Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[NH:10][C:8](=[O:9])[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2].[N:15]#[C:16]Br.C(N(CC)CC)C>CC(C)=O>[N+:1]([C:4]1[CH:5]=[C:6]2[C:7](=[CH:13][CH:14]=1)[C:8](=[O:9])[N:10]([C:16]#[N:15])[C:11]2=[O:12])([O-:3])=[O:2]
Reactant: O=C1NC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: N#CBr
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: N#CN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Reaction time: 0.33 h
Yield: 87.5 %

Procedure:
A 25 mL round-bottomed flask was charged with 4-nitrophthalimide (0.96 g, 5.0 mmol), cyanogen bromide (0.64 g, 6.0 mmol), and 10 mL of reagent grade acetone. The resulting suspension was cooled using an ice/salt bath, and triethylamine (1.0 mL, 7.1 mmol) was added dropwise over a 4 minute period. The mixture was allowed to stir for 20 minutes before being partitioned between ethyl acetate and water. The organic phase was washed with water, saturated brine, dried (MgSO4), and concentrated to give 0.95 g of a yellow solid. This material was recrystallized from ethyl acetate to afford 0.65 g (60%) of yellow crystals, mp 209.5°-210.5° C. (reported in Zh. Org. Khim. 1977, 13, 968 as 215° C.): IR (nujol) 2261 (nitrile), 1811 (carbonyl), 1769 (carbonyl), 1533 (nitro), 1343 (nitro) cm-1 ; 1H NMR (200 MHz, DMSO) δ 8.34 (d, 1, J=8.9 Hz), 8.70-8.78 (m, 2); 13C NMR (50 MHz, DMSO) δ 161.15, 160.92, 152.34, 135.19, 132.10, 131.16, 126.48, 119.76, 102.26; GC/MS (relative intensity) 217 (77.8), 149 (71.7), 103 (64.4), 75 (100), 74 (52.7).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:27]=[CH:26][C:12]([O:13][C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=3[C:22]([F:25])([F:24])[F:23])=[C:11]([F:28])[CH:10]=2)[S:3]1.Cl[CH2:30][CH2:31][N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>>[O:1]=[C:2]1[N:6]([CH2:30][CH2:31][N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:27]=[CH:26][C:12]([O:13][C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=3[C:22]([F:25])([F:23])[F:24])=[C:11]([F:28])[CH:10]=2)[S:3]1
Reactant: ClCCN1CCCC1
Reactant: N#Cc1ccc(Oc2ccc(C=C3SC(=O)NC3=O)cc2F)c(C(F)(F)F)c1
Product: N#Cc1ccc(Oc2ccc(C=C3SC(=O)N(CCN4CCCC4)C3=O)cc2F)c(C(F)(F)F)c1

Procedure:
The title compound was prepared using 4-[4-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-2-fluoro-phenoxy]-3-trifluoromethyl-benzonitrile and 1-(2-Chloro-ethyl)-pyrrolidine as described in Example 1. 1H NMR (400 Hz, DMSO-d6) δ8.49 (s, 1H), 8.21 (dd, 1H), 8.05 (s, 1H), 7.87 (d, 1H), 7.64 (m, 2H), 7.31 (d, 1H), 3.86 (t, 2H), 2.76 (bs, 2H), 2.60 (bs, 4H), 1.73 (bs, 4H); LC/MS (m/z) [M+1]+ 506.2 (calculated for C24H20F4N3O3S, 506.49).
Reaction SMILES: C[N:2]1[CH2:23][CH2:22][N:5]2[C:6]3[CH:21]=[CH:20][CH:19]=[CH:18][C:7]=3[CH2:8][N:9]3[C:17]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[CH:11]=[C:10]3[CH:4]2[CH2:3]1.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>C1(C)C=CC=CC=1.C(OCC)C>[CH2:28]([O:27][C:25]([N:2]1[CH2:23][CH2:22][N:5]2[C:6]3[CH:21]=[CH:20][CH:19]=[CH:18][C:7]=3[CH2:8][N:9]3[C:17]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[CH:11]=[C:10]3[CH:4]2[CH2:3]1)=[O:26])[CH3:29]
Reactant: CN1CCN2c3ccccc3Cn3c(cc4ccccc43)C2C1
Reactant: CCOC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCOC(=O)N1CCN2c3ccccc3Cn3c(cc4ccccc43)C2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 712 mg of 1,3,4,16b-tetrahydro-2-methyl-2H,10H-indolo[2,1-c]pyrazino[1,2-a][1,4]benzodiazepine in 5 ml toluene is added 1.2 g of ethyl chloroformate and the reaction mixture is heated at reflux temperature with stirring for 8 hours. On cooling to room temperature the reaction mixture is diluted with 50 ml of diethyl ether and the resulting precipitate collected by filtration and washed well with ether. The filtrate is evaporated to dryness under reduced pressure to yield 1,3,4,16b-tetrahydro-2-ethoxycarbonyl-2H,10H-indolo[2,1-c]pyrazino[1,2-a][1,4]benzodiazepine as an oil which is used in the next step without further purification.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[O-].[Na+].CO.Cl.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33]Cl.O>CO>[C:1]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:33][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=2)=[CH:15][CH:16]=1)([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2]
Reactant: ClCc1ccccn1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccn2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.9 %

Procedure:
To a solution of N-Boc-tyrosine (281 mg, 1.0 mmol) in methanol (0.5 mL) were added 28% sodium methoxide-methanol solution (0.8 mL, 4.0 mmol) and 2-picolyl chloride hydrochloride (230 mg, 1.4 mmol), and the mixture was stirred at 25° C. for 24 hr. Then, water (3 mL) was added make the system homogeneous, which system was then analyzed by HPLC. As a result, the objective N-Boc-(O-2-picolyl)tyrosine (346 mg, conversion yield 93%) was confirmed.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH2:11][C:12]([NH:16][C:17](=[O:29])[C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=1)([C:14]#[N:15])[CH3:13])[CH:6]=2.[Cl:30]N1C(=O)CCC1=O>C(#N)C.O>[C:14]([C:12]([NH:16][C:17](=[O:29])[C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]([F:26])([F:27])[F:28])=[CH:20][CH:19]=1)([CH3:13])[CH2:11][N:7]1[C:6]([Cl:30])=[C:5]2[C:9]([CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4]2)=[N:8]1)#[N:15]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C#N)(Cn1cc2ccc(Cl)cc2n1)NC(=O)c1ccc(OC(F)(F)F)cc1
Solvent: O
Solvent: CC#N
Product: CC(C#N)(Cn1nc2cc(Cl)ccc2c1Cl)NC(=O)c1ccc(OC(F)(F)F)cc1
Temperature: 60 °C
Yield: 85.1 %

Procedure:
A mixture of N-[2-(6-chloro-2H-indazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide (50 mg, described in Example 143), and N-chlorosuccinimide (16 mg) in acetonitrile (1 mL) was heated to 60° C. for 3.5 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was collected, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue that was purified by chromatography (SiO2, heptane/EA) to afford the title compound (46 mg, 85%). MS (ES): M/Z [M+H]=457. 1H NMR: (400 MHz, CHLOROFORM-d): 1.92 (s, 3H), 4.80 (d, J=14.3 Hz, 1H), 5.03 (d, J=14.3 Hz, 1H), 7.15 (dd, J=9.0, 1.4 Hz, 1H), 7.35 (d, J=8.5 Hz, 2H), 7.57 (d, J=9.0 Hz, 1H), 7.63 (s, 1H), 7.93 (d, J=8.7 Hz, 2H) and 8.65 (s, 1H). 19F NMR (376 MHz, CHLOROFORM-d): −58.1 (s, 3F).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[CH2:16][CH2:15][C:14]4([C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[CH2:19][N:18]([C:26](=[O:28])[CH3:27])[CH2:17]4)[CH2:13][CH2:12]3)[CH2:7][CH2:6]2)[O:4]CC1.[OH-].[K+]>CC(O)=O.O>[C:26]([N:18]1[CH2:17][C:14]2([CH2:13][CH2:12][N:11]([CH:8]3[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]3)[CH2:16][CH2:15]2)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19]1)(=[O:28])[CH3:27]
Reactant: CC(=O)N1Cc2ccccc2C2(CCN(C3CCC4(CC3)OCCO4)CC2)C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)N1Cc2ccccc2C2(CCN(C3CCC(=O)CC3)CC2)C1
Yield: 70.8 %

Procedure:
1-(1′-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-spiro[isoquinoline-4,4′-piperidine]-2(3H)-yl)ethanone 6d (350 mg; 0.83 mmol.) was dissolved in 80% aq. AcOH (20 mL) and the solution was refluxed overnight. The reaction mixture was diluted with water (20 mL), cooled on an ice bath and neutralized by addition of solid KOH. The resulting suspension was extracted with DCM (3×30 mL) and the combined organic extracts were dried on Na2SO4 and concentrated to provide the crude 4-(2-acetyl-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-yl)cyclohexanone 6e (200 mg, 70% yield) as a white foam. LC/MS m/z [M+H]+ 341.0 retention time 1.47 min (10-99% CH3CN—H2O gradient, with 0.05% TFA, 5 min).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[CH:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[C:18]([F:20])[C:17]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[C:16]([C:26]#[CH:27])[CH:15]=2)=[O:11])=[CH:6][CH:5]=[C:4]([C:28]([F:31])([F:30])[F:29])[N:3]=1.[O:32]([CH3:34])[Na]>CO.CCOC(C)=O>[C:26]([C:16]1[CH:15]=[C:14]([CH:19]=[C:18]([F:20])[C:17]=1[NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH2:13][NH:12][C:10](=[O:11])[CH:9]=[CH:8][C:7]1[C:2]([O:32][CH3:34])=[N:3][C:4]([C:28]([F:31])([F:30])[F:29])=[CH:5][CH:6]=1)#[CH:27]
Reactant: C#Cc1cc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2Cl)cc(F)c1NS(C)(=O)=O
Reactant: CO[Na]
Solvent: CO
Solvent: CCOC(C)=O
Product: C#Cc1cc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2OC)cc(F)c1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 20 %

Procedure:
To a suspension of 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl)-acrylamide (50 mg, 0.105 mmol) in CH3OH (1 mL) was added dropwise 30% NaOCH3 in CH3OH (3 eq) at 0° C. The mixture was stirred for 12 hours at room temperature. The reaction was diluted with EtOAc and washed two times with 1N HCl and brine, dried over anhyd. MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography to give the title compound (10 mg, 20%).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.C(N(C(C)C)CC)(C)C>>[CH3:8][C:6]1[C:5]([O:9][CH3:10])=[CH:4][C:3]([N+:11]([O-:13])=[O:12])=[C:2]([NH:14][CH:15]2[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20]2)[CH:7]=1
Reactant: COc1cc([N+](=O)[O-])c(F)cc1C
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc([N+](=O)[O-])c(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1C
Temperature: 75 °C
Reaction time: 8 h

Procedure:
1-Fluoro-5-methyl-4-methoxy-2-nitrobenzene (D17) (0.79 mmol, 146 mg) was treated under argon at room temperature with 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate (0.8 mmol, 160 mg, 1 eq) and diisopropylethylamine (0.8 mmol, 103 mg, 1 eq) then stirred at 75° C. overnight. Completion was not observed, and the mixture was heated at higher temperature, 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate (0.8 mmol, 160 mg, 1 eq) and diisopropylethylamine (0.8 mmol, 103 mg, 1 eq) were added again and allowed to react overnight at 100° C. The mixture was concentrated under reduced pressure, treated with 10% Na2CO3 aqueous solution and extracted twice with ether. Organics were combined, dried on MgSO4, concentrated under reduced pressure and chromatographed (0-50% ethyl acetate/petrol ether) to give the title compound as an orange residue (0.33 mmol, 120 mg, 42% yield). M+H=310.1, main fragment (molecule has lost its tert-butyl group).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[N:3]=1.FC(F)(F)C(O)=O.C(N(CC)CC)C.[CH3:40][N:41]([CH3:51])[C:42]1[CH:47]=[CH:46][C:45]([N:48]=[C:49]=[O:50])=[CH:44][CH:43]=1>>[CH3:40][N:41]([CH3:51])[C:42]1[CH:47]=[CH:46][C:45]([NH:48][C:49]([N:23]2[CH2:22][CH2:21][CH:20]([NH:19][C:4]3[N:3]=[C:2]([NH2:1])[C:7]([C:8](=[O:9])[C:10]4[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=4[O:17][CH3:18])=[CH:6][N:5]=3)[CH2:25][CH2:24]2)=[O:50])=[CH:44][CH:43]=1
Reactant: CN(C)c1ccc(N=C=O)cc1
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(C(=O)Nc3ccc(N(C)C)cc3)CC2)nc1N
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred suspension of the compound of Example 59 in the form of its trifluoroacetic acid salt (45 mg), triethylamine (150 μL, 1.08 mmol) was added followed by 4-dimethylamino-phenyl-isocyanate (Aldrich, 33 mg, 0.20 mmol), and the solution was stirred at room temperature for 1.5 hours. The solution was then concentrated and the residue was purified by reverse phase HPLC to give a solid, (34 mg). MS(ES) (M+H)+=508.
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[CH:6][C:5]([NH2:9])=[C:4]([O:10][CH3:11])[CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1B(O)O.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>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[C:7]1[C:2]([Cl:1])=[CH:3][C:4]([O:10][CH3:11])=[C:5]([NH2:9])[CH:6]=1
Reactant: OB(O)c1cc(Cl)ccc1Cl
Reactant: COc1cc(Cl)c(I)cc1N
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: O
Solvent: C1COCCO1
Product: COc1cc(Cl)c(-c2cc(Cl)ccc2Cl)cc1N
Temperature: 80 °C
Reaction time: 16 h
Yield: 75.2 %

Procedure:
A mixture of 4-chloro-5-iodo-2-methoxybenzenamine (4.1 g, 14.5 mmol), 2,5-dichlorophenylboronic acid (3.3 g, 17.4 mmol), Pd(PPh3)4 (500 mg, 1.45 mmol) and Na2CO3 (4.7 g, 43.5 mmol) in 1,4-dioxane (150 mL) and water (15 mL) was stirred at 80° C. under argon for 16 h. The mixture was allowed to cool to room temperature, and then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate=20:1) to afford the desired product (3.3 g, 75.8% yield) as an off-white solid.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[OH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:22])[CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:8][C:7]=1[O:23][CH3:24]>C(O)(=O)C.C(OCC)(=O)C>[OH:5][C:6]1[C:11]([N+:1]([O-:4])=[O:2])=[CH:10][C:9]([C:12](=[O:22])[CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:8][C:7]=1[O:23][CH3:24]
Reactant: O=[N+]([O-])O
Reactant: COc1cc(C(=O)CCCc2ccccc2)ccc1O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)CCCc2ccccc2)cc([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 0.79 ml of 65 percent nitric acid in 25 ml of glacial acetic acid is added dropwise to a solution of 2.2 g of 4'-hydroxy-3'-methoxy-4- phenylbutyrophenone in 25 ml of glacial acetic acid and the mixture is stirred at room temperature for an additional 2 hours. The mixture is poured into 150 ml of ice-water and, after treatment with 20 ml of 3N hydrochloric acid, extracted three times with 75 ml of ethyl acetate each time. The organic phase is washed with water, dried over sodium sulfate and evaporated. The crude product obtained is taken up in ethyl acetate and filtered over 75 g of silica gel. After recrystallization from acetonitrile, there is obtained 4'-hydroxy-3'-methoxy-5'-nitro-4-phenylbutyrophenone in the form of yellow crystals of m.p. 120°-121°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=O)=[CH:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:5][CH:4]=1.Cl.[NH2:27][OH:28].[Na]>CO.O>[OH:28][N:27]=[C:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[C:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[CH:10][CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)CC=C(C(=O)c1ccc(OC)cc1)c1ccc(OC)cc1
Reactant: NO
Agent: Cl
Agent: [Na]
Solvent: CO
Solvent: O
Product: COC(=O)CC=C(C(=NO)c1ccc(OC)cc1)c1ccc(OC)cc1
Yield: 90 %

Procedure:
A 24.5 g quantity of methyl 4,5-bis(4-methoxyphenyl)-5-oxo-3-pentenoate obtained in Example 1 and 51.5 g of hydroxylamine hydrochloride was refluxed with heating in a mixture of 650 ml of methanol and 72 ml of water for 23 hours. With the progress of reaction at this time, 0.9 equivalent weight of sodium hydrogentarbonate was added in divided portions to the reaction system. On completion of the reaction, the methanol was distilled off at a reduced pressure. The residue was dissolved with water and ethyl acetate, and the organic layer was collected, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium suliate. The organic layer was concentrated at a reduced pressure, and the residue was subjected to silica gel column chromatography (eluants: ethyl acetate-n-hexane) for separation and purification, affording 23 g (yield 90%) of the above-identified compound as an oily product.
Reaction SMILES: CO[CH2:3][N:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][Si](C)(C)C.FC(F)(F)C(O)=O.[CH2:24]([O:26][C:27](=[O:32])[C:28]([CH2:30][F:31])=[CH2:29])[CH3:25]>ClCCl>[CH2:24]([O:26][C:27]([C:28]1([CH2:30][F:31])[CH2:29][CH2:3][N:4]([CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:5]1)=[O:32])[CH3:25]
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: C=C(CF)C(=O)OCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1(CF)CCN(Cc2ccccc2)C1
Temperature: 25 °C

Procedure:
N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (548 μl, 2.14 mmol) was dissolved in the dichloromethane solution of the 2-fluoromethyl-acrylic acid ethyl ester from the previous reaction and chilled to 0 C. A solution of trifluoroacetic acid (67 μl, 0.87 mmol) in dichloromethane (0.5 ml) was added slowly. The reaction mixture was allowed to warm to room temperature in two hours and directly chromatographed on silica gel. Elution with solutions of ethyl acetate in hexanes (1:5, 1:4, 1:3) obtained the title product (143 mg) as oil.
Reaction SMILES: CN1CCOCC1.[Si:8]([O:25][CH2:26][C@H:27]1[CH2:31][CH2:30][C@:29]([CH2:33][OH:34])([CH3:32])[C:28]1([CH3:36])[CH3:35])([C:21]([CH3:24])([CH3:23])[CH3:22])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Si:8]([O:25][CH2:26][C@H:27]1[CH2:31][CH2:30][C@@:29]([CH3:32])([CH:33]=[O:34])[C:28]1([CH3:36])[CH3:35])([C:21]([CH3:23])([CH3:24])[CH3:22])([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC1(C)[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC[C@@]1(C)CO
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC1(C)[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC[C@@]1(C)C=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.8 %

Procedure:
A solution of 4-methylmorpholine (17.33 g, 148 mmol) in CH2Cl2 (400 mL) was dried over Mg2SO4 for 15 min and filtered into a round bottom flask containing ((1R,3S)-3-((tert-butyldiphenylsilyloxy)methyl)-1,2,2-trimethylcyclopentyl)methanol (40.5 g, 99 mmol). To the resulting clear solution was added 4 A° powdered molecular sieves (20 g), tetrapropylammonium perruthenate (TPAP) (0.693 g, 1.972 mmol) and stirred for 4 h at room temperature. The reaction was concentrated to ˜100 mL, diluted with hexane/Et2O (9:1, 500 mL) and filtered through a plug of silica gel. The plug was washed with 500 mL of hexane/Et2O (9:1). The filtrate was concentrated to afford (1R,3S)-3-((tert-butyldiphenylsilyloxy)methyl)-1,2,2-trimethylcyclopentanecarbaldehyde (32.61 g, 80 mmol, 81% yield) as a viscous pale yellow oil. 1H NMR (500 MHz, CDCl3) δ: 9.63 (1 H, s), 7.66 (4 H, dd, J=7.9, 1.5 Hz), 7.35-7.45 (6 H, m), 3.66-3.71 (1 H, dd, J=10.2, 6.9 Hz), 3.56 (1 H, dd, J=10.4, 7.0 Hz), 2.29 (1 H, ddd, J=13.7, 11.4, 6.0 Hz), 2.09-2.18 (1 H, m), 1.87-1.96 (1 H, m), 1.28-1.44 (2 H, m), 1.06 (3 H, s), 1.02-1.05 (12 H, s), 0.81 (3 H, s). LCMS (M+Na) calcd for C26H36NaO2Si: 431.25; found: 431.52.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5])#[N:2].[Li+].CC([N-]C(C)C)C.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][C:31](=O)/[C:30](=[CH:35]/N(C)C)/[CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>C1COCC1>[C:1]([C:3]1[C:4](=[O:5])[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:31]2[CH2:32][CH2:33][N:28]([C:26]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:27])[CH2:29][C:30]=2[CH:35]=1)#[N:2]
Reactant: N#CCC(=O)Nc1ccccc1
Reactant: CN(C)/C=C1\CN(C(=O)OC(C)(C)C)CCC1=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2c(cc(C#N)c(=O)n2-c2ccccc2)C1
Temperature: 25 °C

Procedure:
2-Cyano-N-phenylacetamide (820 mg) in THF (20 mL) was treated with LDA (4.4 mL, 1.8M solution in heptane/THF/ethylbenzene) at −78° C. for 1 h, before (E)-tert-butyl-3-((dimethylamino)methylene)-4-oxopiperidine-1-carboxylate (1 g) was added. The reaction mixture was allowed to warm to room temperature, and quenched with saturated NaHCO3 aqueous solution (20 mL). The aqueous solution was extracted with EtOAc (3×20 mL) and the combined organic layer was dried over MgSO4. Concentration under vacuum provided a residue which was purified by HPLC to afford tert-butyl 3-cyano-2-oxo-1-phenyl-1,2,7,8-tetrahydro-1,6-naphthyridine-6(5H)-carboxylate. LCMS: m/z 352.2 (M+H)+, 1.63 min (method 8). 1H NMR (500 MHz, DMSO-d6) δ ppm 8.19 (s, 1H) 7.48-7.57 (m, 3H) 7.33 (d, J=7.02 Hz, 2H) 4.33 (s, 2H) 3.44 (t, J=5.65 Hz, 2H) 2.19 (t, J=5.80 Hz, 2H) 1.39 (s, 9H).
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4](Cl)=[O:5].[NH2:9][C:10]1[CH:20]=[CH:19][C:13]([C:14]([N:16]([CH3:18])[CH3:17])=[O:15])=[C:12]([Cl:21])[CH:11]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:21][C:12]1[CH:11]=[C:10]([NH:9][C:4](=[O:5])[C:3]([CH3:8])([CH3:7])[CH2:2][Cl:1])[CH:20]=[CH:19][C:13]=1[C:14]([N:16]([CH3:18])[CH3:17])=[O:15]
Reactant: CN(C)C(=O)c1ccc(N)cc1Cl
Reactant: CC(C)(CCl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)c1ccc(NC(=O)C(C)(C)CCl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Chloro-2,2-dimethylpropionyl chloride (1.86 g) was added dropwise over 5 minutes to 4-amino-2-chloro-N,N-dimethylbenzamide (2.00 g) suspended in dry methylene chloride (40 ml) and dry triethylamine (1.21 g) with stirring, keeping the temperature below 10° C. After stirring for 1 hour and warming to room temperature, methylene chloride (40 ml) was added and the solution washed with 2M hydrochloric acid, saturated aqueous sodium bicarbonate and then saturated brine. The solution was then dried and evaporated to yield a sticky yellow solid which was recrystallised from ethyl acetate/chloroform to give 2-chloro-4-(3'-chloro-2',2'-dimethylpropionamido)-N,N-dimethylbenzamide, as a white crystalline solid (2.349 g) m.p. 179°-181° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[Br:25][C:26]1[CH:34]=[CH:33][C:29]2[O:30][CH2:31][O:32][C:28]=2[C:27]=1[C:35](Cl)=[O:36].O=C1CC(=O)N(C2C=CC(C(O)=O)=CC=2)C2C=CC3C(C=2N1)=CC=CC=3>>[Br:25][C:26]1[C:27]([C:35]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]4[C:17]5[C:22]([CH:23]=[CH:24][C:9]3=4)=[CH:21][CH:20]=[CH:19][CH:18]=5)=[CH:4][CH:3]=2)=[O:36])=[C:28]2[O:32][CH2:31][O:30][C:29]2=[CH:33][CH:34]=1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: O=C(Cl)c1c(Br)ccc2c1OCO2
Agent: O=C1CC(=O)N(c2ccc(C(=O)O)cc2)c2ccc3ccccc3c2N1
Product: O=C1CC(=O)N(c2ccc(NC(=O)c3c(Br)ccc4c3OCO4)cc2)c2ccc3ccccc3c2N1
Yield: 64 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione obtained in Example 1, (3), and 5-bromo-1,3-benzodioxol-4-carbonyl chloride, the title compound (yield 64%) was obtained in the same manner as that of Example 1, (4).