Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1.[CH3:21][N:22]1C(=O)CCC1>[C-]#N.[C-]#N.[Zn+2].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>[O:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH:15]1[N:6]1[C:7]2[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=[C:2]([C:21]#[N:22])[C:3]=2[CH:4]=[N:5]1
Reactant: FC(F)(F)c1cc(Br)c2cnn(C3CCCCO3)c2c1
Reactant: CN1CCCC1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cc(C(F)(F)F)cc2c1cnn2C1CCCCO1
Temperature: 85 °C
Reaction time: 16 h
Yield: 79 %

Procedure:
A sealed-cap vial was charged with 4-bromo-1-(tetrahydro-2H-pyran-2-yl)-6-(trifluoromethyl)-1H-indazole (1.03 g, 2.95 mmol), Zn(CN)2 (0.38 g, 3.24 mmol), Pd(PPh3)4 (0.24 g, 0.21 mmol), and NMP (8 mL). The mixture was degassed for 5 min under nitrogen and the mixture then stirred under nitrogen at 85° C. for 16 h. The mixture was filtered and the filtrate concentrated in vacuo. The crude mixture was purified by SiO2 chromatography to afford 1-(tetrahydro-2H-pyran-2-yl)-6-(trifluoromethyl)-1H-indazole-4-carbonitrile as a solid (0.69 g, 79%). MS (ESI) m/z: 296.3 [M+1]+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Br:12][C:13]1[CH:14]=[C:15]([N:19]=[C:20]=[O:21])[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.O>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:20](=[O:21])[NH:19][C:15]3[CH:16]=[CH:17][CH:18]=[C:13]([Br:12])[CH:14]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccc2ncccc2c1
Reactant: O=C=Nc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(Br)c1)Oc1ccc2ncccc2c1

Procedure:
A mixture of quinolin-6-ol (0.29 g, 2 mmol), 3-bromo-phenyl isocyanate (0.47 g., 2.4 mmol), potassium carbonate 0.28 g. (0.28 g. 2 mmol) and potassium iodide (0.32 g.) in dry dimethylformamide (2 ml) was heated at 80° C. for 20 hours. The reaction mixture was diluted with water (5 ml), extracted with ethyl acetate (2×5 ml) and dried over sodium sulphate. The combined ethyl acetate fractions were concentrated under vaccum. The residue was washed with methanol (2×3 ml) to give 1d, yield: 0.34 g. (49.5%).
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH2:14][C:15](=[O:23])[CH2:16][P:17]([O:21][CH3:22])([O:19][CH3:20])=[O:18])[CH2:10][C:11]([OH:13])=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O.C(OCC)(=O)C>[Si:1]([O:8][C@H:9]([CH2:14][C:15](=[O:23])[CH2:16][P:17]([O:19][CH3:20])([O:21][CH3:22])=[O:18])[CH2:10][C:11]([O:13][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:12])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: COP(=O)(CC(=O)C[C@H](CC(=O)O)O[Si](C)(C)C(C)(C)C)OC
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: O
Product: COP(=O)(CC(=O)C[C@H](CC(=O)OCc1ccccc1)O[Si](C)(C)C(C)(C)C)OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 87 %

Procedure:
1.84 g (4.99 mmol.) of (R)-3-t-butyldimethylsilyloxy-6-dimethoxyphosphinyl-5-oxohexanoic acid was dissolved in 11.5 ml of acetone. To the acetone solution were added 2.56 g (15.0 mmol.) of benzyl bromide and 0.76 g (5.5 mmol,) of potassium carbonate, and the resulting mixture was vigorously stirred for 6 hours at room temperature to give a reaction solution. The reaction solution was mixed with 12 ml of water and then extracted with 12 ml of toluene. The toluene portion was dried over anhydrous magnesium sulfate and concentrated to give an oil. The oil was treated by column chromatography (eluent: ethyl acetate) to give 1.99 g (4.34 mmol.) of benzyl (R)-3-t-butyldimethylsilyloxy-6-dimethoxyphosphinyl-5-oxohexanoate (optical purity: 99% ee) as an oil (yield: 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:14]([CH3:15])=[N:13][NH:12][C:11](=O)[C:10]=2[C:17]2[C:22]([F:23])=[CH:21][C:20]([F:24])=[CH:19][C:18]=2[F:25])[CH:5]=[CH:6][C:7]=1[Cl:8].P(Cl)(Cl)([Cl:28])=O>>[Cl:28][C:11]1[N:12]=[N:13][C:14]([CH3:15])=[C:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[C:10]=1[C:17]1[C:22]([F:23])=[CH:21][C:20]([F:24])=[CH:19][C:18]=1[F:25]
Reactant: Cc1n[nH]c(=O)c(-c2c(F)cc(F)cc2F)c1-c1ccc(Cl)c(Cl)c1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nnc(Cl)c(-c2c(F)cc(F)cc2F)c1-c1ccc(Cl)c(Cl)c1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
1.75 g of 5-(3,4-dichlorophenyl)-6-methyl-4-(2,4,6-trifluorophenyl)-2H-pyridazin-3-one and 6 ml of phosphorus oxychloride were mixed and stirred at 110° C. for 1 hour. There action mixture was allowed to cool down to room temperature and concentrated under reduced pressure. To the residue was added ethyl acetate and ice water, and was separated to two layer. The organic layer was washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate, then, concentrated under reduced pressure to obtain 1.80 g of 3-chloro-5-(3,4-dichlorophenyl)-6-methyl-4-(2,4,6-trifluorophenyl)pyridazine (hereinafter, referred to as compound (xxiii) of the present invention).
Reaction SMILES: [CH:1]1([NH:7][C:8]2([CH2:13]O)[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O=S(Cl)[Cl:17]>Cl>[ClH:17].[Cl:17][CH2:13][C:8]1([NH:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=S(Cl)Cl
Reactant: OCC1(NC2CCCCC2)CCCC1
Agent: Cl
Product: ClCC1(NC2CCCCC2)CCCC1
Temperature: 70 °C
Yield: 195.8 %

Procedure:
A 4M HCl solution (p-dioxane, 40 mL) containing 1-(cyclohexylamino)-1-(hydroxymethyl)cyclopentane (Method B4a; 1.9 g, 9.6 mmol) and SOCl2 (0.84 mL, 11.5 mmol) was heated to 70° C. for 18 h. The resulting mixture was cooled to room temp. and concentrated under reduced pressure to yield crude 1-(chloromethyl)-1-(cyclohexylamino)cyclopentane HCl salt (2.84 g), which was used in the next step without firer purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[S:13][C:14]2[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]([CH3:22])[C:15]=2[N:16]=1)[CH2:9][C:10]#[CH:11]>>[CH3:22][C:17]1[C:15]2[N:16]=[C:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[S:13][C:14]=2[C:20]([CH3:21])=[CH:19][CH:18]=1
Reactant: Brc1ccccn1
Reactant: C#CCCc1nc2c(C)ccc(C)c2s1
Product: Cc1ccc(C)c2sc(CCC#Cc3ccccn3)nc12
Yield: 17931 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (46 mg, 0.29 mmol) and 2-but-3-ynyl-4,7-dimethyl-benzo[d]thiazole (63 mg, 0.29 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1 to 98:2) to yield 15 mg (52 mmol, 18%) of 4,7-dimethyl-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]thiazole as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].Br[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[CH:15]=1.C([Li])CCC.O1C2C=CC(C(C3C=C(OC)C=C(OC)C=3)O)=CC=2OCC1>>[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]([C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[CH:15]=1)[OH:6]
Reactant: COc1cc(Br)cc(OC)c1
Reactant: COc1cccc(C=O)c1OC
Agent: COc1cc(OC)cc(C(O)c2ccc3c(c2)OCCO3)c1
Agent: [Li]CCCC
Product: COc1cc(OC)cc(C(O)c2cccc(OC)c2OC)c1
Yield: 88.8 %

Procedure:
2,3-Dimethoxybenzaldehyde (0.84 g, 5.03 mmol), 1-bromo-3,5-dimethoxybenzene (1.20 g, 5.53 mmol), and n-butyl lithium (2.20 ml, 5.53 mmol) were treated in the same manner as described above for the synthesis of (2,3-dihydrobenzo[1,4]dioxin-6-yl)-(3,5-dimethoxyphenyl)methanol. The crude material was purified via flash column chromatography (10% EtOAc in hexane gradient to 50% EtOAc in hexane in about 40 min.) to give (2,3-dimethoxy-phenyl)-(3,5-dimethoxy-phenyl)-methanol as a greenish yellow oil (1.36 g, 89%): 1HNMR (CDCl3) 7.08-7.01 (m, 1H, Ar), 6.93-6.85 (m, 2H, Ar), 6.57 (d, J=2 Hz, 2H, Ar), 6.35 (t, J=2 Hz, 1H, Ar), 5.94 (d, J=6 Hz, 1H, CHOH), 3.86 (s, 3H, OCH3), 3.76 (s, 6H, 2OCH3), 3.66 (s, 3H, OCH3), 3.05 (d, J=6 Hz, 1H, OH). The product was carried over to the next step.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:17][C:18]([F:26])([F:25])[C:19](=[O:24])[C:20]([O:22][CH3:23])=[O:21]>C(Cl)(Cl)Cl>[CH3:23][O:22][C:20](=[O:21])[C:19]([OH:24])([C:18]([F:26])([F:25])[F:17])[C:10]1[C:11](=[O:12])[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[NH:8][C:9]=1[C:13]([F:15])([F:16])[F:14]
Reactant: O=c1cc(C(F)(F)F)[nH]n1-c1ccccc1
Reactant: COC(=O)C(=O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COC(=O)C(O)(c1c(C(F)(F)F)[nH]n(-c2ccccc2)c1=O)C(F)(F)F
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a chloroform solution (5 ml) of 1-phenyl-3-trifluoromethyl-5-pyrazolone (114 mg, 0.5 mmol), methyl trifluoropyruvate (78 mg, 0.5 mmol) was added at room temperature and the mixture was stirred at 80° C. for 2 hours. After removing the solvent under reduced pressure, the title compound was obtained as a colorless solid (172 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14](S(C1C=CC(C)=CC=1)(=O)=O)[CH:13]=[C:12]2[C:28]1[N:33]=[C:32]([N:34]2[CH2:39][CH2:38][CH:37]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:36][CH2:35]2)[CH:31]=[N:30][CH:29]=1.C[O-].[Na+].C1COCC1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[C:28]1[N:33]=[C:32]([N:34]2[CH2:35][CH2:36][CH:37]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:45])([CH3:44])[CH3:46])[CH2:38][CH2:39]2)[CH:31]=[N:30][CH:29]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(N4CCC(NC(=O)OC(C)(C)C)CC4)n3)c3cc(-c4c(F)cccc4Cl)ccc32)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCN(c2cncc(-c3c[nH]c4ccc(-c5c(F)cccc5Cl)cc34)n2)CC1
Reaction time: 1 h
Yield: 72.4 %

Procedure:
To a slurry of tert-butyl 1-(6-(5-(2-chloro-6-fluorophenyl)-1-tosyl-1H-indol-3-yl)pyrazin-2-yl)piperidin-4-ylcarbamate (0.186 g, 0.275 mmol) in 2 mL MeOH was added sodium methanolate 25 wt % in MeOH (0.126 mL, 0.550 mmol). 2 mL THF was added. The cloudy mixture was sealed and stirred rapidly. After 1 h, additional sodium methanolate 25 wt % in MeOH (0.126 mL, 0.550 mmol) was added. The reaction became a clear, orange solution. After 2 h, the reaction was concentrated under a stream of N2, and the solid was partitioned between saturated aqueous NH4Cl and DCM. 1 mL 1N HCl was added to acidify the aqueous layer. The aqueous layer was extracted with DCM 3 times, and the combined organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The material was treated with DCM/MeOH and adsorbed onto 1.5 g silica gel, dried, and purified by silica gel chromatography (40 g column) using 20-80% EtOAc/hexane. The product-containing fractions were concentrated to afford tert-butyl 1-(6-(5-(2-chloro-6-fluorophenyl)-1H-indol-3-yl)pyrazin-2-yl)piperidin-4-ylcarbamate (0.104 g, 0.199 mmol, 72.4% yield) as a orange solid. MS (ESI, pos. ion) m/z: 522 (M+1).
Reaction SMILES: C[O:2][C:3]1[CH:23]=[CH:22][C:6]2[C:7]([CH:10]3[CH2:15][NH:14][CH2:13][CH2:12][N:11]3[C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[N:8][O:9][C:5]=2[CH:4]=1.C(O)(=O)C>CN(C=O)C>[N:19]1[CH:18]=[CH:17][C:16]([N:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH:10]2[C:7]2[C:6]3[CH:22]=[CH:23][C:3]([OH:2])=[CH:4][C:5]=3[O:9][N:8]=2)=[CH:21][CH:20]=1
Reactant: COc1ccc2c(C3CNCCN3c3ccncc3)noc2c1
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Oc1ccc2c(C3CNCCN3c3ccncc3)noc2c1
Yield: 65.8 %

Procedure:
A stirred solution of 6-methoxy-3-[1-(4-pyridyl)piperazinyl]-1,2-benzisoxazole (1.75 g) and sodium ethylthiolate (0.79 g) in DMF (30 ml) was heated to 105-107° C. under N2 and 3 hours. TLC (silica gel 30% MeOH/CH2Cl2) showed no presence of starting material. Glacial acetic acid (5 ml) was added and the solvent was removed in vacuo. The residue was flash chromatographed (silica gel) eluting with 10% MeOH/CH2Cl2 to afford 1.1 g of material. The material was further purified through recrystallization from pyridine to afford 1.0 g of the product, m.p.>250° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[CH2:10]([C:13]1[C:21]2[O:20][N:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[C:17]=2[CH:16]=[CH:15][C:14]=1[O:26][CH2:27][CH2:28][CH2:29]Br)[CH2:11][CH3:12]>>[CH3:1][C:2]1([CH3:9])[CH2:6][C:5](=[O:7])[N:4]([CH2:29][CH2:28][CH2:27][O:26][C:14]2[CH:15]=[CH:16][C:17]3[C:18]([C:22]([F:24])([F:25])[F:23])=[N:19][O:20][C:21]=3[C:13]=2[CH2:10][CH2:11][CH3:12])[C:3]1=[O:8]
Reactant: CCCc1c(OCCCBr)ccc2c(C(F)(F)F)noc12
Reactant: CC1(C)CC(=O)NC1=O
Product: CCCc1c(OCCCN2C(=O)CC(C)(C)C2=O)ccc2c(C(F)(F)F)noc12

Procedure:
3,3-Dimethyl-1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)pyrrolidine-2,5-dione was prepared as for Example 10 from 3,3-dimethylpyrrolidine-2,5-dione and the bromide from Example 7. After aqueous work-up and silica gel chromatography, the title compound was obtained.
Reaction SMILES: [CH3:1][N:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)[C:3](=O)[CH3:4].C1COCC1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:20].CCCCCCC>C(Cl)Cl>[CH3:1][N:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)[C:3](=[S:20])[CH3:4]
Reactant: CC(=O)N(C)Cc1ccc(F)cc1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: CC(=S)N(C)Cc1ccc(F)cc1
Yield: 91.3 %

Procedure:
Combine N-methyl-N-(4-fluorobenzyl)acetamide (364.8 g, 2.01 mol) and THF (9 L). Stir to dissolve and then add phosphorus pentasulfide (537.7 g, 1.21 mol). After 45 min heat to reflux for 3 h, then cool and stir overnight to give a solid. Collect the solid by filtration and rinse the cake with THF (4 L), evaporate the filtrate in vacuo to give a residue, dissolve the residue in methylene chloride (about 500 mL), and passed over a cake of silica gel 60 (1.2 kg) preconditioned with heptane. Elute with 4 L of heptane/methylene chloride (1:1) followed by 100% methylene chloride to afford 217.98 g of N-methyl-N-(4-fluorobenzyl)thioacetamide (55%): mp=99-104° C.; Rf=0.42 (methylene chloride); 1H NMR (CDCl3) 7.35-7.26 (m, 1), 7.14-6.96 (m, 3),5.28 (s, 1.2) and 4.79 (s, 0.8), 3.42 (s, 1.2) and 3.15 (s, 1.8), 2.72 (s, 1.2) and 2.69 (s, 1.8). Note: Partial protons are believed to be due to rotomers.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[N-:10]=[N+:11]=[N-:12].[Na+]>CS(C)=O.O>[N:10]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)=[N+:11]=[N-:12]
Reactant: N#Cc1ccc(F)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccc(N=[N+]=[N-])cc1
Temperature: 25 °C
Yield: 48.7 %

Procedure:
A solution of 4-fluorobenzonitrile (10.0 g, 82.57 mmol, 1.00 equiv) and NaN3 (6.0 g, 92.29 mmol, 1.12 equiv) in DMSO (100 mL) was stirred at 100° C. for 2 h. The reaction was cooled to room temperature and then diluted with 700 mL of water. The precipitate was collected by filtration and air-dried to give 5.8 g (49%) of 4-azidobenzonitrile as a light yellow solid. 1H NMR (300 MHz, DMSO-d6) δ: 7.88 (d, J=13.5 Hz, 2H), 7.31 (d, J=13.5 Hz, 2H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][N:3]=1.C([O-])([O-])[O:11][CH2:12][CH3:13].[C:16]1(C)C=CC(S(O)(=O)=O)=C[CH:17]=1>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH:8]([O:11][CH2:12][CH3:13])[O:9][CH2:16][CH3:17])[CH:5]=[CH:4][N:3]=1
Reactant: CCOC([O-])[O-]
Reactant: O=Cc1ccnc(Cl)c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(OCC)c1ccnc(Cl)c1
Yield: 855.5 %

Procedure:
60 g of 2-chloro-4-pyridinecarboxaldehyde and 90 g of ethyl orthoformate were dissolved in 600 ml of ethanol, and 7 g of p-toluenesulfonic acid was added. The mixture was refluxed for 1 hour. After cooling, the reaction solution was concentrated. The concentrate was taken into ethyl acetate, washed with a saturated aqueous solution of sodium hydrogen carbonate and then a saturated aqueous solution of sodium chloride, and dried. The solvent was then evaporated. The residue was distilled under reduced pressure to give 75 g (yield 82%) of 2-chloro-4-diethoxymethylpyridine.
Reaction SMILES: [OH2:1].O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Br[C@H:23]1[C@H:29](O)[C:28]2[CH:31]=[C:32]([S:35]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[O:36])[CH:33]=[CH:34][C:27]=2[O:26][CH2:25][CH2:24]1.C[Si](C)(C)[O:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=1>>[O:45]=[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][N:47]1[C@@H:29]1[C:28]2[CH:31]=[C:32]([S:35]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[O:36])[CH:33]=[CH:34][C:27]=2[O:26][CH2:25][CH2:24][C@H:23]1[OH:1]
Reactant: O=S(c1ccccc1)c1ccc2c(c1)[C@@H](O)[C@H](Br)CCO2
Reactant: O
Reactant: C[Si](C)(C)Oc1ccccn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: O=c1ccccn1[C@@H]1c2cc(S(=O)c3ccccc3)ccc2OCC[C@H]1O
Temperature: 60 °C
Reaction time: 5 h

Procedure:
8.60 g (27.3 mmol) of tetrabutylammonium fluoride trihydrate are added to a mixture of 4.00 g (10.9 mmol) of trans-4-bromo-5-hydroxy-7-phenylsulfinyl-2,3,4,5-tetrahydro-1-benzoxepin and 6.40 g (38.3 mmol) of 2-trimethylsilyloxypyridine, and a mixture is subsequently stirred at 60° C. for 5 hours. The cooled syrupy liquid is poured onto ice-water and extracted several times with ethyl acetate. The combined ethyl acetate extracts are washed with water and saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated. The foamy residue is crystallized in butyl acetate. White crystals of melting point 181°-184° C. are obtained.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:20])=[C:5]([C:21](OC)=[O:22])[N:4]=1)#[N:2].[NH2:25][CH2:26][C@@H:27]([OH:32])[CH2:28][C:29]([OH:31])=[O:30].C[O-].[Na+]>COCCO>[C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:20])=[C:5]([C:21]([NH:25][CH2:26][C@@H:27]([OH:32])[CH2:28][C:29]([OH:31])=[O:30])=[O:22])[N:4]=1)#[N:2]
Reactant: NC[C@@H](O)CC(=O)O
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: COCCO
Product: N#Cc1nc(C(=O)NC[C@@H](O)CC(=O)O)c(O)c2ccc(Oc3ccccc3)cc12
Temperature: 25 °C

Procedure:
Methyl 1-cyano-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (30 mg, 0.09 mmol), (S)-4-amino-3-hydroxybutanoic acid (67 mg, 0.56 mmol, Sigma-Aldrich) and sodium methoxide (28 mg, 0.53 mmol) were suspended in 2-methoxyethanol (3 mL). The resulting mixture was heated to reflux for 3 hours and then cooled to room temperature. The solvent was removed in vacuo and the residue was dissolved in H2O (15 mL) and EtOAc (15 mL). To the stirred mixture was added 1 N hydrochloric acid until pH was 1. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified by flash chromatography (0-50% EtOAc/hexanes with 0.5% formic acid) to give the title compound in 27 mg. MS: (−) m/z 406.00 (M−1).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]1=[O:18])[CH2:9][C:10]#[CH:11]>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:11]#[C:10][CH2:9][CH2:8][N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]1=[O:18]
Reactant: Ic1ccccn1
Reactant: C#CCCn1ccccc1=O
Product: O=c1ccccn1CCC#Cc1ccccn1
Yield: 22.3 %

Procedure:
The title compound was prepared in accordance with the general method of Example 192(A), from 2-iodopyridine (50 mg, 0.2 mmol) and 1-(but-3-ynyl)pyridin-2(1H)-one (33 mg, 0.2 mmol). The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH: from 100/0 to 97/3 as eluent) to afford 10 mg of 1-(4-(pyridin-2-yl)but-3-ynyl)pyridin-2(1H)-one as a yellow oil (Yield: 20%).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:11]([OH:13])=O)[C@H:7]([CH2:9][CH3:10])[CH3:8])=[O:4].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:29][C:30]([N:38]1[N:42]=[N:41][C:40]([C:43]2[CH:48]=[CH:47][C:46]([CH2:49][N:50]([NH2:75])[CH2:51][C@H:52]([OH:74])[C@@H:53]([NH:61][C:62](=[O:73])[C@H:63]([C:69]([CH3:72])([CH3:71])[CH3:70])[NH:64][C:65]([O:67][CH3:68])=[O:66])[CH2:54][C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)=[CH:45][CH:44]=2)=[N:39]1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH3:31]>CN(C=O)C>[CH3:31][C:30]([N:38]1[N:42]=[N:41][C:40]([C:43]2[CH:44]=[CH:45][C:46]([CH2:49][N:50]([NH:75][C:11](=[O:13])[C@H:6]([C@H:7]([CH2:9][CH3:10])[CH3:8])[NH:5][C:3]([O:2][CH3:1])=[O:4])[CH2:51][C@H:52]([OH:74])[C@@H:53]([NH:61][C:62](=[O:73])[C@H:63]([C:69]([CH3:71])([CH3:70])[CH3:72])[NH:64][C:65]([O:67][CH3:68])=[O:66])[CH2:54][C:55]3[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=3)=[CH:47][CH:48]=2)=[N:39]1)([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH3:29]
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)O
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2nnn(C(C)(C)c3ccccc3)n2)cc1)C(C)(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)NN(Cc1ccc(-c2nnn(C(C)(C)c3ccccc3)n2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C
Reaction time: 0.25 h

Procedure:
With the exclusion of air, 261 mg (1.38 mmol) of N-methoxycarbonyl-(L)-iso-leucine, 496 mg (2.58 mmol) of EDC and 232 mg (1.72 mmol) of HOBT are dissolved in 7.5 ml of DMF. After 15 min, 0.72 ml (5.17 mmol) of TEA and 585 mg (0.86 mmol) of 1-{4-[2-(1-methyl-1-phenyl-ethyl)-2H-tetrazol-5-yl]-phenyl}-4(S)-hydroxy-2-amino-5(S)-N-(N-methoxycarbonyl-(L)-tert-leucyl)amino-6-phenyl-2-azahexane hydrochloride (Example 25h) in 3.5 ml of DMF are added. After 20 hours, the mixture is worked up as described under Example 25i. Precipitation with DIPE from a concentrated solution in methylene chloride yields the title compound: HPLC20-100 : tRet =17.5; FAB MS (M+H)+ =814.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:5]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:6]([CH:10]=[CH:11][CH:12]=1)[N:7]([CH3:9])[CH3:8].[CH:21](O)=O>>[CH2:14]([O:13][C:5]1[C:6]([N:7]([CH3:8])[CH3:9])=[CH:10][CH:11]=[C:12]2[C:4]=1[CH2:3][CH2:2][NH:1][CH2:21]2)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CN(C)c1cccc(CCN)c1OCc1ccccc1
Reactant: O=CO
Product: CN(C)c1ccc2c(c1OCc1ccccc1)CCNC2
Temperature: 55 °C
Reaction time: 8 h

Procedure:
Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 3-(2-aminoethyl)-2-(benzyloxy)-N,N-dimethylaniline (1 g, 3.70 mmol, 1.00 equiv), formic acid (10 mL) and (CHOH)n (89 mg). The resulting solution was stirred overnight at 55° C. in an oil bath. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 10 mL of water. The pH value of the solution was adjusted to 10 with sodium hydroxide (10 mol/L). The resulting solution was extracted with 1×50 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2×20 mL of water. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 1 g (96%) of 5-(benzyloxy)-N,N-dimethyl-1,2,3,4-tetrahydroisoquinolin-6-amine as brown oil. MS (ESI) m/z 283 ([M+H]+).