Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[N:3]=1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.CCN(C(C)C)C(C)C>C1COCC1.CC(O)C>[N:20]1([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=3)[N:3]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Reactant: C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CC(C)O
Product: NS(=O)(=O)Cc1cccc(Nc2ncnc(N3CCOCC3)n2)c1
Temperature: 60 °C

Procedure:
To a solution of triazine A1 (300 mg, 1.0 mmol) in a mixture of THF (4 mL) and iPrOH (4 mL) were added morpholine (87 mg, 1.0 mmol) and DIPEA (200 μL, 1.15 mmol). The mixture was heated for 2 hours at 60° C. and the solvent removed under reduced pressure. The residue was treated with MeOH and the solid title compound (B10) collected by filtration, washed with MeOH, and dried in vacuo. Yield: 93.3 mg (27%), colorless amorphous solid. MS (ES) C14H18N6O3S requires: 350. found: 351 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]([CH2:20][C:21](O)=[O:22])[S:10]([C:13]2[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=2)(=[O:12])=[O:11])=[CH:5][CH:4]=1.[CH2:24]([NH:31][CH2:32][CH3:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([N:31]([CH2:32][CH3:33])[C:21](=[O:22])[CH2:20][N:9]([C:6]1[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[S:10]([C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=1)(=[O:11])=[O:12])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCNCc1ccccc1
Reactant: COc1ccc(N(CC(=O)O)S(=O)(=O)c2ncccc2C)cn1
Product: CCN(Cc1ccccc1)C(=O)CN(c1ccc(OC)nc1)S(=O)(=O)c1ncccc1C

Procedure:
prepared by reaction of [(6-methoxy-pyridin-3-yl)-(3-methyl-pyridine-2-sulfonyl)-amino]-acetic acid with benzyl-ethyl-amine
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]2[C:9]3[CH2:14][CH2:13][NH:12][CH2:11][C:10]=3[C:15](=[O:17])[O:16][C:4]=2[CH:3]=1.C(N(CC)CC)C.Cl.Cl[CH2:27][CH2:28][N:29]1[CH2:35][CH:34]2[CH2:36][CH2:37][CH:31]([CH2:32][CH2:33]2)[CH2:30]1>C(O)C>[CH:34]12[CH2:36][CH2:37][CH:31]([CH2:32][CH2:33]1)[CH2:30][N:29]([CH2:28][CH2:27][N:12]1[CH2:13][CH2:14][C:9]3[C:5]4[CH:6]=[C:7]([CH3:8])[C:2]([CH3:1])=[CH:3][C:4]=4[O:16][C:15](=[O:17])[C:10]=3[CH2:11]1)[CH2:35]2
Reactant: Cc1cc2oc(=O)c3c(c2cc1C)CCNC3
Reactant: ClCCN1CC2CCC(CC2)C1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc2oc(=O)c3c(c2cc1C)CCN(CCN1CC2CCC(CC2)C1)C3
Temperature: 25 °C
Yield: 46.5 %

Procedure:
A mixture of 1,2,3,4-tetrahydro-8,9-dimethyl-5H-[1]benzopyrano[3,4-c]pyridin-5-one (6.0 g, 0.026 moles), triethylamine (6.1 g, 0.060 moles), and 3-(2-chloroethyl)-3-azabicyclo[3.2.2]nonane hydrochloride (6.3 g, 0.028 moles) in absolute ethanol (150 ml) is stirred at reflux under a nitrogen atmosphere for 24 hours. The crude product precipitates as the free base as the reaction mixture is cooled slowly to room temperature. The product is filtered and recrystallized from absolute ethanol to yield the final product (4.6 g), mp 174°-175° C.
Reaction SMILES: O1CC[O:3][CH:2]1[C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:10]=[C:9]2I.[CH:24]1([CH2:27][OH:28])[CH2:26][CH2:25]1>C(O)C>[CH:24]1([CH2:27][O:28][C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[C:6]([CH:2]=[O:3])[CH:7]=3)[N:11]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:20])([CH3:21])[CH3:22])[N:10]=2)[CH2:26][CH2:25]1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2cc(C3OCCO3)ccc21
Reactant: OCC1CC1
Solvent: CCO
Product: C[Si](C)(C)CCOCn1nc(OCC2CC2)c2cc(C=O)ccc21

Procedure:
The title compound was prepared in close analogy to the procedure described in Example 11A using 166 mg (0.372 mmol) 5-(1,3-dioxolan-2-yl)-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazole (Example 6A) and 4 ml cyclopropylmethanol (instead of ethanol). The reaction mixture was filtered, and the filtrate was purified by preparative RP-HPLC (acetonitrile/water+0.05% TFA gradient) to afford 53 mg (57% of th.) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[N+:26]([C:29]1[CH:37]=[C:36]2[C:32]([C:33]([CH:38]=O)=[CH:34][NH:35]2)=[CH:31][CH:30]=1)([O-:28])=[O:27]>CO.N1CCCCC1>[OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])/[C:7](=[CH:38]/[C:33]3[C:32]4[C:36](=[CH:37][C:29]([N+:26]([O-:28])=[O:27])=[CH:30][CH:31]=4)[NH:35][CH:34]=3)/[O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]1
Reactant: O=Cc1c[nH]c2cc([N+](=O)[O-])ccc12
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Solvent: CO
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4cc([N+](=O)[O-])ccc24)C3=O)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 67.2 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.050 g, 0.14 mmol) obtained in Example A16, Step 1 in methanol (2.0 mL) was added with 6-nitro-1H-indole-3-carboxaldehyde (0.026 g, 0.14 mmol). Then, the mixture was added with 5 drops of piperidine, and the mixture was stirred at 50° C. for 2 hours. The solvent was evaporated under reduced pressure, and then the residue was washed with a mixed solvent of chloroform and methanol to obtain tert-butyl (Z)-4-({6-hydroxy-2-[(6-nitro-1H-indol-3-yl)methylene]-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.049 g, 67%).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][NH:6][C:7]([CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:11][CH2:10]1)=[O:8])=O>P(Cl)(Cl)(Cl)=O>[Cl:1][CH2:2][C:3]1[O:8][C:7]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[CH2:11][CH2:10]2)=[N:6][N:5]=1
Reactant: O=C(CCl)NNC(=O)C1CCN(c2ccccn2)CC1
Solvent: O=P(Cl)(Cl)Cl
Product: ClCc1nnc(C2CCN(c3ccccn3)CC2)o1
Yield: 78 %

Procedure:
The hydrazide of Preparation 3 (20.4 g, 69 mmol) was suspended in phosphorus oxychloride (150 ml) at 100° C. for 4 hours. The mixture was cooled and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and was added to water. The aqueous layer was basified by addition of solid sodium hydrogen carbonate and the phases were separated. The aqueous phase was extracted with ethyl acetate (×2) and the combined organic layers were dried over magnesium sulphate and evaporated under reduced pressure. The material isolated was triturated with diethyl ether to give the title compound as a beige solid (15 g).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].Cl[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][O:11][C:6]1[CH:5]=[CH:4][C:3]([C:12](=[O:14])[CH3:13])=[C:2]([OH:1])[C:7]=1[CH2:8][CH2:9][CH3:10])[CH3:21]
Reactant: CCOC(=O)CCl
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(OCC(=O)OCC)ccc(C(C)=O)c1O

Procedure:
A mixture of 24.25 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 16.0 ml of ethyl chloroacetate and 26 g anhydrous potassium carbonate in 375 ml of anhydrous acetone was stirred at reflux for 17 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to an oil which was crystallized from ethanol to give 27.2 g of (4-acetyl-3-hydroxy-2-propylphenoxy)acetic acid ethyl ester, the titled compound, mp 61°-64°, (78% yield) in two crops.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7](Br)=[CH:8][C:9]=1[NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].Br[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=2)=[CH:8][C:9]=1[NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: Fc1ccc(Br)nc1
Reactant: COC(=O)c1sc(Br)cc1NC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1sc(-c2ccc(F)cn2)cc1NC(=O)OC(C)(C)C
Temperature: 90 °C

Procedure:
Palladium(II) acetate (20 mg) was added to a solution of 5-bromo-3-tert-butoxycarbonylaminothiophene-2-carboxylic acid methyl ester (300 mg), 2-bromo-5-fluoropyridine (235.5 mg), bis(pinacolato)diboron (462.2 mg), tri-t-butylphosphonium tetrafluoroborate (77.64 mg) and cesium carbonate (871.9 mg) in dioxane/water (6 mL/1.5 mL). The solution was heated at 90° C. for 3 h. The reaction solution was then mixed with ethyl acetate and water. The aqueous phase was extracted several times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated. The crude product was purified by preparative HPLC. The product with the molecular weight of 352.39 (C16H17FN2O4S) was obtained in this way; MS (ESI): 353 (M+H+).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:19][CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][C:14]=3[CH:27]=2)=[CH:8][N:9]=1)(=[O:3])[CH3:2].[ClH:28]>CO.O1CCOCC1>[ClH:28].[O:19]1[C:13]2[CH:12]=[CH:11][C:10]([C:7]3[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][CH:8]=3)=[CH:27][C:14]=2[CH2:15][NH:16][CH2:17][CH2:18]1
Reactant: CC(=O)Nc1ncc(-c2ccc3c(c2)CN(C(=O)OC(C)(C)C)CCO3)s1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(=O)Nc1ncc(-c2ccc3c(c2)CNCCO3)s1
Yield: 99 %

Procedure:
A mixture 1,1-dimethylethyl 7-[2-(acetylamino)-1,3-thiazol-5-yl]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (0.29 g, 0.75 mmol), in methanol (2 mL) and 4 M hydrogen chloride in 1,4-dioxane (2 mL) was stirred at 70° C. for 15 minutes. The reaction mixture was cooled and concentrated, and dried in vacuum to give the de-protected product N-[5-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1,3-thiazol-2-yl]acetamide hydrochloride (0.24 g, 0.24 mmol, 99% yield); MS (EI) for C14H15N3O2S: 290 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH:13][C@H:14]2[C:27](=[O:28])[N:16]3[C:17]([C:24]([O-:26])=[O:25])=[C:18]([CH:21]([CH3:23])[CH3:22])[CH2:19][S:20][C@H:15]23)=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2]>FC(F)(F)C(O)=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH:13][C@H:14]2[C:27](=[O:28])[N:16]3[C:17]([C:24]([OH:26])=[O:25])=[C:18]([CH:21]([CH3:22])[CH3:23])[CH2:19][S:20][C@H:15]23)=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)C1=C(C(=O)[O-])N2C(=O)[C@H](NC(=O)Cc3ccc([N+](=O)[O-])cc3)[C@H]2SC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C1=C(C(=O)O)N2C(=O)[C@H](NC(=O)Cc3ccc([N+](=O)[O-])cc3)[C@H]2SC1
Reaction time: 0.25 h

Procedure:
A solution of 1.06 g of the ester of Step A in 10 ml of trifluoroacetic acid stood for 5 minutes and was then evaporated to dryness. The residue was taken up in benzene and evaporated to dryness. The residue was empasted with 20 ml of ether, stirred for 15 minutes, vacuum filtered, washed with ether and dried to obtain 790 mg of DL cis 7-p-nitrophenylacetamido-3-isopropyl-3-cepheme-4-carboxylic acid melting at 190° C decomposition. The product occurred as colorless crystals slightly soluble in ethanol and insoluble in water.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>[OH-].[Na+]>[CH2:21]([O:20][C:18]([N:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH:10]1[C:14]([OH:16])=[O:15])=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCNC(C(=O)O)C1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C(C(=O)O)C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 37.9 %

Procedure:
0.1 g of 4-(tert.butoxycarbonyl)-piperazine-2-carboxylic acid was dissolved in 10 ml of 1N sodium hydroxide solution, cooled to 0° C. and treated with 0.2 g of benzyl chloroformate. The mixture was allowed to warm to room temperature and was then stirred overnight. The mixture was extracted with diethyl ether. The aqueous phase was then acidified to pH 4 with 2M hydrochloric acid and extracted with ethyl acetate to give 0.06 g of 1-(benzyloxycarbonyl)-4-(tert.butoxycarbonyl)-2-piperazinecarboxylic acid as a white solid; MS: m/e 365 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[Br:22][C:23]1[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=1[O:25][CH2:26][CH2:27][NH2:28]>CCCCO>[Br:22][C:23]1[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=1[O:25][CH2:26][CH2:27][NH:28][C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2
Reactant: NCCOc1ccccc1Br
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Solvent: CCCCO
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(NCCOc3ccccc3Br)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 8-mL pressure tank reactor, was placed methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (150 mg, 0.44 mmol, 1.00 equiv), 2-(2-bromophenoxy)ethanamine (750 mg, 1.74 mmol, 3.98 equiv, 50%), n-BuOH (2 mL). The resulting solution was stirred overnight at 100° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with PE/EA (10:1). This resulted in 163.9 mg (crude) of methyl 3-(2-(2-bromophenoxy)ethylamino)-2-phenylquinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:26])[C:7]3[C:17](=[O:18])[N:16](C(OC(C)(C)C)=O)[S:15][C:8]=3[N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:27].[C:28]([O:32][C:33](=[O:54])[NH:34][CH:35]1[CH2:44][CH2:43][C:42]2[C:37](=[CH:38][CH:39]=[C:40](B3OC(C)(C)C(C)(C)O3)[CH:41]=2)[CH2:36]1)([CH3:31])([CH3:30])[CH3:29].CN(C)C=O.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO>[C:28]([O:32][C:33](=[O:54])[NH:34][CH:35]1[CH2:44][CH2:43][C:42]2[C:37](=[CH:38][CH:39]=[C:40]([C:2]3[CH:11]=[C:10]4[C:5]([C:6](=[O:26])[C:7]5[C:17](=[O:18])[NH:16][S:15][C:8]=5[N:9]4[CH:12]4[CH2:14][CH2:13]4)=[CH:4][C:3]=3[F:27])[CH:41]=2)[CH2:36]1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)NC1CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc2C1
Reactant: CC(C)(C)OC(=O)n1sc2c(c(=O)c3cc(F)c(Br)cc3n2C2CC2)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCc2cc(-c3cc4c(cc3F)c(=O)c3c(=O)[nH]sc3n4C3CC3)ccc2C1

Procedure:
A mixture containing 7-bromo-9-cyclopropyl-6-fluoro-9H-isothiazolo[5,4-b]quinoline-3,4-dione (8) (31.8 mg, 0.090 mmol), 30 (68.0 mg, 0.182 mmol), tetrakis(triphenylphosphine)palladium(0) (7.2 mg, 0.006 mmol), dimethylformamide (1.5 mL), and a 1 M aqueous solution of sodium bicarbonate (360 μL, 0.360 mmol) is sparged with argon gas and irradiated with microwaves (5-min irradiation at 120° C.). The resulting green, gelatinous mixture was filtered and evaporated to dryness under reduced pressure (˜6 mm Hg, 40° C.). The recovered residue (orange oil) is washed with diethyl ether (10 mL) to give a yellow solid. This material is dissolved in a mixture containing 25% methanol in chloroform (2.0 mL), precipitated via addition of diethyl ether (10 mL), and collected by filtration; this process is repeated once. The product is washed further with water (2×10 mL) and dried in vacuo to give (rac)-tert-Butyl[6-(9-cyclopropyl-6-fluoro-3,4-dioxo-2,3,4,9-tetrahydro-isothiazolo[5,4-b]quinolin-7-yl)-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate as a yellow solid (93% purity by HPLC; the remaining material is 9-cyclopropyl-6-fluoro-9H-isothiazolo[5,4-b]quinoline-3,4-dione). 1HNMR (CDCl3/CD3OD (12:1 v/v), 50° C.): δ 1.10 (m, 2H, c-Pr CH2), 1.21 (m, 2H, c-Pr CH2), 1.48 (s, 9H, C(CH3)3), 1.76 (m, 1H, H-3), 2.10 (m, 1H, H-3), 2.68 (m, 1H, H-1), 2.86 (m, 2H, H-4), 3.08 (m, 1H, c-Pr CH), 3.12 (m, 1H, H-1), 3.94 (m, 1H, H-2), 7.11 (m, 1H, aromatic), 7.20 (m, 2H, aromatic), 7.71 (m, 1H, aromatic), 7.92 (m, 1H, aromatic). 19F{1H} NMR (CDCl3/CD3OD (12:1 v/v), 50° C.): δ −123.8 (s). NMR spectra collected at room temperature contained broad, unresolved signals. LCMS m/z calcd for C28H28FN3O4S ([M]+) 521. Found 522 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14](Cl)=[O:15])=[CH:4][CH:3]=1.[Cl:17][C:18]1[C:23]2[CH:24]=[C:25]([CH2:27][CH:28]3[NH:33][CH2:32][CH2:31][N:30]([CH3:34])[CH2:29]3)[O:26][C:22]=2[CH:21]=[C:20]([Cl:35])[CH:19]=1>>[Cl:17][C:18]1[C:23]2[CH:24]=[C:25]([CH2:27][CH:28]3[CH2:29][N:30]([CH3:34])[CH2:31][CH2:32][N:33]3[C:14]([C:9]3[N:10]=[C:11]([CH3:13])[S:12][C:8]=3[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[O:15])[O:26][C:22]=2[CH:21]=[C:20]([Cl:35])[CH:19]=1
Reactant: CN1CCNC(Cc2cc3c(Cl)cc(Cl)cc3o2)C1
Reactant: Cc1nc(C(=O)Cl)c(-c2ccc(F)cc2)s1
Product: Cc1nc(C(=O)N2CCN(C)CC2Cc2cc3c(Cl)cc(Cl)cc3o2)c(-c2ccc(F)cc2)s1

Procedure:
The title compound (107 mg) was prepared from 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carbonyl chloride (241 mg) and 3-(4,6-dichloro-benzofuran-2-ylmethyl)-1-methyl-piperazine, D78 (263 mg) by a procedure similar to that described for Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH2:29][NH2:30])[CH:26]=[N:27][CH:28]=1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:30][CH2:29][C:25]2[CH:26]=[N:27][CH:28]=[C:23]([O:22][CH3:21])[CH:24]=2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: COc1cncc(CN)c1
Product: COc1cncc(CNC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)c1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (28 mg, 0.08 mmol) and (5-methoxypyridin-3-yl)methanamine (13.8 mg, 0.1 mmol). The title compound was obtained as a solid (20 mg, 43% yield). MS m/z: 470.98, 472.98 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][CH2:16][C:17]3[CH:22]=[C:21]([NH:23]C(=O)OC(C)(C)C)[CH:20]=[CH:19][N:18]=3)[CH:12]=[CH:13][CH:14]=2)[C:5]([F:31])=[CH:4][N:3]=1.[ClH:32]>O1CCOCC1>[ClH:1].[ClH:32].[NH2:23][C:21]1[CH:20]=[CH:19][N:18]=[C:17]([CH2:16][CH2:15][C:11]2[CH:10]=[C:9]([NH:8][C:6]3[C:5]([F:31])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:14]=[CH:13][CH:12]=2)[CH:22]=1
Reactant: CC(C)(C)OC(=O)Nc1ccnc(CCc2cccc(Nc3nc(Cl)ncc3F)c2)c1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1ccnc(CCc2cccc(Nc3nc(Cl)ncc3F)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To a mixture of tert-butyl [2-(2-{3-[(2-chloro-5-fluoropyrimidin-4-yl)amino]phenyl}ethyl)pyridin-4-yl]carbamate (123 mg, 0.28 mmol) in 1,4-dioxane (0.51 mL) was added 4 M hydrogen chloride in 1,4-dioxane (1.21 mL). The resultant reaction mixture was stirred at rt for 1 hour. The reaction mixture was concentrated under vacuum to provide the desired product as an off-white powder (113 mg, 98%). LCMS for C17H16ClFN5 (M+H)+: m/z=344.0.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[OH-].[Na+].[N:13]1([N:19]2[C:28]3[C:23](=[CH:24][C:25]([CH2:29][N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[CH:26][CH:27]=3)[C:22](=[O:36])[C:21]([C:37](OCC)=[O:38])=[CH:20]2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>O>[Br:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:8][C:37]([C:21]2[C:22](=[O:36])[C:23]3[C:28](=[CH:27][CH:26]=[C:25]([CH2:29][N:30]4[CH2:31][CH2:32][O:33][CH2:34][CH2:35]4)[CH:24]=3)[N:19]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH:20]=2)=[O:38])=[CH:5][CH:4]=1
Reactant: NCc1ccc(Br)cc1
Reactant: CCOC(=O)c1cn(N2CCOCC2)c2ccc(CN3CCOCC3)cc2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(NCc1ccc(Br)cc1)c1cn(N2CCOCC2)c2ccc(CN3CCOCC3)cc2c1=O
Temperature: 190 °C
Yield: 68 %

Procedure:
4-Bromobenzylamine hydrochloride (2.22 g) is suspended in water (5 mL) and neutralized with 2N aqueous NaOH (5 mL). The free amine is extracted with dichloromethane (2×25 mL). The organic layers are combined, washed with brine (5 mL), and dried with Na2SO4. The solution is concentrated in vacuo to afford 1.48 g of a clear, colorless oil which is then combined with ethyl 1-(4-morpholinyl)-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylate (0.48 g) from Preparation No. 56 and heated to 190° C. for 3 hours. The reaction mixture is allowed to cool to room temperature, and the resulting solid is recrystallized in ethyl acetate to afford 0.44 g of the title compound as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:15]([CH3:17])([CH3:16])[CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[F:18][C:19]([F:29])([F:28])[C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[CH2:27])=[CH:22][N:21]=1.[OH-].[K+]>CN1C(=O)CCC1>[F:29][C:19]([F:18])([F:28])[C:20]1[N:21]=[CH:22][C:23]([CH2:26][CH2:27][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[C:15]([CH3:17])([CH3:16])[CH2:14][C:5]2=3)=[CH:24][CH:25]=1
Reactant: C=Cc1ccc(C(F)(F)F)nc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)C(C)(C)C3
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C(F)(F)F)nc2)CC(C)(C)N(C)C1

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-2,3,3,8-tetramethyl-1H-pyrido[4,3-b]indole, 2-(trifluoromethyl)-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:38])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([C:33]#[N:34])([CH3:32])[CH3:31])=[CH:26][C:25]=3[O:35][CH2:36][CH3:37])=[N:9]2)=[CH:4][CH:3]=1.C(C1C=CC(C2N(C([N:72]3[CH2:77][CH2:76][N:75]([CH2:78][CH2:79][CH2:80][S:81]([CH2:84][CH3:85])(=[O:83])=[O:82])[CH2:74][CH2:73]3)=O)[C@@](C3C=CC(Cl)=CC=3)(C)[C@@](C3C=CC(Cl)=CC=3)(C)N=2)=C(OCC)C=1)(C)(C)C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:38])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21]([N:72]3[CH2:73][CH2:74][N:75]([CH2:78][CH2:79][CH2:80][S:81]([CH2:84][CH3:85])(=[O:82])=[O:83])[CH2:76][CH2:77]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([CH3:31])([CH3:32])[C:33]#[N:34])=[CH:26][C:25]=3[O:35][CH2:36][CH3:37])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(=O)(=O)CC)CC1
Reactant: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(=O)(=O)CC)CC1

Procedure:
In a manner analogous to the method described in example 5, (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-(3-ethanesulfonyl-propyl)-piperazine dihydrochloride (example 167) to give the title compound. HR-MS (ES, m/z) calculated for C38H48N5O4SCl2 [(M+H)+] 752.2799, observed 752.2799.