Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BrH:1].[C:2]1([S:8]([CH2:11][CH2:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH:17]=[CH:16]3)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[CH2:24][CH2:25]OC>>[BrH:1].[CH3:19][N:18]1[CH2:17][CH2:16][CH2:15][C@@H:24]1[CH2:25][C:16]1[C:15]2[C:19](=[CH:20][CH:21]=[C:13]([CH2:12][CH2:11][S:8]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)(=[O:10])=[O:9])[CH:14]=2)[NH:18][CH:17]=1
Reactant: COCCOC
Reactant: O=S(=O)(CCc1ccc2[nH]ccc2c1)c1ccccc1
Agent: Br
Product: CN1CCC[C@@H]1Cc1c[nH]c2ccc(CCS(=O)(=O)c3ccccc3)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
49% w/w Hydrobromic acid (27.86 ml, 0.25 mol) was added over 1 hour to a stirred solution of 3N-methyl-2(R)-pyrrolidinylmethyl)-5-(2-phenylsulphonylethyl)-1H-indole (92.86 g, 0.24 mol) in 1,2-dimethoxyethane (2.08 l) at about 5° C. The cooling bath was removed and the resulting slurry was allowed to granulate by stirring at room temperature for a further 18 hours. Filtration, followed by washing with 1,2-dimethoxyethane and drying in vacuo, afforded the required product (97.9 g) as a solid, m.p. 150-151° C. Found: C,56.77; H,5.87; N,5.85. C22H26N2O2S; HBr requires C,57.02; H,5.87; N,6.04%.
Reaction SMILES: [C:1]1([C:11]([OH:13])=[O:12])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[N+:14]([O-])([OH:16])=[O:15]>>[N+:14]([C:3]1[CH:2]=[C:1]([C:11]([OH:13])=[O:12])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=1)([O-:16])=[O:15]
Reactant: O=C(O)c1cccc2c1CCCC2
Reactant: O=[N+]([O-])O
Product: O=C(O)c1cc([N+](=O)[O-])cc2c1CCCC2
Temperature: 2 °C

Procedure:
Fuming red nitric acid (150 ml.) was cooled to 2° C. and 27.3 g. of 5,6,7,8-tetrahydronaphthalene-1-carboxylic acid was added portionwise over 0.5 hour with stirring maintaining the temperature at 2°-6° C. After another 45 minutes at about 5° C. the mixture was poured into 1500 ml. of crushed ice. The precipitate was collected and washed well with 5 × 500 ml. portions of water. The dried precipitate was heated with about 200 ml. of benzene. The insoluble material was collected and recrystallized from ethyl acetate to give 3-nitro-5,6,7,8-tetrahydronaphthalene-1-carboxylic acid, m.p. 209°-212° C.
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH3:23][CH:24]([CH3:28])[CH:25]([NH2:27])[CH3:26]>CS(C)=O>[CH3:26][CH:25]([NH:27][C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2)[CH:24]([CH3:28])[CH3:23]
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Reactant: CC(C)C(C)N
Solvent: CS(C)=O
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC(C)C(C)C
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Prepared according to Example 127, using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 40 mg, 0.135 mmol), rac-3-methylbutan-2-amine (35.3 mg, 0.405 mmol, Sigma Aldrich), and DMSO (1.4 mL) stirring at 80° C. for 2 h. Purification by high throughput parallel purification (Rilas Technologies, Woburn, Mass.) provided 2-(3-(((±)-1,2-dimethylpropyl)amino)-2-methyl-5-quinoxalinyl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one. 1H NMR (DMSO-d6) δ: 11.95-12.11 (m, 1H), 7.81-7.91 (m, 1H), 7.49-7.67 (m, 1H), 7.26-7.37 (m, 1H), 7.08-7.21 (m, 1H), 6.86-7.02 (m, 1H), 6.65-6.84 (m, 1H), 4.01-4.20 (m, 1H), 3.38-3.50 (m, 2H), 2.84-2.96 (m, 2H), 2.58 (s, 3H), 1.98-2.13 (m, 1H), 1.21-1.34 (m, 3H), 0.93-1.12 (m, 6H). m/z (ESI, +ve) 364.1 (M+H)+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:18]=[CH:17][C:16]3[C:11](=[C:12]([C:19]4[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=4)[CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH2:4][CH2:3]1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:33][CH2:34][N:35]([CH3:43])[C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39]>CN(C=O)C>[OH:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9]2[N:18]=[CH:17][C:16]3[C:11](=[C:12]([C:19]4[CH:20]=[CH:21][C:22]([O:25][CH2:33][CH2:34][N:35]([CH3:43])[C:36](=[O:42])[O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[CH:23][CH:24]=4)[CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH2:6][CH2:7]1
Reactant: Oc1ccc(-c2cccc3cnc(N[C@H]4CC[C@H](O)CC4)nc23)cc1
Reactant: CN(CCCl)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN(CCOc1ccc(-c2cccc3cnc(N[C@H]4CC[C@H](O)CC4)nc23)cc1)C(=O)OC(C)(C)C
Temperature: 85 °C
Reaction time: 3 h

Procedure:
To the flask were added 4-{2-[(trans-4-hydroxycyclohexyl)amino]quinazolin-8-yl}phenol (110 mg, 0.33 mmol), Cs2CO3 (1345 mg, 4.13 mmol), tert-butyl (2-chloroethyl)methylcarbamate (290 mg, 1.45 mmol) and DMF (5 mL). The mixture was stirred for 3 hours at 85° C. The reaction was completed as judged by TLC. The mixture was concentrated in vacuo to afford crude tert-butyl [2-(4-{2-[(trans-4 hydroxycyclohexyl)amino]quinazolin-8-yl}phenoxy)ethyl]methylcarbamate
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([I:12])=[C:10](S(C)=O)[N:9]=[C:8]([NH2:16])[N:7]=1.[C:17]1([CH2:23][CH2:24][CH2:25][OH:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([I:12])=[C:10]([O:26][CH2:25][CH2:24][CH2:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:9]=[C:8]([NH2:16])[N:7]=1
Reactant: OCCCc1ccccc1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1I
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1nc(OCCCc2ccccc2)c(I)c(-c2ccco2)n1

Procedure:
From 4-furan-2-yl-5-iodo-6-methanesulfinyl-pyrimidin-2-yl-amine, 3-phenylpropanol and DBU in THF. ES-MS m/e (%): 422 (M+H+, 100).
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[CH:19]=[C:18]([C:20]3[CH:25]=[N:24][C:23]([N:26](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[C:22]4[O:41][C:42]([Sn](C)(C)C)=[CH:43][C:21]=34)[CH:17]=[N:16]2)[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.Br[C:49]1[C:57]2[S:56][N:55]=[N:54][C:53]=2[CH:52]=[C:51]([C:58]2[CH:62]=[CH:61][NH:60][N:59]=2)[CH:50]=1>>[NH2:26][C:23]1[N:24]=[CH:25][C:20]([C:18]2[CH:17]=[N:16][N:15]([C@H:12]3[CH2:13][CH2:14][C@H:9]([OH:8])[CH2:10][CH2:11]3)[CH:19]=2)=[C:21]2[CH:43]=[C:42]([C:49]3[C:57]4[S:56][N:55]=[N:54][C:53]=4[CH:52]=[C:51]([C:58]4[CH:62]=[CH:61][NH:60][N:59]=4)[CH:50]=3)[O:41][C:22]=12
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(-c2cnn([C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)CC3)c2)c2cc([Sn](C)(C)C)oc12
Reactant: Brc1cc(-c2cc[nH]n2)cc2nnsc12
Product: Nc1ncc(-c2cnn([C@H]3CC[C@H](O)CC3)c2)c2cc(-c3cc(-c4cc[nH]n4)cc4nnsc34)oc12

Procedure:
The title compound was prepared from di-tert-butyl {4-[1-(trans-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-1H-pyrazol-4-yl]-2-(trimethylstannanyl)furo[2,3-c]pyridin-7-yl}imidodicarbonate and 7-bromo-5-(1H-pyrazol-3-yl)-1,2,3-benzothiadiazole by a procedure analogous to Example 373, Step B. 1H NMR (400 MHz, CD3OD): δ 1.50-1.61 (m, 2 H), 1.93-2.06 (m, 2 H), 2.13-2.21 (m, 2 H), 2.25-2.33 (m, 2 H), 3.75 (tdd, J=10.9, 10.9, 4.2, 4.0 Hz, 1 H), 4.27 (tdd, J=12.0, 12.0, 4.3, 4.1 Hz, 1 H), 6.97 (d, J=2.3 Hz, 1 H), 7.58 (s, 1 H), 7.78 (d, J=2.3 Hz, 1 H), 7.88 (s, 1 H), 7.93 (s, 1 H), 7.94 (s, 1 H), 8.92 (br. s, 1 H), 9.04 (d, J=1.3 Hz, 1 H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[Mg]Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl.[OH-].[Na+]>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[O:22][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Br[Mg]c1ccccc1OCc1ccccc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: OC1(c2ccccc2OCc2ccccc2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.8 %

Procedure:
A solution of 1-benzyl-4-piperidone (0.5 g, 2.6 mmol) in THF (10 mL) was cooled to −78° C. and 2-(benzyloxy)phenyl magnesium bromide (3.2 mmol) was added. The mixture was stirred for 0.5 hours then allowed to warm to room temperature. Hydrochloric acid (1 N, 10 mL) was added carefully and the mixture stirred for 0.1 hour before adding a solution of aqueous sodium hydroxide (1 N, 30 mL). The products were extracted into ethyl acetate, dried over magnesium sulphate, filtered and the solvent removed by evaporation under vacuum. The residue was purified by flash chromatography on silica eluting with 0-50% ethyl acetate/hexane. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.6 g) as a clear, colourless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:17]1[C:22]([N+:23]([O-])=O)=[CH:21][C:20]([F:26])=[CH:19][N:18]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:13][C:17]2[C:22]([NH2:23])=[CH:21][C:20]([F:26])=[CH:19][N:18]=2)=[CH:14][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(F)cnc1Cl
Reactant: Nc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(F)cnc1Nc1ccc(OCc2ccccc2)cc1
Temperature: 120 °C
Reaction time: 5 h
Yield: 24.3 %

Procedure:
A mixture of 4-(benzyloxy)aniline (2.26 g), 2-chloro-5-fluoro-3-nitropyridine (2 g) and K2CO3 (3.13 g) in DMF (20 ml) was stirred at 120° C. for 5 h, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was suspended in IPE and collected by filtration. The obtained solid was dissolved in EtOH (20 ml), and Pt/C (2 g) was added. Under H2 atmosphere, the mixture was stirred for 1 h, filtered and evaporated. The residue was chromatographed on silica gel eluting with Hexane/AcOEt to give the title compound (0.85 g).
Reaction SMILES: [C:1]([N:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]#[C:16][CH2:17][OH:18])=[CH:12][CH:13]=2)[C:8](=[O:19])[C:7]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=[O:21])=[CH:6]1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C1COCC1.CO.[Pt]=O>[C:1]([N:5]1[C:14]2[C:9](=[CH:10][C:11]([CH2:15][CH2:16][CH2:17][OH:18])=[CH:12][CH:13]=2)[C:8](=[O:19])[C:7]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=[O:21])=[CH:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCO)ccc21
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)n1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCCO)ccc21
Yield: 96.1 %

Procedure:
A mixture of 303 mg of 1-(tert-butyl)-N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide from Preparation No. 11 and 15 mg of platinum oxide in 10 mL of 1: 1 THF-methanol is stirred under 1 atm of hydrogen gas for 3 h, then filtered through diatomaceous earth and concentrated under reduced pressure. The mixture was purified by flash chromatography on silica using 2-3% methanol in dichloromethane to afford 294 mg of the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:15](=[O:16])[C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[C:25]([C:30]#[N:31])=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:20][CH:19]=3)=[C:13]([CH2:32][CH2:33][CH3:34])[N:12]=[C:11]2[CH3:35])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:36][Mg]Br.S([O-])(O)(=O)=O.[K+]>O1CCCC1>[OH:3][C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:15](=[O:16])[C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[C:25]([C:30]#[N:31])=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:20][CH:19]=3)=[C:13]([CH2:32][CH2:33][CH3:34])[N:12]=[C:11]2[CH3:35])=[CH:8][CH:9]=1)([CH3:36])[CH3:2]
Reactant: CCCc1nc(C)n(-c2ccc(C(C)=O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: C[Mg]Br
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: CCCc1nc(C)n(-c2ccc(C(C)(C)O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 1 h
Yield: 35 %

Procedure:
4′-{[1-(4-Acetylphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.2 g) was dissolved in tetrahydrofuran (12 mL), methylmagnesium bromide (1.0 M tetrahydrofuran solution, 6.4 mL) was added at −78° C., and the mixture was stirred for 1 hr. A 5% aqueous potassium hydrogen sulfate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.45 g, 35%) as a pale-yellow liquid.
Reaction SMILES: [CH:1]([O-])=[O:2].[Na+].[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11]([CH3:28])[C:12]2[O:18][C:17]3[C:19]([Cl:24])=[CH:20][C:21]([NH2:23])=[CH:22][C:16]=3[CH2:15][S:14](=[O:26])(=[O:25])[C:13]=2[CH:27]=1)=[O:8]>C(O)=O>[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11]([CH3:28])[C:12]2[O:18][C:17]3[C:19]([Cl:24])=[CH:20][C:21]([NH:23][CH:1]=[O:2])=[CH:22][C:16]=3[CH2:15][S:14](=[O:26])(=[O:25])[C:13]=2[CH:27]=1)=[O:8]
Reactant: O=C[O-]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N)cc(Cl)c1O2
Agent: [Na+]
Solvent: O=CO
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NC=O)cc(Cl)c1O2
Temperature: 0 °C

Procedure:
Sodium formate (7.29 g, 0.108 mol) was added to a suspension of compound of Example 1 (20 g, 0.054 mol) in formic acid (200 mL) and refluxed for 1.5 h. The reaction mixture was cooled and poured into ice water (800 mL). The solid precipitated was filtered, washed with water and dried. The crude product was purified by column chromatography (silica gel, 1% methanol in chloroform) to obtain the title compound. Yield: 18 g, (83%); mp 258-262° C. (decomposed); 1H NMR (DMSO-d6, 300 MHz): δ 2.64 (s, 3H, CH3), 3.86 (s, 3H, OCH3), 5.25 (s, 2H, CH2, trans minor isomer), 5.33 (s, 2H, CH2, cis major isomer), 7.33 (d, 1H, Ar, trans minor isomer), 7.50 (d, 1H, Ar, trans minor isomer), 7.69 (d, 1H, Ar, cis major isomer), 7.86 (d, 1H, Ar, cis major isomer), 8.10 (s, 1H, Ar), 8.15 (s, 1H, Ar), 8.30 (s, 1H, CHO, cis major isomer), 8.80 (d, 1H, CHO, trans minor isomer), 10.40 (d, 1H, NH, trans minor isomer), 10.57 (s, 1H, NH, cis major isomer); MS: m/e (ES−) 394 (M−1); analysis: C17H14ClNO6S requires C, 51.54,H, 3.56, N, 3.54, Cl, 8.96, S, 8.10; found: C, 51.96,H, 3.63, N, 3.60, Cl, 9.43, S, 8.50%.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:19]=[CH:18][C:7]2[C:8](=[O:17])[C:9]3[C:14]([CH2:15][S:16][C:6]=2[CH:5]=1)=[CH:13][CH:12]=[CH:11][N:10]=3.O>CO>[Cl:3][C:4]1[CH:19]=[CH:18][C:7]2[CH:8]([OH:17])[C:9]3[C:14]([CH2:15][S:16][C:6]=2[CH:5]=1)=[CH:13][CH:12]=[CH:11][N:10]=3
Reactant: O=C1c2ccc(Cl)cc2SCc2cccnc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OC1c2ccc(Cl)cc2SCc2cccnc21
Reaction time: 0.67 h
Yield: 64.2 %

Procedure:
Add sodium borohydride (2.60 g, 0.0688 mol) portionwise over 15 minutes to a stirred suspension of 8-chloro-5,11-dihydro[1]benzothiepino[4,3-b]pyridin-11-one (15.0 g, 0.0573 mol) in methanol (150 mL) at 25°-35° C. and under an atmosphere of nitrogen. Stir the mixture for 40 minutes at 25°-30° C. Concentrate the mixture in vacuo to provide a suspension, and then pour it into water (150 mL), and extract with CH2Cl2 (3×100 mL). Combine the extracts, wash with water (3×75 mL), dry over Na2SO4, filter, and concentrate in vacuo. Purify the crude product (18.4 g) via flash chromatography by eluting with EtOAc/hexanes (1:1) to obtain the title compound (9.70 g, 64% yield).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[O:12]([CH2:11][CH2:10][CH2:9][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1CCNCC1
Reactant: ClCCCOc1ccccc1
Product: O=C1CCN(CCCOc2ccccc2)CC1

Procedure:
1-(3-Phenoxypropyl)-4-piperidone is prepared from 4-piperidone and 1-chloro-3-phenoxypropane essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: S[C:2]1[O:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.CN(C=O)C.S(Cl)([Cl:20])=O>>[Cl:20][C:2]1[O:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: COc1ccc2nc(S)oc2c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccc2nc(Cl)oc2c1
Reaction time: 0.17 h

Procedure:
Finally, pure 2-mercapto-6-methoxybenzoxazole (4.0 g, 22.2 mmol) was dissolved in thionyl chloride (15 mL). DMF (1 mL) was added to the solution and the reaction mixture was stirred at r.t for 10 min. The solvent was removed under reduced pressure. The crude product was dissolved in ethyl acetate, washed with water, dried over Na2SO4, and concentrated to give crude 2-chloro-6-methoxybenzoxazole, which was purified by chromatography with petroleum ether/ethylacetate (3:1 v/v) to afford 2-chloro-6-methoxybenzoxazole, compound 25, (3.7 g, yield 92%).
Reaction SMILES: [C:1]([CH:5]1[C:10](=[O:11])[CH2:9][CH:8]([C:12]([S:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)([CH3:14])[CH3:13])[CH2:7][C:6]1=[O:23])(=O)[CH2:2][CH3:3].[CH2:24]([O:27][NH2:28])[CH:25]=C.C1C=CC=CC=1>C(O)C>[CH2:24]([O:27][NH:28][C:1](=[C:5]1[C:10](=[O:11])[CH2:9][CH:8]([C:12]([S:15][C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)([CH3:14])[CH3:13])[CH2:7][C:6]1=[O:23])[CH2:2][CH3:3])[CH3:25]
Reactant: CCC(=O)C1C(=O)CC(C(C)(C)Sc2ccc(C)cc2)CC1=O
Reactant: C=CCON
Solvent: c1ccccc1
Solvent: CCO
Product: CCONC(CC)=C1C(=O)CC(C(C)(C)Sc2ccc(C)cc2)CC1=O
Yield: 68.1 %

Procedure:
1.3 g of 2-propionyl-5-[1-(p-tolylthio)isopropyl]cyclohexane-1,3-dione was allowed to react with 0.3 g of allyloxyamine at room temperature for 15 hours in the mixture of 10 ml of benzene and 3 ml of ethanol. After completion of the reaction, the resulting reaction solution was treated as in Example 1 to obtain 1 g of the desired compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][C:25]2[CH:30]=[CH:29]C(C(F)(F)F)=CN=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1N=NC(C#C)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1.[F:59][C:60]1C=CC(I)=[CH:62][C:61]=1[CH3:67]>>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][C:25]2[CH:30]=[CH:29][C:60]([F:59])=[C:61]([CH3:67])[CH:62]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)nc1
Reactant: Cc1cc(I)ccc1F
Agent: C#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Product: Cc1cc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)ccc1F
Yield: 67 %

Procedure:
Prepared as described for 3,4-bis(benzyloxy)-6-{[5-(trifluoromethyl)pyridin-2-yl]ethynyl}pyridazine (Intermediate 6) from 3,4-bis(benzyloxy)-6-ethynylpyridazine (Intermediate 5) and 1-fluoro-4-iodo-2-methylbenzene in 67% yield.
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[C:8]#[N:9])[CH:5]=[N:4][CH:3]=[N:2]1.[ClH:14]>C(O)C.[Pd]>[ClH:14].[N:1]1([C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[CH2:8][NH2:9])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: N#Cc1ccccc1-n1cncn1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: NCc1ccccc1-n1cncn1
Reaction time: 2 h
Yield: 75 %

Procedure:
Intermediate 98, 2-(1H-1,2,4-triazol-1-yl)benzonitrile (4.25 g, 25 mmol) was dissolved in ethanol (50 mL) and 1N HCl (25 mL). 10% Pd—C (1 g) was added and the mixture shaken under H2 for 2 h at 50 psi. After filtration through Celite and concentration, the residue was triturated with diethyl ether and the title compound was collected as a white solid. (3.94 g, 75% yield). 1H-NMR (300 MHz, CD3OD) δ ppm: 9.01 (1H, s), 8.32 (1H, s), 7.78-7.64 (4H, m), 4.15 (2H, s). LCMS [M+H]+ calcd for C9H11N4: 175.09; found: 175.17.
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]([C:25]2[N:26]=[C:27]([N:30]3[CH2:33][CH:32]([OH:34])[CH2:31]3)[O:28][CH:29]=2)=[O:24])[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:35][S:36](Cl)(=[O:38])=[O:37].C(N(CC)CC)C>C(Cl)Cl>[Si:1]([O:18][CH:19]1[CH2:20][N:21]([C:23]([C:25]2[N:26]=[C:27]([N:30]3[CH2:33][CH:32]([O:34][S:36]([CH3:35])(=[O:38])=[O:37])[CH2:31]3)[O:28][CH:29]=2)=[O:24])[CH2:22]1)([C:14]([CH3:15])([CH3:17])[CH3:16])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)[Si](OC1CN(C(=O)c2coc(N3CC(O)C3)n2)C1)(c1ccccc1)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](OC1CN(C(=O)c2coc(N3CC(OS(C)(=O)=O)C3)n2)C1)(c1ccccc1)c1ccccc1
Reaction time: 0.17 h
Yield: 79.5 %

Procedure:
To a solution of 1-[4-(3-t-butyldiphenylsilyloxyazetidine-l-carbonyl)-1,3-oxazol-2-yl]-3-hydroxyazetidine (1.68 g, 3.53 mmol) (obtained as described in Reference Example 74(1)) in methylene chloride (84 ml) were added methanesulfonyl chloride (820 μl, 10.6 mmol) and triethylamine (1.49 ml, 10.6 mmol) in an ice bath and the mixture was stirred for 10 minutes and then at room temperature for 0.5 hour. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using methylene chloride:ethyl acetate (1:1) as the eluant to afford 1-[4-(3-t-butyldiphenylsilyloxyazetidine-1-carbonyl)-1,3-oxazol-2-yl]-3-methanesulfonyloxyazetidine (1.56 g, yield 80%) as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH3:25])=[C:13]([NH:15][C:16]([C:18]3[N:22]([CH3:23])[N:21]=[C:20]([CH3:24])[CH:19]=3)=[O:17])[CH:14]=2)=[CH:4][CH:3]=1.[N:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:27]=[S:28].CS(C)=O>O>[CH3:23][N:22]1[C:18]([C:16]([NH:15][C:13]2[CH:14]=[C:9]([CH:10]=[CH:11][C:12]=2[CH3:25])[O:8][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:27]([NH:26][C:29](=[O:30])[O:31][CH2:32][CH3:33])=[S:28])=[N:7][CH:6]=2)=[O:17])=[CH:19][C:20]([CH3:24])=[N:21]1
Reactant: Cc1cc(C(=O)Nc2cc(Oc3ccc(N)nc3)ccc2C)n(C)n1
Reactant: CCOC(=O)N=C=S
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)NC(=S)Nc1ccc(Oc2ccc(C)c(NC(=O)c3cc(C)nn3C)c2)cn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 94.3 %

Procedure:
A mixture of N-{5-[(6-aminopyridin-3-yl)oxy]-2-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (214 mg, 0.634 mmol), ethyl isothiocyanatoformate (108 mg, 0.824 mmol) and DMSO (5 mL) was stirred at room temperature for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was collected by filtration and washed with ethyl acetate-hexane to give ethyl ({[5-(3-{[(1,3-dimethyl-1H-pyrazol-5-yl) carbonyl]amino}-4-methylphenoxy)pyridin-2-yl]amino}carbonothioyl)carbamate (280 mg, 94%) as a white solid. A mixture of ethyl ({[5-(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}-4-methylphenoxy)pyridin-2-yl]amino}carbonothioyl)carbamate (270 mg, 0.576 mmol) thus-obtained, hydroxylammonium chloride (280 mg, 4.03 mmol), N,N-diisopropylethylamine (502 μL, 2.88 mmol), ethanol (10 mL) and methanol (10 mL) was stirred at 80° C. for 8 hr. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was collected by filtration and washed with ethyl acetate-hexane to give the title compound (164 mg, 75%) as a white solid.