Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([CH2:8][O:9][C:10](=[O:16])[CH:11]([O:13]CC)O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:19]([S:22][C@H:23]1[NH:26][C:25](=[O:27])[C@@H:24]1[O:28][CH3:29])(=[O:21])[CH3:20]>C1(C)C=CC=CC=1.CN(C)C=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10](=[O:16])[CH:11]([N:26]2[C@H:23]([S:22][C:19](=[O:21])[CH3:20])[C@@H:24]([O:28][CH3:29])[C:25]2=[O:27])[OH:13])=[CH:17][CH:18]=1)([O-:3])=[O:2]
Reactant: CO[C@H]1C(=O)N[C@@H]1SC(C)=O
Reactant: CCOC(O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CO[C@H]1C(=O)N(C(O)C(=O)OCc2ccc([N+](=O)[O-])cc2)[C@@H]1SC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
714 mg of 2-ethoxy-2-hydroxyacetic acid p-nitrobenzyl ester and 4 g of molecular sieve A4 are added to a solution of 245 mg of (3S,4R)-4-acetylthio-3-methoxy-2-oxoazetidine in a mixture of 8 ml of toluene and 2 ml of dimethylformamide and the mixture is stirred overnight at room temperature. The molecular sieves are filtered off from the mixture and the filtrate is concentrated by evaporation in vacuo. The residue is chromatographed over silica gel, and by elution with toluene/ethyl acetate (9:1 and 4:1) the title compound, contamined with some glyoxylate, is obtained.
Reaction SMILES: [S:1](S([O-])=O)([O-:4])(=[O:3])=[O:2].[Na+].[Na+].[O:10]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=[O:21])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CO>O.C(OC(C)C)(C)C>[S:1](=[O:2])([OH:4])[O-:3].[O:10]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=[O:21])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=S([O-])S(=O)(=O)[O-]
Agent: O=Cc1cccc(Oc2ccccc2)c1
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC(C)OC(C)C
Product: O=S([O-])O
Reaction time: 3 h

Procedure:
A solution of 200 g of sodium metabisulfite in 800 ml of water was added to a solution of 200 g of m-phenoxy-benzaldehyde in 800 ml of isopropyl ether and after the addition of 250 ml of methanol, the mixture was stirred for 3 hours and was vacuum filtered. The recovered precipitate was washed with 1--1 water-methanol mixture and then with isopropyl ether and was dried to obtain 295 g of the combination bisulfite of m-phenoxy-benzaldehyde (titer of 95.5% mobile hydrogen). The product was crystallized from 4 volumes of ethyl acetate to obtain a 97.6% yield of the product with a titer of mobile hydrogen of 98%.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=[C:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH:11]=2)=[N:7][CH:8]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:30](=O)[O:31]C2C=CC=CC=2)[N:24]=1.C(N(CC)CC)C>C(#N)C>[CH3:2][C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[CH:16]=[C:17]2[CH2:22][CH2:21][N:20]([C:30]([NH:29][C:25]3[N:24]=[N:23][CH:28]=[CH:27][CH:26]=3)=[O:31])[CH2:19][CH2:18]2)=[N:7][CH:8]=1
Reactant: O=C(Nc1cccnn1)Oc1ccccc1
Reactant: Cc1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc(Oc2cccc(C=C3CCN(C(=O)Nc4cccnn4)CC3)c2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.9 %

Procedure:
5-Methyl-2-(3-(piperidin-4-ylidenemethyl)phenoxy)pyridine hydrochloride (507 mg, 1.6 mmol, from Example 44, Step 5), phenyl pyridazin-3-ylcarbamate (430 mg, 2.0 mmol) and triethylamine (0.892 mL, 6.4 mmol) were combined in acetonitrile (10 mL) and stirred at room temperature. After 16 h, the reaction was concentrated and the residue was partitioned between EtOAc and water. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-10%, MeOH:CH2Cl2) to afford the title compound (526 mg) as a foamy white solid. MS APCI M+ 402.1, 281.2 M− 400.1; 1H NMR (400 MHz, CD3OD) δ ppm 2.29 (s, 3H) 2.46 (td, J=5.71, 0.93 Hz, 2H) 2.58 (td, J=5.74, 1.06 Hz, 2H) 3.52-3.61 (m, 2H) 3.65-3.71 (m, 2H) 6.44 (s, 1H) 6.85 (dd, J=8.41, 0.33 Hz, 1H) 6.89-6.96 (m, J=4.21, 4.21, 2.47, 1.01 Hz, 2H) 7.04-7.11 (m, J=7.63, 1.41, 1.04, 0.83 Hz, 1H) 7.31-7.42 (m, 1H) 7.59 (dd, J=9.09, 4.70 Hz, 1H) 7.66 (ddd, J=8.39, 2.49, 0.66 Hz, 1H) 7.97 (td, J=1.63, 0.77 Hz, 1H) 8.12 (d, J=9.32 Hz, 1H) 8.79 (d, J=4.37 Hz, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10](O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:34]>>[CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([Cl:34])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: O[C@@H]1CCN(Cc2ccccc2)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cl[C@H]1CCN(Cc2ccccc2)C1
Reaction time: 20 h
Yield: 72 %

Procedure:
To a stirred solution of (R)-1-benzyl-3-pyrrolidinol (886 mg, 5.0 mmol) in CCl4(20 ml) was added triphenylphosphine(1.574 g, 6.0 mmol) at rt. After 20 h stirring at reflux temperature, the solvent was evaporated. Saturated NaHCO3 aqueous solution and water was added to the residue, and the mixture was extracted with AcOEt. The extract was brine, dried(Na2SO4), and concentrated to give brown oil, which was purified by column chromatography (silica gel; 100 g, CH2Cl2/MeOH: 50/1-45/1) to give 706 mg(72%) of pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[CH:13])[CH:10]=2)[S:5][CH2:4][CH2:3]1.C([Li])CCC.Cl[C:21]1[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][N:22]=1>O1CCCC1.CCCCCC.[Cl-].[Cl-].[Zn+2]>[CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[C:13][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][N:22]=3)[CH:10]=2)[S:5][CH2:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCS2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCS3)nc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Reaction vessels used in this procedure were flame dried under vacuum and all operations carried out in an oxygen-free, argon or nitrogen atmosphere. To a solution of 465.7 mg (2.3019 mmol) of 4,4-dimethyl-6-ethynyl-thiochroman in 4 ml of dry tetrahydrofuran at 0° C. was added dropwise 1.5 ml of 1.6M (2.4 mmol) n-butyllithium in hexane. This was stirred at 0° C. for 10 minutes and at room temperature for 10 minutes, cooled again to 0° C. and then treated with a solution of 330 mg (2.4215 mmol) of fused ZnCl2 in 4 ml dry tetrahydrofuran using a double ended needle. Thereafter the solution was stirred at 0° C. for 30 minutes, then at room temperature for 10 minutes. A solution of 426.3 mg (2.2967 mmol) of ethyl 6-chloronicotinoate (from Example 5) in 4 ml dry tetrahydrofuran was transferred by double ended needle into a suspension of 430 mg (0.37 mmol) of tetrakistriphenylphosphine palladium in 4 ml dry tetrahydrofuran and stirred at room temperature for 10 minutes, then treated by double ended needle with the solution of the alkynylzinc prepared above. This mixture was stirred at room temperature for 18 hours, then quenched with 100 ml water. Product was recovered by extraction with 3×75 ml ether. Ether fractions were combined and washed with saturated NaCl solutions and dried (mgSO4). Solvent was removed in vacuo and the residue purified by flash chromatography (silica; 5% ethyl acetate in hexane) followed by HPLC (Whatman Partisil M-9 10/50; 4% ethyl acetate in hexane) to give the title compound as a white solid.
Reaction SMILES: F[C:2](F)(F)[C:3]([O-:5])=O.[S:8]1[CH:12]=[CH:11][C:10](B(O)O)=[CH:9]1.Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=[CH:19][CH:18]=1>>[N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17]([N:20]2[CH2:19][C:18]3[CH:17]=[C:26]([C:10]4[CH:11]=[CH:12][S:8][CH:9]=4)[CH:25]=[CH:2][C:3]=3[O:5][CH2:22][CH2:21]2)=[CH:18][CH:19]=1
Reactant: OB(O)c1ccsc1
Reactant: Clc1ccnc2ccccc12
Reactant: O=C([O-])C(F)(F)F
Product: c1ccc2c(N3CCOc4ccc(-c5ccsc5)cc4C3)ccnc2c1

Procedure:
Prepared as the trifluoroacetate salt according to the method of example 3 by using thiophen-3-ylboronic acid in step 1 and 4-chloroquinoline in step 3. 1H NMR (400 MHz, d6-DMSO): 8.56 (d, 1H), 8.32 (d, 1H), 8.01-7.91 (m, 3H), 7.85 (s, 1H), 7.71-7.65 (m, 2H), 7.63-7.58 (m, 2H), 6.97-6.91 (m, 2H), 5.25 (s, 2H), 4.60 (t, 2H), 4.40 (t, 2H); MS (EI) for C22H18N2OS: 359 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:11][NH2:12].[CH:13]1([N:17]2[CH2:22][CH2:21][CH:20]([O:23][C:24]3[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=3)[CH2:19][CH2:18]2)[CH2:16][CH2:15][CH2:14]1>>[CH:13]1([N:17]2[CH2:22][CH2:21][CH:20]([O:23][C:24]3[CH:31]=[CH:30][C:27]([C:28]4[N:12]([CH3:11])[C:4](=[O:6])[C:3]5[CH:7]=[CH:8][CH:9]=[N:10][C:2]=5[N:1]=4)=[CH:26][CH:25]=3)[CH2:19][CH2:18]2)[CH2:16][CH2:15][CH2:14]1
Reactant: O=Cc1ccc(OC2CCN(C3CCC3)CC2)cc1
Reactant: CN
Reactant: Nc1ncccc1C(=O)O
Product: Cn1c(-c2ccc(OC3CCN(C4CCC4)CC3)cc2)nc2ncccc2c1=O

Procedure:
The entitled compound was obtained according to the method of Example 15 but starting from 2-aminonicotinic acid, methylamine and 4-[(1-cyclobutyl-4-piperidinyl)oxy]benzaldehyde. The obtained compound was recrystallized from diethyl ether to give a colorless solid (m.p. 146.0-150.0° C.).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[CH2:12]([OH:15])[CH2:13][OH:14]>ClCCl>[OH:14][CH2:13][CH2:12][O:15][C:7](=[O:8])[C:6]1[CH:10]=[C:2]([Br:1])[C:3]([Cl:11])=[N:4][CH:5]=1
Reactant: OCCO
Reactant: O=C(Cl)c1cnc(Cl)c(Br)c1
Solvent: ClCCl
Product: O=C(OCCO)c1cnc(Cl)c(Br)c1
Temperature: 25 °C
Yield: 77.9 %

Procedure:
5-Bromo-6-chloro-nicotinoyl chloride (W. J. Thompson et al., J. Org. Chem. 49 (1984), 5237-5243, raw material; 7.00 g, apx 50% purity) was diluted with dichloromethane (50 ml), ethylenglycol (17 g) was added slowly and the mixture was stirred at room temperature over night. The mixture was partitioned between ether and water and the aqueous phase was extracted three times with ether. Each ether extract was washed with new water. The combined organic layers were dried over sodium chloride and evaporated to dryness in vacuo to yield the title compound (6.0 g) as raw material.
Reaction SMILES: [NH:1]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C@H:2]([C:27](O)=[O:28])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:26])[NH:8][S:9]([C:12]1[C:24]([CH3:25])=[C:23]2[C:17]([O:18][C:19]([CH2:22]2)([CH3:21])[CH3:20])=[C:15]([CH3:16])[C:13]=1[CH3:14])(=[O:11])=[O:10].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:70]([O:77][C:78](=[O:84])[N:79]([CH2:81][CH2:82][NH2:83])[CH3:80])[C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1.Cl>CN(C=O)C.CCOC(C)=O>[C:33]([O:32][C:30](=[O:31])[NH:1][C@H:2]([C:27](=[O:28])[NH:83][CH2:82][CH2:81][N:79]([C:78]([O:77][CH2:70][C:71]1[CH:72]=[CH:73][CH:74]=[CH:75][CH:76]=1)=[O:84])[CH3:80])[CH2:3][CH2:4][CH2:5][NH:6]/[C:7](/[NH2:26])=[N:8]/[S:9]([C:12]1[C:24]([CH3:25])=[C:23]([CH3:22])[C:17]2[O:18][C:19]([CH3:21])([CH3:20])[CH2:16][C:15]=2[C:13]=1[CH3:14])(=[O:10])=[O:11])([CH3:35])([CH3:34])[CH3:36]
Reactant: Cc1c(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)c(C)c2c1OC(C)(C)C2
Reactant: CN(CCN)C(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c(C)c(S(=O)(=O)/N=C(\N)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)NCCN(C)C(=O)OCc2ccccc2)c(C)c2c1OC(C)(C)C2
Reaction time: 1 h

Procedure:
A solution of Boc-Arg(Pbf)-OH (3.33 g, 6.32 mmol), HATU (2.88 g, 7.58 mmol) and DIEA (7.4 ml, 31.6 mmol) in DMF (40 ml) was maintained at room temperature for 20 min, followed by the addition of compound C hydrochloride (1.45 g, 6.95 mmol). Stirring was continued for additional 1 h. The reaction mixture was diluted with EtOAc (500 ml) and extracted with water (3×75 ml) and brine (75 ml). The organic layer was dried over MgSO4 and then evaporated to provide compound D (4.14 g, 5.77 mmol) as yellowish amorphous solid. LC-MS [M+H] 717.6 (C35H52N6O8S+H, calc: 717.9).
Reaction SMILES: [F:1][C:2]([F:13])([C:9]([F:12])([F:11])[F:10])[CH2:3][CH2:4][CH2:5][S:6][CH:7]=[CH2:8].OO.[OH2:16].C(O)(=[O:19])C>>[F:13][C:2]([F:1])([C:9]([F:10])([F:11])[F:12])[CH2:3][CH2:4][CH2:5][S:6]([CH:7]=[CH2:8])(=[O:19])=[O:16]
Reactant: O
Reactant: CC(=O)O
Reactant: C=CSCCCC(F)(F)C(F)(F)F
Agent: OO
Product: C=CS(=O)(=O)CCCC(F)(F)C(F)(F)F
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A solution of 34 g of (4,4,5,5,5-pentafluoropentyl)-vinyl sulfide in 74 ml of glacial acetic acid is mixed drop by drop with 59 ml of 30% hydrogen peroxide in such a way that the reaction temperature does not exceed 70° C. Then, it is stirred for one hour at a bath temperature of 70° C. Then, it is added to water, extracted three times with ethyl acetate, washed with sodium thiosulfate, water and common salt solution, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with hexane/ethyl acetate. 12.3 g of (4,4,5,5,5-pentafluoropentyl)-vinyl sulfone is obtained as an oil.
Reaction SMILES: [OH2:1].[CH3:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:4]=1[S:11][C:12]1[N:16]=[CH:15][NH:14][N:13]=1.C[OH:18]>>[CH3:10][C:5]1[CH:6]=[C:7]([CH3:9])[CH:8]=[C:3]([CH3:2])[C:4]=1[S:11]([C:12]1[N:16]=[CH:15][NH:14][N:13]=1)(=[O:18])=[O:1]
Reactant: Cc1cc(C)c(Sc2nc[nH]n2)c(C)c1
Reactant: O
Reactant: CO
Product: Cc1cc(C)c(S(=O)(=O)c2nc[nH]n2)c(C)c1
Temperature: 60 °C

Procedure:
A mixture of OXONE monopersulfate compound (50 g) and water (100 ml) was heated on an oil bath at 60° C., to which was added dropwise a mixture of 3-(2,4,6-trimethylphenyl)thio-1H-1,2,4-triazole (Example 32-a) (5.00 g) and methanol (150 ml) over 1 hour with stirring. After the addition was completed, the reaction mixture was heated and refluxed for 3 hours, and then cooled to room temperature and stirred overnight. Precipitated crystals were collected by filtration, and washed with water to yield the title compound (5.03 g).
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[C:15]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])[C:14]([CH3:27])=[C:13]([CH3:28])[N:12]=1.O>O1CCCC1>[CH3:28][C:13]1[C:14]([CH3:27])=[C:15]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])[C:16]([N+:17]([O-:19])=[O:18])=[C:11]([O:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:12]=1
Reactant: Oc1ccccc1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(NCCCCCO)c1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(Oc2ccccc2)c([N+](=O)[O-])c(NCCCCCO)c1C
Temperature: 25 °C
Yield: 75.2 %

Procedure:
Under a nitrogen atmosphere, tetrahydrofuran (THF) (150 mL) was cooled to 0° C. Sodium hydride (9.30 g, 233 mmol), available as a 60% dispersion in mineral oil, was added with stirring. A solution of phenol (21.1 g, 225 mmol) in THF (80 mL) was added dropwise over a period of one hour. A solution of 5-(2-chloro-5,6-dimethyl-3-nitropyridin-4-ylamino)pentan-1-ol (44.5 g, 155 mmol) in THF (80 mL) was then added dropwise over a period of 40 minutes. The reaction was allowed to warm to room temperature and heated at reflux overnight. An analysis by thin layer chromatography (TLC) indicated that the reaction was incomplete. Additional reagent was prepared as described above by adding phenol (7.1 g, 75 mmol) to sodium hydride (3.2 g, 80 mmol) in THF (50 mL), and the reagent was added to the reaction solution at room temperature. The reaction was heated at reflux overnight and then allowed to cool to room temperature. Water (50 mL) was added, and the solvent was removed under reduced pressure. The aqueous solution was extracted with ethyl acetate. The organic solution was washed with water (3×) and brine (1×), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide the crude product. The crude product was purified twice by column chromatography on silica gel (eluting sequentially with 50:50 hexane:ethyl acetate and 25:75 hexane:ethyl acetate) to provide 40.24 g of 5-(2,3-dimethyl-5-nitro-6-phenoxy-pyridin-4-ylamino)pentan-1-ol as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([CH3:11])(=[O:10])=[O:9])[C:3]=1F.[NH2:13][C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1.Cl[C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([OH:31])[CH:29]=2)[N:24]=[CH:23][N:22]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([CH3:11])(=[O:10])=[O:9])[C:3]=1[O:31][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][CH:27]=1)[N:24]=[CH:23][N:22]=[C:21]2[NH:13][C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1
Reactant: CS(=O)(=O)c1cccc(F)c1F
Reactant: Nc1cnccn1
Reactant: Oc1ccc2ncnc(Cl)c2c1
Product: CS(=O)(=O)c1cccc(F)c1Oc1ccc2ncnc(Nc3cnccn3)c2c1

Procedure:
The compound of Example 97 was manufactured by the same method as in Example 95, by a similar method thereto or by a combination of such a method with a conventional method using 1,2-difluoro-3-methanesulfonylbenzene, 2-aminopyrazine and 4-chloro-6-hydroxy-quinazoline.
Reaction SMILES: CCO.CC(O)C.[CH3:8][N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][CH2:17][N:18](C(OCC2C=CC=CC=2)=O)[C:19]([NH:21]C(OCC2C=CC=CC=2)=O)=[NH:20])[CH2:11][CH2:10]1.[H][H]>[Pd].O>[CH3:8][N:9]1[CH2:10][CH2:11][CH:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]([NH2:21])=[NH:20])[CH2:13][CH2:14]1
Reactant: CN1CCC(CCCN(C(=N)NC(=O)OCc2ccccc2)C(=O)OCc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(C)O
Solvent: O
Solvent: CCO
Product: CN1CCC(CCCNC(=N)N)CC1
Reaction time: 1.5 h

Procedure:
A 13 gal (50 liter) Hastelloy pressure reactor equipped with a mechanical agitator, cooling/heating jacket, and addition lines was charged with a solution of 95/5 EtOH/IPA (27.00 kg) and N-[3-(1-methylpiperidin-4-yl) -propyl]-N,N′-di-Cbz-guanidine (7.28 kg, 14.97 mol). To the resultant solution, under nitrogen, was then added 10% Pd/C (50% wet, 0.50 kg). The reactor was sealed and sequentially placed under vacuum, nitrogen and vacuum to displace any air in the system. The reaction was stirred at 1000 RPM and 300-350 PSI of hydrogen while keeping the temperature below 35° C. using cooling water on the jacket. The reaction ceased to be exothermic after approximately 1.5 hours and was stirred for an additional hour at 300-350 PSI. The resultant slurry was filtered over Celite® to yield a solution containing the title compound. The solution was stored at 5° C. and used in the next step without further isolation or purification.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:5]=[N:4]1.Cl[CH2:14][C:15]1[N:16]=[C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[C:21]=2[F:30])[O:18][CH:19]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O.C(OCC)(=O)C>[F:30][C:21]1[C:22]([C:26]([F:29])([F:27])[F:28])=[CH:23][CH:24]=[CH:25][C:20]=1[C:17]1[O:18][CH:19]=[C:15]([CH2:14][N:3]2[CH:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:5]=[N:4]2)[N:16]=1
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: Fc1c(-c2nc(CCl)co2)cccc1C(F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(Cc2coc(-c3cccc(C(F)(F)F)c3F)n2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.6 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 0.08 g) in N,N-dimethylformamide (2 ml) was added ethyl 1H-pyrazole-4-carboxylate (0.21 g). After stirring at room temperature for 30 min, the compound (0.42 g) obtained in Example 105a was added to the reaction mixture. After stirring at room temperature for 2 hr, 10% aqueous citric acid solution and ethyl acetate were added to the reaction mixture. The ethyl acetate layer was separated, washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: hexane-ethyl acetate) to give the title compound (0.44 g) as colorless crystals.
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].I[C:19]1[S:20][CH:21]=[CH:22][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C(#N)C>[CH3:17][C:3]1([C:1]#[C:2][C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Reactant: Ic1cccs1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C#Cc1cccs1)O2
Reaction time: 4 h
Yield: 56 %

Procedure:
A mixture of 4.6 g (20 mmol) of rac-3,4-dihydro-2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol, 6.3 g (30 mmol) of 2-iodothiophene, 0.8 g of triphenylphosphine, 0.19 g of cuprous iodide, 6 ml of triethylamine and 200 ml of acetonitrile was stirred and degassed with argon for 15 minutes. Palladium acetate, 220 mg, was then added and stirring under argon was continued for 4 hours. The solvent was removed under reduced pressure and the residue was partitioned between methylene chloride and saturated aqueous sodium bicarbonate solution. The organic phase was separated, dried and evaporated. The residue was chromatographed over 200 g of silica gel (Merck 70-230 mesh) using methylene chloride. Crystallization of the combined clean fractions from ether/hexane yielded 3.5 g (56%) of rac-3,4-dihydro-2,5,7,8-tetramethyl-2-[(2-thienyl)ethynyl]-2H-1-benzopyran-6-ol with m.p. 112°-114° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][C:7]=1[O:15][CH3:16].FC(F)(F)C(=O)CI(C1C=CC=CC=1)CC(C(F)(F)F)=[O:24].O.C(C(O)=O)(F)(F)F>CC#N>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH2:13][OH:24])=[CH:8][C:7]=1[O:15][CH3:16]
Reactant: O=C(CI(CC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: O
Product: COc1cc(C(=O)CO)ccc1OCCCCl
Yield: 32.8 %

Procedure:
A solution of 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (4.3 g, 17.7 mmol), [bis(trifluoroacetony)iodo]benzene (15.6 g, 36.2 mmol), H2O (18 ml), CF3CO2H (2.8 ml) and CH3CN (90 ml) was refluxed for 3 hours. The CH3CN was removed under reduced pressure and the resulting yellow liquid was partitioned between H2O and CH2Cl2. The biphasic mixture was filtered, the organic phase collected, washed with saturated NaHCO3 solution and concentrated to afford 1.5 g of an amorphous brown solid. The solid was flash chromatographed on silica gel, eluting the column with 5% EtOAc/CH2Cl2. Concentration of similar fractions afforded 0.7 g of the compound as a pale yellow solid, m.p. 99-101° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[CH:11]=[C:4]2[N:3]=1.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[C:6]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:5]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[CH:11]=[C:4]2[N:3]=1
Reactant: C1COCCN1
Reactant: Clc1cc(Cl)n2nc(-c3ccccn3)cc2n1
Solvent: C1COCCO1
Solvent: O
Product: Clc1cc(N2CCOCC2)n2nc(-c3ccccn3)cc2n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 75 %

Procedure:
There was suspended, in 1,4-dioxane (5 mL), 5,7-dichloro-2-pyridin-2-yl-pyrazolo[1,5-a]pyrimidine (348 mg. 1.31 mM), then morpholine (230 μL, 2.64 mM) was added to the suspension and the mixture was stirred at room temperature for 20 minutes. The solvent was distilled off from the reaction mixture, the residue obtained was diluted with water and then extracted with ethyl acetate. The extracts thus obtained were combined, dried over anhydrous sodium sulfate, the solvent was distilled off and the resulting solid was washed with diethyl ether to thus give the title compound (312 mg, yield: 75%). 1H-NMR (300 MHz, CDCl3): δ 3.84-3.87 (m, 4H), 3.99-4.02 (m, 4H), 6.12 (s, 1H), 7.16 (s, 1H), 7.30 (ddd, 1H, J=1.2, 5.0, 7.7 Hz), 7.78 (dt, 1H, J=1.8, 7.7 Hz), 8.11 (d, 1H, J=7.7 Hz), 8.70 (m, 1H); MS (ESI) m/z 316 (M+H)+.