Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:9]=[C:8]([CH2:10]I)[N:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[C:19](=[O:27])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[N:6]=1)=[O:4].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>CO>[CH3:1][O:2][C:3]([C:5]1[N:9]=[C:8]([CH2:10][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[N:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[C:19](=[O:27])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(CI)n(-c2ccc(Cl)cc2C(=O)c2ccccc2Cl)n1
Reactant: C1COCCN1
Solvent: CO
Product: COC(=O)c1nc(CN2CCOCC2)n(-c2ccc(Cl)cc2C(=O)c2ccccc2Cl)n1
Reaction time: 8 h

Procedure:
A mixture of 38.7 g (0.075 mole) of 1-[2-(o-chlorobenzoyl)-4-chlorophenyl]-5-(iodomethyl)-1H-1,2,4-triazole-3-carboxylic acid methyl ester and 13.1 g (0.150 mole) of morpholine in 750 ml of methanol is stirred for 8 hours at 40°. The reaction mixture is then concentrated in vacuo; water is added to the residue and extraction is performed twice with methylene chloride. The organic phase is washed three times with water and twice with saturated sodium chloride solution; it is dried over sodium sulphate and concentrated in vacuo. The residue is triturated with ether, whereupon the reaction product is obtained in crystalline form. After filtration with suction and drying in vacuum, there is obtained 1-[2-(o-chlorobenzoyl)-4-chlorophenyl]-5-(morpholinomethyl)-1H-1,2,4-triazole-3-carboxylic acid methyl ester, m.p. 141°-143°.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.[Cl:20][CH2:21][C:22](Cl)=[O:23]>C(Cl)Cl>[Br:1][C:2]1[CH:8]=[CH:7][C:6]([C:9]([F:10])([F:11])[F:12])=[CH:5][C:3]=1[NH:4][C:22](=[O:23])[CH2:21][Cl:20]
Reactant: O=C(Cl)CCl
Reactant: Nc1cc(C(F)(F)F)ccc1Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)Nc1cc(C(F)(F)F)ccc1Br
Temperature: 0 °C

Procedure:
To a solution of 2-bromo-5-trifluoromethylaniline (10.0 g) in methylene chloride (100 ml) was added triethylamine and the solution was cooled to 0° C. To this solution was slowly added choroacetyl chloride and the reaction mixture was allowed to cool to room temperature overnight. The solution was concentrated and the resulting solid was extracted with ethyl acetate. The organic extract was first washed with 10% HCl (2×2 ml), then with water (12×25 ml) and was collected, dried and evaporated to obtain the title compound (yield, 10.2 g). 1HNMR (250 MHz, CDCl3): 4.22 (s, 2 H), 7.26 (d, J=8 Hz, 1 H), 7.66 (d, J=8 Hz, 1 Hz), 8.68 (s, 1 H), 9.02 (br s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9](=[O:13])[CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][C:3]=1[OH:14].CC[O:17][C:18]([C:20]1(Br)[CH2:23][CH2:22][CH2:21]1)=[O:19].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9](=[O:13])[CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][C:3]=1[O:14][C:20]1([C:18]([OH:19])=[O:17])[CH2:23][CH2:22][CH2:21]1
Reactant: CCCC(=O)c1ccc(O)c(Cl)c1Cl
Reactant: CCOC(=O)C1(Br)CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCC(=O)c1ccc(OC2(C(=O)O)CCC2)c(Cl)c1Cl
Temperature: 65 °C

Procedure:
A mixture of 2,3-dichloro-4-butyrylphenol (7 g, 0.03 mole), ethyl α-bromocyclobutanecarboxylate (10.23 g, 0.049 mole) and potassium carbonate (7.5 g, 0.054 mole) in N,N-dimethylformamide (60 ml) was stirred and heated at 65° C. for 18 hours. The reaction mixture was poured into ice water and the resulting mixture was extracted with ether. The ether extract was washed with a 1% sodium hydroxide solution, then with water and finally dried over MgSO4. The ether was evaporated in vacuo and the residue treated with acetic acid (60 ml) and 5% hydrochloric acid (15 ml). The mixture was stirred and refluxed overnight. The solvents were evaporated in vacuo. The residue was chromatographed over a column containing silica gel (140 g) using methylene chloride/tetrahydrofuran/acetic acid 50/1/1 as the eluent. The pertinent fractions were united, treated with toluene and evaporated in vacuo to obtain 1-(2,3-dichloro-4-butyrylphenoxy)cyclobutane-1-carboxylic acid as a liquid whose identity was confirmed by NMR and purity by thin layer chromatography.
Reaction SMILES: C(O[C:4]([C:6]1[S:7][C:8]([Br:11])=[CH:9][CH:10]=1)=[NH:5])C.[CH3:12][NH:13][NH2:14]>N1C=CC=CC=1>[CH3:12][NH:13][NH:14][C:4]([C:6]1[S:7][C:8]([Br:11])=[CH:9][CH:10]=1)=[NH:5]
Reactant: CNN
Reactant: CCOC(=N)c1ccc(Br)s1
Solvent: c1ccncc1
Product: CNNC(=N)c1ccc(Br)s1
Yield: 161.9 %

Procedure:
The 5-bromo-thiophene 2-carboximidic acid ethyl ester (3BW) (13 g, 34.3 mmols) was dissolved in pyridine (100 ml). Methylhydrazine (2.7, 51.45 mmols) was added with stirring and the resulted mixture was allowed to stir overnight. The reaction mixture was concentrated under reduced pressure, and added ether, filtered, washed with ether three times and dried to provide the titled compound (4BW) (13 g).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:45])=[C:16]([N:18]2[C:25](=[O:26])[C:24]3[CH:23]=[C:22]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[O:33][CH3:34])[N:21]([CH:35]([CH3:37])[CH3:36])[C:20]=3[CH:19]2[C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=2)[CH:17]=1.[CH3:46]I>C1COCC1.CCOC(C)=O>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:45])=[C:16]([N:18]2[C:25](=[O:26])[C:24]3[CH:23]=[C:22]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[O:33][CH3:34])[N:21]([CH:35]([CH3:37])[CH3:36])[C:20]=3[C:19]2([C:38]2[CH:39]=[CH:40][C:41]([Cl:44])=[CH:42][CH:43]=2)[CH3:46])[CH:17]=1
Reactant: COc1ccccc1-c1cc2c(n1C(C)C)C(c1ccc(Cl)cc1)N(c1cc(Cl)ccc1C)C2=O
Reactant: CI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccccc1-c1cc2c(n1C(C)C)C(C)(c1ccc(Cl)cc1)N(c1cc(Cl)ccc1C)C2=O
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
KHMDS (1M/THF) (0.237) was added to a solution of 5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-2-(2-methoxy-phenyl)-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one (Example 9) (0.198 mmol) in THF (2 mL) at −78° C. and the mixture was stirred at −78° C. for 15 min. Methyl iodide (0.594 mmol) was added and the mixture was allowed to warm to rt. After 2.5 h, the reaction mixture was diluted with EtOAc and washed with a 5% aqueous citric acid solution. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified using a RediSep® silica gel column to afford the title compound as a white solid. tR: 1.49 min (HPLC 3); ESI-MS: tR=1.43 min, [M]+ 519/521/523 (LC-MS 1); TLC: Rf=0.41 (1:1 EtOAc/heptanes).
Reaction SMILES: [CH3:1][C@:2]1([CH2:23][CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27])[O:19][C:18](=[O:20])[C:17]2[N:21]=[C:14]([S:15][CH:16]=2)[S:13][CH2:12][CH2:11][N:10]2[C@H:6]([CH2:7][O:8][C:9]2=[O:22])[CH:5]=[CH:4][CH2:3]1.[OH:30][C@@H](C(C)(C)CCCC)/C=C/[C@H]1COC(=O)N1CCSC1SC=C(C(OCC)=O)N=1.O1CCCC1>CO>[O:22]=[C:9]1[N:10]([CH2:11][CH2:12][S:13][C:14]2[S:15][CH:16]=[C:17]([C:18]([OH:19])=[O:20])[N:21]=2)[C@@H:6](/[CH:5]=[CH:4]/[CH2:3][C@@:2]([OH:30])([CH3:1])[CH2:23][CH2:24][CH2:25][C:26]([F:27])([F:29])[F:28])[CH2:7][O:8]1
Reactant: CCCCC(C)(C)[C@H](O)/C=C/[C@H]1COC(=O)N1CCSc1nc(C(=O)OCC)cs1
Reactant: C[C@@]1(CCCC(F)(F)F)CC=C[C@H]2COC(=O)N2CCSc2nc(cs2)C(=O)O1
Solvent: CO
Solvent: C1CCOC1
Product: C[C@](O)(C/C=C/[C@H]1COC(=O)N1CCSc1nc(C(=O)O)cs1)CCCC(F)(F)F

Procedure:
By the same procedure as the reaction of Example 8 using the compound 64-1 (Less polar) instead of the compound 7 and using a mixture of tetrahydrofuran and methanol instead of methanol, the title compound having the following physical data was obtained.
Reaction SMILES: [C:1]([O:9]CC)(=O)[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Cl[CH2:15][C:16]([NH2:18])=[O:17]>CN(C)C=O>[CH2:6]([O:5][C:3]([CH:2]1[CH2:15][C:16](=[O:17])[NH:18][C:1]1=[O:9])=[O:4])[CH3:7]
Reactant: NC(=O)CCl
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1CC(=O)NC1=O
Temperature: 25 °C
Reaction time: 0.13 h

Procedure:
To a solution of diethyl malonate (6.1 ml) in N,N-dimethylformamide (30 ml) are added 60% sodium hydride (1.6 g) at 0° C. and, after 8 minutes, chloroacetamide (1.87 g). After stirring at room temperature for 3.5 hours, the mixture in neutralized with acetic acid and extracted with ethyl acetate. The extract is washed with water and concentrated to give 2,5-dioxopyrrolidine-3-carboxylic acid ethyl ester. Oil.
Reaction SMILES: C(O[C:5]1[CH:10]=[C:9]([C:11](=[O:13])[CH3:12])[C:8]([OH:14])=[C:7](C)[C:6]=1C)(=O)C.[C:17]1(=O)CCC1.N1CCCC1>C1(C)C=CC=CC=1>[CH:5]1[CH:6]=[CH:7][C:8]2[O:14][CH2:17][CH2:12][C:11](=[O:13])[C:9]=2[CH:10]=1
Reactant: O=C1CCC1
Reactant: CC(=O)Oc1cc(C(C)=O)c(O)c(C)c1C
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Product: O=C1CCOc2ccccc21

Procedure:
2,3-Dimethyl-1,4-phenylene diacetate (5.5 g) was heated up with boron trifluoride-acetic acid complex (25 mL) at 120° C. for 5 hours. The mixture was poured into ice, and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate water solution to pH about 7. Evaporation gave 5.5 g of 5-acetyl-4-hydroxy-2,3-dimethylphenyl acetate as yellow solid. Refluxing 5-acetyl-4-hydroxy-2,3-dimethylphenyl acetate (5.5 g) with cyclobutanone (1.9 g, 27 mmol) and pyrrolidine (2.1 mL, 24.8 mmol) in toluene failed to give chromanone but gave 3.4 g of 1-(2,5-dihydroxy-3,4-dimethylphenyl)-ethanone as a solid.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([C:8]([O-:10])=[O:9])[CH:2]2[C:11]([O-:13])=[O:12].[Na+].[Na+].S(=O)(=O)(O)O>O>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([C:8]([OH:10])=[O:9])[CH:2]2[C:11]([OH:13])=[O:12]
Reactant: O=C([O-])C1C2CCC(C2)C1C(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)C1C2CCC(C2)C1C(=O)O
Temperature: 25 °C

Procedure:
100.0 g (438.3 mmoles) of disodium bicyclo[2.2.1]heptane-2,3-dicarboxylate (228.15 g/mole) and 280 ml of water was charged into a 2L Erlenmeyer flask with stirring. To this solution was added fuming sulfuric acid until the pH of the resulting solution was ˜1. As the pH became acidic, a white flocculent precipitate formed. The solution was stirred and cooled to room temperature. The precipitate was removed by vacuum filtration and dried overnight in a vacuum oven at 110° C. The resulting product was dried and milled. An IR analysis was consistent with that of the expected structure.
Reaction SMILES: Br[C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[C:3]1=[C:12]1[CH:19]3[CH2:20][CH:15]4[CH2:16][CH:17]([CH2:21][CH:13]1[CH2:14]4)[CH2:18]3)[CH2:9]2.[Cl:22][CH2:23][CH2:24][OH:25]>O1CCOCC1>[Cl:22][CH2:23][CH2:24][O:25][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[C:3]1=[C:12]1[CH:19]3[CH2:20][CH:15]4[CH2:16][CH:17]([CH2:21][CH:13]1[CH2:14]4)[CH2:18]3)[CH2:9]2
Reactant: BrC12CC3CC(CC(C3)C1=C1C3CC4CC(C3)CC1C4)C2
Reactant: OCCCl
Solvent: C1COCCO1
Product: ClCCOC12CC3CC(CC(C3)C1=C1C3CC4CC(C3)CC1C4)C2
Yield: 89.7 %

Procedure:
The bromo-substituted compound having formula 16 (220 mg, 0.58 mmol) was dissolved in dry dioxane (10 cm3) and 2-chloroethanol (5 cm3) was added. The mixture was refluxed for 18 hours, cooled, and concentrated at a reduced pressure. Water (50 cm3) was added and the product was twice extracted with n-hexane, with the combined extracts being washed with brine. The hexane solution was dried with MgSO4, filtered and concentrated at a reduced pressure. Columnchromatography over Al2O3 (act. II/III), using hexane as the eluent, produced 180 mg (0.52 mmol, 89.7%) of pure compound having formula 23 in the form of a colourless oil. IR (neat) 2950 (s), 1455 (m), 1100 (s) and 785 cm-1 (s) 1H-NMR (CCl4, TMS): δ 3.6 (double triplet, 4H), 3.25 (m, 1H), 2.85 (m, 5H), δ 2.4-1.1 (m, 22H), 13C-NMR (CBCl3): δ 135.8; 130.8; 82.6 (d); 67.9 (t); 43.2 (t); 39.7; 39.6; 39.5; 39.1; 37.1; 36.8; 35.7; 33.0; 32.4; 32.1; 31.8; 31.0; 30.1; 28.4 and 27.6. Mass: M+ at m/e 346 (100%). Exact mass: calculated for C22H31ClO: 346.206. Found 346.205.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:14])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[S:10][CH:11]=[CH:12][N:13]=1.[H-].[Na+].[CH2:17](I)[CH:18]([CH3:20])[CH3:19].O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:14][CH2:17][CH:18]([CH3:20])[CH3:19])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[S:10][CH:11]=[CH:12][N:13]=1
Reactant: CC(C)CI
Reactant: Oc1ccc(Oc2nccs2)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)COc1ccc(Oc2nccs2)c(Cl)c1
Reaction time: 0.25 h
Yield: 45.1 %

Procedure:
To a solution of Example 9B (3.4 g, 0.015 mol) in N,N-dimethyl formamide was added sodium hydride (0.7 g, 0.018 mol) in portions at room temperature. After stirring for 15 minutes, isobutyl iodide (4.2 g, 0.023 mol) was added rapidly and the mixture was stirred at room temperature for 24 hours. More sodium hydride and isobutyl iodide were added later to complete the reaction. Water was added and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and purified on silica gel (5˜35% ethyl acetate in hexane) to give 1.92 g of product as clear oil (45% yield), 1H NMR (300 MHz, CDCl3) δ ppm 1.02 (d, J=6.62 Hz, 6H) 1.98-2.18 (m, 1H) 3.71 (d, J=6.62 Hz, 1H) 6.79 (d, J=4.04 Hz, 1H) 6.83 (d, J=2.94 Hz, 1H) 6.86 (d, J=2.94 Hz, 1H) 7.00 (d, J=2.94 Hz, 1H) 7.19 (d, J=4.04 Hz, 1H) 7.24 (s, 1H). MS (ESI) m/z 284.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4](Cl)[C:5]2[N:10]=[C:9](Cl)[N:8]=[C:7](Cl)[C:6]=2[N:13]=1.NC1C=CC=CC=1>C(Cl)(Cl)Cl>[N:10]1[C:5]2[CH:4]=[N:3][CH:2]=[N:13][C:6]=2[CH:7]=[N:8][CH:9]=1
Reactant: Clc1nc(Cl)c2nc(Cl)nc(Cl)c2n1
Solvent: Nc1ccccc1
Solvent: ClC(Cl)Cl
Product: c1ncc2ncncc2n1
Yield: 199.2 %

Procedure:
In accord with the synthesis illustrated above, 4 g (19 mmol) of 2,4,6,8-tetrachloropyrimidopyrimidine was added to 50 ml of chloroform, and 8.7 ml (95 mmol) of aniline was slowly added in droplets thereto in a bath at 0° C. After the completion of the reaction was confirmed through TLC, the resulting reaction solution was washed with an aqueous ammonium chloride solution and then extracted with chloroform to separate an organic layer. Thereafter, the organic layer was distilled under reduced pressure to remove the solvent and then dried in an oven, yielding 5 g of a pale yellow solid 5a NMR analysis of the pale yellow solid produced the following data: 1H-NMR (DMSO-d6) d(ppm) 7.23 (t, 2H, J=7.3 z), 7.46 (t, 41, J=7.8 Hz), 7.87 (t, 4H, J=8.1 Hz), 8.66 (s, 2H).
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH:7]([CH3:9])[CH3:8])[CH:2]([CH3:4])[CH3:3].Br[CH2:11][C:12]([O:14][CH3:15])=[O:13]>>[CH2:1]([N:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CNCC(C)C
Reactant: COC(=O)CBr
Product: COC(=O)CN(CC(C)C)CC(C)C

Procedure:
Following a procedure similar to that described in Preparation 47(a) 5.17 g (40 mmole) of N,N-diisobutylamine and 3.06 g (20 mmole) of methyl bromoacetate were reacted together, to give 4.02 g of the title compound as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:17]2[O:41][C:20]3=[N:21][CH:22]=[CH:23][C:24]([NH:25][CH2:26][CH2:27][N:28]4[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]4)=[C:19]3[C:18]=2[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:17]2[O:41][C:20]3[N:21]=[CH:22][CH:23]=[C:24]([NH:25][CH2:26][CH2:27][N:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)[C:19]=3[C:18]=2[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][N:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCNc2ccnc3oc(-c4ccc(OCCN5CCCCC5)c(F)c4)c(-c4ccccc4)c23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1cc(-c2oc3nccc(NCCN4CCNCC4)c3c2-c2ccccc2)ccc1OCCN1CCCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 20437.1 %

Procedure:
A solution of tert-butyl 4-(2-(2-(3-fluoro-4-(2-(piperidin-1-yl)ethoxy)phenyl)-3-phenylfuro[2,3-b]pyridin-4-ylamino)ethyl)piperazine-1-carboxylate (0.058 g, 0.090 mmol) in dichloromethane (2.0 mL) was cooled to 0° C. Trifluoroacetic acid (1.0 mL) was added and the solution stirred under a nitrogen atmosphere at 0° C. for 2 h. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic phase was separated and washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated to afford a yellow oil. This oil was purified via preparative thin layer chromatography (eluting with 90:10:1, dichloromethane/methanol/ammonium hydroxide) to afford 2-(3-fluoro-4-(2-(piperidin-1-yl)ethoxy)phenyl)-3-phenyl-N-(2-(piperazin-1-yl)ethyl)furo[2,3-b]pyridin-4-amine 10 g as a white solid. MS (MH+) 544.3; Calculated 543 for C32H38FN5O2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C@H:8]1[CH2:13][C@@H:12]([N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])[CH2:11][C:10]([CH3:26])([CH3:25])[CH2:9]1.[Br:27][C:28]1[N:33]=[C:32]([C:34](O)=[O:35])[CH:31]=[CH:30][C:29]=1[F:37]>CCOC(C)=O>[Br:27][C:28]1[N:33]=[C:32]([C:34]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[C@H:8]2[CH2:13][C@@H:12]([N:14]3[C:15](=[O:24])[C:16]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:22]3=[O:23])[CH2:11][C:10]([CH3:26])([CH3:25])[CH2:9]2)=[O:35])[CH:31]=[CH:30][C:29]=1[F:37]
Reactant: CC1(C)C[C@@H](c2ccncc2N)C[C@@H](N2C(=O)c3ccccc3C2=O)C1
Reactant: O=C(O)c1ccc(F)c(Br)n1
Solvent: CCOC(C)=O
Product: CC1(C)C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(Br)n2)C[C@@H](N2C(=O)c3ccccc3C2=O)C1

Procedure:
Following Method 9, 2-((1R,5R)-5-(3-aminopyridin-4-yl)-3,3-dimethylcyclohexyl)isoindoline-1,3-dione and 6-bromo-5-fluoropicolinic acid were coupled and following addition of EtOAc and washing with H2O, NaCl(sat.) and drying over MgSO4, 6-bromo-N-(4-((1R,5R)-5-(1,3-dioxoisoindolin-2-yl)-3,3-dimethylcyclohexyl)pyridin-3-yl)-5-fluoropicolinamide was obtained. LCMS (m/z): 551/553 (MH+), Rt=0.95 min.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[N:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:11]([CH3:20])[C:10](=[O:21])[CH:9]=1.[CH3:22][O-:23].[Na+]>O1CCCC1>[CH3:22][O:23][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[N:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:11]([CH3:20])[C:10](=[O:21])[CH:9]=1
Reactant: C[O-]
Reactant: Cn1c(N2CCOCC2)nc(-c2ccncc2F)cc1=O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cnccc1-c1cc(=O)n(C)c(N2CCOCC2)n1
Temperature: 60 °C
Yield: 63.8 %

Procedure:
A suspension of 6-(3-fluoropyridin-4-yl)-3-methyl-2-(morpholin-4-yl)-3H-pyrimidin-4-one obtained in Example 6-1 (0.60 g, 2.07 mmol), and sodium methoxide (1.37 g, 25.4 mmol) in tetrahydrofuran (15 ml) was heated at 60° C. for 3 hours. The resulting suspension was partitioned between chloroform and brine and the aqueous layer was extracted with chloroform. The combined organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting 5-10% methanol in chloroform to furnish 6-(3-methoxypyridin-4-yl)-3-methyl-2-(morpholin-4-yl)-3H-pyrimidin-4-one (0.40 g, 1.32 mmol, 64%) as white crystals.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5](=[N:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]([CH2:14][CH2:15][CH2:16][NH:17]C(=O)OC(C)(C)C)[C:3]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl>O1CCOCC1>[NH2:17][CH2:16][CH2:15][CH2:14][N:4]1[C:3]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:2]([CH3:1])[S:6][C:5]1=[N:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1sc(=Nc2ccccc2)n(CCCNC(=O)OC(C)(C)C)c1-c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1sc(=Nc2ccccc2)n(CCCN)c1-c1ccccc1
Yield: 115.7 %

Procedure:
t-Butyl 3-[5-methyl-4-phenyl-2-(phenylimino)thiazol-3(2H)-yl]propylcarbamate (370 mg) and a 4N solution of hydrogen chloride in dioxane (4 ml) were treated in a similar manner to in Example 9. (2) to give the title compound (327 mg) as hydrochloride.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([NH:16][C:17]2[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=2)[N:3]=1.[NH2:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=1>>[CH3:22][C:20]1[NH:19][N:18]=[C:17]([NH:16][C:4]2[N:3]=[C:2]([NH:23][C:24]3[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[CH:21]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: COc1cc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2cc1OC
Product: COc1cc2cc(Nc3cc(C)[nH]n3)nc(Nc3ccc(C#N)cc3)c2cc1OC

Procedure:
Similar procedure as described in example 273 was used, starting from (1-chloro-6,7-dimethoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 4-amino-benzonitrile to give 4-[3-(5-methyl-1H-pyrazol-3-ylamino)-6,7-dimethoxy-isoquinolin-1-ylamino]-benzonitrile. LC-MS m/e 401(MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:10])[CH:9]=1)[CH2:5]O.S(Cl)([Cl:13])=O>C(Cl)Cl>[Cl:13][CH2:5][C:4]1[CH:3]=[C:2]([CH:9]=[C:8]([CH3:10])[CH:7]=1)[NH2:1]
Reactant: Cc1cc(N)cc(CO)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1cc(N)cc(CCl)c1
Yield: 142.6 %

Procedure:
To a stirred solution of 3-amino-5-methyl-benzyl alcohol (6.32 g; 42.8 mmol; GL Syntech LLC, Hatfield, Pa.) in DCM (140 mL) at 0° C. was added dropwise thionylchloride (9.4 mL; 128 mmol). The mixture was allowed to react at room temperature overnight. Then, the mixture was concentrated under reduced pressure. The resulting material was dissolved in DCM again and evaporated to dryness to give crude 3-(chloromethyl)-5-methylaniline (9.5 g).
Reaction SMILES: [C:1]([C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[OH:10])#[N:2].[N+:11]([O-])([O-:13])=[O:12].[Na+].S(=O)(=O)(O)O.N([O-])=O.[Na+]>C(Cl)Cl>[N+:11]([C:5]1[CH:6]=[CH:7][C:8]([Cl:9])=[C:3]([C:1]#[N:2])[C:4]=1[OH:10])([O-:13])=[O:12]
Reactant: N#Cc1c(O)cccc1Cl
Reactant: O=[N+]([O-])[O-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1c(Cl)ccc([N+](=O)[O-])c1O
Reaction time: 24 h
Yield: 28.9 %

Procedure:
2-cyano-3-chlorophenol(2.8 g, 18.3 mmol) was dissolved in methylene chloride(40 ml) followed by the addition of sodium nitrate (1.70 g, 20.1 mmol). The addition of sulfuric acid (15 ml/ 3M) is then made, followed by addition of a catalytic amount of sodium nitrite. The mixture is allowed to stir. After 24 hrs, the reaction mixture is diluted with methylene chloride and extracted with water. The organic layer is dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/CH2Cl2) gave the desired product(1.05 g, 29.2%). 1H NMR (CD3COCD3): δ8.09 (d,1H), 6.55 (d, 1H).
Reaction SMILES: [Na].[C:2]1([C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][O:4]1)=[O:3].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O.Cl>C(O)C>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:17]2[C:2](=[O:3])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]2=[O:4])[CH:19]=[CH:20][CH:21]=1
Reactant: COc1cccc(C=O)c1
Reactant: O=C1OCc2ccccc21
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: COc1cccc(C2C(=O)c3ccccc3C2=O)c1
Yield: 44.1 %

Procedure:
Sodium (1.1 g) was dissolved in anhydrous Ethanol (90 ml). This solution was added with Phthalide (4.43 g, 33.04 mmol) and m-Methoxy benzaldehyde (3.00 g, 22.03 mmol). The reaction mixture was heated for 3 hrs under reflux. The reaction mixture was concentrated in a vacuum. White solid was obtained by adding conc.HCl. And then the white solid was recrystalized in ethylacetate:hexane (=1:2) to afford the title compound (2.45 g, 44%).