Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[NH:11][C:10]3[C:12]([CH3:20])([CH3:19])[CH2:13][S:14][CH2:15][C:16]([CH3:18])([CH3:17])[C:9]=3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I([O-])(=O)(=O)=[O:22].[Na+]>CO.O>[C:1]1([C:7]2[NH:11][C:10]3[C:12]([CH3:20])([CH3:19])[CH2:13][S:14](=[O:22])[CH2:15][C:16]([CH3:18])([CH3:17])[C:9]=3[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC1(C)CSCC(C)(C)c2[nH]c(-c3ccccc3)nc21
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC1(C)CS(=O)CC(C)(C)c2[nH]c(-c3ccccc3)nc21
Temperature: 2 °C

Procedure:
1.43 g of 2-phenyl-4,5,7,8-tetrahydro-4,4,8,8-tetramethyl-1-H-thiepino[4,5-d]imidazole are dissolved in 75 ml of methanol and cooled to 2° C. with stirring. The solution is treated dropwise at this temperature with a solution of 1.3 g of sodium periodate in 28 ml of water. The mixture is left to react-out at the same temperature for 3 hours. Thereupon, 25 ml of methanol are added. After stirring for 5 hours at room temperature, the solution is concentrated. The product is left to crystallize-out while cooling with ice. The precipitate is removed by filtration and the crystals are covered with acetone and ether. After filtration, the 2-phenyl-4,5,7,8-tetrahydro-4,4,8,8-tetramethyl-1-H-thiepino-[4,5-d]-imidazole 6-oxide is recrystallized from ethanol/n-hexane, m.p. 273°-275° C.; m.p. of the hydrochloride: 300° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([CH:16]([OH:19])[CH2:17][OH:18])[CH:13]=[C:12]([C:20](O)=[O:21])[CH:11]=1)#[N:2].[CH3:23][C:24]1[N:29]=[CH:28][C:27]([CH2:30][NH2:31])=[CH:26][CH:25]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([CH:16]([OH:19])[CH2:17][OH:18])[CH:13]=[C:12]([C:20]([NH:31][CH2:30][C:27]2[CH:28]=[N:29][C:24]([CH3:23])=[CH:25][CH:26]=2)=[O:21])[CH:11]=1)#[N:2]
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(O)CO)c2)c(C#N)c1
Reactant: Cc1ccc(CN)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(C(=O)NCc3ccc(C)nc3)cc(C(O)CO)c2)c(C#N)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2′-cyano-5-(1,2-dihydroxyethyl)-4′-methylbiphenyl-3-carboxylic acid (30 mg, 0.10 mmol) in N,N-dimethylformamide (1 mL) were added (6-methylpyridin-3-yl)methanamine (35 mg, 0.26 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (100 mg, 0.26 mmol), and N,N-diisopropylethylamine (100 μL, 0.57 mmol). The reaction mixture was stirred for 16 hours at 25° C., and then purified by preparative HPLC to afford the final product as a light color solid.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[S:8][CH2:9][C:10]([NH2:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N.[OH2:20]>ClCCl>[C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[S:8]([CH2:9][C:10]([NH2:12])=[O:11])=[O:20])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(=O)CSC(c1ccccc1)c1ccccc1
Reactant: O
Agent: N
Solvent: ClCCl
Product: NC(=O)CS(=O)C(c1ccccc1)c1ccccc1
Yield: 80 %

Procedure:
10 g (38.9 mmoles) of 2-[(diphenylmethyl)thio]acetamide are dissolved in 100 ml of dichloromethane. The solution is added with 15.7 g of 68% w/w ε-phthalimidoperhexanoic acid, keeping the temperature at about 20° C., and after 6 h is diluted with water, adjusting the pH to 8–9 with aqueous ammonia. The resulting phases are separated and the organic one is evaporated to dryness, to obtain 8.5 g of 2-[(diphenylmethyl)sulfinyl]acetamide (modafinil). Molar yield: 80%.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[NH4+:18].[OH-]>>[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])(=[O:3])[NH2:18]
Reactant: [NH4+]
Reactant: O=C(O)c1cc(C(F)(F)F)cc(S(=O)(=O)Cl)c1
Agent: [OH-]
Product: NS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a 3-chlorosulfonyl-5-(trifluoromethyl)benzoic acid (0.4 g) was added 28% ammonia aqueous solution (5.0 ml) at 0° C. The mixture was stirred at 0° C., and then allowed to stand at room temperature overnight. The mixture was concentrated to dryness, and then 1N hydrochloric acid (5 ml) was added to the mixture, and stirred at 0° C. for 30 minutes. The resulted powder was collected by filtration and dried under reduced pressure to give 3-sulfamoyl-5-(trifluoromethyl)benzoic acid (299.4 mg) as a pale yellow powder.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.NC(N)=[S:16].C(O)=O.[OH-].[Na+]>C(O)C>[CH3:13][NH:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2](=[S:16])[N:11]=1
Reactant: NC(N)=S
Reactant: CNc1nc(Cl)nc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Solvent: CCO
Product: CNc1nc(=S)[nH]c2ccccc12
Temperature: 25 °C
Yield: 18.1 %

Procedure:
A mixture of 2-chloro-N-methylquinazolin-4-amine (Example 39) (100 mg, 0.52 mmol), thiourea (47.5 mg, 0.62 mmol) and formic acid (0.02 mL, 0.52 mmol) in ethanol (5 mL) was refluxed for 1.5 h. After cooling to room temperature, the reaction mixture was neutralized with diluted NaOH aqueous solution. The solvent was removed under vacuum and the residue was purified by preparative HPLC eluting with acetonitrile and water to give the title compound (18 mg, 18%). 1H NMR (400 MHz, DMSO-d6) δ 2.99 (d, J=4.8 Hz, 3H), 7.25 (t, J=7.6 Hz, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.65-7.61 (m, 1H), 8.0 (d, J=8.0 Hz, 1H), 8.70 (d, J=4.4 Hz, 1H), 12.32 (s, 1H). MS 192 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cl:12][C:13]1[C:17](Cl)=[N:16][S:15][N:14]=1.Cl>CN(C=O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:17]2[C:13]([Cl:12])=[N:14][S:15][N:16]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Clc1nsnc1Cl
Reactant: CCOC(=O)C1CCNCC1
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(c2nsnc2Cl)CC1
Reaction time: 4 h
Yield: 106.2 %

Procedure:
Piperidine-4-carboxylic acid ethyl ester (14.0 mL, 91 mmol) was dissolved in DMF (15.0 mL) and heated to 100 C. 3,4-Dichloro-1,2,5-thiadiazole (4.0 mL, 42 mmol) was added and the mixture heated at 100 C. for 4 h. The reaction mixture was poured into 1N HCl and extracted with EtOAc (4×). The combined EtOAc extractions were washed with H2O (1×), sat'd NaCl (1×), dried (Na2SO4), and concentrated in vacuo to give 12.3 g (105%) of 1-(4-chloro-[1,2,5]thiadiazol-3-yl)-piperidine-4-carboxylic acid ethyl ester which was used without further purification. 1H NMR (CDCl3) 4.30-4.13 (m, 2H), 4.06-3.93 (m, 2H), 3.12-2.99 (m, 2H), 2.59 (m, 1H), 2.03 (m, 4H), 1.42-1.26 (m, (3H) ppm. LC-MS (MH+)=276.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH2:15][CH2:16][CH3:17])[C:13]=1[OH:14])[N:10]=[C:9]([C:18]([OH:20])=[O:19])[CH:8]=[C:7]2[CH3:21])(=[O:3])[CH3:2].O.[CH2:23](O)[CH3:24]>>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH2:15][CH2:16][CH3:17])[C:13]=1[OH:14])[N:10]=[C:9]([C:18]([O:20][CH2:23][CH3:24])=[O:19])[CH:8]=[C:7]2[CH3:21])(=[O:3])[CH3:2]
Reactant: CCCc1c(O)c(C(C)=O)cc2c(C)cc(C(=O)O)nc12
Reactant: CCO
Solvent: O
Product: CCCc1c(O)c(C(C)=O)cc2c(C)cc(C(=O)OCC)nc12

Procedure:
The product of step (b) (6.5 g) was dissolved in dry ethanol (500 mls). Dry hydrogen chloride gas was then bubbled into this solution until a saturated solution resulted. This solution was heated on a steam bath for 1.5 hours. The mixture was poured into water and extracted into ether. The ethereal layer was washed with water, saturated sodium bicarbonate solution, dried using magnesium sulphate and filtered. On partial removal of the solvent a yellow solid crystallised out of solution. This was filtered off affording (1.1 g) of the sub-title compound. M.P. 150°-151° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([C:10]2[CH:19]=[CH:18][C:17]3[NH:16][C:15](=[O:20])[CH2:14][CH2:13][C:12]=3[N:11]=2)[CH:7]=[N:6][CH:5]=1.[H-].[Na+].[CH3:24]I.O>C1COCC1>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([C:10]2[CH:19]=[CH:18][C:17]3[N:16]([CH3:24])[C:15](=[O:20])[CH2:14][CH2:13][C:12]=3[N:11]=2)[CH:7]=[N:6][CH:5]=1
Reactant: COC(=O)c1cncc(-c2ccc3c(n2)CCC(=O)N3)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cncc(-c2ccc3c(n2)CCC(=O)N3C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
To a stirred solution of 5-(6-oxo-5,6,7,8-tetrahydro-[1,5]naphthyridin-2-yl)-nicotinic acid methyl ester (430 mg, 1.52 mmol) in THF (15.0 mL) was added 60% NaH (91 mg, 2.28 mmol) at 0° C. and the reaction mixture was stirred at 2-5° C. for 0.5 h before CH3I (0.3 mL, 4.56 mmol) was added. After stirring overnight at RT, it was poured into water (5.0 mL). After extraction with EtOAc, the organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give 5-(5-methyl-6-oxo-5,6,7,8-tetrahydro-[1,5]naphthyridin-2-yl)-nicotinic acid methyl ester (383.7 mg, 85%) as a light yellow solid. MS: 298.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[N:6][C:7](=[O:15])[NH:8]2.[CH3:16][Mg]Br>O1CCCC1.CCOCC>[CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]([CH3:16])[NH:6][C:7](=[O:15])[NH:8]2
Reactant: COc1ccc2[nH]c(=O)ncc2c1OC
Reactant: C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc2c(c1OC)C(C)NC(=O)N2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a partial solution of 5,6-dimethoxy-2(1H)quinazolinone (10.0 g, 48.5 mM) in dry tetrahydrofuran (1100 ml) under nitrogen, is added at 0° C. over 20 minutes, an excess of methyl magnesium bromide in ether (62.60 ml of a 3.1 M solution in ether, 194.06 mM). The reaction mixture is then removed from the cooling bath, allowed to reach room temperature and is stirred at room temperature for 16 hours. Additional methyl magnesium bromide is added (15.65 ml of a 3.1 M solution in ether; 48.52 mM) and the reaction mixture is heated at reflux for 2 hours, cooled in an ice-water bath and an aqueous solution of NH4Cl (100 ml of saturated NH4Cl and 100 ml H2O) is added with stirring. After the addition is complete, 10% aqueous HCl is added until a pH of ~6.0 is reached. The layers are separated and the aqueous layer is extracted with CHCl3 (3×250 ml). The CHCl3 extract is combined with the previously separated tetrahydrofuran layer, and the combined organic layers are washed with a saturated aqueous solution of NaCl (200 ml) and dried (Na2SO4). Filtration followed by concentration to ~250 ml affords an off-white precipitate which is filtered and recrystallized from isopropanol (200 ml) to give the product as a colorless solid; yield 9.7 g (87.8%), m.p. 210°-212° C.
Reaction SMILES: [Na].Cl.[NH2:3][OH:4].[C:5](#[N:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CO>[C:5](=[N:3][OH:4])([NH2:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: N#Cc1ccccc1
Reactant: NO
Agent: Cl
Agent: [Na]
Solvent: CO
Product: NC(=NO)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
To a stirred solution of sodium (0.48 g, 210 mmol) in methanol (210 ml) was added a solution of hydroxylamine hydrochloride (15.4 g, 221 mmol) in methanol (70 ml). The mixture was stirred at room temperature for 10 minutes before addition of benzonitrile (20.4 ml, 200 mmol) and the reaction stirred at room temperature overnight. The mixture was filtered through a pad of Celite and the flitrate concentrated in vacuo to approximately 100 ml. Diethyl ether (200 ml) was added and the precipitate filtered. The filtrate was evaporated in vacuo to dryness, and on drying the title compound was obtained as a waxy white solid (27.1 g, 100%). δH (DMSO-d6) 5.92 (2H, br s, NH2), 7.35-7.41 (3H, m, ArH), 7.65-7.91 (2H, m, ArH), 9.69 (1H, br s, OH).
Reaction SMILES: [F:1][CH:2]([F:6])[C:3](O)=[O:4].[CH2:7]([Li])[CH2:8][CH2:9][CH3:10]>CCOCC>[F:1][CH:2]([F:6])[C:3](=[O:4])[CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: O=C(O)C(F)F
Reactant: [Li]CCCC
Solvent: CCOCC
Product: CCCCC(=O)C(F)F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a 3 liter, three-neck, round bottom flask, equipped with a magnetic stirrer, a dropping funnel filled with 39.9 g. of difluoroacetic acid and 200 ml. of ether, and a rubber septum is added 1350 ml. of ether. After cooling in a dry ice-acetone bath under nitrogen, one mole of n-butyl lithium (2.2 M, hexane) is added via a double tip needle. The difluoroacetic acid solution is slowly added to the cooled n-butyl lithium solution via the dropping funnel over 3 hours. The thick mixture is stirred at -78° C. for one hour and then quenched by pouring into a mixture of one liter of 4 N hydrochloric acid and one liter of ice, divided into three flasks, with stirring. The organic layers are combined and washed with water and brine. The 1500 ml. of solution is distilled at atmospheric pressure in a water bath. After the forerun is collected, the residue is fractionally distilled giving 18.8 g (b.p. 100°-110° C.) of product that is 75% real.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[S:5]1[CH:9]=[CH:8][C:7]2[CH:10]=[CH:11][CH:12]=[C:13]([C:14](O)=[O:15])[C:6]1=2>C(O)C>[CH2:1]([O:3][C:14]([C:13]1[C:6]2[S:5][CH:9]=[CH:8][C:7]=2[CH:10]=[CH:11][CH:12]=1)=[O:15])[CH3:2]
Reactant: CC(=O)Cl
Reactant: O=C(O)c1cccc2ccsc12
Solvent: CCO
Product: CCOC(=O)c1cccc2ccsc12
Yield: 86.4 %

Procedure:
Acetyl chloride (14.8 mmol; 1.05 mL) is added to a solution of benzo[b]thiophene-7-carboxylic acid (4.94 mmol; 880 mg) in ethanol (20 mL) and the mixture is stirred at reflux for 24 h. The solvent is removed. Ethyl acetate is added to the residue and the resulting solution is washed with water, dried (Na2SO4), filtered and concentrated to obtain the title compound (880 mg, 92%) as colorless oil. 1H NMR (CDCl3): δ 8.12 (dd, 1H, J=7.2 Hz, 0.6 Hz), 8.03 (dd, 1H, J=7.6 Hz, 1.2 Hz), 7.58 (d, 1H, J=5.6 Hz), 7.46 (t, 1H, J=7.6 Hz), 7.41 (t, 1H, J=5.2 Hz), 4.50 (c, 2H, J=7.3 Hz), 1.47 (t, 3H, J=7.3 Hz).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Cl[C:12]1[N:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][N:13]=1>>[CH2:18]([C:15]1[CH:14]=[N:13][C:12]([N:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)=[N:17][CH:16]=1)[CH3:19]
Reactant: CCc1cnc(Cl)nc1
Reactant: C1CC2(CCN1)OCCO2
Product: CCc1cnc(N2CCC3(CC2)OCCO3)nc1

Procedure:
The title compound is prepared from 1,4-dioxa-8-azaspiro[4.5]decane and 2-chloro-5-ethyl-pyrimidine following a procedure analogous to that described for Intermediate 61.
Reaction SMILES: CC1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[O:11][CH3:12])=[O:9])[C:4](=[O:21])O1.[S:23]([C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:36])[CH3:35])=[CH:29][CH:28]=1)(=[O:26])(=[O:25])[NH2:24]>>[F:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][N:10]([O:11][CH3:12])[C:8](=[O:9])[CH:7]=[C:5]([OH:6])[C:4]([NH:24][S:23]([C:27]2[CH:28]=[CH:29][C:30]([NH:33][C:34](=[O:36])[CH3:35])=[CH:31][CH:32]=2)(=[O:25])=[O:26])=[O:21])=[CH:19][CH:18]=1
Reactant: CC(=O)Nc1ccc(S(N)(=O)=O)cc1
Reactant: CON(Cc1ccc(F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Product: CON(Cc1ccc(F)cc1)C(=O)C=C(O)C(=O)NS(=O)(=O)c1ccc(NC(C)=O)cc1

Procedure:
2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-benzyl)-N-methoxy-acetamide was treated with N-(4-sulfamoyl-phenyl)-acetamide as described in the preparation of compound 1 to yield the title compound. 1H NMR (500 MHz, DMSO) δ: 2.07 (s, 3), 3.60 (s, 3), 4.71 (s, 2), 6.26 (s, 1), 6.94 (m, 2), 7.21 (m, 2), 7.72 (m, 2), 7.86 (m, 2).
Reaction SMILES: [NH2:1][C:2](=C)/[CH:3]=[CH:4]/[C:5](/[NH:8][C:9]1[C:18]2[CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[C:15](=[O:28])[NH:14][C:13]=2[N:12]=[CH:11][CH:10]=1)=[CH:6]/[CH3:7].[F:30][C:31]1[CH:32]=[C:33]([S:38](Cl)(=[O:40])=[O:39])[CH:34]=[CH:35][C:36]=1[F:37]>>[F:30][C:31]1[CH:32]=[C:33]([S:38]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9]3[C:18]4[CH2:17][N:16]([CH2:19][C:20]5[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=5)[C:15](=[O:28])[NH:14][C:13]=4[N:12]=[CH:11][CH:10]=3)=[CH:4][CH:3]=2)(=[O:40])=[O:39])[CH:34]=[CH:35][C:36]=1[F:37]
Reactant: O=S(=O)(Cl)c1ccc(F)c(F)c1
Reactant: C=C(N)/C=C/C(=C/C)Nc1ccnc2c1CN(Cc1ccc(OC)cc1)C(=O)N2
Product: COc1ccc(CN2Cc3c(Nc4ccc(NS(=O)(=O)c5ccc(F)c(F)c5)cc4)ccnc3NC2=O)cc1

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 62 using 5-[(Z)-4-amino-1-eth-(E)-ylidene-penta-2,4-dienylamino]-3-(4-methoxy-benzyl)-3,4-dihydro-1 H-pyrido[2,3-d]pyrimidin-2-one and 3,4-difluoro-benzenesulfonyl chloride. LC-MS (M+H=552, obsd.=552).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:27]=[CH:26][C:9]2[N:10]=[C:11]([NH:14][CH:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][C:22]=4[O:24][CH3:25])[CH2:17][CH2:16]3)[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4].[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>C(#N)C>[CH3:25][O:24][C:22]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:23]=1[CH:15]([NH:14][C:11]1[O:12][CH2:13][C:8]3[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:32]4[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]4)[CH:27]=[CH:26][C:9]=3[N:10]=1)[CH2:16][CH2:17]2
Reactant: COc1cccc2c1C(NC1=Nc3ccc(NC(=O)CCl)cc3CO1)CC2
Reactant: CN1CCNCC1
Solvent: CC#N
Product: COc1cccc2c1C(NC1=Nc3ccc(NC(=O)CN4CCN(C)CC4)cc3CO1)CC2
Yield: 77.3 %

Procedure:
Prepared from rac-2-chloro-N-[2-(7-methoxy-indan-1-ylamino)-4H-benzo[d][1,3]oxazin-6-yl]-acetamide (Example 55 step A) (100 mg, 0.259 mmol) and 1-methylpiperazine (0.289 ml 2.595 mmol) in acetonitrile (1 ml) according to the procedure described for Example 3 step B. Obtained the title compound as a light yellow foam (90 mg, 77%), MS (ISP) m/e=450.2 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.C1COCC1.C1(C)C=CC=CC=1.CON(C)[C:25]([C:27]1[C:32]([NH2:33])=[N:31][CH:30]=[CH:29][N:28]=1)=[O:26].Cl>C1COCC1>[NH2:33][C:32]1[C:27]([C:25]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:26])=[N:28][CH:29]=[CH:30][N:31]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: CON(C)C(=O)c1nccnc1N
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Nc1nccnc1C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 0.9 M 4-chlorophenyl magnesium bromide in THF/toluene (9.15 ml, 8.24 mmol) is added dropwise to a solution of 3-amino-pyrazine-2-carboxylic acid methoxy-methylamide (0.5 g, 2.74 mmol) in THF (15 ml) at 0° C. The reaction is allowed to warm to room temperature and stirred for 1.5 hours. The reaction mixture is cooled to 0° C. and 2 M HCl (20 ml) is added. The product is extracted into EtOAc (3×40 ml), dried (MgSO4) and concentrated in vacuo. Purification by flash chromatography (SiO2, 0-5% MeOH in DCM) yields (3-Amino-pyrazin-2-yl)-(4-chloro-phenyl)-methanone as a yellow solid.
Reaction SMILES: C1(C)C=CC(S([N:10]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[Br:19])[CH2:11]2)(=O)=O)=CC=1.C1(O)C=CC=CC=1.Br>C(O)(=O)CC>[Br:19][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:17]=1[CH2:18][NH:10][CH2:11]2
Reactant: Cc1ccc(S(=O)(=O)N2Cc3cccc(Br)c3C2)cc1
Agent: Br
Solvent: Oc1ccccc1
Solvent: CCC(=O)O
Product: Brc1cccc2c1CNC2
Yield: 92.5 %

Procedure:
The procedure of Reference Example 6-(3) was followed using 9.61 g of 2-(p-toluenesulfonyl)-4-bromoisoindoline, 10 g of phenol, 120 ml of 48% hydrobromic acid, and 20 ml of propionic acid. Purification of the crude product by vacuum distillation gave 5.0 g of 4-bromoisoindoline.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:10][CH2:9][C:8]([CH3:12])([CH3:11])[C:5]2=[N:6][CH:7]=1.Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([F:24])=[CH:21][CH:22]=2)[N:17]=[C:16]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[C:15]=1[CH:31]([CH3:33])[CH3:32].Cl.O1CCOCC1>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]([C:14]3[C:23]4[C:18](=[CH:19][C:20]([F:24])=[CH:21][CH:22]=4)[N:17]=[C:16]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)[C:15]=3[CH:31]([CH3:33])[CH3:32])[CH2:9][C:8]([CH3:12])([CH3:11])[C:5]2=[N:6][CH:7]=1
Reactant: CC1(C)CNc2cc(Br)cnc21
Reactant: CC(C)c1c(-c2ccccn2)nc2cc(F)ccc2c1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: CC(C)c1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC(C)(C)c2ncc(Br)cc21
Temperature: 150 °C

Procedure:
Prepared according to procedure L using 6-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (94 mg, 0.416 mmol), 4-chloro-7-fluoro-3-isopropyl-2-(pyridin-2-yl)quinoline (125 mg, 0.416 mmol) and 4.0M solution of HCl in 1,4-dioxane (0.10 mL, 0.416 mmol) in NMP (0.6 mL) and heating in the microwave for 5 h at 150° C. After purification 4-(6-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-7-fluoro-3-isopropyl-2-(pyridin-2-yl)quinoline was obtained as a colorless film. Mass Spectrum (ESI) m/e=491 [(M+1) (79Br)] and 493 [(M+1) (81Br)].
Reaction SMILES: [Cl:1]/[C:2](/[C:9]([O:11][CH3:12])=[O:10])=[C:3](\Cl)/[C:4]([O:6][CH3:7])=[O:5].C([O-])(=O)C.[NH4+:17]>CN(C)C=O>[NH2:17]/[C:3](/[C:4]([O:6][CH3:7])=[O:5])=[C:2](\[Cl:1])/[C:9]([O:11][CH3:12])=[O:10]
Reactant: [NH4+]
Reactant: COC(=O)/C(Cl)=C(/Cl)C(=O)OC
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: COC(=O)/C(N)=C(/Cl)C(=O)OC
Temperature: 120 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
53.25 g (0.25 mol) of dimethyl dichloromaleate were dissolved in 100 ml of dimethylformamide, and 48.16 g (0.625 mol) of ammonium acetate were added. The mixture was rapidly heated to 120° C. and stirred at 110° C. to 120° C. for one hour. The solvent was subsequently removed by distillation, the residue was taken up in methylene chloride, and the solution was washed with water. The methylene chloride was removed by distillation on an evaporator, and, after recrystallization, 40 g (83% yield) of dimethyl aminochloromaleate were obtained in the form of yellowish, cubic crystals (m.p. 96°-98° C.)
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([C@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4].[NH2:31][CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[OH:30][C:6]1[C:5]([C:3]([NH:31][CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:4])=[N:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[C:9]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:10](=[O:23])[N:11]2[C@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16]
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2[C@@H](C)c2ccccc2)c1O
Reactant: NCCCC(=O)O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: C[C@@H](c1ccccc1)n1c(=O)c(-c2ccccc2)cc2c(O)c(C(=O)NCCCC(=O)O)ncc21
Temperature: 25 °C
Yield: 36.1 %

Procedure:
A mixture of (S)-5-hydroxy-2-oxo-3-phenyl-1-(1-phenyl-ethyl)-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (40 mg, 0.1 mmol), 4-aminobutyric acid (825 mg, 8.0 mmol) and NaOMe solution (12 mL, 6.0 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (5-60% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 17 mg of the title compound. MS: (+) m/z 472.34 (M+1).