Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:6][CH:5]=[C:4]([C:7]#[N:8])[C:3]=1[C:9]1[S:10][CH:11]=[CH:12][N:13]=1.[O:14]=[C:15]1[CH2:24][CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][N:21]=2)[N:16]1[CH2:25][C:26](O)=[O:27]>>[C:7]([C:4]1[C:3]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[C:2]([NH:1][C:26](=[O:27])[CH2:25][N:16]2[C:17]3[C:22](=[N:21][CH:20]=[CH:19][CH:18]=3)[CH2:23][CH2:24][C:15]2=[O:14])[S:6][CH:5]=1)#[N:8]
Reactant: O=C(O)CN1C(=O)CCc2ncccc21
Reactant: N#Cc1csc(N)c1-c1nccs1
Product: N#Cc1csc(NC(=O)CN2C(=O)CCc3ncccc32)c1-c1nccs1
Yield: 4.3 %

Procedure:
The title compound was prepared from 5-amino-4-(thiazol-2-yl)thiophene-3-carbonitrile (67 mg, 0.32 mmol) and 2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetic acid (100 mg, 0.48 mmol) according to protocol A. The crude product was purified by column chromatography (2% methanol/methylene chloride) and HPLC to give N-(4-cyano-3-(thiazol-2-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetamide (5.4 mg) as a white solid. LCMS m/z 396.1, method [7] retention time 2.611 min. 1H-NMR (300 MHz, CDCl3) δ 8.39 (d, J=4.1 Hz, 1H), 7.76 (d, J=3.3 Hz, 2H), 7.62 (s, 1H), 7.58 (d, J=7.4 Hz, 1H), 7.44 (m, 2H), 3.46 (t, J=7.1 Hz, 2H), 3.02 (t, J=7.2 Hz, 2H).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][C:6]2[N:7]([CH3:32])[C:8]3[C:13]([N:14]=2)=[C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:11]=[C:10]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH2:30][CH3:31])[N:9]=3)[CH2:2]1.[CH3:33][C:34]1([O:37][CH2:36]1)[CH3:35]>>[CH2:30]([C:22]1[N:21]([C:10]2[N:9]=[C:8]3[C:13]([N:14]=[C:6]([CH2:5][CH:3]4[CH2:2][N:1]([CH2:33][C:34]([CH3:36])([OH:37])[CH3:35])[CH2:4]4)[N:7]3[CH3:32])=[C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[N:11]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=1)[CH3:31]
Reactant: CC1(C)CO1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CNC3)n(C)c2n1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(CC(C)(C)O)C3)n(C)c2n1

Procedure:
Following General Procedure C, 4-(8-(azetidin-3-ylmethyl)-2-(2-ethyl-1H-benzo[d]imidazol-1-yl)-9-methyl-9H-purin-6-yl)morpholine and isobutylene oxide were reacted at room temperature to give 534. LCMS m/z: 253.2 (2M+H+)
Reaction SMILES: C(OC([N:11]([C:23]1([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:27][C:26](=[O:28])[NH:25][C:24]1=[O:29])[NH:12]C(OCC1C=CC=CC=1)=O)=O)C1C=CC=CC=1.[H][H]>C(O)C>[NH:11]([C:23]1([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:27][C:26](=[O:28])[NH:25][C:24]1=[O:29])[NH2:12]
Reactant: [H][H]
Reactant: CCOC(=O)C1(N(NC(=O)OCc2ccccc2)C(=O)OCc2ccccc2)CC(=O)NC1=O
Solvent: CCO
Product: CCOC(=O)C1(NN)CC(=O)NC1=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 100.8 %

Procedure:
To a solution of the compound of Example 1 (1.00 g) in ethanol (30 ml) was added 5% palladium-carbon ethylenediamine complex (100 mg). The mixture was stirred vigorously at room temperature under hydrogen (atmospheric pressure) for 2.5 hours. During this reaction, to remove carbon dioxide generated with the progress of the reaction, the gas in the reactor was replaced with hydrogen gas several times. The reaction mixture was filtered through a Celite pad and then the Celite was washed with ethanol. The filtrate combined with the washers was concentrated to give the desired product (432 mg, quantitative) as oil
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][N:6]1[C:11]1[C:20]([N+:21]([O-])=O)=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][N:12]=1)=O.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1.[H][H]>ClCCl.N.O[V](=O)=O.[Pt]>[O:2]=[C:3]1[NH:21][C:20]2[CH:19]=[C:14]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=[N:12][C:11]=2[N:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C@@H:5]12
Reactant: [H][H]
Reactant: COC(=O)c1cnc(N2CCCC[C@H]2C(=O)OC)c([N+](=O)[O-])c1
Agent: O=[V](=O)O
Agent: [Pt]
Agent: N
Solvent: ClCCl
Product: COC(=O)c1cnc2c(c1)NC(=O)[C@@H]1CCCCN21
Reaction time: 16 h
Yield: 88.9 %

Procedure:
In a bomb hydroginator, (S)-methyl 6-(2-(methoxycarbonyl)piperidin-1-yl)-5-nitronicotinate (1.95 g, 6.03 mmol), triphenyl phosphite (0.019 ml, 0.060 mmol), ammonium vanadate (0.056 g, 0.483 mmol) and platinum (5% on carbon, 0.235 g, 0.060 mmol) were mixed in dichloromethane (Volume: 30.2 ml) to give a suspension. The bomb was sealed and pressurized to 110 psi with hydrogen gas. The reaction was stirred at 110 psi 16 h, depressurized, diluted with DCM (100 mL) and refluxed 10 minutes. The hot mixture was filtered through celite and washed with DCM (50 mL). The filtrate was concentrated in vacuo to yield 1.4 g (89%) of the product as a white solid and used without further purification. [M+H] calc'd for C, 13; H, 15; N, 3O, 3, 262; found, 262.
Reaction SMILES: [F:1][CH2:2][C:3]([N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22])([CH2:8][C:9](O)=[O:10])[C:4]([O:6][CH3:7])=[O:5].N1C=CC=CC=1.S(Cl)([Cl:31])=O.Cl.N1C=CC=CC=1>CCOCC>[F:1][CH2:2][C:3]([N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22])([CH2:8][C:9]([Cl:31])=[O:10])[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)C(CF)(CC(=O)O)N1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: COC(=O)C(CF)(CC(=O)Cl)N1C(=O)c2ccccc2C1=O

Procedure:
A solution of methyl 2-fluoromethyl-2-phthalimido-3-carboxy-propionate (2.37 g, 13.7 mmol) and pyridine (1.10 g, 13.7 mmol) in dry ether (50 ml) is treated with thionyl chloride (10 ml) at room temperature overnight. After addition of more ether (100 ml), pyridine hydrochloride is removed by filtration, and the solvent is evaporated to give the title compound as an orange oil (2.80 g).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]([O:11][CH2:12]/[C:13](/[C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1)=[C:14](/[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)\[C:15]([OH:17])=[O:16])=[O:10].[CH2:34](I)[CH3:35].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]([O:11][CH2:12]/[C:13](/[C:24]1[CH:25]=[CH:26][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:28][CH:29]=1)=[C:14](/[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)\[C:15]([O:17][CH2:34][CH3:35])=[O:16])=[O:10]
Reactant: CCI
Reactant: CS(=O)(=O)c1ccc(/C(COC(=O)OCCCCCCBr)=C(/C(=O)O)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C(=C(\COC(=O)OCCCCCCBr)c1ccc(S(C)(=O)=O)cc1)c1ccccc1
Reaction time: 1 h

Procedure:
To a solution of 2.6 g of (2Z)-4-({[(6-bromohexyl)oxy]carbonyl}oxy)-3-[4-(methylsulfonyl)phenyl]-2-phenylbut-2-enoic acid in 20 mL of DMF at rt was added 3.8 mL of ethyl iodide and 670 mg of potassium carbonate under nitrogen. The reaction was stirred for 1 h, quenched by saturated aqueous NH4Cl, extracted with EtOAc, washed with water (3×), brine, and dried over sodium sulfate. Purification by flash chromatography afforded 1.86 g of the titled compound as a brownish oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:22])=[C:4]([F:21])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([O:17]CC)=[O:16])[C:7]2=[O:20].C(O)(=O)C.S(=O)(=O)(O)O>O>[Br:1][C:2]1[C:3]([F:22])=[C:4]([F:21])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:20]
Reactant: CCOC(=O)c1cn(C2CC2)c2c(Br)c(F)c(F)cc2c1=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cn(C2CC2)c2c(Br)c(F)c(F)cc2c1=O
Temperature: 0 °C
Yield: 88.7 %

Procedure:
A mixture of ethyl 8-bromo-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate (1.0 g), acetic acid (4 ml), water (3 ml) and concentrated sulfuric acid (0.5 ml) was heated on an oil bath (90°-100° C.) for an hour under stirring, then for an hour at room temperature and poured into ice water (20 ml). The resulting precipitate was collected by filtration and washed with water to give the title compound (0.82 g), mp 224°-225.5° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]2[C:10]=1[S:11]([C:14]1[N:18]=[CH:17][NH:16][N:15]=1)(=[O:13])=[O:12].C(=O)([O-])[O-].[K+].[K+].[CH3:25][N:26]([CH3:30])[C:27](Cl)=[O:28]>CN(C)C=O>[CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]2[C:10]=1[S:11]([C:14]1[N:18]=[CH:17][N:16]([C:27](=[O:28])[N:26]([CH3:30])[CH3:25])[N:15]=1)(=[O:13])=[O:12]
Reactant: CN(C)C(=O)Cl
Reactant: Cc1nc2ccccn2c1S(=O)(=O)c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc2ccccn2c1S(=O)(=O)c1ncn(C(=O)N(C)C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-(2-methylimidazo[1,2-a]pyridin-3-yl)sulfonyl-1H-1,2,4-triazole (100 mg), anhydrous potassium carbonate (105 mg) and N,N-dimethylformamide (0.5 ml) was added dimethylcarbamoyl chloride (0.06 ml), and the reaction mixture was stirred at room temperature overnight. The reaction solution was extracted with ethyl acetate-water. The organic layer was washed with water, followed by saturated aqueous sodium chloride solution, and concentrated. The residue was subjected to a silica-gel column chromatography with 30 to 50% (20% 2-propanol/ethyl acetate)/hexane to yield the title compound (107 mg).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[N+:8]([C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Cl)=[CH:13][CH:12]=1)([O-:10])=[O:9].O>O1CCCC1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:15][C:14]2[CH:17]=[CH:18][C:11]([N+:8]([O-:10])=[O:9])=[CH:12][CH:13]=2)[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Solvent: C1CCOC1
Solvent: O
Product: CN1CCN(Cc2ccc([N+](=O)[O-])cc2)CC1
Yield: 50 %

Procedure:
Monomethylpiperazine (15 mL) and tetrahydrofuran (60 mL) were placed in a 200 mL eggplant shaped flask, and a solution of 4-nitrobenzylchloride (8.58 g, 50 mmol) in tetrahydrofuran was added dropwise to the mixture at room temperature while stirring. After finishing the instillation, the mixture was stirred at room temperature for 24 hours. The reaction mixture was mixed with distilled water, and the precipitated solids were collected by filtration and dried under reduced pressure to obtain the title compound (5.9 g, 50%).
Reaction SMILES: [CH:1]1[C:6]([C:7]2[CH:13]=[C:12]([NH2:14])[C:10](=[O:11])[NH:9][CH:8]=2)=[CH:5][CH:4]=[N:3][CH:2]=1.[C:15]([C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16]>N1C=CC=CC=1>[C:15]([C:19]1[CH:20]=[CH:21][C:22]([C:23]([NH:14][C:12]2[C:10](=[O:11])[NH:9][CH:8]=[C:7]([C:6]3[CH:1]=[CH:2][N:3]=[CH:4][CH:5]=3)[CH:13]=2)=[O:24])=[CH:26][CH:27]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: Nc1cc(-c2ccncc2)c[nH]c1=O
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(C(=O)Nc2cc(-c3ccncc3)c[nH]c2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.9 %

Procedure:
Amrinone (200 mg, 1.07 mmol) was suspended in pyridine (5 mL) and 4-tert-butylbenzoyl chloride (209 μL, 1.07 mmol) was added. The reaction mixture was stirred overnight at room temperature. The solid was filtered and rinsed with MeOH to give the title compound as a pink solid (33 mg, 9% yield). MS (ES+) m/e=348. 1H NMR (DMSO-d6) δH 1.43 (9H, s), 7.57-7.62 (4H, m), 7.81 (1H, s), 7.88 (2H, d), 8.59 (2H, d), 8.78 (1H, d), 9.32 (1H, s), 12.61 (1H, s).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)[CH3:3].Cl[CH2:19][CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:3][N:2]([CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:19][CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:13][CH:12]=2)[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1)[CH3:1]
Reactant: CN(C)CC1(c2ccc(O)cc2)CCOCC1
Reactant: CCN(CC)CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)CCCOc1ccc(C2(CN(C)C)CCOCC2)cc1
Yield: 21.6 %

Procedure:
4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (500 mg, 2.13 mmol), (3-chloro-propyl)-diethyl-amine (319 mg, 2,13 mmol), DMF (10 ml) and K2CO3 (1.18 g, 8.52 mmol) were reacted together according to general procedure B. Purification by chromatography on silica, eluant (36% EtOH: 1% NH3 in DCM) gave the title compound as a pale yellow clear oil (160 mg, 22%). 1H NMR (400 MHz, CDCl3) δ7.20 (d, 2H), 6.86 (d, 2H), 4.00 (t, 2H), 3.75 (dt, 2H), 3.55 (td, 2H), 2.61 (t, 2H), 2.54 (q, 4H), 2.40 (s, 2H), 2.15-1.82 (m, 6H), 1.97 (s, 6H), 1.02 (t, 6H).
Reaction SMILES: N1C=CN=CC=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[S:22])=[CH:16][CH:15]=1>CCOCC>[F:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH:8]2[C:9]2[CH:8]=[N:7][CH:12]=[CH:11][N:10]=2)=[S:22])=[CH:16][CH:15]=1
Reactant: c1cnc(N2CCNCC2)cn1
Reactant: Fc1ccc(N=C=S)cc1
Solvent: CCOCC
Product: Fc1ccc(NC(=S)N2CCNCC2c2cnccn2)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 4.92 g. of 1-(2-pyrazinyl)piperazine in 50 ml. of anhydrous ether is added dropwise a solution of 4.59 g. of 4-fluorophenyl isothiocyanate in 50 ml. of anhydrous ether with stirring. Stirring is continued for 30 minutes and the resulting solid is collected. This solid is dissolved in a mixture of 200 ml. of ethanol, and 75 ml. of acetone with heat, then concentrated to 200 ml. and cooled giving 7.43 g. of the desired product as a white solid, m.p. 195°-197° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH3:25])[O:10][C:11]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)([C:13]([F:16])([F:15])[F:14])[CH:12]=2)=[CH:4][C:3]=1[CH3:26].[Li]CCCC.[C:32](=[O:34])=[O:33].Cl>C1COCC1.CCCCCC.CCOCC>[Cl:24][C:19]1[CH:18]=[C:17]([C:11]2([C:13]([F:16])([F:15])[F:14])[O:10][N:9]([CH3:25])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:32]([OH:34])=[O:33])=[C:3]([CH3:26])[CH:4]=3)=[CH:12]2)[CH:22]=[C:21]([Cl:23])[CH:20]=1
Reactant: Cc1cc(C2=CC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)ON2C)ccc1Br
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: Cc1cc(C2=CC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)ON2C)ccc1C(=O)O
Temperature: -90 °C
Reaction time: 1 h

Procedure:
210 mg of 3-(4-Bromo-3-methyl-phenyl)-5-(3,5-dichloro-phenyl)-2-methyl-5-trifluoromethyl-2,5-dihydro-isoxazole (IIIa) was dissolved in 20 ml of dry THF, cooled to −90° C. and treated with 0.625 ml BuLi 1.6M in hexane. The mixture was stirred for 1 hour at −80° C. and then a great excess of solid CO2 was added to the mixture. The temperature was allowed to rise up to −30° C. (1 hour) and 5 ml of 1M HCl was added followed with ether. The organic layer was dried and evaporated to dryness. The residual resin was used in the final step without purification.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(CC)CC.C(Cl)(Cl)(Cl)Cl.[NH:32]=[C:33]([NH:35][NH:36][C:37]([C:39]1[C:44]([NH:45][C:46]2[CH:51]=[CH:50][C:49]([Br:52])=[CH:48][C:47]=2[F:53])=[C:43]([F:54])[C:42](=[O:55])[N:41]([CH3:56])[CH:40]=1)=O)[CH3:34]>C(Cl)Cl.C(OCC)(=O)C>[Br:52][C:49]1[CH:50]=[CH:51][C:46]([NH:45][C:44]2[C:39]([C:37]3[NH:32][C:33]([CH3:34])=[N:35][N:36]=3)=[CH:40][N:41]([CH3:56])[C:42](=[O:55])[C:43]=2[F:54])=[C:47]([F:53])[CH:48]=1
Reactant: CC(=N)NNC(=O)c1cn(C)c(=O)c(F)c1Nc1ccc(Br)cc1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1nnc(-c2cn(C)c(=O)c(F)c2Nc2ccc(Br)cc2F)[nH]1
Temperature: 50 °C
Reaction time: 2 h
Yield: 42.1 %

Procedure:
PPh3 (0.12 g, 0.45 mmol), Et3N (0.17 mL, 1.21 mmol), and CCl4 (0.044 mL, 0.45 mmol) were added to a stirred suspension of 4-(4-bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid N′-(1-imino-ethyl)-hydrazide (0.073 g, 0.18 mmol) in methylene chloride (2 mL). The reaction mixture was stirred at 50° C. for 2 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed with water, dried (MgSO4) and concentrated. Purification by flash column chromatography (4% MeOH in methylene chloride) gave clean desired product (30 mg, 50%); MS APCI (−) m/z 394, 396 (M−, Br pattern) detected; 1H NMR (400 MHz, CD3OD) δ 8.16 (s, 1H), 7.31 (dd, 1H), 7.25 (d, 1H), 7.01 (td, 1H), 3.67 (s, 3H), 2.51 (s, 3H).
Reaction SMILES: CC1(C)[O:6][CH:5]([CH2:7][O:8][NH:9][C:10]([C:12]2[C:20]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:23]=3[Cl:29])=[C:19]([F:30])[C:15]3[N:16]=[N:17][S:18][C:14]=3[CH:13]=2)=[O:11])[CH2:4][O:3]1.Cl.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[OH:6][CH:5]([CH2:4][OH:3])[CH2:7][O:8][NH:9][C:10]([C:12]1[C:20]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:23]=2[Cl:29])=[C:19]([F:30])[C:15]2[N:16]=[N:17][S:18][C:14]=2[CH:13]=1)=[O:11]
Reactant: CC1(C)OCC(CONC(=O)c2cc3snnc3c(F)c2Nc2ccc(Br)cc2Cl)O1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(NOCC(O)CO)c1cc2snnc2c(F)c1Nc1ccc(Br)cc1Cl
Yield: 75.8 %

Procedure:
To a solution of N-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-fluoro-5-((4-bromo-2-chlorophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxamide (60 mg, 0.11 mmol) in CH2Cl2 (10 mL) was added 1.0 N HCl (aq., 1 mL, 1.0 mmol). The mixture was stirred for 1 h and neutralized with saturated sodium bicarbonate (aq.). The aqueous layer was extracted by CH2Cl2 (10 mL×2). The combined organic layers were washed by water (10 mL) and brine (10 mL) sequentially, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (CH2Cl2/MeOH, 20:1, v/v) to afford the desired product (yellow solid, 41 mg, 61.5% yield for two steps). 1H NMR (400 MHz, CD3OD): δ 11.13 (s, 1H), 8.59 (s, 1H), 7.66 (d, 1H), 7.34 (dd, 1H), 6.76 (m, 1H), 3.79 (m, 1H), 3.71 (m, 2H), 3.35 (m, 2H). MS APCI (+) m/z: m/z 492.8, [M+H].
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][C:13]1[CH:21]=[C:17]([C:18]([OH:20])=[O:19])[C:16]([OH:22])=[CH:15][CH:14]=1.Cl>N1C=CC=CC=1>[CH2:5]([O:4][C:2]([NH:12][C:13]1[CH:21]=[C:17]([C:18]([OH:20])=[O:19])[C:16]([OH:22])=[CH:15][CH:14]=1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc(O)c(C(=O)O)c1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(O)c(C(=O)O)c1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 25.5 %

Procedure:
Benzyl chloroformate (5.5 g) was added to a suspension of 5-aminosalicylic acid (4.6 g) in dry pyridine (25 ml) at 0° C. during a period of 5 minutes. The mixture was allowed to warm to 25° C. and was stirred for 20 hours, and was then poured into a mixture of ice (100 g) and concentrated hydrochloric acid (50 ml). The solid that precipitated was then filtered off and dissolved in ethanol (50 ml) and treated with a little charcoal. The mixture was filtered and the filtrate was evaporated to dryness to give 5-benzyloxycarbonylaminosalicylic acid (2.2 g), m.p. 222°-224° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:9]=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:24][CH2:25][CH2:26]Br.[NH4+].[Cl-]>CN(C=O)C>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([C:15]3([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:26][CH2:25][CH2:24]3)[CH:9]=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[CH2:2][CH2:3]1
Reactant: BrCCCBr
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])c(OCC2CC2)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(c2ccc([N+](=O)[O-])c(OCC3CC3)c2)CCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
Ethyl 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)acetate (5 g, 17.9 mmol) was dissolved in 50 mL anhydrous DMF, NaH (60% wt. in oil, 1.43 g, 35.9 mmol) was added at 0° C. The reaction mixture was stirred for 0.5 h at 25° C. and 1,3-dibromopropane (1.91 mL, 17.9 mmol) was added drop wise at 0° C. The reaction mixture was stirred at 0° C. for 1 h and saturated NH4Cl solution (10 mL) was added. The reaction mixture was extracted with EtOAc (3×20 mL) and the combined organic phases were washed with water (3×20 mL) and brine (20 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give ethyl 1-(3-(cyclopropylmethoxy)-4-nitrophenyl)cyclobutanecarboxylate (2.8 g) as a colorless oil.
Reaction SMILES: COC1C=C2C(=CC=1OC)C(=O)CCC2.[N:16]1C=CC=CC=1.[N+:22]([C:25]1[CH:47]=[CH:46][C:28]([CH2:29][O:30]/[N:31]=[C:32]2\[CH2:33][CH2:34][CH2:35][C:36]3[C:41]\2=[CH:40][C:39]([O:42][CH3:43])=[C:38]([O:44][CH3:45])[CH:37]=3)=[CH:27][CH:26]=1)([O-])=[O:23].C(OCC)(=O)C.CCCCCC>C(O)C>[N:22]1[O:23][N:16]=[C:47]2[CH:46]=[C:28]([CH2:29][O:30]/[N:31]=[C:32]3\[CH2:33][CH2:34][CH2:35][C:36]4[C:41]\3=[CH:40][C:39]([O:42][CH3:43])=[C:38]([O:44][CH3:45])[CH:37]=4)[CH:27]=[CH:26][C:25]=12
Reactant: c1ccncc1
Reactant: COc1cc2c(cc1OC)/C(=N/OCc1ccc([N+](=O)[O-])cc1)CCC2
Agent: COc1cc2c(cc1OC)C(=O)CCC2
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CCCCCC
Product: COc1cc2c(cc1OC)/C(=N/OCc1ccc3nonc3c1)CCC2
Yield: 88 %

Procedure:
6,7-Dimethoxy-1-tetralone (40 mg, 0.19 mmol) was subjected to reaction with 0-(benzo[c][1,2,5]oxadiazol-5-ylmethyl)hydroxylamine hydrochloride (41 mg, 0.20 mmol) in ethanol (2 mL) and pyridine (0.2 mL, 2.58 mmol) under the same conditions as described for (E)-6,7-dimethoxy-3,4-dihydronaphthalen-1(2H)-one O-4-nitrobenzyl oxime. Subjection of the material obtained on work up to flash chromatography (3:7 v/v ethyl acetate/hexane elution) afforded the title compound as white crystals (60 mg, 88%), m.p. 139-140° C., Rf 0.4.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:7])[S:5][CH:6]=1.CC(C)C(O)=O.[CH3:14][N:15]([CH3:18])[CH:16]=O>>[CH3:14][N:15]([CH3:18])[CH:16]=[N:7][C:4]1[S:5][CH:6]=[C:2]([CH3:1])[N:3]=1
Reactant: Cc1csc(N)n1
Reactant: CN(C)C=O
Solvent: CC(C)C(=O)O
Product: Cc1csc(N=CN(C)C)n1

Procedure:
prepared by reaction of 4-methyl-thiazol-2-ylamine with N,N-dimethylformamide dimethyl acetate. LC-MS: tR=0.51 min; [M+H]+=170.1.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.I[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[CH3:20].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:19]=3[CH3:20])[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: Cc1ccncc1I
Reactant: O=C1NCCc2ccc(Cl)cc21
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCc2ccc(Cl)cc2C1=O
Yield: 31.1 %

Procedure:
Using analogous reaction conditions as described in Example 1, 7-chloro-3,4-dihydro-2H-isoquinolin-1-one (I-1d: 150 mg, 0.824 mmol) was reacted with 3-iodo-4-methyl-pyridine (216 mg, 0.989 mmol), 1,4-dioxane (10 mL), copper iodide (15.69 mg, 0.0824 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (35.10 mg, 0.2472 mmol) and potassium phosphate (524 mg, 2.472 mmol) to afford the crude product. Purification by column chromatography on silica gel (1% methanol in CHCl3) afforded 70 mg of the product (31.25% yield).