Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].CN1C2CCNCC=2C(C)=N1.[CH3:19][N:20]1[C:35]([CH3:36])=[C:23]2[CH2:24][N:25](C(OC(C)(C)C)=O)[CH2:26][CH2:27][C:22]2=[N:21]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:19][N:20]1[C:35]([CH3:36])=[C:23]2[CH2:24][NH:25][CH2:26][CH2:27][C:22]2=[N:21]1
Reactant: Cc1c2c(nn1C)CCN(C(=O)OC(C)(C)C)C2
Agent: Cc1nn(C)c2c1CNCC2
Solvent: O=C(O)C(F)(F)F
Product: Cc1c2c(nn1C)CCNC2

Procedure:
Prepared in a manner similar to 1,3-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine trifluoroacetic acid salt, except using tert-butyl 2,3-dimethyl-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate instead of tert-butyl 1,3-dimethyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate. LCMS-ESI+: calc'd for C8H13N3: 152.1 (M+H+); Found: 152.0 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[CH:9]=2)[O:4][C:3]=1[C:25](=[O:30])[C:26]([OH:29])([CH3:28])[CH3:27].[C:31](OC(=O)C)(=[O:33])[CH3:32]>C(O)(=O)C>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:7]1[N:6]=[C:5]2[O:4][C:3]([C:25](=[O:30])[C:26]([OH:29])([CH3:27])[CH3:28])=[C:2]([NH:1][C:31](=[O:33])[CH3:32])[C:10]2=[CH:9][C:8]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(O)C(=O)c1oc2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)cc2c1N
Solvent: CC(=O)O
Product: CC(=O)Nc1c(C(=O)C(C)(C)O)oc2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)cc12
Temperature: 85 °C

Procedure:
The product of Example 100 (0.200 g), acetic anhydride (1.25 mL) and acetic acid (0.25 mL) were combined and then heated to 85° C. After 3 h the reaction was concentrated and the residue was dissolved in dichloromethane and washed twice with aqueous sodium bicarbonate. The solution was then concentrated and the residue was purified via flash chromatography on silica gel with gradient elution of 0–60% ethyl acetate in hexanes affording the title compound. HPLC/MS: 483.0 (M+1), 484.8 (M+3); Rt=3.95-min.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][C:18]([F:21])([F:20])[F:19])[CH2:13][CH2:12]3)[N:9]=[CH:10][C:5]2=[C:4]([N:22]2[CH2:28][CH:27]3[O:29][CH:24]([CH2:25][CH2:26]3)[CH2:23]2)[N:3]=1.[NH2:30][C:31]1[CH:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][CH:32]=1>C1(C)C=CC=CC=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].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>[CH:27]12[O:29][CH:24]([CH2:25][CH2:26]1)[CH2:23][N:22]([C:4]1[N:3]=[C:2]([C:34]3[CH:35]=[CH:36][C:31]([NH2:30])=[CH:32][CH:33]=3)[N:7]=[C:6]3[N:8]([CH:11]4[CH2:12][CH2:13][N:14]([CH2:17][C:18]([F:19])([F:20])[F:21])[CH2:15][CH2:16]4)[N:9]=[CH:10][C:5]=13)[CH2:28]2
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: FC(F)(F)CN1CCC(n2ncc3c(N4CC5CCC(C4)O5)nc(Cl)nc32)CC1
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: Cc1ccccc1
Solvent: CCO
Product: Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(CC(F)(F)F)CC4)c3n2)cc1
Temperature: 120 °C

Procedure:
A mixture of 3-(6-chloro-1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (0.55 g, 1.3 mmol), 4-aminophenylboronic acid pinacol ester (0.42 g, 1.9 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.15 g, 10 mol %) in toluene/ethanol (1:1, 10 mL) and 2 M aqueous sodium carbonate solution (2 mL) was heated in a 10-20 mL Smith process vial in the microwave reactor for one hour at 120° C. The cooled mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted three times with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude residue was purified via reverse-phase high performance liquid chromatography using a Phenomenex Prodigy 21 mm×250 mm column, running a gradient elution of 10% acetonitrile/90% of 0.1% aqueous trifluoroacetic acid to 95% acetonitrile over 30 minutes. After the concentration of fractions under reduced pressure, 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)aniline was obtained as a maroon oil that solidified upon standing. MS (ES+): 488.4 (M+H)+
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:9]3[C:14]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[CH:21]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Br:29])[CH:24]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:29][C:25]1[CH:24]=[C:23]([N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]2[C:9]3[C:14]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[CH:21]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:28]=[CH:27][CH:26]=1
Reactant: Brc1cccc(Br)c1
Reactant: c1ccc(Nc2cc3ccccc3c3ccccc23)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Brc1cccc(N(c2ccccc2)c2cc3ccccc3c3ccccc23)c1
Reaction time: 12 h
Yield: 41 %

Procedure:
N-phenylphenanthren-9-amine (4.51 g, 16.74 mmol), 1,3-dibromobenzene (6.05 mL, 50.23 mmol), Pd2(dba)3 (307 mg, 0.355 mmol), tris-o-tolyphosphine (0.255 mL, 0.837 mmol), sodium tert-butoxide (3.2 g, 33.49 mmol) were put in a 250 mL two-neck flask and dissolved in toluene. The solution was refluxed and stirred for 12 hours. After completion of the reaction, the solution was extracted with DI water/methylenechloride and distilled under reduced pressure to remove the solvent. The resultant was columned with a solution of n-hexane and methylenechloride (7:1). The resultant was distilled under reduced pressure and re-crystallized such that the wax compound was obtained, (2.9 g, yield: 41%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:41][C:42]1[CH:43]=[C:44](/[C:49](/[C:57]2[CH:62]=[CH:61][C:60]([CH:63]3[CH2:65][CH2:64]3)=[C:59]([O:66][CH3:67])[N:58]=2)=[CH:50]\[C@@H:51]2[NH:55][C:54](=[O:56])[CH2:53][CH2:52]2)[CH:45]=[CH:46][C:47]=1O>C1(C)C=CC=CC=1.O1CCCC1>[Cl:41][C:42]1[CH:43]=[C:44](/[C:49](/[C:57]2[CH:62]=[CH:61][C:60]([CH:63]3[CH2:64][CH2:65]3)=[C:59]([O:66][CH3:67])[N:58]=2)=[CH:50]\[C@@H:51]2[NH:55][C:54](=[O:56])[CH2:53][CH2:52]2)[CH:45]=[CH:46][C:47]=1[O:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: OC1CCOCC1
Reactant: COc1nc(/C(=C/[C@H]2CCC(=O)N2)c2ccc(O)c(Cl)c2)ccc1C1CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1nc(/C(=C/[C@H]2CCC(=O)N2)c2ccc(OC3CCOCC3)c(Cl)c2)ccc1C1CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Tetrahydro-4-pyranol (127 mg), a 2.2 M solution of diisopropyl azodicarboxylate in toluene (0.655 mL) and triphenylphosphine (326 mg) were added to a solution of (5R)-5-[(E)-2-(3-chloro-4-hydroxyphenyl)-2-(5-cyclopropyl-6-methoxypyridin-2-yl)ethenyl]pyrrolidin-2-one (160 mg) in tetrahydrofuran (3 mL), and the mixture was stirred at room temperature for four hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1→0:1) to give (5R)-5-[(E)-2-[3-chloro-4-(tetrahydro-2H-pyran-4-yloxy)phenyl]-2-(5-cyclopropyl-6-methoxypyridin-2-yl)ethenyl]pyrrolidin-2-one as a colorless amorphous (120 mg, 61%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:13][CH:12]3[C:14](=O)[CH:9]([CH2:10][CH2:11]3)[CH2:8][C:7]=2[CH:16]=1.Cl.[NH2:18][OH:19]>C(O)C.N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:13][CH:12]3[C:14](=[N:18][OH:19])[CH:9]([CH2:10][CH2:11]3)[CH2:8][C:7]=2[CH:16]=1
Reactant: NO
Reactant: COc1ccc2c(c1)CC1CCC(C2)C1=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: COc1ccc2c(c1)CC1CCC(C2)C1=NO
Yield: 86.9 %

Procedure:
2-Methoxy-11-oxo-5,6,7,8,9,10-hexahydro-6,9-methanobenzocyclooctene (20.0 g; 0.1 mole) is reacted with hydroxylamine hydrochloride (20.0 g; 0.29 mole) in ethanol (100 ml) and pyridine (100 ml) to yield 20.1 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:9][CH2:10][C:11]([NH:14][C:15]1[CH:16]=[C:17]([CH:28]=[CH:29][C:30]=1[N+:31]([O-])=O)[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C>CO.[Zn]>[NH2:31][C:30]1[CH:29]=[CH:28][C:17]([C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])=[CH:16][C:15]=1[NH:14][C:11]([CH3:13])([CH2:10][CH2:9][N:8]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH3:12]
Reactant: CC(C)(CCN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)Nc1cc(C(=O)OCc2ccccc2)ccc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(CCN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)Nc1cc(C(=O)OCc2ccccc2)ccc1N
Reaction time: 0.33 h
Yield: 94.8 %

Procedure:
To a stirred suspension of benzyl 3-({4-[bis(tert-butoxycarbonyl)amino]-2-methylbutan-2-yl}amino)-4-nitrobenzoate (280 mg, 0.50 mmol) and zinc dust (344 mg, 5.27 mmol) in methanol (9 mL) is added acetic acid (0.34 mL), dropwise. The mixture is stirred for 20 min, methanol (50 mL) is added and the mixture is filtered through Celite. The filtrate is concentrated and partitioned between EtOAc and H2O, adjusting the pH to 5 by adding 1M HCl. The organic layer is washed with NaHCO3 and H2O, dried (MgSO4) and evaporated to afford the title compound (250 mg, 94%) which is used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][CH2:17][CH2:18]Br)=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH3:5].[CH2:21]([C:23]1[N:24]=[C:25]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([O:35][CH3:36])[CH:29]=2)[O:26][CH:27]=1)[CH3:22].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:20])[CH:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][CH2:17][CH2:18][O:34][C:31]3[CH:32]=[CH:33][C:28]([C:25]4[O:26][CH:27]=[C:23]([CH2:21][CH3:22])[N:24]=4)=[CH:29][C:30]=3[O:35][CH3:36])=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH3:5]
Reactant: COC(=O)C(C)n1ccc2cc(OCCCBr)ccc21
Reactant: CCc1coc(-c2ccc(O)c(OC)c2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1coc(-c2ccc(OCCCOc3ccc4c(ccn4C(C)C(=O)OC)c3)c(OC)c2)n1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
2-[5-(3-Bromo-propoxy)-indol-1-yl]-propionic acid methyl ester (Example 48, 170.20 mg, 0.50 mmol) and 4-(4-ethyl-oxazol-2-yl)-2-methoxy-phenol (Example 39, 109.68 mg, 0.50 mmol) were dissolved in DMF (2 mL) at rt. Cesium carbonate (244.5 mg, 0.75 mmol) was added to the solution, followed by three drops of water. The mixture was stirred at rt for 17 h. The crude reaction mixture was filtered and purified by HPLC. The desired product was isolated as a white solid (143.8 mg, 60.1%). LC/MS m/z 479.3 (M+H)+; RT 3.59 min. 1H NMR (400 MHz, CD2Cl2) δ 7.58 (d, 1H), 7.56 (s, 1H), 7.41 (m, 1H), 7.24 (d, 1H), 7.19 (d, 1H), 7.11 (d, 1H), 7.00 (d, 1H), 6.88 (dd, 1H), 6.46 (d, 1H), 5.11 (q, 1H), 4.28 (t, 2H), 4.22 (t, 2H), 3.93 (s, 3H), 3.71 (s, 3H), 2.61 (q, 2H), 2.34 (m, 2H), 1.82 (d, 3H), 1.29 (t, 3H).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:14][C:15](=[O:17])[CH3:16])[CH:13]=1)[C:8](O)=[O:9])(=[O:3])[CH3:2].O=S(Cl)[Cl:20]>>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:14][C:15](=[O:17])[CH3:16])[CH:13]=1)[C:8]([Cl:20])=[O:9])(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)Oc1cc(OC(C)=O)cc(C(=O)O)c1
Product: CC(=O)Oc1cc(OC(C)=O)cc(C(=O)Cl)c1
Temperature: 80 °C

Procedure:
3,5-Dihydroxybenzoic acid (7.2 g, 50 mM) was dissolved in 11 ml of acetic anhydride. To the resulting solution were added 5 drops of sulfuric acid, followed by stirring at room temperature for 20 minutes. Subsequently, 10 g of ice was added and 12 ml of 1N hydrochloric acid was then added. After sonication, a precipitated crystal was recovered by filtration. Washing the crystal with toluene gave 3,5-diacetoxybenzoic acid (10.23 g). The obtained 3,5-diacetoxybenzoic acid (2.38 g, 10 mM) was dissolved in 5 ml of SOCl2 and the solution was heated under reflux at 80° C. for 1 hour. The solvent SOCl2 was distilled off under reduced pressure to yield 3,5-diacetoxybenzoyl chloride (2.44 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11](=[O:28])[NH:10]2)=[C:5]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:4]=1)#[N:2].[H-].[Na+].[F:35][C:36]([F:49])([F:48])[O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[S:44](Cl)(=[O:46])=[O:45]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11](=[O:28])[N:10]2[S:44]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[O:37][C:36]([F:35])([F:48])[F:49])(=[O:46])=[O:45])=[C:5]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:4]=1)#[N:2]
Reactant: O=S(=O)(Cl)c1ccccc1OC(F)(F)F
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)NC(=O)N1c1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(S(=O)(=O)c2ccccc2OC(F)(F)F)C(=O)N1c1cccc(C(F)(F)F)c1
Yield: 77.4 %

Procedure:
Analogously to the preparation of Example 27, (4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (100 mg, 217 μmol; Example 6), sodium hydride (60%, 11.2 mg, 282 μmol) and [2-(trifluoromethoxy)phenyl]sulfonyl chloride (73.6 mg, 282 μmol) were reacted with one another for 16 h. This gave the title compound as a colorless solid (115 mg, 77% of theory).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10](C)=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C@H:24]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35](F)=[CH:34][CH:33]=2)[C:25]([O:27][CH2:28]C)=[O:26])=[CH:19][CH:18]=1.[Cl:39]C1C=CC=CC=1C=O>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C@H:24]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[Cl:39])[C:25]([O:27][CH3:28])=[O:26])=[CH:19][CH:18]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCc2nc(-c3ccc(C)cc3)oc2C)cc1)NCc1ccc(F)cc1
Reactant: O=Cc1ccccc1Cl
Product: COC(=O)[C@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)NCc1ccccc1Cl

Procedure:
In the same manner as in Example 7, 466.5 mg of the title compound was obtained as colorless oil from 609.3 mg of Referential Compound 3 and 230 μL of 2-chlorobenzaldehyde.
Reaction SMILES: [CH2:1]([C:5]12[CH2:11][C:9]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=3)([CH2:10]1)[C:8](=[O:21])[N:7]([CH2:22][CH2:23][CH3:24])[C:6]2=[O:25])[CH:2]([CH3:4])[CH3:3].CCCCCC.CCOCC>C(OCC)(=O)C.[Pd]>[NH2:18][C:15]1[CH:14]=[CH:13][C:12]([C:9]23[CH2:11][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])([CH2:10]2)[C:6](=[O:25])[N:7]([CH2:22][CH2:23][CH3:24])[C:8]3=[O:21])=[CH:17][CH:16]=1
Reactant: CCCN1C(=O)C2(CC(C)C)CC(c3ccc([N+](=O)[O-])cc3)(C2)C1=O
Agent: [Pd]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCCN1C(=O)C2(CC(C)C)CC(c3ccc(N)cc3)(C2)C1=O

Procedure:
In a manner analogous to that described in Example 12a, 5.2 g of 5-isobutyl-1-(4-nitrophenyl)-3-n-propyl-3-azabicyclo[3.1.1]heptane-2,4-dione in 100 ml of ethyl acetate are hydrogenated in the presence of 0.5 g of 5% palladium-on-carbon and worked up. Melting point 86.5°-87° (from n-hexane/ether).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[N:10]=[C:9]([CH2:11][N:12]2[C:17]3[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[S:20][C:16]=3[C:15](=[O:27])[N:14]([CH:28]3[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]3)[C:13]2=[O:41])[O:8][N:7]=1.C(OCC)C.[ClH:47]>O1CCOCC1>[ClH:47].[CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[N:10]=[C:9]([CH2:11][N:12]2[C:17]3[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[S:20][C:16]=3[C:15](=[O:27])[N:14]([CH:28]3[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]3)[C:13]2=[O:41])[O:8][N:7]=1
Reactant: COCCCc1noc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: COCCCc1noc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Tert-butyl 4-[1-{[3-(3-methoxypropyl)-1,2,4-oxadiazol-5-yl]methyl}-2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl]piperidine-1-carboxylate (780 mg, compound B68) is dissolved in a solution of hydrogen chloride in 1,4-dioxane (20 ml, 6.8 M). The reaction mixture is stirred for 30 min at RT. Then diethyl ether is added and the resulting precipitate is filtered off, washed with diethyl ether and dried in vacuo to afford the title compound as a solid.
Reaction SMILES: [C:1]([NH:9][C:10]([C:37]([O:39][CH3:40])=[O:38])=[CH:11][C:12]1[N:13]=[C:14]([F:36])[N:15]([C:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na]>CCOC(C)=O.[Pt]=O>[C:1]([NH:9][CH:10]([C:37]([O:39][CH3:40])=[O:38])[CH2:11][C:12]1[N:13]=[C:14]([F:36])[N:15]([C:17]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1)NC(=O)c1ccccc1
Agent: O=[Pt]
Agent: [Na]
Solvent: CCOC(C)=O
Product: COC(=O)C(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1)NC(=O)c1ccccc1
Reaction time: 72 h

Procedure:
4-(2-Benzoylamino-2-methoxycarbonylvinyl)-2-fluoro-1-triphenylmethylimidazole was hydrogenated in EtOAc using a prehydrogenated sodium--containing platinum oxide catalyst (Adams' catalyst), for 3 days. Removal of catalyst and evaporation gave 4-(2-benzoylamino-2-methoxycarbonylethyl)-2-fluoro-1-triphenylmethylimidazole, having the following n.m.r. in CDCl3 : 3.0 (d, 2H); 3.65 (s, 3H); 4.92 and 5.0 (d of t, 1H); 6.3 (s, 1H); 7.0-7.5 (m, 19H); 7.65-8.0 (m, 2H).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1([CH2:14][NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([CH3:26])[CH:24]=3)[N:19]=[C:18]([N:27]3[CH2:33][C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[S:30](=[O:39])(=[O:38])[CH2:29][CH2:28]3)[CH:17]=2)[CH2:13]C[O:11][CH2:10]1)C1C=CC=CC=1.N[CH2:48]C1(N(CC2C=CC=CC=2)CC2C=CC=CC=2)COC1>>[NH2:8][C:9]1([CH2:14][NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([CH3:26])[CH:24]=3)[N:19]=[C:18]([N:27]3[CH:33]([CH3:48])[C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[S:30](=[O:38])(=[O:39])[CH2:29][CH2:28]3)[CH:17]=2)[CH2:13][O:11][CH2:10]1
Reactant: NCC1(N(Cc2ccccc2)Cc2ccccc2)COC1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC3(N(Cc4ccccc4)Cc4ccccc4)CCOC3)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3C)cc(NCC3(N)COC3)c2c1

Procedure:
The title compound was prepared in analogy to Example 2-1 in Scheme 4 by using 4-(4-chloro-6-methylquinolin-2-yl)-5-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 5-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine and 2,4-dichloro-6-methylquinoline) and 3-(aminomethyl)-N,N-dibenzyloxetan-3-amine. MS obsd. (ESI+) [(M+H)+] 453, 1H NMR (400 MHz, CD3OD) δ ppm 8.03 (dd, J=7.96, 1.39 Hz, 1 H), 7.90 (d, J=6.57 Hz, 1 H), 7.71-7.64 (m, 2 H), 7.46 (ddd, J=8.15, 6.63, 1.64 Hz, 2 H), 7.33 (dd, J=8.59, 1.77 Hz, 1 H), 6.15 (s, 1 H), 5.86 (d, J=6.82 Hz, 1 H), 4.64-4.53 (m, 4 H), 4.40-4.25 (brs, 2 H), 3.70 (d, J=8.59 Hz, 1 H), 3.62-3.58 (m, 2 H), 3.57-3.49 (m, 1 H), 2.43 (s, 3 H), 2.00 (d, J=7.07 Hz, 3 H).
Reaction SMILES: C([O:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]=[C:23]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([N:31]5[CH:35]=[CH:34][N:33]=[CH:32]5)[CH:26]=4)[CH2:22][C:21](=[O:36])[NH:20][C:19]=3[CH:37]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>[Ni]>[N:31]1([C:27]2[CH:26]=[C:25]([C:23]3[CH2:22][C:21](=[O:36])[NH:20][C:19]4[CH:37]=[C:15]([C:12]5[CH:11]=[CH:10][C:9](=[O:8])[NH:14][CH:13]=5)[CH:16]=[CH:17][C:18]=4[N:24]=3)[CH:30]=[CH:29][CH:28]=2)[CH:35]=[CH:34][N:33]=[CH:32]1
Reactant: O=C1CC(c2cccc(-n3ccnc3)c2)=Nc2ccc(-c3ccc(OCc4ccccc4)nc3)cc2N1
Agent: [Ni]
Product: O=C1CC(c2cccc(-n3ccnc3)c2)=Nc2ccc(-c3ccc(=O)[nH]c3)cc2N1

Procedure:
Prepared from 8-(6-benzyloxy-pyridin-3-yl)-4-(3-imidazol-1-yl-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 74) by catalytic hydrogenation with Raney-Ni according to the general procedure G (method a). Obtained as a light yellow solid (17 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:14])=[C:4]([C:9]([Br:13])=[C:10]([F:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[N:15]([O-])=O.[Na+]>C(O)(=O)C.O>[Br:13][C:9]1[C:10]([F:12])=[CH:11][C:2]2[NH:1][N:15]=[CH:14][C:3]=2[C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1c(C)c(N)cc(F)c1Br
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1c(Br)c(F)cc2[nH]ncc12
Reaction time: 1.5 h
Yield: 50.4 %

Procedure:
To a solution of methyl 3-amino-6-bromo-5-fluoro-2-methylbenzoate (1.33 g, 5.09 mmol) in acetic acid (25 mL) heated to 50° C. was added a solution of sodium nitrite (369 mg, 5.34 mmol) in water (1 mL), and the mixture was stirred for 1.5 hr and concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=5/95→40/60) to give the title compound (700 mg, yield 52%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:9](=[CH:15]\[CH3:16])/[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].C(O)C.[CH3:20][NH:21][CH3:22]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:15]([N:21]([CH3:22])[CH3:20])[CH3:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CNC
Reactant: C/C=C(/C(=O)OCC)c1ccc(Cl)c(Cl)c1
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(c1ccc(Cl)c(Cl)c1)C(C)N(C)C
Temperature: 50 °C
Reaction time: 10 h

Procedure:
In a Parr bomb containing 45 g. of ethyl 2-(3,4-dichlorophenyl)crotonate in 250 ml. of ethanol add 100 ml. of aqueous 33 percent (w/v) dimethylamine and 0.8 ml. of acetic acid. The mixture is maintained with stirring at 50° C for 10 hours, then the solvent is evaporated in vacuo and the residue, after suspension in water, is extracted several times with ether. After evaporation of the dried organic layer, 60 g. of the title compound is obtained which boils at 124° C/0.2 mm Hg. The product is an approximately 50:50 mixture of the two stereoisomers
Reaction SMILES: [C:1]([CH:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([OH:13])[C:7]=2[CH2:6][CH:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:4]1)#[N:2].C1C=C[NH+]=CC=1.[Br:26][Br-]Br>C(O)(=O)C>[Br:26][C:9]1[C:8]2[C@H:3]([C:1]#[N:2])[O:4][C@@H:5]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:6][C:7]=2[C:12]([OH:13])=[CH:11][CH:10]=1
Reactant: N#CC1OC(c2ccccc2)Cc2c(O)cccc21
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Product: N#C[C@@H]1O[C@@H](c2ccccc2)Cc2c(O)ccc(Br)c21
Yield: 28 %

Procedure:
A solution of 0.94 g (3.8 mmol) of 1-cyano-3,4-dihydro-5-hydroxy-3-phenyl-1H-2-benzopyran, the product of Step 3 of Example 89 in 10 mL of glacial acetic acid was treated with a solution of 1.2 g (3.8 mmol) of pyridine hydrobromide perbromide in 50 mL of glacial acetic acid and the resultant mixture was stirred for 48 h at ambient temperature. The precipitate was filtered to afford 351 mg (28% yield) of the title compound. An additional 229 mg (18% yield) of the desired product precipitated from the filtrate after concentration in vacuo, to give a total of 580 mg (46% yield) of [1R,3R] 8-bromo-1-cyano-3,4-dihydro-5-hydroxy-3-phenyl-1H-2-benzopyran.