Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[C:8]1[N:12]2[CH:13]=[C:14]([O:17][C@H:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C@@H:21]([NH2:28])[CH2:20][CH2:19]3)[CH:15]=[CH:16][C:11]2=[N:10][N:9]=1.ClC(Cl)(Cl)C[O:32][C:33](=O)[NH:34][C:35]1[N:36]([CH2:44][CH2:45][OH:46])[N:37]=[C:38]([C:40]([CH3:43])([CH3:42])[CH3:41])[CH:39]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:40]([C:38]1[CH:39]=[C:35]([NH:34][C:33]([NH:28][C@@H:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C@H:18]([O:17][C:14]3[CH:15]=[CH:16][C:11]4[N:12]([C:8]([C@@H:3]5[CH2:4][CH2:5][CH2:6][CH2:7][N:2]5[CH3:1])=[N:9][N:10]=4)[CH:13]=3)[CH2:19][CH2:20]2)=[O:32])[N:36]([CH2:44][CH2:45][OH:46])[N:37]=1)([CH3:43])([CH3:41])[CH3:42]
Reactant: CN1CCCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(CCO)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CN1CCCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4CCO)c4ccccc43)cn12
Temperature: 50 °C
Reaction time: 8 h
Yield: 6.8 %

Procedure:
A mixture of Intermediate 120c (35 mg, 0.10 mmol), Intermediate 110b (54 mg, 0.15 mmol) and DIPEA (53 pt, 0.30 mmol) in dioxane (1 mL) was stirred at 50° C. overnight. After cooling, the reaction mixture was loaded onto an SCX cartridge. The cartridge was washed with MeOH and the product eluted with 2M NH3 in MeOH. The resultant residue was purified by FCC on silica, using a gradient of 1-8% MeOH in DCM followed by MDAP (Method 7) purification, to afford the title compound (4 mg, 7%) as a glassy white solid. LCMS (Method 5): Rt 3.02 min, m/z 586 [MH+]. 1H NMR (400 MHz, d4-MeOD): 1.20-1.30 (2H, m), 1.25 (9H, s), 1.40-1.52 (1H, m), 1.63-1.83 (3H, m), 1.85-1.92 (2H, m), 2.01 (3H, s), 2.06-2.20 (3H, m), 2.24 (1H, td, J=11.7, 3.1 Hz), 2.31-2.38 (1H, m), 3.04-3.09 (1H, m), 3.76-3.81 (1H, m), 3.81 (2H, t, J=5.4 Hz), 4.08 (2H, t, J=5.4 Hz), 4.98 (1H, dd, J=8.1, 6.5 Hz), 5.36 (1H, t, J=3.8 Hz), 6.12 (1H, s), 7.24 (1H, t, J=7.4 Hz), 7.28-7.37 (3H, m), 7.44 (1H, d, J=7.8 Hz), 7.66 (1H, dd, J=9.9, 0.6 Hz), 8.46 (1H, d, J=1.9 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.C1COCC1.[CH2:21]([Mg]Br)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH2:21]([C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[N:6][CH:7]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: COc1ccc(-c2ccc(Br)cn2)cc1
Reactant: CCCCCCCC[Mg]Br
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCc1ccc(-c2ccc(OC)cc2)nc1

Procedure:
To a flask containing 13A (1 g) and dichloro[1,3-bis (diphenylphosphino)propane]nickle(II) (15 mg, prepared as in Kumada et al., Org. Syn. Coll. Vol. VI, p 407) is added THF (11 ml) and octyl magnesium bromide (2M, 2.74 ml). The solution is refluxed for 16 hrs, then poured into water and extracted three times with ethyl acetate. The combined organic layers are washed with brine and dried over sodium sulfate, and the solvent is removed in vacuo.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12]Br.C(=O)=O.[CH2:17]([Mg]Br)[CH3:18].[Cl-].[NH4+]>C(OCC)C.[Cu]I.C(#N)C.O1CCCC1>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][CH2:17][CH3:18]
Reactant: COC(=O)c1ccc(Br)c(CBr)c1
Reactant: CC[Mg]Br
Agent: [Cu]I
Agent: O=C=O
Agent: [Cl-]
Solvent: CC#N
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCc1cc(C(=O)OC)ccc1Br
Temperature: -40 °C

Procedure:
In a 6-liter reactor equipped with a condenser, a central mechanical stirrer, a thermometer and a dropping funnel, introduce under nitrogen 141 g (0.46 mol) of methyl 4-bromo-3-bromomethylbenzoate, 4 liters of tetrahydrofuran and 8.9 g (0.045 mol) of copper (I) iodide. Cool the mixture to −40° C. using a bath of acetonitrile and dry ice. Add 168 cm3 of a 3M solution of ethylmagnesium bromide in diethyl ether and then allow the reaction temperature to increase to 0° C. After two hours of reaction hydrolyze the reaction mixture with 1 liter of 2.5M ammonium chloride solution. Separate the phases and extract the aqueous phase with 0.7 liter of methylene chloride. Combine the organic phases and evaporate the solvents. Pour heptane onto the product obtained and filter off the insoluble product which has formed. Evaporate the heptane and purify the resulting product by chromatography on silica gel (heptane/ethyl acetate=95/5). This gives 51 g of methyl 4-bromo-3-propylbenzoate in the form of colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:32][C:33]([C@:35]2([C:39]([NH:41][C:42]3[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=3)=[O:40])[CH2:37][C@H:36]2[CH3:38])=[O:34])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:22][CH2:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[C:16]([O:19][CH:20]=O)[CH:17]=2)[N:12]=[CH:11][CH:10]=1.Cl.ClCCCN1CCOCC1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:32][C:33]([C@:35]2([C:39]([NH:41][C:42]3[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=3)=[O:40])[CH2:37][C@H:36]2[CH3:38])=[O:34])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:22][CH2:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[C:16]([O:19][CH3:20])[CH:17]=2)[N:12]=[CH:11][CH:10]=1
Reactant: C[C@@H]1C[C@@]1(C(=O)Nc1ccc(F)cc1)C(=O)Nc1ccc(Oc2ccnc3cc(OCCCN4CCOCC4)c(OC=O)cc23)c(F)c1
Agent: Cl
Agent: ClCCCN1CCOCC1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc2c(Oc3ccc(NC(=O)[C@]4(C(=O)Nc5ccc(F)cc5)C[C@H]4C)cc3F)ccnc2cc1OCCCN1CCOCC1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To a solution of the 7-hydroxyquinoline (80 mg, 0.15 mmol) in DMF (2 mL) was added 4-(3-chloropropyl)morpholine hydrochloride (62 mg, 0.31 mmol) and K2CO3 (64 mg, 0.46 mmol). The reaction mixture was then stirred at 80° C. for 5 h. After cooling, EtOAc (20 mL) was added. The EtOAc solution was washed twice with brine, and dried over Na2SO4. Removal of EtOAc and purification by column chromatography (CH2Cl2:MeOH=10:1) gave ′(1R,2R)—N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)-2-methylcyclopropane-1,1-dicarboxamide. The product was then dissolved in ethyl ether, and treated with 1.5 equiv. of 1N HCl/ether. Filtration and lyophilization gave the HCl salt of ′(1R,2R)—N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)-2-methylcyclopropane-1,1-dicarboxamide: 1H NMR (400 MHz, DMSO-d6) δ 10.65 (br s, 1H), 10.54 (br s, 1H), 9.74 (s, 1H), 8.75 (br s, 1H), 8.01 (br d, J=12.9 Hz, 1H), 7.80-7.50 (m, 6H), 7.20-7.10 (m, 2H), 6.84 (br s, 1H), 4.34 (br t, J=5 Hz, 2H), 4.04 (s, 3H), 4.05-3.95 (m, 2H), 3.77 (br t, J=11 Hz, 2H), 3.52 (br d, J=12.7 Hz, 4H), 3.12 (br q, J=9.0 Hz, 2H), 2.40-2.30 (m, 2H), 2.10-1.95 (m, 1H), 1.40-1.30 (m, 2H), 1.10 (d, J=6.2 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]2[C@@H:13]([CH2:21][N:22]([CH3:31])[CH:23]2[CH2:26][CH:25]([C:27](OC)=[O:28])[CH2:24]2)[O:12]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:19])([CH3:20])[O:18][C@@H:14]2[C@@H:13]([CH2:21][N:22]([CH3:31])[CH:23]2[CH2:24][CH:25]([CH2:27][OH:28])[CH2:26]2)[O:12]1
Reactant: COC(=O)C1CC(N(C)C[C@H]2O[C@@H](n3cnc4c(N)ncnc43)[C@@H]3OC(C)(C)O[C@@H]32)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(CO)C1
Reaction time: 8 h

Procedure:
To a solution of methyl 3-((((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)(methyl)amino)cyclobutanecarboxylate (1.0 g, 2.31 mmol) in THF (40 ml) was added LiAlH4 (0.53 g, 13.89 mmol) at 0° C. and the mixture was stirred overnight. Water (1.0 g) and 15% NaOH solution (3.0 g) were added slowly to the mixture and upon stirring for 15 min, the mixture was filtered. The filtrate was concentrated to obtain the crude title compound which was used directly in the next step.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:21])OC2C=CC=CC=2)[N:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:8]=1)([CH3:6])[CH3:5])[CH3:2].[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH3:41])[N:36]=[CH:35][N:34]=[C:33]2[O:42][C:43]1[CH:44]=[C:45]([CH:47]=[CH:48][CH:49]=1)[NH2:46].C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH3:41])[N:36]=[CH:35][N:34]=[C:33]2[O:42][C:43]1[CH:44]=[C:45]([NH:46][C:13]([NH:12][C:10]2[N:9]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:8]=[C:7]([C:4]([O:3][CH2:1][CH3:2])([CH3:5])[CH3:6])[CH:11]=2)=[O:21])[CH:47]=[CH:48][CH:49]=1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: CCOC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(C)(C)c1cc(NC(=O)Nc2cccc(Oc3ncnc4cc(OC)c(OC)cc34)c2)n(-c2ccccc2)n1
Temperature: 50 °C
Yield: 60.2 %

Procedure:
Using the procedure described in Example 159B, phenyl 3-(2-ethoxypropan-2-yl)-1-phenyl-1H-pyrazol-5-ylcarbamate (0.115 g, 0.33 mmol), 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (0.098 g, 0.33 mmol), and N,N-diisopropylethylamine (0.8 mL) in THF (6 mL) were heated at 50° C. for 5 hours, to afford 1-[3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl]-3-[3-(2-ethoxypropan-2-yl)-1-phenyl-1H-pyrazol-5-yl]urea as solid (0.113 g, 60%). 1H NMR (300 MHz, DMSO-d6) δ 9.25 (br, 1H), 8.55 (s, 1H), 8.54 (s, 1H), 7.54 (m, 6H), 7.39 (m, 3H), 7.18 (d, 1H), 6.93 (d, 1H), 6.41 (s, 1H), 3.77 (s, 3H), 3.98 (s, 3H), 3.25 (q, 2H), 1.45 (s, 6H), 1.03 (t, 3H); LC-MS (ESI) m/z 523 (M−OEt)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[N:9]=[CH:10][C:11]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C:12]=3[N:13]=2)[CH2:3][CH2:2]1.C(Cl)Cl.Cl.O1CCOCC1>CCOCC.CO.CO>[O:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8]2[N:9]=[CH:10][C:11]3[CH2:17][CH2:16][NH:15][CH2:14][C:12]=3[N:13]=2)[CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCc2cnc(NC3CCOCC3)nc2C1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: CCOCC
Product: c1nc(NC2CCOCC2)nc2c1CCNC2
Reaction time: 18 h
Yield: 77 %

Procedure:
A round-bottom flask was charged with 26 (27.5 g, 82.2 mmol), DCM (100 mL) and MeOH (25 mL) and maintained under nitrogen. A 4N solution of HCl in dioxane (103 mL, 411 mmol) was added and the resulting solution stirred for 18 h. The reaction mixture was concentrated and re-suspended in DCM (150 mL). A methanolic NH3 solution (25 mL, 7 N) and additional DCM (100 mL) was added. The precipitated salts were filtered and the filtrate concentrated to afford a brown solid which was stirred with Et2O/MeOH (95:5) for 1 h. A fine light brown solid precipitated and recovered by filtration to afford 15 g, (99% purity, 77% yield) of N-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine (28): MS m/z (APCI-pos) M+1=235.2.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:23])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:25]1[CH2:30][CH2:29][CH2:28][C@@H:27]([NH:31]C(=O)OC(C)(C)C)[CH2:26]1.CCN(C(C)C)C(C)C.C(O)(C(F)(F)F)=O>CN1CCCC1=O.C(Cl)Cl.C(OCC)(=O)C>[NH2:31][C@@H:27]1[CH2:28][CH2:29][CH2:30][N:25]([C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12](=[O:23])[C:13]4[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=4)[C:4]=23)[CH2:26]1
Reactant: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)c1ccc(C(F)(F)F)cn1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)c4ccc(C(F)(F)F)cn4)c23)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 10.3 %

Procedure:
N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl) picolinamide (195 mg, 0.48 mmol), (R)-tert-butyl piperidin-3-ylcarbamate (290 mg, 1.45 mmol) and DIEA (0.17 mL, 0.97 mmol) in N-methylpyrrolidone (“NMP”; 2 mL) were stirred at 148° C. (bath) for 18 hours and at 160° C. for 5 hours. Ethyl acetate (20 mL) was added, and the mixture was washed with water (10 mL), brine (10 mL) and dried over sodium sulfate. After removal of the solvent, the residue was purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column, 45-85% CH3CN/water gradient; 30 CV) to give a solid. This solid was dissolved in DCM (3 mL), and TFA (0.5 mL) was added. The mixture was stirred at room temperature for 1 hour. The solvent was removed. The residue was dissolved in DCM (1 mL), and 2N HCl in ether (3 mL) was added. The solid formed was collected by filtration to give (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl) picolinamide (24 mg, 8% yield) as a solid. 1H NMR (400 MHz, D2O) δ 8.77 (s, 1H), 8.15 (s, 1H), 8.11 (d, 1H), 7.95 (d, 1H), 7.82 (s, 1H), 3.74 (m, 1H), 3.59 (m, 1H), 3.48 (m, 1H), 3.32 (m, 1H), 2.88 (m, 1H), 2.22 (m, 1H), 2.03 (m, 1H), 1.79 (m, 1H), 1.53 (m, 1H); LCMS (APCI+) m/z 483 (M+H)+.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:22]=[C:23]([Cl:25])[CH:24]=1)[O:7][C:8]1[C:9]([CH2:20][CH3:21])=[N:10][N:11]([CH2:15][C:16]([O:18]C)=[O:17])[C:12]=1[CH2:13][CH3:14]>O1CCCC1>[Cl:3][C:4]1[CH:5]=[C:6]([CH:22]=[C:23]([Cl:25])[CH:24]=1)[O:7][C:8]1[C:9]([CH2:20][CH3:21])=[N:10][N:11]([CH2:15][C:16]([OH:18])=[O:17])[C:12]=1[CH2:13][CH3:14]
Reactant: CCc1nn(CC(=O)OC)c(CC)c1Oc1cc(Cl)cc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1nn(CC(=O)O)c(CC)c1Oc1cc(Cl)cc(Cl)c1
Yield: 78 %

Procedure:
Aqueous sodium hydroxide solution (1N, 6.2 ml, 6.2 mmol) was added dropwise to a stirred solution of the ester (2 g, 5.6 mmol) of Example 9 in tetrahydrofuran (20 ml) at 0° C. After 1 hour the solvent was removed under reduced pressure and aqueous hydrochloric acid (20 ml) was added with vigorous stirring. The resulting white precipitate was collected by filtration, washed with ether (3×30 ml) and dried in a vacuum pistol at 6° C./10 mmHg to afford the title compound as a white solid (1.5 g), m.p. 157–158° C.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][CH2:7][C:8]2[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:9]=2[OH:10])=[CH:4][CH:3]=1.CC(N(C)C)=O.[CH2:24]([S:32](Cl)(=[O:34])=[O:33])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].Cl>N1C=CC=CC=1>[CH2:24]([S:32]([NH:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][CH2:7][C:8]2[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:9]=2[OH:10])=[CH:4][CH:3]=1)(=[O:34])=[O:33])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: Nc1ccc(CCc2cc(O)ccc2O)cc1
Reactant: CCCCCCCCS(=O)(=O)Cl
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: c1ccncc1
Product: CCCCCCCCS(=O)(=O)Nc1ccc(CCc2cc(O)ccc2O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In 1 l-volume three-necked flask were charged 100 g of (4-aminophenethyl)hydroquinone, 500 ml of dimethylacetamide, and 36 ml of pyridine, and 85 ml of octanesulfonyl chloride were slowly added dropwise thereto at room temperature while stirring. After the dropwise addition, the stirring was continued for 4 hours. The reaction mixture was poured into a hydrochloric acid aqueous solution and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and concentrated to obtain 129 g of the entitled compound as an oily substance.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[Cl:27][C:28]1[CH:42]=[CH:41][C:31]2[N:32]=[C:33]([N:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[S:34][C:30]=2[CH:29]=1>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:38]2[CH2:39][CH2:40][N:35]([C:33]3[S:34][C:30]4[CH:29]=[C:28]([Cl:27])[CH:42]=[CH:41][C:31]=4[N:32]=3)[CH2:36][CH2:37]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: Clc1ccc2nc(N3CCNCC3)sc2c1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3nc4ccc(Cl)cc4s3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 6-chloro-2-piperazin-1-yl-benzothiazole.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12]Cl)=[C:4]([CH3:14])[N:3]=1.[CH:15]1[C:22]([CH:23]([CH3:25])[CH3:24])=[CH:21][CH:20]=[C:18]([CH3:19])[C:16]=1[OH:17].O>CN(C=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][O:17][C:16]2[CH:15]=[C:22]([CH:23]([CH3:24])[CH3:25])[CH:21]=[CH:20][C:18]=2[CH3:19])=[C:4]([CH3:14])[N:3]=1
Reactant: Cc1ccc(C(C)C)cc1O
Reactant: Cc1nc(Cl)c2ccccc2c1CCl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C(C)C)cc1OCc1c(C)nc(Cl)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.1 %

Procedure:
A solution of 1-chloro-4-chloromethyl-3-methyl-isoquinoline (150 mg, 0.66 mmol) is added to a mixture of carvacrol (199 mg, 1.33 mmol) and CsCO3 (645 mg, 1.98 mmol) in DMF (8 ml). After stirring overnight at room temperature, water is added and the mixture is extracted with ether. The combined extracts are washed with saturated brine, dried over Na2SO4, and concentrated in vacuo. The residue is chromatographed on silica gel to give 220 mg of 1-chloro-4-(5-isopropyl-2-methyl-phenoxymethyl)-3-methyl-isoquinoline. A mixture of 1-chloro-4-(5-isopropyl-2-methyl-phenoxymethyl)-3-methyl-isoquinoline (220 mg, 0.65 mmol), 5-isopropylindazole-4-boronic acid (173 mg, 0.85 mmol), Pd(PPh3)4 (38 mg, 0.033 mmol), and Na2CO3 (1.3 ml of 2M in H2O) in dioxane (8 ml) The mixture is heated for 18 h at 100° C. After cooling to room temperature, water is added and the resulting mixture is extracted with EtOAc. The combined extracts are dried over Na2SO4 and concentrated in vacuo. The residue is chromatographed on silica gel to give 133 mg of 1-(5-isopropyl-1H-indazol-4-yl)-4-(5-isopropyl-2-methyl-phenoxymethyl)-3-methyl-isoquinoline
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]#[N:19])[CH:16]=3)[N:11](C3CCCCO3)[N:10]=2)=[CH:5][CH:4]=1.O1CCOCC1.Cl.O>CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]#[N:19])[CH:16]=3)[NH:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2nn(C3CCCCO3)c3ccc(C#N)cc23)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(-c2n[nH]c3ccc(C#N)cc23)cc1
Temperature: 65 °C
Yield: 68.7 %

Procedure:
A mixture of 251 mg (0.753 mmol) of 3-(4-methoxyphenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile, 5.0 mL of dioxane, and 5.0 mL of 6.0 N aq. HCl was heated at 65° C. for 22 h. The reaction mixture was added to a mixture of 10.0 mL of H2O and 20.0 mL of EtOAc with stirring. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were added to 60 mL of sat. aq. NaHCO3 with rapid stirring. The layers were separated, and the organic layer was washed with sat. aq. NaHCO3, and dried (Na2SO4). Purification of the crude material by silica gel chromatography using 30-50% EtOAc in hexanes afforded the title compound (129 mg, 71% yield): ES-MS (m/z) 250 [M+1]+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]1[CH2:17][N:16]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[C@H:15]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[C@@H:14]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:13]1.C(N(CC)CC)C>C(Cl)Cl.C(OCC)(=O)C>[O:11]=[C:12]1[CH2:17][N:16]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[C@H:15]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[C@@H:14]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:13]1
Reactant: CC(C)(C)OC(=O)[C@H]1CC(O)CN(C(=O)OCc2ccccc2)[C@@H]1C(=O)OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)[C@H]1CC(=O)CN(C(=O)OCc2ccccc2)[C@@H]1C(=O)OCc1ccccc1
Temperature: 78 °C
Reaction time: 0.5 h
Yield: 63.6 %

Procedure:
To a cooled solution of oxalyl chloride (315 mg) in methylene chloride (2.5 mL) was added dropwise a solution of DMSO (0.30 mL) in methylene chloride (3.0 mL) at 78° C. The mixture was stirred at 78° C. for 30 min, 1,2-dibenzyl 3-tert-butyl(2S,3S)-5-hydroxypiperidine-1,2,3-tricarboxylate of step 1m (900 mg) in methylene chloride (4 mL) was added dropwise. The mixture was stirred at 78° C. to 60° C. for 1 h. Triethylamine (620 mg) in methylene chloride (2.5 mL) was added. The mixture was allowed to warm to RT during a period of 2 h. The mixture was diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was flash chromatographed on silica gel column to afford 1,2-dibenzyl 3-tert-butyl(2S,3S)-5-oxopiperidine-1,2,3-tricarboxylate (570 mg). MS (ESI): 490.3 (M+Na+); 368.2 (M+H+—COO(t-Bu)).
Reaction SMILES: [C:1]([C:3](=[C:7](SC)[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[C:18]1([CH3:26])[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][NH2:25].[OH-].[Na+].C(OCC)(=O)C>CCCCCC>[NH2:2][C:1]1[N:24]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH3:26])[N:25]=[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: Cc1ccccc1NN
Reactant: CSC(=C(C#N)C(N)=O)c1ccc(C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2nn(-c3ccccc3C)c(N)c2C(N)=O)cc1
Yield: 4.9 %

Procedure:
The title compound was prepared from 2-cyano-3-methylthio-3-(4-tolyl) acrylamide (464 mg, 2.0 mmol), 2-tolylhydrazine hydrochloride (350 mg, 2.2 mmol) and sodium hydroxide (88 mg, 2.2 mmol) following the procedure used for the compound of Example 12. The crude product was subjected to column chromatography (SiO2, 75% ethyl acetate in hexane) to give the title compound as a yellow solid (30 mg) m.p. 133-135°. δH (CDCl3) 7.52 (2H, d, J 8.1 Hz), 7.38 (4H, m), 7.28 (2H, d, J 7.4 Hz), 5.40 (4H, m), 2.40 (3H, s) and 2.23 (3H, s).
Reaction SMILES: [C:1](#[N:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:9]=[N+:10]=[N-:11].[Na+].Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>O>[C:2]1([C:1]2[NH:11][N:10]=[N:9][N:8]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: c1ccc(-c2nnn[nH]2)cc1
Yield: 84 %

Procedure:
Into the same device as used in Example 1 were placed 5.16 g (0.050 mole) of benzonitrile, 4.23 g (0.065 mole) of sodium azide, 8.95 g (0.065 mole) of triethylamine hydrochloride, 52 ml of toluene and 2.6 g of water. The mixture was reacted at a temperature of 85 to 95° C. for 8 hours, giving 6.12 g (0.042 mole) of 5-phenyl-1H-tetrazole (yield 83.7% based on benzonitrile).
Reaction SMILES: [CH3:1][N:2]([C:11](SC)=[C:12]([C:15]#[N:16])[C:13]#[N:14])[N:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:19][NH:20][CH3:21]>C(O)C>[CH3:1][N:2]([C:11]([N:20]([CH3:21])[CH3:19])=[C:12]([C:15]#[N:16])[C:13]#[N:14])[N:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CNC
Reactant: CSC(=C(C#N)C#N)N(C)N=Cc1ccccc1
Solvent: CCO
Product: CN(C)C(=C(C#N)C#N)N(C)N=Cc1ccccc1
Temperature: 0 °C

Procedure:
The product of stage (a) (26 g), aqueous dimethylamine (6.6 g) and ethanol (250 ml) were heated under reflux for 4 hours and then cooled to 0° C. Benzaldehyde N-methyl-N-[2,2-dicyano-1-(dimethylamino)ethenyl]hydrazone (19.8 g) precipitated, m.p. 127°-128° C.