Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([O:20][CH3:21])[CH:14]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:22]([C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1)([CH3:24])[CH3:23].C(N(CC)CC)C>O1CCCC1>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][S:31]([C:28]3[CH:29]=[CH:30][C:25]([CH:22]([CH3:24])[CH3:23])=[CH:26][CH:27]=3)(=[O:33])=[O:32])=[C:15]([O:20][CH3:21])[CH:14]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cc(C2CCN(Cc3ccccc3)C2)ccc1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(C2CCN(Cc3ccccc3)C2)ccc1NS(=O)(=O)c1ccc(C(C)C)cc1
Temperature: 25 °C
Yield: 129.7 %

Procedure:
4-(1-Benzyl-pyrrolidin-3-yl)-2-methoxy-phenylamine (220 mg, 0.78 mmol) and 4-isopropylphenylsulfonyl chloride (170 mg, 0.78 mmol) were dissolved in tetrahydrofuran (20 ml). Triethylamine (0.32 ml, 2.34 mmol) was added and the reaction mixture stirred over night at room temperature (10% conversion) and subsequently refluxed for 4 h (70% conversion). One small portion of 4-isopropylphenylsulfonyl chloride and triethylamine were added and the reaction mixture was stirred 15 min at 150° C. in the microwave (CEM). The solvent was evaporated under reduced pressure, the residue treated with ethyl acetate (50 ml) and extracted twice with slightly acidic water. The organic layer was dried over magnesium sulfate, filtered, and the solvent evaporated under reduced pressure to give an oil (470 mg). The crude product was purified via silica gel chromatography with cyclohexane/ethyl acetate (gradient 0-100%). Fractions containing the product were combined, the solvent evaporated to yield an oil (143 mg, 40%).
Reaction SMILES: C[C@@H]1CCCN(C(C2C=C(C)C=CC=2C2C=NN(C)C=2)=O)[C@@H]1CNC1C=CC(C(F)(F)F)=CN=1.[NH2:35][CH2:36][C@@H:37]1[C@H:42]([CH3:43])[CH2:41][CH2:40][CH2:39][N:38]1[C:44]([C:46]1[CH:51]=[C:50]([CH3:52])[CH:49]=[CH:48][C:47]=1[N:53]1[CH:57]=[N:56][C:55]([C:58]([F:61])([F:60])[F:59])=[N:54]1)=[O:45].Cl[C:63]1[CH:70]=[CH:69][C:66]([C:67]#[N:68])=[CH:65][N:64]=1>>[CH3:43][C@@H:42]1[CH2:41][CH2:40][CH2:39][N:38]([C:44](=[O:45])[C:46]2[CH:51]=[C:50]([CH3:52])[CH:49]=[CH:48][C:47]=2[N:53]2[CH:57]=[N:56][C:55]([C:58]([F:61])([F:60])[F:59])=[N:54]2)[C@@H:37]1[CH2:36][NH:35][C:63]1[CH:70]=[CH:69][C:66]([C:67]#[N:68])=[CH:65][N:64]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: Cc1ccc(-n2cnc(C(F)(F)F)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Agent: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)c1
Product: Cc1ccc(-n2cnc(C(F)(F)F)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C#N)cn2)c1

Procedure:
The title compound was synthesized following the same general protocol as described for ((2S,3R)-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)phenyl)methanone and 6-chloronicotinonitrile. ESI-MS (m/z): 484 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.[Li]CCCC.CC[O:29][C:30]([CH:32]([F:34])[F:33])=O>C1COCC1>[Br:1][C:2]1[S:3][C:4]([C:30](=[O:29])[CH:32]([F:34])[F:33])=[CH:5][CH:6]=1
Reactant: CCOC(=O)C(F)F
Reactant: Brc1cccs1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(c1ccc(Br)s1)C(F)F
Temperature: -78 °C
Reaction time: 1 h
Yield: 69.1 %

Procedure:
A solution of 2-bromothiophene (0.5 g, 3.00 mmol) in dry THF (5 mL) was cooled to −78° C. and freshly prepared lithium diisopropylamide (prepared from diisopropyl amine (0.5 mL, 3.60 mmol) and nBuLi (2.3 mL, 3.60 mmol, 1.6M in THF) was added dropwise. The reaction mixture was stirred at −78° C. for 1 h. Ethyl difluoro acetate (409 mg, 3.30 mmol) was added dropwise at −78° C. and the reaction mixture was stirred for 1 h, then slowly warmed up to room temperature and quenched with saturated NH4Cl solution. The organic product was extracted with EtOAc and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure to get 1-(5-bromothiophen-2-yl)-2,2-difluoroethanone (500 mg, yield 69%). 1H NMR (400 MHz, CDCl3) δ 7.77-7.75 (m, 1H), 7.21-7.20 (d, J=4.1 Hz, 1H), 6.27-6.00 (m, 1H).
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16](Cl)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1.[NH:25]1[CH2:29][CH2:28][CH:27]([OH:30])[CH2:26]1>>[F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([N:25]4[CH2:29][CH2:28][CH:27]([OH:30])[CH2:26]4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1
Reactant: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: OC1CCNC1
Product: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(N3CCC(O)C3)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide, and pyrrolidin-3-ol. 1H NMR (400 MHz, DMSO-d6): δ 8.74 (t, J=5.62 Hz, 1H), 7.72 (d, J=9.61 Hz, 1H), 7.52 (dd, J=9.21, 8.20 Hz, 2H), 6.96 (d, J=9.23 Hz, 1H), 4.97-5.01 (m, 1H), 3.55-3.61 (m, 4H), 3.22-3.25 (m, 2H), 2.02-2.04 (m, 3H), 1.73-1.94 (m, 6H), 1.15-1.32 (m, 2H). m/z: 424.2 [M+H]+
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][CH2:16]OS(C)(=O)=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1.O>C(#N)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][CH2:16][N:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCOS(C)(=O)=O)CC1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCCC2)CC1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture of methanesulfonic acid trans-2-(4-tert-butoxycarbonylamino-cyclohexyl)-ethyl ester (3.2 g, 10 mmol), potassium carbonate (1.4 g, 10 mmol) and pyrrolidine (1.25 mL, 15 mmol) in acetonitrile (40 mL) was stirred at 60° C. for 2 hours. The mixture was cooled to room temperature and poured into water (200 mL). The precipitated white crystals were filtered off and washed with water to yield 1.9 g (64%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O>C(OCC)(=O)C.CO.[Pd]>[NH2:9][C:8]1[CH:7]=[CH:6][C:5]([CH2:12][C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(CC(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(CC(=O)OC(C)(C)C)ccc1N
Reaction time: 2 h
Yield: 96.2 %

Procedure:
A mixture of t-butyl 3-methoxy-4-nitrophenylacetate (0.144 g, 0.539 mmol) and 10% Pd on carbon (0.155 g) in ethyl acetate (8 mL) and methanol (2 mL) was stirred under H2 (40–60 psi) for 2 h. The mixture was filtered through Celite and the filtrate concentrated to afford t-butyl 4-amino-3-methoxyphenylacetate (0.123 g, 96%) as a light yellow oil: 1H NMR (CDCl3, 300 MHz, ppm) 6.70 (m, 3H), 4.04 (bs, 2H), 3.84 (s, 3H), 3.42 (s, 2H), 1.43 (s, 9H).
Reaction SMILES: Br[CH:2]([CH2:7][C:8]1[CH:9]=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH3:27])=[CH:22][N:21]=1)[CH:12]=2)[C:3]([O:5]C)=O.[NH2:28][C:29]([NH2:31])=[S:30].C([O-])(=O)C.[Na+]>C(O)C>[CH2:26]([C:23]1[CH:24]=[CH:25][C:20]([CH2:19][O:18][C:13]2[CH:12]=[C:11]3[C:16]([CH:17]=[C:8]([CH2:7][CH:2]4[S:30][C:29](=[NH:28])[NH:31][C:3]4=[O:5])[CH:9]=[N:10]3)=[CH:15][CH:14]=2)=[N:21][CH:22]=1)[CH3:27]
Reactant: NC(N)=S
Reactant: CCc1ccc(COc2ccc3cc(CC(Br)C(=O)OC)cnc3c2)nc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CCc1ccc(COc2ccc3cc(CC4SC(=N)NC4=O)cnc3c2)nc1

Procedure:
In ethanol (20 mL) was dissolved the crude residue (790 mg) of methyl 2-bromo-3-[7-(5-ethyl-2-pyridylmethoxy)-3-quinolyl]propionate. The solution was heated under reflux for 15 hours after addition of thiourea (140 mg, 1.84 mmol.) and sodium acetate (150 mg, 1.84 mmol.). After the completion of reaction was confirmed, ethanol was distilled off. To the residue were added ethyl acetate and aqueous sodium hydrogen carbonate. The organic portion was recovered, washed with water, and dried over sodium sulfate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20]Br)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:22]([NH2:24])[CH3:23]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][NH:24][CH2:22][CH3:23])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: BrCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Reactant: CCN
Product: CCNCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1

Procedure:
In analogy to example 3.1, 3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole and Ethylamine were converted to yield {3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-propyl}-ethyl-amine as white solid, MS: 391 (MH+,1Br).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[C:3]=1[C:4]([NH:6][C:7]1[S:18][C:10]2[C:11]([CH3:17])([CH3:16])[O:12][C:13]([CH3:15])([CH3:14])[C:9]=2[C:8]=1[C:19]([OH:21])=O)=[O:5].[CH2:30]([NH2:33])[CH2:31][CH3:32]>>[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:29])[F:27])[C:3]=1[C:4]([NH:6][C:7]1[S:18][C:10]2[C:11]([CH3:17])([CH3:16])[O:12][C:13]([CH3:14])([CH3:15])[C:9]=2[C:8]=1[C:19]([NH:33][CH2:30][CH2:31][CH3:32])=[O:21])=[O:5]
Reactant: CCCN
Reactant: CC1(C)OC(C)(C)c2c1sc(NC(=O)c1c(F)cccc1C(F)(F)F)c2C(=O)O
Product: CCCNC(=O)c1c(NC(=O)c2c(F)cccc2C(F)(F)F)sc2c1C(C)(C)OC2(C)C

Procedure:
The title compound was prepared from the product of Example 45A and propylamine using the procedure described in Example 2B. 1H NMR (DMSO-d6, 300 MHz) δ 0.85 (t, J=7.3 Hz, 3H), 1.42-1.49 (m, 2H), 1.44 (s, 6H), 1.48 (s, 6H), 3.08-3.14 (m, 2H), 7.67-7.8 (m, 3H), 8.05 (t, J=5.4 Hz, 1H), 11.54 (br s, 1H). MS (ESI+) m/z 473 (M+H)+. Anal. calcd. for C22H24F4N2O3S: C, 55.92; H, 5.12; N, 5.93. Found: C, 55.39; H, 4.65; N, 5.69.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]2[NH:8][C:9](=[O:13])[CH2:10][CH2:11][CH2:12][C:6]=2[CH:5]=1)([O-:3])=[O:2].Br[CH2:17][C:18]([O:20][CH3:21])=[O:19].[H-].[Na+]>CN(C=O)C>[CH3:21][O:20][C:18](=[O:19])[CH2:17][N:8]1[C:9](=[O:13])[CH2:10][CH2:11][CH2:12][C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:15]=[CH:14][C:7]1=2
Reactant: COC(=O)CBr
Reactant: O=C1CCCc2cc([N+](=O)[O-])ccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)CCCc2cc([N+](=O)[O-])ccc21
Temperature: 60 °C
Yield: 90 %

Procedure:
7-Nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (375 mg, 1.82 mmol) and methyl bromoacetate (417 mg, 2.73 mmol) were dissolved in anhydrous DMF. Sodium hydride (60% in mineral oil, 146 mg, 3.64 mmol) was added, and the mixture was heated to 60° C. for 2 hours. After cooling to room temperature, the mixture was partitioned between ethyl acetate and water, washed once with water, and concentrated to a brown oil. Preparative TLC (50% EtOAc/hexane) afforded (7-Nitro-2-oxo-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)-acetic acid methyl ester as a yellow solid, 454 mg. (90% yield) 1H NMR (400 MHz, DMSO-d6) δ 8.23 (s, 1H), 8.12-8.18 (m, 1H), 7.51-7.56 (m, 1H), 4.60 (s, 2H), 3.62 (s, 3H), 2.93-3.00 (m, 2H), 2.05-2.20 (m, 4H); MS (m/e) 279 (M+1). 8b) 7-Nitro-2-oxo-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)-acetic acid methyl ester 9 (454 mg, 1.63 mmol), ammonium formate (400 mg), and 10% palladium on carbon (200 mg) were suspended in ethanol (8 ml) and heated to reflux 30 minutes. The heat was removed, and additional amounts of ammonium formate (400 mg) and 10% palladium on carbon (200 mg) were added. The mixture was refluxed an additional 30 minutes, cooled to room temperature, filtered through Celite, and concentrated. The resulting brown residue was partitioned between ethyl acetate and water, washed once with water, and concentrated. Preparative TLC (50% EtOAc/hexane) afforded (7-Amino-2-oxo-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)-acetic acid methyl ester as a white foam, 270 mg. (67% yield) 1H NMR (400 MHz, DMSO-d6) δ 6.86-6.91 (m, 1H), 6.38-6.44 (m, 2H), 5.06 (s, 2H), 4.44 (s, 2H), 3.61 (s, 3H), 2.51-2.82 (m, 2H), 1.92-2.22 (m, 4H); MS (m/e) 249 (M+1). 8c) 7-Amino-2-oxo-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)-acetic acid methyl ester (270 mg, 1.09 mmol), 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzenesulfonamide (362 mg, 1.09 mmol) and 4N HCl in dioxane (0.273 ml, 1.09 mmol) were dissolved in 2-methoxyethanol (5 ml) and heated to 120° C. for 18 hours. The mixture was concentrated to a brown oil. Preparative TLC (5% MeOH/CH2Cl2) gave the title compound as a white solid, 327 mg. (55% yield) 1H NMR (400 MHz, DMSO-d6) δ 9.58 (s, 1H), 9.23 (s, 1H), 8.38-8.50 (m, 1H), 8.29 (s, 1H), 7.72-7.87 (m, 2H), 7.60-7.68 (m, 1H), 7.54 (s, 1H), 7.46-7.51 (d, 1H), 7.28-7.35 (m, 1H), 7.22-7.29 (m, 1H), 4.48 (s, 2H), 3.63 (s, 3H), 2.53-2.84 (m, 2H), 2.44 (s, 3H), 1.96-2.26 (m, 4H); MS (m/e) 545 (M+1); retention time 8.28 minute; mp 237-239° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][CH3:10])[N:4]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:18]([O:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=1)=[S:19].O>CC(C)=O>[CH3:1][O:2][C:3]1[N:4]=[C:5]([N:9]([CH3:10])[C:18](=[S:19])[O:20][C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CNc1cccc(OC)n1
Reactant: S=C(Cl)Oc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COc1cccc(N(C)C(=S)Oc2ccc3ccccc3c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.9 %

Procedure:
1.38 g of 2-methoxy-6-methylaminopyridine and 1.38 g of anhydrous potassium carbonate were added to 20 ml of acetone, to which 2.23 g of 2-naphthyl chlorothioformate dissolved in 20 ml of acetone was added at room temperature under stirring. The stirring was continued for 30 minutes under the same conditions and then the mixture was heated to reflux for 2 hours. The reaction mixture was poured into water after it was cooled to room temperature and the products were extracted with benzene. The benzene solution was subsequently washed with water and aqueous saturated sodium chloride solution and then benzene was removed by distillation under reduced pressure after drying over anhydrous magnesium sulfate. The residue was purified by the column chromatography (eluted with benzene on a silica gel) to give 2.75 g of O-2-naphthyl N-(6-methoxy-2-pyridyl)-N-methylthiocarbamate (Yield: 85%). A part of the product was recrystallized from acetone-hexane. Colorless crystalls having melting point of 95.5° to 97° C. were obtained.
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:27])[CH2:7][CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][C:22]([S:25][CH3:26])=[CH:21][CH:20]=3)[N:13]=2)[CH2:9][C:10]=1[OH:11])(=[O:4])[CH2:2][CH3:3].I([O-])(=O)(=O)=[O:29].[Na+]>CO.O>[C:1]([C:5]1[C:6](=[O:27])[CH2:7][CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:20]=[CH:21][C:22]([S:25]([CH3:26])=[O:29])=[CH:23][CH:24]=3)[N:13]=2)[CH2:9][C:10]=1[OH:11])(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)C1=C(O)CC(c2cccc(Oc3ccc(SC)cc3)n2)CC1=O
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCC(=O)C1=C(O)CC(c2cccc(Oc3ccc(S(C)=O)cc3)n2)CC1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5.5 g (0.0143 mol) of 2-propionyl-3-hydroxy-5-(6-(4-(methylthio)phenoxy)-2-pyridyl)cyclohex-2-en-1-one in 250 mL of methanol was added a solution of 3.22 g (0.0151 mol) of sodium periodate in 25 mL of water. The resulting mixture was stirred at ambient temperature for 24 hours and the sodium iodate by-product was filtered off. The filtrate was reduced in vacuo and the residue dissolved in 150 mL of CH2Cl2 and washed with water (3×150 mL) and dried over Na2SO4 and the solvent removed in vacuo. The crude product was dissolved in CH2Cl2 and placed on a column of silica gel. The column was initially eluted with CH2Cl2 and then with a 90:10 CH2Cl2 :acetone mixture. The product fractions were combined and the solvent removed in vacuo giving the above named product in a yield of 3.2 g (56 percent of theoretical). The product melted at 78°-86° C.: Rf -0.24 (silica gel, 5:95 methanolCH2Cl2), 1H NMR (CDCl3) δ1.1 (t, 3H, CH3CH2 --), 2.5-3.6 (m, 7H, ring protons and CH3CH2 --), 2.72 (s, 3H, CH3S(O)--), 6.7-7.8 (m, 7H, ArH), 18.0 (s, 1H, OH).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1.[C:11]1(=O)[O:16][C:14](=[O:15])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.C(O)(=O)C>O>[OH:8][CH2:7][CH2:6][C:5]1[CH:9]=[CH:10][C:2]([N:1]2[C:14](=[O:15])[C:13]3[C:12](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:11]2=[O:16])=[CH:3][CH:4]=1
Reactant: Nc1ccc(CCO)cc1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC(=O)O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1c1ccc(CCO)cc1
Temperature: 100 °C
Yield: 61.6 %

Procedure:
A flask containing 4-aminophenethyl alcohol (1 g, 7.29 mmol), phthalic anhydride (1.13 g, 7.65 mmol) and acetic acid (6 mL) was heated at 100° C. for 1 h. The reaction mixture was poured into water (50 mL) and the solid was filtered off and washed with water. The crude was purified by flash column chromatography to afford the desired product as white solid (1.2 g, 62%). 1H NMR: 2.92 (t, 2H, J=6.6 Hz), 3.89 (t, 2H, J=6.6 Hz), 7.38 (s, 3H), 7.77-7.82 (m, 2H), 7.92-7.97 (m, 21-1).
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[NH:5][C:6](=[O:14])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2.O>C(O)(=O)C>[Br:1][C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:14])[NH:5][C:4]=1[CH3:3]
Reactant: BrBr
Reactant: Cc1cc2ccccc2c(=O)[nH]1
Solvent: CC(=O)O
Solvent: O
Product: Cc1[nH]c(=O)c2ccccc2c1Br
Reaction time: 3 h
Yield: 87.5 %

Procedure:
A solution of bromine 491 mL, 9.58 mmol) in acetic acid (10 mL) is added to a stirred solution of 3-methyl-2H-isoquinolin-1-one (1.45 g, 9.12 mmol) in acetic acid (1 mL). After 3 hr, water (60 mL) is added and the resulting solids are collected by filtration to afford 4-bromo-3-methyl-2H-isoquinolin-1-one (1.90 g, 88% yield) as a white solid. LC/MS: MS m/e=238/240 (M+H); RT 2.97 min.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:30]=1.[C:31](Cl)(=[O:35])[O:32][CH2:33][CH3:34].C(N(CC)CC)C>O1CCCC1>[F:26][C:25]([F:28])([F:27])[C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[C:18]([NH:17][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:10][C:7]1[CH:8]=[CH:9][C:4]2[N:5]([CH:30]=[C:2]([NH:1][C:31](=[O:35])[O:32][CH2:33][CH3:34])[N:3]=2)[N:6]=1)=[O:29]
Reactant: CCOC(=O)Cl
Reactant: Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Yield: 62 %

Procedure:
Using N-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide (150 mg, 0.362 mmol), ethyl chlorocarbonate (41 μL, 0.435 mmol), triethylamine (75 μL, 0.544 mmol) and tetrahydrofuran (3 mL) as starting materials and in the same manner as in Example 388, the title compound (109 mg, 62%) was obtained as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[C:18]4([NH:21][C:22](=[O:31])[C:23](=[O:30])[N:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)[CH2:19][CH2:20][CH:15]([CH2:16][CH2:17]4)[CH2:14][N:13]3[C:32](=[O:35])[C:33]=2[OH:34])=[O:9])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:47][N:48]([CH3:53])[S:49](Cl)(=[O:51])=[O:50]>ClCCl>[CH3:47][N:48]([CH3:53])[S:49]([N:27]1[CH2:26][CH2:25][N:24]([C:23](=[O:30])[C:22]([NH:21][C:18]23[CH2:19][CH2:20][CH:15]([CH2:16][CH2:17]2)[CH2:14][N:13]2[C:32](=[O:35])[C:33]([OH:34])=[C:10]([C:8]([NH:7][CH2:6][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:37][CH:36]=4)=[O:9])[N:11]=[C:12]32)=[O:31])[CH2:29][CH2:28]1)(=[O:51])=[O:50]
Reactant: O=C(NC12CCC(CC1)Cn1c2nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O)C(=O)N1CCNCC1
Reactant: CN(C)S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)S(=O)(=O)N1CCN(C(=O)C(=O)NC23CCC(CC2)Cn2c3nc(C(=O)NCc3ccc(F)cc3)c(O)c2=O)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 49.2 %

Procedure:
To a suspension of N-(4-fluorobenzyl)-3-hydroxy-4-oxo-10-((oxo(1-piperazinyl)acetyl)amino)-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxamide (0.025 g, 0.040 mmol) in dichloromethane (1 mL) was added diisopropyl ethylamine (0.028 mL, 0.160 mmol) and the solution was stirred at room temperature for 5 min. Added to this was dimethylsulfamoyl chloride (4.26 μL, 0.040 mmol) and the solution was stirred at room temperature for 16 h. The reaction solution was concentrated and purified by preparative HPLC: Solvent A=10% methanol/90% H2O/0-1% trifluoroacetic acid; Solvent B=90% methanol/10% H2O/0.1% trifluoroacetic acid; Start % B=20; Final % B=100; Gradient time=20 min; Stop time=30 min; Column=XTERRA® 19×50 mm, C18, 5 μm to give the title compound as a white solid (12.2 mg, 45% yield). LCMS (M+H) calcd for C27H35FN7O7S: 620.23; found: 620.74. 1H NMR (500 MHz, CDCl3) δ: 12.00 (1 H, s), 8.45 (1 H, s), 8.39 (1 H, t, J=5.95 Hz), 7.36 (2H, dd, J=8.55, 5.49 Hz), 7.01 (2 H, t, J=8.55 Hz), 4.55 (2 H, d, J=6.10 Hz), 4.16 (2 H, d, J=3.66 Hz), 4.02-4.09 (2 H, m), 3.52-3.61 (2 H, m), 3.26-3.36 (2 H, m), 3.18-3.26 (2 H, m), 2.84 (6 H, s), 2.58 (2 H, ddd, J=14.19, 9.16, 5.65 Hz), 2.50 (1H, brs), 1.86-2.11 (4 H, m), 1.66-1.80 (2 H, m).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][NH:22]1.CN(C=O)C>C(Cl)(Cl)Cl>[CH:21]1([C:5]2[N:4]([CH:1]3[CH2:3][CH2:2]3)[C:13]3[C:8]([C:7](=[O:17])[C:6]=2[C:18]([OH:20])=[O:19])=[CH:9][C:10]([F:16])=[CH:11][C:12]=3[F:14])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][NH:22]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: c1ccc2c(c1)CNC2
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=C(O)c1c(C2NCc3ccccc32)n(C2CC2)c2c(F)cc(F)cc2c1=O
Temperature: 120 °C
Yield: 67 %

Procedure:
A mixture of 136 mg of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 180 mg of isoindoline, and 1.5 ml of anhydrous DMF was heated at 120° C. for 1.5 hours while stirring. The resulting reaction mixture was evaporated under reduced pressure to dryness. The residue thus obtained was dissolved into 20 ml of chloroform. The solution was washed with 5% acetic acid and brine in this order, dried over anhydrous sodium sulfate, and condensed. The residue was crystallized by the addition of hot ethanol. After cooling the mixture, the crystals were collected by filtration and recrystallized from a mixed solvent of chloroform, methanol, and ethanol to obtain 123 mg of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[F:20])[C:5]([NH:7][C:8]1[N:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][N:9]=1)=[O:6].[H][H]>CCO.CO.[Pt]>[NH2:14][C:11]1[CH:12]=[N:13][C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:17]=[CH:18][C:19]([F:20])=[C:2]([Cl:1])[CH:3]=2)=[N:9][CH:10]=1
Reactant: O=C(Nc1ncc([N+](=O)[O-])cn1)c1ccc(F)c(Cl)c1
Reactant: [H][H]
Agent: [Pt]
Solvent: CO
Solvent: CCO
Product: Nc1cnc(NC(=O)c2ccc(F)c(Cl)c2)nc1
Yield: 80 %

Procedure:
To 1C (1.16 g, 3.92 mmol) in a mixture of 60 mL EtOH and 10 mL MeOH was added 10% Pt/C (300 mg). The reaction was stirred under 1 atmosphere of hydrogen for 1.5 h, filtered, and concentrated to give 850 mg (80% yield) ID. RP HPLC ret. t.: 1.58 min. and (M+H)+: 267.