Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[S:11][C:10]2[C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:8][C:7]([Cl:18])=[N:6][C:5]=2[CH:4]=1.[CH2:19]1[NH:24][CH2:23][CH2:22][N:21]2[CH2:25][CH2:26][CH2:27][C@@H:20]12.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:18][C:7]1[N:8]=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:10]2[S:11][C:3]([CH2:2][N:24]3[CH2:23][CH2:22][N:21]4[CH2:25][CH2:26][CH2:27][C@H:20]4[CH2:19]3)=[CH:4][C:5]=2[N:6]=1
Reactant: C1C[C@H]2CNCCN2C1
Reactant: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1nc(N2CCOCC2)c2sc(CN3CCN4CCC[C@H]4C3)cc2n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 76.7 %

Procedure:
To a solution of 6-bromomethyl-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (150 mg, 0.43 mmol) in DMF (4 mL) were added (S)-octahydro-pyrrolo[1,2-a]pyrazine (81 mg, 0.642 mmol) and potassium carbonate (117 mg, 0.847 mmol). The resulting mixture was stirred at RT for 17 h, then concentrated in vacuo. The resulting residue was triturated with water to give the title compound as an off-white solid (130 mg, 77%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)[CH:6]=[CH:5][C:3]=1[NH2:4].[N:18]([C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1)=[C:19]=[O:20]>O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:8]=[C:7]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)[CH:6]=[CH:5][C:3]=1[NH:4][C:19]([NH:18][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1)=[O:20]
Reactant: CC1(C)OB(c2ccc(N)c(F)c2)OC1(C)C
Reactant: O=C=Nc1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc(NC(=O)Nc3ccncc3)c(F)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 128.7 %

Procedure:
A mixture of 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (100 mg, 0.42 mmol) and 4-isocyanatopyridine (56 mg, 0.47 mmol) in tetrahydrofuran (2 ml) was stirred at room temperature overnight. The mixture was diluted with ethyl acetate and washed with water, brine, dried over sodium sulphate, filtered and evaporated under reduced pressure to give 193 mg (100% yield) of the title compound. This crude was used in the following step without any further purification. Purity 77%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[C:10]1[S:11][C:12]2[CH:13]=[N+:14]([O-])[CH:15]=[C:16]([F:19])[C:17]=2[N:18]=1.P(Cl)(Cl)([Cl:23])=O.C(=O)(O)[O-].[Na+]>ClCCCl>[Cl:23][C:13]1[C:12]2[S:11][C:10]([C:3]3[C:2]([Cl:1])=[CH:7][C:6]([I:8])=[CH:5][C:4]=3[Cl:9])=[N:18][C:17]=2[C:16]([F:19])=[CH:15][N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: [O-][n+]1cc(F)c2nc(-c3c(Cl)cc(I)cc3Cl)sc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: Fc1cnc(Cl)c2sc(-c3c(Cl)cc(I)cc3Cl)nc12
Yield: 34 %

Procedure:
To a suspension of 2-(2,6-dichloro-4-iodophenyl)-7-fluorothiazolo[5,4-c]pyridine-5-oxide (2.8 g, 6.4 mmol) in 1,2-dichloroethane (80 mL) was added phosphorus oxychloride (1.8 mL, 19.1 mmol). The reaction mixture was heated under reflux for 16 hours. Upon cooling, the resultant mixture was treated cautiously with aqueous sodium bicarbonate to achieve pH 6-7, and then extracted with dichloromethane (×2). The combined organic extracts were dried (MgSO4), filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with 0-50% diethyl ether in petroleum ether to afford the title compound as a white solid (1.0 g, 34% yield). 1H NMR (400 MHz, CDCl3): δ 8.35 (d, J=1.5 Hz, 1H), 7.82 (s, 2H).
Reaction SMILES: [CH2:1]([N:4]1[CH2:15][CH:14]2[CH2:16][CH:6]([C:7](=[O:19])[C:8]3[C:9]([O:17]C)=[CH:10][CH:11]=[CH:12][C:13]=32)[CH2:5]1)[CH:2]=[CH2:3].B(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>ClCCl>[CH2:1]([N:4]1[CH2:15][CH:14]2[CH2:16][CH:6]([C:7](=[O:19])[C:8]3[C:9]([OH:17])=[CH:10][CH:11]=[CH:12][C:13]=32)[CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCN1CC2CC(C1)c1cccc(OC)c1C2=O
Agent: ClB(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C=CCN1CC2CC(C1)c1cccc(O)c1C2=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 44.1 %

Procedure:
11-Allyl-6-methoxy-11-aza-tricyclo[7.3.1.02,7]trideca-2(7),3,5-trien-8-one (1.20 g, 4.66 mmol) in dichloromethane (25 mL) was cooled to −78° C. and treated with BCl3 (10.3 mL, 1M in dichloromethane). The mixture was allowed to stir to ambient temperature for 18 h. The mixture was treated with half saturated aqueous NaHCO3 solution (100 mL), the layers were separated and extracted with dichloromethane (3×40 mL). The organic layer was washed with H2O (50 mL) and saturated aqueous NaCl solution (50 mL), dried through a cotton plug and concentrated to an oil. Purification by chromatography on silica gel eluting with 15% EtOAc/hexanes afforded an oil (500 mg, 44%). (TLC 25% EtOAc/hexanes Rf 0.52); 1H NMR (400 MHz, CDCl3) δ 7.33 (dd, J=8.3, 7.5 Hz, 1H), 6.78 (dd, J=8.3, 1.0 Hz, 1H), 6.67 (dd, J=7.5, 1.0 Hz, 1H), 5.52 (m, 1H), 4.95 (m, 2H), 3.16 (br d, J=10.8 Hz, 1H), 3.05 (br s, 1H), 2.85 br, d, J=6.0 Hz, 2H), 2.78 (dd, J=9.5, 1.3 Hz, 1H), 2.65 (d, J=1.7 Hz, 1H), 2.41 (dd, J=10.8, 2.4 Hz, 1H), 2.33 (m, 2H), 1.86 (ddd, J=12.9, 5.9, 2.9 Hz, 1H); GCMS m/z 243 (M)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][CH:16]1[CH2:21][CH2:20][CH:19]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]1.[F:26][C:27]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[C:29]([F:42])[C:28]=1[OH:43].C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:56].Cl>>[ClH:1].[ClH:56].[F:26][C:27]1[CH:32]=[C:31]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]2)[CH:30]=[C:29]([F:42])[C:28]=1[OH:43]
Reactant: CC1(C)OB(c2cc(F)c(O)c(F)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1NC1CCC(CN(C)C)CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(F)c3)nc2c1N[C@H]1CC[C@H](CN(C)C)CC1

Procedure:
Following general procedure II, 1-(6-chloro-4-{4-[(dimethylamino)methyl]cyclohexyl-amino}-1,5-naphthyridin-3-yl)ethanone (65 mg, 0.18 mmol) was reacted with 2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (69 mg, 0.27 mmol) followed by formation of the dihydrochloride salt to afford the desired product (87 mg, 90%) as an off-white solid: 1H NMR (500 MHz, CD3OD) δ 9.13 (s, 1H), 8.44 (d, J=9.0 Hz, 1H), 8.35 (d, J=9.0 Hz, 1H), 7.78 (dd, J=7.8, 1.7 Hz, 2H), 5.66-5.62 (m, 1H), 3.09 (d, J=6.6 Hz, 2H), 2.94 (s, 6H), 2.76 (s, 3H), 2.47-2.44 (m, 2H), 2.08-2.04 (m, 3H), 1.72-1.68 (m, 2H), 1.37-1.28 (m, 2H); ESI MS m/z 455 [M+H]+; HPLC>99% (AUC), tR=9.49 min.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:14]([O:16]CC)=[O:15])[CH:6]=[C:7]([CH:13]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9].O.O.[OH-].[Li+]>C(O)C>[CH2:11]([O:10][C:8]([C:7]1[CH:6]=[C:5]([CH:4]=[C:3]([CH2:2][OH:1])[CH:13]=1)[C:14]([OH:16])=[O:15])=[O:9])[CH3:12]
Reactant: CCOC(=O)c1cc(CO)cc(C(=O)OCC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(CO)cc(C(=O)O)c1

Procedure:
A mixture of diethyl 1,3,5-benzenetricarboxylate (5.2 g) and borane methylsulfide complex (6.1 g) is stirred in THF (150 mL) at 20–25 degrees C. overnight. The mixture is then treated with methanol, concentrated to dryness, and chouromatographed (silica gel) to give diethyl 5-(hydroxymethyl)isophthalate. Diethyl 5-(hydroxymethyl)isophthalate (3.4 g) is hydroyzed in ethanol and water with lithium hydroxide monohydrate (0.57 g) at 20–25 degrees C. for 3.5 hours at which time the solvents are removed under reduced pressure. Water (100 mL) is added and the mixture is acidified to pH=4 with concentrated hydrochloric acid. The mixture is extracted with ethyl acetate and dried over magnesium sulfate, filtered, and concentrated to give 3-(ethoxycarbonyl)-5-(hydroxymethyl)benzoic acid, high resolution MS MH+=225.0769. 3-(Ethoxycarbonyl)-5-(hydroxymethyl)benzoic acid (2.3 g), EDC (3.0 g), 1-HOBT (2.1 g), diisopropylethylamine (2.7 mL), dipropyl amine (2.8 mL), and DMF (50 mL) are stirred at 20–25 degrees C. overnight. The mixture is then partitioned between ethyl acetate, water, and saline. The organic phase is separated and dried over magnesium sulfate, filtered, and concentrated. Chromatography (silica gel) gives ethyl 3-[(dipropylamino)carbonyl]-5-(hydroxymethyl)benzoate, NMR (CDCl3) δ 0.77, 1.0, 1.4, 1.6, 1.7, 3.2, 3.5, 4.4, 4.8, 7.6, 8.0 and 8.1.
Reaction SMILES: Cl[CH2:2][O:3][C:4](=[O:29])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:21]=[N:20][C:19]3[C:18]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[N:17][C:16]([Cl:28])=[N:15][C:14]=3[CH:13]=2)[CH:7]=1.[C:30]([OH:33])(=[O:32])[CH3:31]>C(Cl)(Cl)Cl>[C:30]([O:33][CH2:2][O:3][C:4](=[O:29])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:21]=[N:20][C:19]3[C:18]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)=[N:17][C:16]([Cl:28])=[N:15][C:14]=3[CH:13]=2)[CH:7]=1)(=[O:32])[CH3:31]
Reactant: CC(=O)O
Reactant: O=C(Nc1cccc(-c2cnc3c(N4CCOCC4)nc(Cl)nc3c2)c1)OCCl
Solvent: ClC(Cl)Cl
Product: CC(=O)OCOC(=O)Nc1cccc(-c2cnc3c(N4CCOCC4)nc(Cl)nc3c2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
To a 100 mL round bottom flask, chloromethyl(3-(2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)phenyl)carbamate (1.2 g, 0.0028 mol) and acetic acid (20 mL) were added. To the reaction mixture was added mercuric acetate (0.968 g, 0.0031 mol) and the mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with chloroform and washed with water. The organic layer was washed with brine, dried over anhydrous sodium sulphate and evaporated under reduced pressure to provide the title compound as a yellow solid (1.1 g, 87%). 1H NMR (400 MHz, DMSO-d6): δ 10.25 (br s, 1H), 9.05 (d, J=1.6 Hz, 1H), 8.19 (d, J=1.2 Hz, 1H), 7.93 (s, 1H), 7.59-7.48 (m, 3H), 5.77 (s, 2H), 4.64-3.98 (br s, 4H), 3.81 (t, J=4.4 Hz, 4H), 2.10 (s, 3H). LC-MS (ESI): Calculated mass: 457.12; Observed mass [M+H]+: 457.9 (RT: 1.57 min).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C@@H:23]3[C@@H:30]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29][C:26]4([CH2:28][CH2:27]4)[CH2:25][NH:24]3)=[O:22])=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C=O.[C:40](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(OCC)(=O)C>[CH3:40][N:24]1[C@H:23]([C:21]([NH:20][C:17]2[CH:18]=[CH:19][C:14]([O:13][CH2:12][C:10]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=[C:2]([CH3:1])[CH:11]=3)=[CH:15][CH:16]=2)=[O:22])[C@@H:30]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29][C:26]2([CH2:27][CH2:28]2)[CH2:25]1
Reactant: Cc1cc(COc2ccc(NC(=O)[C@H]3NCC4(CC4)C[C@@H]3C(=O)OC(C)(C)C)cc2)c2ccccc2n1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cc(COc2ccc(NC(=O)[C@@H]3[C@@H](C(=O)OC(C)(C)C)CC4(CC4)CN3C)cc2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.4 %

Procedure:
To a solution of tert-butyl (6S,7S)-6-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}amino)carbonyl]-5-azaspiro[2.5]octane-7-carboxylate (140 mg, 0.27 mmol) in methanol (3.0 mL) was added formaldehyde (37% solution in water, 0.5 mL) and sodium triacetoxyborohydride (0.25 g, 1.2 mmol). The mixture was then stirred at room temperature for 2 h. The reaction was diluted with ethyl acetate, washed with saturated NaHCO3, water and brine. Dried and concentrated. tert-butyl (6S,7S)-5-methyl-6-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}amino)carbonyl]-5-azaspiro[2.5]octane-7-carboxylate (105.0 mg) was obtained by column using CH2Cl2/Methanol (10%). ESI (M+H)+ 516.5.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:10])=[C:6]([CH2:8]O)[CH:7]=1.P(Br)(Br)[Br:12].C(Cl)Cl.C([O-])(O)=O.[Na+]>CCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:10])=[C:6]([CH2:8][Br:12])[CH:7]=1
Reactant: OCc1cc(Br)ccc1I
Reactant: BrP(Br)Br
Agent: CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: BrCc1cc(Br)ccc1I
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 52 %

Procedure:
To a stirred mixture of (5-Bromo-2-iodo-phenyl)-m-ethanol (9.14 g, 29.2 mmol) in CH3Cl (150 mL) under argon was added 1M PBr3 in CH2Cl2 (35.0 mL, 35.0 mmol). The reaction mixture was stirred at room temperature for 20 min and then poured into a mixture of ice and saturated NaHCO3 solution (300 mL). The pH was adjusted to basic by addition of solid NaHCO3. This aqueous layer was extracted with EtOAc (1×600 mL, 2×400 mL). The combined EtOAc extracts were washed with brine (1×100 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo to give 4-bromo-2-bromomethyl-1-iodo-benzene (5.69 g, 52%). 1H NMR (CDCl3): δ 7.68 (d, 1H, J=8.80 Hz), 7.59 (s, 1H), 7.18 (d, 1H, J=8.80 Hz), 4.51 (s, 2H). HPLC: Rt=3.87 min.
Reaction SMILES: [F:1][C:2]1[C:3]([C:14](=[CH2:19])[C:15]([O:17][CH3:18])=[O:16])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([O:12][CH3:13])=[N:5]2.[NH:20]1[CH2:25][CH2:24][CH:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22][CH2:21]1.CN(C)C(N(C)C)=N>CN(C)C=O>[CH3:32][C:29]([O:28][C:27]([NH:26][CH:23]1[CH2:22][CH2:21][N:20]([CH2:19][CH:14]([C:3]2[C:2]([F:1])=[CH:11][CH:10]=[C:9]3[C:4]=2[N:5]=[C:6]([O:12][CH3:13])[CH:7]=[N:8]3)[C:15]([O:17][CH3:18])=[O:16])[CH2:25][CH2:24]1)=[O:33])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: C=C(C(=O)OC)c1c(F)ccc2ncc(OC)nc12
Agent: CN(C)C(=N)N(C)C
Solvent: CN(C)C=O
Product: COC(=O)C(CN1CCC(NC(=O)OC(C)(C)C)CC1)c1c(F)ccc2ncc(OC)nc12
Temperature: 65 °C
Yield: 90.5 %

Procedure:
A mixture of methyl 2-[6-fluoro-3-(methyloxy)-5-quinoxalinyl]-2-propenoate (13.64 g, 52.1 mmol), 1,1-dimethylethyl 4-piperidinylcarbamate (11.45 g, 57.3 mmol) and 1,1,3,3-tetramethylguanidine (3.12 ml) in dry dimethylformamide (300 ml) was heated at 65° C. (bath temp.) for 17 h. The solvent was evaporated and the residue was dissolved in ethyl acetate and water. The aqueous phase was extracted twice with ethyl acetate and the combined organic fractions were dried and evaporated. Chromatography on silica (1000 g), eluting with 2-5% methanol/dichloromethane gave the product (21.81 g, 91%).
Reaction SMILES: [C:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15](OCC)[CH3:16]>C([Mg]Br)C>[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=[CH:9][C:10]([CH:11]([OH:12])[CH2:15][CH3:16])=[CH:13][CH:14]=1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Reactant: CCOCC
Agent: CC[Mg]Br
Product: CCC(O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-phenylbenzaldehyde (1.20 g) in diethyl ether (13.2 mL), ethylmagnesium bromide (about 3.0 mol/L, solution in diethyl ether, 3.29 mL) was added at 0° C. After stirring the mixture at room temperature for 3 hours, the precipitate was recovered by filtration. After dissolving the recovered precipitate in a liquid mixture of ethyl acetate and a saturated aqueous solution of ammonium chloride, three extractions were conducted with ethyl acetate. The combined organic layers were washed with saturated brine. After passage through a phase separator, the washed organic layers were concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0-70:30) to give 1-(biphenyl-4-yl)propan-1-ol as a colorless solid (1.27 g).
Reaction SMILES: C[C:2]1[C:7]([C:8]#[C:9]CO)=[CH:6][N:5]=[C:4]([F:12])[C:3]=1C.[OH-].[Na+]>C1(C)C=CC=CC=1>[F:12][C:4]1[N:5]=[CH:6][C:7]([C:8]#[CH:9])=[CH:2][CH:3]=1
Reactant: Cc1c(C#CCO)cnc(F)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: C#Cc1ccc(F)nc1
Temperature: 120 °C
Yield: 32.1 %

Procedure:
0.830 mg (4.63 mmol) of Dimethylhydroxymethyl-2-fluoro-5-pyridylacetylene and 195 mg (4.86 mmol) of NaOH (KISHIDA CHEMICAL CO., Ltd., 0.7 mm granular, 98%) were placed in a 50 mL two-neck flask equipped with a reflux condenser and the air inside the flask was replaced with Ar. 23 mL of toluene was added thereto and the mixture was refluxed at 120° C. for 1 hour. Toluene was added to the reaction mixture and the mixture was washed with a saturated aqueous ammonium chloride solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure at 95 mmHg/72° C. to give 6-fluoro-3-pyridylethyne as an orange-color liquid (0.18 g, yield: 32%).
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([NH2:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[CH3:13][O:14][CH2:15][N:16]=[C:17]=[O:18]>C1(C)C=CC=CC=1>[CH3:13][O:14][CH2:15][NH:16][C:17]([NH:10][CH:5]1[CH2:6][C:7]([CH3:8])([CH3:9])[N:2]([CH3:1])[C:3]([CH3:12])([CH3:11])[CH2:4]1)=[O:18]
Reactant: COCN=C=O
Reactant: CN1C(C)(C)CC(N)CC1(C)C
Solvent: Cc1ccccc1
Product: COCNC(=O)NC1CC(C)(C)N(C)C(C)(C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
34 parts of 1,2,2,6,6-pentamethyl-4-aminopiperidine are dissolved in 100 parts of toluene, followed by the dropwise addition at 25° C. of 18.8 parts of 93% methoxymethyl isocyanate. After stirring for 1 hour at 25° C., the toluene is evaporated off in vacuo and the residue is crystallised from cleaning spirit, giving 42.5 g of colourless crystals melting at 105° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=2)[N:3]=1.[CH3:17][N:18]([CH3:22])[CH2:19][CH2:20][NH2:21]>O>[Cl:8][C:6]1[CH:7]=[C:2]([NH:21][CH2:20][CH2:19][N:18]([CH3:22])[CH3:17])[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=2)[N:5]=1
Reactant: CN(C)CCN
Reactant: Clc1cc(Cl)nc(-c2ccc(Cl)c(Cl)c2)n1
Solvent: O
Product: CN(C)CCNc1cc(Cl)nc(-c2ccc(Cl)c(Cl)c2)n1

Procedure:
Seven grams of 4,6-dichloro-2-(3,4-dichlorophenyl)pyrimidine is added in small portions to 25 ml. of N,N-dimethylethylenediamine with slight warming and stirring. The resulting mixture is heated on a steam bath for several minutes then poured into 500 ml. of water. The product thus obtained is recrystallized from n-heptane to afford 4-chloro-2-(3,4-dichlorophenyl)-6-[2-(dimethylamino)ethylamino]-pyrimidine, m.p. 99.5°-102°C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[C:15]3[C@H:14]4[CH2:16][C@H:13]4[CH2:12][C:11]=3[C:10]([C:17](O)=[O:18])=[N:9]2)[CH:3]=1.Cl.[NH2:21][C:22]([CH2:29][F:30])([CH2:27][F:28])[C:23](OC)=[O:24].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:28][CH2:27][C:22]([NH:21][C:17]([C:10]1[C:11]2[CH2:12][C@@H:13]3[CH2:16][C@@H:14]3[C:15]=2[N:8]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=2)[N:9]=1)=[O:18])([CH2:29][F:30])[CH2:23][OH:24]
Reactant: O=C(O)c1nn(-c2cc(Cl)ccn2)c2c1C[C@@H]1C[C@H]21
Reactant: COC(=O)C(N)(CF)CF
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NC(CO)(CF)CF)c1nn(-c2cc(Cl)ccn2)c2c1C[C@@H]1C[C@H]21
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of (1aS,5aS)-2-(4-chloro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (100 mg, 0.363 mmol), methyl 2-amino-3-fluoro-2-(fluoromethyl)propanoate hydrochloride (76 mg, 0.399 mmol) and triethylamine (0.101 mL, 0.725 mmol) in DMF (2 mL) was added HATU (138 mg, 0.363 mmol). The reaction was stirred at 50° C. for 2 h, then concentrated. The residue was purified by silica gel flash chromatography to give the title compound as a white solid. LCMS m/z=411.2 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 0.46 (td, J=4.7, 3.3 Hz, 1H), 1.25 (td, J=7.8, 4.7 Hz, 1H), 2.24-2.30 (m, 1H), 2.79-2.84 (m, 1H), 2.89 (d, J=16.8 Hz, 1H), 2.99 (dd, J=16.4, 6.2 Hz, 1H), 3.89 (s, 3H), 4.81-5.12 (m, 4H), 7.22 (dd, J=5.3, 1.8 Hz, 1H), 7.51 (s, 1H), 7.98 (d, J=1.8 Hz, 1H), 8.36 (d, J=5.3 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([NH:14][C:15]2[S:19][N:18]=[C:17]([CH3:20])[C:16]=2Br)=[O:13])=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1.[NH:22]1[CH:26]=[CH:25][CH:24]=[N:23]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[NH2:1][C:2]1[C:11]([C:12]([NH:14][C:15]2[S:19][N:18]=[C:17]([CH3:20])[C:16]=2[N:22]2[CH:26]=[CH:25][CH:24]=[N:23]2)=[O:13])=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1
Reactant: c1cn[nH]c1
Reactant: Cc1nsc(NC(=O)c2c(N)nn3cc(F)cnc23)c1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1nsc(NC(=O)c2c(N)nn3cc(F)cnc23)c1-n1cccn1
Temperature: 140 °C

Procedure:
A mixture of 2-amino-N-(4-bromo-3-methyl-isothiazol-5-yl)-6-fluoro-pyrazolo[1,5-a]pyrimidine-3-carboxamide (20 mg, 0.05388 mmol), 1H-pyrazole (7.339 mg, 0.1078 mmol), Cut (21 mg, 0.1103 mmol), Cs2CO3 (71 mg, 0.2179 mmol) in DMF (2 mL) was degassed with nitrogen and heated at 140° C. in a microwave for 1 h. The insoluble material was filtered off and the filtrate was purified by fractionlynx. The clean fractions were freeze-dried yielding 2-amino-6-fluoro-N-(3-methyl-4-(1H-pyrazol-1-yl)isothiazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide as a pale yellow solid. (0.63 mg, 1.9%). MS (ES+) 359.1.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]2[CH2:15][CH2:16][CH3:17])=O.COC1C=CC(/C=[C:33]2/[C:34]([NH:36][C:37]([S:39]/2)=[NH:38])=[O:35])=CC=1OC1CCCC1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[NH2:38][C:37]1[S:39]/[C:33](=[CH:1]\[C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]3[CH2:15][CH2:16][CH3:17])/[C:34](=[O:35])[N:36]=1
Reactant: COc1ccc(/C=C2\SC(=N)NC2=O)cc1OC1CCCC1
Reactant: CCCc1c(C#N)cnc2ccc(C=O)cc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCc1c(C#N)cnc2ccc(/C=C3\SC(N)=NC3=O)cc12

Procedure:
Similar procedure as described in example 28c was used, starting from 6-formyl-4-propyl-quinoline-3-carbonitrile (example 71c), pseudothiohydantoin, sodium acetate and acetic acid to give 6-[2-amino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-propyl-quinoline-3-carbonitrile. LC-MS m/e 323 (MH+).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C:3]([CH3:6])([CH3:5])[CH3:4].[C:10](OC(=O)C)(=[O:12])[CH3:11]>C(O)(=O)C>[C:10]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[C:3]([CH3:6])([CH3:5])[CH3:4])(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)[C@H](N)C(=O)O
Solvent: CC(=O)O
Product: CC(=O)N[C@H](C(=O)O)C(C)(C)C

Procedure:
L-tert-Leucine (manufactured by Tokyo Kasei Kogyo) (4.7 g) was suspended in glacial acetic acid (manufactured by Nakarai Tesk, 40 mL) and heated at 40 to 50° C. together with addition of thrice molar acetic acid anhydride (manufactured by Nakarai Tesk) thereto whereupon the reaction was conducted. After glacial acetic acid was removed in vacuo, the crude crystals were obtained. After that, the crude crystals were recrystallized from 20% isopropyl alcohol. The precipitate was ground in a mortar and dried to give powder of N-acetyl-L-tert-leucine. Details thereof are mentioned in J. P. Greenstein, Chemistry of Amino Acids, 1961, 3.