Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4]([CH3:7])(=[O:6])=[O:5].Cl[C:9]1[N:14]=[C:13]([C:15]2[S:19][C:18]([CH:20]([CH3:22])[CH3:21])=[N:17][C:16]=2[C:23]2[CH:24]=[C:25]([NH:29][S:30]([C:33]3[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=3)(=[O:32])=[O:31])[CH:26]=[CH:27][CH:28]=2)[CH:12]=[CH:11][N:10]=1>>[CH3:22][CH:20]([C:18]1[S:19][C:15]([C:13]2[CH:12]=[CH:11][N:10]=[C:9]([NH:1][CH2:2][CH2:3][S:4]([CH3:7])(=[O:6])=[O:5])[N:14]=2)=[C:16]([C:23]2[CH:24]=[C:25]([NH:29][S:30]([C:33]3[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=3)(=[O:32])=[O:31])[CH:26]=[CH:27][CH:28]=2)[N:17]=1)[CH3:21]
Reactant: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3cccnc3)c2)c(-c2ccnc(Cl)n2)s1
Reactant: CS(=O)(=O)CCN
Product: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3cccnc3)c2)c(-c2ccnc(NCCS(C)(=O)=O)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Example 1 using 2-aminoethyl-methyl-sulfone (391 mg, 3.18 mmol) and N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]phenyl}-3-pyridinesulfonamide (150 mg, 0.318 mmol) the title compound was obtained as a white foam (72 mg, 41% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.60 (s, 1H) 8.84 (d, J=1.8 Hz, 1H) 8.76 (dd, J=4.8, 1.3 Hz, 1H) 8.02-8.13 (m, 2H) 7.58 (dd, J=7.9, 4.8 Hz, 1H) 7.46 (t, J=5.3 Hz, 1H) 7.32 (t, J=8.2 Hz, 1H) 7.12-7.27 (m, 3H) 5.98-6.16 (m, 1H) 3.64 (dd, J=2.4, 1.3 Hz, 2H) 3.31-3.37 (m, 2H) 3.16-3.29 (m, 1H) 2.99 (s, 3H) 1.33 (d, J=6.9 Hz, 6H). MS (ESI): 559.0 [M+H]+.
Reaction SMILES: [OH-].[Li+].C([O:5][C:6]([CH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]3[C:21](=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]#[N:31])[CH:25]=4)[N:23]=2)[N:20]=[CH:19][CH:18]=[CH:17]3)[CH2:10][CH2:9]1)=[O:7])C>O.CN1C(=O)CCC1>[C:30]([C:26]1[CH:25]=[C:24]([C:22]2[N:23]=[C:14]([CH:11]3[CH2:10][CH2:9][CH:8]([C:6]([OH:7])=[O:5])[CH2:13][CH2:12]3)[CH:15]=[C:16]3[C:21]=2[N:20]=[CH:19][CH:18]=[CH:17]3)[CH:29]=[CH:28][CH:27]=1)#[N:31]
Reactant: CCOC(=O)C1CCC(c2cc3cccnc3c(-c3cccc(C#N)c3)n2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: N#Cc1cccc(-c2nc(C3CCC(C(=O)O)CC3)cc3cccnc23)c1

Procedure:
A solution of lithium hydroxide (6.5 mg, 0.155 mmol) in water (160 μl) is added to a solution of 4-[8-(3-cyano-phenyl)-[1,7]naphthyridin-6-yl]-cyclohexane carboxylic acid ethyl ester (60 mg, 0.155 mmol) in NMP(0.16 ml). Upon completion, the reaction is diluted with water and washed with ethyl acetate (5 ml). The aqueous layer is acidified with 5% citric acid and the product is extracted into ethyl acetate. The organic layer is dried over brine (10 ml) and anhydrous MgSO4, filtered and evaporated. Purification by flash chromatography using Keiselgel 40-63 grade silica and eluting with 1.5% CH3OH:0.5% CH3COOH: dichloromethane affords the title compound. MH+ 357.0. mp 179.8-180.3° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]2[CH:30]=[CH:29][C:28]([O:31]C(=O)C)=[CH:27][CH:26]=2)=[O:24])=[CH:18][CH:17]=1.[OH-].[K+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:23]([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[O:24])=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)c4ccc(OC(C)=O)cc4)cc3)c2cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cc2nccc(Oc3ccc(NC(=O)c4ccc(O)cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.3 %

Procedure:
N-{4-[(6,7-Dimethoxy-4-quinolinyl)oxy]phenyl}-(4-acetoxyphenyl)carboxamide (103 mg) was dissolved in methanol (4 ml), 35% aqueous potassium hydroxide (2 ml) was added, and the admixture was stirred at room temperature for 5 hours. The reaction mixture was partitioned with ethyl acetate/water, and the ethyl acetate layer was washed with brine and then dried with anhydrous sodium sulfate. The solvent was removed by reduced-pressure distillation, and the resulting crystals were washed with ether to obtain 77 mg of the title compound (yield: 82%).
Reaction SMILES: [CH:1]([N:4]([C@H:23]1[CH2:28][CH2:27][C@H:26]([C:29]([O:31][CH3:32])=[O:30])[CH2:25][CH2:24]1)[S:5]([C:8]1[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=1)[C:11]([O:13]CC[Si](C)(C)C)=[O:12])(=[O:7])=[O:6])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].Cl>C1COCC1>[CH:1]([N:4]([C@H:23]1[CH2:28][CH2:27][C@H:26]([C:29]([O:31][CH3:32])=[O:30])[CH2:25][CH2:24]1)[S:5]([C:8]1[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=1)[C:11]([OH:13])=[O:12])(=[O:7])=[O:6])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@H]1CC[C@H](N(C(C)C)S(=O)(=O)c2cccc(C(=O)OCC[Si](C)(C)C)c2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC[C@H](N(C(C)C)S(=O)(=O)c2cccc(C(=O)O)c2)CC1

Procedure:
A mixture of 305 mg of 2-(trimethylsilyl)ethyl 3-{isopropyl[trans-4-(methoxycarbonyl)cyclohexyl]sulfamoyl}benzoate, a solution of TBAF in THF (1.0 M, 1.0 mL), and 3.0 mL of THF was stirred at room temperature for 2 hours. To the reaction mixture was added 0.2 M hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with 0.2 M hydrochloric acid, water, and saturated brine in this order, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 240 mg of 3-{isopropyl[trans-4-(methoxycarbonyl)cyclohexyl]sulfamoyl}benzoic acid as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][CH3:10])=[C:6]([CH:8]=1)[NH2:7].[Br:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:7][C:6]2[CH:8]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[S:9][CH3:10])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: CSc1ccc(Cl)cc1N
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Product: CSc1ccc(Cl)cc1NS(=O)(=O)c1ccc(Br)cc1

Procedure:
Following General Procedure B, the title compound was prepared from 5-chloro-2-(methylthio)aniline and 4-bromo-benzenesulfonyl chloride.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([C:11]3[C:20]4[C:15](=[C:16]([Cl:21])[CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([CH3:22])[C:12]=3[CH3:23])[CH2:9][C:8]3([CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:5]2=[N:6][CH:7]=1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[N:14]=[C:13]([CH3:22])[C:12]([CH3:23])=[C:11]2[N:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[CH:3]=2)[C:8]2([CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[CH2:9]1
Reactant: C1COCCN1
Reactant: Cc1nc2c(Cl)cccc2c(N2CC3(CCOCC3)c3ncc(Br)cc32)c1C
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1nc2c(Cl)cccc2c(N2CC3(CCOCC3)c3ncc(N4CCOCC4)cc32)c1C

Procedure:
Prepared according to procedure N by stirring 6′-bromo-1′-(8-chloro-2,3-dimethylquinolin-4-yl)-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]-pyridine] (25 mg, 0.054 mmol), morpholine (4.75 μL, 0.054 mmol), Pd2dba3 (5 mg, 5.4 μmol) and XPhos (5.2 mg, 10.9 μmol) in toluene (2.0 mL) at reflux for 14 h. Purification by reverse phase HPLC (10 to 60% acetonitrile in water) gave 1′-(8-chloro-2,3-dimethyl-4-quinolinyl)-6′-(4-morpholinyl)-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine]. 1H NMR (400 MHz, chloroform-d) δ ppm 7.78 (1H, dd, J=7.4, 1.4 Hz), 7.58-7.62 (2H, m), 7.32-7.36 (1H, m), 5.68 (1H, d, J=2.3 Hz), 4.11-4.20 (2H, m), 3.95-4.00 (1H, m), 3.85-3.91 (1H, m), 3.74 (4H, dd, J=5.3, 4.5 Hz), 3.52-3.62 (2H, m), 2.92-3.05 (4H, m), 2.84 (3H, s), 2.33-2.42 (2H, m), 2.31 (3H, s), 1.73-1.87 (2H, m). Mass Spectrum (ESI) m/e=465.2 (M+1).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:31]=[CH:30][C:10]([C:11]([NH:13][CH:14]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=2)[C:15](O)=[O:16])=[O:12])=[CH:9][CH:8]=1.[CH3:34][NH2:35]>>[CH3:34][NH:35][C:15](=[O:16])[CH:14]([NH:13][C:11](=[O:12])[C:10]1[CH:30]=[CH:31][C:7]([O:6][CH2:5][CH2:4][CH2:3][C:2]([F:33])([F:32])[F:1])=[CH:8][CH:9]=1)[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=1
Reactant: O=C(NC(Cc1ccc(OC(F)(F)F)cc1)C(=O)O)c1ccc(OCCCC(F)(F)F)cc1
Reactant: CN
Product: CNC(=O)C(Cc1ccc(OC(F)(F)F)cc1)NC(=O)c1ccc(OCCCC(F)(F)F)cc1

Procedure:
A reaction similar to that described in Example 32 (32c) was conducted using 2-{[4-(4,4,4-trifluorobutoxy)benzoyl]amino}-3-[4-(trifluoromethoxy)phenyl]propanoic acid (360 mg) prepared in Example 82 (82a) and methylamine (450 μL, 2 M methanol solution) to give 270 mg of the title compound (white powder).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH3:17])([CH3:16])[CH2:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12].[BH4-].[Na+]>CO.C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH3:17])([CH3:16])[CH2:9][CH:10]([OH:15])[C:11]([F:13])([F:14])[F:12]
Reactant: CC(C)(CC(=O)C(F)(F)F)c1ccccc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(CC(O)C(F)(F)F)c1ccccc1Br
Temperature: 25 °C
Reaction time: 24 h
Yield: 58.3 %

Procedure:
To a round bottom flask was added 4-(2-bromophenyl)-1,1,1-trifluoro-4-methylpentan-2-one (3.0 g, 9.7 mmol) in 70 mL of MeOH and 70 mL of THF at 0° C., followed by the slow addition of NaBH4 (1.1 g, 29.1 mmol). The reaction mixture was stirred at room temperature for 24 hours and then concentrated in vacuo. The residue was diluted with 1000 mL of ethyl acetate, washed with 200 mL of saturated aqueous sodium bicarbonate solution, 200 mL of brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude mixture was purified by flash chromatography. The column was eluted with 0-20% EtOAc/hexanes to afford 1.76 g (58%) of 4-(2-bromophenyl)-1,1,1-trifluoro-4-methylpentan-2-ol.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([CH3:16])[CH:4]=1.C(Br)(Br)(Br)[Br:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClCCl.O>ClCCl>[Br:18][CH2:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([CH3:16])[CH:4]=1
Reactant: CCOC(=O)/C=C/c1ccc(CO)cc1C
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)/C=C/c1ccc(CBr)cc1C
Reaction time: 8 h

Procedure:
A solution of ethyl(2E)-3-[4-(hydroxymethyl)-2-methylphenyl]prop-2-enoate (intermediate 19, 1.389 g) in dry dichloromethane (40 ml) was cooled to 0° C. and treated with carbon tetrabromide (2.3 g) followed by, in small portions, triphenylphosphine (1.82 g). The resulting solution was stirred thus overnight, then poured into dichloromethane/water and the organic phase separated and washed with more water, brine and dried over sodium sulfate then evaporated in vacuo. The isolated product was further purified by flash column chromatography using cyclohexane:ethyl acetate (9:1) as an eluent which gave the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[C:12]2[CH:17]=C)=[O:5].I([O-])(=O)(=O)=[O:25].[Na+].C(=O)(O)[O-].[Na+]>O1CCOCC1.O.C(O)(C)(C)C.[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[C:12]2[CH:17]=[O:25])=[O:5]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Agent: O=[Os](=O)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CC(C)(C)O
Product: O=Cc1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Reaction time: 0.08 h
Yield: 56.3 %

Procedure:
To a suspension of 8-(2,6-dichlorobenzoylamino)-4-vinylquinoline (150 mg) in dioxane and water was added catalytic amount of osmium tetroxide in tert-butanol under ice-cooling, and the mixture was stirred for 5 minutes. To the mixture was added sodium periodate (206 mg) under ice-cooling, and the mixture was stirred for 30 minutes at the same temperature and for 6 hours at ambient temperature. To the mixture was added saturated sodium bicarbonate solution and extracted with dichloromethane. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash chromatography (dichloromethane-n-hexane) to give 8-(2,6-dichlorobenzoylamino)-4-formylquinoline (85 mg).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:15]=[C:14]([CH2:16][CH2:17]OS(C4C=CC(C)=CC=4)(=O)=O)[CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:29]=[N+:30]=[N-:31].[Na+]>CN(C=O)C>[N:29]([CH2:17][CH2:16][C:14]1[CH:13]=[CH:12][C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[NH:8][C:9]=2[CH:15]=1)=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc3nc(-c4ccccc4)[nH]c3c2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCc1ccc2nc(-c3ccccc3)[nH]c2c1
Temperature: 50 °C

Procedure:
Tosylate 191 (0.2 g) was dissolved in DMF (10 mL) and NaN3 (99 mg) was added as a solid. A condenser was affixed under nitrogen, and the mixture was heated to 50° C. for 16 h. The reaction was cooled to rt before being extracted with EtOAc. The organic layer was rinsed several times with water to ensure complete removal of DMF. The organic layer was then separated and dried over Na2SO4 before the solvent was removed under reduced pressure to give 192.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5](Cl)[C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]2.[CH3:17][C:18]([NH2:21])([CH3:20])[CH3:19]>CS(C)=O.C(Cl)Cl>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([NH:21][C:18]([CH3:20])([CH3:19])[CH3:17])[C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]2
Reactant: CC(C)(C)N
Reactant: FC(F)(F)c1nc2cccc(Br)c2nc1Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)Nc1nc2c(Br)cccc2nc1C(F)(F)F
Yield: 77 %

Procedure:
A solution of 5-bromo-3-chloro-2-(trifluoromethyl)quinoxaline (239 mg, 0.767 mmol) and 2-methylpropan-2-amine (243 μl, 2.302 mmol; Aldrich) in DMSO (7.6 ml) was stirred at 100° C. for 7 h (more 2-methylpropan-2-amine (243 μl, 2.302 mmol) was added after 3 h). The mixture was then diluted with DCM (150 ml), added to a separatory funnel, and washed with saturated aq. NaHCO3 (2×100 ml) before the organic layer was separated, dried over Na2SO4, and concentrated. Purification by silica gel (100% hexanes to 20% EtOAc in hexanes) provided 8-bromo-N-(tert-butyl)-3-(trifluoromethyl)quinoxalin-2-amine (224d, 77% yield) as a light yellow solid. MS (ESI, pos. ion) m/z: 348.0/350.2 (M+1).
Reaction SMILES: [CH:1](=[N:8]/[OH:9])/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10]N1C(=O)CCC1=O>CN(C=O)C>[OH:9]/[N:8]=[C:1](\[Cl:10])/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O/N=C\c1ccccc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: O/N=C(\Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.3 %

Procedure:
To a solution of (E)- and/or (Z)-benzaldehyde-oxime (5.27 g, 44 mmol) in DMF (44 mL) was added N-chlorosuccinimide (5.81 g, 44 mmol) portionwise over 1 h, keeping the temperature below 35° C. The reaction mixture was stirred at room temperature overnight. The mixture was then poured onto ice-water, and extracted with ethyl acetate. The combined organic layers were then washed with water and brine, dried over sodium sulphate and evaporated to afford the title compound (5.91 g, 87%) which was obtained as a light yellow solid. MS m/e (EI): 155.0 [M].
Reaction SMILES: C([NH:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16]Cl)=[C:7]([O:19][CH2:20][C:21]2[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[CH:22]=2)[CH:6]=1)(=O)C.N1CCCCC1.[CH3:37][CH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[NH2:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][N:41]2[CH2:42][CH2:43][CH:38]([CH3:37])[CH2:39][CH2:40]2)=[C:7]([O:19][CH2:20][C:21]2[CH:22]=[C:23]([O:29][CH3:30])[CH:24]=[C:25]([O:27][CH3:28])[CH:26]=2)[CH:6]=1
Reactant: CC1CCNCC1
Reactant: COc1cc(COc2cc(NC(C)=O)c(Cl)cc2C(=O)CCCCCl)cc(OC)c1
Solvent: C1CCNCC1
Product: COc1cc(COc2cc(N)c(Cl)cc2C(=O)CCCCN2CCC(C)CC2)cc(OC)c1

Procedure:
Proceeding as in Example 4, Step (c), but replacing 1-(4-acetylamino-5-chloro-2-methoxyphenyl)-5-chloropentan-1-one with 1-[4-acetylamino-5-chloro-2-(3,5-dimethoxybenzyloxy)phenyl]-5-chloropentan-1-one and piperidine with 4-methylpiperidine, gave 1-[4-amino-5-chloro-2-(3,5-dimethoxybenzyloxy)phenyl]-5-(4-methylpiperidin-1-yl)pentan-1-one, m.p. 136-137° C.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19]/[C:20](/[C:29]([O:31][CH2:32]C)=[O:30])=[CH:21]\[C:22]2C=C[CH:25]=[CH:24][C:23]=2F)[O:7][C@H:6]1[CH2:34][O:35][C:36](=[O:38])[CH3:37])(=[O:3])[CH3:2].O=C(CC1[S:47]C=CC=1)C(OC)=O.[H-].[Na+].[Br-].C(O[C@@H]1[C@@H](OC(=O)C)[C@H](OC(=O)C)[C@@H](COC(=O)C)O[C@@H]1O)(=O)C>>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19]/[C:20](/[C:29]([O:31][CH3:32])=[O:30])=[CH:21]\[C:22]2[S:47][CH:25]=[CH:24][CH:23]=2)[O:7][C@H:6]1[CH2:34][O:35][C:36](=[O:38])[CH3:37])(=[O:3])[CH3:2]
Reactant: CCOC(=O)/C(=C/c1ccccc1F)O[C@H]1O[C@@H](COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: COC(=O)C(=O)Cc1cccs1
Agent: CC(=O)OC[C@H]1O[C@H](O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Br-]
Agent: [H-]
Product: COC(=O)/C(=C/c1cccs1)O[C@H]1O[C@@H](COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 18 %

Procedure:
The title compound was prepared as described for C4 using methyl 2-oxo-3-(thiophen-2-yl)propanoate B15 (Otava, 100 mg, 0.543 mmol), sodium hydride (13.03 mg, 0.373 mmol) and 2,3,4,6-tetra-O-acetyl-α-D-glucose bromide (223 mg, 0.543 mmol). The compound was isolated in the form of white solid in 18% yield.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[F:11][C:12]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:13]=1[C:14](O)=O.N>>[F:11][C:12]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:13]=1[C:14]1[O:1][N:2]=[C:3]([C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[N:10]=1
Reactant: O=C(O)c1ccc(F)cc1F
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: Fc1ccc(-c2nc(-c3cccnc3)no2)c(F)c1

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 2,4-difluorobenzoic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.23-7.36 (m, 2H), 7.64 (ddd, J=8.1, 5.0, 0.8 Hz, 1H), 8.35 (td, J=8.5, 6.4 Hz, 1H), 8.56 (dt, J=7.8, 1.9 Hz, 1H), 8.74 (dd, J=5.1, 1.7 Hz, 1H), 9.30 (dd, J=2.2, 0.8 Hz, 1H) ppm; MS (DCI/NH3) m/z 260 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:12]=[N:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[N:21]2[CH2:27][C@H:26]3[C@H:23]([CH2:24][N:25]3C(OC(C)(C)C)=O)[CH2:22]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[ClH:35]>C(O)C.C(O)(C)C>[ClH:35].[C@H:23]12[CH2:24][NH:25][C@H:26]1[CH2:27][N:21]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]3[C:14]=1[N:13]=[CH:12][C:11]([S:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)(=[O:10])=[O:9])=[CH:20]3)[CH2:22]2
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cccc4cc(S(=O)(=O)c5cccc(F)c5)cnc34)C[C@@H]21
Agent: Cl
Solvent: CC(C)O
Solvent: CCO
Product: O=S(=O)(c1cccc(F)c1)c1cnc2c(N3C[C@H]4CN[C@H]4C3)cccc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.150 g of (1S,5R)-tert-butyl 3-(3-(3-fluorophenylsulfonyl)quinolin-8-yl)-3,6-diazabicyclo[3.2.0]heptane-6-carboxylate from Example 27 were dissolved in 5 ml of ethanol. 5 mL 5N HCl in isopropanol was added and the mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated and the residue was dissolved in small amounts of ethanol and precipitated with addition of diethyl ether. Recrystallization from ethanol/isopropanol (2:1) yielded 0.0275 g of the product.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH2:24]([O:26][C:27]1[C:32]([N:33]([CH3:37])[C:34](=[O:36])[CH3:35])=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]=1)[CH3:25]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:30]5[CH:31]=[C:32]([N:33]([CH3:37])[C:34](=[O:36])[CH3:35])[C:27]([O:26][CH2:24][CH3:25])=[N:28][CH:29]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: CCOc1ncc(B2OC(C)(C)C(C)(C)O2)cc1N(C)C(C)=O
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: CCOc1ncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cc1N(C)C(C)=O

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and N-[2-ethoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-N-methyl-acetamide (Stage 63.1.1) to give the title compound as a white solid. (HPLC: tR 2.64 min (Method A); M+H=486 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.97 (s, 1H), 8.40-8.28 (m, 1H), 8.18-8.06 (m, 2H), 8.04-7.91 (m, 1H), 7.85-7.69 (m, 1H), 7.54-7.41 (m, 1H), 4.52-4.33 (m, 2H), 3.88 (s, 3H), 3.58 (s, 3H), 3.08 (s, 3H), 1.93 (s, 3H), 1.75 (s, 3H), 1.32 (t, 3H))
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][NH2:19])=[CH:14][CH:13]=2)[N:4]=1.C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>ClCCl>[F:21][C:2]([F:1])([F:20])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][NH:19][S:30]([CH3:29])(=[O:32])=[O:31])=[CH:14][CH:13]=2)[N:4]=1
Reactant: NCc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)NCc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1

Procedure:
A mixture of ({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)amine (1.563 g, 5.29 mmol), triethylamine (1.48 ml, 10.58 mmol) in dichloromethane (40 ml) was stirred under argon in an ice bath. Methanesulfonyl chloride (1.213 g, 0.82 ml, 10.58 mmol) was added dropwise with stirring. The resulting mixture was allowed to stir at room temperature for 5 h. Then the reaction mixture was partitioned between dichloromethane and water. The organic layer was separated and dried over sodium sulphate. The desired product was isolated by column chromatography on silica using 10 to 70% ethyl acetate in n-pentane to give an oil which was then triturated with n-pentane to give the title compound as a white solid (1.602 g, 81%).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:8][CH2:7][CH2:6]1)=[O:4].[S-:9][C:10]#[N:11].[K+]>C(O)C>[S:9]([CH2:2][C:3]([N:5]1[CH2:8][CH2:7][CH2:6]1)=[O:4])[C:10]#[N:11]
Reactant: O=C(CCl)N1CCC1
Reactant: N#C[S-]
Agent: [K+]
Solvent: CCO
Product: N#CSCC(=O)N1CCC1
Reaction time: 4 h

Procedure:
1-(α-Chloroacetyl) azetidine (13 grams; 0.1 mol), potassium thiocyanate (18 grams; 0.18 mol) and ethanol (100 ml) are charged into a glass reaction flask equipped with stirrer and reflux condenser. The reaction mixture is then heated at reflux, with stirring, for a period of about 4 hours. After this time the reaction mixture is cooled and filtered. The filtrate is then stripped of ethanol leaving a residue. The residue is extracted twice with hot benzene and the two benzene extracts are combined. The benzene extract is then evaporated under reduced pressure to yield 1-(α-thiocyanoacetyl) azetidine as a residue.