Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10](Cl)=[N:9][C:8]=2[N:7]=[C:6]1[N:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1)[C:2]#[C:3][CH3:4].[C-:30]#[N:31].[Na+].O>CN1CCCC1=O>[CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10]([C:30]#[N:31])=[N:9][C:8]=2[N:7]=[C:6]1[N:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2nc(Cl)n(C)c(=O)c21
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2nc(C#N)n(C)c(=O)c21
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
176 mg of t-butyl 4-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl]piperazine-1-carboxylate was dissolved in 2 ml of N-methylpyrrolidone, and 100 mg of sodium cyanide was added thereto. The mixture was stirred at 50° C. for 0.5 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was concentrated to give 170 mg of t-butyl 4-[7-(2-butynyl)-2-cyano-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl]piperazine-1-carboxylate. 98 mg of this compound was dissolved in a mixture of 3 ml of tetrahydrofuran and 2 ml of methanol, and 0.5 ml of an aqueous solution of 20% ammonia and 0.5 ml of an aqueous solution of 30% hydrogen peroxide were added thereto. The mixture was stirred at room temperature overnight. Ethyl acetate was added to the reaction solution, and the mixture was washed with water. The organic layer was dried over anhydrous magnesium sulfate, then filtered. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 77 mg of the title compound was obtained from the fraction eluted with ethyl acetate-methanol.
Reaction SMILES: S(=O)(=O)(O)O.[Si]([O:13][C:14]1[CH:15]=[C:16]([CH:28]=[CH:29][C:30]2[CH:31]=[C:32]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([CH3:50])([CH3:49])[O:42]C3CCCCO3)[CH:33]=[CH:34][CH:35]=2)[CH:17]=[CH:18][C:19]=1[O:20][Si](C(C)(C)C)(C)C)(C(C)(C)C)(C)C>C1COCC1.O>[OH:42][C:41]([CH3:50])([CH3:49])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][C:32]1[CH:31]=[C:30]([CH:29]=[CH:28][C:16]2[CH:15]=[C:14]([OH:13])[C:19]([OH:20])=[CH:18][CH:17]=2)[CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)(CCCCCc1cccc(C=Cc2ccc(O[Si](C)(C)C(C)(C)C)c(O[Si](C)(C)C(C)(C)C)c2)c1)OC1CCCCO1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(O)CCCCCc1cccc(C=Cc2ccc(O)c(O)c2)c1

Procedure:
In a manner similar to Example 25(d), by reacting 0.118 ml of concentrated sulphuric acid with 1.38 g (2.11 mmol) of 2-[6-(3-{2-[3,4-bis(tert-butyldimethylsilanyloxy)phenyl]vinyl}phenyl)-1,1-dimethylhexyloxy]tetrahydropyran in 20 ml of THF and 10 ml of water, after purification on a silica column (ethyl acetate 45-heptane 55), a solid having a cottony appearance (m=522 mg; Y=77%) is obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([O:13][C:14]2[CH:21]=[CH:20][C:17]([CH2:18]O)=[CH:16][C:15]=2[N+:22]([O-:24])=[O:23])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:29])=O>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([O:13][C:14]2[CH:21]=[CH:20][C:17]([CH2:18][Cl:29])=[CH:16][C:15]=2[N+:22]([O-:24])=[O:23])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cc(CO)ccc1Oc1ccc(OCc2ccccc2)cc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1cc(CCl)ccc1Oc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 4-[4-(benzyloxy)-phenoxy]-3-nitrobenzyl alcohol (9.43 g, 26.9 mmol) in chloroform (60 ml) was added thionyl chloride (2 ml), followed by stirring at room temperature for 6 hours. After allowing to stand overnight, the reaction solution was washed with water and dried, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [eluent; hexane - chloroform (1:1)] to give 4-[4-(benzyloxy)-phenoxy]-3-nitrobenzyl chloride (7.63 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][C:4]([CH3:10])=[N:3]1.[CH3:11][CH2:12][CH2:13][CH:14]([NH2:18])[CH2:15][CH2:16][CH3:17]>>[CH3:11][CH2:12][CH2:13][CH:14]([NH:18][C:7]([C:6]1[N:2]([CH3:1])[N:3]=[C:4]([CH3:10])[CH:5]=1)=[O:9])[CH2:15][CH2:16][CH3:17]
Reactant: CCCC(N)CCC
Reactant: Cc1cc(C(=O)O)n(C)n1
Product: CCCC(CCC)NC(=O)c1cc(C)nn1C

Procedure:
Prepared in a similar manner to example 4 using 1,3-dimethyl-1H-pyrazole-5-carboxylic acid and 4-heptylamine. 1H NMR (500 MHz, CDCl3): δ 0.90 (t, 6H, J=7.2 Hz), 1.41 (m, 4H), 1.50 (m, 4H), 2.27 (s, 3H), 3.77 (s, 3H), 4.09 (m, 1H), 6.49 (d, 1H), 6.53 (s, 1H). MS (M+H, 238).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:19]=1)[NH:7][C:8](=[O:18])[CH2:9][N:10]=[C:11]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H-].[Na+].[CH3:22]I>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:19]=1)[N:7]([CH3:22])[C:8](=[O:18])[CH2:9][N:10]=[C:11]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1CN=C(c2ccccc2)c2ccc(Br)cc2N1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)CN=C(c2ccccc2)c2ccc(Br)cc21
Yield: 59.2 %

Procedure:
Title compound 354 (3.1 g, 11.8 mmol), sodium hydride (565 mg, 14.14 mmol) and methyliodide (0.88 mL, 14.14 mmol) were stirred together in DMF (60 mL) at room temperature for 6 hours. DMF was removed and the residue was partitioned in EtOAc and water. The organic layer was dried, filtered and evaporated. The crude product was purified by flash chromatography (3:1 to 1:2 hexane:ethyl acetate) to afford title compound 357 (2.3 g, 60%) as a white solid.
Reaction SMILES: [Na].[C:2]([NH:5][CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3].[N:17]([CH2:20][CH2:21][CH2:22][CH2:23]Br)=[N+:18]=[N-:19]>CCO>[C:2]([NH:5][C:6]([CH2:23][CH2:22][CH2:21][CH2:20][N:17]=[N+:18]=[N-:19])([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: [N-]=[N+]=NCCCCBr
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(CCCCN=[N+]=[N-])(NC(C)=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
To a solution of 0.598 g (0.026 mol) sodium metal in 25 ml absolute EtOH, 5.65 g diethyl acetamidomalonate (0.026 mol) was added, following previously published procedures (Chenault, H. K. et al., 1989). The mixture was stirred for 30 min at room temperature. By dropwise addition, azidobutylbromide 1a (4.82 g, 0.027 mol) was added with stirring. The reaction mixture was stirred for 2 h at room temperature and refluxed for 6 h at 80° C. After cooling overnight, the reaction mixture was concentrated to dryness, and the residue was extracted with diethyl ether. The combined ether extracts were washed with water, sat. NaHCO3, water, and brine, and were dried over MgSO4 and then concentrated. Silica gel chromatography (Hex:EtOAc=1:1) gave a product (63%) as a clear, viscous oil. 1H NMR (300 MHz, CDCl3): δ 6.77 (1H, s), 4.24 (4H, q, J=6.9 Hz), 3.26 (2H, t, J=6.9 Hz), 2.31-2.37 (2H, m), 2.04 (3H, s), 1.59 (2H, p, J=7.5 Hz), 1.26 (6H, t, J=6 Hz), 1.16-1.27 (2H, m). ESI-MS m/e 315.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[Br:27])[O:23][CH2:22][C:21]2[N:16]3[CH:17]([CH3:29])[C:18](=[O:28])[NH:19][N:20]=2)[CH2:9]1)=O)(C)(C)C.[C:30]([OH:36])([C:32]([F:35])([F:34])[F:33])=[O:31]>C(Cl)Cl>[F:33][C:32]([F:35])([F:34])[C:30]([OH:36])=[O:31].[NH:8]1[CH2:9][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[Br:27])[O:23][CH2:22][C:21]2[N:16]3[CH:17]([CH3:29])[C:18](=[O:28])[NH:19][N:20]=2)[CH2:11]1
Reactant: CC1C(=O)NN=C2COc3cc(Br)c(NC4CN(C(=O)OC(C)(C)C)C4)cc3N21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1C(=O)NN=C2COc3cc(Br)c(NC4CNC4)cc3N21
Temperature: 25 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
To a solution of 3-(7-bromo-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (Example 1, Step B, 0.053 g, 0.114 mmol) in DCM (2 mL) was added TFA (0.5 mL) and the mixture was stirred at ambient temperature for 2 h. The solvent was removed in vacuo to give 6-(azetidin-3-ylamino)-7-bromo-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one trifluoroacetic acid (0.040 g, 76%) as a white solid. LC/MS (Table 1, Method 5) Rt=1.865 min.; MS m/z: 366 [M+H]+.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:28][C:29]1[CH:30]=[CH:31][C:32]([S:83][CH:84]2[CH2:86][CH2:85]2)=[C:33]([CH2:35][N:36]([CH3:82])[C:37]([CH:39]([NH:55][C:56]2[CH:57]=[C:58]3[C:63](=[CH:64][CH:65]=2)[C:62]([N:66]([C:74]([O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[O:75])[C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68])=[N:61][CH:60]=[C:59]3[F:81])[C:40]2[CH:45]=[C:44]([CH3:46])[C:43]([CH2:47][CH:48]([OH:53])[CH2:49][C:50]([OH:52])=O)=[C:42]([CH3:54])[CH:41]=2)=[O:38])[CH:34]=1>CN(C1C=CN=CC=1)C.ClCCl.CN(C=O)C>[C:77]([O:76][C:74]([N:66]([C:62]1[C:63]2[C:58](=[CH:57][C:56]([NH:55][C@H:39]3[C:37](=[O:38])[N:36]([CH3:82])[CH2:35][C:33]4[CH:34]=[C:29]([CH:30]=[CH:31][C:32]=4[S:83][CH:84]4[CH2:85][CH2:86]4)[NH:28][C:50](=[O:52])[CH2:49][CH:48]([OH:53])[CH2:47][C:43]4[C:42]([CH3:54])=[CH:41][C:40]3=[CH:45][C:44]=4[CH3:46])=[CH:65][CH:64]=2)[C:59]([F:81])=[CH:60][N:61]=1)[C:67](=[O:68])[O:69][C:70]([CH3:71])([CH3:72])[CH3:73])=[O:75])([CH3:78])([CH3:79])[CH3:80]
Reactant: Cc1cc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ncc(F)c3c2)C(=O)N(C)Cc2cc(N)ccc2SC2CC2)cc(C)c1CC(O)CC(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc2cc(C)c1CC(O)CC(=O)Nc1ccc(SC3CC3)c(c1)CN(C)C(=O)[C@@H]2Nc1ccc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ncc(F)c2c1
Reaction time: 4 h
Yield: 32.6 %

Procedure:
To a solution of BOP (234 mg, 0.529 mmol), TEA (0.074 mL, 0.529 mmol) and DMAP (129 mg, 1.058 mmol) in dichloromethane (10 mL) and DMF (10 mL) was added 2E in dichloromethane (10 mL) via a syringe pump over 10.0 h. The reaction was continued at rt for 4 h, quenched by water and extracted by EtOAc (×3). The combined organics were washed by brine, dried with Na2SO4 and concentrated. The crude product was purified by flash chromatography (loading in chloroform, 0% to 100% ethyl acetate in hexane over 10 min using a 4 g silica gel cartridge) to give a mixture of diastereoisomers (92 mg, 43% yield). The diastereoisomers were separated to give 2F (30 mg, 0.037 mmol, 32.6% yield) using a R,R-Welko-O 1 column (21.1 mm×250 mm, 10 micron, Regis Technologies, Inc.). MS (ESI) m/z: 814.7 (M+H)+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][CH2:6][C:7](Cl)=[O:8].Cl.[CH3:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=1>>[Cl:5][CH2:6][C:7]([C:17]1[CH:16]=[C:15]([CH3:18])[CH:14]=[CH:13][C:12]=1[CH3:11])=[O:8]
Reactant: O=C(Cl)CCl
Reactant: Cc1ccc(C)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1ccc(C)c(C(=O)CCl)c1
Temperature: 13.5 °C
Reaction time: 2 h

Procedure:
293.2 g [2.2 mol] of aluminum chloride are metered over the course of about 75 minutes into a mixture of 800 g p-xylene and 226 g [2 mol] of chloroacetyl chloride at 12-15° C. The reaction mixture is stirred at 12-15° C. for 2 hours, allowed to reach room temperature, stirred at room temperature for 30 minutes and then poured into 3000 ml of ice-water with 70 g of conc. hydrochloric acid. The cloudy organic phase is separated off, and the aqueous phase is extracted three times with 300 ml of ethyl acetate each time, and the combined organic phases are extracted twice with 200 ml of water each time and once with 100 ml of saturated aqueous NaCl solution. The organic phase is dried, evaporated and distilled as far as a bath temperature of 70° C./1 mbar. 363.6 g of yellowish oil result and, according to GC, contain 97.2% target product (96.8% of theory).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]1[CH2:14][CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH2:25][C:26]([NH2:28])=[O:27])[CH:23]=2)[NH:18][CH:17]=1.[CH3:29]I.O>CN(C)C=O>[O:3]=[C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]1[CH2:14][CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH2:25][C:26]([NH2:28])=[O:27])[CH:23]=2)[N:18]([CH3:29])[CH:17]=1
Reactant: NC(=O)Cc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(CCN2C(=O)c3ccccc3C2=O)c2cc(CC(N)=O)ccc21
Reaction time: 0.5 h

Procedure:
Sodium hydride (80% dispersion in oil) (0.14 g) was added to a solution of 3-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-1H-indole-5-acetamide (1.5 g) in dry dimethylformamide (10 ml). After stirring the red solution for 30 min, methyl iodide (0.41 ml) was added and the mixture was stirred for a further 16 h. Water (40 ml) was added, the solid collected by filtration and crystallised from propan-2-ol to give the title compound as a yellow powder (1.25 g), m.p. 200°-2° C.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Br:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]Br.O>CN(C)C=O>[Br:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N:11]1[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:9]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:8]=[C:7]1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCCCCCCCCBr
Reactant: c1ccc(-c2nc(-c3ccccc3)c(-c3ccccc3)[nH]2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: BrCCCCCCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1-c1ccccc1
Temperature: 45 °C
Reaction time: 1 h
Yield: 49.9 %

Procedure:
2,4,5-Triphenylimidazole (5 g) was added to a suspension of sodium hydride (1.0 g) (50% dispersion in oil, washed with hexane) in dry dimethylformamide (80 ml) under nitrogen. The reaction was stirred at 45° C. for 1 h, cooled and added, over 1 h to a solution of 1,8-dibromo-octane (30 g) in dry dimethylformamide (100 ml) under nitrogen. The reaction was stirred at room temperature for 24 h, water was carefully added and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate (500 ml), washed with water (250 ml), 2N aqueous hydrochloric acid (250 ml), saturated sodium chloride solution (250 ml), dried over anhydrous magnesium sulphate and evaporated to dryness in vacuo. Distillation to remove 1,8-dibromooctane and chromatography on silica gel eluted with dichloromethane gave 1-(8-bromooctyl)-2,4,5-triphenylimidazole (4.1 g, 50%) as an oil; NMR d (CDCl3) 0.9-1.7 (12H, m, 6×CH2), 3.3 (2H, t, BrCH2), 3.9 (2H, t, N--CH2), 7.1-7.7(15H, m, 3×Ph) ppm.
Reaction SMILES: C([NH:4][CH2:5][C:6]1[O:20][C:9]2=[C:10]3[C:15](=[C:16]([CH3:18])[CH:17]=[C:8]2[CH:7]=1)[NH:14][C:13](=[O:19])[CH:12]=[CH:11]3)(=O)C.[OH-].[K+]>CO.O>[NH2:4][CH2:5][C:6]1[O:20][C:9]2=[C:10]3[C:15](=[C:16]([CH3:18])[CH:17]=[C:8]2[CH:7]=1)[NH:14][C:13](=[O:19])[CH:12]=[CH:11]3
Reactant: CC(=O)NCc1cc2cc(C)c3[nH]c(=O)ccc3c2o1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc2cc(CN)oc2c2ccc(=O)[nH]c12
Temperature: 90 °C
Reaction time: 11 h
Yield: 76.3 %

Procedure:
2-(N-Acetylaminomethyl)-6,7-dihydro-5-methylfuro[2,3-f]quinoline-7-one (475 mg) was suspended in methanol (4 mg), to which KOH (1.16 g) in water (1 ml) was added. The mixture was stirred at 90° C. for 11 hours. After completion of the reaction, the solvent was removed under reduced pressure, and water (50 ml) was added. The resulting mixture was made into acidic with 2N-HCl. The aqueous phase was washed with chloroform. Potassium carbonate was added thereto up to definite alkaline pH, followed by extraction with chloroform. The chloroform phase was washed with aqueous NaCl solution, and dried. After the solvent was removed under reduced pressure, 306 mg of 2-aminomethyl-6,7-dihydro-5-methylfuro[2,3-f]quinoline-7-one (76.3%) was obtained. This product was converted into a hydrochloride, and recrystallized from methanol. As a result, a hydrochloric acid salt of 2-aminomethyl-6,7-dihydro-5-methylfuro[2,3-f]quinoline-7-one was obtained as pale yellow prisms (mp.: higher than 300° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([C:18](O)=[O:19])[N:9]=1.C(N(CC)CC)C.ClC(OCC)=O.[CH3:34][NH:35][CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>C(Cl)(Cl)Cl>[CH:36]1([N:35]([CH3:34])[C:18]([C:10]2[N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:17]3[C:12]([CH:11]=2)=[CH:13][CH:14]=[CH:15][CH:16]=3)=[O:19])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: O=C(O)c1cc2ccccc2c(-c2ccccc2Cl)n1
Reactant: CNC1CCCCC1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CN(C(=O)c1cc2ccccc2c(-c2ccccc2Cl)n1)C1CCCCC1
Yield: 64.8 %

Procedure:
Operations are carried out as for Example 7, starting from 2.83 g of 1-(2-chloro phenyl) isoquinoline 3-carboxylic acid, 1.15 g of triethylamine, 1.24 g of ethyl chloroformate and 1.46 g of N-methyl cyclohexylamine in 100 ml of chloroform. 2.45 g of N-cyclohexyl N-methyl 1-(2-chloro phenyl) isoquinoline 3-carboxamide melting at 131° C., are obtained.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:31])[C:14]=2[C@H:15]2[O:21][CH2:20][C@H:19]([F:22])[C@H:18]([NH:23]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[O:8])[N:6]=1.[F:32][C:33]1[C:38]([F:39])=[CH:37][CH:36]=[C:35]([F:40])[C:34]=1B(O)O>>[NH2:23][C@H:18]1[C@@H:19]([F:22])[CH2:20][O:21][C@H:15]([C:14]2[N:13]([CH3:31])[N:12]=[CH:11][C:10]=2[NH:9][C:7]([C:5]2[N:6]=[C:2]([C:34]3[C:35]([F:40])=[CH:36][CH:37]=[C:38]([F:39])[C:33]=3[F:32])[S:3][CH:4]=2)=[O:8])[CH2:16][CH2:17]1
Reactant: OB(O)c1c(F)ccc(F)c1F
Reactant: Cn1ncc(NC(=O)c2csc(Br)n2)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)CO1
Product: Cn1ncc(NC(=O)c2csc(-c3c(F)ccc(F)c3F)n2)c1[C@@H]1CC[C@@H](N)[C@@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl ((3R,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate (Intermediate 100), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2,3,6-trifluorophenyl)boronic acid gave 230. 1H NMR (400 MHz, DMSO-d6) δ 10.00 (s, 1H), 8.68 (s, 1H), 7.85 (s, 1H), 7.75 (qd, J=9.4, 4.9 Hz, 1H), 7.43 (tdd, J=9.7, 4.0, 2.1 Hz, 1H), 5.09-4.78 (m, 2H), 4.19-3.91 (m, 2H), 3.75 (s, 3H), 3.44-3.30 (m, 1H), 2.24-2.12 (m, 1H), 1.93-1.65 (m, 3H). LCMS (ES+) m/z 470 (M+1).
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[C:15]([O:23][CH2:24][CH3:25])(=[O:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>CS(C)=O.CCOC(C)=O>[F:8][C:7]1[C:2]([CH:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:15]([O:23][CH2:24][CH3:25])=[O:22])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Fc1cccnc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C(=O)OCC)c1ncccc1F
Temperature: 100 °C
Yield: 60.3 %

Procedure:
A mixture of 2,3-difluoropyridine (2.00 g, 17.4 mmol), Cs2CO3 (13.59 g, 41.7 mmol) and diethyl malonate (6.68 g, 41.7 mmol) in DMSO (19 mL) was heated at 100° C. for 4.5 h. The mixture was poured onto ice, diluted with EtOAc, and the organic phase was separated, washed sequentially with water and brine, and dried and concentrated. The residue was purified by column chromatography on silica gel (80 g), eluting with EtOAc-hexanes (sequentially 10%, 20% and 30%), to provide diethyl 2-(3-fluoropyridin-2-yl)malonate as a pale colored oil (2.68 g, 60% yield). 1H NMR (400 MHz, chloroform-d) δ 8.42 (dt, J=4.6, 1.3 Hz, 1H), 7.43 (ddd, J=9.4, 8.3, 1.4 Hz, 1H), 7.30 (dt, J=8.5, 4.3 Hz, 1H), 5.09 (d, J=1.1 Hz, 1H), 4.30 (q, J=7.0 Hz, 4H), 1.33-1.26 (m, 6H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[C:14]([F:24])=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.[F-].[K+].Cl.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH:31]([CH3:35])[C:30]1=[O:36]>CN1C(=O)CCC1>[F:24][C:14]1[C:13]([CH:11]([C:8]2[N:6]3[N:7]=[C:2]([N:32]4[CH2:33][CH2:34][N:29]([CH3:28])[C:30](=[O:36])[CH:31]4[CH3:35])[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH3:12])=[C:22]([F:23])[CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[N:19]2
Reactant: CC1NCCN(C)C1=O
Reactant: CC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(Cl)nn12
Agent: Cl
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(N3CCN(C)C(=O)C3C)nn12
Temperature: 180 °C
Reaction time: 20 h

Procedure:
(rac)-6-[1-(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-ethyl]-5,7-difluoro-quinoline (Intermediate C, 50 mg, 0.145 mmol), KF (84 mg, 1.450 mmol), 1,3-dimethylpiperazin-2-one HCl salt (75 mg, 0.435 mmol) were suspended in NMP (483 μL). The RM was stirred at 180° C. for 20 h. The mixture was purified by preparative UPLC with acetonitrile and water (+0.1% TFA) The fractions were collected and acetonitrile was removed. It was taken up with MeOH and passed through an SPE cartridge of PL-HCO3 MP from polymer lab. The solvent was removed and a brown solid was obtained (tR 0.9 min (conditions 4), MH+=437).
Reaction SMILES: C([O:3][C:4](=O)[C:5]([CH2:11][CH2:12][CH2:13][CH3:14])=[C:6]([NH2:10])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][C:36]=1[Cl:37])[CH2:31][NH:32][NH2:33]>C(O)C>[NH2:10][C:6]1[NH:33][N:32]([CH2:31][C:30]2[CH:34]=[CH:35][C:36]([Cl:37])=[C:28]([Cl:27])[CH:29]=2)[C:4](=[O:3])[C:5]=1[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCC(C(=O)OCC)=C(N)OCC
Reactant: NNCc1ccc(Cl)c(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCCCc1c(N)[nH]n(Cc2ccc(Cl)c(Cl)c2)c1=O
Reaction time: 2 h

Procedure:
To a solution of 41.1 g α-n-butyl-β-amino-β-ethoxyacrylic acid ethyl ester and a spatula tipfull of p-toluenesulphonic acid in 100 ml ethanol were added dropwise, under nitrogen, 36.5 g 3,4-dichlorobenzylhydrazine. After the mixture had been stirred afterwards for two hours, it was left to stand overnight. The solvent was distilled off, a mixture of ether/petroleum ether (1:1) was added to the residue; the product crystallized through.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:11]([OH:13])=O)[S:9][CH:10]=1)=[O:5])[CH3:2].CN(C)CCCN=C=NCC.Cl.[CH3:26][C:27]1[CH:28]=[C:29]([CH:32]=[C:33]([CH3:35])[CH:34]=1)[CH2:30][NH2:31]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:11](=[O:13])[NH:31][CH2:30][C:29]2[CH:32]=[C:33]([CH3:35])[CH:34]=[C:27]([CH3:26])[CH:28]=2)[S:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: Cc1cc(C)cc(CN)c1
Reactant: CCOC(=O)c1csc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)c1csc(C(=O)NCc2cc(C)cc(C)c2)c1
Reaction time: 8 h
Yield: 73.2 %

Procedure:
0.5 g 2-carboxy-thiophen-4-carboxylic acid ethyl ester (M. Janda, J. Srogl, M. Nemec, I. Stibor; Org. Prep. and Proced. Int. 3 (6) (1971) 295.) and 0.67 g N′-(3-dimethylaminopropyl)-N-ethylcarbodiimid×HCl are stirred in 50 mL DCM for 15 min. Then, 0.338 g 3,5-dimethylbenzylamin are added and the mixture is stirred overnight. The solution is extracted with 2N HCl and water, then evaporated. The residue is titurated with isohexan, and the resulting crystals are filtrated and air-dried, yielding 0.58 g (73%) crude 5-(3,5-Dimethyl-benzylcarbamoyl)-thiophene-3-carboxylic acid ethyl ester (7b). This ester in converted to title compound by reaction with hydroxylamine hydrochloride in a manner similar to that described for the conversion of 4b into 4a in example 4. After chromatography (silica, ethylacetate), thiophene-2,4-dicarboxylic acid 2-(3,5-dimethyl-benzylamide) 4-hydroxyamide (7a) is obtained as crystals; 44 mg, 9%, mp: 181° C. (decomp.).