Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[S:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.[C:13](OCC)(=[O:18])[CH2:14][C:15]([CH3:17])=[O:16]>C1(C)C=CC=CC=1>[F:12][C:2]([F:11])([F:1])[S:3][C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:13](=[O:18])[CH2:14][C:15](=[O:16])[CH3:17])=[CH:6][CH:5]=1
Reactant: Nc1ccc(SC(F)(F)F)cc1
Reactant: CCOC(=O)CC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)Nc1ccc(SC(F)(F)F)cc1
Yield: 94.5 %

Procedure:
A mixture of 7.72 g (40 mmol of 4-(trifluoromethylthio)aniline and 5.2 g (40 mmol) of ethyl acetoacetate in 80 ml of dry toluene was refluxed for 8 hours using a Dean-Stark trap to remove the ethanol formed during the reaction. The reaction mixture was cooled in an ice-bath to obtain 10.48 g (95%) of N-[4-(trifluoromethylthio)phenyl]-3-oxobutanamide as a white crystalline solid, melting at 120°-2° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].[CH2:27]([NH2:35])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:17](=[O:19])[NH:35][CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:20][CH:21]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: NCCc1ccccc1
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccccc4)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
To a stirred solution of 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation 1) (75 mg, 0.20 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N,N′-tetramethyluronium hexafluorophosphate (84 mg, 0.22 mmol) in N,N-dimethylformamide (1 mL) at ambient temperature was added phenethylamine (28 μL, 0.22 mmol) and N,N-diisopropylethylamine (105 μL, 0.60 mmol). The resulting yellow solution was stirred at ambient temperature for 1 hour. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL). The organic layer was washed with brine (5 mL), then dried over sodium sulfate and concentrated to afford ethyl 6-chloro-7-(4-(phenethylcarbamoyl)phenoxy)chroman-4-carboxylate as an off-white solid (89 mg, 93% yield).
Reaction SMILES: [CH3:1][CH:2]([CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:3][PH:4](=[O:6])[OH:5].[C:12]([O:31][CH3:32])(=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C(OOC(CC)(C)C)(CC)(C)C>[CH3:32][O:31][C:12](=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([P:4]([OH:5])([CH2:3][CH:2]([CH3:1])[CH2:7][C:8]([CH3:10])([CH3:9])[CH3:11])=[O:6])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CC(C[PH](=O)O)CC(C)(C)C
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OC
Agent: CCC(C)(C)OOC(C)(C)CC
Product: CCCCCCCCC(CCCCCCCCC(=O)OC)P(=O)(O)CC(C)CC(C)(C)C
Temperature: 140 °C
Yield: 97.1 %

Procedure:
10 g (0.056 moles) of 2,4,4-trimethylpentyl phosphinic acid, 15.82 g (0.056 moles) of methyl oleate (CE-1897 from P&G Chemical) and 0.5 mL (0.0023 moles) of di-tert-amylperoxide are mixed in a 100 mL single neck flask. The mixture is purged with argon to remove oxygen and is heated under argon for 6 hours at 140° C. Tert-amyl alcohol is removed by distillation and 25.8 g (quantitative yield) of 10-[hydroxy-(2,4,4-trimethyl-pentyl)-phosphinoyl]-octadecanoic acid methyl ester is obtained as a slightly yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:8]=[C:7]([CH:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH3:22])=[CH:17][CH:16]=3)[CH2:12][N:11]([C:23]([N:25]3[CH2:30][CH2:29][S:28][CH2:27][CH2:26]3)=[O:24])[CH2:10]2)[O:6][N:5]=1)[CH3:2].ClC1C=CC=C(C(OO)=[O:39])C=1>>[CH2:1]([O:3][C:4]1[N:8]=[C:7]([CH:9]2[CH2:14][CH:13]([C:15]3[CH:16]=[CH:17][C:18]([CH2:21][CH3:22])=[CH:19][CH:20]=3)[CH2:12][N:11]([C:23]([N:25]3[CH2:30][CH2:29][S:28](=[O:39])[CH2:27][CH2:26]3)=[O:24])[CH2:10]2)[O:6][N:5]=1)[CH3:2]
Reactant: CCOc1noc(C2CC(c3ccc(CC)cc3)CN(C(=O)N3CCSCC3)C2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CCOc1noc(C2CC(c3ccc(CC)cc3)CN(C(=O)N3CCS(=O)CC3)C2)n1
Yield: 41.7 %

Procedure:
55.0 mg (0.128 mmol) of the compound from Example 55 were reacted according to General Method 2 with 39.7 mg (0.115 mmol) of meta-chloroperbenzoic acid. Enantiomer separation of 50.7 mg of the racemate according to Method 4D gave 22.1 mg of the title compound from Example 56 (enantiomer 1) and 21.4 mg of the title compound from Example 57 (enantiomer 2).
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([CH2:16][C:17]([OH:19])=O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[CH3:21][NH:22][O:23][CH3:24]>>[CH:12]1[C:8]2[CH2:9][CH2:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH:6]([CH2:16][C:17]([N:22]([O:23][CH3:24])[CH3:21])=[O:19])[C:7]=2[CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)CC1c2ccccc2CCc2ccccc21
Reactant: CNOC
Agent: Cl
Product: CON(C)C(=O)CC1c2ccccc2CCc2ccccc21

Procedure:
In analogy to example 55, step 1, from 10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-acetic acid (CAS RN: [4037-50-7]) and N,O-dimethylhydroxylamine hydrochloride was prepared the title compound as a colorless oil, MS (ESI+): m/z=296.3 ([M+H]+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:14]4[C:15]([NH2:19])=[N:16][CH:17]=[CH:18][C:13]=4[O:12][CH:11]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Cl:20][C:21]1[CH:22]=[C:23]([CH2:28][C:29](O)=[O:30])[CH:24]=[C:25]([F:27])[CH:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C)C=O.O>[Cl:20][C:21]1[CH:22]=[C:23]([CH2:28][C:29]([N:1]2[C:9]3[C:4](=[CH:5][C:6]([C:10]4[C:14]5[C:15]([NH2:19])=[N:16][CH:17]=[CH:18][C:13]=5[O:12][CH:11]=4)=[CH:7][CH:8]=3)[CH2:3][CH2:2]2)=[O:30])[CH:24]=[C:25]([F:27])[CH:26]=1
Reactant: Nc1nccc2occ(-c3ccc4c(c3)CCN4)c12
Reactant: O=C(O)Cc1cc(F)cc(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1nccc2occ(-c3ccc4c(c3)CCN4C(=O)Cc3cc(F)cc(Cl)c3)c12
Temperature: 25 °C
Reaction time: 96 h
Yield: 90 %

Procedure:
A mixture of 3-(2,3-dihydro-1H-indol-5-yl)furo[3,2-c]pyridin-4-amine (150 mg, 0.440 mmol), 3-chloro-5-fluorophenylacetic acid (89 mg, 0.472 mmol), HATU (184 mg, 0.484 mmol), and Hunig's base (0.31 mL, 1.775 mmol) in N,N-Dimethylformamide (DMF) (3 mL) was stirred at room temperature for 4 days. Water (10 mL) was added, the mixture was stirred for about an hour, and the precipitate was collected by vacuum filtration. The solid was dried in the vacuum oven overnight to give 3-{1-[(3-chloro-5-fluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}furo[3,2-c]pyridin-4-amine (176 mg, 0.396 mmol, 90% yield) as a beige solid. LC/MS (ES) m/z=422, 424 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 3.27 (t, 2H), 3.96 (s, 2H), 4.26 (t, J=8.46 Hz, 2H), 5.53 (s, 2H), 6.93 (d, J=5.81 Hz, 1H), 7.14-7.22 (m, 1H), 7.27 (s, 1H), 7.28-7.38 (m, 2H), 7.40 (s, 1H), 7.86 (d, J=5.81 Hz, 1H), 7.92 (s, 1H), 8.15 (d, J=8.34 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:43]=[CH:42][CH:41]=[CH:40][C:24]=3[C:25]([N:27]3[CH2:31][CH2:30][CH:29]([NH:32]C(=O)OC(C)(C)C)[CH2:28]3)=[O:26])[CH:8]=2)[N:3]=1.Cl>O1CCOCC1>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:43]=[CH:42][CH:41]=[CH:40][C:24]=3[C:25]([N:27]3[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28]3)=[O:26])[CH:8]=2)[N:3]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)c2ccccc2-c2ccc3nc(N)nc(C(=O)N4Cc5ccccc5C4)c3c2)C1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3ccccc3C(=O)N3CCC(N)C3)ccc2n1

Procedure:
The product is obtained analogously to “A34” by reaction of 2-[2-amino-4-(1,3-dihydroisoindole-2-carbonyl)quinazolin-6-yl]benzoic acid with tert-butyl pyrrolidin-3-ylcarbamate. The resultant tert-butyl (1-{2-[2-amino-4-(1,3-dihydroisoindole-2-carbonyl)quinazolin-6-yl]benzoyl}pyrrolidin-3-yl)carbamate is treated directly with 1 M HCl in dioxane, causing the protecting group to be cleaved. The purification is carried out by means of column chromatography;
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[N:11][N:10]([CH2:13][S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]=1[NH2:21].N1C=CC=CC=1.[Cl:28][CH:29]([CH:33]1[CH2:36][CH2:35][CH2:34]1)[C:30](Cl)=[O:31]>CN(C)C=O>[Cl:28][CH:29]([CH:33]1[CH2:36][CH2:35][CH2:34]1)[C:30]([NH:21][C:9]1[N:10]([CH2:13][S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:11]=[N:12][C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])=[O:31]
Reactant: O=C(Cl)C(Cl)C1CCC1
Reactant: Nc1c(-c2ccccc2F)nnn1CSc1ccccc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Nc1c(-c2ccccc2F)nnn1CSc1ccccc1)C(Cl)C1CCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 31359.2 %

Procedure:
To a cooled (0° C.), stirred solution of 5-(2-fluorophenyl)-3-phenylsulfenylmethyl-3H-1,2,3-triazol-4-ylamine (1 g, 3.33 mmol) in dimethylformamide (15 ml) was added pyridine (460μl, 4.33 mmol) followed by 2-chloro-2-cyclobutylacetyl chloride (810 mg, 3.83 mmol) and the reaction stirred at 0° C. for 1 hour. The reaction was quenched by partitioning between ethyl acetate (100 ml) and water (100 ml). The layers were separated and the aqueous layer extracted with ethyl acetate (100 ml). The combined organic extracts were washed with citric acid (50 ml, 10% aqueous), sodium bicarbonate (50 ml, sat. aqueous), brine (50 ml). dried (Na2SO4) and the solvent removed in vacuo. The crude product was purified by flash chromatography (40% EtOAc/hexanes) to afford 2-chloro-2-cyclobutyl-N-[5-(2-fluorophenyl)-3-phenylsulfenylmethyl-3H-1,2,3-triazol-4-yl]acetamide (450 g, 31%; 52% based on recovered starting material) as a crystalline solid, m.p. 103-104° C.; δH (400 MHz, CDCl3) 1.79-2.18 (6H, m, CH(CH2)3), 2.83-2.93 (1H, m, CH(CH2)3), 4.28 (1H, d, J=8 Hz, CHCl), 5.58 (1H, d, J=14.3 Hz, PhSCH2A), 5.64 (1H, d, J=14.3 Hz, PhSCH2B), 7.10-7.16 (1H, m, ArH), 7.23-7.41 (7H, m, ArH), 7.79-7.85 (1H, m, ArH), 8.00-8.10 (1H, br m, NH); m/z (ES+) 431 (100%) (35ClM+H+), 433 (40%) (37 ClM+H+).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl.CCOCC>O1CCCC1>[CH2:1]([O:11][C:12]1[CH:13]=[CH:14][C:15]([CH:16]=[O:17])=[CH:19][CH:20]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCOc1ccc(C(=O)O)cc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCCCCCOc1ccc(C=O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of 27.8 g (0.1 mole) of 4-(decyloxy)benzoic acid in 500 ml of tetrahydrofuran cooled to 0° C. is slowly added 16.2 g (0.1 mole) of N,N'-carbonyldiimidazole. The mixture is heated to reflux for 1 hour then cooled to -20° C. To the cooled mixture is added 1.9 g (0.05 mole) of lithium aluminum hydride and stirring is continued at -20° C. for 1 hour. To the reaction mixture is slowly added 100 ml of 5% aqueous hydrochloric acid followed by the addition of ether. The ether layer is separated and washed with 5% aqueous hydrochloric acid, water, and 5% aqueous sodium bicarbonate then dried over sodium sulfate, filtered and evaporated to dryness to give 4-(decyloxy)benzaldehyde.
Reaction SMILES: [CH:1]([C:3]1[CH:21]=[C:6]2[C:7]([C:13]3[CH:14]([CH3:20])[CH2:15][C:16](=[O:19])[NH:17][N:18]=3)=[CH:8][CH:9]=[C:10]([O:11][CH3:12])[N:5]2[N:4]=1)=O.C([O-])(=O)C.[Na+].Cl.[NH2:28][OH:29]>CO>[CH3:12][O:11][C:10]1[N:5]2[N:4]=[C:3]([CH:1]=[N:28][OH:29])[CH:21]=[C:6]2[C:7]([C:13]2[CH:14]([CH3:20])[CH2:15][C:16](=[O:19])[NH:17][N:18]=2)=[CH:8][CH:9]=1
Reactant: NO
Reactant: COc1ccc(C2=NNC(=O)CC2C)c2cc(C=O)nn12
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C2=NNC(=O)CC2C)c2cc(C=NO)nn12
Reaction time: 0.33 h

Procedure:
The compound of Example 237 (24.0 mg) was dissolved in methanol (3 mL). To this solution, sodium acetate (41.3 mg) and hydroxylamine hydrochloride (17.5 mg) were added at room temperature and the reaction mixture was stirred for 20 min. The solvent was evaporated under reduced pressure and water was added to the residue. The mixture was filtered to afford the title compound as a white powder (15.3 mg, a mixture of E-form and Z-form (E:Z=1:5)).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:15])[NH:9][C:10]1[CH:14]=[CH:13][O:12][N:11]=1)([CH3:6])([CH3:5])[CH3:4].[F:16][C:17]1[CH:18]=[C:19]([N:24]2[CH2:28][C@H:27]([CH2:29]OS(C)(=O)=O)[O:26][C:25]2=[O:35])[CH:20]=[CH:21][C:22]=1[I:23]>CN(C)C=O.C(=O)(O)[O-].[Na+]>[C:3]([O:7][C:8](=[O:15])[N:9]([CH2:29][C@@H:27]1[O:26][C:25](=[O:35])[N:24]([C:19]2[CH:20]=[CH:21][C:22]([I:23])=[C:17]([F:16])[CH:18]=2)[CH2:28]1)[C:10]1[CH:14]=[CH:13][O:12][N:11]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)Nc1ccon1
Reactant: CS(=O)(=O)OC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(C[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1)c1ccon1
Yield: 57.1 %

Procedure:
To sodium hydride (60% in oil, 9.04 mM) suspended in dry N,N-dimethylformamide (10 ml) under nitrogen, N-isoxazol-3-yl-carbamic acid tert-butyl ester (1.66 g, 9.04 mM) in N,N-dimethylformamide (10 ml) was added dropwise at ambient temperature. Methanesulfonic acid (5R)-3-(3-fluoro-4-iodo-phenyl)-2-oxo-oxazolidin-5-ylmethyl ester (2.5 g, 6.02 mM) in N,N-dimethylformamide (10 ml) was added slowly, and the mixture heated to 75° for 2 hours. After cooling, the mixture was diluted with aqueous sodium bicarbonate (5%, 300 ml), and extracted with ethyl acetate (3×100 ml). The organic phase was washed with water (100 ml) and brine (100 ml), dried (magnesium sulfate), evaporated and crude product purified by chromatography on a 50 g silica Mega Bond Elut® column, eluting with dichloromethane. Relevant fractions were combined to give the title compound (1.73 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:5]=2[S:6][C:7]=1[C:8](O)=O.COC1C2C=CC=CC=2SC=1C[C:27]([O:29][CH3:30])=[O:28]>>[CH3:1][O:2][C:3]1[C:4]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:5]=2[S:6][C:7]=1[CH2:8][C:27]([O:29][CH3:30])=[O:28]
Reactant: COc1c(C(=O)O)sc2ccc(C(F)(F)F)cc12
Reactant: COC(=O)Cc1sc2ccccc2c1OC
Product: COC(=O)Cc1sc2ccc(C(F)(F)F)cc2c1OC

Procedure:
When 3-methoxy-5-(trifluoromethyl)benzo[b]thiophene-2-carboxylic acid was used in place of the starting benzthiophene of Example C-1, and carried through the same sequence of reactions, methyl 3-methoxy-5-(trifluoromethyl)benzo[b]thiophene-2-acetate is obtained.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[O:7][CH2:8][CH:9]1[O:13][C:12](=[O:14])[NH:11][CH2:10]1.Br[CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[O:7][CH2:8][CH:9]1[O:13][C:12](=[O:14])[N:11]([CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:10]1
Reactant: O=C1NCC(COc2cccc(Cl)c2)O1
Reactant: CCOC(=O)CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCN1CC(COc2cccc(Cl)c2)OC1=O
Yield: 50 %

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 0.52 g of sodium hydride (as a 55% by weight dispersion in mineral oil), 30 ml of anhydrous dimethylformamide, 2.00 g of 5-(3-chlorophenoxymethyl)oxazolidin-2-one and 2.34 g of ethyl 4-bromobutyrate were used, to give 1.50 g of the title compound having an Rf value of 0.39 (on silica gel thin layer chromatography, using a 2:1 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.CCN(CC)CC.[CH2:19]1[C:24]2([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:23][CH2:22][N:21]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:20]1.CCOC(C)=O>CS(C)=O>[CH3:9][O:8][C:6]([C:5]1[CH:10]=[CH:11][C:2]([N:27]2[CH2:28][CH2:29][C:24]3([CH2:23][CH2:22][N:21]([C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])[CH2:20][CH2:19]3)[CH2:25][CH2:26]2)=[N:3][CH:4]=1)=[O:7]
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)CC1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(N2CCC3(CCN(C(=O)OC(C)(C)C)CC3)CC2)nc1
Temperature: 100 °C

Procedure:
A mixture of methyl 6-chloronicotinate (800 mg, 3.15 mmol), NEt3 (1.00 mL, 7.19 mmol) and tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (1.00 g, 3.94 mmol) in 5 mL of DMSO was heated to 100° C. for 1 h with microwave irradiation. The reaction mixture was poured into EtOAc and washed with 2 N NaOH, 2H HCl, brine and dried (Na2SO4), filtered and concentrated giving tert-butyl 9-[5-(methoxycarbonyl)pyridin-2-yl]-3,9-diazaspiro[5.5]undecane-3-carboxylate.
Reaction SMILES: CN(C)C=O.[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([O:18][C:19]3[C:20]([CH3:29])=[N:21][C:22]4[C:27]([CH:28]=3)=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:13][CH:14]=[N:15]2)=[CH:10][C:9]=1[OH:30].C(=O)([O-])[O-].[K+].[K+].[CH2:37]([CH:39]1[O:41][CH2:40]1)Br>O>[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([O:18][C:19]3[C:20]([CH3:29])=[N:21][C:22]4[C:27]([CH:28]=3)=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:13][CH:14]=[N:15]2)=[CH:10][C:9]=1[O:30][CH2:37][CH:39]1[CH2:40][O:41]1
Reactant: COc1cc2nccc(Oc3cc4ccccc4nc3C)c2cc1O
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3cc4ccccc4nc3C)c2cc1OCC1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.7 %

Procedure:
N,N-Dimethylformamide (6 ml) was added to 7-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-6-ol (189 mg), potassium carbonate (236 mg), and epibromohydrin (234 mg), and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using hexane-acetone to give 7-methoxy-4-(2-methyl-quinolin-3-yloxy)-6-oxiranylmethoxy-quinoline (59 mg, yield 27%).
Reaction SMILES: [C:1]([NH2:4])(=[O:3])[CH3:2].[H-].[Na+].[Cl:7][C:8]1[CH:9]=[C:10]([F:15])[C:11](F)=[N:12][CH:13]=1.[Cl-].[NH4+]>CN(C=O)C>[C:1]([NH:4][C:11]1[C:10]([F:15])=[CH:9][C:8]([Cl:7])=[CH:13][N:12]=1)(=[O:3])[CH3:2]
Reactant: Fc1cc(Cl)cnc1F
Reactant: CC(N)=O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ncc(Cl)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.6 %

Procedure:
Under a nitrogen atmosphere, acetamide (4.1 g, 70 mmol) was dissolved in DMF (30 mL). Sodium hydride (content: 50% to 72%, 2.4 g, 60 mmol (the content being regarded as 60%)) was added thereto at 0° C. in three portions. The compound 5-chloro-2,3-difluoropyridine (3.0 g, 20 mmol) was then added dropwise at 0° C., and the mixture was stirred for 3 hours, during which time the temperature was allowed to increase to room temperature. The reaction mixture was cooled to 0° C., a saturated ammonium chloride aqueous solution was added, and after the mixture was warmed to room temperature, extraction was performed with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was suspended in a mixed solvent of heptane and t-butyl methyl ether (15:1), and the suspension was stirred at room temperature. The suspension was filtered, and the obtained solid was dried under reduced pressure to obtain the title compound (2.7 g).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([S:20](=[O:28])(=[O:27])[NH:21][C:22]3[S:23][CH:24]=[CH:25][N:26]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+].Cl>C(Cl)Cl>[NH2:7][CH:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH:21][C:22]3[S:23][CH:24]=[CH:25][N:26]=3)(=[O:28])=[O:27])=[CH:16][CH:15]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(S(=O)(=O)Nc3nccs3)cc2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CCN(c2ccc(S(=O)(=O)Nc3nccs3)cc2)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 39.4 %

Procedure:
Prepared using general procedure 28, method A. A mixture of tert-butyl-1-(4-(N-thiazol-2-ylsulfamoyl)phenyl)piperidin-4-ylcarbamate (657 mg, 1.5 mmol), TFA (1.5 mL) and CH2Cl2 (10 mL) was stirred at RT under an N2 atmosphere for 2.5 h. The reaction was poured into saturated NaHCO3 solution (50 mL) and acidified to pH 3-4 with a 1 M HCl solution. The mixture was then extracted with CH2Cl2 (3×50 mL). Since LCMS analysis showed that the product was still in the aqueous layer, it was neutralized with saturated NaHCO3 resulting in precipitation of a white solid which was filtered, washed with MeOH, and dried under vacuum to obtain 4-(4-aminopiperidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide (200 mg, 38% over 2 steps). 1H NMR (400 MHz, DMSO-d6) δ 7.57-7.45 (m, 4H), 6.94-6.89 (m, 3H), 6.44 (d, J=3.9 Hz, 1H), 3.83 (d, J=13.5 Hz, 2H), 3.20-3.14 (m, 1H), 2.83 (t, J=11.8 Hz, 2H), 1.84 (d, J=9.3 Hz, 2H), 1.51-1.41 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]([C:23]([OH:25])=O)=[CH:21][N:22]=2)[CH2:14][C@@H:13]1[F:26])=[O:10].CN([C:30]([O:34][N:35]1N=NC2C=CC=N[C:36]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.CNOC>CN(C=O)C.O>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]([C:23]([N:35]([O:34][CH3:30])[CH3:36])=[O:25])=[CH:21][N:22]=2)[CH2:14][C@@H:13]1[F:26])=[O:10]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1[nH]c(C(=O)N[C@@H]2CCN(c3ncc(C(=O)O)s3)C[C@@H]2F)c(Cl)c1Cl
Agent: CNOC
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cnc(N2CC[C@@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@@H](F)C2)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-((3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-fluoropiperidin-1-yl)-1,3-thiazole-5-carboxylic acid (10 mg, 0.024 mmol) was dissolved in dry DMF (10 ml), HATU (9.1 mg, 0.024 mmol), triethylamine (7.27 mg, 0.072 mmol) and N,O-dimethylhydroxyamine (4.65 mg, 0.048 mmol) were added. The mixture was stirred at room temperature for 30 minutes, then was poured into cold water (30 ml), the precipitate was filtered, washed with water and collected as the desired product (off white solid, 10 mg).
Reaction SMILES: CO.C([O:10][CH2:11][CH2:12][S:13]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([C:25]1[N:30]=[CH:29][N:28]=[C:27]([O:31][CH:32]3[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]3)[CH:26]=1)[CH2:20][CH2:19]2)(=[O:15])=[O:14])C1C=CC=CC=1.[H][H]>[OH-].[Pd+2].[OH-].C(OCC)(=O)C>[OH:10][CH2:11][CH2:12][S:13]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([C:25]1[N:30]=[CH:29][N:28]=[C:27]([O:31][CH:32]3[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]3)[CH:26]=1)[CH2:20][CH2:19]2)(=[O:14])=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(N3CCc4cc(S(=O)(=O)CCOCc5ccccc5)ccc43)ncn2)CC1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(N3CCc4cc(S(=O)(=O)CCO)ccc43)ncn2)CC1
Yield: 80 %

Procedure:
Palladium hydroxide (100 mg) was added to a methanol (10 mL)/ethyl acetate (10 mL) mixed solution of the tert-butyl 4-{[6-(5-{[2-(benzyloxy)ethyl]sulfonyl}indolin-1-yl)pyrimidin-4-yl]oxy}piperidine-1-carboxylate (486 mg, 0.817 mmol) produced in Reference Example 44, and the mixture was stirred for 19.5 hours in a hydrogen atmosphere. The reaction solution was filtered through Celite (trade name), and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:2-4:1, V/V) to obtain the title compound as white foam (330 mg, yield: 80%).