>[Cl:19][C:17]1[N:18]=[C:14]([S:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[S:15][CH:16]=1
Reactant: SCc1ccccc1
Reactant: Clc1csc(Cl)n1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: Clc1csc(SCc2ccccc2)n1
Reaction time: 0.25 h
Yield: 90.7 %

Procedure:
Benzylmercaptan (24.8 g) was added dropwise to a solution of 10.8 g of sodium methoxide in 100 ml ethanol. After stirring 15 minutes, the ehtanolic solution of sodium benzylmercaptide was added dropwise to a solution of 30.8 g 2,4-dichlorothiazole [prepared by the method of P. Reynaud et al., Bull. Soc. Chim. France, 1735 (1962)], resulting in a temperature increase of 28° to 48°. When the exotherm subsided, the suspension was refluxed 1 hour, then the solvent was evaporated. Cold water (300 ml) was added to the oily residue, and the aqueous mixture was extracted with methylene chloride. The organic solution was washed with water, followed by saturated brine, then dried over magnesium sulfate, filtered and the solvent evaporated to give 43.8 g of 4-chloro-2-phenylmethylthiothiazole as a brown oil.
Reaction SMILES: [O:1]=[C:2]1[NH:7][N:6]=[C:5]([C:8]([OH:10])=[O:9])[CH:4]=[CH:3]1.[CH:11]1(I)[CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>CN(C=O)C>[CH:11]1([O:9][C:8]([C:5]2[CH:4]=[CH:3][C:2](=[O:1])[N:7]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[N:6]=2)=[O:10])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C(O)c1ccc(=O)[nH]n1
Reactant: IC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(OC1CCCC1)c1ccc(=O)n(C2CCCC2)n1

Procedure:
6-Oxo-1,6-dihydropyridazine-3-carboxylic acid (1 g, 7.14 mmol) was stirred with cyclopentyl iodide (2.05 ml, 17.8 mmol) and potassium carbonate (3 g, 21.4 mmol) in 15 ml DMF for 14 h at room temperature. 50 ml CH2Cl2 was added and the reaction mixture was filtered. The filtrate was concentrated and the title compound was purified by prep HPLC. Yield: 20 mg (0.072 mmol, 1%, MS m/z: 277(100%, M+1)).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12](=[O:20])OC2C=CC=CC=2)[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8].[N+:21]([C:24]1[CH:25]=[C:26]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:27]=[C:28]([N+:30]([O-:32])=[O:31])[CH:29]=1)([O-:23])=[O:22]>>[CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12]([N:36]2[CH2:37][CH2:38][N:33]([C:26]3[CH:27]=[C:28]([N+:30]([O-:32])=[O:31])[CH:29]=[C:24]([N+:21]([O-:23])=[O:22])[CH:25]=3)[CH2:34][CH2:35]2)=[O:20])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8]
Reactant: O=[N+]([O-])c1cc(N2CCNCC2)cc([N+](=O)[O-])c1
Reactant: COc1nc(C)c(C)nc1NC(=O)Oc1ccccc1
Product: COc1nc(C)c(C)nc1NC(=O)N1CCN(c2cc([N+](=O)[O-])cc([N+](=O)[O-])c2)CC1
Yield: 64.5 %

Procedure:
Phenyl N-(5,6-dimethyl-2-methoxypyrazin-3-yl)carbamate and 1-(3,5-dinitrophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:26]=[CH:25][C:15]([C:16]([N:18]3[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20][CH2:19]3)=[O:17])=[CH:14][CH:13]=2)=[N:2]1.C(N(CC)CC)C.[N:34]1([C:40](Cl)=[O:41])[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:13]=[CH:14][C:15]([C:16]([N:18]3[CH2:19][CH2:20][CH:21]([NH:24][C:40]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)=[O:41])[CH2:22][CH2:23]3)=[O:17])=[CH:25][CH:26]=2)=[N:2]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: NC1CCN(C(=O)c2ccc(/C=C/c3n[nH]c4ccccc34)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1CCN(C(=O)c2ccc(/C=C/c3n[nH]c4ccccc34)cc2)CC1)N1CCOCC1
Reaction time: 4 h
Yield: 0.3 %

Procedure:
Compound 64 (500 mg, 1.19 mmol) was dissolved in dichloromethane, and the solution was added with triethylamine (0.498 mL, 3.57 mmol), 4-morpholinecarbonyl chloride (468 mg, 2.62 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (200.2 mg, 1.04 mmol) at 0° C., followed by stirring for 4 hours to obtain Compound 99 (1.5 mg, 0.3%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9](Br)=[N:8][CH:7]=1)=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].[C:18]1([SH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCO>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([S:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: Sc1ccccc1
Reactant: CCOC(=O)c1cnc(Br)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1cnc(Sc2ccccc2)s1
Yield: 48 %

Procedure:
A suspension of 2-bromo-1,3-thiazole-5-carboxylic acid ethyl ester (1.5 g, 6.15 mmol, 1 eq) and K2CO3 (1.7 g, 12.3 mmol, 2 eq) in EtOH (60 mL) is cooled in an ice bath, and thiophenol (0.631 mL, 6.15 mmol, 1 eq) is added. The reaction is monitored by HPLC until the starting material is consumed. The reaction mixture is filtered (to remove a solid by-product), and the solvent is removed in vacuo. The crude mixture is purified by silica gel chromatography using a Biotage Flash 40S column using 2% EtOAc in hexanes to afford the product as an oil (0.784 g, 46%). MS (ESI) for C12H11NO2S2 m/z 266.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[N:8]=[C:7]2[OH:13].[CH3:14][C:15]([NH2:18])([CH3:17])[CH3:16]>C(Cl)Cl.CO>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:18][C:15]([CH3:17])([CH3:16])[CH3:14])[NH:8][C:7]2=[O:13]
Reactant: CC(C)(C)N
Reactant: Oc1nc(Cl)nc2c(Br)cccc12
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)Nc1nc2c(Br)cccc2c(=O)[nH]1
Temperature: 80 °C
Yield: 56.1 %

Procedure:
A mixture of 8-bromo-2-chloroquinazolin-4-ol (407c, 0.20 g, 0.77 mmol) in 2-methylpropan-2-amine (1.62 mL, 15.42 mmol) was sealed and heated to 80° C. overnight. The reaction was transferred to a microwave vessel and heated to 170° C. for 30 min. The reaction was transferred to a flask with DCM/MeOH and concentrated in vacuo. The material was taken up in DCM/MeOH and adsorbed onto 1.3 g silica gel and dried in vacuo. The material was purified by silica gel chromatography (24 g column) using 0-100% EtOAc/hexanes. The product-containing fractions were concentrated to afford 8-bromo-2-(tert-butylamino)quinazolin-4(3H)-one (408a, 0.128 g, 0.432 mmol, 56% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.59 (1H, s), 7.85-7.90 (2H, m), 7.00 (1H, t, J=7.7 Hz), 6.22 (1H, s), 1.48 (9H, s). m/z (ESI, +ve ion) 296.0/298.0 (M+H)+.
Reaction SMILES: O=[C:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:9]([O:11][CH3:12])=[O:10].[NH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]>>[CH2:17]([O:16][C:14]([NH:13][C:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]=1[C:9]([O:11][CH3:12])=[O:10])=[O:15])[CH3:18]
Reactant: COC(=O)C1CCCCCC1=O
Reactant: CCOC(N)=O
Product: CCOC(=O)NC1=C(C(=O)OC)CCCCC1

Procedure:
Using the method of Example 1 Part A, methyl 2-oxocycloheptanecarboxylate (50.5 g, 0.30 mole) was reacted with urethane to provide 59 g of methyl 2-[(ethoxycarbonyl)amino]-1-cycloheptene-1-carboxylate as an oil.
Reaction SMILES: O[CH2:2][C:3]1[C:8]2[N:9]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:10](=[O:14])[CH2:11][CH2:12][CH2:13][C:7]=2[CH:6]=[CH:5][CH:4]=1.S(Cl)([Cl:25])=O.N1C=CC=CC=1.[Cl-].[Li+]>CN(C)C=O>[Cl:25][CH2:2][C:3]1[C:8]2[N:9]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:10](=[O:14])[CH2:11][CH2:12][CH2:13][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: C[Si](C)(C)CCOCN1C(=O)CCCc2cccc(CO)c21
Reactant: O=S(Cl)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: C[Si](C)(C)CCOCN1C(=O)CCCc2cccc(CCl)c21
Temperature: 45 °C
Reaction time: 2 h

Procedure:
Analogously to Method E, 0.320 g of 9-hydroxymethyl-1-(2-trimethylsilanylethoxymethyl)-1,3,4,5-tetrahydrobenz[b]azepin-2-one is reacted with 0.100 ml of thionyl chloride and 0.080 ml of pyridine. The resulting intermediate is subsequently dissolved in 30 ml of N,N-dimethylformamide and the solution is admixed with 0.190 g of lithium chloride. The reaction mixture is subsequently stirred at 45° C. over 2 hours and subsequently concentrated by evaporation. The residue is taken up in 100 ml of tert-butyl methyl ether and the solution is washed with 80 ml of water. The aqueous phase is extracted with 60 ml of tert-butyl methyl ether and the combined organic phases are subsequently dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a yellow resin from the residue by means of flash chromatography (SiO2 60F). Rf=0.20 (1:1 EtOAc-heptane); Rt=5.38.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:15])=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[NH:8][C:7](=[O:13])[C:6](=[O:14])[NH:5]2.[N+:16]([O-])([O-:18])=[O:17].[K+]>>[Cl:1][C:2]1[C:3]([F:15])=[C:4]2[C:9]([NH:8][C:7](=[O:13])[C:6](=[O:14])[NH:5]2)=[C:10]([N+:16]([O-:18])=[O:17])[C:11]=1[F:12]
Reactant: O=c1[nH]c2cc(F)c(Cl)c(F)c2[nH]c1=O
Reactant: O=[N+]([O-])[O-]
Agent: [K+]
Product: O=c1[nH]c2c(F)c(Cl)c(F)c([N+](=O)[O-])c2[nH]c1=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 57.4 %

Procedure:
To a solution of 120 mg (5.16 mmol) of 6-chloro-5,7-difluoro-1,4-dihydroquinoxaline-2,3-dione in 1 mL of H2S4 (97%) kept in an ice bath was added portionwise 60 mg (0.59 mmol) of KNO3. The solution was stirred at room temperature for 14 h and 60 mg of KNO3 was added. It was stirred at room temperature for 24 h, then diluted with ice-water (4 mL), filtered, washed with water, and dried to leave a yellow solid (94 mg, 65%). The solid was purified by NaOH/HCl precipitation to leave 63 mg of yellow solid; mp>250° C.; 1H NMR (DMSO-d6), 12.11 (mb, 1), 12.503 (s, 1).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].C(N(CC)CC)C.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl>[C:16]([O:7][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH3:8])[CH:1]=1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cccc(O)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(OC(=O)c2ccccc2)c1
Temperature: 25 °C

Procedure:
To a chilled (0°-5° C.) solution of 5.0 g (0.046 mol) of m-cresol in 20 mL of methylene chloride containing 5.16 g (0.051 mol) of triethylamine was added dropwise a solution containing 6.47 g (0.046 mol) of benzoyl chloride in 20 mL of methylene chloride. A precipitate formed upon addition. The reaction mixture was stirred several hours at room temperature and was then filtered. The filtrate was washed with water (25 mL) and then with brine (25 mL). The organic phase was removed and dried over magnesium sulfate, filtered and evaporated to dryness in a rotary evaporator. The crude product amounted to 9.66 g. An analytical sample (m.p. 51°-54° C.) was obtained by recrystallization from petroleum ether.