Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[N:10][NH2:11])[C@H:2]([C@@H:4]([C@@H:6]([CH2:8][OH:9])[OH:7])[OH:5])[OH:3].[H][H]>C(O)C.O.[Pt]=O>[NH:10]([CH2:1][C@H:2]([C@@H:4]([C@@H:6]([CH2:8][OH:9])[OH:7])[OH:5])[OH:3])[NH2:11]
Reactant: [H][H]
Reactant: NN=C[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=[Pt]
Solvent: CCO
Solvent: O
Product: NNC[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
A 1.5 portion of D-arabinose hydrazone in 40 ml of ethanol and 20 ml of water was reduced with 200 mg of platinum oxide and hydrogen for 4 hours. The mixture was then filtered and the filtrate evaporated to dryness. The residue was dissolved in 40 ml of methanol and then evaporated to dryness, giving 1.24 g of 1-deoxy-1-hydrazino-D-arabinitol.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([C:18]4(C(O)=O)[CH2:20][CH2:19]4)[CH:15]=[N:16][CH:17]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]1=[O:24].C1(P([N:39]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.CC([O-])(C)C.[K+]>C1(C)C=CC=CC=1.C1COCC1>[NH2:39][C:18]1([C:14]2[CH:13]=[C:12]([C:8]3[CH:7]=[C:6]4[C:11](=[CH:10][CH:9]=3)[N:2]([CH3:1])[C:3](=[O:24])[CH:4]=[CH:5]4)[CH:17]=[N:16][CH:15]=2)[CH2:20][CH2:19]1
Reactant: CN1C(=O)CCc2cc(-c3cncc(C4(C(=O)O)CC4)c3)ccc21
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cn1c(=O)ccc2cc(-c3cncc(C4(N)CC4)c3)ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 38.3 %

Procedure:
To solution of 1-(5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)cyclopropanecarboxylic acid (example 59 [C], 0.3 g, 0.931 mmol) in toluene (15 mL) were added TEA (0.141 g, 1.4 mmol) and diphenylphosphoryl azide (0.384 g, 1.4 mmol) and then the reaction mixture was heated to reflux for 4 h. The mixture was concentrated in vacuo, the residue was dissolved in THF (30 mL) and the solution cooled to 0° C. Then, a solution of KOtBu (0.627 g, 5.58 mmol) in THF (13 mL) was added and the mixture was stirred for 1 h at 0° C. and then over night at room temperature. The mixture was concentrated in vacuo, the residue was preadsorbed on silica gel and purified by silica gel flash chromatography eluting with a 0 to 10% MeOH-DCM gradient to give a yellow amorphous solid (0.104 g). This material was then further purified by reverse phase HPLC on a Gemini-NX column, eluting with a MeOH—H2O (0.05% TEA) gradient to give the title compound (0.02 g, 7%) as a colorless amorphous solid. MS: 292.3 (M+H+).
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.COB(OC)OC.B.CSC.CO>C1COCC1>[C:1]1([NH:7][C:8]2[C:13]([CH2:14][OH:15])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1cccnc1Nc1ccccc1
Agent: B
Agent: COB(OC)OC
Solvent: C1CCOC1
Solvent: CO
Solvent: CSC
Product: OCc1cccnc1Nc1ccccc1
Reaction time: 0.5 h
Yield: 49.3 %

Procedure:
To a refluxing solution of 6.5 g (30.4 mmole) of 2-phenylamino-3-pyridinecarboxylic acid and 7.5 mL (64.2 mmoles) of trimethylborate in 40 mL of THF under N2 was added dropwise, 65 mL (130 mmole) of 2M borane-methyl sulfide over a 30 min period. The reaction mixture was refluxed for 2 hrs, then cooled, and 50 mL of CH3OH was added dropwise with stirring over a period of 30 min. The mixture was refluxed for 5 min, and the solvents were evaporated to leave a gummy light yellow semi-solid which was partitioned between 250 mL of 2N HCl and 150 mL of CH2Cl2. The aqueous layer was separated and brought to pH 8 (NaHCO3), and the mixture was extracted with CH2Cl2 (700 mL). The CH2Cl2 was evaporated to leave 3.0 g of semi-solid which was purified by dry-column chromatography (glass column, 4×60 cm; 235 gm of silica; eluted with CH2Cl2). The fractions containing the product were extracted with CH2Cl2 then with CH3OH. The solvents were evaporated, and the oily residue was converted to the HCl salt in acetone-Et2O to give 1.4 g (40%) of creamcolored solid; mp 180°-182° C. (J. Med. Chem. 11, 894 (1968), mp 189°-190° C.). MS (EI) m/e (relative intensity): 200 (M+, 27), 199 (24), 182 (65), 181 (100).
Reaction SMILES: [CH2:1]([N:5]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[C:7]([CH3:17])=[N:6]1)[CH2:2][C:3]#[CH:4].Br[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>>[F:16][C:13]1[CH:12]=[CH:11][C:10]([C:8]2[C:7]([CH3:17])=[N:6][N:5]([CH2:1][CH2:2][C:3]#[C:4][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[N:9]=2)=[CH:15][CH:14]=1
Reactant: Brc1ccccn1
Reactant: C#CCCn1nc(C)c(-c2ccc(F)cc2)n1
Product: Cc1nn(CCC#Cc2ccccn2)nc1-c1ccc(F)cc1
Yield: 86.2 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-(but-3-ynyl)-4-(4-fluorophenyl)-5-methyl-2H-1,2,3-triazole (265 mg, 1.16 mmol) and 2-bromopyridine (201 mg, 1.27 mmol). Reaction time: 2 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 306 mg (1.00 mmol, 86%) of 2-(4-(4-(4-fluorophenyl)-5-methyl-2H-1,2,3-triazol-2-yl)but-1-ynyl)pyridine as a brown oil.
Reaction SMILES: Br[C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[S:14]1[C:18](B(O)O)=[CH:17][C:16]2[CH:22]=[CH:23][CH:24]=[CH:25][C:15]1=2.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:14]1[C:18]([C:2]2[C:3]([O:12][CH3:13])=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=2)[CH:7]=[O:8])=[CH:17][C:16]2[CH:22]=[CH:23][CH:24]=[CH:25][C:15]1=2
Reactant: COc1cc(OC)c(C=O)cc1Br
Reactant: OB(O)c1cc2ccccc2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(OC)c(-c2cc3ccccc3s2)cc1C=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 79.6 %

Procedure:
Ex-6A: 5-Bromo-2,4-dimethoxybenzaldehyde (4.9 g, 20.0 mmol) was dissolved in ethylene glycol dimethyl ether (50 mL). Tetrakis(triphenylphosphine)palladium(0) (2.32 g, 2 mmol) was added, and the mixture was stirred at room temperature under nitrogen for 5 min. Benzo[b]thiophene-2-boronic acid (4.27 g, 24 mmol) and sodium carbonate solution (2 M, 20 mL) were added. The mixture was stirred at reflux under nitrogen for 24 hours. Upon cooling to room temperature, it was poured into water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and evaporated. Silica gel chromatography (hexane/ethyl acetate 2:1 then 1:1) gave 4.75 g (83%) of the desired 5-(benzo[b]thien-2-yl)-2,4-dimethoxybenzaldehyde.
Reaction SMILES: [N:1]12[CH2:7][C:4]([C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[OH:9])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:22][CH2:23][CH3:24]>CC#N>[Br-:22].[CH2:23]([N+:1]12[CH2:7][C:4]([C:8]([OH:9])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)([CH2:5][CH2:6]1)[CH2:3][CH2:2]2)[CH3:24]
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)C2
Reactant: CCBr
Solvent: CC#N
Product: CC[N+]12CCC(C(O)(c3ccccc3)c3ccccc3)(CC1)C2
Product: [Br-]
Yield: 65.3 %

Procedure:
Following the general procedure outlined in Example 2, 1-azabicyclo[2.2.1]hept-4-yl(diphenyl)methanol (31.3 mg, 0.112 mmol) and bromoethane (0.03 mL, 0.4 mmol) in 2 CH3CN/3 CHCl3 (2.5 mL) were reacted to give the desired product (28.4 mg, 65%). EI-MS m/z 308 (M+) Rt (1.49 min).
Reaction SMILES: [CH:1]1([C@@H:4]([NH:6][CH2:7][C:8]2[NH:9][C:10](=[O:18])[C:11]3[CH2:17][O:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH3:5])[CH2:3][CH2:2]1.[F:19][C:20]1[CH:37]=[CH:36][C:23]([C:24]([CH:26]2[CH2:31][CH2:30][N:29]([CH2:32][C:33](O)=[O:34])[CH2:28][CH2:27]2)=[O:25])=[CH:22][CH:21]=1>>[CH:1]1([C@@H:4]([N:6]([CH2:7][C:8]2[NH:9][C:10](=[O:18])[C:11]3[CH2:17][O:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[C:33](=[O:34])[CH2:32][N:29]2[CH2:30][CH2:31][CH:26]([C:24](=[O:25])[C:23]3[CH:22]=[CH:21][C:20]([F:19])=[CH:37][CH:36]=3)[CH2:27][CH2:28]2)[CH3:5])[CH2:3][CH2:2]1
Reactant: C[C@H](NCc1nc2c(c(=O)[nH]1)COCC2)C1CC1
Reactant: O=C(O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Product: C[C@@H](C1CC1)N(Cc1nc2c(c(=O)[nH]1)COCC2)C(=O)CN1CCC(C(=O)c2ccc(F)cc2)CC1

Procedure:
Following general procedure of Example 4, the title compound was prepared (29 mg) from (S)-2-((1-cyclopropylethylamino)methyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one and 2-(4-(4-fluorobenzoyl)piperidin-1-yl)acetic acid. Exact mass calculated for C27H33FN4O4 496.6. found 497.6 (ESI, M+H); 1H NMR (400 MHz, DMSO-d6) δ ppm 7.98-8.21 (m, 2H) 7.40 (t, J=8.84 Hz, 2H) 4.25-4.54 (m, 5H) 3.84 (ddd, J=17.31, 5.56, 5.43 Hz, 3H) 3.70 (d, J=6.06 Hz, 1H) 3.56 (br. s., 2H) 3.23 (br. s., 1H) 2.99-3.20 (m, 2H) 1.99 (br. s., 4H) 1.00-1.29 (m, 4H) 0.68-0.94 (m, 1H) 0.46-0.68 (m, 1H) 0.38 (d, J=5.05 Hz, 1H) 0.24-0.34 (m, 1H) 0.15-0.24 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9](Cl)=[O:10])[CH2:6]1.[OH-].[NH4+:21]>O1CCCC1.O>[Cl:1][C:2]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9]([NH2:21])=[O:10])[CH2:6]1
Reactant: [NH4+]
Reactant: O=C(Cl)N1CC(Oc2ccc(C(F)(F)F)cc2Cl)C1
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)N1CC(Oc2ccc(C(F)(F)F)cc2Cl)C1
Reaction time: 16 h
Yield: 83.5 %

Procedure:
A solution of 2 g (0.0065 mole) of 3-[2-chloro-4-(trifluoromethyl)phenoxy]-1-azetidinecarbonyl chloride in 15 ml of tetrahydrofuran was treated while stirring with 1 ml (0.013 mole) of 57% ammonium hydroxide. After stirring for 16 h the reaction mixture was diluted with 100 ml of water and the solid which precipitated was collected by filtration (2.4 g). Recrystallization from benzene/ligroin yielded 1.6 g (83.5%) of white crystals, mp. 156°-159° C.
Reaction SMILES: [F:1][C:2]([F:33])([C:25](=[O:32])[N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C:3](=[N:18][S:19]([C:21]([CH3:24])([CH3:23])[CH3:22])=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[CH:6][CH:5]=1.[Si]([C:38]([F:41])([F:40])[F:39])(C)(C)C>CCCC[N+](CCCC)(CCCC)CCCC.C1C=CC([Si-](F)(F)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C.C1COCC1>[CH3:22][C:21]([S:19]([NH:18][C:3]([C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][CH2:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[CH:8][CH:9]=1)([C:2]([F:1])([F:33])[C:25](=[O:32])[N:26]1[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1)[C:38]([F:41])([F:40])[F:39])=[O:20])([CH3:24])[CH3:23]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CC(C)(C)S(=O)N=C(c1ccc(OCCCC(F)(F)F)cc1)C(F)(F)C(=O)N1CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: F[Si-](F)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)NC(c1ccc(OCCCC(F)(F)F)cc1)(C(F)(F)F)C(F)(F)C(=O)N1CCCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 57.9 %

Procedure:
To a solution of TBAT (3.43 g, 6.36 mmol) in DMF (5.89 mL) was added a solution of Intermediate 103C (1.17 g, 2.356 mmol) in THF (5.89 mL). The solution was cooled to 0° C., and then 2 M TMSCF3 (3.53 mL, 7.07 mmol) in THF was added dropwise. The reaction was stirred at 0° C. for 1 h, and then quenched with brine (20 mL) at 0° C. The mixture was warmed to rt and diluted with water and EtOAc. The layers were separated. The aqueous layer was washed with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (80 g silica gel, eluted with EtOAc in hexanes) to afford the desired product (773 mg, 58%) as a yellow gum. LCMS Anal. Calc'd for C23H30F8N2O3S 566.18, found [M+H] 567.1. 1H NMR (500 MHz, CD3OD) δ 7.69 (d, J=8.53 Hz, 2H), 6.91 (d, J=9.08 Hz, 2H), 4.03 (t, J=5.91 Hz, 2H), 3.50-3.62 (m, 2H), 3.34-3.45 (m, 2H), 2.23-2.35 (m, 2H), 1.98-2.07 (m, 2H), 1.48-1.69 (m, 6H), 1.26 (s, 9H).
Reaction SMILES: [C:1]1([C:7]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][C:16]#[N:17])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.CCOCC>C1COCC1.C(Cl)Cl>[NH2:17][CH2:16][CH2:15][CH2:14][CH2:13][N:10]1[CH2:11][CH2:12][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:8][CH2:9]1
Reactant: N#CCCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCOCC
Product: NCCCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 4-(4,4-diphenylpiperidin-1-yl)butyronitrile (4.65 g, 15.3 mmol, 1.0 equiv) in anhydrous THF (20 mL) under argon was added a solution of BH3 in THF (1.0M, 54 mL, 54 mmol, 3.5 equiv) at room temperature. The mixture was refluxed for 4.5 hours and then cooled to room temperature and concentrated to a volume of about 40 mL. Aqueous HCl (6N, 55 mL) was added cautiously at 0° C. and stirring was continued for 2 hours at 55-65° C. The mixture was cooled to 0° C., basified to pH 10 by addition of 6N aq. NaOH, and extracted with CH2Cl2 (3×100 mL). The combined organic solutions were dried over MgSO4 and concentrated. To a solution of the residue in CH2Cl2 (50 mL) was added HCl in ether (1.0M, 30 mL, 2.0 equiv). After removal of the solvents, the residue was dissolved in CH2Cl2 (10 mL) and this solution was added dropwise into ether (150 mL) with swirling. The resulting solid was filtered and washed with ether (100 mL). This solid was taken up in water (30 mL), which was basified to pH 10 by addition of 1M aqueous NaOH, and extracted with CH2Cl2 (3×50 mL). The combined organic solutions were dried over MgSO4 and concentrated to give 4.51 g (95%) of light brown oil, which was characterized spectroscopically.
Reaction SMILES: Cl[C:2]([O:4][CH:5]=[CH2:6])=[O:3].[CH:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.N1C=CC=CC=1.[Cl:21]CCCl>>[C:2](=[O:3])([O:4][CH:5]=[CH2:6])[O:14][CH:7]([Cl:21])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=Cc1ccccc1
Reactant: C=COC(=O)Cl
Reactant: ClCCCl
Solvent: c1ccncc1
Product: C=COC(=O)OC(Cl)c1ccccc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 50 %

Procedure:
Vinyl chloroformate (3.0 g, 0.028 mol) and benzaldehyde (4.14 g, 0.039 mol) were dissolved in 1,2-dichloroethane (30 ml) and pyridine (0.1 g, 1.28 mol) was added dropwise to the stirred solution. The solution was stirred for 1 day at 80° C., washed with water (25 ml), and the aqueous phase was back extracted with methylene chloride (25 ml). The combined organic phases were dried (MgSO4) and concentrated to give 3.0 g (50%) of the title product.
Reaction SMILES: C([O:5][C:6](=[O:27])[NH:7][CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([OH:18])=[CH:13][CH:14]=2)[CH:9]1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)(C)(C)C.C(OC(=O)N[CH:35]1[CH2:44][CH2:43][C:42]2[C:37](=CC(O)=CC=2)[CH:36]1[CH2:46]C1C=CC(Cl)=C(Cl)C=1)(C)(C)C.C(N(CC)CC)C.C(Cl)(=O)OCC1C=CC=CC=1>CN(C)C=O>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][CH:9]2[C:10]3[C:15](=[CH:14][CH:13]=[C:12]([OH:18])[CH:11]=3)[CH2:16][CH2:17][CH:8]2[NH:7][C:6](=[O:27])[O:5][CH2:46][C:36]2[CH:37]=[CH:42][CH:43]=[CH:44][CH:35]=2)=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)NC1CCc2ccc(O)cc2C1Cc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NC1CCc2ccc(O)cc2C1Cc1ccc(Cl)c(Cl)c1
Agent: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NC1CCc2ccc(O)cc2C1Cc1ccc(Cl)cc1)OCc1ccccc1
Temperature: 25 °C

Procedure:
tert-Butyl[1-(4-chlorobenzyl)-7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate (2 g, 6.95 mmol, prepared analogously to tert-butyl[1-(3,4-dichlorobenzyl)-7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate, cf. example 34.2 were suspended in dimethylformamide (40 mL). Triethylamine (0.969 mL, 6.95 mmol) and benzyl carbonochloridate (1.186 g, 6.95 mmol) were added. The reaction mixture was stirred at room temperature over night. The solvent was evaporated in vacuo. To the crude product ethyl acetate and water were added. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, dichloromethane, methanol). Yield: 393 mg (0.931 mmol, 13.4%, colorless foam).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])[CH2:4][CH2:3]1.C1N=CN([C:22]([N:24]2C=N[CH:26]=[CH:25]2)=[O:23])C=1.CI.[N:31]1[CH:36]=[CH:35]C=[CH:33][C:32]=1CN>C(#N)C.O>[N:12]1([C:10]([NH:9][CH2:8][CH:5]2[CH2:6][CH2:7][CH:2]([O:1][C:22](=[O:23])[NH:24][CH2:25][C:26]3[CH:35]=[CH:36][N:31]=[CH:32][CH:33]=3)[CH2:3][CH2:4]2)=[O:11])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: NCc1ccccn1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(NCC1CCC(O)CC1)N1CCCC1
Solvent: CI
Solvent: CC#N
Solvent: O
Product: O=C(NCc1ccncc1)OC1CCC(CNC(=O)N2CCCC2)CC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
To a solution of 4-hydroxymethylcyclohexanol (2 mmol) in THF (10 mL) were added Ms-Cl (2.2 mmol) and triethylamine (3 mmol) at 0° C. and the resulting mixture was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in 10 mL of DMF, and then NaN3(6 mmol) was added. After overnight stirring at 60° C., the reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Then, the obtained compound was dissolved in methanol, and 10% Pd—C (0.2 mmol) was added. After overnight stirring under hydrogen atmosphere, the reaction mixture was filtered, washed with methanol and concentrated under reduced pressure to provide 4-aminomethyl-cyclohexanol. To a solution of 4-aminomethyl-cyclohexanel in dichloromethane (10 mL) were added 1-pyrrolidinecarbonyl chloride (2 mmol) and triethylamine (3 mmol). After overnight stirring at room temperature, the reaction mixture was diluted with water, followed by few times of extraction with methylene chloride. The combined organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexane:ethyl acetate=1:1) to provide a pyrrolidine-1-carboxylic acid (4-hydroxy-cyclohexylmethyl)-amide. The pyrrolidine-1-carboxylic acid (4-hydroxy-cyclohexylmethyl)-amide compound was dissolved in acetonitrile (10 mL), and then CDI (2.2 mmol) was added. After 1 hours stirring at 80° C., methyl iodide (10 mmol) was added and stirred for additional 1 hour at 80° C. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in acetonitrile (10 mL) and C-pyridine-2-yl-methylamine (3 mmol) was added. After 4 hours stirring at 80° C., the reaction mixture was diluted with water, followed by few times of extraction with methylene chloride. The combined organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexane:ethyl acetate=1:3), thereby completing the preparation of a target compound (180 mg, 25% yield).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.C(O)C.[N+:14]([C:17]1[C:22]([CH:23]=O)=[CH:21][C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=1)([O-:16])=[O:15].C(O)(=O)C>C(Cl)(Cl)Cl>[N+:14]([C:17]1[C:22]([CH:23]=[C:6]2[CH2:7][O:8][CH2:9][CH2:10][N:5]2[CH2:4][CH2:3][CH2:2][NH2:1])=[CH:21][C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=1)([O-:16])=[O:15]
Reactant: COc1cc(C=O)c([N+](=O)[O-])cc1OC
Reactant: NCCCN1CCOCC1
Solvent: CC(=O)O
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: COc1cc(C=C2COCCN2CCCN)c([N+](=O)[O-])cc1OC
Yield: 94.1 %

Procedure:
A solution of N-(γ-aminopropyl)morpholine (63 g, 0.44 mole) and ethanol (50 ml) was introduced to a heated suspension of 6-nitroveratraldehyde (84 g, 0.4 mole), ethanol (600 ml) and acetic acid (1 ml). The resulting solution was refluxed for 1.5 hrs and allowed to cool overnight. The solvent was stripped leaving a dark oil which was dissolved in chloroform (300 ml) and washed with water. The chloroform was stripped giving 127 g (95%) of the product.
Reaction SMILES: [CH3:1][N:2]([CH2:9][CH2:10][OH:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.F[C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1>>[CH3:1][N:2]([CH2:9][CH2:10][O:11][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: CN(CCO)c1ccccn1
Reactant: O=Cc1ccc(F)cc1
Product: CN(CCOc1ccc(C=O)cc1)c1ccccn1

Procedure:
The title compound was prepared from 2-(N-methyl-N-(2-pyridyl)amino)ethanol (8.9 g) and 4-fluorobenzaldehyde by a similar procedure to that described in Preparation 22.
Reaction SMILES: C1COCC1.Br[C:7](Br)=[CH:8][CH2:9][CH2:10]/[CH:11]=[C:12](\[CH3:22])/[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[Li]CCCC>CCCCCC>[CH3:22]/[C:12](/[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:11]\[CH2:10][CH2:9][C:8]#[CH:7]
Reactant: CCCCCCCCC/C(C)=C/CCC=C(Br)Br
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C#CCC/C=C(\C)CCCCCCCCC
Temperature: 0 °C
Yield: 87.9 %

Procedure:
To a stirred and cooled THF (400 ml) solution of the (E)-1,1-dibromo-6-methyl-1,5-pentadecadiene (6) (37.0 g, 97.6 mmols), an n-hexane solution of n-BuLi (1.5 M, 150 ml, 225 mmols) was added dropwise at −70° C. under an Ar gas. The mixture was stirred for 1 hour at −70° C. and for 1.5 hours at room temperature. Then, the reaction mixture was poured into 1.5 liters of ice water, and extracted with n-hexane. The hexane solution was washed with water, dried with sodium sulfate, and concentrated in a vacuum. The residue was subjected to silica gel column chromatography, and eluted with n-hexane to obtain 18.9 g (88.0%) of (E)-6-methyl-5-pentadecen-1-yne (7) as oily matter.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:22][C:21](=[O:23])[C:20]4[C:15](=[C:16](C#C)[CH:17]=[C:18]5[CH:26]=[N:25][NH:24][C:19]5=4)[N:14]=3)=[CH:11][C:10]([C:29]([F:32])([F:31])[F:30])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:33]([NH2:36])([CH3:35])[CH3:34].[C:37](#[N:39])C.O>>[CH:33]([NH:36][C:21]([C:20]1[C:15]([NH:14][C:13]([C:12]2[N:8]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=3)[N:9]=[C:10]([C:29]([F:32])([F:31])[F:30])[CH:11]=2)=[O:22])=[C:16]([C:37]#[N:39])[CH:17]=[C:18]2[C:19]=1[NH:24][N:25]=[CH:26]2)=[O:23])([CH3:35])[CH3:34]
Reactant: CC(C)N
Reactant: CC#N
Reactant: C#Cc1cc2cn[nH]c2c2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Solvent: O
Product: CC(C)NC(=O)c1c(NC(=O)c2cc(C(F)(F)F)nn2-c2ncccc2Cl)c(C#N)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 426 mg of the above 7-[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-3-yl]-5-ethynyl-1H-8-oxa-1,2,6-triaza-cyclopenta[a]naphthalen-9-one in 7 mL of 4:1 (v/v) mixture of acetonitrile/water is added 0.79 mL (9.3 mmol) of isopropylamine. The reaction mixture is stirred during 4 hours at ambient temperature and then concentrated in vacuo. After purification by flash chromatography (SiO2, hexane/ethyl acetate 4:1), 250 mg (38%) of product are obtained as a yellow solid; LC/MS:516/518 (M+H)+; m.p.: 226-229° C.
Reaction SMILES: [CH3:1][C:2]1[O:12][C:5]2[CH2:6][NH:7][CH2:8][CH2:9][CH:10]([OH:11])[C:4]=2[CH:3]=1.[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1F>>[ClH:13].[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[O:11][CH:10]1[CH2:9][CH2:8][NH:7][CH2:6][C:5]2[O:12][C:2]([CH3:1])=[CH:3][C:4]1=2
Reactant: Cc1cc2c(o1)CNCCC2O
Reactant: Fc1cccc(Cl)c1Cl
Product: Cc1cc2c(o1)CNCCC2Oc1cccc(Cl)c1Cl
Product: Cl

Procedure:
The same method as in Example 3 was conducted using 2-methyl-5,6,7,8-tetrahydro-4H-furo[2,3-c]azepin-4-ol (Reference Example 44) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 2,3-dichloro-1-fluorobenzene instead of 1,3-difluorobenzene to give the objective compound.