Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@:10]1([CH2:42][CH2:43][OH:44])[O:40][CH3:41])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[S:51](Cl)([C:54]1[CH:60]=[CH:59][C:57]([CH3:58])=[CH:56][CH:55]=1)(=[O:53])=[O:52]>C(Cl)Cl>[CH3:58][C:57]1[CH:59]=[CH:60][C:54]([S:51]([O:44][CH2:43][CH2:42][C@@:10]2([O:40][CH3:41])[C@H:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C@@H:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@H:13]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[O:11]2)(=[O:53])=[O:52])=[CH:55][CH:56]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CO[C@@]1(CCO)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CO[C@@]1(CCOS(=O)(=O)c2ccc(C)cc2)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 50 °C
Yield: 54.7 %

Procedure:
2-((2S,3R,4S,5R,6R)-3,4,5-Tris(benzyloxy)-6-(benzyloxymethyl)-2-methoxytetrahydro-2H-pyran-2-yl)ethanol (8) (0.46 g, 0.77 mmol) was dissolved in CH2Cl2 (2 mL). Pyridine (0.31 mL, 3.85 mmol) and TsCl (0.29 g, 1.54 mmol) were added and the reaction mixture was heated at 50° C. for 18 h. Additional TsCl (0.05 g, 0.26 mmol) was then added and the reaction mixture was heated at 50° C. for another 4 hours. The mixture was concentrated onto celite and chromatographed over SiO2, (ISCO system, 0-40% EtOAc/hexanes) to provide an oil (0.317 g, 55%). 1H NMR (300 MHz, CDCl3) δ ppm: 7.66 (d, J=8.4 Hz, 2H), 7.14-7.32 (m, 22H), 4.77-4.89 (m, 4H), 4.46-4.57 (m, 4H), 3.86-4.07 (m, 1H), 3.48-3.64 (m, 4H), 3.31 (d, J=9.3 Hz, 1H), 3.17 (s, 3H), 2.36 (s, 3H), 2.13 (t, J=8.1 Hz, 1H). LC/MS tR=3.37 min, calcd for C44H48O9S: 752.3, found 775.2 (M+Na)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:14])[CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:5][N:4]=1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH3:22][S:23]([O:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:14])[CH2:10][CH:11]([CH3:12])[CH3:13])=[CH:5][N:4]=1)(=[O:25])=[O:24]
Reactant: CC(C)CC(=O)c1ccc(CO)nc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CC(=O)c1ccc(COS(C)(=O)=O)nc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
Dissolve 2-hydroxymethyl-5-(3-methyl-butyryl)-pyridine (190 mg, 0.98 mmol) in dichloromethane (10 mL). Cool to 0° C. and add triethylamine (0.151 mL, 1.08 mmol) and methanesulfonyl chloride (0.083 mL, 1.08 mmol). Allow the mixture to warm to room temperature and stir for 2 h. Dilute the reaction mixture with dichloromethane and wash with saturated aqueous NaHCO3. Dry the organic phase over Na2SO4, filter and concentrate in vacuo to provide the title compound as oil (263 mg, 98%).
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][C:5]([C:6](OC)=[O:7])=[CH:4][CH:3]=1.COC(=O)CC1C=CC([NH2:22])=CC=1>>[C:6]([NH2:22])(=[O:7])[C:5]1[CH:10]=[CH:11][CH:2]=[CH:3][CH:4]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: COC(=O)Cc1ccc(N)cc1
Product: NC(=O)c1ccccc1

Procedure:
Reacting 3,4-dialkoxy benzoic acid with methyl 4-aminobenzoate or 4-aminophenyl acetic acid methylester to produce a benzamide compound;
Reaction SMILES: C(OC([NH:8][C:9]1[CH2:10][C:11]([C:31](=[O:40])[N:32]([CH2:36][CH2:37][CH2:38][F:39])[CH2:33][CH2:34][CH3:35])=[CH:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=3)=[CH:16][C:14]=2[N:15]=1)=O)(C)(C)C>ClCCl.C(O)(C(F)(F)F)=O>[NH2:8][C:9]1[CH2:10][C:11]([C:31](=[O:40])[N:32]([CH2:36][CH2:37][CH2:38][F:39])[CH2:33][CH2:34][CH3:35])=[CH:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=3)=[CH:16][C:14]=2[N:15]=1
Reactant: CCCN(CCCF)C(=O)C1=Cc2ccc(-c3ccc(C(=O)OCC)cc3)cc2N=C(NC(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCN(CCCF)C(=O)C1=Cc2ccc(-c3ccc(C(=O)OCC)cc3)cc2N=C(N)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 36 %

Procedure:
The crude product from Step E was then taken up in 2 mls of dichloromethane and 1 ml of TFA, and stirred at room temperature for one hour. The mixture was concentrated under reduced pressure and the resulting crude product was taken up in DCM (10 mls) and concentrated ammonium hydroxide (5 mls) and stirred at room temperature for 15 minutes, then extracted with dichloromethane. The extracts were dried over sodium sulfate and concentrated under reduced pressure. Preparative thin layer chromatography (2×0.5 mm plates, 7% MeOH/DCM/0.5% NH4OH) afforded 17 mgs (36%) of ethyl 4-((1E,4E)-2-amino-4-((3-fluoropropyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)benzoate. 1H NMR (400 MHz, CDCl3) δ 8.09-8.14 (m, 2H), 7.70-7.74 (m, 2H), 7.52-7.55 (m, 1H), 7.32-7.41 (m, 2H), 6.87 (m, 1H), 5.11 (br s, 1H), 4.57-4.63 (m, 1H), 4.46-4.52 (m, 1H), 4.37-4.45 (m, 2H), 3.57-3.73 (m, 2H), 3.42-3.55 (m, 2H), 2.82 (s, 2H), 1.99-2.15 (m, 2H), 1.62-1.76 (m, 2H), 1.38-1.45 (m, 3H), 0.89-0.98 (m, 3H); m/z (APCI-pos) M+1=452.2.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][CH:3]=1.[OH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1>>[I:8][C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]2=[O:9])=[CH:3][CH:4]=1
Reactant: Ic1ccc(I)cc1
Reactant: Oc1ccccn1
Product: O=c1ccccn1-c1ccc(I)cc1

Procedure:
74.1 Using the method described in example 73.1, 1,4-diiodobenzene was reacted with 2-hydroxypyridine to give 1-(4-iodo-phenyl)-1H-pyridin-2-one. Pale yellow solid. MS: 298.1 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH2:9][C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH:9]([C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:7])=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)CNC(=O)c1ccc(F)cc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC(NC(=O)c1ccc(F)cc1)C(=O)C(C)C
Yield: 90.2 %

Procedure:
5.6 g of N-(4-fluorobenzoyl)isobutyrylmethylamine, 1.2 g of 61% sodium hydride and 4.61 g of ethyl bromoacetate are treated in the same manner as described in Preparation 1-(5). 7.0 g of ethyl 3-(4-fluorobenzoylamino)-3-isobutyrylpropionate are thereby obtained as oil. Yield: 90.0%
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([NH:8][CH3:9])[CH:7]=1.[NH2:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([OH:21])=[CH:16][C:15]=1[CH3:22].CC(C)([O-])C.[K+].O>CN(C)C(=O)C.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>[NH2:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([O:21][C:2]2[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([NH:8][CH3:9])[CH:7]=2)=[CH:16][C:15]=1[CH3:22]
Reactant: CNc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Cc1cc(O)cc(C)c1N
Agent: CC(C)(C)[O-]
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CNc1cc(Oc2cc(C)c(N)c(C)c2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 93 %

Procedure:
To a solution of N-(5-chloro-2-nitrophenyl)-N-methylamine (8.00 g) in N,N-dimethylacetamide (112 ml) was added 2,6-di-t-butyl-4-methylphenol (0.24 g). Furthermore, to the resulting mixture were added 4-amino-3,5-dimethylphenol (6.47 g) and potassium t-butoxide (5.29 g) with stirring, and the resulting mixture was stirred at 60° C. for 30 minutes. After stirring, water (4 ml) was added to the reaction mixture, and furthermore water (120 ml) was added dropwise over a 2-hour interval, and then the resulting mixture was cooled gradually to room temperature. The crystalline solid precipitated was collected by filtration, washed with water (80 ml) and dried in vacuo to afford the title compound (11.45 g, yield: 93%) as a yellow crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[C:9]([OH:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Na].C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[Cl:1][C:2]1[C:9]([O:10][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COc1ccc(C=O)c(Cl)c1O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na]
Solvent: O
Solvent: CCO
Product: COc1ccc(C=O)c(Cl)c1OCc1ccccc1

Procedure:
A mixture of 78 g of 2-chloro-3-hydroxy-4-methoxybenzaldehyde, 60.7 g of benzyl chloride, 3.9 g of sodium jodide, 74.6 g of potassium carbonate in 0.5 l of 95% ethanol was refluxed for 2 hours. After cooling the mixture was poured in water, the separated product was filtered and then recrystallized from absolute ethanol. 2-chloro-3-benzyloxy-4-methoxybenzaldehyde was obtained, m.p. 86°-88° C.
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]([C:5]([O:7][C@@H:8]1[C@@H:13]2[C@@H:14]([CH2:19][CH2:20][C@H:21]3[O:27][C:25](=[O:26])[CH2:24][C@H:23]([OH:28])[CH2:22]3)[C@@H:15]([CH3:18])[CH:16]=[CH:17][C:12]2=[CH:11][C@H:10]([CH3:29])[CH2:9]1)=[O:6])[CH3:4].[CH2:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1.COC(C)(C)C>[CH2:30]([NH:37][C:25]([CH2:24][CH:23]([OH:28])[CH2:22][CH:21]([OH:27])[CH2:20][CH2:19][CH:14]1[CH:13]2[C:12](=[CH:11][CH:10]([CH3:29])[CH2:9][CH:8]2[O:7][C:5](=[O:6])[CH:3]([CH3:4])[CH2:2][CH3:1])[CH:17]=[CH:16][CH:15]1[CH3:18])=[O:26])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: NCc1ccccc1
Reactant: CC[C@H](C)C(=O)O[C@H]1C[C@@H](C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: CCC(C)C(=O)OC1CC(C)C=C2C=CC(C)C(CCC(O)CC(O)CC(=O)NCc3ccccc3)C21
Temperature: 25 °C

Procedure:
To a solution of 0.13 g (0.32 mmol) of mevinolin in 15 ml of THF are added 0.5 ml (5 mmol) benzylamine. The stirred reaction mixture is heated at reflux for 7 hours. After cooling to room temperature the reaction is diluted with 20 ml of methyl-t-butyl ether and washed successively with 0.1 N HCl and brine. The organic phase is then dried over sodium sulfate and the solvent evaporated. The crude product is purified by silica gel chromatography (ethyl acetate) to afford the desired product as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:24])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]=[CH:20][N:21]([CH3:23])[CH:22]=3)[S:17][C:10]=12.FC1C=C(NC(NC(=O)CC2C=CC=CC=2)=S)C=CC=1OC1C=CN=C2C=C(C3C=CC(S(C)(=O)=O)=CC=3)SC=12.[CH3:65][O:66][C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][C:68]=1[CH2:73][C:74]([N:76]=[C:77]=[S:78])=[O:75]>>[F:1][C:2]1[CH:3]=[C:4]([NH:24][C:77]([NH:76][C:74](=[O:75])[CH2:73][C:68]2[CH:69]=[CH:70][CH:71]=[CH:72][C:67]=2[O:66][CH3:65])=[S:78])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]=[CH:20][N:21]([CH3:23])[CH:22]=3)[S:17][C:10]=12
Reactant: Cn1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1
Reactant: COc1ccccc1CC(=O)N=C=S
Agent: CS(=O)(=O)c1ccc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4F)c3s2)cc1
Product: COc1ccccc1CC(=O)NC(=S)Nc1ccc(Oc2ccnc3cc(-c4cn(C)cn4)sc23)c(F)c1
Yield: 52 %

Procedure:
Starting from the amine 177, following the procedure described above for the synthesis of compound 50 (scheme 10, example 55) but replacing 2-phenylacetyl isothiocyanate with 2-(2-methoxyphenyl)acetyl isothiocyanate, title compound 179 was obtained in 52% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm: 12.58 (s, 1H), 11.75 (s, 1H), 8.46 (d, 1H, J=5.5 Hz), 8.72 (dd, 1H, J=12.3/2.2 Hz), 7.86 (d, 1H, J=1.2 Hz), 7.72 (d, 1H, J=0.8 Hz), 7.70 (s, 1H), 7.57-7.49 (m, 2H), 7.30-7.23 (m, 2H), 7.00 (d, 1H, J=7.8 Hz), 6.92 dt, 1H, J=7.3/0.9 Hz), 6.58 (d, 1H, J=5.1 Hz), 3.82 (s, 2H), 3.79 (s, 3H), 3.72 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:26][CH2:25][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[CH:14]([CH3:23])[NH:13][C:12]2=[O:24])[CH2:10][CH2:9]1)=[O:7].Cl[CH2:37][CH2:38][N:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>>[F:35][C:2]([F:1])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[CH:14]([CH3:23])[N:13]([CH2:37][CH2:38][N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)[C:12]2=[O:24])[CH2:25][CH2:26]1)=[O:7]
Reactant: Cc1ccccc1N1C(C)NC(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2
Reactant: ClCCN1CCOCC1
Product: Cc1ccccc1N1C(C)N(CCN2CCOCC2)C(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2

Procedure:
The title compound, MS: m/e=613.2 (M+H+), was prepared in accordance with the general method of example 99 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2-methyl-1-o-tolyl-1,3,8-triaza-spiro[4.5]decan-4-one and 4-(chloroethyl)morpholine.
Reaction SMILES: [C:1]([NH:5][C:6]1[C:11]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]4[CH2:25][CH2:24]4)=[C:19]([F:26])[C:18]=3[F:27])[N:15]=[N:14][N:13]=2)=[CH:10][CH:9]=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].[Br:28]N1C(=O)CCC1=O>C(#N)C>[C:1]([NH:5][C:6]1[C:11]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]4[CH2:25][CH2:24]4)=[C:19]([F:26])[C:18]=3[F:27])[N:15]=[N:14][N:13]=2)=[CH:10][C:9]([Br:28])=[CH:8][N:7]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)Nc1ncccc1-c1nnnn1-c1ccc(C2CC2)c(F)c1F
Solvent: CC#N
Product: CC(C)(C)Nc1ncc(Br)cc1-c1nnnn1-c1ccc(C2CC2)c(F)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15.3 %

Procedure:
Compound 1084 (200 mg, 0.54 mmol) was dissolved in 10 mL of acetonitrile. N-Bromosuccinimide (96 mg, 0.54 mmol) was added to the solution and the reaction mixture was stirred at room temperature for 30 minutes. The reaction was quenched with 1 M Na2S2O3 and the mixture extracted with ethyl acetate. The organice layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a white solid that was purified by silica gel chromatography to afford 37 mg of N-tert-butyl-5-bromo-3-(1-(4-cyclopropyl-2,3-difluorophenyl)-1H-tetrazol-5-yl)pyridin-2-amine (Compound 1085); MS (M+1)=449.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@H:23]2[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]2[OH:29])[C:12]3=[O:30])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:37][N:38]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[N:39]1>C1COCC1.C(OCC)(=O)C.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[OH:29][C@@H:24]1[C@@H:23]([N:13]2[C:12](=[O:30])[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]4=[C:9]([CH2:8][C:5]4[CH:6]=[N:7][C:2]([C:41]5[CH:40]=[N:39][N:38]([CH3:37])[CH:42]=5)=[CH:3][CH:4]=4)[CH:10]=3)[N:15]=[CH:14]2)[CH2:28][CH2:27][O:26][CH2:25]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=c1c2cc(Cc3ccc(Cl)nc3)c3ccccc3c2ncn1[C@H]1CCOC[C@@H]1O
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1cc(-c2ccc(Cc3cc4c(=O)n([C@H]5CCOC[C@@H]5O)cnc4c4ccccc34)cn2)cn1
Temperature: 85 °C
Reaction time: 24 h

Procedure:
To a solution of 6-[(6-chloropyridin-3-yl)methyl]-3-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]benzo[h]quinazolin-4(3H)-one (Example 1, 0.040 g, 0.095 mmol) in 1 mL of THF under an atmosphere of nitrogen was added cesium carbonate (0.19 mL, 1 N aqueous, 0.19 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.040 g, 0.19 mmol), and bis(tri-tert-butylphosphine)palladium(0) (10 mol %). The reaction was heated at 85° C. for 20 h, and additional 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.040 g, 0.19 mmol), and bis(tri-tert-butylphosphine)palladium(0) (10 mol %) were added. After 24 h, the reaction was cooled to rt, diluted with ethyl acetate, and washed with saturated aqueous sodium bicarbonate and brine. The solution was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-5% methanol in dichloromethane, to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 467.53 for [M+H]+: 1H NMR (400 MHz, CD3OD) δ 8.87 (d, J=7.9 Hz, 1H), 8.35 (s, 1H), 8.23 (s, 1H), 7.80-7.78 (m, 2H), 7.72 (s, 2H), 7.66-7.55 (m, 2H), 7.22-7.19 (m, 1H), 7.08 (d, J=8.2 Hz, 1H), 4.80-4.73 (m, 1H), 4.28-4.15 (m, 1H), 4.08-4.04 (m, 1H), 3.85 (s, 3H), 3.61-3.51 (m, 1H), 3.34-3.29 (m, 1H), 2.28-2.18 (m, 1H), 1.99-1.95 (m, 1H).
Reaction SMILES: [O:1]=[C:2]([C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16][CH2:15]2)[CH:3]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)[CH2:4][CH3:5].Br[C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].O>CCOCCO.[Cu]>[O:1]=[C:2]([C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16][CH2:15]2)[CH:3]([N:6]1[CH2:11][CH2:10][N:9]([C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)[CH2:8][CH2:7]1)[CH2:4][CH3:5]
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Reactant: CCC(C(=O)c1ccc2c(c1)CCC(=O)N2)N1CCNCC1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCCO
Product: CCC(C(=O)c1ccc2c(c1)CCC(=O)N2)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1

Procedure:
1.8 Grams of 6-(1-oxo-2-piperazinylbutyl)-3,4-dihydrocarbostyril, 2.0 g of p-bromonitrobenzene, 1.2 g of potassium carbonate and 0.1 g of copper powder were dispersed in 80 ml of ethyl cellosolve and stirred at 120°-150° C. by heating for 5 hours. The reaction mixture was concentrated under a reduced pressure and the residue thus obtained was added water and extracted with chloroform. The chloroform layer was washed with water, dried and the chloroform was removed by distillation. The residue thus obtained was separated and purified by a separative thin layer chromatography and recrystallized from ethanol to obtain 0.2 g of 6-{1-oxo-2-[4-(4-nitrophenyl)-1-piperazinyl]-butyl}-3,4-dihydrocarbostyril in yellow powdery crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:12]([NH:14][CH2:15][CH3:16])[CH3:13].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClC(Cl)C>[CH2:12]([N:14]([CH2:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[CH2:15][CH3:16])[CH3:13]
Reactant: CCNCC
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCN(CC)Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 137.2 %

Procedure:
To a solution of 2.11 g (14 mmol) of 4-nitrobenzaldehyde in 50 mL dichloroethane was added diethylamine (1.13 g, 15.4 mmol) followed by sodium triacetoxyborohydride (4.45 g, 21 mmol). The mixture was stirred at room temperature overnight. A solution of saturated aqueous sodium bicarbonate (25 mL) was added to the reaction mixture and the resulting solution was extracted with ethyl acetate (1×150 mL, 2×50 mL). The combined organic extract was dried (sodium sulfate), filtered, and solvent removed under reduced pressure to provide crude N-ethyl-N-(4-nitrobenzyl)ethanamine as an oil (4.0 g). The material was used in the next step without further purification.
Reaction SMILES: [C:1]([CH:5]([C:9]([OH:11])=O)[C:6]([OH:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[Mg+2].[Cl-].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:27]([C:29]1[CH:34]=[CH:33][C:32]([C:35](C)([CH3:39])[C:36](O)=O)=[CH:31][C:30]=1[I:41])[CH3:28]>COCCOC>[C:1]([CH:5]([C:9](=[O:11])[C:35]([C:32]1[CH:33]=[CH:34][C:29]([CH2:27][CH3:28])=[C:30]([I:41])[CH:31]=1)([CH3:39])[CH3:36])[C:6]([OH:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C(C(=O)O)C(=O)O
Reactant: CCc1ccc(C(C)(C)C(=O)O)cc1I
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [Mg+2]
Solvent: COCCOC
Product: CCc1ccc(C(C)(C)C(=O)C(C(=O)O)C(C)(C)C)cc1I
Reaction time: 2 h

Procedure:
Mono-tert-butyl malonic acid (72.5 g) was dissolved in DME (360 ml), added with TEA (189 ml) and magnesium chloride (29.63 g) and the mixture was stirred for 2 hrs. In a separate vessel, CDI (52.75 g) was added to the DME (360 ml) solution of 2-(4-ethyl-3-iodophenyl)-2-methylpropanoic acid (90 g) and stirred at room temperature for 1 hr to prepare a solution. This solution was then added dropwise to the aforementioned mixture, and the resulting solution was washed with DME (90 ml) and stirred at 70° C. for 3 hrs. The reaction mixture was diluted with isopropyl acetate (225 ml) and heptane (225 ml), and the organic layer was washed with 2 N hydrochloric acid (684 ml), 0.17 N hydrochloric acid (540 ml), 15% aqueous solution of ammonium chloride (540 ml), 1 N aqueous solution of sodium hydroxide (540 ml) and 15% brine (540 ml) in order. The organic layer was concentrated under reduced pressure to obtain the title compound as a crude product, which was used for the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]2[C@H:10]([CH2:11]2)[C@H:9]1[CH2:14][NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:16]([N:18]1[C:22]([C:23](O)=[O:24])=[CH:21][C:20]([CH3:26])=[N:19]1)[CH3:17]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]2[C@H:10]([CH2:11]2)[C@H:9]1[CH2:14][NH:15][C:23]([C:22]1[N:18]([CH2:16][CH3:17])[N:19]=[C:20]([CH3:26])[CH:21]=1)=[O:24])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@@H]2[C@H]1CN
Reactant: CCn1nc(C)cc1C(=O)O
Product: CCn1nc(C)cc1C(=O)NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)OC(C)(C)C

Procedure:
prepared by reaction of (1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester with 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. 1H-NMR (CDCl3): δ=0.19 (q, J=4.3 Hz, 1H); 0.73 (dt, J=7.7 Hz, J=5.5 Hz, 1H); 1.30-1.36 (m, 1H); 1.38-1.43 (m, 3H); 1.45 (s, 9H); 1.46-1.53 (m, 1H); 2.24 (s, 3H); 3.34-3.42 (m, 2H); 3.55-3.64 (m, 2H); 4.18 (dd, J=10.8 Hz, J=3.0 Hz, 1H); 4.47-4.62 (m, 2H); 6.36 (s, 1H); 7.76 (bs, 1H).