Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([N:15]2[N:19]=[C:18]3[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:17]3=[N:16]2)[C:6]=1[OH:25])([CH3:4])([CH3:3])[CH3:2].CN([Zr:29]([N:36]([CH3:38])[CH3:37])([N:33]([CH3:35])[CH3:34])N(C)C)C>CCCCC>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([N:15]2[N:19]=[C:18]3[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:17]3=[N:16]2)[C:6]=1[O:25][Zr:29]([O:25][C:6]1[C:7]([N:15]2[N:19]=[C:18]3[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:17]3=[N:16]2)=[CH:8][C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:10][C:5]=1[C:1]([CH3:2])([CH3:3])[CH3:4])([N:33]([CH3:34])[CH3:35])[N:36]([CH3:37])[CH3:38])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)[Zr](N(C)C)(N(C)C)N(C)C
Reactant: CC(C)(C)c1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)C)c1
Solvent: CCCCC
Product: CN(C)[Zr](Oc1c(-n2nc3ccc(Cl)cc3n2)cc(C(C)(C)C)cc1C(C)(C)C)(Oc1c(-n2nc3ccc(Cl)cc3n2)cc(C(C)(C)C)cc1C(C)(C)C)N(C)C
Reaction time: 1 h

Procedure:
In a dry box, 2,4-di-tert-butyl-6-(5-chloro-2H-benzo-triazol-2-yl)phenol (25 g, 70.11 mmol) was transferred to a 1 L round bottom flask and dissolved in pentane (150 ml) to from a solution. Tetrakis(dimethylamino)zirconium (9.38 g, 35.05 mmol) in pentane (150 ml) was added to this solution. The mixture was stirred for one hour and then the volatiles were removed under vacuum to obtain yellow solid. The yellow solid was used without further purification (yield, 91%).
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH2:7][NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:16][CH2:17][CH2:18][C:19](Cl)=[O:20].[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:16][CH2:17][CH2:18][C:19]([N:6]1[CH2:7][C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[CH2:10][C:11]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]1=2)=[O:20]
Reactant: O=C(Cl)CCCl
Reactant: c1ccc2c(c1)CNc1ccccc1C2
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=C(CCCl)N1Cc2ccccc2Cc2ccccc21
Temperature: 95 °C

Procedure:
In a 100 ml round bottom flask equipped with magnetically stirring, thermometer, reflux condenser and addition funnel, 6,11-dihydro-5H-dibenz[b,e]azepine (1.0 g, 5,1 mmol, prepared in a similar way as described in Coll. Czech. Chem. Commun., 23, 1958, 1330) was dissolved in dry toluene (25 ml). 3-Chloropropionyl chloride (0.78 g, 6,1 mmol) was added slowly. When addition was complete, the reaction mixture was heated at 95° C. for 30 minutes and then allowed to cool to room temperature. With stirring, 0.2N sodium hydroxide (2.5 ml) was added. More toluene (50 ml) was added and the phases were separated. The organic phase was washed with 0.2N sodium hydroxide (10 ml) until pH>10, and then with water (3×10 ml) and brine (10 ml). After drying (MgSO4), the solvent was evaporated in vacuo affording 3-chloro-1-(6,11-dihydro-5H-dibenz[b,e]azepin-5-yl)-1-propanone as an oil which was obtained in quantitative yield and used for further reactions without purification.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2([CH2:17][CH2:16][N:15]([C:18](=[O:33])[C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=3)[CH2:14][CH2:13]2)[C:11](=[O:34])[N:10]([CH3:35])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:36]C1C=C(C=CC=1)C=O>>[F:28][C:25]([F:26])([F:27])[C:23]1[CH:24]=[C:19]([CH:20]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:22]=1)[C:18]([N:15]1[CH2:16][CH2:17][C:12]2([N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[C:6]([Cl:36])[CH:7]=3)[CH2:9][N:10]([CH3:35])[C:11]2=[O:34])[CH2:13][CH2:14]1)=[O:33]
Reactant: CN1CN(Cc2ccccc2)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)C1=O
Reactant: O=Cc1cccc(Cl)c1
Product: CN1CN(Cc2cccc(Cl)c2)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)C1=O

Procedure:
The title compound, MS: m/e=534.2 (M+H+), was prepared in accordance with the general method of example 88 from 1-benzyl-8-(3,5-bis-trifluoromethyl-benzoyl)-3-methyl-1,3,8-triaza-spiro[4.5]decan-4-one and 3-chlorobenzaldehyde.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]([CH3:29])=[CH:7][C:5]=2[N:6]=1.[CH3:30][C:31]1[N:48]([CH3:49])[C:34]2=[N:35][CH:36]=[C:37](B3OC(C)(C)C(C)(C)O3)[CH:38]=[C:33]2[N:32]=1.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:25]([O:24][C@@H:18]([C:9]1[C:8]([CH3:29])=[CH:7][C:5]2[N:6]=[C:2]([C:37]3[CH:38]=[C:33]4[N:32]=[C:31]([CH3:30])[N:48]([CH3:49])[C:34]4=[N:35][CH:36]=3)[S:3][C:4]=2[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH3:28])([CH3:27])[CH3:26]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Reactant: Cc1nc2cc(B3OC(C)(C)C(C)(C)O3)cnc2n1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cnc4c(c3)nc(C)n4C)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
A microwave vial was charged with (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (50 mg, 0.10 mmol), 2,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-imidazo[4,5-b]pyridine (102 mg, 0.37 mmol), then Pd(PPh3)4 (23 mg, 0.02 mmol). The vial was flushed with argon, diluted with dioxane (2 mL) and to this was added 2M aqueous K2CO3 (0.2 mL, 0.4 mmol). The vial was sealed then heated to 100° C. for 16 hours and then allowed to cool to room temperature. The mixture was diluted with EtOAc, dried over Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (0-100% THF/CH2Cl2 gradient) to afford the desired product. LCMS-ESI+: calc'd for C30H32ClN4O3S: 563.2 (M+H+); Found: 563.2 (M+H+).
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[C:8]1([C:14]2([C:21]([OH:23])=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CO.C1(C)C=CC=CC=1>[CH3:1][O:22][C:21]([C:14]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:23]
Reactant: O=C(O)C1(c2ccccc2)CCCCCC1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)C1(c2ccccc2)CCCCCC1

Procedure:
A 2.0 M solution of trimethylsilyl diazomethane (29.2 mL) was added dropwise to a solution of 1-phenyl-cycloheptanecarboxylic acid (Example 14c) (9.8 g) in methanol (85 mL) and toluene (300 mL) under an atmosphere of nitrogen.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1/C(=N\O)/C.[CH3:13][C:14]([N:16](C)C)=O.P(Cl)(Cl)(Cl)=O.C([O-])(O)=O.[Na+]>C(#N)C>[CH3:13][C:14]1[O:1][C:2]2[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=2[N:16]=1
Reactant: CC(=O)N(C)C
Reactant: C/C(=N/O)c1ccc(O)cc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc2ccc(O)cc2o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cooled (ice-water) solution of (1Z)-1-(2,4-dihydroxyphenyl)ethanone oxime (9.7 g, 57.7 mmol) and dimethylacetamide (11 mL) in acetonitrile (65 mL) was added phosphorous oxychloride (5.6 mL, 60.3 mmol) dropwise. The temperature was not allowed to exceed 10° C. during the reaction. After 1 hour stirring at room temperature the yellow slurry was poured into a mixture of aqueous NaHCO3 and ice. The resulting precipitate was filtered off and dried to give the sub-title compound (6.3 g).
Reaction SMILES: [C:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=2)[N:6]=[CH:5][C:4]=1[C:15]([O:17]CC)=O)#[N:2].[CH3:20][NH2:21]>>[C:1]([C:3]1[N:7]([C:8]2[CH:9]=[CH:10][C:11]([Br:14])=[CH:12][CH:13]=2)[N:6]=[CH:5][C:4]=1[C:15]([NH:21][CH3:20])=[O:17])#[N:2]
Reactant: CN
Reactant: CCOC(=O)c1cnn(-c2ccc(Br)cc2)c1C#N
Product: CNC(=O)c1cnn(-c2ccc(Br)cc2)c1C#N

Procedure:
A solution of 3.2 g of 5-cyano-1-(4-bromophenyl)-1H-pyrazole-4-carboxylic acid, ethyl ester in 40 ml of 3 A alcohol and 10 ml of 40% aqueous monomethylamine was refluxed for approximately 2 hours. Ten additional milliliters of 40% aqueous monomethylamine was added to the reaction mixture which was then refluxed for an additional 3 hours. The mixture was cooled and the precipitated solid was collected by filtration to provide 1 g of 5-cyano-1-(4-bromophenyl)-N-methyl-1H-pyrazole-4-carboxamide. MP=240°-241° C.
Reaction SMILES: [C:1]1([C:7]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][OH:16])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23]=[C:24]1[O:28][C:26](=[O:27])[CH2:25]1>C1(C)C=CC=CC=1.CC(C)=O>[C:1]1([C:7]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][O:16][C:26](=[O:27])[CH2:25][C:24]([CH3:23])=[O:28])[CH2:11][CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Reactant: C=C1CC(=O)O1
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)OCCCN1CCC(c2ccccc2)(c2ccccc2)CC1

Procedure:
23.6 g of 3-(4,4-diphenylpiperid-1-yl)-propanol was dissolved in 100 ml of absolute toluene, and 16 ml of a 50% strength solution of diketene in acetone was added with stirring. After standing for several days at room temperature (monitored by thin layer chromatography), the mixture was concentrated, and the residue was dried under high vacuum. The pale yellow, viscous oil which remains was employed without further purification for the next stage.
Reaction SMILES: [N:1]([CH:4]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[CH2:5][N:6]1[C:14]2[CH:13]=[CH:12][C:11]([CH3:15])=[CH:10][C:9]=2[C:8]2[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20][C:7]1=2)=[N+]=[N-].[Cl-].[NH4+]>C(O)C.O.[Zn]>[CH3:21][N:18]1[CH2:17][CH2:16][C:8]2[C:9]3[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][C:14]=3[N:6]([CH2:5][CH:4]([C:22]3[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=3)[NH2:1])[C:7]=2[CH2:20][CH2:19]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(N=[N+]=[N-])c2ccncc2)CCN(C)CC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CCO
Product: Cc1ccc2c(c1)c1c(n2CC(N)c2ccncc2)CCN(C)CC1
Temperature: 85 °C
Reaction time: 0.75 h
Yield: 25.8 %

Procedure:
To a solution of 6-(2-azido-2-(pyridin-4-yl)ethyl)-3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (188 mg, 0.522 mmol) in ethanol-water (9 mL:1 mL), zinc dust (135 mg, 2.08 mmol) and ammonium chloride (110 mg, 2.08 mmol) were added and the reaction mixture was stirred at 85° C. for 45 min. The reaction mixture was filtered and the filtrate concentrated. The residue was basified with aqueous ammonia and extracted with EtOAc (2×50 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by reverse phase HPLC to yield 2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(pyridin-4-yl)ethanamine (45 mg). The racemate can be further separated into the optically active forms by chiral preparative HPLC. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.6 (d, 2H), 7.6 (d, 2H), 7.22 (s, 1H), 7.0 (s, 1H), 6.9 (s, 1H), 4.9 (m, 3H), 4.8 (m, 1H), 4.7 (m, 1H), 3.8-3.6 (m, 2H), 3.2 (m, 2H), 3.18-2.97 (m, 4H), 2.8 (bs, 1H), 2.38 (s, 3H).
Reaction SMILES: [CH:1]([C@@H:9]1[C@@H:13]([CH2:14][OH:15])[O:12][C@@H:11]([N:16]2[C:25]3[N:24]=[CH:23][N:22]=[C:20]([NH2:21])[C:19]=3[N:18]=[CH:17]2)[CH2:10]1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O[N:27]1[C:31](=[O:32])[C:30]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:29]2[C:28]1=[O:37]>>[C:31]1(=[O:32])[N:27]([O:15][CH2:14][C@H:13]2[O:12][C@@H:11]([N:16]3[C:25]4[N:24]=[CH:23][N:22]=[C:20]([NH2:21])[C:19]=4[N:18]=[CH:17]3)[CH2:10][C@@H:9]2[CH:1]=[CH:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:28](=[O:37])[C:29]2=[CH:36][CH:35]=[CH:34][CH:33]=[C:30]12
Reactant: Nc1ncnc2c1ncn2[C@H]1C[C@H](C=Cc2ccccc2)[C@@H](CO)O1
Reactant: O=C1c2ccccc2C(=O)N1O
Product: Nc1ncnc2c1ncn2[C@H]1C[C@H](C=Cc2ccccc2)[C@@H](CON2C(=O)c3ccccc3C2=O)O1
Yield: 76 %

Procedure:
2',3'-Dideoxy-3'-C-styryladenosine underwent standard Mitsunobu reaction with N-hydroxyphthalimide to provide 2',3'-dideoxy-5'-O-phthalimido-3'-C-styryladenosine in 76% yield with a melting point of 145°-147° C. Anal.: C26H22N6O4.1/4 H2O Calcd.: C% 64.12; H% 4.65; N% 17.25; Found: C% 63.96; H% 4.58; N% 17.51.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:17]=[CH:16][C:11]3[B:12]([OH:15])[O:13][CH2:14][C:10]=3[CH:9]=2)=[CH:5][CH:4]=1.[C:20]1([N:26]=[C:27]=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>C(Cl)Cl>[OH:15][B:12]1[C:11]2[CH:16]=[CH:17][C:8]([O:7][C:6]3[CH:18]=[CH:19][C:3]([CH2:2][NH:1][C:27]([NH:26][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:28])=[CH:4][CH:5]=3)=[CH:9][C:10]=2[CH2:14][O:13]1
Reactant: NCc1ccc(Oc2ccc3c(c2)COB3O)cc1
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Solvent: O
Product: O=C(NCc1ccc(Oc2ccc3c(c2)COB3O)cc1)Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 20 mL scintillation vial containing 5-(4-aminomethyl-phenoxy)-3H-benzo[c][1,2]oxaborol-1-ol (150 mg, 0.59 mmol, 1.0 eq.) in DCM (5.0 mL) was added phenylisocyanate (71 μL, 0.65 mmol, 1.1 eq.). The mixture was stirred at room temperature overnight. The mixture was treated with H2O (5 mL). The precipitate was collected by filtration and washed with H2O to give 1-[4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzyl]-3-phenyl-urea as a white solid. LCMS (m/z) 375 (M+H); 1H NMR (DMSO-d6) δ: 9.07 (s, 1H), 8.51 (s, 1H), 7.67 (d, J=8.0 Hz, 1H), 7.37 (dd, J=8.6, 1.0 Hz, 2H), 7.30-7.35 (m, J=8.6 Hz, 2H), 7.19 (t, J=8.0 Hz, 2H), 6.99-7.04 (m, 2H), 6.88-6.95 (m, 3H), 6.58 (s, 1H), 4.89 (s, 2H), 4.27 (d, J=5.9 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]([NH:16][C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][C:25]([O:27]C)=[O:26])[CH:20]=[CH:21][CH:22]=3)=[O:15])[CH:5]=[CH:4][C:3]1=2.C1COCC1.[OH-].[Li+].Cl>O>[CH3:1][C:2]1([CH3:29])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]([NH:16][C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][C:25]([OH:27])=[O:26])[CH:20]=[CH:21][CH:22]=3)=[O:15])[CH:5]=[CH:4][C:3]1=2
Reactant: COC(=O)C=Cc1cccc(NC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(C(=O)Nc3cccc(C=CC(=O)O)c3)ccc21

Procedure:
2.9 g (7.4 mmol) of methyl 3-{3-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenecarbonyl)-amino]phenyl}acrylate obtained in Example 18, 50 ml of THF and 3.1 g (74 mmol) of lithium hydroxide are introduced into a round-bottomed flask. The reaction medium is refluxed for 24 h ours and then poured into water, acidified to pH 1 with concentrated hydrochloric acid and extracted with ethyl acetate, and the organic phase is separated out after settling has taken place, washed with water, dried over magnesium sulphate and evaporated. The residue obtained is triturated from heptane, filtered off and dried. 2.8 g (100%) of 3-{3-[(5,5,8,8- tetramethyl-5,6,7,8-tetrahydro-2-naphthalenecarbonyl) amino]phenyl}acrylic acid, with a melting point of 215-6° C., are collected.
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)C=O.ClC1C=C(C=CC=1)C(OO)=[O:18].[OH-].[Na+].CO>C(Cl)Cl>[OH:18][C:7]1[CH:6]=[C:5]([O:4][CH2:3][CH2:2][F:1])[CH:12]=[CH:11][CH:10]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=Cc1cccc(OCCF)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: Oc1cccc(OCCF)c1
Yield: 76.2 %

Procedure:
In a manner similar to that described by Godfrey et al., (J. Chem. Soc. Perkin I, 1353-1354 (1974), the reaction of 7.0 grams (0.042 mole) of 3-(2-fluoroethoxy)benzaldehyde with 3-chloroperoxybenzoic acid (14.0 grams of 75% technical, 0.061 mole) in 100 ml of dry methylene chloride followed by treatment with an aqueous, 15% sodium hydroxide solution and methanol yielded 5.0 grams of 2-fluoroethyl 3-hydroxyphenyl ether as an oil.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]1([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.[CH2:19]([Mg]Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[CH2:19]([C:6]1([OH:9])[CH2:7][CH2:8][C:3]([N:2]([CH3:1])[CH3:18])([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[CH2:4][CH2:5]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CN(C)C1(Cc2cccc(F)c2)CCC(=O)CC1
Reactant: Cl[Mg]Cc1ccccc1
Solvent: C1CCOC1
Product: CN(C)C1(Cc2cccc(F)c2)CCC(O)(Cc2ccccc2)CC1

Procedure:
4.67 g 4-dimethylamino-4-(3-fluorobenzyl)cyclohexanone were reacted with 1.0 molar benzylmagnesium chloride solution in THF analogously to the preparation of 4-dimethylamino-4-(4-fluorobenzyl)-1-phenethylcyclohexanol. After chromatography over silica gel, the nonpolar diastereoisomer of 1-benzyl-4-dimethylamino-4-(3-fluorobenzyl)cyclohexanol obtained was converted into 261 mg of the corresponding hydrochloride as described for example 4.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[C:18]([C:20]3[N:25]=[C:24]([CH:26]([F:28])[F:27])[CH:23]=[C:22]([C:29]4[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=4)[N:21]=3)[CH:17]=[CH:16][N:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:28][CH:26]([F:27])[C:24]1[CH:23]=[C:22]([C:29]2[CH:30]=[CH:31][C:32]([C:35]([F:36])([F:37])[F:38])=[CH:33][CH:34]=2)[N:21]=[C:20]([C:18]2[CH:17]=[CH:16][N:15]=[C:14]([C:11]3[S:10][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:13][CH:12]=3)[CH:19]=2)[N:25]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)F)n3)ccn2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)F)n3)ccn2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 46.2 %

Procedure:
To a cooled and stirred solution of 5-{4-[4-difluoromethyl-6-(4-trifluoromethylphenyl)-pyrimidin-2-yl]-pyridin-2-yl}-thiophene-2-sulfonic acid tert-butylamide (0.24 g) in dichloromethane (5 ml) was added TFA (5 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N Na2CO3 solution (20 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by flash-chromatography on silica gel (ethyl acetate/hexane) and crystallization (dichloromethane) yielded the title compound as an off-white solid (0.1 g, 20%). MS (ISP) 513.3 [(M+H)+]; mp 242° C.
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[C:12]([O:13][CH2:14][CH2:15][F:16])=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[O:8].[Cr](O)(O)(=O)=[O:18]>CC(C)=O.Cl>[F:1][CH2:2][CH2:3][O:4][C:5]1[C:12]([O:13][CH2:14][CH2:15][F:16])=[CH:11][CH:10]=[CH:9][C:6]=1[C:7]([OH:18])=[O:8]
Reactant: O=Cc1cccc(OCCF)c1OCCF
Reactant: O=[Cr](=O)(O)O
Agent: Cl
Solvent: CC(C)=O
Product: O=C(O)c1cccc(OCCF)c1OCCF
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 3.0 grams (0.013 mole) of 2,3-di(2-fluoroethoxy)benzaldehyde in 10 ml of acetone was added 4.9 ml of a 2.6 M solution of aqueous chromic acid in acetone (Jones' reagent). The mixture was stirred at room temperature for 30 minutes, and the solvent was removed by evaporation under reduced pressure leaving a residue. This residue was dissolved in 30 ml of 1 N hydrochloric acid, and the acidic solution was extracted with five 30 ml portions of diethyl ether. The combined organic phase was extracted with three 35 ml portions of an aqueous, 10% sodium hydroxide solution. The basic extracts were combined and acidified. The acidic solution was extracted with five 30 ml portions of diethyl ether. The extracts were combined and washed with two 25 ml portion of an aqueous, saturated sodium chloride solution. The washed organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure leaving a solid residue. This solid was recrystallized from toluene to yield 1.4 gram of 2,3-di(2-fluoroethoxy)benzoic acid, mp 104°-105° C.
Reaction SMILES: [CH2:1]([N:8]([CH3:26])[C:9]1[CH:10]=[C:11]([NH:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:12]2[N:13]([C:15]([CH3:18])=[N:16][N:17]=2)[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][O:28][CH2:29][CH2:30]Br.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH2:1]([N:8]([CH3:26])[C:9]1[CH:10]=[C:11]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([CH2:30][CH2:29][O:28][CH3:27])[CH2:22][CH2:21]2)[C:12]2[N:13]([C:15]([CH3:18])=[N:16][N:17]=2)[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCBr
Reactant: Cc1nnc2c(NC3CCNCC3)cc(N(C)Cc3ccccc3)nn12
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COCCN1CCC(Nc2cc(N(C)Cc3ccccc3)nn3c(C)nnc23)CC1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
N6-Benzyl-3,N6-dimethyl-N8-piperidin-4-yl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (0.05 g; 0.11 mmol) was slurred up in 0.3 ml DMA. 2-bromoethyl methyl ether (0.01 ml; 0.14 mmol) and DIPEA (0.04 ml; 0.23 mmol) were added and stirred at 50° C. for 16 hours. The crude material was purified by using reversed phase chromatography under basic conditions.
Reaction SMILES: [CH2:1]=O.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][NH:28][CH3:29])=[CH:23][CH:22]=3)=[O:19])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1>C(O)=O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13](/[CH:16]=[CH:17]/[C:18]([NH:20][C:21]3[CH:22]=[CH:23][C:24]([CH2:27][N:28]([CH3:1])[CH3:29])=[CH:25][CH:26]=3)=[O:19])=[CH:14][CH:15]=2)=[CH:6][CH:5]=1
Reactant: CNCc1ccc(NC(=O)/C=C/c2ccc(-c3ccc(Cl)cc3)cc2)cc1
Reactant: C=O
Solvent: O=CO
Product: CN(C)Cc1ccc(NC(=O)/C=C/c2ccc(-c3ccc(Cl)cc3)cc2)cc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
1.00 mL formaldehyde (37% in water) was added at 0° C. to a solution of 0.100 g (0.280 mmol) (E)-3-(4′-chloro-biphenyl-4-yl)-N-(4-methylaminomethyl-phenyl)-acrylamide (Example 180) in 1 mL formic acid and the mixture was stirred for 1 h at RT and 2 h at 90° C. The reaction mixture was poured onto ice water and the aqueous phase was exhaustively extracted with EtOAc. The combined org. phases were dried over sodium sulphate, evaporated down i. vac. and the residue stirred with ether. The precipitate was filtered off, washed with ether and dried i. vac. at 100° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH:29]=[CH2:30])[C:21]3[C:20](=[O:31])[N:19](COC(=O)C(C)(C)C)[C:18](=[O:40])[N:17]([CH3:41])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH:29]=[CH2:30])[C:21]3[C:20](=[O:31])[NH:19][C:18](=[O:40])[N:17]([CH3:41])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=Cc1ccccc1-n1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)n(COC(=O)C(C)(C)C)c(=O)n2C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: C=Cc1ccccc1-n1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)[nH]c(=O)n2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.3 %

Procedure:
4-[1-(2,2-Dimethylpropionyloxymethyl)-7-(2-vinylphenyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (187 mg) was dissolved in methanol (3 ml), and sodium hydride (14 mg) was added thereto. The reaction solution was stirred at room temperature overnight, then neutralized with 1 N hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was removed by distillation. The residue was purified by silica gel chromatography to obtain 108 mg of 4-[3-methyl-2,6-dioxo-7-(2-vinylphenyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester from a fraction eluted with hexane-ethyl acetate (3:2). This was dissolved in trifluoroacetic acid (2 ml), and the solution was concentrated. The residue was purified by NH-silica gel to obtain 84 mg of the title compound from a fraction eluted with ethyl acetate-methanol (15:1).