Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:10])([CH3:9])[C:4](=[O:8])[CH2:5][C:6]#[N:7].[OH-].[Na+].Cl.[NH2:14]O.Cl>C(O)C.O>[NH2:7][C:6]1[CH:5]=[C:4]([C:3]([CH3:10])([CH3:9])[CH2:2][OH:1])[O:8][N:14]=1
Reactant: NO
Reactant: CC(C)(CO)C(=O)CC#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(CO)c1cc(N)no1
Temperature: 60 °C
Reaction time: 2 h
Yield: 54.2 %

Procedure:
A mixture of 5-hydroxy-4,4-dimethyl-3-oxopentanenitrile from Step B (1 g, 7.09 mmol), sodium hydroxide (378 mg, 9.45 mmol), and hydroxylamine hydrochloride (656 mg, 9.43 mmol) in a mixture of ethanol (100 mL) and water (100 mL), was heated at 60° C. for 22 h. After cooling to rt, concentrated HCl (1 g) was added and stirred at 50° C. for 2 h followed by 80° C. for a further 1 h. After concentration under reduced pressure, the mixture was treated with 30% sodium hydroxide solution and extracted with chloroform (3×100 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over Na2SO4, and filtered. Concentrated under reduced pressure, followed by purification via recrystallisation from diethyl ether, afforded 2-(3-aminoisoxazol-5-yl)-2-methylpropan-1-ol as a colorless solid (600 mg, 54%). 1H NMR (300 MHz, CDCl3) δ 5.64 (s, 1H), 3.65 (s, 2H), 2.30 (brs, 2H), 1.31 (s, 6H); LC-MS (ESI) m/z 156 (M+H)+.
Reaction SMILES: C[O-].[Na+].Cl.[NH2:5][OH:6].[C:7](/[N:9]=[C:10](\SC)/[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)#[N:8]>C(O)C>[F:19][C:18]([F:21])([F:20])[C:14]1[CH:13]=[C:12]([NH:11][C:10]2[N:9]=[C:7]([NH2:8])[O:6][N:5]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: CS/C(=N\C#N)Nc1cccc(C(F)(F)F)c1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Nc1nc(Nc2cccc(C(F)(F)F)c2)no1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium methanolate (9.26 ml, 4.63 mmol, Eq: 3.00) was added into a solid hydroxylamine hydrochloride (322 mg, 4.63 mmol, Eq: 3.00) at rt. Stirred at rt for 0.5 hrs, a solution of (Z)-methyl N′-cyano-N-(3-(trifluoromethyl)phenyl)carbamimidothioate (400 mg, 1.54 mmol, Eq: 1.00) in ethanol was added and the mixture was heated to 63° C. overnight.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=3)[N:12]=[C:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[OH:26])[N:10]=2)[CH2:4]1.C(N(CC)CC)C.Cl[C:35]([O:37][C@@H:38]1[CH2:42][CH2:41][O:40][CH2:39]1)=[O:36]>>[O:40]1[CH2:41][CH2:42][C@@H:38]([O:37][C:35](=[O:36])[NH:1][CH2:2][C@H:3]2[CH2:8][CH2:7][CH2:6][N:5]([C:9]3[C:18]4[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=4)[N:12]=[C:11]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[OH:26])[N:10]=3)[CH2:4]2)[CH2:39]1
Reactant: Cc1ccc2c(N3CCC[C@H](CN)C3)nc(-c3ccccc3O)nc2c1
Reactant: O=C(Cl)O[C@@H]1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc2c(N3CCC[C@H](CNC(=O)O[C@@H]4CCOC4)C3)nc(-c3ccccc3O)nc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2-(4-((R)-3-(aminomethyl)piperidin-1-yl)-7-methylquinazolin-2-yl)phenol (150 mg, 0.43 mmol) under an N2 atmosphere at 0° C. was added triethylamine (87 mg, 0.86 mmol) followed by the dropwise addition of (R)-tetrahydrofuran-3-yl chloroformate (65 mg, 0.43 mmol). The reaction was allowed to warm to room temperature and was stirred for 2 h. The mixture was partitioned between H2O and CH2Cl2 and separated, and the aqueous layer was extracted twice with CH2Cl2. The organic layers were combined, dried over Na2SO4, filtered, and concentrated. Purification via silica gel chromatography using 4:1 CH2Cl2:EtOAc afforded (R)-tetrahydrofuran-3-yl((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate. LC/MS: m/z 463.5 (M+H)+ at 2.34 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6](Cl)[C:7]2[CH:11]=[CH:10][S:9][CH:8]=2)=[CH:2]1.[OH:13][CH:14]1[CH2:19][CH2:18][N:17]([CH:20]([CH3:33])[CH2:21][CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[N+:30]([O-:32])=[O:31])[CH2:16][CH2:15]1.OC1CCN(CCCOC2C=CC=CC=2[N+]([O-])=O)CC1>>[S:1]1[CH:5]=[CH:4][C:3]([CH:6]([C:7]2[CH:11]=[CH:10][S:9][CH:8]=2)[O:13][CH:14]2[CH2:15][CH2:16][N:17]([CH:20]([CH3:33])[CH2:21][CH2:22][O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[N+:30]([O-:32])=[O:31])[CH2:18][CH2:19]2)=[CH:2]1
Reactant: ClC(c1ccsc1)c1ccsc1
Reactant: CC(CCOc1ccccc1[N+](=O)[O-])N1CCC(O)CC1
Agent: O=[N+]([O-])c1ccccc1OCCCN1CCC(O)CC1
Product: CC(CCOc1ccccc1[N+](=O)[O-])N1CCC(OC(c2ccsc2)c2ccsc2)CC1

Procedure:
The procedure of Example 36 (a) was repeated except for using di(3-thienyl)methyl chloride and 4-hydroxy-1-[1-methyl-3-(2-nitrophenoxy)propyl]piperidine instead of phenyl-2-thienylmethyl chloride and 4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give oily 4-di(3-thienyl)methoxy-1-[1-methyl-3-(2-nitrophenoxy)propyl]piperidine
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:12])/[CH:9]=[CH:10]\[CH3:11])=[CH:4][CH:3]=1.[OH-].[K+].[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]/[CH:9]=[CH:10]\[CH2:11][OH:22])=[CH:4][CH:3]=1.[CH3:25][C:15]1[CH:20]=[CH:19][C:18]([S:21]([O-:12])(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: C/C=C\C(O)c1ccc(Cl)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Product: OC/C=C\Cc1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
Dissolve 6.7 g (0.036 mole) of (Z)-1-(4-chlorophenyl)-2-buten-1-ol in 100 ml of anhydrous ether, add 3.2 g of powdered KOH. Stir the mixture and with cooling add a solution of 7.0 g p-toluenesulfonylchloride in 30 ml of anhydrous ether. Continue to stir with cooling for 30 minutes, then allow to warm to room temperature overnight. Filter, wash the filtrate three times with saturated aqueous sodium bicarbonate, then with water and dry over sodium sulfate. Evaporate off solvents and triturate residue with petroleum ether, cyclohexane. Recrystallize residue from cyclohexane to yield the title compound.
Reaction SMILES: C(OCC(Cl)=O)C1C=CC=CC=1.[CH2:13]([O:20][CH2:21][C:22]([N:24]=[C:25]=[S:26])=[O:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[CH:34][CH:33]=[C:32]2[O:41][C:42]1[CH:48]=[CH:47][C:45]([NH2:46])=[CH:44][C:43]=1[F:49].C1(C)C=CC=CC=1>C(O)C>[CH2:13]([O:20][CH2:21][C:22]([N:24]=[C:25]=[S:26])=[O:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH2:13]([O:20][CH2:21][C:22]([NH:24][C:25]([NH:46][C:45]1[CH:47]=[CH:48][C:42]([O:41][C:32]2[C:31]3[C:36](=[CH:37][C:38]([O:39][CH3:40])=[C:29]([O:28][CH3:27])[CH:30]=3)[N:35]=[CH:34][CH:33]=2)=[C:43]([F:49])[CH:44]=1)=[S:26])=[O:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Agent: O=C(COCc1ccccc1)N=C=S
Agent: O=C(Cl)COCc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)COCc4ccccc4)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
2-(Benzyloxy)ethanoyl isothiocyanate was prepared using commercially available 2-(benzyloxy)ethanoyl chloride (80 mg) as a starting compound according to the description of the literature. 2-(Benzyloxy)ethanoyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (33 mg, yield 40%).
Reaction SMILES: [C:1]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(N(CC)CC)C.C(OC(Cl)=O)C(C)C.Cl.[CH3:36][O:37][C:38]([C:40]1[CH:45]=[CH:44][C:43]([CH2:46][NH:47][CH2:48][C:49]2[CH:58]=[CH:57][C:52]([C:53]([O:55][CH3:56])=[O:54])=[C:51]([O:59][CH2:60][C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)[CH:50]=2)=[CH:42][C:41]=1[O:67][CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)=[O:39]>Cl.CN(C)C=O>[CH3:36][O:37][C:38]([C:40]1[CH:45]=[CH:44][C:43]([CH2:46][N:47]([CH2:48][C:49]2[CH:58]=[CH:57][C:52]([C:53]([O:55][CH3:56])=[O:54])=[C:51]([O:59][CH2:60][C:61]3[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=3)[CH:50]=2)[C:17](=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:1]([O:3][CH2:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2])=[CH:42][C:41]=1[O:67][CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)=[O:39]
Reactant: COC(=O)c1ccc(CNCc2ccc(C(=O)OC)c(OCc3ccccc3)c2)cc1OCc1ccccc1
Reactant: O=C(O)CCCCCNC(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN(Cc2ccc(C(=O)OC)c(OCc3ccccc3)c2)C(=O)CCCCCNC(=O)OCc2ccccc2)cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 76 %

Procedure:
Dissolved N-Cbz-6-aminohexanoic acid (784 mg, 2.96 mmole) into 10 mL of N,N-dimethylformamide and cooled to 0° C. Added triethylamine (1.65 mL, 11.8 mmole), stirred for 10 minutes, then added isobutylchloroformate (385 uL, 2.68 mmole). Stirred for 45 minutes and then added the crude methyl 4-[({[4-(methoxycarbonyl)-3-(phenylmethoxy)phenyl]methyl}-amino)-methyl]-2-(phenylmethoxy)benzoate hydrochloride from the step above (830 mg, 1.48 mmole). Let warm to room temperature and stirred for 3 hours. Diluted the reaction mixture with 1 N HCl and extracted with ethyl acetate. Dried the ethyl acetate layers with brine and anhydrous magnesium sulfate. Filtered, removed solvents in vacuo, and chromatographed on silica gel. Collected 870 mg (76% yield) of product.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH3:22])=[C:17]([CH2:23][C:24]3[CH:33]=[CH:32][C:27]4[O:28][CH2:29][CH2:30][O:31][C:26]=4[CH:25]=3)[CH:16]=2)[O:8][CH:7]([O:34][CH3:35])[C@H:6]1[O:36]C(=O)C)(=O)C.[OH-].[Li+]>CO.C1COCC1.O>[O:28]1[C:27]2[CH:32]=[CH:33][C:24]([CH2:23][C:17]3[CH:16]=[C:15]([C@H:9]4[C@H:10]([OH:11])[C@@H:5]([OH:4])[C@H:6]([OH:36])[C@@H:7]([O:34][CH3:35])[O:8]4)[CH:20]=[CH:19][C:18]=3[CH2:21][CH3:22])=[CH:25][C:26]=2[O:31][CH2:30][CH2:29]1
Reactant: CCc1ccc([C@@H]2OC(OC)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1Cc1ccc2c(c1)OCCO2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCc1ccc([C@@H]2O[C@H](OC)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.3 %

Procedure:
Step-IV: To a stirred solution of acetic acid (3S,4R,5S,6S)-4,5-diacetoxy-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-2-methoxy-tetrahydro-pyran-3-yl ester (300 mg, 0.55 mmol) in methanol:THF:water (3:2:1 mixture, 6 ml) was added lithium hydroxide (46 mg, 1.10 mmol). After stirring for 2 h at room temperature, volatiles were evaporated under reduced pressure. The resulting residue was taken in ethyl acetate (10 ml) and washed with brine (5 ml), brine containing 1 ml of 5% aqueous KHSO4 (5 ml), brine (5 ml), dried over sodium sulfate, concentrated and purified by preparative HPLC to furnish 90 mg (2S,3R,4R,5S,6S)-2-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-methoxy-tetrahydro-pyran-3,4,5-triol as white solid. 1H NMR (400 MHz, CD3OD): δ 0.56-0.58 (m, 2H), 0.84-0.87 (m, 2H), 1.80-1.85 (m, 1H), 3.27-3.44 (m, 3H), 3.48 (s, 3H), 4.05 (d, J=6.4 Hz, 2H), 4.10 (d, J=9.3 Hz, 1H), 4.17 (s, 4H), 4.30 (d, J=7.8 Hz, 1H), 6.62 (d, J=8.4 Hz, 1H), 6.69 (d, J=8.4 Hz, 2H), 6.98 (d, J=7.8 Hz, 1H), 7.16-7.19 (m, 2H). MS (ES) m/z 446.3 (M+18).
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]1[C:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3Cl)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N12CCC[N:40]=[C:39]1[CH2:38][CH2:37][CH2:36]CC2.Cl.NCC1CC1.O>C(O)C>[C:1]([O:9][CH2:10][C@@H:11]1[C:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3[NH:40][CH2:39][CH:38]2[CH2:37][CH2:36]2)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(Cl)ncnc32)[C@]1(C)F
Agent: Cl
Agent: NCC1CC1
Solvent: O
Solvent: CCO
Product: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(NCC4CC4)ncnc32)[C@]1(C)F
Yield: 72.2 %

Procedure:
To a stirred solution of ((2R,4R)-3-acetoxy-5-(6-chloro-9H-purin-9-yl)-4-fluoro-3,4-dimethyl-tetrahydrofuran-2-yl)methyl benzoate (about 0.30 g, 0.64 mmol) in ethanol (about 5 ml) was added 1,8-Diazabicyclo[5.4.0]undec-7-ene (about 0.14 ml, 0.97 mmol) and aminomethyl cyclopropane hydrochloride (about 0.14 g, 1.2 mmol) at room temperature and refluxed for about 30 minutes. Completion of the reaction monitored by thin-layer chromatography, water added to the reaction mixture and the aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with water, brine and dried over sodium sulphate. Concentration under reduced pressure and purification by silica gel column chromatography using 5% methanol in dichloromethane as eluent furnished title compound (0.23 g) as a colorless solid. Yield: 67%; 1H NMR (300 MHz, CDCl3): δ 8.39 (s, 1H), 8.06-8.04 (m, 2H), 7.99 (d, 1H, J=3.6 Hz), 7.60-7.55 (m, 1H), 7.47-7.42 (m, 2H), 6.54 (d, 1H, J=23.1 Hz), 5.93 (bs, 1H), 4.84-4.78 (m, 2H), 4.49-4.42 (m, 1H), 3.49 (bs, 2H), 2.16 (s, 3H), 1.89 (d, 3H, J=2.4 Hz), 1.44 (d, 3H, J=23.1 Hz), 1.19-1.08 (m, 1H), 0.59-0.55 (m, 2H), 0.34-0.31 (m, 2H); ES Mass: [M+1]+ 498 (100%), [M+Na] 520 (45%); HPLC: 96%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([N:14]1[CH:22]=[C:21]2[C:16]([CH:17]=[CH:18][CH:19]=[C:20]2[F:23])=[N:15]1)[CH2:11][C:12]#[CH:13]>>[F:23][C:20]1[C:21]2[C:16]([CH:17]=[CH:18][CH:19]=1)=[N:15][N:14]([CH2:10][CH2:11][C:12]#[C:13][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1)[CH:22]=2
Reactant: FCc1cccc(Br)n1
Reactant: C#CCCn1cc2c(F)cccc2n1
Product: FCc1cccc(C#CCCn2cc3c(F)cccc3n2)n1
Yield: 40 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)-pyridine (0.12 g, 0.61 mmol) and 2-but-3-ynyl-4-fluoro-2H-indazole (104 mg, 0.5 mmol). Reaction time: 3 hours. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 3:2) to yield 60 mg (0.20 mmol, 36%) of 4-fluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-indazole as a brown solid.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]=12.CC1(C)O[C:16](=O)[CH2:15][C:14](=O)O1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([N:28]2[CH2:33][CH2:32][N:31]([CH2:16][CH2:15][CH2:14][C:3]3[N:4]4[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]4=[N:1][CH:2]=3)[CH2:30][CH2:29]2)=[CH:26][CH:27]=1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: c1cn2c(n1)CCCCC2
Reactant: CC1(C)OC(=O)CC(=O)O1
Product: Clc1ccc(N2CCN(CCCc3cnc4n3CCCCC4)CC2)cc1

Procedure:
By the same reaction and treatment as in Example 91 using 6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepine, 2,2-dimethyl-1,3-dioxane-4,6-dione and 1-(4-chlorophenyl)piperazine, 3-(3-(4-(4-chlorophenyl)piperazin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepine is obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH:4]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:5]1[N:6]([CH3:28])[C:7](=[O:27])[C:8]2[C:13]([C:14]=1[C:15]1[C:16]([CH3:25])=[C:17]3[C:22](=[CH:23][CH:24]=1)[O:21][CH2:20][CH2:19][CH2:18]3)=[CH:12][CH:11]=[C:10]([OH:26])[CH:9]=2.C([O-])([O-])=O.[K+].[K+].BrC[CH2:43][CH2:44][OH:45]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:34])[CH:4]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])[C:5]1[N:6]([CH3:28])[C:7](=[O:27])[C:8]2[C:13]([C:14]=1[C:15]1[C:16]([CH3:25])=[C:17]3[C:22](=[CH:23][CH:24]=1)[O:21][CH2:20][CH2:19][CH2:18]3)=[CH:12][CH:11]=[C:10]([O:26][CH2:43][CH2:44][OH:45])[CH:9]=2
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc3c(c2C)CCCO3)c2ccc(O)cc2c(=O)n1C
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(OC(C)(C)C)c1c(-c2ccc3c(c2C)CCCO3)c2ccc(OCCO)cc2c(=O)n1C
Yield: 34.6 %

Procedure:
To a solution of tert-Butoxy-[7-hydroxy-2-methyl-4-(5-methyl-chroman-6-yl)-1-oxo-1,2-dihydro-isoquinolin-3-yl]-acetic acid methyl ester (50 mg, 0.17 mmol) in DMF (1 ml) was added K2CO3 (44.5 mg, 0.322 mmol) and 3-bromopropan-1-ol (40.3 mg, 0.322 mmol) at RT. The resultant mixture was stirred at 70° C. for 3 hr. The reaction mixture was diluted with water and extracted with EA (10 mL*3), dried over sodium sulfate and concentrated to dryness. The mixture was purified by Pre-TLC to afford the title product (30 mg, 55%). LCMS (10-80 AB—2MIN.M): Rt=1.223, purity=93.7%, M+1=510.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:31])=[C:6]([C:8]2[O:12][N:11](CC3C=CC(OC)=CC=3OC)[C:10]([CH3:30])([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:9]=2)[CH:7]=1.FC(F)(F)C(O)=O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:31])=[C:6]([C:8]2[O:12][NH:11][C:10]([CH3:30])([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:9]=2)[CH:7]=1
Reactant: COc1ccc(CN2OC(c3cc(Cl)ccc3F)=CC2(C)c2ccccc2)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(c2ccccc2)C=C(c2cc(Cl)ccc2F)ON1
Reaction time: 7 h

Procedure:
To a solution of 5-(5-chloro-2-fluorophenyl)-2-(2,4-dimethoxybenzyl)-3-methyl-3-phenyl-2,3-dihydroisoxazole (2-3, 0.88 g, 1.99 mmol) in anhydrous CH2Cl2 (5 mL) was added trifluoroacetic acid (5 mL) and the resulting purple colored reaction sat for 7 h. 2M Na2CO3 was added until the color changed from purple to peach, and the reaction was immediately extracted with CH2Cl2, dried with MgSO4, filtered and concentrated to provide crude 5-(5-chloro-2-fluorophenyl)-3-methyl-3-phenyl-2,3-dihydroisoxazole (2-4). This crude material was suitable for further transformations. 1H NMR (300 MHz, CDCl3) δ 7.56 (m, 3H), 7.36 (m, 3H), 7.25 (m, 1H), 7.05 (app t, J=9.6 Hz), 6.20 (br s, 1H), 6.03 (d, J=3.4 Hz, 1H), 1.78 (s, 3H). LRMS see table.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=O.[F:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[C:11]([CH3:16])[CH:10]=1>C1(C)C=CC=CC=1>[CH2:6]([O:5][C:1](=[O:4])[CH2:2][NH:13][C:12]1[CH:14]=[CH:15][C:9]([F:8])=[CH:10][C:11]=1[CH3:16])[CH3:7]
Reactant: CCOC(=O)C=O
Reactant: Cc1cc(F)ccc1N
Solvent: Cc1ccccc1
Product: CCOC(=O)CNc1ccc(F)cc1C

Procedure:
A solution of ethyl glyoxalate (50% solution in toluene—40.8 mL) in toluene (180 mL) was heated to reflux for 1.5 hours under a Nitrogen atmosphere, in a flask equipped with a Dean Stark apparatus. Then, a solution of 4-fluoro-2-methyl-aniline (10 g) in dry toluene (20 mL) was slowly added. The mixture was heated to reflux for 3 hours, then it was concentrated in vacuo. The residue was purified by flash chromatography (toluene/CH/AcOEt 4:4:2) to give the title compound (13.06 g) as a yellow oil.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:31]=[CH:30][C:6]([C:7]([NH:9][C:10]2[C:11]([CH3:29])=[CH:12][CH:13]=[C:14]([NH:16][C:17]3[N:22]=[C:21]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)[CH:20]=[CH:19][N:18]=3)[CH:15]=2)=[O:8])=[CH:5][CH:4]=1.N1C=CC=CC=1.[CH3:38][N:39]1[CH2:45][CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>O1CCCC1>[CH3:38][N:39]1[CH2:45][CH2:44][CH2:43][N:42]([CH2:2][C:3]2[CH:31]=[CH:30][C:6]([C:7]([NH:9][C:10]3[CH:15]=[C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=5)[CH:20]=[CH:19][N:18]=4)[CH:13]=[CH:12][C:11]=3[CH3:29])=[O:8])=[CH:5][CH:4]=2)[CH2:41][CH2:40]1
Reactant: Cc1ccc(Nc2nccc(-c3cccnc3)n2)cc1NC(=O)c1ccc(CCl)cc1
Reactant: CN1CCCNCC1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1ccc(Nc2nccc(-c3cccnc3)n2)cc1NC(=O)c1ccc(CN2CCCN(C)CC2)cc1
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
N-(5-(4-chloromethylbenzoylamino)-4-methylphenyl)-4-(3-pyridyl)-2-pyrimidine-amine (1.5 g, 3.49 mmol) was dissolved in tetrahydrofuran (30 ml), pyridine (560 μl, 6.98 mmol) was added, and the mixture was stirred for 30 minutes. N-methylhomopiperazine (660 μl, 5.23 mmol) was added thereto, and the resulting mixture was refluxed for 12 hours and then filtered. The filtrate was concentrated and crystallized from dimethylether to give 4-(4-methylhomopiperazin-1-ylmethyl)-N-[2-methyl-5-(4-(pyridin-3-yl)pyrimidin-2-yl)aminophenyl]benzamide (1.2 g).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[N:5][C:6]([C:9]([F:12])([F:11])[F:10])=[N:7][CH:8]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:25]=[N+:26]=[N-:27].[Na+]>ClCCl.O>[N:25]([CH2:2][C:3]1[CH:4]=[N:5][C:6]([C:9]([F:12])([F:11])[F:10])=[N:7][CH:8]=1)=[N+:26]=[N-:27]
Reactant: [N-]=[N+]=[N-]
Reactant: OCc1cnc(C(F)(F)F)nc1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: [N-]=[N+]=NCc1cnc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To a solution of 5-(hydroxymethyl)-2-(trifluoromethyl)pyrimidine (Description 119; 580 mg, 3.26 mmol) and triethylamine (0.55 ml, 3.91 mmol) in anhydrous dichioromethane (15 ml) cooled in an ice-bath was added dropwise methanesulfonyl chloride (0.28 ml, 3.59 mmol), and the resulting mixture stirred at room temperature for 1 hour. The mixture was washed with water and sat NaCl, dried over Na2SO4, filtered and evaporated. The residue was dissolved in anhydrous N,N-dimethylformamide (15 ml), sodium azide (233 mg, 3.59 mmol) was added and the resulting mixture stirred at room temperature overnight. The mixture was poured into water (100 ml) and extracted with EtOAc (3×15 ml). The combined EtOAc layers were washed with water (2×50 ml), saturated NaCl (25 ml), dried over Na2SO4, filtered and evaporated to give the title compound (660 mg, 100%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=2)[C:5]2[N:15]([CH2:28][C@H:29]3[CH2:34][CH2:33][C@H:32]([CH3:35])[CH2:31][CH2:30]3)[C:16]([C:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][N:22]=3)(O)[CH3:19])=[N:17][C:4]=2[CH:3]=1.N1C=CC=CC=1.S(Cl)(Cl)=O>ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=2)[C:5]2[N:15]([CH2:28][C@H:29]3[CH2:30][CH2:31][C@H:32]([CH3:35])[CH2:33][CH2:34]3)[C:16]([C:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH2:19])=[N:17][C:4]=2[CH:3]=1
Reactant: CC(O)(c1ncccc1F)c1nc2cc(Cl)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=C(c1ncccc1F)c1nc2cc(Cl)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (1RS)-1-{6-chloro-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-2-yl}-1-(3-fluoropyridin-2-yl)ethanol (Example 8.6/8.7, Step 3; 1.2 g, 2.33 mmol) and pyridine (1.88 mL, 23.3 mmol) in dichloromethane (20 mL) was added thionyl chloride (0.85 mL, 11.67 mmol) dropwise at 0° C., and the reaction was stirred at 0° C. for 1 h. The reaction was quenched with saturated NaHCO3 solution and extracted with dichloromethane (2×25 mL). The combined organic extracts were washed with water (1×25 mL) and brine (1×25 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified on a silica gel column (eluting with 40-60% EtOAc/petroleum ether) to afford 6-chloro-4-(5-chloropyridin-3-yl)-2-[1-(3-fluoropyridin-2-yl)ethenyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine. MS ES/APCl calcd. for C26H24Cl2FN5 [M+H]+ 496. found 496.