Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[CH:19]([CH:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23]1)([CH3:21])[CH3:20].Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[CH:19]([CH:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]1[C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1)([CH3:21])[CH3:20]
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: CC(C)C1Cc2ccccc2N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)C1Cc2ccccc2N1C(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Yield: 67.5 %

Procedure:
The product is prepared by following the procedure described in example 1c using 0.27 g of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 0.15 g of (+)-2-isopropylindoline and 0.24 g of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 0.23 ml of pyridine and 3.8 ml of N,N-dimethylformamide. 0.24 g of (+)-2-[2-(2-isopropyl-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one (reference example 12c) is thus obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].[Cl:8][C:9]1[C:14]([F:15])=[C:13](Cl)[N:12]=[CH:11][N:10]=1>C1COCC1>[Cl:8][C:9]1[C:14]([F:15])=[C:13]([O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)[N:12]=[CH:11][N:10]=1
Reactant: OCC1CC1
Reactant: Fc1c(Cl)ncnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Fc1c(Cl)ncnc1OCC1CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
0.55 mL (5.99 mmol) cyclopropane methanol in 15 mL THF are charged with 0.31 g (7.19 mmol) NaH and the reaction mixture is stirred at r.t. for 10 min. Then 1.00 g (5.99 mmol) 4,6-dichloro-5-fluoro-pyrimidine are added and stirred at r.t. for 1 h. Afterwards the reaction is quenched by the addition of water and extracted with EtOAc. The organic layers are combined, washed with water (2×), dried over MgSO4, filtered and the solvent is removed in vacuo.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2Cl)=[CH:4][C:3]=1[F:13].C([O-])(=[O:16])C.[NH4+]>C(O)(=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][NH:8][C:9]2=[O:16])=[CH:4][C:3]=1[F:13]
Reactant: Fc1cc2ccnc(Cl)c2cc1Br
Reactant: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=c1[nH]ccc2cc(F)c(Br)cc12
Temperature: 100 °C
Reaction time: 3 h
Yield: 82.7 %

Procedure:
12.9 g (49.5 mmol) 7-bromo-1-chloro-6-fluoro-isoquinoline (94) were dissolved in 250 ml of acetic acid. After addition of 38.7 g (0.5 mol) of ammonium acetate, the solution is stirred at 100° C. After 3 h, the solvent was removed under reduced pressure and the residue was poured into water. The precipitate is filtered and dried to yield 9.91 g (83%) of the title compound. Rt=1.15 min (Method C). Detected mass: 242.2/244.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:15]([CH3:17])=O)[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8].[N+:18]([C:21]1[CH:30]=[C:29]([C:31]([NH:33][NH2:34])=[O:32])[CH:28]=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24])([O-:20])=[O:19]>>[N+:18]([C:21]1[CH:30]=[C:29]([C:31]([NH:33][N:34]=[C:15]([C:12]2[C:13]([OH:14])=[C:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[S:10][CH:11]=2)[CH3:17])=[O:32])[CH:28]=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24])([O-:20])=[O:19]
Reactant: CC(=O)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Reactant: COC(=O)c1ccc(C(=O)NN)cc1[N+](=O)[O-]
Product: COC(=O)c1ccc(C(=O)NN=C(C)c2csc(-c3ccc(Cl)c(Cl)c3)c2O)cc1[N+](=O)[O-]

Procedure:
Using 2-(3,4-dichlorophenyl)-3-hydroxy-4-methylcarbonylthiophene (100 mg, 0.35 mmol) and methyl 2-nitro-4-hydrazinocarbonylbenzoate (93 mg, 0.39 mmol) as the starting materials, the desired product was obtained in the same manner as in Synthetic Example 65 as a yellow solid (147 mg, yield 83%).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:19])[N:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)[N:5]=[CH:6][C:7]=1[Cl:8].[N+](C1C=CC(CCl)=CC=1)([O-])=O.NC1C=CC(CN2C(=O)C(Cl)=C(Cl)C=N2)=CC=1.[CH3:48][S:49](Cl)(=[O:51])=[O:50]>C(O)(=O)C.N1C=CC=CC=1.[Fe]>[Cl:1][C:2]1[C:3](=[O:19])[N:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][S:49]([CH3:48])(=[O:51])=[O:50])=[CH:12][CH:11]=2)[N:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CS(=O)(=O)Cl
Reactant: O=c1c(Cl)c(Cl)cnn1Cc1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: Nc1ccc(Cn2ncc(Cl)c(Cl)c2=O)cc1
Agent: O=[N+]([O-])c1ccc(CCl)cc1
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: CS(=O)(=O)Nc1ccc(Cn2ncc(Cl)c(Cl)c2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.8 %

Procedure:
4.5 g (15 mmoles) of 4,5-dichloro-2-(4-nitrobenzyl)-3(2H)-pyridazinone (prepared according to method III but using 4-nitrobenzyl chloride instead of 3-phenyl-2-propenyl chloride (M.P. 128-130 celsius)) are dissolved in 150 ml of 99.5% acetic acid solution. Then 7.5 g of iron dust are added to the solution at such a rate that the temperature should not exceed 20° C., and the suspension is stirred at room temperature for 8 hours. By working up the reaction mixture in the usual manner 3.15 g (77%) of 2-(4-aminobenzyl)-4,5-dichloro-3(2H)-pyridazinone melting at 187°-189° C. are obtained, which is dissolved in 34 ml of anhydrous pyridine. To the solution 1.24 ml (16 moles) of methanesulfonyl chloride are dropped under stirring and cooling at such a rate that the inner temperature should remain between 0° C. and 5° C. The mixture is then stirred at room temperature for 4 hours and poured onto water. The separated crystals are filtered and washed with water. Thus 2.34 g (57%) of the desired compound are obtained. M.p.: 152°-154° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16](=O)([O-])[O-].[K+].[K+].COP(C(=[N+]=[N-])C(=O)C)(=O)OC>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[CH:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Solvent: CO
Product: C#CC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
At 0 C., to a stirred mixture of 4-formyl-piperidine-1-carboxylic acid tert-butyl ester (358 mg, 1.68 mmols) and potassium carbonate (464 mg, 3.36 mmols) in methanol (16 ml) was added dropwise a solution of (1-diazo-2-oxo-propyl)-phosphonic acid dimethyl ester (323 mg, 1.68 mmols) in methanol (2 ml). The resulting mixture was stirred at room temperature overnight, filtered and concentrated. The residue was chromatographed on silica gel using a solution of ethyl acetate in hexanes (1:5) to provide the title compound (308 mg, 88%) as colorless crystals. LCMS m/e (154, M−t-Bu+2H). (J. Am. Chem. Soc. 2003, 125, 3714.)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:58]=[CH:57][C:6]([CH2:7][N:8]([CH2:48][C:49]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:33][C:34]4[CH:35]=[CH:36][C:37]([NH:40]C(=O)OC(C)(C)C)=[N:38][CH:39]=4)=[N:18][CH:19]=[C:20]([CH2:22][N:23]4[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:25][CH2:24]4)[CH:21]=3)[N:10]=2)=[CH:5][CH:4]=1.C(O)(C(F)(F)F)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:56][O:55][C:52]1[CH:51]=[CH:50][C:49]([CH2:48][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:58][CH:57]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:33][C:34]4[CH:35]=[CH:36][C:37]([NH2:40])=[N:38][CH:39]=4)=[N:18][CH:19]=[C:20]([CH2:22][N:23]4[CH2:24][CH2:25][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:27][CH2:28]4)[CH:21]=3)[N:10]=2)=[CH:54][CH:53]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)CC4)cnc3Nc3ccc(NC(=O)OC(C)(C)C)nc3)n2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)CC4)cnc3Nc3ccc(N)nc3)n2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.5 %

Procedure:
tert-Butyl 5-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-2-ylamino)pyridin-2-ylcarbamate (0.306 g, 0.377 mmol) was dissolved into DCM (5 mL total) in two 20 mL scintillation vials. TFA (2.5 mL total) was added and the solutions were stirred at rt for 3 h. The reaction mixtures were combined and poured into 20 mL of saturated aqueous sodium bicarbonate. The aqueous phase was extracted with 25% iPrOH in CHCl3+1% NH4OH (2×20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (25 g, eluent: iPrOH (w/10% NH4OH) in CHCl3 0%-20%) to give N5-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-2-yl)pyridine-2,5-diamine (0.221 g, 82% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 11.44 (br. s., 1H); 8.69 (br. s., 1H); 8.15-8.21 (m, 1H); 8.12 (br. s., 1H); 7.69-7.79 (m, 1H); 7.21 (d, J=8.61 Hz, 4H); 6.85 (dd, J=15.75, 8.51 Hz, 4H); 6.49 (d, J=8.80 Hz, 1H); 4.83 (d, J=15.85 Hz, 4H); 4.27 (br. s., 2H); 3.75-3.85 (m, 6H); 3.48 (br. s., 2H); 3.18 (br. s., 4H); 2.68-2.76 (m, 3H); 2.49-2.61 (m, 7H). m/z (ESI, +ve ion) 711.0 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C@H:12]1[CH2:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[CH:15]2[CH2:23][CH2:24][CH:25]=[CH:26][N:14]2[C:13]1=[O:27].S(=O)(=O)(O)O.[CH:33]([OH:35])=[O:34].[C]=O>>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]1[CH2:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[CH:15]2[CH2:23][CH2:24][CH2:25][C@@H:26]([C:33]([OH:35])=[O:34])[N:14]2[C:13]1=[O:27]
Reactant: O=C1[C@@H](N2C(=O)c3ccccc3C2=O)Cc2ccccc2C2CCC=CN12
Reactant: O=CO
Agent: O=S(=O)(O)O
Agent: [C]=O
Product: O=C(O)[C@@H]1CCCC2c3ccccc3CC(N3C(=O)c4ccccc4C3=O)C(=O)N21
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Combine (S)-7-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)]-1,2,6,7,8,12b-hexahydro-6-oxopyrido[2,1-a][2]benzazepine (800 mg, 2.2 mmol) and sulfuric acid (24 mL) in a pressure vessel. Carefully, add formic acid (4.0 mL, 87 mmol) to minimize mixing and thereby the formation of carbon monoxide. Seal the pressure vessel and add carbon monoxide to 300 psi before stirring. (Caution, upon mixing a sharp rise in pressure will occur.) After 16 hours, vent the vessel and add the reaction mixture to an ice/water mixture (160 mL). Extract repeatedly with ethyl acetate. Combine the organic layers and extract repeatedly with aqueous 10% potassium bicarbonate solution. Combine the potassium bicarbonate solution layers and cool in an ice-bath. Acidify to pH 1 using aqueous 6M hydrochloric acid solution. Extract the acidified aqueous layer repeatedly with ethyl acetate. Combine the organic layers and extract with saturated aqueous sodium chloride solution, dry over MgSO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[N:5]1[C:10]2[NH:11][C:12]3[CH:20]=[N:19][CH:18]=[CH:17][C:13]=3[CH2:14][C:15](=[O:16])[C:9]=2[CH:8]=[CH:7][CH:6]=1>O.C(O)(=O)C>[N:5]1[C:10]2[NH:11][C:12]3[CH:20]=[N:19][CH:18]=[CH:17][C:13]=3/[C:14](=[N:1]/[OH:3])/[C:15](=[O:16])[C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: O=C1Cc2ccncc2Nc2ncccc21
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=c1/c(=N\O)c2ccncc2[nH]c2ncccc12
Reaction time: 1.5 h
Yield: 87 %

Procedure:
A solution of sodium nitrite (3.3 g, 0.048 mol) in water (14.4 mL) was added dropwise to a solution of 6,11-dihydro-5H-dipyrido[2,3-b:4′,3′-f]azepin-5-one (4.22 g, 0.02 mol) in acetic acid (80 mL) at room temperature. After the addition was completed, the reaction was stirred for 1.5 hours and 100 mL of water was then added. The mixture was stirred for additional 10 minutes, filtered and dried to give 4.18 g of the desired product. 1H NMR (400 MHz, CD3OD): δ 8.70 (s, 1H), 8.48-8.51 (m, 2H), 8.32 (d, 1H, J=5.2 Hz), 7.56 (d, 1H, J=5.6 Hz), 7.07 (dd, 1H, J1=8 Hz, J2=4.8 Hz). MS [M+H]=241.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12](/[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:22][CH:21]=3)\[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[C:33]1([CH2:39][C:40](Cl)=[O:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[C:33]1([CH2:39][C:40]([NH:1][C:2]2[CH:10]=[C:9]3[C:5](/[C:6](=[C:12](/[NH:19][C:20]4[CH:25]=[CH:24][C:23]([CH2:26][N:27]5[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]5)=[CH:22][CH:21]=4)\[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)/[C:7](=[O:11])[NH:8]3)=[CH:4][CH:3]=2)=[O:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: Nc1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCCCC2)cc1)c1ccccc1
Reactant: O=C(Cl)Cc1ccccc1
Product: O=C(Cc1ccccc1)Nc1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCCCC2)cc1)c1ccccc1

Procedure:
Prepared from 6-amino-3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-phenyl-methylidene}-2-indolinone and phenylacetic acid chloride
Reaction SMILES: [CH3:1]I.[OH:3][C:4]1[CH:9]=[CH:8][N:7]([C:10]2[S:11][C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:13]([CH3:15])[N:14]=2)[C:6](=[O:21])[CH:5]=1>>[CH3:1][O:3][C:4]1[CH:9]=[CH:8][N:7]([C:10]2[S:11][C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:13]([CH3:15])[N:14]=2)[C:6](=[O:21])[CH:5]=1
Reactant: CCOC(=O)c1sc(-n2ccc(O)cc2=O)nc1C
Reactant: CI
Product: CCOC(=O)c1sc(-n2ccc(OC)cc2=O)nc1C
Yield: 54 %

Procedure:
Following the procedure as described in Example 15, making variations only as required to use methyl iodide in place of (bromomethyl)cyclopropane to react with ethyl 2-(4-hydroxy-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylate, the title compound was obtained as a yellowish solid in 54% yield: mp 163-165° C. (hexane/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 8.67 (d, J=8.1 Hz, 1H), 6.16 (dd, J=8.1, 2.7 Hz, 1H), 6.00 (d, J=2.7 Hz, 1H), 4.32 (q, J=7.1 Hz, 2H), 3.83 (s, 3H), 2.68 (s, 3H), 1.36 (t, J=7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 168.3, 162.9, 162.2, 156.6, 155.7, 131.3, 119.7, 103.8, 96.3, 60.9, 56.0, 17.3, 14.3; MS (ES+) m/z 295.2 (M+1).
Reaction SMILES: [CH2:1]([Zn]CC)C.ClCI.[OH:9][CH2:10][C:11](=[CH2:25])[CH2:12][CH2:13][N:14]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=[O:24].[NH4+].[Cl-]>C(Cl)Cl>[O:24]=[C:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22](=[O:23])[N:14]1[CH2:13][CH2:12][C:11]1([CH2:10][OH:9])[CH2:1][CH2:25]1
Reactant: C=C(CO)CCN1C(=O)c2ccccc2C1=O
Reactant: CC[Zn]CC
Agent: ClCI
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1CCC1(CO)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.2 %

Procedure:
To a cold (0° C.), stirred solution of diethyl zinc (1.0 M in hexanes, 4.0 mL, 4.0 mmol) in CH2Cl2 (10 mL) was added neat ClCH2I (0.59 mL, 8.10 mmol) drop wise by syringe. After 30 minutes, a solution of 2-(3-Hydroxymethyl-but-3-enyl)-isoindole-1,3-dione (0.456 g, 1.97 mmol) in CH2Cl2 (6 mL) was added by cannula. After 60 minutes, the reaction mixture was treated with saturated aqueous NH4Cl (20 mL), diluted with CH2Cl2 (20 mL), and warmed to room temperature. The phases were separated and the aqueous phase was extracted with CH2Cl2 (3×20 mL). The combined organic extracts were dried (Na2SO4) and concentrated. The crude material was purified by column chromatography on silica gel (1:1 hexanes-ethyl acetate) and provided 0.31 g (64%) of 1-[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-cyclopropane-methanol as a white solid. 1H NMR (CDCl3) δ 0.31-0.34 (m, 2H), 0.38-0.43 (m, 2H), 1.75 (t, 2H, J=6.9 Hz), 3.54 (s, 2H), 3.90 (t, 2H, J=6.6 Hz), 7.70-7.73 (m, 2H), 7.81-7.85 (m, 2H);
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:32])=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=4)[C:26](O)=[O:27])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[F:33][C:34]1[CH:35]=[N:36][C:37]([C:40]2([NH2:43])[CH2:42][CH2:41]2)=[N:38][CH:39]=1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:29]=[C:25]([C:26](=[O:27])[NH:43][C:40]5([C:37]6[N:38]=[CH:39][C:34]([F:33])=[CH:35][N:36]=6)[CH2:42][CH2:41]5)[C:24]([O:30][CH3:31])=[CH:23][C:22]=4[CH3:32])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: NC1(c2ncc(F)cn2)CC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)cc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ncc(F)cn5)CC4)c(OC)cc3C)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.04 g, 0.092 mmol, 1 eq), 1-(5-fluoropyrimidin-2-yl)cyclopropanamine (130 mg, crude), Py-Bop (0.062 g, 0.12 mmol, 1.3 eq) in DMF at ambient temperature under nitrogen was added triethylamine (0.028 g, 0.3 mmol, 3 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was purified by preparative HPLC. Yield: 0.03 g (57%). 1H NMR (400 MHz, CD3OD): δ 8.59 (s, 2H), 8.04-7.93 (m, 2H), 7.90 (s, 1H), 7.65 (s, 1H), 7.59 (d, J=1.5 Hz, 1H), 7.34 (dd, J=1.8, 8.5 Hz, 1H), 7.31-7.25 (m, 2H), 7.15 (s, 1H), 4.07 (s, 3H), 3.00-2.92 (m, 3H), 2.37 (s, 3H), 1.80-1.72 (m, 2H), 1.54-1.43 (m, 2H). 19F NMR (376.47 MHz, CD3OD): δ−113.44, 146.33 LCMS: (ES+) m/z=569.2 (M+H)+
Reaction SMILES: [Na].[C:2]([CH2:4][C:5]([O:7][CH2:8]C)=[O:6])#[N:3].[CH:10](I)([CH3:12])[CH3:11]>CO>[CH:10]([CH:4]([C:2]#[N:3])[C:5]([O:7][CH3:8])=[O:6])([CH3:12])[CH3:11]
Reactant: CCOC(=O)CC#N
Reactant: CC(C)I
Agent: [Na]
Solvent: CO
Product: COC(=O)C(C#N)C(C)C
Temperature: 25 °C

Procedure:
In 20 ml of absolute methanol was dissolved 520 mg of metallic sodium, and 2.12 g of ethyl cyanoacetate was added thereto with stirring at room temperature, after which 4.0 of isopropyl iodide was added dropwise over a period of 10 minutes. After completion of the dropwise addition, the resulting mixture was stirred at room temperature for 3 hours, refluxed for 1 hour, subjected to a conventional post-treatment, and then distilled under reduced pressure to obtain 2.1 g of methyl α-isopropylcyanoacetate.
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[NH:3][CH2:2]1.CN(C)C=O.[OH-].[K+].[Br:14][CH2:15][CH2:16][CH2:17][CH2:18]Br>O>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][N:3]1[C:4](=[O:6])[CH2:5][S:1][CH2:2]1
Reactant: O=C1CSCN1
Reactant: BrCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CSCN1CCCCBr
Reaction time: 44 h

Procedure:
A mixture of 4-thiazolidinone (25 g), dimethylformamide (DMF hereafter, 500 ml) and KOH (27.16 g) was stirred under N2 at room temperature for 1.5 h. To the resulting mixture was added 1,4-dibromobutane (101 ml), which rapidly caused the reaction mixture to turn milky white. Stirring was continued at room temperature for 44 h. The reaction mixture was poured into H2O (1000 ml) and the aqueous mixture was extracted with ethyl acetate (EtOAc hereafter, 3×300 ml). the combined extracts were washed successively with H2O (300 ml) and brine (300 ml), dried over Na2SO4, and concentrated in vacuo to an amber oil. HPLC (high performance liquid chromatography) of a 44.95 g aliquot yielded 7.15 g of an oil which upon distillation yielded a clear liquid, b.p. 134°-137° C./0.12 mm Hg.
Reaction SMILES: [C:1]([C:4]1[NH:5][CH:6]=[NH+:7][C:8]=1[O-:9])(=[O:3])[NH2:2].C(N(CC)CC)C.[C:17]12([C:27](Cl)=[O:28])[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]3)[CH2:18]1)[CH2:24]2>CN(C)C=O>[C:17]12([C:27]([O:9][C:8]3[N:7]=[CH:6][NH:5][C:4]=3[C:1](=[O:3])[NH2:2])=[O:28])[CH2:24][CH:23]3[CH2:22][CH:21]([CH2:20][CH:19]([CH2:25]3)[CH2:18]1)[CH2:26]2
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: NC(=O)c1[nH]c[nH+]c1[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=O)c1[nH]cnc1OC(=O)C12CC3CC(CC(C3)C1)C2
Reaction time: 15 h
Yield: 61.3 %

Procedure:
To a suspension of 4-carbamoylimidazolium-5-olate (4.064 g) in dimethylformamide (80 ml) was added triethylamine (7.768 g) at 0°-5° C. and then 1-adamantanecarbonylchloride (14.00 g) in dimethylformamide (80 ml) dropwisely over 22 minutes. The reaction mixture was stirred at 0°-5° C. for 15 hours. The solvent was removed under reduced pressure. To the residue was added ethyl acetate (100 ml) and water (100 ml), and stirred at room temperature for 1 hours. The insoluble solid was filtered and washed with ethyl acetate to give almost pure 5-carbamoyl-1H-imidazol-4-yl 1-adamantanecarboxylate (5.67 g, β form, m.p. 207°-210° C. (dec.)).
Reaction SMILES: [CH3:1][C:2]1[NH:3][N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5](=[O:7])[CH:6]=1.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]2[S:33][C:32](SCC)=[N+:31]([CH2:37][CH3:38])[C:30]=2[CH:39]=1.C(N(CC)CC)C>CO>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]2[S:33](=[C:6]3[C:5](=[O:7])[N:4]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[NH:3][CH:2]3[CH3:1])[CH2:32][N:31]([CH2:37][CH3:38])[C:30]=2[CH:39]=1
Reactant: Cc1cc(=O)n(-c2ccccc2)[nH]1
Reactant: CCSc1sc2ccc(Cl)cc2[n+]1CC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CO
Solvent: CCN(CC)CC
Product: CCN1CS(=C2C(=O)N(c3ccccc3)NC2C)c2ccc(Cl)cc21
Reaction time: 1 h

Procedure:
3-Methyl-1-phenylpyrazolin-5-one (1.74 g, 0.01) was mixed with 4.3 g (0.01 mol) 5-chloro-2-ethylthio-3-ethylbenzothiazolium tosylate in 15 ml methanol. Triethylamine (1.01 g, 0.01 mol) was added. The mixture was stirred for 1 hour, then filtered and washed with methanol. After drying the yield was 2.20 g (59%), mp 161°-162.5° C., λmax=382 (ε=21,000).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH:8]2[C:13]3[CH:14]=[C:15]([C:18]#[N:19])[CH:16]=[CH:17][C:12]=3[O:11][C:10]([CH3:21])([CH3:20])[CH2:9]2)[CH:5]=[CH:4][CH:3]=1.C([OH:25])(C)C>>[NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH:8]2[C:13]3[CH:14]=[C:15]([C:18]#[N:19])[CH:16]=[CH:17][C:12]=3[O:11][C:10]([CH3:21])([CH3:20])[CH2:9]2)[N+:7]=1[O-:25]
Reactant: CC(C)O
Reactant: CC1(C)CC(c2cccc(N)n2)c2cc(C#N)ccc2O1
Product: CC1(C)CC(c2cccc(N)[n+]2[O-])c2cc(C#N)ccc2O1

Procedure:
In an analogous manner to that described in the first paragraph of Example 7, from 4-(6-amino-2-pyridyl)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile there was obtained 2-amino-6-(6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)pyridine N-oxide of melting point 210°-212° C. (from isopropanol).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][CH2:9][CH2:10][CH2:11][S:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]([CH2:9][CH2:10][CH2:11][S:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[C:26](=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: c1ccc(CNCCCSc2ccncc2)nc1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)N(CCCSc1ccncc1)Cc1ccccn1
Yield: 58.9 %

Procedure:
To a solution of 1.60 g (6.17 mmol) of 4-[3-(N-2-pyridylmethylamino)propylthio)pyridine and 1.05 ml (7.40 mmol) of triethylamine in 10 ml of methylene chloride, 0.86 ml (7.40 mmol) of benzoyl chloride was added under ice-cooling with stirring. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and water and dried, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate/methanol=10:1) to obtain 1.32 g of the desired compound (yield: 58.9%, yellow oil).