Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:16].[C:17]12([S:27][CH2:28][C:29](O)=[O:30])[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]3)[CH2:18]1)[CH2:24]2>>[C:17]12([S:27][CH2:28][C:29]([NH:1][N:2]3[N:11]=[C:10]([C:12]([F:15])([F:13])[F:14])[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:3]3=[O:16])=[O:30])[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]3)[CH2:18]1)[CH2:24]2
Reactant: Nn1nc(C(F)(F)F)c2ccccc2c1=O
Reactant: O=C(O)CSC12CC3CC(CC(C3)C1)C2
Product: O=C(CSC12CC3CC(CC(C3)C1)C2)Nn1nc(C(F)(F)F)c2ccccc2c1=O

Procedure:
The product from Example 11B and 2-(adamantan-1-ylthio)acetic acid were treated using a method similar to that described in Example 17C to give the title compound 1H NMR (400 MHz, DMSO-d6) δ ppm 11.68-11.85 (bs, 1H), 8.43 (ddd, J=8.0, 1.4, 0.7 Hz, 1H), 8.13 (ddd, J=8.0, 7.4, 1.4 Hz, 1H), 8.03-8.08 (m, 1H), 8.00-8.05 (m, 1H), 3.44 (s, 2H), 2.01-2.04 (m, 3H), 1.86-1.89 (m, 6H), 1.65-1.69 (m, 6H); MS (APCI+) M/Z 438 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(N(CC)CC)C.[NH2:17][C@@H:18]([CH2:20][OH:21])[CH3:19]>C(#N)C>[Br:1][C:2]1[C:3]([NH:17][C@H:18]([CH3:19])[CH2:20][OH:21])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: C[C@@H](N)CO
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[C@H](CO)Nc1nc(Cl)ncc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 22.8 g (100 mmol) of 5-bromo-2,4-dichloropyrimidine in 100 ml of acetonitrile is mixed at 0° C. first with 17.0 ml (125 mmol) of triethylamine and then with 9.4 g (125 mmol) of D-alaninol. The batch is stirred overnight at room temperature. The precipitate that is formed is suctioned off, washed with water, and completely dried. 21.5 g (81 mmol, corresponding to 81% of theory) of the product is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([F:15])[C:11](F)=[N:12][CH:13]=2)=[N:6][CH:7]=1.[NH2:16][NH2:17]>CC(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([F:15])[C:11]([NH:16][NH2:17])=[N:12][CH:13]=2)=[N:6][CH:7]=1
Reactant: Fc1cc(-c2ccc(Cl)cn2)cnc1F
Reactant: NN
Solvent: O
Solvent: CC(C)O
Product: NNc1ncc(-c2ccc(Cl)cn2)cc1F
Temperature: 60 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a solution of 5-(5-chloropyridin-2-yl)-2,3-difluoropyridine (2.4 g, 11 mmol) in IPA (35 mL, 0.3 M) at room temperature was added hydrazine (4 mL, 127 mmol). The reaction mixture was stirred at 60° C. for 2 h, at which point the reaction was cooled to room temperature and concentrated in vacuo. The concentrated material was suspended in saturated NaHCO3 and filtered to obtain product as a white, fluffy solid. The material was re-suspended in water (30 mL), and filtered to obtain 1-(5-(5-chloropyridin-2-yl)-3-fluoropyridin-2-yl)hydrazine (2.1 g, 83% yield). MS m/z=239.2 [M+1]+. Calc'd for C10H8ClFN4: 238.6.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:11]=[N:12][C:13]([CH:16]([NH:18][C:19]([C:21]3O[CH:23]=[CH:24][CH:25]=3)=[O:20])[CH3:17])=[CH:14][N:15]=2)=[CH:5][CH:4]=1.NC(C1N=NC(NC2C=CC(OC)=CC=2)=NC=1)C.[F:44][C:45]1C=C(C=C[CH:53]=1)C(Cl)=O>>[F:44][C:45]1[CH:53]=[C:21]([CH:25]=[CH:24][CH:23]=1)[C:19]([NH:18][CH:16]([C:13]1[N:12]=[N:11][C:10]([NH:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[N:15][CH:14]=1)[CH3:17])=[O:20]
Reactant: COc1ccc(Nc2ncc(C(C)NC(=O)c3ccco3)nn2)cc1
Reactant: O=C(Cl)c1cccc(F)c1
Agent: COc1ccc(Nc2ncc(C(C)N)nn2)cc1
Product: COc1ccc(Nc2ncc(C(C)NC(=O)c3cccc(F)c3)nn2)cc1

Procedure:
In a similar manner as described for Intermediate 59, using 6-(1-aminoethyl)-N-[4-(methyloxy)phenyl]-1,2,4-triazin-3-amine (Intermediate 47) (100 mg, 0.41 mmol), and 3-fluorobenzoyl chloride (0.059 mL, 0.45 mmol) to afford 3-fluoro-N-[1-(3-{[4-(methyloxy)phenyl]amino}-1,2,4-triazin-6-yl)ethyl]benzamide (130 mg) as a yellow solid. MS m/z 368 (M+1).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])[CH3:3].[CH3:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=1[NH:25][C:26](=[O:29])[CH:27]=[CH2:28].C(N(CC)CC)C>CO>[CH3:4][C:2]([C:5]1[CH:10]=[C:9]([S:11][CH2:28][CH2:27][C:26]([NH:25][C:19]2[C:20]([CH3:24])=[CH:21][CH:22]=[CH:23][C:18]=2[CH3:17])=[O:29])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:1])[CH3:3]
Reactant: C=CC(=O)Nc1c(C)cccc1C
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1cccc(C)c1NC(=O)CCSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
2.6-bis-(1,1-Dimethylethyl)-4-mercaptophenol(1.19 g, 0.005 mole), N-(2,6-dimethylphenyl)-2-propenamide (0.87 g, 0.005 mole) and triethylamine (0.5 ml) in methanol (100 ml) were stirred at room temperature under argon for 12 hours. The solvent and triethylamine were removed on a rotary evaporator and the product purified by chromatography on silica. The solvents were removed and the product recrystallized from ethyl acetate/hexane, filtered and dried in vacuo to yield the title compound, m.p. ca. 142.5°-144° C.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[NH:11][N:10]=[C:9]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])[S:8]1)=[N+:2]=[N-:3].[C:26]([N:33]1C=CN=C1)(N1C=CN=C1)=[S:27].[NH2:38]N>C1COCC1>[N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:11]([C:26](=[S:27])[NH:33][NH2:38])[N:10]=[C:9]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])[S:8]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCCC1(c2ccccc2)NN=C(c2cc(F)ccc2F)S1
Reactant: NN
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: [N-]=[N+]=NCCCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1C(=S)NN
Temperature: 23 °C
Reaction time: 12 h
Yield: 19.3 %

Procedure:
2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazole (577 mg, 1.61 mmol) was dissolved in 8 mL THF, followed by addition of thio-carbonyldiimidazole (458 mg, 2.57 mmol), and heated to reflux for 1 hour. The reaction mixture was cooled to 23° C., and hydrazine (257 mg, 8.03 mmol) was added. The reaction mixture was stirred for 12 hours. The crude reaction mixture was then concentrated and purified by flash column chromatography, eluting with 4:1 (hexanes/ethyl acetate), to afford the desired product (135 mg, 20%).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]([CH3:13])([CH3:12])[NH:7][C:8](=[O:11])[CH2:9][CH2:10][C:4]=2[CH:3]=1.[Cl:16][C:17]1[C:18]([NH:27][C:28]2[C:33]([Cl:34])=[CH:32][N:31]=[C:30](Cl)[N:29]=2)=[C:19]([CH:24]=[CH:25][CH:26]=1)[C:20]([NH:22][CH3:23])=[O:21]>>[Cl:16][C:17]1[C:18]([NH:27][C:28]2[C:33]([Cl:34])=[CH:32][N:31]=[C:30]([NH:1][C:2]3[CH:15]=[CH:14][C:5]4[C:6]([CH3:13])([CH3:12])[NH:7][C:8](=[O:11])[CH2:9][CH2:10][C:4]=4[CH:3]=3)[N:29]=2)=[C:19]([CH:24]=[CH:25][CH:26]=1)[C:20]([NH:22][CH3:23])=[O:21]
Reactant: CC1(C)NC(=O)CCc2cc(N)ccc21
Reactant: CNC(=O)c1cccc(Cl)c1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1cccc(Cl)c1Nc1nc(Nc2ccc3c(c2)CCC(=O)NC3(C)C)ncc1Cl

Procedure:
Following a procedure analogous to Example 1826d, 7-amino-1,1-dimethyl-1,2,4,5-tetrahydrobenzo[c]azepin-3-one and 3-chloro-2-(2,5-dichloropyrimidin-4-ylamino)-N-methylbenzamide were converted to 3-chloro-2-(5-chloro-2-(1,1-dimethyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-ylamino)pyrimidin-4-ylamino)-N-methylbenzamide, TFA salt: 1H NMR (300 MHz, CD3OD) δ 8.3 (s, 1H), 7.9 (dd, 1H), 7.75 (dd, 1H), 7.65 (t, 1H), 7.4 (d, 1H), 7.3 (d, 2H), 7.2 (dd, 1H), 3.1 (m, 2H), 3.0 (s, 3H), 2.7 (m, 2H), 1.8 (s, 6H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].C1([Mg]Br)C=CC=CC=1.C[O:22][B:23](OC)[O:24]C.C(Cl)Cl>C1COCC1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([B:23]([OH:24])[OH:22])=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: COc1ccc(I)c([N+](=O)[O-])c1
Reactant: COB(OC)OC
Agent: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(B(O)O)c([N+](=O)[O-])c1
Reaction time: 0.5 h

Procedure:
To a solution of 1-iodo-4-methoxy-2-nitrobenzene (5 g, 17.9 mmol) in THF (50 mL) cooled to −60° C. was added phenylmagnesium bromide (10.4 mL, 25 wt %, 19.7 mmol) which gave a dark red solution. Trimethylborate (2.4 mL, 21.5 mmol) was then added dropwise. After 30 min, the reaction was quenched with 1 N HCl (40 mL) and extracted with ether. The organic layer was then dried over Na2SO4 and the solvent was removed in vacuo to give a dark brown oil which was tritrated with DCM to yield (4-methoxy-2-nitrophenyl)boronic acid as grey solid. A portion of this material (1.57 g, 8 mmol) was then taken up in DME (1 mL) and 1-bromo-4-iodo-2-methoxybenzene (C1, step 1) (2.5 g, 8 mmol), CsF (2.73 g, 18 mmol), and tetrakistriphenylphosphine palladium (0.92 g, 0.8 mmol) under nitrogen. The mixture was then heated to 100° C. for 18 h. The mixture was then extracted with water and EtOAc. The organic layer was then dried over Na2SO4 and the solvent was removed in vacuo. The crude material was then purified on silica (gradient elution, 3-50% EtOAc/hexanes) to yield the title compound as a yellow solid.
Reaction SMILES: [CH:1]1([CH:4]([OH:16])[CH2:5][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N+:13]([O-:15])=[O:14])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[CH3:24][S:25]([O:16][CH:4]([CH:1]1[CH2:3][CH2:2]1)[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14])(=[O:27])=[O:26]
Reactant: O=[N+]([O-])c1ccccc1CCC(O)C1CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC(CCc1ccccc1[N+](=O)[O-])C1CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 0.5 g of 1-cyclopropyl-3-(2-nitrophenyl)-propan-1-ol (2.26 mmol), 0.26 g of triethylamine (2.6 mmol) and 12 ml of dichloromethane is cooled to a temperature of 5° C. and 0.28 g of methanesulfonic acid chloride, dissolved in 3 ml of dichloromethane, is added dropwise. The resulting mixture is stirred for 16 hours at ambient temperature. The organic phase is washed with ice-water and dried over sodium sulfate and concentrated by evaporation. 1-Cyclopropyl-3-(2-nitrophenyl)-propyl methanesulfonate is obtained in the form of a crude product, which is used directly in the cyclisation.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].[NH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:15])=[N:13][CH:14]=1.Cl.CN(C)CCCN=C=NCC.Cl>C(OCC)(=O)C.C(Cl)(Cl)Cl.ClCCl>[Cl:15][C:12]1[N:13]=[CH:14][C:9]([CH2:8][NH:7][C:4](=[O:6])[CH2:3][C:1]#[N:2])=[CH:10][CH:11]=1
Reactant: NCc1ccc(Cl)nc1
Reactant: N#CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: N#CCC(=O)NCc1ccc(Cl)nc1
Reaction time: 8 h
Yield: 96.7 %

Procedure:
Cyanoacetic acid (2.6 g, 0.030 mmol), 5-aminomethyl-2-chloropyridine (4.3 g, 0.030 mmol) and 1-[3-(dimethylamino) propyl]-3-ethylcarbodiimide hydrochloric acid salt (5.8 g, 0.030 mol) were added to dichloromethane (50 ml), and stirred overnight. Chloroform and 1N hydrochloric acid were added thereto, and crystals were separated out. The crystals were filtered off, dissolved in ethyl acetate, and water was added thereto and subjected to extraction. The organic phase was washed with a saturated sodium bicarbonate and a saturated brine, and then dried anhydrous sodium sulfate. The residue obtained by filtrating and concentrating was washed with hexane and a little amount of ethyl acetate to obtain N-(6-chloro-3-pyridylmethyl)-2-cyanoacetic acid amide (6.1 g, 0.029 mmol, 97%).
Reaction SMILES: [C:1]12([CH2:11][OH:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[H-].[Na+].Cl[C:16]1[CH:21]=[CH:20][N+:19]([O-:22])=[CH:18][CH:17]=1>CN(C=O)C>[C:1]12([CH2:11][O:12][C:16]3[CH:21]=[CH:20][N+:19]([O-:22])=[CH:18][CH:17]=3)[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: OCC12CC3CC(CC(C3)C1)C2
Reactant: [O-][n+]1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [O-][n+]1ccc(OCC23CC4CC(CC(C4)C2)C3)cc1
Temperature: 25 °C
Yield: 96.9 %

Procedure:
To a solution of adamantanemethanol (1.2 g, 7.4 mmol) in DMF (8 mL) was added NaH (0.3 g, 7.4 mmol) in a single portion. After gas evolution subsided, 4-chloropyridine N-oxide (0.8 g, 6.17 mmol) was added. The reaction mixture was stirred at room temperature under Ar until the reaction was complete. The mixture was quenched with water and extracted with CH2Cl2. The organic layer was washed with H2O and 5% LiCl, dried over Na2SO4, filtered and concentrated to dryness. Purification by flash column chromatography (silica gel, 10% CH3OH in CH2Cl2) gave 4-(adamantylmethoxy)pyridine N-oxide (1.55 g, 97%) as a yellow solid. This material was suspended in Ac2O (5 mL), heated to 140° C. and stirred at 140° C. for 4 h. After cooling, the mixture was diluted with CH3OH and H2O (10 mL, 1:1 mixture) and stirred at room temperature for 1 h. The mixture was concentrated, and the residue was purified by flash column chromatography (silica gel, 10% CH3OH in CH2Cl2) to give 4-(adamantylmethoxy)pyridin-2(1H)-one (1.08 g, 70%) as a brown solid. Following the procedure of Example 62 (step f), but substituting 5-bromo-1-(2-(pyrrolidin-1-yl)ethyl)-1H-indazole for 4-(2-(5-iodo-1H-indazol-1-yl)ethyl)morpholine, 4-(adamantylmethoxy)pyridin-2(1H)-one for 4-phenethylpyridin-2(1H)-one, and 1,2-trans-cyclohexyldiamine for 8-hydroxyquinoline, the title compound (142 mg, 79%) was obtained as a yellow powder: mp 252-254° C.; 1H NMR (500 MHz, CD3OD) δ 8.24 (s, 1H), 7.82 (d, J=2.0 Hz, 1H), 7.78 (d, J=9.0 Hz, 1H), 7.58 (d, J=7.5 Hz, 1H), 7.46 (dd, J=9.0, 2.0 Hz, 1H), 6.29 (dd, J=7.5, 3.0 Hz, 1H), 6.04 (d, J=2.5 Hz, 1H), 4.87 (t, J=6.5 Hz, 2H), 3.86 (t, J=5.5 Hz, 2H), 3.69-3.72 (m, 2H), 3.63 (s, 2H), 3.16-3.20 (m, 2H), 2.16-2.19 (m, 2H), 2.00-2.03 (m, 3H), 1.71-1.84 (m, 12H), 1.24-1.31 (m, 2H); ESI MS m/z 473 [M+H]+; HPLC (Method D) 98.9% (AUC), tR=15.4 min.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH:13]1([Mg]Cl)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C(OCC)C>[CH2:10]([O:9][C:7](=[O:8])[C:6]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)([OH:12])[C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH3:11]
Reactant: Cl[Mg]C1CCCCC1
Reactant: CCOC(=O)C(=O)c1cccs1
Solvent: CCOCC
Product: CCOC(=O)C(O)(c1cccs1)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred, cooled (0° C.) solution of ethyl thiophene-2-glyoxylate (125.6 g, 0.683 mol) in diethyl ether (2 litres) is added dropwise 2M cyclohexyl magnesium chloride in ether (400 ml, 0.8 mol) over 1 hour. After stirring at room temperature for 2 hours, the reaction is quenched by addition of saturated ammonium chloride solution (1 litre of a 270 g/l solution) and water (1 litre) ensuring the temperature does not rise above 20° C. The organic portion is separated and washed with brine (1 litre), dried over magnesium sulphate and concentrated in vacuo, to yield the titled compound as an orange oil which is used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([O:8][N:9]1[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][S:17](Cl)(=[O:19])=[O:18].CCOC(C)=O.O>C1COCC1>[CH3:16][S:17]([O:15][CH:12]1[CH2:13][CH2:14][N:9]([O:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:10][CH2:11]1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)ON1CCC(O)CC1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)ON1CCC(OS(C)(=O)=O)CC1
Reaction time: 2.5 h
Yield: 87.9 %

Procedure:
To a solution of 1-[(tert-butoxycarbonyl)oxy]piperidin-4-ol (10.0 g, 49.7 mmol) in THF (200 mL), were added TEA (20.7 mL, 149 mmol) and methanesulfonyl chloride (7.69 mL, 99.4 mmol) at 0° C. The mixture was stirred for 2.5 h at the same temperature. To the mixture was added EtOAc (100 mL) and water (100 mL) and then organic layer has been separated. The aqueous layer has been extracted with EtOAc (50 mL) and the combined organic layer was washed with brine (30 mL). The organic layer was dried over anhydrous magnesium sulfate and then insoluble materials were removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (EtOAc/hexane 20/80→350/50). Concentration of appropriate fractions afforded crude product, which was washed with a 1:1 mixture of diethyl ether and hexane (50 mL) to give title compound (12.9 g, 92%) as a pale yellow solid.
Reaction SMILES: Cl[CH:2]1[NH+:11]2[CH2:12][CH2:13][C:14]3[C:19]([C:10]2=[CH:9][C:8]2[CH:7]=[CH:6][C:5]([O:23][CH3:24])=C(OC)[C:3]1=2)=[CH:18][C:17]1[O:20][CH2:21][O:22][C:16]=1[CH:15]=3.[Cl-].C[Mg]Cl.O1CCC[CH2:32]1.[CH2:36]([O:38][CH2:39][CH3:40])C>>[CH3:36][O:38][C:39]1[C:40]2[C:2]([CH3:3])([CH3:32])[N:11]3[CH2:12][CH2:13][C:14]4[C:19]([C:10]3=[CH:9][C:8]=2[CH:7]=[CH:6][C:5]=1[O:23][CH3:24])=[CH:18][C:17]1[O:20][CH2:21][O:22][C:16]=1[CH:15]=4
Reactant: COc1ccc2c(c1OC)C(Cl)[NH+]1CCc3cc4c(cc3C1=C2)OCO4
Reactant: CCOCC
Reactant: C1CCOC1
Agent: C[Mg]Cl
Agent: [Cl-]
Product: COc1ccc2c(c1OC)C(C)(C)N1CCc3cc4c(cc3C1=C2)OCO4
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
To a suspension of 8-chloro-9,10-dimethoxy-5,6-dihydro-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinolin-7-ylium; chloride (2 g, 5 mmol) in anhydrous diethyl ether (150 mL) at 0° C. was added a solution of methylmagnesium chloride in tetrahydrofuran (3 M, 18 mL, 54 mmol) dropwise. After stirring at 0° C. for 30 min, the reaction was quenched by adding saturated aqueous ammonium chloride solution (50 mL). The mixture was extracted with diethyl ether (2×100 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was re-crystallized from diethyl ether to afford 9,10-dimethoxy-8,8-dimethyl-5,8-dihydro-6H-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinoline (1.6 g, 87%). LC/MS m/e calcd for C22H23NO4 (M+H)+: 366.43, observed: 366.0; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.65 (s, 6 H) 2.73 (t, J=5.56 Hz, 2 H) 3.27 (t, J=5.56 Hz, 2 H) 3.76 (s, 6 H) 5.69 (s, 1 H) 5.99 (s, 2 H) 6.59 (d, J=8.34 Hz, 1 H) 6.74 (s, 1 H) 6.81 (d, J=8.34 Hz, 1 H) 7.21 (s, 1 H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].C(OC(=O)C)(=O)C.[CH3:12][C:13]1[S:17][C:16]([C:18]([OH:20])=[O:19])=[CH:15][CH:14]=1>>[CH3:12][C:13]1[S:17][C:16]([C:18]([OH:20])=[O:19])=[CH:15][C:14]=1[N+:1]([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(C(=O)O)s1
Solvent: CC(=O)OC(C)=O
Product: Cc1sc(C(=O)O)cc1[N+](=O)[O-]
Temperature: -78 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
Under N2, fuming nitric acid (4.7 mL, 112.0 mmol) was added slowly over 10 min to acetic anhydride (16.6 mL, 175.6 mmol) cooled in a dry ice/acetone bath to −78° C. 5-methyl-2-thiophene carboxylic acid (5.0 g, 35.2 mmol) was added in 1 g portions over 10 min to the solution. The reaction was kept at −20° C. for 1 h before quenching over ice. The yellow solid was filtered off and washed with water (200 mL). The crude product was recrystallized from 95% EtOH to give 5-methyl-4-nitro-2-thiophene carboxylic acid as a pale yellow solid (4.6 g, 70%). 1H NMR (400 MHz, CD3OD) δ (ppm) 8.13 (s, 1H) 2.82 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][N:3]=1.[CH2:11]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH3:12].C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[CH2:11]([N:13]1[CH2:18][CH2:17][N:16]([C:2]2[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][N:3]=2)[CH2:15][CH2:14]1)[CH3:12]
Reactant: CCN1CCNCC1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCN1CCN(c2cc([N+](=O)[O-])ccn2)CC1
Temperature: 100 °C
Yield: 66.1 %

Procedure:
A mixture of 2 g (13 mmol) 2-chloro-4-nitropyridine, 1.73 g (15 mmol) 1-ethyl-piperazine and 0.81 g (6 mmol) N,N-diisopropylethylamine (DIPEA) in 19 ml DMF and 20 ml water was heated to 100° C. for 24 h. The precipitate was filtered off and washed three times with 4 ml of water and dried for 24 h under vacuum to yield 2.03 g (68%) of the title compound as yellow oil (m/e): 236.7 (MH+; 100%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:30][C:12]2=[CH:13][C:14]3[C:15](=[O:29])[N:16]([CH:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)[C:17](=[O:21])[C:18]=3[C:19]([CH3:20])=[C:11]2[N:10]=1.[F:31][C:32]1[CH:33]=[CH:34][C:35]([CH3:42])=[C:36]([CH2:38][CH:39]([NH2:41])[CH3:40])[CH:37]=1.CCN(C(C)C)C(C)C>C(O)CCC>[F:31][C:32]1[CH:33]=[CH:34][C:35]([CH3:42])=[C:36]([CH2:38][CH:39]([NH:41][C:2]2[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=2[C:9]2[NH:30][C:12]3=[CH:13][C:14]4[C:15](=[O:29])[N:16]([CH:22]5[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]5)[C:17](=[O:21])[C:18]=4[C:19]([CH3:20])=[C:11]3[N:10]=2)[CH3:40])[CH:37]=1
Reactant: Cc1c2c(cc3[nH]c(-c4c(Cl)cc[nH]c4=O)nc13)C(=O)N(C1CCN(C)CC1)C2=O
Reactant: Cc1ccc(F)cc1CC(C)N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1ccc(F)cc1CC(C)Nc1cc[nH]c(=O)c1-c1nc2c(C)c3c(cc2[nH]1)C(=O)N(C1CCN(C)CC1)C3=O
Yield: 100.1 %

Procedure:
A mixture of 2-(4-chloro-2-oxo-1,2-dihydropyridin-3-yl)-4-methyl-6-(1-methylpiperidin-4-yl)imidazo[4,5-f]isoindole-5,7(1H,6H)-dione (1.00 g, 2.35 mmol), 1-(5-fluoro-2-methylphenyl)propan-2-amine (0.47 g, 2.82 mmol), Hunig's base (1.52 g, 0.011 mol), and 20 mL of anhydrous 1-butanol was heated at reflux for 14-15 h under an argon atmosphere. Product was purified by a silica gel column using methylene chloride and methanol (9:1 v/v) as eluent to afford 1.31 g (99%) of the designed compound as yellowish solid. 1H NMR (300 MHz, DMSO-d6) δ 13.37 (s, 1H, NH), 11.25 (d, J=6.3 Hz, 1H, NH), 11.02 (d, J=8.1 Hz, 1H, NH), 7.98 (s, 1H, ArH), 7.32 (t, J=7.2 Hz, 1H, ArH), 7.16-7.07 (m, 2H, ArH), 6.92-6.86 (m, 1H, ArH), 6.17 (d, J=7.5 Hz, 1H, ArH), 4.34-4.19 (m, 2H, 2×CH), 3.51-3.47 (m, 2H, CH2), 3.18-3.11 (m, 2H, CH2), 2.97 (d, J=6.3 Hz, 2H, CH2), 2.83 (s, 3H, CH3), 2.76 (s, 31-1, CH3), 2.69-2.61 (m, 2H, CH2), 2.27 (s, 3H, CH3), 1.95-1.91 (m, 2H, CH2), 1.34 (d, J=6.3 Hz, 3H, CH3); Mass (ESI, positive) m/z 557.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:10](/[C:11](=[N:13]/[OH:14])/[NH2:12])=[C:4]2[CH:3]=1.[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24].N12CCCN=C1CCCCC2>O1CCOCC1.Cl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:10]([C:11]3[NH:12][C:23](=[O:24])[O:14][N:13]=3)=[C:4]2[CH:3]=1
Reactant: COc1ccc(-c2nn3ccc(Br)cc3c2/C(N)=N/O)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(-c2nn3ccc(Br)cc3c2-c2noc(=O)[nH]2)cc1
Yield: 78.1 %

Procedure:
A mixture of Example 19G (0.74 g, 2.049 mmol), 1,1′-carbonyldiimidazole (0.365 g, 2.254 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.340 mL, 2.254 mmol) in dioxane (10 mL) was refluxed for 1 hour, cooled and diluted with 1 M aqueous HCl. The resulting solid was collected by filtration, washed with water and dried. The solid was triturated twice with 1% methanol in dichloromethane to give the title compound (0.62 g, 78%). MS (ESI+) m/z 387/389 (M+H)+.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:9][C:10]1[C:15]([C:16]([C:18]2[CH2:22][CH2:21][CH2:20][C:19]=2N2CCCC2)=[O:17])=[CH:14][CH:13]=[CH:12][N:11]=1.C(O)(C)(C)C>C(N(CC)CC)C>[Cl:9][C:10]1[C:15]([C:16]([C:18]2[CH2:22][CH2:21][CH2:20][C:19]=2[NH:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:17])=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CCOC(=O)CN
Reactant: O=C(C1=C(N2CCCC2)CCC1)c1cccnc1Cl
Agent: Cl
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC1=C(C(=O)c2cccnc2Cl)CCC1

Procedure:
Add equimolar amounts of ethyl glycinate hydrochloride, triethylamine, and (2-chloro-3-pyridinyl)[2-(1-pyrrolidinyl)-1-cyclopenten-1-yl]methanone to t-butyl alcohol (170 ml per 0.020 mole of amine). Reflux the resulting mixture for 34 hrs, monitoring the reaction by thin-layer chromatography as needed. Cool the reaction mixture, and evaporate solvent. Wash a CHCl3 solution of the residue with water and with saturated aqueous NaCl solution. After drying the organic solution, evaporate the solvent to obtain the resulting enaminoketone, (2-chloro-3-pyridinyl)[2-(1-ethoxycarbonylmethanaminyl)-1-cyclopenten-1-yl]methanone, m.p. 114.5°-117.5° C., after recrystallization from isopropanol.