Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].C(Cl)Cl.[NH2:15][C:16]1[CH:17]=[CH:18][C:19]2[C:23]([Cl:24])=[C:22]([C:25]#[N:26])[S:21][C:20]=2[CH:27]=1>N1C=CC=CC=1>[C:2]([NH:15][C:16]1[CH:17]=[CH:18][C:19]2[C:23]([Cl:24])=[C:22]([C:25]#[N:26])[S:21][C:20]=2[CH:27]=1)([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3]
Reactant: N#Cc1sc2cc(N)ccc2c1Cl
Reactant: O=C(Cl)OCc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#Cc1sc2cc(NC(=O)OCc3ccccc3)ccc2c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 19.0 g. of benzyl chloroformate in 100 ml. of methylene chloride was added to a stirred solution of 0.1 mole of the amine in 500 ml. of methylene chloride containing 20 ml. of pyridine. The reaction mixture was stirred overnight at room temperature and then concentrated to dryness in vacuo. The solid residue was triturated with 5% hydrochloric acid solution and then recrystallized from ethanol to yield 6-carbobenzyloxyamino-3-chlorobenzo[b]thiophene-2-carbonitrile, m.p. 155°-166° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[C:6]([OH:19])[CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][CH:29]=[CH2:30]>CC(C)=O>[CH2:30]([O:19][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][C:7]=1[C:10]1[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=1)[CH2:29][CH:28]=[CH2:27]
Reactant: O=[N+]([O-])c1ccc(-c2ccc([N+](=O)[O-])cc2O)cc1
Reactant: C=CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCCOc1cc([N+](=O)[O-])ccc1-c1ccc([N+](=O)[O-])cc1
Yield: 41.4 %

Procedure:
Next, 10.4 g of the resulting 4,4'-dinitro-2-hydroxybiphenyl were dissolved in 95 mL dry acetone, and 5.52 g potassium carbonate and 7.56 g 4-bromo-1-butene were added and the mixture was refluxed for 71 h. The substance was then purified by a common method to obtain 5.20 g of 2-(3-butenyloxy)-4,4'dinitrobiphenyl (yield 41.4%) in the form of a light yellow powder. The boiling point of the product was 146°-147° C.
Reaction SMILES: [ClH:1].[Cl-:2].[NH2:3][C:4]([CH3:17])([CH3:16])[CH2:5][CH2:6][N+:7]1([CH3:15])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[CH2:9][CH2:8]1.C(O[Cl:23])(C)(C)C>CO.O>[Cl-:23].[Cl:1][N:3]([Cl:2])[C:4]([CH3:17])([CH3:16])[CH2:5][CH2:6][N+:7]1([CH3:15])[CH2:12][CH2:11][C:10]([CH3:13])([CH3:14])[CH2:9][CH2:8]1
Reactant: Cl
Reactant: CC(C)(N)CC[N+]1(C)CCC(C)(C)CC1
Reactant: CC(C)(C)OCl
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: CC1(C)CC[N+](C)(CCC(C)(C)N(Cl)Cl)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-(3-amino-3-methylbutyl)-1,4,4-trimethylpiperidinium chloride hydrochloride (0.50 g, 1.73 mmol) in a mixture of methanol (10 mL) and water (8 mL) was cooled in an ice bath for 15 min. t-BuOCl (0.62 mL, 3 equiv, 5.21 mmol) was added in one portion via syringe to the colorless solution to give a deep yellow solution. The reaction mixture was stirred for 30 min at 0° C., then concentrated under reduced pressure to yield a colorless oil. This oil was dissolved into water and purified via reverse phase chromatography on a Shimadzu Prep-LC utilizing water/acetonitrile and 0.05% acetic acid as modifier. Fractions were collected monitoring UV absorbance at 215 nm. Fractions were pooled and concentrated via rotovap with the water bath set at 25° C. to give a pale yellow foam, (0.373 g, 67.8%). 1H NMR (D2O, 400 MHz): δ 1.06 (s, 3H), 1.07 (s, 3H), 1.46 (s, 6H), 1.64-1.80 (m, 4H), 2.21-2.27 (m, 2H), 3.05 (s, 3 H), 3.35-3.45 (m, 6H). LRMS (ESI+) for C13H27Cl2N2+ (281.1); Found: 281, 283 (M+, M2H+).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([CH2:15][C:16]3([NH:20]C(=O)OCC4C=CC=CC=4)[CH2:19][O:18][CH2:17]3)[NH:13][CH:14]=2)=[CH:6][CH:5]=1.[H][H]>CO.C(OCC)(=O)C>[F:32][C:2]([F:1])([F:31])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[C:12]([CH2:15][C:16]3([NH2:20])[CH2:17][O:18][CH2:19]3)[NH:13][CH:14]=2)=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: O=C(NC1(Cc2nc(-c3ccc(OC(F)(F)F)cc3)c[nH]2)COC1)OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CO
Product: NC1(Cc2nc(-c3ccc(OC(F)(F)F)cc3)c[nH]2)COC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Benzyl [3-({4-[4-(trifluoromethoxy)phenyl]-1H-imidazol-2-yl}methyl)oxetan-3-yl]-carbamate (Preparation 11, 311 g, 695 mmol) was dissolved in methanol (3.2 L). 5% Palladium on carbon E105 R/W (EVONIK) (22 g, 7 wt %) was added and the reaction hydrogenated at 40° C., 100 psi for 18 hours. Hydrogen uptake was monitored and showed the reaction to be complete after 4 hours. The mixture was cooled to room temperature and filtered over Arbocel©. The filter cake was washed with methanol (2×1 L) and the filtrate concentrated in vacuo to afford a solid. The solid was dissolved in ethyl acetate (1 L) and filtered through a carbon tablet to remove traces of palladium. The solution was warmed to 50° C. and heptane (1 L) added. The solution was cooled slowly whereupon at 40° C. crystallisation was observed. The mixture was stirred at room temperature for 72 hours. The solid was collected by filtration and washed with ethyl acetate: heptane (1:1, 250 mL). The solid was dried in vacuo at 40° C. for 18 hours to afford the title compound as a crystalline solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([NH2:7])=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[NH:4][N:3]=1.C(N(CC)CC)C.[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26](Cl)=[O:27]>C(Cl)Cl>[CH3:1][C:2]1[C:6]([NH:7][C:26]([C:22]2[O:21][CH:25]=[CH:24][CH:23]=2)=[O:27])=[C:5]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:4][N:3]=1
Reactant: Cc1n[nH]c(-c2ccccc2)c1N
Reactant: O=C(Cl)c1ccco1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1n[nH]c(-c2ccccc2)c1NC(=O)c1ccco1
Reaction time: 2 h

Procedure:
To a RT solution of 337.3 mg of 3-methyl-5-phenyl-1H-pyrazol-4-ylamine in 4 mL methylene chloride was added 407 μL of triethylamine and 201 μL of 2-furoyl chloride. After 2 h at RT, the reaction mixture was concentrated under reduced pressure and the residue was dissolved in chloroform and washed with saturated aqueous sodium carbonate and brine. The organic portion was dried with sodium sulfate and concentrated under reduced pressure. The residue contained the title compound as a yellow, amorphous solid and was used without further purification.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:19][C:20]3[CH:25]=[C:24]([O:26][C:27]([O:29][CH3:30])=[O:28])[C:23]([CH3:31])=[CH:22][C:21]=3[F:32])=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:33][CH3:34])C1C=CC=CC=1.[H][H]>CN(C=O)C.CO.ClC(Cl)Cl.[Pd]>[F:32][C:21]1[CH:22]=[C:23]([CH3:31])[C:24]([O:26][C:27]([O:29][CH3:30])=[O:28])=[CH:25][C:20]=1[NH:19][C:13]1[C:12]2[C:17](=[CH:18][C:9]([OH:8])=[C:10]([O:33][CH3:34])[CH:11]=2)[N:16]=[CH:15][N:14]=1
Reactant: [H][H]
Reactant: COC(=O)Oc1cc(Nc2ncnc3cc(OCc4ccccc4)c(OC)cc23)c(F)cc1C
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)Oc1cc(Nc2ncnc3cc(O)c(OC)cc23)c(F)cc1C
Yield: 109.1 %

Procedure:
A solution of 7-benzyloxy-4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-6-methoxyquinazoline (700 mg, 1.4 mmol) in DMF (10 ml), methanol (10 ml) and trichloromethane (10 ml) containing 10% palladium-on-charcoal (100 mg) was stirred under 1 atmosphere of hydrogen for 1 hour. After filtration and evaporation of the solvent, the residue was triturated with ether, filtered and dried under vacuum to give 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline (570 mg, 98%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11]Cl)[N:10]=2)[CH:7]=1.[N:13]1([C:19]2[CH:27]=[CH:26][C:22]([C:23]([NH2:25])=[O:24])=[CH:21][CH:20]=2)[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(N(CC)CC)C>C(O)CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:16]3[CH2:15][CH2:14][N:13]([C:19]4[CH:20]=[CH:21][C:22]([C:23]([NH2:25])=[O:24])=[CH:26][CH:27]=4)[CH2:18][CH2:17]3)[N:10]=2)[CH:7]=1
Reactant: NC(=O)c1ccc(N2CCNCC2)cc1
Reactant: ClCc1cn2cc(Cl)ccc2n1
Solvent: OCCO
Solvent: CCN(CC)CC
Product: NC(=O)c1ccc(N2CCN(Cc3cn4cc(Cl)ccc4n3)CC2)cc1
Yield: 43.5 %

Procedure:
Following the general procedure of Example 2, Step 3, and making noncritical variations, 6-chloro-2-(chloromethyl)imidazo[1,2-a]pyridine (0.500 g), 4-(piperaziny-1-yl)benzamide (Example 3, Step 1; 0.536 g), triethylamine (0.477 g), and ethylene glycol (6 mL) give 0.40 g of the title compound after chromatography on silica gel using methanol/dichloromethane (8/92) and crystallization from methanol/dichloromethane; mp 240-241° C.; IR (mineral oil) 1612, 1646, 1331, 3359, 1501 cm-1. 1H NMR (DMSOd6) δ2.60, 3.25, 3.66, 6.92, 7.04, 7.25, 7.54, 7.72, 7.73, 7.84, 8.80.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][O:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:17][C:16]3([N:21]([CH3:22])[CH2:20][CH2:19][CH2:18]3)[CH2:15]2)[C:11]([NH2:23])=[CH:10][C:9]=1[NH:24][C:25]1[N:30]=[C:29]([C:31]2[CH:32]=[N:33][N:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=23)[CH:28]=[CH:27][N:26]=1>C(Cl)Cl.CO>[CH3:6][O:7][C:8]1[C:9]([NH:24][C:25]2[N:30]=[C:29]([C:31]3[CH:32]=[N:33][N:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=34)[CH:28]=[CH:27][N:26]=2)=[CH:10][C:11]([NH:23][C:1](=[O:4])[CH:2]=[CH2:3])=[C:12]([N:14]2[CH2:15][C:16]3([N:21]([CH3:22])[CH2:20][CH2:19][CH2:18]3)[CH2:17]2)[CH:13]=1
Reactant: C=CC(=O)Cl
Reactant: COc1cc(N2CC3(CCCN3C)C2)c(N)cc1Nc1nccc(-c2cnn3ccccc23)n1
Solvent: ClCCl
Solvent: CO
Product: C=CC(=O)Nc1cc(Nc2nccc(-c3cnn4ccccc34)n2)c(OC)cc1N1CC2(CCCN2C)C1
Reaction time: 0.5 h
Yield: 51.8 %

Procedure:
A solution of acryloyl chloride (0.766 mL, 0.77 mmol, 1.0 M in CH2Cl2) was added dropwise over 10 minutes to 4-methoxy-6-(8-methyl-2,8-diazaspiro[3.4]octan-2-yl)-N′-(4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)benzene-1,3-diamine (Intermediate 162, 333 mg, 0.73 mmol) in CH2Cl2 (6 mL), which was cooled in an ice/CH3OH bath. The mixture was then stirred for 0.5 h, then diluted with 10% CH3OH in CH2Cl2. The resulting solution was washed with sat. NaHCO3, dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 1-10% methanolic ammonia in CH2Cl2 gave the title compound (193 mg, 52%) as an beige solid after trituration with diethyl ether; 1H NMR: 1.69 (2H, dt), 2.03-2.08 (2H, m), 2.38 (3H, s), 2.63 (2H, t), 3.65 (2H, d), 3.83 (3H, s), 3.94 (2H, d), 5.68 (1H, dd), 6.19 (1H, dd), 6.25 (1H, s), 6.47 (1H, dd), 7.06 (1H, td), 7.19 (1H, d), 7.44 (1H, dd), 7.67 (1H, s), 7.98 (1H, s), 8.29 (1H, d), 8.47 (1H, d), 8.75 (1H, s), 8.78 (1H, d), 9.25 (1H, s); m/z: ES+ MH+ 511.34.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])=[N:4][CH:3]=1.[CH:15]1([Mg]Cl)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(OCC)C.[Cl-].[NH4+]>C1COCC1.O>[CH:9]1([C:7]([C:5]2[O:6][C:2]([CH3:1])=[CH:3][N:4]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[OH:8])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Cl[Mg]C1CCCCC1
Reactant: Cc1cnc(C(=O)c2ccccc2)o1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cnc(C(O)(c2ccccc2)C2CCCCC2)o1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of (5-methyl-oxazol-2-yl)-phenyl-methanone (intermediate 2) (3.0 g, 16 mmol) in 32 mL dry THF at 0° C. under nitrogen was treated dropwise over 10 min with a 2 M solution of cyclohexylmagnesium chloride in diethyl ether (10 mL, 20 mmol). The resulting deep yellow solution was stirred at 0° C. for about 30 min during which time a precipitate was formed, and then at RT for 1.5 h. The reaction mixture was cooled to 0° C. again and treated cautiously with satd. ammonium chloride solution (aq.). The mixture was stirred at RT for 10 min then diluted with water (10 mL). The phases were separated and the organic phase was washed with brine. The combined aqueous phase was extracted with DCM and the combined organic phase was dried (MgSO4) and concentrated in vacuo to give the crude product, which was triturated with ether, filtered off and dried.
Reaction SMILES: [CH2:1]1[CH2:5][O:4][CH2:3][CH2:2]1.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.C(O[CH2:18][CH3:19])C>>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C@H:19]2[CH:18]=[CH:5][C:1]3[C:2](=[CH:5][CH:1]=[CH:2][CH:3]=3)[C@@H:3]2[OH:4])=[CH:10][CH:9]=1
Reactant: C1CCOC1
Reactant: CCOCC
Reactant: COc1ccc(O)cc1
Product: COc1ccc(O[C@H]2C=Cc3ccccc3[C@@H]2O)cc1
Temperature: 80 °C
Reaction time: 0.37 h

Procedure:
To a flame dried round-bottomed flask, [Rh(COD)Cl]2 (1.7 mg, 0.0035 mmol), (S)-(R)-PPF-PtBu2 (3.8 mg, 0.0069 mmol) and 1 (100 mg, 0.694 mmol) were added followed by addition of THF (2.5 mL) and 4-methoxyphenol (431 mg, 3.47 mmol). The mixture was heated at 80° C. for 6 hours, then poured into diethyl ether and extracted 3 times with 10% aqueous sodium hydroxide solution. The aqueous extracts were combined and back-extracted three times with diethyl ether. The combined ether extracts were washed with brine and dried with anhydrous sodium sulfate. The solvents were removed in vacuo, yielding a solid which was purified by flash chromatography on silica gel (10% ethyl acetate in hexanes) as a white crystalline solid 12 (159 mg, 85%). The ee was determined to be 95% by HPLC analysis on a CHIRALCEL OD column, λ=256 nm. Retention times in 4% isopropanol in hexanes were 22.1 min (major) and 25.9 min. Rf=0.33 on silica (20% ethyl acetate in hexanes); mp 91-92° C. (Et2O); [α]25D=+129° (c=9.9, CHCl3); IR (KBr, cm−1) 3349 (br), 3050 (w), 2822 (w), 1508 (s), 1233 (s), 1046 (m), 825 (m), 751 (m), 695 (w); 1H NMR (400 MHz, CDCl3): δ 7.66-7.64 (1H, m), 7.30-7.27 (2H, m), 7.12-7.10 (1H, m), 6.91 (2H, ddd, J=2.3, 2.3, 9.1 Hz), 6.84 (2H, ddd, J=2.4, 2.4, 9.2 Hz), 6.49 (1H, dd, J=2.0, 9.9 Hz), 6.02 (1H, dd, J=2.4, 9.9 Hz), 5.17 (1H, dd, J=3.3, 10.1 Hz), 5.02 (1H, ddd, J=2.0, 2.0, 10.3 Hz), 3.77 (3H, s), 3.12 (1H, d, J=3.4 Hz). 13C NMR (400 MHz, CDCl3): δ 154.3, 151.2, 135.5, 131.9, 128.7, 128.1, 127.9, 126.4, 126.3, 125.2, 117.2, 114.8, 80.0, 72.4, 55.7. HRMS calcd for (M+) (C17H14O2): 250.0994. Found: 250.1006.
Reaction SMILES: [C:1]([C:4]1[C:5](Br)=[N:6][CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[C:11]([C:13]1[CH:14]=[C:15]([O:23][CH3:24])[C:16]([O:21][CH3:22])=[C:17]([O:19][CH3:20])[CH:18]=1)#[CH:12].C(N(CC)CC)C.[Cl-]>C1COCC1.C(Cl)Cl>[CH3:24][O:23][C:15]1[CH:14]=[C:13]([C:11]#[C:12][C:5]2[C:4]([C:1](=[O:3])[CH3:2])=[CH:9][CH:8]=[CH:7][N:6]=2)[CH:18]=[C:17]([O:19][CH3:20])[C:16]=1[O:21][CH3:22]
Reactant: CC(=O)c1cccnc1Br
Reactant: C#Cc1cc(OC)c(OC)c(OC)c1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc(C#Cc2ncccc2C(C)=O)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.8 %

Procedure:
Step 1 (=Reaction 1): 100 mg 3-Acetyl-2-bromopyridine, 140 mg 5-ethynyl-1,2,3-trimethoxybenzene 2.1, 101 μL triethylamine, 17 mg triphenylphosphinpalladium(II) chlorid, 1 mg Cu(I)I were suspended in 4 mL THF under argon atmosphere and stirred for 1 h at 25° C. The mixture was diluted with DCM and extracted with diluted aq. NH3 and saturated NH4Cl solution. The organic phase was concentrated and the mixture separated via FCC (10 g SiO2, Cyclohexane→cyclohexane/ethylacetate 70:30) to yield 90 mg 1-(2-(3,4,5-trimethoxyphenylethynyl)pyridin-3-yl)ethanone as solid. Analysis: HPLC-MS: Rt=1.21 min (method E) M+H=312.
Reaction SMILES: C([O:4][C:5]1[CH:35]=[CH:34][C:8]([CH2:9][N:10]2[C:15](=[O:16])[C:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[C:13]([C:24]3[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=3)[CH:12]=[N:11]2)=[CH:7][CH:6]=1)(=O)C.O.[OH-].[Li+].CO.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O>[OH:4][C:5]1[CH:35]=[CH:34][C:8]([CH2:9][N:10]2[C:15](=[O:16])[C:14]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)=[C:13]([C:24]3[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=3)[CH:12]=[N:11]2)=[CH:7][CH:6]=1
Reactant: CC(=O)Oc1ccc(Cn2ncc(-c3ccc(S(C)(=O)=O)cc3)c(-c3ccc(F)cc3)c2=O)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2cnn(Cc3ccc(O)cc3)c(=O)c2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-(4-acetoxybenzyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (0.2 g, 4.06 mmol) (Example 114) in THF (20 mL) was treated with a solution of lithium hydroxide monohydrate (0.05 g, 1.22 mmol) in water (5 mL). Methanol (2 mL) was added to provide a homogeneous solution which was stirred at room temperature overnight. The reaction mixture was then acidified with 10% aqueous citric acid and extracted with ethyl acetate. The ethyl acetate layer was dried over MgSO4 and filtered. The filtrate was concentrated in vacuo to provide a white foam which was purified by column chromatography (silica gel, 65:35 hexanes/ethyl acetate). Product fractions were combined and concentrated in vacuo. The residue was crystallized from ethyl acetate/hexanes (yield: 195 mg, 70%). mp 225-226° C. 1H NMR (300 MHz, CDCl3) δ 3.05 (s, 3H), 4.86 (s, 1H), 5.33 (s, 2H), 6.80 (d, J=8.5 Hz, 2H), 6.95 (t, J=9 Hz, 2H), 7.15 (dd, J=9 Hz, 5 Hz, 2H), 7.30 (d, J=8.5 Hz, 2H), 7.46 (d, J=8.5 Hz, 2H), 7.83 (s, 1H), 7.87 (d, J=8.5 Hz, 2H). MS (DCI/NH3) m/z 451 (M+H)+. Anal. calc. for C24H19FN2O4S: C, 63.99; H, 4.25; N, 6.22. Found: C, 63.73; H, 4.16; N, 6.11.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:18]([O-])=O)=[CH:5][C:6]([CH3:17])=[C:7]([C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:10])[CH:8]=1.O.O.Cl[Sn]Cl.[OH-].[Na+].C(Cl)Cl>C(O)C.O>[NH2:18][C:4]1[C:3]([O:2][CH3:1])=[CH:8][C:7]([C:9]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)=[O:10])=[C:6]([CH3:17])[CH:5]=1
Reactant: COc1cc(C(=O)N2CCOCC2)c(C)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: COc1cc(C(=O)N2CCOCC2)c(C)cc1N
Temperature: 65 °C
Yield: 92.3 %

Procedure:
To (5-methoxy-2-methyl-4-nitrophenyl)(morpholino)methanone (324 mg, 1.16 mmol) in ethanol (20 mL) and water (2 mL) was added SnCl2.2H2O (1.05 g, 4.64 mmol). The mixture was heated to 65° C. for 36 h and then 2 M aqueous sodium hydroxide solution (20 mL) and DCM (20 mL) were added. The organic phase was passed through a hydrophobic frit and the solvent was removed in vacuo to give (4-amino-5-methoxy-2-methylphenyl)(morpholino)methanone (268 mg, 92%) as an off-white solid. LCMS (10 cm_ESCI_Formic_MeCN): [M+H]+=251 at 2.14 min. 1H NMR (400 MHz, CDCl3): δ 6.60 (s, 1H), 6.52 (s, 1H), 3.87-3.52 (br m, 6H), 3.84 (br s, 2H), 3.82 (s, 3H), 3.36-3.23 (br m, 2H), 2.17 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([CH3:14])=[C:12]([C:15]([OH:17])=O)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([N:27]2[CH2:32][CH2:31][CH:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[CH2:29][CH2:28]2)=[C:23]([CH:26]=1)[C:24]#[N:25]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([CH3:14])=[C:12]([C:15]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([N:27]4[CH2:32][CH2:31][CH:30]([N:33]5[CH2:34][CH2:35][O:36][CH2:37][CH2:38]5)[CH2:29][CH2:28]4)=[C:23]([C:24]#[N:25])[CH:26]=3)=[O:17])[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(Cl)c(Cl)c1
Reactant: N#Cc1cc(N)ccc1N1CCC(N2CCOCC2)CC1
Product: Cc1c(C(=O)Nc2ccc(N3CCC(N4CCOCC4)CC3)c(C#N)c2)cnn1-c1ccc(Cl)c(Cl)c1
Yield: 40.2 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-(3,4-dichlorophenyl)-5-methylpyrazole-4-carboxylic acid (1.5 g) and 5-amino-2-(4-morpholinopiperidin-1-yl)benzonitrile (1.7 g), the title compound (1.2 g) was obtained, melting point: 242° C.
Reaction SMILES: Cl[C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:10]=2)=[O:7])=[CH:4][N:3]=1.[OH:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>C(O)CCC>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:22]=[CH:23][C:2]([N:28]3[CH2:29][CH2:30][CH:25]([OH:24])[CH2:26][CH2:27]3)=[N:3][CH:4]=2)=[CH:10][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: OC1CCNCC1
Reactant: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(Cl)nc1
Solvent: CCCCO
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(N2CCC(O)CC2)nc1

Procedure:
Procedure F was performed using 50 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)nicotinamide and 74 mg of 4-hydroxypiperidine in 0.5 mL of BuOH. Purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(4-hydroxypiperidin-1-yl)nicotinamide. MS (Q1) 409.3 (M)+.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=1[C:18]([F:21])([F:20])[F:19]>>[F:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[CH:13][C:12]=1[C:18]([F:19])([F:20])[F:21]
Reactant: Oc1ccc(F)c(C(F)(F)F)c1
Reactant: O=Cc1ccc(F)cc1
Product: O=Cc1ccc(Oc2ccc(F)c(C(F)(F)F)c2)cc1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 4-fluorobenzaldehyde and 4-fluoro-3-(trifluoromethyl)phenol.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[C:7]1[CH:12]=[CH:11][C:10]([CH:13]=O)=[CH:9][C:8]=1[CH3:15])([CH3:4])([CH3:3])[CH3:2].[C:17]([O-])(=O)C.[Na+].Cl.[CH3:23][NH:24][OH:25]>O1CCCC1.O.C(OCC)(=O)C.O>[C:1]([O:5][C:6]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[C:23]=[N+:24]([CH3:17])[O-:25])=[CH:9][C:8]=1[CH3:15])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C=O)ccc1C(=O)OC(C)(C)C
Reactant: CNO
Reactant: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(C=C=[N+](C)[O-])ccc1C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 15 h
Yield: 76.8 %

Procedure:
To a solution of 4-formyl-2-methyl-benzoic acid tert-butyl ester (Example I2) (1.57 g) in tetrahydrofuran/water (3:1) (20 ml) was added sodium acetate (0.67 g) and N-methylhydroxylamine hydrochloride (0.69 g). The reaction mixture was stirred at 50° C. for 15 hours. The reaction mixture was diluted with ethyl acetate and water. The phases were separated and the organic layer was washed with water, dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: methanol/ethyl acetate 5:5) to give (4-tert-butoxycarbonyl-3-methyl-benzylidene)-N-methyl-nitrone (1.43 g) as yellow oil. 1H-NMR (CDCl3, 400 MHz): 8.10 (s, 1H), 8.02 (d, 1H), 7.85 (d, 1H), 7.35 (s, 1H), 3.90 (s, 3H), 2.60 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:16][C@@H:17]2[CH2:23][CH2:22][CH2:21][CH2:20][N:19]([C:24]([N:26]([CH3:28])[CH3:27])=[O:25])[CH2:18]2)=[N:7][C:8]=1[NH:9][C:10]1[S:14][N:13]=[C:12]([CH3:15])[CH:11]=1)#[N:2].Cl.CC#N.C(O)(C(F)(F)F)=[O:34]>OS(O)(=O)=O.O.CO>[C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:16][C@@H:17]2[CH2:23][CH2:22][CH2:21][CH2:20][N:19]([C:24]([N:26]([CH3:27])[CH3:28])=[O:25])[CH2:18]2)=[N:7][C:8]=1[NH:9][C:10]1[S:14][N:13]=[C:12]([CH3:15])[CH:11]=1)(=[O:34])[NH2:2]
Reactant: Cc1cc(Nc2nc(N[C@@H]3CCCCN(C(=O)N(C)C)C3)cnc2C#N)sn1
Reactant: O=C(O)C(F)(F)F
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: CC#N
Solvent: O
Product: Cc1cc(Nc2nc(N[C@@H]3CCCCN(C(=O)N(C)C)C3)cnc2C(N)=O)sn1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
(R)-3-(5-Cyano-6-(3-methylisothiazol-5-ylamino)pyrazin-2-ylamino)-N,N-dimethylazepane-1-carboxamide (510) (20 mg, 0.050 mmol) was dissolved in 5 mL TFA, and the solution was heated to 80° C. Concentrated H2SO4 (7 drops) was added dropwise, and the reaction was allowed to stir for 30 min Additional H2SO4 (15 drops) was added dropwise and the reaction was allowed to stir for 30 minutes. The reaction was cooled to RT, and diluted with 2 mL water and 2 mL methanol. The mixture was then directly subjected to reverse phase preparative HPLC using 5 mM HCl (aq) and neat MeCN as mobile phases, and lyophilized to give (R)-3-(5-carbamoyl-6-(3-methylisothiazol-5-ylamino)pyrazin-2-ylamino)-N,N-dimethylazepane-1-carboxamide (511) (16 mg, 0.038 mmol, 76% yield). LC-MS (ESI): m/z (M+1) 419.6. Proton NMR (DMSO-d6): δ 12.27 (1H, s), 8.05 (1H, s), 7.81 (1H, s), 7.48-7.44 (2H, m), 6.85 (1H, s), 4.46 (1H, m), 3.35 (4H, m), 2.70 (6H, s), 2.30 (3H, s), 2.02 (1H, m), 1.79 (2H, m), 1.70 (1H, m), 1.57 (2H, m) ppm.