Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:9]([CH3:15])[CH:10]([CH3:14])[C:11](O)=[O:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:17][NH2:18]>C(O)C>[CH3:14][CH:10]1[CH:9]([CH3:15])[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:18][NH:17][C:11]1=[O:12]
Reactant: NN
Reactant: CC(C(=O)O)C(C)C(=O)c1ccccc1
Solvent: CCO
Solvent: O
Product: CC1C(=O)NN=C(c2ccccc2)C1C

Procedure:
A 200 g. portion of 3-benzoyl-2,3-dimethyl-propionic acid and 60 g. of hydrazine hydrate are added to one liter of ethyl alcohol and stirred at reflux for 18 hours. The reaction mixture is then cooled in an ice bath and collected in a conventional manner to afford 4,5-dihydro-4,5-dimethyl-6-phenyl-3(2H)-pyridazinone as a cream colored solid. This product is partially dissolved in 600 ml. of glacial acetic acid. To this is added, portionwise, a solution of 50 ml. of bromine in 100 ml. of glacial acetic acid, while warming on a steam bath (approximately 15% of the bromine solution is added to the reaction mixture before warming is started and about one hour is required to complete the addition during which time quantities of hydrogen bromide gas are given off). After the addition is completed, the reaction mixture is heated on the steam bath for one hour, and then the mixture is poured onto crushed ice. The resulting solid is vacuum filtered, washed copiously with water, and air dried to give 4,5-dimethyl-6 -phenyl-3(2H)-pyridazinone as a cream colored solid. This material is added to 800 ml. of phosphorus oxychloride and is heated on a steam bath for 5 hours. The reaction mixture is concentrated to remove the excess phosphorus oxychloride and is then diluted with cold water. The resulting solid is vacuum filtered, washed copiously with water, and air dried to give 3-chloro-4,5-dimethyl-6-phenylpyridazine as a pinkish solid. A 10 g. portion of this product plus 8 g. of N-acetylhydrazine and 100 ml. of n-butyl alcohol is allowed to stir at reflux for 48 hours. The reaction mixture is cooled in an ice bath and the resulting solid is vacuum filtered, washed first with petroleum ether and then with water, and is air dried. The solid is recrystallized from ethyl alcohol after treatment with activated charcoal and is dried in vacuo to give 3,7,8-trimethyl-6-phenyl-1,2,4-triazolo[4,3-b]pyridazine as a white solid.
Reaction SMILES: [F:1][CH:2]([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[O-:11][C:12]#[N:13].[Na+]>C(O)(=O)C.O>[F:1][CH:2]([F:10])[C:3]1[CH:4]=[C:5]([NH:6][C:12]([NH2:13])=[O:11])[CH:7]=[CH:8][CH:9]=1
Reactant: N#C[O-]
Reactant: Nc1cccc(C(F)F)c1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: NC(=O)Nc1cccc(C(F)F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Water (10 mL) is added dropwise to a mixture of 3-(difluoromethyl)aniline (2.00 g, 13.97 mmol) in glacial acetic acid (6 mL). A solution of sodium cyanate (1.00 g, 15.38 mmol) in water (10 mL) is added dropwise, and the mixture is stirred at room temperature for 4 h. The precipitate is filtered, washed with water and dried under reduced pressure. Yield: 1.80 g; ESI mass spectrum [M+H]+=187, Retention time HPLC: 0.70 min (Z012_S04).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2.[CH3:14][N:15]([CH3:28])[CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1.[OH-].[K+]>C(O)C>[CH3:28][N:15]([CH3:14])[CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH:24]=[C:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]2=[O:13])=[CH:26][CH:27]=1
Reactant: COc1ccc2c(c1)CCCC2=O
Reactant: CN(C)CCCOc1ccc(C=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2c(c1)CCC(=Cc1ccc(OCCCN(C)C)cc1)C2=O
Yield: 81.4 %

Procedure:
Interaction of 16 g of 6-methoxy-1-tetralone and 19 g of 4-(3-dimethylaminopropoxy)benzaldehyde in 95 ml of ethanol in the presence of 0.6 g of potassium hydroxide following the procedure described in Example 1A, yields 27 g of crude product; melting point 68-71° C. Following crystallization from 70 ml of diisopropyl ether, the product weighs 18.6 g, melting point 76°-78° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:20]=[CH:19][C:13]3[N:14]=[C:15]([S:17][CH3:18])[S:16][C:12]=3[CH:11]=2)[C:5]([NH2:21])=[CH:4][CH:3]=1.Br[C:23]1C=C(N)C(NCC2C=CC3N=C(SC)SC=3C=2)=CC=1OC>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:21]=[CH:23][N:8]([CH2:9][C:10]3[CH:20]=[CH:19][C:13]4[N:14]=[C:15]([S:17][CH3:18])[S:16][C:12]=4[CH:11]=3)[C:6]=2[CH:7]=1
Reactant: COc1cc(NCc2ccc3nc(SC)sc3c2)c(N)cc1Br
Reactant: CSc1nc2ccc(CNc3cc(Br)ccc3N)cc2s1
Product: CSc1nc2ccc(Cn3cnc4ccc(Br)cc43)cc2s1

Procedure:
6-((6-Bromo-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole was synthesized as a yellow solid (701 mg, 70%) using a procedure analogous to that described in Step 3 of Example 41, substituting 5-bromo-N1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)benzene-1,2-diamine from the previous step for 4-bromo-5-methoxy-N1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)benzene-1,2-diamine used in Example 41. LCMS (ESI) m/z 389, 391 (M+H)+.
Reaction SMILES: ClN1C(=O)CCC1=O.[CH3:9][S:10][CH3:11].[CH:12]([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([N:24]2[CH2:41][CH2:40][C:27]3([C:32]4=[CH:33][CH:34]=C[N:31]4[C:30]4[CH:36]=[CH:37][CH:38]=[CH:39][C:29]=4[O:28]3)[CH2:26][CH2:25]2)=[O:23])=[CH:18][C:17]=1[CH3:42])([CH3:14])[CH3:13]>ClCCl.C1(C)C=CC=CC=1>[CH:12]([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([N:24]2[CH2:41][CH2:40][C:27]3([O:28][C:29]4[CH:39]=[CH:38][CH:37]=[CH:36][C:30]=4[N:31]4[C:9]([S:10][CH3:11])=[CH:34][CH:33]=[C:32]34)[CH2:26][CH2:25]2)=[O:23])=[CH:18][C:17]=1[CH3:42])([CH3:14])[CH3:13]
Reactant: Cc1cc(C(=O)N2CCC3(CC2)Oc2ccccc2-n2cccc23)ccc1OC(C)C
Reactant: CSC
Agent: O=C1CCC(=O)N1Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CSc1ccc2n1-c1ccccc1OC21CCN(C(=O)c2ccc(OC(C)C)c(C)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 110.3 %

Procedure:
A solution of 1-chloropyrrolidine-2,5-dione (92 mg, 0.70 mmol) in dry dichloromethane (3.2 mL) was added dropwise at −10° C. to a solution of methylsulfanylmethane (82 μL, 1.1 mmol) in dry dichloromethane (800 μL) over a period of 5 minutes. The reaction was allowed to warm to room temperature and was stirred for 30 minutes. The mixture was then cooled to −55° C. and a solution of (4-isopropoxy-3-methyl-phenyl)-spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-yl-methanone (210 mg, 0.49 mmol) in dry dichloromethane (800 μL) was added dropwise. The cooling bath was removed and the mixture was gradually warmed up to room temperature and was stirred overnight. The solvent was removed under vacuum and the pink residue that was obtained was dissolved in dry toluene (7 mL) and was heated at 50° C. for 5 minutes. The solvent was removed to afford (4-isopropoxy-3-methylphenyl)(1-(methylthio)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone (250 mg, 78%). ESI-MS m/z calc. 462.2. found 463.5 (M+1)+; Retention time: 2.43 minutes (3 min run).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].C([N:13]1[CH2:18][CH:17]=[C:16]([CH2:19][CH2:20][N:21]2[CH2:25][CH2:24][CH2:23][S:22]2(=[O:27])=[O:26])[CH2:15][CH2:14]1)C1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:5][O:4][C:2]([N:13]1[CH2:14][CH:15]=[C:16]([CH2:19][CH2:20][N:21]2[CH2:25][CH2:24][CH2:23][S:22]2(=[O:27])=[O:26])[CH2:17][CH2:18]1)=[O:3]
Reactant: COC(=O)Cl
Reactant: O=S1(=O)CCCN1CCC1=CCN(Cc2ccccc2)CC1
Solvent: Cc1ccccc1
Product: COC(=O)N1CC=C(CCN2CCCS2(=O)=O)CC1

Procedure:
Methyl chloroformate (3.3 cm3) was added at room temperature to a stirred solution of 2-[2-(1-benzyl-1,2,3,6-tetrahydropyrid-4-yl)ethyl]isothiazolidine-1,1-dioxide (4.5 g) in toluene (20 cm3) and the mixture was heated under reflux for 16 hours. Volatile material was removed in vacuo to give the crude 2-[2-(1-methoxycarbonyl-1,2,3,6-tetrahydropyrid-4-yl)ethyl]isothiazolidine-1,1-dioxide as an oil (5.0 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH2:9][C:10]#[N:11])[C:6]([N+:12]([O-:14])=[O:13])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]([O:25][CH3:26])=[O:24]>C(#N)C>[C:10]([CH:9]([C:7]1[C:6]([N+:12]([O-:14])=[O:13])=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]=1)[CH2:22][C:23]([O:25][CH3:26])=[O:24])#[N:11]
Reactant: COC(=O)CBr
Reactant: COc1ccc([N+](=O)[O-])c(CC#N)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)CC(C#N)c1nc(OC)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Under argon, 2-(6-methoxy-3-nitropyridin-2-yl)acetonitrile (500 mg, 2.59 mmol) was dissolved in acetonitrile (11 mL) in a flame dried round-bottom flask. Two equivalents of anhydrous potassium carbonate (0.72 g, 5.18 mmol) were added to this solution, and methyl 2-bromoacetate (245 μL, 2.59 mmol) was introduced dropwise. The reaction mixture was stirred at room temperature until the starting materials were consumed, approximately four hours. The crude material was combined with CH2Cl2 and inorganic debris was filtered off using a phase separator syringe equipped with a sodium sulfate drying cartridge. The filter cake was washed with small quantities of CH2Cl2 and all organic filtrates were collected and combined. The organic solvents were evaporated in vacuo at 40° C. and the resulting viscous dark brownish oil either directly used in the next reaction step or purified by flash chromatography on a short silica-gel column (ethyl acetate/hexane gradient) prior to its further chemical reaction. C11H11N3O5, Mr=265.22; 1H NMR (400 MHz, DMSO-d6) d: 3.15-3.29 (m, 2H), 3.64 (s, 3H), 3.99 (s, 3H), 5.22 (t, J=7.2 Hz, 1H), 7.08 (d, J=9.2 Hz, 1H), 8.48 (d, J=8.8 Hz, 1H); LCMS (ESI) tR: 1.98 min (96-100%, UV220, UV254, ELSD), m/z: 266.2 [M+1]+.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH:11]3[CH2:13]C3)[CH:10]=[C:6]2[CH:5]=[C:4]([NH:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][C:19]([C:22]([OH:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=2)[N:3]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>CN1C(=O)CCC1>[CH2:11]([C:9]1[CH:10]=[C:2]2[N:3]=[C:4]([NH:14][C:15](=[O:26])[C:16]3[CH:17]=[CH:18][C:19]([C:22]([OH:25])([CH3:24])[CH3:23])=[CH:20][CH:21]=3)[CH:5]=[C:6]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[N:7]2[N:8]=1)[CH3:13]
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc3cc(C4CC4)nn3c(Cl)n2)cc1
Reactant: C1COCCN1
Solvent: CN1CCCC1=O
Product: CCc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(N3CCOCC3)n2n1
Temperature: 25 °C
Yield: 50 %

Procedure:
In a 2 mL microwave vial was placed N-(7-chloro-2-cyclopropylpyrazolo[1,5-c]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2H, 75 mg, 0.21 mmol) and morpholine (36 mg, 0.42 mmol). To the sealed vial was then added NMP (2 ml) and the mixture was then heated in the microwave at 120° C. for 30 minutes. After cooling to room temperature, the reaction mixture was partitioned between brine and EtOAc. The aqueous layer was extracted once more with EtOAc, and the combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by recrystallization from ether and EtOAC to give the titled compound (43 mg, 50% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ=10.87 (s, 2 H), 8.05-7.92 (m, 2 H), 7.59 (d, J=8.6 Hz, 2 H), 7.36 (s, 1 H), 6.19 (s, 1 H), 5.18 (s, 1 H), 3.91-3.79 (m, 4 H), 3.77-3.69 (m, 4 H), 2.74 (q, J=7.6 Hz, 2 H), 1.45 (s, 6 H), 1.35-1.23 (m, 3 H); ESI-MS: m/z 410 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:15])[CH2:13][CH3:14])[CH2:7][CH2:6][C:5]2=[O:16].Br[CH2:18][C:19]([O:21][CH3:22])=[O:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:22][O:21][C:19]([CH2:18][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:15])[CH2:13][CH3:14])[CH2:7][CH2:6][C:5]2=[O:16])=[O:20]
Reactant: CCC(=O)N1CCC(=O)c2cc(O)ccc21
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(=O)N1CCC(=O)c2cc(OCC(=O)OC)ccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 119.1 %

Procedure:
A mixture of 6-hydroxy-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (1.314 g), methyl bromoacetate (1.01 g), and potassium carbonate (0.828 g) in N,N-dimethylformamide (10 ml) was stirred at room temperature for 24 hours, poured into water, and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (15 g) with chloroform as an eluent to give 6-methoxycarbonylmethoxy-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (2.08 g).
Reaction SMILES: [O:1]([CH2:8][CH2:9][NH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:11]([N:18]([CH2:23][C:24](O)=[O:25])[CH2:19][C:20](O)=[O:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)(Cl)Cl>[O:1]([CH2:8][CH2:9][N:10]1[C:20](=[O:21])[CH2:19][N:18]([CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:23][C:24]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCOc1ccccc1
Reactant: O=C(O)CN(CC(=O)O)Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C1CN(Cc2ccccc2)CC(=O)N1CCOc1ccccc1
Yield: 64.8 %

Procedure:
2-Phenoxyethylamine (1.37 g) and N-benzyliminodiacetic acid (2.23 g) were mixed and heated to 225°, and maintained at this temperature for 15 min. After cooling, chloroform was added and the product purified by column chromatography (SiO2 /CHCl3) to give the title compound as a reddish oil (2.1 g).
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([O:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[C:15]=1[O:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[C:10](O)=[O:11])[CH:2]=[C:3]([CH3:5])[CH3:4].[NH2:28][CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][N:31]1[CH2:35][CH3:36]>>[CH2:35]([N:31]1[CH2:32][CH2:33][CH2:34][CH:30]1[CH2:29][NH:28][C:10](=[O:11])[C:9]1[CH:8]=[C:7]([O:6][CH2:1][CH:2]=[C:3]([CH3:5])[CH3:4])[C:15]([O:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[C:14]([O:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[CH:13]=1)[CH3:36]
Reactant: CCN1CCCC1CN
Reactant: CC(C)=CCOc1cc(C(=O)O)cc(OCC=C(C)C)c1OCC=C(C)C
Product: CCN1CCCC1CNC(=O)c1cc(OCC=C(C)C)c(OCC=C(C)C)c(OCC=C(C)C)c1
Yield: 79 %

Procedure:
In a manner identical to Example 15, 3,4,5-triprenyloxybenzoic acid (0.94 g) was subjected to a condensation reaction with 2-aminomethyl-1-ethylpyrrolidine (0.35 g, thereby yielding 1.21 g (79%) of the aimed compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:13]2[C:18]([C:19]#[N:20])=[C:17]([CH3:21])[N:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:15](=[O:32])[N:14]2[CH3:33])=[C:7]([S:9](Cl)(=[O:11])=[O:10])[CH:8]=1)#[N:2].S([O-])([O-])=O.[Na+:38].[Na+].C(=O)(O)[O-].[Na+]>C1COCC1.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:13]2[C:18]([C:19]#[N:20])=[C:17]([CH3:21])[N:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:31])[F:29])[CH:23]=3)[C:15](=[O:32])[N:14]2[CH3:33])=[C:7]([S:9]([O-:11])=[O:10])[CH:8]=1)#[N:2].[Na+:38]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)(=O)Cl)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)[O-])N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Cyano-2-{(4S)-5-cyano-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzenesulfonyl chloride (600 mg) was dissolved in THF (4.25 ml). Sodium sulfite (195 mg, 1.55 mmol; 1.5 eq.) and sodium bicarbonate (303 mg, 3.61 mmol; 3.5 eq.), dissolved in water (1.7 ml), were then added. The mixture was stirred at RT for 1 h. The reaction solution was then lyophilized directly. This gave a solid as product (962 mg, 58% of theory, purity 32%) which was used without further purification in the subsequent reactions.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:11][N:12]([CH2:23][C:24]2[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=2)[CH:13]2[C:22]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:16][CH2:15][CH2:14]2)=[C:7]([CH2:9][OH:10])[CH:8]=1.[C:32]1([C@@H:38]([CH2:42][CH3:43])[C:39](O)=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:30][C:29]1[C:24]([CH2:23][N:12]([CH2:11][C:6]2[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:39](=[O:40])[CH:38]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:42][CH3:43])=[CH:8][C:7]=2[CH2:9][OH:10])[CH:13]2[C:22]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:16][CH2:15][CH2:14]2)=[N:25][CH:26]=[C:27]([CH3:31])[CH:28]=1
Reactant: CC[C@@H](C(=O)O)c1ccccc1
Reactant: Cc1cnc(CN(Cc2ccc(CN)cc2CO)C2CCCc3cccnc32)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(C(=O)NCc1ccc(CN(Cc2ncc(C)cc2C)C2CCCc3cccnc32)c(CO)c1)c1ccccc1
Yield: 41 %

Procedure:
Using General Procedure G: To a solution of (5-aminomethyl-2-{[(3,5-dimethyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-phenyl)-methanol (0.12 g, 0.26 mmol) dissolved in CH2Cl2 (10 mL) was added (R)-2-phenylbutyric acid (60 μl, 0.39 mmol), EDCI (0.08 g, 0.39 mmol), HOBT (0.05 g, 0.39 mmol), and DIPEA (67 μl, 0.39 mmol). Purification via column chromatography on silica gel (CH2Cl2:MeOH, 97:3, v/v) afforded the product as a colorless oil (0.06 g, 36%). 1H NMR (CDCl3) δ 0.88 (m, 3H), 1.51 (m, 1H), 1.86 (m, 1H), 2.05 (m, 1H), 2.11 (m, 3H), 2.14 (s, 3H), 2.24 (s, 3H), 2.79 (m, 2H), 3.20 (m, 1H), 3.70 (m, 4H), 4.09 (m, 2H), 4.33 (m, 3H), 5.69 (s, 1H), 6.95 (m, 2H), 7.13 (m, 2H), 7.22 (m, 7H), 8.15 (s, 1H), 8.35 (s, 1H); ES-MS m/z 564 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:29])[N:5]([C@@H:12]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH3:28])[CH:19]=1)[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:6]2=[O:11].C(N(C(C)C)CC)(C)C.[CH2:39]([O:46][CH2:47][C:48](Cl)=[O:49])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(Cl)Cl>[CH2:39]([O:46][CH2:47][C:48]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:29])[N:5]([CH:12]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH3:28])[CH:19]=1)[CH2:13][S:14]([CH3:17])(=[O:15])=[O:16])[C:6]2=[O:11])=[O:49])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CCOc1cc([C@@H](CS(C)(=O)=O)N2C(=O)c3cccc(N)c3C2=O)ccc1OC
Reactant: O=C(Cl)COCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc(NC(=O)COCc4ccccc4)c3C2=O)ccc1OC
Temperature: 22.5 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
To a solution of (1S)-4-amino-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-isoindole-1,3-dione (1.0 g, 2.4 mmol) in methylene chloride (20 mL), was added diisopropyl ethylamine (0.45 mL, 2.6 mmol), followed by benzyloxy-acetyl chloride (0.37 mL, 2.4 mmol) at 0° C. After 1 hour, the mixture was allowed to warm to 20-25° C. After 15 minutes, the mixture was cooled back to 0° C. To the cooled mixture, was added diisopropyl ethylamine (0.18 mL), and benzyloxy-acetyl chloride (0.14 mL). After 2 hours, the mixture was concentrated, and the resulting residue was purified by Silica Gel column chromatograph to give (1S) 2-benzyloxy-N-{2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}-acetamide (1.2 g, 88% yield).
Reaction SMILES: [Na].S(O)(O)(=O)=O.[CH3:7][O:8][C:9](=[NH:11])[NH2:10].[C:12]([CH2:20][C:21](OCC)=[O:22])(=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO>[CH3:7][O:8][C:9]1[N:10]=[C:21]([OH:22])[CH:20]=[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:11]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: COC(=N)N
Agent: O=S(=O)(O)O
Agent: [Na]
Solvent: CO
Product: COc1nc(O)cc(-c2ccccc2)n1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 8.2 %

Procedure:
Sodium (4.14 g, 180 mmol) was dissolved in dry methanol (120 ml) and the solution was cooled to 0-5° C. O-Methylisourea sulfat (10.3 g, 60 mmol) and ethyl benzoylacetate (11.5 g, 60 mmol) was added and the mixture was stirred for two hours at room temperature and then refluxed for twelve hours. The mixture was evaporated, acidified with 2M HCl and extracted three tines with ethyl acetate and three times with DCM. The organic phase was dried and evaporated and the residue was suspended in diethyl ether, the solid filtered off, washed and dried which gave the title compound, (1.0 g) MS+1=203.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[NH2:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=O>>[CH:17]1[C:13]2[C:14](=[O:16])[NH:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[NH:11][C:12]=2[CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccccc1C(=O)O
Reactant: O=[N+]([O-])c1ccccc1F
Product: O=C1Nc2ccccc2Nc2ccccc21
Yield: 30.9 %

Procedure:
2-Fluoronitrobenzene (847 g, 6 mmol) and 2-aminobenzoic acid (274 mg, 2.0 mmol) were reacted according to GP7 to give 130 mg of the title compound (160FE15A).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:14])[NH:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][N:9]=2)[CH:7]=1.C[O-].[Na+].N1C=CC=C[C:19]1=O>CN(C)C=O.CO>[Br:1][C:2]1[C:3](=[O:14])[N:4]([CH3:19])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][N:9]=2)[CH:7]=1
Reactant: O=c1[nH]cc(-c2ccncn2)cc1Br
Reactant: O=c1cccc[nH]1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: Cn1cc(-c2ccncn2)cc(Br)c1=O
Temperature: 60 °C

Procedure:
20 g of 3-bromo-5-(4-pyrimidyl)-2(1H)-pyridone are suspended in 200 ml of dimethylformamide. A solution of 4.6 g of sodium methoxide in 300 ml of dry dimethylformamide and 15 ml of methanol is added to the pyridone suspension with stirring. The reaction mixture is filtered, 5.3 ml of methyl iodide are added to the filtrate and the mixture heated to 60° C. for 2 hours. After cooling to RT, the solution is concentrated in vacuo resulting in a liquid residue which crystallizes out upon addition of distilled H2O. The solid is stirred with 400 ml of distilled H2O, filtered, washed with H2O, isopropyl alcohol, and ether and dried, yielding 3-bromo-1-methyl-5-(4-pyrimidyl)-2-pyridone, M.P. 208°-210° C.
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:8]=2[O:7][CH2:6][CH2:5][CH2:4]1)[CH3:2].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[CH3:30][NH:31][C:32]([C:34]1[S:35][CH:36]=[CH:37][C:38]=1[NH:39][C:40]1[C:45]([Cl:46])=[CH:44][N:43]=[C:42](Cl)[N:41]=1)=[O:33].C(=O)(O)[O-].[Na+]>C(O)(C)C.O>[CH3:30][NH:31][C:32]([C:34]1[S:35][CH:36]=[CH:37][C:38]=1[NH:39][C:40]1[C:45]([Cl:46])=[CH:44][N:43]=[C:42]([NH:14][C:11]2[CH:12]=[CH:13][C:8]3[O:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[C:9]=3[CH:10]=2)[N:41]=1)=[O:33]
Reactant: CCN1CCCOc2ccc(N)cc21
Reactant: CNC(=O)c1sccc1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CCN1CCCOc2ccc(Nc3ncc(Cl)c(Nc4ccsc4C(=O)NC)n3)cc21
Yield: 48.7 %

Procedure:
9-Ethyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-ylamine (57 mg, 0.30 mmol), 10-Camphorsulfonic acid (72.3 mg, 0.311 mmol) and 3-(2,5-Dichloro-pyrimidin-4-ylamino)-thiophene-2-carboxylic acid methylamide (9.0E1 mg, 0.30 mmol) in Isopropyl alcohol (2.0 mL) was irradiated in a CEM microwave (120° C., 30 min). The mixture was diluted with satd. sodium bicarbonate (1 mL) and water (6 mL). The flocculent solids were separated from an oily residue on the sides of the vial, filtered and washed with water. Drying in vacuo of the solids furnished 3-[5-Chloro-2-(9-ethyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]-thiophene-2-carboxylic acid methylamide (67 mg, 49%). MP=153-155° C.; LCMS: 459 (M+H); 1H-NMR (CDCl3): 11.27 (s, 1H), 8.31 (d, 1H, J=5.1 Hz), 8.08 (s, 1H), 6.92 (s, 1H), 6.88 (m, 2H), 6.71 (s, 1H), 5.67 (s, 1H), 4.14 (m, 2H), 3.29 (m, 2H), 3.27 (m, 2H), 3.02 (d, 3H, J=4.8 Hz), 2.03 (m, 2H), 1.18 (t, 3H, J=6.4 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=[S:10].[C:11]([NH:14][NH2:15])(=O)[CH3:12]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:11]([CH3:12])=[N:14][N:15]=[C:9]1[SH:10]
Reactant: Fc1ccccc1N=C=S
Reactant: CC(=O)NN
Product: Cc1nnc(S)n1-c1ccccc1F

Procedure:
Using the method of Example 1, Part A of U.S. Pat. No. 4,338,453, 2-fluorophenyl isothiocyanate and acethydrazide are reacted to produce 4-(2-fluorophenyl)-5-methyl-4H-1,2,4-triazole-3-thiol (mp 236°-237° C., C:H:N:S:F ratio 51.69:3.86:20.10:15.84:9.10) which is converted to 4-(2-fluorophenyl)-3-methyl-4H-1,2,4-triazole (mp 119°-120° C., C:H:N:F ratio 61.28:4.83:23.58:10.42).