Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8](N)=[CH:7][C:6]([CH2:10][CH3:11])=[C:5]([CH3:12])[N:4]=1.N([O-])=[O:14].[Na+]>S(=O)(=O)(O)O.O>[CH3:1][O:2][C:3]1[C:8]([OH:14])=[CH:7][C:6]([CH2:10][CH3:11])=[C:5]([CH3:12])[N:4]=1
Reactant: CCc1cc(N)c(OC)nc1C
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CCc1cc(O)c(OC)nc1C
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 43.9 %

Procedure:
A batch of 2-methoxy-3-amino-5-ethyl-6-methylpyridine (171 mg, 1.05 mmol) was dissolved in 5% aqueous sulfuric acid (4 mL), cooled in an ice bath, then a solution of sodium nitrite (78 mg, 1.13 mmol) in water (1 mL) was added dropwise. After 0.5 hour, the resulting mixture was added dropwise to 5% aqueous sulfuric acid (6 mL) warmed at 110° C. The solution was stirred for 0.5 hour, cooled and the product extracted into chloroform, then dried (Na2SO4), filtered and evaporated to yield 77 mg (43%) of product.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20]4[C:28]5[C:27]([NH2:29])=[N:26][CH:25]=[N:24][C:23]=5[N:22]([CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)[CH:21]=4)=[CH:17][CH:18]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:6][CH:7]=1.[C:36](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20]4[C:28]5[C:27]([NH2:29])=[N:26][CH:25]=[N:24][C:23]=5[N:22]([CH:30]5[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]5)[CH:21]=4)=[CH:17][CH:18]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(CC(=O)N2CCc3cc(-c4cn(C5CCNCC5)c5ncnc(N)c45)ccc32)c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1cccc(CC(=O)N2CCc3cc(-c4cn(C5CCN(C)CC5)c5ncnc(N)c45)ccc32)c1
Yield: 43.1 %

Procedure:
To a solution of 5-{1-[(3-methylphenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-(4-piperidinyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (97 mg, 0.193 mmol) in DMF (3 mL) was added cesium carbonate (188 mg, 0.578 mmol) then iodomethane (0.013 mL, 0.212 mmol). After 2 hr the reaction was filtered and the filtrate was concentrated and then loaded on to a 10 g SNAP column. Elution with 0 to 10% MeOH in DCM gradient provided 5-{1-[(3-methylphenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-(1-methyl-4-piperidinyl)-7H-pyrrolo[2, 3-d]pyrimidin-4-amine (40 mg, 43.2% yield) as a white solid. LC-MS (ES) m/z=481.4 [M+H]+.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][C:12]([OH:14])=O.C(=O)=O.[OH:18][C:19]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>O1CCCC1>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][C:12]([N:22]1[CH2:23][CH2:24][C:19]([OH:18])([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:20][CH2:21]1)=[O:14]
Reactant: O=C(O)CC1COc2ccccc2O1
Reactant: OC1(c2ccccc2)CCNCC1
Agent: O=C=O
Solvent: C1CCOC1
Product: O=C(CC1COc2ccccc2O1)N1CCC(O)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the stirred solution of 11.64 g of 2-(1,4-benzodioxan-2-yl)-acetic acid in 60 ml of tetrahydrofuran is added 12 g of 1,1-carbonyldiimidazole. After the evolution of carbon dioxide has ceased, 10.6 g of 4-hydroxy-4-phenylpiperidine are added and the mixture stirred overnight at room temperature. It is evaporated, the residue taken up in ethyl acetate, the solution washed with water, N hydrochloric acid and water, dried and evaporated, to yield the 1-[2-(1,4-benzodioxan-2-yl)-acetyl]-4-hydroxy-4-phenylpiperidine.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[C:6]([NH:8][C@H:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]([O:20]C)=[O:19])[CH:16]=2)[CH2:11][CH2:10]1)=[O:7]>C(O)C.O>[CH3:3][C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[C:6]([NH:8][C@H:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]([OH:20])=[O:19])[CH:16]=2)[CH2:11][CH2:10]1)=[O:7]
Reactant: COC(=O)c1ccc2c(c1)[C@H](NC(=O)c1ccccc1C)CC2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccccc1C(=O)N[C@@H]1CCc2ccc(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
KOH (1 mol/laq) (2 eq.) was added to a suspension of (R)-methyl 3-(2-methylbenzamido)-2,3-dihydro-1H-indene-5-carboxylate (B-09) (0.61 mmol, 1 eq.) in a mixture of ethanol (3.6 ml) and water (0.8 ml). The reaction mixture was stirred at room temperature overnight. Ethanol was removed in vacuo and the aqueous residue was diluted with diethyl ether and dist. water. The phases were separated and the aqueous phase was acidified with 1N HCl to pH 3 and then extracted 4× with ethyl acetate. The combined organics were dried over sodium sulfate and concentrated in vacuo to yield the desired product (E-09). Yield: 88%
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]2[N:12]=[CH:13][CH:14]=[CH:15][C:10]2=[N:9][C:8]=1[CH:16]([NH2:18])[CH3:17].[NH2:19][C:20]1[C:25]([C:26]#[N:27])=[C:24](Cl)[N:23]=[CH:22][N:21]=1.CCN(C(C)C)C(C)C>C(O)CCC>[NH2:19][C:20]1[C:25]([C:26]#[N:27])=[C:24]([NH:18][CH:16]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[N:12][N:11]3[C:7]=2[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH3:17])[N:23]=[CH:22][N:21]=1
Reactant: CC(N)c1nc2cccnn2c1-c1ccccn1
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc(N)c1C#N)c1nc2cccnn2c1-c1ccccn1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a mixture of 1-(3-pyridin-2-yl-imidazo[1,2-b]pyridazin-2-yl)-ethylamine (450 mg, 2.09 mmol) and 4-amino-6-chloro-pyrimidine-5-carbonitrile (325 mg, 2.09 mmol) in n-butanol (8 mL) was added DIEA (0.6 mL, 3.01 mmol) at rt. The reaction mixture was stirred at 110° C. overnight. The mixture was concentrated in vacuo. The residue was purified by column chromatography using silica gel (100-200 mesh) and 0-60% acetone in hexane to provide 4-amino-6-[1-(3-pyridin-2-yl-imidazo[1,2-b]pyridazin-2-yl)-ethyl amino]-pyrimidine-5-carbonitrile: 1H NMR (400 MHz, DMSO-d6) δ 1.272 (d, J=6.4 Hz, 3H), 6.047-6.118 (m, 1H), 7.375 (br s, 2H), 7.446-7.477 (m, 2H), 8.022-8.060 (m, 2H), 8.230-8.280 (m, 1H), 8.400-8.490 (m, 2H), 8.727 (s, 1H), 8.878 (s, 1H). LC-MS (ESI) m/z 358.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[N:9]1[NH:10][N:11]=[CH:12][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[N:9]1([C:2]2[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=2)[CH:13]=[CH:12][N:11]=[N:10]1
Reactant: c1cn[nH]n1
Reactant: Brc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Brc1ccc(-n2ccnn2)nc1
Reaction time: 24 h

Procedure:
In 20 ml of 1-methyl-2-pyrrolidone was dissolved 1.72 g of 2,5-dibromopyridine, followed by the addition of 500 mg of 2H-(1,2,3)-triazole and 3 g of potassium carbonate at room temperature. Reaction was conducted at 100° C. for 24 hours. After completion of the reaction, the same post-treatment as in Preparation Example 3 was carried out to obtain the title compound. 120 mg.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:5][CH:4]=1.[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[NH:33][CH3:34]>>[F:29][C:30]1[CH:31]=[C:32]([N:33]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[C:10]([NH:15][S:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=3)=[CH:5][CH:4]=2)[CH3:34])[CH:35]=[CH:36][CH:37]=1
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1C(F)(F)F
Reactant: CNc1cccc(F)c1
Product: CN(Cc1ccc(-c2nccnc2NS(=O)(=O)c2ccccc2C(F)(F)F)cc1)c1cccc(F)c1
Yield: 69 %

Procedure:
Following the general method as outlined in Example 1 (Method B), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzenesulfonamide (Intermediate 9), and 3-Fluoro-N-methylaniline, the title compound was isolated as a yellow solid in 69% yield (92% purity by HPLC).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O>ClCCCl.[Pt]>[NH2:1][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: CC(C)(C)OC(=O)NCCCNc1c([N+](=O)[O-])cnc2ccccc12
Agent: [Pt]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCCCNc1c(N)cnc2ccccc12
Yield: 93.3 %

Procedure:
A solution of tert-butyl 3-[(3-nitroquinolin-4-yl)amino]propylcarbamate (50.0 g, 144 mmol) in 1,2-dichloroethane (450 mL) and 5% platinum on carbon (16.9 g, 86.6 mmol) were added to a Parr vessel, which was placed under hydrogen pressure (30 psi, 2.1×105 Pa) and shaken until the reaction was complete. The reaction mixture was filtered and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and the resulting solution was filtered to remove an insoluble impurity, washed sequentially with brine (3×) and dilute aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 42.52 g of tert-butyl 3-[(3-aminoquinolin-4-yl)amino]propylcarbamate.
Reaction SMILES: [N+](=[CH2:3])=[N-].[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([OH:15])=[O:14])[CH:11]=2)[CH:6]=[CH:5]1>C(OCC)C>[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:3])=[O:14])[CH:11]=2)[CH:6]=[CH:5]1
Reactant: C=[N+]=[N-]
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Solvent: CCOCC
Product: COC(=O)c1ccc2cc[nH]c2c1

Procedure:
An ethereal solution of diazomethane (620 mL) was added slowly to a cooled, (−15° C.) stirred suspension of 6-indole carboxylic acid (45 g, 0.27 mol.) in diethyl ether (250 mL). Upon addition, the reaction mixture was stirred for a further 1 h at −15° C., after which the reaction was quenched by the slow addition of acetic acid (50 mL). The resultant mixture was then concentrated under reduced pressure, and the residue purified using flash chromatography on silica (60-120), using DCM as eluant.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[CH2:14]=[CH:15][C:16](=[O:20])/[CH:17]=[CH:18]/[CH3:19]>C(#N)C>[CH2:1]([N:8]1[CH2:14][CH2:15][C:16](=[O:20])[CH2:17][CH:18]1[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: C=CC(=O)/C=C/C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC1CC(=O)CCN1Cc1ccccc1
Temperature: 16 °C
Reaction time: 0.25 h
Yield: 58.3 %

Procedure:
To a stirred solution of benzylamine (5.2 mL, 47 mmol) in acetonitrile (30 mL) was added aqueous NaHCO3 solution (20 mL, 1.8 M, 36 mmol). After cooling to 16° C., the crude product obtained in step A (3.46 g, 32.9 mmol) dissolved in acetonitrile (30 mL) was added slowly over 40 minutes. After addition, the solution was heated to reflux for 1 h. The solvent was evaporated in vacuo to approximate 25 mL volume and ethyl acetate (60 mL) added. The resulting solution was stirred for 15 minutes. The organic layer was separated, washed with water (60 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue purified by flash column chromatography (SiO2, 8:1 to 7:3 hexanes/ethyl acetate) to give 1-benzyl-2-methylpiperidin-4-one (3.9 g, 54%) as a brown oil: 1H NMR (CDCl3, 300 MHz) δ 7.39-7.26 (m, 5H), 3.96 (d, J=13.5 Hz, 1H), 3.45 (d, J=13.2 Hz, 1H), 3.03-2.95 (m, 2H), 2.56-2.51 (m, 2H), 2.39-2.31 (m, 2H), 2.28-2.24 (m, 1H), 1.17 (d, J=6.3 Hz, 3H).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([CH3:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:12][N:13]([CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[CH3:12][N:13]([CH:22]1[CH2:27][CH2:26][N:25]([C:2]2[C:3]3[C:10]([CH3:11])=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:24][CH2:23]1)[C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CN(C(=O)c1ccccc1)C1CCNCC1
Reactant: Cc1c[nH]c2ncnc(Cl)c12
Solvent: CCO
Product: Cc1c[nH]c2ncnc(N3CCC(N(C)C(=O)c4ccccc4)CC3)c12
Temperature: 150 °C

Procedure:
To 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine D4 (0.154 g) and N-methyl-N-4-piperidinylbenzamide D15 (0.2 g) was added Ethanol (5 mL) and the reaction was heated at 150° C. for 30 minutes in the microwave. The reaction was heated again at 150° C. for 20 minutes. During the cooling, a white precipitate formed. This precipitate was filtered off and washed with Ethanol before being dried in vacuo at 40° C. to afford product in 49 mg. The filtrate was removed in vacuo and the crude residue purified by MDAP using the formic acid method. Fractions corresponding to the desired product were combined and solvent removed to give the product E32 in 22 mg. LCMS [M+H]+350.12@0.66 min (2 min run)
Reaction SMILES: [C:1](=[O:6])=[N:2][C:3](Cl)=[O:4].[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:23][O:24][C:25]1[CH:26]=[C:27](/[C:31](/[CH2:36][CH3:37])=[CH:32]\[CH2:33][NH:34][OH:35])[CH:28]=[CH:29][CH:30]=1.Cl>C1COCC1>[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:23][O:24][C:25]1[CH:26]=[C:27](/[C:31](/[CH2:36][CH3:37])=[CH:32]/[CH2:33][N:34]2[C:3](=[O:4])[NH:2][C:1](=[O:6])[O:35]2)[CH:28]=[CH:29][CH:30]=1
Reactant: O=C=NC(=O)Cl
Reactant: CC/C(=C/CNO)c1cccc(OCc2nc(-c3ccc(C(F)(F)F)cc3)oc2C)c1
Agent: Cl
Solvent: C1CCOC1
Product: CC/C(=C\Cn1oc(=O)[nH]c1=O)c1cccc(OCc2nc(-c3ccc(C(F)(F)F)cc3)oc2C)c1
Reaction time: 0.5 h
Yield: 63.8 %

Procedure:
N-(Chlorocarbonyl)isocyanate (0.12 ml, 1.5 mmol) was added dropwise to a cold (-5° C.) mixture of (Z)-N-(3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-pent-2-enyl)-hydroxylamine (0.65 g, 1.5 mmol) in THF (10 ml). The mixture was stirred for 30 minutes, then poured into HCl (1N) and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography on acid washed (5% H3PO4 /MeOH) silica gel (hexane/EtOAc 2/1) gave a white solid (0.48 g, 64% yield, mp 126°-127° C.).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[C:4]([NH2:9])[CH:5]=[N:6][C:7]=1[CH3:8].[N:11]([O-])=O.[Na+]>C(O)(=O)C>[Br:1][C:2]1[C:7]([CH3:8])=[N:6][CH:5]=[C:4]2[NH:9][N:11]=[CH:10][C:3]=12
Reactant: Cc1ncc(N)c(C)c1Br
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1ncc2[nH]ncc2c1Br
Temperature: 60 °C
Yield: 52.5 %

Procedure:
To a solution of 5-bromo-4,6-dimethylpyridin-3-amine (1.00 g, 4.98 mmol) in acetic acid (12 mL) at ambient temperature was added sodium nitrite (364 mg, 5.28 mmol) and the mixture heated to 60° C. for 1.5 hr. The cooled reaction mixture was concentrated in vacuo, the residue partitioned between ethyl acetate and saturated aqueous sodium bicarbonate and the biphasic mixture filtered through a celite pad. The separated aqueous phase was extracted with ethyl acetate, and the combined organic phases washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica, ISCO, 10-100% ethyl acetate in heptane) to afford the title compound as a pale brown solid (554 mg, 53%). 1H NMR (300 MHz, DMSO) δ 13.91 (s, 1H), 8.95 (s, 1H), 8.14 (s, 1H), 2.67 (s, 3H). LCMS: M+H+=212 & 214.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:18][O:19][CH2:20]Cl>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:18][O:19][CH3:20])=[CH:13][N:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(OCc2ccccc2)nc1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1ccc(OCc2ccccc2)nc1
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 85.6 %

Procedure:
To a solution of 6-(benzyloxy)pyridin-3-ol (2.0 g, 10 mmol, 1 eq.) in DMF (20 mL) was added NaH (60% in mineral oil; 0.6 g, 15 mmol, 1.5 eq.) at 0-5° C. portion-wise. Upon the completion of addition, the mixture was continued to stir at 0-5° C. for 15 min, added chloromethyl methyl ether (0.88 g, 11 mmol, 1.1 eq.), stirred at 0-5° C. for another 20 min, and quenched with NH4Cl(sat) solution. The aqueous layer was extracted with EtOAc (3×20 mL) and the combined organic layers were washed with water and brine, dried over Na2SO4, concentrated, and purified on silica gel using 25% EtOAc/hexanes as eluent to give 2-(benzyloxy)-5-(methoxymethoxy)pyridine (2.1 g, 87%) as a colorless oil. MS (ESI) m/z 246.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.[NH2:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32]>C(Cl)Cl>[N+:12]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[CH:10][CH:9]=[CH:8][CH:7]=2)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: CC(C)(C)OC(=O)NCCOCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCOCCNc1c([N+](=O)[O-])cnc2ccccc12
Reaction time: 8 h
Yield: 76.7 %

Procedure:
A stirred solution of 4-chloro-3-nitroquinoline (31.4 g, 0.151 mol) in 500 mL of anhydrous CH2Cl2, under N2, was treated with triethylamine (43 mL, 0.308 mol) and tert-butyl 2-(2-aminoethoxy)ethylcarbamate (0.151 mol). After stirring overnight, the reaction mixture was washed with H2O (2×300 mL) and brine (300 mL). The organic portion was dried over Na2SO4 and concentrated to give a bright yellow solid. Recrystallization from ethyl acetate/hexanes gave 43.6 g of tert-butyl 2-{2-[(3-nitroquinolin-4-yl)amino]ethoxy}ethylcarbamate as bright yellow crystals.
Reaction SMILES: FC(F)(F)C(O[C:6]1[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH:11]=1)=O.[F:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.[F-].[Cs+]>COCCOC.CO.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>[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:6]2[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:10][CH:11]=2)=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(OC(=O)C(F)(F)F)CC1
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(F)cc2)CC1
Reaction time: 8 h
Yield: 78.1 %

Procedure:
A solution of Example 6A (4.0 g, 12 mmol) and 4-fluorophenylboronic acid (1.68 g, 12 mmol) in 1,2-dimethoxyethane (100 mL) and methanol (50 mL) was treated with tetrakis(triphenylphosphine)palladium(0) (0.416 g, 0.36 mmol) and CsF (3.64 g, 24 mmol), heated to reflux, and stirred overnight. The reaction was concentrated and the concentrate was dissolved in ethyl acetate (100 mL) and water (50 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL) and the combined extracts were washed with water and brine, dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 1:6 ethyl acetate/hexanes to provide the desired product (2.6 g, 78%). MS(CI) m/e 278 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([C:14]([F:17])([F:16])[F:15])([OH:13])CO)[CH:7]=1.I([O-])(=O)(=O)=O.[Na+]>CO.CCOCC>[F:17][C:14]([F:15])([F:16])[C:10](=[O:13])[CH2:9][C:8]([C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[O:20][CH3:21])([CH3:19])[CH3:18]
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CO)C(F)(F)F
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CO
Solvent: CCOCC
Product: COc1ccc(F)cc1C(C)(C)CC(=O)C(F)(F)F
Reaction time: 4 h
Yield: 87.6 %

Procedure:
To a solution of 4.9 g (15.8 mmol) of the above 4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-trifluoromethylpentane-1,2-diol in 100 mL of MeOH was added 10 g (45.9 mmol) of sodium periodate. The mixture was stirred for 4 hours and was then diluted with 100 mL of ether and 100 mL of hexanes, filtered through diatomaceous earth, and concentrated in vacuo. The crude residue was dissolved in hexanes and passed through a pad of silica gel eluting first with hexanes then with EtOAc-hexanes (2:98, then 4:96) to afford 3.85 g (87%) of 1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-one as a clear oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10][CH2:9][CH2:8][C:7]=2[CH:20]=1)#[N:2].Cl.[NH2:22][OH:23].C(=O)(O)[O-].[Na+].CCOCC>C(O)C>[OH:23][NH:22][C:1](=[NH:2])[C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:10][CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CCCc2cc(C#N)ccc2C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCc2cc(C(=N)NO)ccc2C1
Temperature: 55 °C
Reaction time: 5 h
Yield: 81.5 %

Procedure:
1,1-Dimethylethyl 7-cyano-1,3,4,5-tetrahydro-2H-2-benzazepine-2-carboxylate (Preparation 4) (350 mg, 1.285 mmol), hydroxylamine hydrochloride (223 mg, 3.21 mmol) and sodium bicarbonate (540 mg, 6.43 mmol) were suspended in ethanol (15 ml) and stirred at 55° C. for 5 hours. The reaction mixture was left standing overnight. LC/MS showed a single major product. Inorganics were removed by filtration, washing well with 10% MeOH/DCM to dissolve any precipitated product. Solvent evaporation yielded a white solid. Trituration with ether gave the title compound (320 mg). MS (ES) C16H23N3O3 requires 305; found 306.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([C:9]2[C:13](O)=[C:12]([C:15]([OH:17])=[O:16])[S:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1.[Na]>>[F:19][C:2]([F:1])([F:18])[C:3]1[CH:4]=[C:5]([C:9]2[CH:13]=[C:12]([C:15]([OH:17])=[O:16])[S:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)c1snc(-c2cccc(C(F)(F)F)c2)c1O
Agent: [Na]
Product: O=C(O)c1cc(-c2cccc(C(F)(F)F)c2)ns1

Procedure:
3-(3-trifluoromethylphenyl)-4-hydroxyisothiazole-5-carboxylic acid, sodium salt
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[C:23]1([S:29]([CH2:32][CH2:33][CH2:34]Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:34][CH2:33][CH2:32][S:29]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:30])=[O:31])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: O=S(=O)(CCCCl)c1ccccc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCS(=O)(=O)c2ccccc2)CC1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride and 3-phenylsulfonylpropyl chloride were reacted and treated in the same manner as in Example 199 to give 4-amino-5-chloro-2-methoxy-N-((1-(3-(phenylsulfonyl)propyl)piperidin-4-yl)methyl)-benzamide.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6]4=[C:7]([C:17](=[O:27])[C:18]([CH2:20][C:21]5[CH:22]=[N:23][CH:24]=[N:25][CH:26]=5)=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([OH:16])[CH:10]=3.Cl[CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6]4=[C:7]([C:17](=[O:27])[C:18]([CH2:20][C:21]5[CH:22]=[N:23][CH:24]=[N:25][CH:26]=5)=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:16][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[CH:10]=3
Reactant: ClCCN1CCCCC1
Reactant: O=c1c(Cc2cncnc2)cn2c3c(cc(O)cc13)Sc1ccc(Br)cc1-2
Product: O=c1c(Cc2cncnc2)cn2c3c(cc(OCCN4CCCCC4)cc13)Sc1ccc(Br)cc1-2
Yield: 51.5 %

Procedure:
According to Example 34, the compound (110 mg) produced in Example 76 was reacted with 1-(2-chloroethyl)piperidine (69 mg) to obtain the title compound (71 mg; 51%).