Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH3:12])[CH:5]=[CH:4][CH:3]=1.[Br:13]N1C(=O)CCC1=O>>[Br:13][CH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH3:12])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc2cccc(C)c12
Product: Cc1cccc2cccc(CBr)c12

Procedure:
Using general procedure A (Exp. 1.3.), 1,8-dimethyl-naphthalene was reacted with N-bromosuccinimide to give 1-bromomethyl-8-methyl-naphthalene as white solid. MS: 234.1 ([M]+). Using general procedure B, ethyl 2-indole carboxylate was coupled with 1-bromomethyl-8-methyl-naphthalene to give 1-(8-methyl-naphthalen-1-ylmethyl)-1H-indole-2-carboxylic acid ethyl ester which was hydrolyzed as described in the general procedure B (Exp. 2.2) to give the title compound as a white solid. MS: 314.4 ([M−H]−).
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:10]([C:19](OC)=[O:20])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C>C1COCC1.C1(C)C=CC=CC=1>[C:1]1([CH2:7][N:8]2[CH2:12][CH:11]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:10]([CH2:19][OH:20])[CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)C1CN(Cc2ccccc2)CC1c1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OCC1CN(Cc2ccccc2)CC1c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
A solution of 2.61 g (8.8 mmol) of 1-phenylmethyl-3-(SR)-carbomethoxy-4-(SR)-phenylpyrrolidine (from Example 1, Step A) in 100 mL of THF at -78 ° C. was treated with 9.2 mL of 1.5 M diisobutyl-aluminum hydride solution in toluene. The reaction was warmed to 0 ° C. and stirred for 1 h. The reaction was quenched with 50 mL of sat'd sodium potassium tartrate solution, diluted with 100 mL of ether and stirred at rt for 20 h. The layers were separated and the organic layer was washed with 75 mL of H2O, dried over MgSO4 and concentrated in vacuo. Flash chromatography on 100 g of silica gel using 1:1 v/v, then 3:2 v/v EtOAc/hexanes as the eluant afforded 1.99 g (84%) of the title compound as a solid. 1H NMR (500 MHz, CDCl3): δ2.56-2.63 (m, 1H), 2.80 (dd, J=4.3, 9.4, 1H), 2.91-2.98 (m, 2H), 3.05 (dd, J=6.9, 9.6, 1H), 3.27 (dd, J=5.0, 10.7, 1H), 3.44 (dd, J=5.5, 10.8, 1H), 3.62 (q, J=9.0, 1H), 3.76 (ABq, J=24.2, 2H), 7.22-7.40 (10H). Mass Spectrum (NH3 -CI): m/z 268 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[N:9]=[C:10](I)[C:3]=12.[F:25][C:26]1[CH:41]=[CH:40][CH:39]=[CH:38][C:27]=1[O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[N:9]=[C:10]([C:32]3[CH:31]=[CH:30][C:29]([O:28][C:27]4[CH:38]=[CH:39][CH:40]=[CH:41][C:26]=4[F:25])=[CH:34][CH:33]=3)[C:3]=12
Reactant: OB(O)c1ccc(Oc2ccccc2F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1Cn1nc(I)c2c(N)ncnc21
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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3ccccc3F)cc2)c2c(N)ncnc21
Temperature: 100 °C
Reaction time: 8 h
Yield: 58.3 %

Procedure:
Into a 100 mL 3-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed a solution of tert-butyl (2R)-2-([4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidine-1-carboxylate (300 mg, 0.68 mmol, 1.00 equiv) in dioxane/H2O (7/3=V/V) (30 mL), [4-(2-fluorophenoxy)phenyl]boronic acid (500 mg, 2.16 mmol, 3.19 equiv), sodium carbonate (500 mg, 4.72 mmol, 6.99 equiv), and Pd(PPh3)4 (200 mg, 0.17 mmol, 0.26 equiv). The resulting solution was stirred overnight at 100° C. in an oil bath and then concentrated under vacuum. The residue was loaded onto a silica gel column with dichloromethane/methanol (100:1) to give 0.2 g (59%) of tert-butyl (2S)-2-([4-amino-3-[4-(2-fluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)-pyrrolidine-1-carboxylate as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[C:3]=1[N:13]1[C:17]([C:18]([F:21])([F:20])[F:19])=[N:16][N:15]=[C:14]1[SH:22].Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C1COCC1.O>[CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[C:3]=1[N:13]1[C:17]([C:18]([F:21])([F:20])[F:19])=[N:16][N:15]=[C:14]1[S:22][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CCOC(=O)CBr
Reactant: Cc1cc(C)c(-n2c(S)nnc2C(F)(F)F)c2c1CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CSc1nnc(C(F)(F)F)n1-c1c(C)cc(C)c2c1CCCC2
Temperature: 60 °C
Yield: 54.2 %

Procedure:
To a solution of 4-(2,4-Dimethyl-5,6,7,8-tetrahydronaphthalen-1-yl)-5-(trifluoromethyl)-4H-1,2,4-triazole-3-thiol (0.2 g, 0.611 mmol) in THF (2.44 mL) was added ethyl 2-bromoacetate (68 μL, 0.611 mmol) and potassium carbonate (0.17 g, 1.22 mmol), and the mixture heated at 60° C. for 18 hours. The mixture was concentrated, ethyl 2-bromoacetate (68 mL, 0.611 mmol) and DMF (1.2 mL) added, and the mixture heated at 60° C. for 24 hours. Water (40 mL) was added and the mixture extracted with ethyl acetate (2×40 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, concentrated and purified by SGC (0-50% ethyl acetate/Hexanes) to afford ethyl 2-(4-(2,4-dimethyl-5,6,7,8-tetrahydronaphthalen-1-yl)-5-(trifluoromethyl)-4H-1,2,4-triazol-3-ylthio)acetate as a clear oil (0.137 g, 54%).
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.[F:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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.O1CCOCC1>[F:21][C:22]1[CH:27]=[C:26]([C:2]2[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=3)[N:3]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3cccc(F)c3)c(N(C)C(C)C)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 10-mL sealed tube, was placed methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (110 mg, 0.38 mmol, 1.00 equiv), 3-fluorophenylboronic acid (157.4 mg, 1.12 mmol, 3.00 equiv), Pd(PPh3)4 (86.5 mg, 0.07 mmol, 0.20 equiv), K3PO4 (318 mg, 1.51 mmol, 4.00 equiv), 1,4-dioxane (4 mL). The resulting solution was stirred for overnight at 100° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:30). This resulted in 75 mg (57%) of methyl 2-(3-fluorophenyl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](Cl)=[C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15]CC)=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:24]([C:26]1[CH:31]=[CH:30][C:29]([NH:32][NH:33][CH3:34])=[CH:28][CH:27]=1)#[N:25].C(N(C(C)C)CC)(C)C>C(O)CC>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:33]([CH3:34])[N:32]([C:29]3[CH:28]=[CH:27][C:26]([C:24]#[N:25])=[CH:31][CH:30]=3)[C:13](=[O:15])[C:12]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:7][CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOC(=O)C(C(=O)OCC)=C(Cl)c1ccc(C(C)(C)C)cc1
Reactant: CNNc1ccc(C#N)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCO
Product: CCOC(=O)c1c(-c2ccc(C(C)(C)C)cc2)n(C)n(-c2ccc(C#N)cc2)c1=O
Yield: 40 %

Procedure:
A mixture of 73.19 g of ethyl 3-(4-t-butylphenyl)-3-chloro-2-ethoxycarbonyl-acrylate, 33.6 g of 1-(4-cyanophenyl)-2-methyl-hydrazine, 44.3 g of diisopropylethylamine and 500 ml of 1-propanol was refluxed under heating for 7 days. The reaction mixture was evaporated under reduced pressure. After addition of 1N hydrochloric acid, the resulting residue was extracted with chloroform. The extract was washed with 1N hydrochloric acid and saturated aqueous sodium chloride successively and dried over anhydrous sodium sulfate, and the solvent was removed by evaporation. The residue was recrystallized in ethyl acetate to give 34.9 g of the title compound as colorless crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[CH:17]=[C:18]([C@@:23]3([OH:50])[C@H:28]([O:29][Si](C)(C)C)[C@@H:27]([O:34][Si](C)(C)C)[C@H:26]([O:39][Si](C)(C)C)[C@@H:25]([CH2:44][O:45][Si](C)(C)C)[O:24]3)[CH:19]=[CH:20][C:21]=2[Cl:22])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:51]S(O)(=O)=O.C(=O)(O)[O-].[Na+]>O1CCCC1.CO>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[CH:17]=[C:18]([C@@:23]3([O:50][CH3:51])[C@H:28]([OH:29])[C@@H:27]([OH:34])[C@H:26]([OH:39])[C@@H:25]([CH2:44][OH:45])[O:24]3)[CH:19]=[CH:20][C:21]=2[Cl:22])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)OC[C@H]1O[C@@](O)(c2ccc(Cl)c(Cc3ccc(OCc4ccccc4)cc3)c2)[C@H](O[Si](C)(C)C)[C@@H](O[Si](C)(C)C)[C@@H]1O[Si](C)(C)C
Reactant: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCc4ccccc4)cc3)c2)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 12 h
Yield: 54.5 %

Procedure:
To a solution of (2S,3R,4S,5R,6R)-2-[3-[(4-benzyloxyphenyl)methyl]-4-chloro-phenyl]-3,4,5-tris(trimethylsilyloxy)-6-(trimethylsilyloxymethyl)tetrahydropyran-2-ol 25d in anhydrous tetrahydrofuran was added a solution of methylsulfonic acid (0.2 mL, 2.82 mmol) in methanol (20 mL) at −78° C. The mixture was warmed up to room temperature and stirred for 12 hours. The reaction mixture was neutralized with saturated aqueous sodium bicarbonate till pH becomes 6-7 and extracted with ethyl acetate (50 mL×4). The combined organic layers were washed with water (60 mL×2) and saturated aqueous sodium chloride (60 mL×2) in turn, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by re-crystallization from a toluene/n-hexane mixture ((v/v)=1/20, 500 mL) to give the title compound 25e as a white solid (1.28 g, 54.5%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 545.3[M+HCOO]−.
Reaction SMILES: O[CH:2]1[CH2:7][CH2:6][S:5](=[O:9])(=[O:8])[C:4]2[S:10][C:11]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:12][C:3]1=2.S(=O)(=O)(O)O>FC(F)(F)C(O)=O>[S:10]1[C:4]2[S:5](=[O:8])(=[O:9])[CH2:6][CH:7]=[CH:2][C:3]=2[CH:12]=[C:11]1[S:13]([NH2:16])(=[O:14])=[O:15]
Reactant: NS(=O)(=O)c1cc2c(s1)S(=O)(=O)CCC2O
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1cc2c(s1)S(=O)(=O)CC=C2
Temperature: 50 °C
Yield: 87.8 %

Procedure:
A mixture of 5,6-dihydro-4-hydroxy-4H-thieno[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide (0.90 g, 0.0031 m), concentrated sulfuric acid (3 ml), and trifluoroacetic acid (20 ml) was stirred and heated at 50° C. for 20.5 hours. After removal of trifluoroacetic acid under reduced pressure, the residue was dissolved in ethyl acetate (25 ml) and the solution was washed with water, twice with saturated sodium bicarbonate solution, twice more with water and dried over sodium sulfate. The solvent was concentrated in vacuo to yield 0.74 g (90%) of crude product. The product was purified by recrystallization from nitromethane after treatment with decolorizing carbon. An analytical sample melted at 214.5°-216° C. (See Example 26).
Reaction SMILES: [CH3:1][C:2]([CH3:15])=[CH:3][CH2:4][NH:5][C:6]1[N:14]=[CH:13][N:12]=[C:11]2[C:7]=1[NH:8][CH:9]=[N:10]2.[Br:16][CH2:17][CH2:18]Br.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>CS(C)=O>[CH3:1][C:2]([CH3:15])=[CH:3][CH2:4][NH:5][C:6]1[N:14]=[CH:13][N:12]=[C:11]2[C:7]=1[N:8]=[CH:9][N:10]2[CH2:18][CH2:17][Br:16]
Reactant: CC(C)=CCNc1ncnc2nc[nH]c12
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)=CCNc1ncnc2c1ncn2CCBr
Yield: 70 %

Procedure:
Mixture of 6-[(3-methylbut-2-en-1-yl)amino]purine (2 g, 9.8 mmol), 1,2-dibromoethane (12.94 g, 6 ml, 69 mmol) and K2CO3 (2.5 g, 24 mmol) was stirred in 50 ml DMSO for 12 h. Reaction mixture was poured onto drift ice and after ice dissolution 30 ml ethyl acetate was added. Ethyl acetate layer was purified by charcoal and SiO2 and then it was evaporated in vacuo. The pure product was recrystallised from methanol; yellow solid was obtained. Yield: 70%. 1H NMR (DMSO-d6): 1.75 (3H, s), 1.59 (3H, s), 4.12 (2H, t, J=5.76), 4.10 (2H, s (br)), 4.6 (2H, t, J=5.76), 5.3 (1H, t, J=6.57), 8.1 (1H, s (br)), 8.3 (1H, s).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:8]=[C:7]([C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=1.[C:12]1([S:18]([N:21]2[C:29]3[CH:28]=[C:27]([C:30]4[CH:31]=[C:32]5[CH:38]=[N:37][N:36]([S:39]([C:42]6[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=6)(=[O:41])=[O:40])[C:33]5=[N:34][CH:35]=4)[CH:26]=[C:25]([NH2:48])[C:24]=3[CH:23]=[N:22]2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN(C(C)C)C(C)C.O>C(Cl)(Cl)Cl>[Cl:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]([NH:48][C:25]2[CH:26]=[C:27]([C:30]3[CH:31]=[C:32]4[CH:38]=[N:37][N:36]([S:39]([C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=5)(=[O:41])=[O:40])[C:33]4=[N:34][CH:35]=3)[CH:28]=[C:29]3[C:24]=2[CH:23]=[N:22][N:21]3[S:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:20])=[O:19])=[O:10])[CH:6]=[CH:5][CH:4]=1
Reactant: Nc1cc(-c2cnc3c(cnn3S(=O)(=O)c3ccccc3)c2)cc2c1cnn2S(=O)(=O)c1ccccc1
Reactant: O=C(Cl)c1cccc(CCl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(Nc1cc(-c2cnc3c(cnn3S(=O)(=O)c3ccccc3)c2)cc2c1cnn2S(=O)(=O)c1ccccc1)c1cccc(CCl)n1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 6-(hydroxymethyl)-2-pyridinecarboxylic acid (500 mg, 3.27 mmol) in chloroform (10 ml) and N,N-dimethylformamide (DMF) (0.1 ml) was added thionyl chloride (1 ml, 13.70 mmol) and the mixture heated at 65° C. for 1 hr. Solvent was removed in vacuo and the residue was azeotroped with chloroform (5 ml) then dried on a high vacuum line for 30 mins to afford an orange oil (650 mg), presumed to be 6-(chloromethyl)-2-pyridinecarbonyl chloride. To solution of 1-(phenylsulfonyl)-6-[1-(phenylsulfonyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-1H-indazol-4-amine (581 mg, 1.095 mmol) in chloroform (5 ml) at 0° C. was added DIPEA (0.383 ml, 2.190 mmol). 6-(chloromethyl)-2-pyridinecarbonyl chloride (330 mg, 1.737 mmol) in chloroform (5 ml) was added dropwise and the mixture was stirred at 0° C. for 15 min then allowed to warm to room temperature and stirred for another 30 mins. Water (10 ml) was added to quench the reaction and the mixture was extracted with DCM (2×20 ml), separating the layers using a hydrophobic frit. The solvent was removed in vacuo to give a brown solid, which was triturated with ether (5 ml). The resultant cream solid was filtered off and dried in a vacuum oven for 30 mins to afford the title compound (658 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][O:14][C:15](=[O:17])[NH2:16])[O:10][N:9]=2)=[CH:4][CH:3]=1.[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:12]=[C:11]([CH2:13][O:14][C:15](=[O:17])[NH2:16])[O:10][N:9]=3)=[CH:6][CH:7]=2)=[CH:21][CH:20]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: NC(=O)OCc1cc(-c2ccc(N)cc2)no1
Product: NC(=O)OCc1cc(-c2ccc(NCc3ccc(F)cc3)cc2)no1

Procedure:
An experiment was performed using the above-obtained carbamic acid 3-(4-amino-phenyl)-isoxazol-5-ylmethyl ester (150 mg, 0.64 mmol) as a starting material and 4-fluorobenzaldehyde (82 μl, 0.77 mmol) in the same manner as in Example 74.4 to obtain carbamic acid 3-[4-(4-fluoro-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:30][CH2:29][C:28]4[C:23](=[CH:24][CH:25]=[C:26]([O:31]C)[CH:27]=4)[C:22]3=[O:33])=[CH:17][C:16]=2[O:34][CH3:35])[CH2:10][CH2:9]1)=O)(C)(C)C.[OH-].[Na+]>Br>[N:11]1([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:30][CH2:29][C:28]4[C:23](=[CH:24][CH:25]=[C:26]([OH:31])[CH:27]=4)[C:22]3=[O:33])=[CH:17][C:16]=2[O:34][CH3:35])[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1
Reactant: COc1ccc2c(c1)CCN(c1ccc(N3CCCN(C(=O)OC(C)(C)C)CC3)c(OC)c1)C2=O
Agent: Br
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(N2CCc3cc(O)ccc3C2=O)ccc1N1CCCNCC1

Procedure:
A solution of 4-[2-methoxy-4-(6-methoxy-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-phenyl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester in 48% HBr (10 mL) was stirred for 48 h at 80° C. The mixture was neutralized with sodium hydroxide solution, extracted with dichloromethane, dried over magnesium sulfate and concentrated. In this way the product was obtained with molecular weight 367.45 (C21H25N3O3); MS (ESI): 368 (M+H+).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11].[F:16]C1C=C(C=CC=1)CBr.[Mg].C(OCC)(=O)C(OCC)=O>>[F:16][C:7]1[CH:2]=[C:3]([CH2:8][C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:4]=[CH:5][CH:6]=1
Reactant: Fc1cccc(CBr)c1
Reactant: CCOC(=O)C(=O)Cc1ccccc1F
Agent: [Mg]
Solvent: CCOC(=O)C(=O)OCC
Product: CCOC(=O)C(=O)Cc1cccc(F)c1
Yield: 80 %

Procedure:
The title compound was prepared as described for B4 using 3-fluorobenzyl bromide (1.250 g, 8.64 mmol), magnesium (0.231 g, 9.51 mmol) and diethyl oxalate (2.52 g, 17.30 mmol) in the form of colorless oil in 80% yield and used instantly in next step.
Reaction SMILES: [Si:1]([O:8][CH:9]([C:44]1[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=1)[CH2:10][CH2:11][CH:12]([C:30](N1C(C2C=CC=CC=2)COC1=O)=[O:31])[CH:13]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[C:25]#[N:26])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.COC(C)(C)C>C(O)(=O)C>[Si:1]([O:8][CH:9]([C:44]1[CH:45]=[CH:46][C:47]([F:50])=[CH:48][CH:49]=1)[CH2:10][CH2:11][CH:12]1[C:30](=[O:31])[N:14]([C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)[CH:13]1[C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[C:25]#[N:26])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC(CCC(C(=O)N1C(=O)OCC1c1ccccc1)C(Nc1ccc(F)cc1)c1cccc(C#N)c1)c1ccc(F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: [F-]
Solvent: COC(C)(C)C
Solvent: CC(=O)O
Product: CC(C)(C)[Si](C)(C)OC(CCC1C(=O)N(c2ccc(F)cc2)C1c1cccc(C#N)c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
Under argon, a mixture of 13 g of 3-[5-(tert-butyldimethylsilanyloxy)-5-(4-fluorophenyl)-1-(4-fluorophenylamino)-2-(2-oxo-4-phenyloxazolidine-3-carbonyl)pentyl]benzonitrile 12, 50 ml of bistrimethylsilylacetamide, 0.5 g of tetrabutylammonium fluoride and 100 ml of tert-butyl methyl ether is stirred at room temperature for 10 h. After the reaction has ended, 5 ml of acetic acid are added slowly with ice-cooling, and the mixture is concentrated. The residue is separated by silica gel chromatography (ethyl acetate/heptane=1/8). This gives 13:
Reaction SMILES: [Cl:1][C:2]1[C:19]([O:20][CH3:21])=[CH:18][C:5]2[CH:6]([C:11]3[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=3)[CH2:7][NH:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.[CH:22](=O)C1C=CC=CC=1.Cl.[OH-].[Na+]>C(O)=O.O>[Cl:1][C:2]1[C:19]([O:20][CH3:21])=[CH:18][C:5]2[CH:6]([C:11]3[CH:12]=[CH:13][C:14]([Br:17])=[CH:15][CH:16]=3)[CH2:7][N:8]([CH3:22])[CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: COc1cc2c(cc1Cl)CCNCC2c1ccc(Br)cc1
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=CO
Product: COc1cc2c(cc1Cl)CCN(C)CC2c1ccc(Br)cc1
Temperature: 25 °C

Procedure:
To a solution of benzazepine 3 (7.20 g, 19.6 mmol) in formic acid (2.3 g) was added 37% benzaldehyde (1.8 g). The mixture was heated to 90°-100° C. for four hours. After cooling the reaction mixture to room temperature, 4N hydrochloric acid solution (5.16 mL) was added. The mixture was condensed to dryness under reduced pressure. The residue was dissolved in water and then made basic with 25% sodium hydroxide solution. The mixture was extracted three times with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate. The solvent was evaporated to obtain a solid which was purified by column chromatography (silica gel; CH2Cl2 :MeOH:NH4OH;95:5:1) to give 4, 6.0 g (80%): mp 116°-118° C.; FT-IR (KBr)λ1500, 1380, 1270 and 1060 cm-1 ; 1H NMR (CDCl3)δd 7.65-7.35 and 7.21-6.90 (AA'BB',4H, ArH'), 7.13 (S, 1H, ArH #6), 6.38 (S, 1H, ArH #9), 4.40-4.10 (m, 1H, CH), 3.70 (S, 3H, OCH3), 3.10-2.45 (m, 6H, (CH2)3), 2.37 (S, 3H, NCH3). Anal. Calcd for C18H19BrCINO: C,H,N.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][C:10]2=[O:13])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:14][CH:15](O)[CH:16]=[CH2:17].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>COC(OC)(C)C>[CH2:14]([CH:9]1[CH2:8][C:7]2[C:11](=[CH:12][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=2)[C:10]1=[O:13])[CH:15]=[CH:16][CH3:17]
Reactant: C=CC(C)O
Reactant: CC(C)c1ccc2c(c1)C(=O)CC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: COC(C)(C)OC
Product: CC=CCC1Cc2ccc(C(C)C)cc2C1=O
Yield: 38 %

Procedure:
A solution of 11.2 g of 6-isopropyl-1-indanone, 13.3 ml of 3-buten-2-ol and 110 mg of p-toluenesulfonic acid in 110 ml of 2,2-dimethoxy-propane was boiled under reflux for 89 hours on a water separator filled with molecular sieve (0.4 nm, 2 mm pearl shaped). The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/diethyl ether 5:1). In addition to 6.6 g of educt, there were obtained 5.6 g (38%) of (RS)-2-(2-buten-1-yl)-6-isopropyl-1-indanone as a yellow oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([F:10])([F:9])[F:8])=[C:5]([C:11](Cl)=[O:12])[CH:4]=[N:3]1.[CH3:14][CH:15]([CH3:33])[CH2:16][CH2:17][NH:18][C:19]([C:21]1[N:22]=[N:23][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:25][CH:26]=1)=[O:20]>>[CH3:14][CH:15]([CH3:33])[CH2:16][CH2:17][NH:18][C:19]([C:21]1[N:22]=[N:23][C:24]([N:27]2[CH2:32][CH2:31][N:30]([C:11]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[C:6]=3[C:7]([F:10])([F:9])[F:8])=[O:12])[CH2:29][CH2:28]2)=[CH:25][CH:26]=1)=[O:20]
Reactant: Cn1ncc(C(=O)Cl)c1C(F)(F)F
Reactant: CC(C)CCNC(=O)c1ccc(N2CCNCC2)nn1
Product: CC(C)CCNC(=O)c1ccc(N2CCN(C(=O)c3cnn(C)c3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 3, making variations only as required to use 1-methyl-5-trifluoromethyl-1H-pyrazole-4-carbonyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl)amide, the title compound was obtained as a white powder (47% yield). 1H NMR (300 MHz, CDCl3) δ 8.04, 7.82, 7.54, 6.99, 3.97, 3.90-3.54, 3.51-3.44, 1.75-1.62, 1.53-1.46, 0.92. MS (ES+) m/z 454.3 (M+1).