Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:13](=[O:14])[N:12]([CH3:15])[C:11]([CH:16]([F:18])[F:17])=[N:10]2)=[C:4]([F:19])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:27]([CH3:35])[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([F:19])[C:5]([N:9]2[C:13](=[O:14])[N:12]([CH3:15])[C:11]([CH:16]([F:17])[F:18])=[N:10]2)=[CH:6][C:7]=1[O:8][CH:27]([CH3:35])[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]
Reactant: CC(Br)C(=O)OC(C)(C)C
Reactant: Cn1c(C(F)F)nn(-c2cc(O)c(Cl)cc2F)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(Oc1cc(-n2nc(C(F)F)n(C)c2=O)c(F)cc1Cl)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 92.8 %

Procedure:
A mixture of 0.7 g (0.0023 mole) of 1-(4-chloro-2-fluoro-5-hydroxyphenyl)-3-difluoromethyl-4,5-dihydro-4-methyl-1,2,4-triazol-5(1H)-one, 0.9 g (0.0067 mole) of potassium carbonate, and 0.6 g (0.0027 mole) of tert-butyl 2-bromopropionate in 40 mL of acetone was stirred at room temperature for approximately 72 hours. The reaction mixture was partitioned between water and methylene chloride and the organic phase was washed with water. After drying over anhydrous magnesium sulfate the organic phase was filtered. Evaporation of the filtrate under reduced pressure yielded 0.9 g of tert-butyl 2-[2-chloro-4-fluoro-5-(3-difluoromethyl-4,5-dihydro-4-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenoxy]propionate as an oil, Compound 40.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[C:9](OC(=O)C)(=[O:11])[CH3:10].C(N(CC)CC)C>O1CCCC1>[CH3:10][C:9]([O:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8])=[O:11]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1CCC(=O)N1O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)ON1C(=O)CCC1=O

Procedure:
N-Hydroxysuccinimide (17.33 g, 0.5 mol) was suspended in 120 ml tetrahydrofuran and cooled in an ice bath. Acetic anhydride (16 ml, 0.17 ml) and then triethylamine (22 ml, 0.16 mol) were added slowly. A solution formed, and then gradually a white precipitate appeared. After one half hour an equal volume of petroleum ether was added, and the crystalline product was collected. Yield 21.22 g (90%, mp 128°-130° C., lit. 15 mp 131°-132° C.). Analysis (C6H7NO4): calc. 45.87% C, 4.49% H, 8.91% N; found 45.86%, C, 4.31% H, 8.61% N.
Reaction SMILES: CS([C:4]1[S:5][C:6]2[CH:12]=[C:11]([CH2:13][C:14]3[N:18]4[N:19]=[C:20]([C:23]#[N:24])[CH:21]=[CH:22][C:17]4=[N:16][CH:15]=3)[CH:10]=[CH:9][C:7]=2[N:8]=1)=O.[NH2:25][C@@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]1[OH:32].CCN(C(C)C)C(C)C.O>CN1C(=O)CCC1>[OH:32][C@@H:27]1[CH2:28][CH2:29][CH2:30][CH2:31][C@H:26]1[NH:25][C:4]1[S:5][C:6]2[CH:12]=[C:11]([CH2:13][C:14]3[N:18]4[N:19]=[C:20]([C:23]#[N:24])[CH:21]=[CH:22][C:17]4=[N:16][CH:15]=3)[CH:10]=[CH:9][C:7]=2[N:8]=1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: CS(=O)c1nc2ccc(Cc3cnc4ccc(C#N)nn34)cc2s1
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc2ncc(Cc3ccc4nc(N[C@@H]5CCCC[C@H]5O)sc4c3)n2n1
Temperature: 135 °C
Reaction time: 8 h
Yield: 27.5 %

Procedure:
A mixture of 3-((2-(methylsulfinyl)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-b]pyridazine-6-carbonitrile (300 mg, 0.9 mmol), (1R,2R)-2-aminocyclohexanol (293 mg, 2.5 mmol) and DIEA (219 mg, 1.7 mmol) in NMP (16 mL) was stirred at 135° C. overnight. The mixture was cooled to rt and water (40 mL) was added. The mixture was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 50:1 to 20:1 DCM/MeOH to afford 3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-b]pyridazine-6-carbonitrile as a brown solid (100 mg, 30%). 1H NMR (300 MHz, DMSO-d6) δ 8.40 (d, J=9.3 Hz, 1H), 7.87-7.84 (m, 2H), 7.70 (d, J=9.3 Hz, 1H), 7.55 (d, J=1.5 Hz, 1H), 7.28 (d, J=8.1 Hz, 1H), 7.13 (dd, J=1.5, 8.1 Hz, 1H), 4.72 (d, J=5.1 Hz, 1H), 4.36 (s, 2H), 3.54-3.51 (m, 1H), 3.39-3.36 (m, 1H), 2.06-2.02 (m, 1H), 1.90-1.86 (m, 1H), 1.65-1.59 (m, 2H), 1.31-1.17 (m, 4H). LCMS (ESI) m/z 405 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([NH:9][CH2:10][CH2:11][C:12]2[CH:17]=[C:16]([CH3:18])[C:15]([O:19]C)=[CH:14][C:13]=2[CH3:21])=[N:7][CH:8]=1)[CH3:2].[F:22][C:23]([F:34])([F:33])[O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]Br>>[CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]([CH2:28][C:27]2[CH:30]=[CH:31][CH:32]=[C:25]([O:24][C:23]([F:22])([F:33])[F:34])[CH:26]=2)[CH2:10][CH2:11][C:12]2[C:13]([CH3:21])=[CH:14][C:15]([OH:19])=[C:16]([CH3:18])[CH:17]=2)=[N:7][CH:8]=1)[CH3:2]
Reactant: FC(F)(F)Oc1cccc(CBr)c1
Reactant: CCc1cnc(NCCc2cc(C)c(OC)cc2C)nc1
Product: CCc1cnc(N(CCc2cc(C)c(O)cc2C)Cc2cccc(OC(F)(F)F)c2)nc1

Procedure:
Similarly prepared from 5-ethyl-N-[2-(4-methoxy-2,5-dimethylphenyl)ethyl]pyrimidin-2-amine and 3-trifluoromethoxy benzyl bromide.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH2:12][CH2:13][CH3:14])=[C:10]2[C:5]([C:6](=[O:19])[CH:7]=[C:8]([C:15]([O:17][CH3:18])=[O:16])[O:9]2)=[CH:4][CH:3]=1.[CH2:20]([C:23]1[C:33]([OH:34])=[C:32]([C:35](=[O:37])[CH3:36])[CH:31]=[CH:30][C:24]=1[O:25][CH2:26][CH2:27][CH2:28]Br)[CH2:21][CH3:22]>>[C:15]([C:8]1[O:9][C:10]2[C:5]([C:6](=[O:19])[CH:7]=1)=[CH:4][CH:3]=[C:2]([O:1][CH2:28][CH2:27][CH2:26][O:25][C:24]1[CH:30]=[CH:31][C:32]([C:35](=[O:37])[CH3:36])=[C:33]([OH:34])[C:23]=1[CH2:20][CH2:21][CH3:22])[C:11]=2[CH2:12][CH2:13][CH3:14])([O:17][CH3:18])=[O:16]
Reactant: CCCc1c(OCCCBr)ccc(C(C)=O)c1O
Reactant: CCCc1c(O)ccc2c(=O)cc(C(=O)OC)oc12
Product: CCCc1c(OCCCOc2ccc3c(=O)cc(C(=O)OC)oc3c2CCC)ccc(C(C)=O)c1O
Yield: 69 %

Procedure:
Using the procedure of Example 2, 5.25 g (120 mmole) of methyl 7-hydroxy-8-n-propylchromone-2-carboxylate and 6.93 g (22 mmole) of the compound of Example 14 gave 7.54 g (76%) of the title compound, mp. 113°-115°. Calc: C, 67.73; H, 6.50; Found: C, 67.71; H, 6.49.
Reaction SMILES: C([O:8][CH2:9][C@H:10]([O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=2)=[CH:26][CH:25]=1)[CH2:11][O:12][Si:13]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])C1C=CC=CC=1>[Pd].CCOC(C)=O.CCO>[F:40][C:37]([F:38])([F:39])[O:36][C:33]1[CH:32]=[CH:31][C:30]([C:27]2[CH:28]=[CH:29][C:24]([O:23][C@H:10]([CH2:11][O:12][Si:13]([CH:17]([CH3:19])[CH3:18])([CH:20]([CH3:21])[CH3:22])[CH:14]([CH3:16])[CH3:15])[CH2:9][OH:8])=[CH:25][CH:26]=2)=[CH:35][CH:34]=1
Reactant: CC(C)[Si](OC[C@H](COCc1ccccc1)Oc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1)(C(C)C)C(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)[Si](OC[C@H](CO)Oc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1)(C(C)C)C(C)C
Reaction time: 4 h

Procedure:
A mixture of the benzyl ether 80 (10.79 g, 0.019 mol) and 5% Pd—C (500 mg) in 1:1 EtOAc/EtOH (250 mL) was hydrogenated at 60 psi for 4 h. The catalyst was removed by filtration through Celite and the filtrate was concentrated under reduced pressure to give (2S)-2-{[4′-(trifluoromethoxy)[1,1′-biphenyl]-4-yl]oxy}-3-[(triisopropylsilyl)oxy]-1-propanol (81) as a viscous oil, sufficiently pure for use in the next step. Iodine (6.03 g, 0.024 mol) was added in portions at 20° C. to a vigorously stirred solution of the crude alcohol 81, triphenylphosphine (6.23 g, 0.024 mol) and imidazole (2.49 g, 0.036 mol) in benzene (100 mL) and stirring was continued for 1 h. After dilution with EtOAc the mixture was washed with water, 2N Na2SO3 and water again. The extract was evaporated and chromatographed on silica gel, eluting with EtOAc/petroleum ether (1:19), to give 4-[((1R)-2-iodo-1-{[(triisopropylsilyl)oxy]methyl}ethyl)oxy]-4′-(trifluoromethoxy)-1,1′-biphenyl (82) (9.08 g, 81% overall) as a colourless oil; 1H NMR (CDCl3) δ 7.54 (d, J=8.8 Hz, 2H), 7.48 (d, J=8.8 Hz, 2H), 7.26 (br d, J=8.8 Hz, 2H), 7.02 (d, J=8.8 Hz, 2H), 4.31-4.25 (m, 1H), 4.03 (dd, J=10.4, 4.8 Hz, 1H), 3.93 (dd, J=10.4, 5.6 Hz, 1H), 3.55 (dd, J=10.5, 5.6 Hz, 1H), 3.45 (dd, J=10.5, 4.8 Hz, 1H), 1.15-1.06 (m, 21H). APCI MS m/z 595 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[S:9]([NH:12][C:13]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=O)(=[O:11])=[O:10].Cl.[Cl:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=1[CH:32]([CH3:35])[CH2:33][NH2:34].ClC1C=C(Cl)C=CC=1CC#N>>[Cl:22][C:20]1[CH:19]=[CH:18][C:14]([C:15]([NH:34][CH2:33][CH:32]([C:26]2[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:25]=2[Cl:24])[CH3:35])=[O:17])=[C:13]([NH:12][S:9]([C:3]2[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])(=[O:10])=[O:11])[CH:21]=1
Reactant: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1c(F)cccc1F
Reactant: CC(CN)c1ccc(Cl)cc1Cl
Agent: Cl
Agent: N#CCc1ccc(Cl)cc1Cl
Product: CC(CNC(=O)c1ccc(Cl)cc1NS(=O)(=O)c1c(F)cccc1F)c1ccc(Cl)cc1Cl

Procedure:
The title compound was prepared from 2-(2,6-difluoro-benzenesulfonylamino)-4-chloro-benzoic acid and 2-(2,4-dichloro-phenyl)-propylamine hydrochloride (prepared as in EXAMPLE 5, substituting 2,4-dichlorophenyl-acetonitrile in Part A) as in Example 1, Part C. HPLC: RT=11.20 min. MS (ESI−): mass calcd. for C22H17Cl3F2N2O3S, 533.8; m/z found, 533 [M−H]−. 1H NMR (400 MHz, CDCl3): 11.62 (s, 1H), 7.73 (d, J=1.9, 1H), 7.52-7.45 (m, 1H), 7.40 (d, J=1.8, 1H), 7.28-7.25 (m, 2H), 7.18 (d, J=8.5, 1H), 7.01-6.96 (m, 3H), 6.05 (br m, 1H), 3.76-3.70 (m, 1H), 3.68-3.57 (m, 1H), 3.57-3.49 (m, 1H), 1.32 (d, J=6.8, 3H).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O[C:35](=O)[NH:36][CH2:37][CH2:38][NH:39]C)(C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:28][N:26]([CH3:27])[C:25]([C:7]1[N:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[C:10]2[N:11]=[C:12]([NH:15][C:16]3[CH:24]=[CH:23][C:19]([C:20](=[O:21])[N:36]([CH2:37][CH2:38][NH2:39])[CH3:35])=[CH:18][N:17]=3)[N:13]=[CH:14][C:9]=2[CH:8]=1)=[O:29]
Reactant: CNCCNC(=O)OC(C)(C)C
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N(C)CCN)cn3)nc2n1C1CCCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 88.8 %

Procedure:
A solution of 6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinic acid (100 mg, 0.25 mmol) in DMF is added (2-methylamino ethyl)-carbamic acid tert-butyl ester (53 mg, 0.25 mmol), HBTU (140 mg, 0.38 mmol), and DIPEA (0.088 mL, 0.51 mmol). After 48 h stirring at room temperature, the resulting mixture is concentrated and diluted with saturated NaHCO3 solution and extracted with ethyl acetate (3×100 mL). The combine organics are dried over Na2CO3 and concentrated to give a reddish residue. Followed by deprotection using General Procedure A to give 2-{5-[(2-amino-ethyl)-methyl-carbamoyl]-pyridin-2-ylamino}-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 77%). MS (ESI) m/z 451.3 (M+H)|
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10]2[S:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:16]=3)=[CH:13][CH:14]=2)[N:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]([F:34])([F:33])[F:32])[N:6]=1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:44])=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10]2[S:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([S:21]([CH3:24])(=[O:22])=[O:23])[CH:16]=3)=[CH:13][CH:14]=2)[N:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]([F:33])([F:34])[F:32])[N:6]=1)=[S:44]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COC(=O)c1cc(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)n(-c2ccccc2C(F)(F)F)n1
Solvent: Cc1ccccc1
Product: COC(=S)c1cc(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)n(-c2ccccc2C(F)(F)F)n1
Yield: 89.8 %

Procedure:
To a 50 mL round bottom flask attached with condenser was added 5-[5-(3-Methanesulfonyl-phenyl)-thiophen-2-yl]-1-(2-trifluoromethyl-phenyl)-1H-pyrazole-3-carboxylic acid methyl ester (326 mg, 644 μmmol), Lawesson's reagent (520 mg, 129 mmol) and anhydrous toluene (23 mL). The reaction solution was stirred at reflux for 1 day. The reaction solution was concentrated in vacuo, and the crude material was chromatographed through a 25 g SiO2 column using a gradient of 100% Hx to 50% EtOAc to afford 302 mg (90% yield) of the title compound. MS (ES) 523.3 [M+H]+, 545.0 (M+Na)+.
Reaction SMILES: [CH3:1][C:2]([C:5]1[N:10]=[CH:9][C:8]([CH:11]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][N:6]=1)([CH3:4])[CH3:3].[F:21][C:22]1[C:29]([F:30])=C(C)[C:27]([F:32])=[C:26]([F:33])[C:23]=1[CH2:24]O>[Ti].C1(C)C=CC=CC=1>[CH3:4][C:2]([C:5]1[N:6]=[CH:7][C:8]([CH:11]([C:17]([CH3:19])([CH3:18])[CH3:20])[C:12]([O:14][CH2:15][C:16]2[C:29]([F:30])=[C:22]([F:21])[C:23]([CH3:24])=[C:26]([F:33])[C:27]=2[F:32])=[O:13])=[CH:9][N:10]=1)([CH3:1])[CH3:3]
Reactant: Cc1c(F)c(F)c(CO)c(F)c1F
Reactant: CCOC(=O)C(c1cnc(C(C)(C)C)nc1)C(C)(C)C
Agent: [Ti]
Solvent: Cc1ccccc1
Product: Cc1c(F)c(F)c(COC(=O)C(c2cnc(C(C)(C)C)nc2)C(C)(C)C)c(F)c1F
Yield: 46.6 %

Procedure:
A mixture of ethyl (RS)-2-[2-(1,1-dimethylethyl)pyrimidin-5-yl]-3,3-dimethylbutanoate (0.07 g), 2,3,5,6-tetrafluoro-4-methylbenzyl alcohol (0.1 g), titanium VI ethoxide (catalytic amount) and dry toluene (2 cm3) was heated at the reflux temperature for 10 hours. After cooling, the solvent was evaporated under reduced pressure to leave a brown gum, which was purified by preparative thin layer chromatography on 20 cm×20 cm×0.2 cm silica gel plates, eluting with dichloromethane containing 2% by volume ethyl acetate, to give the title compound (0.05 g) as an oil which solidified on standing.
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:16]([O-])([OH:18])=[O:17]>O>[C:1]1([C:7]2[S:8][C:9]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])O
Reactant: c1ccc(-c2nc3ccccc3s2)cc1
Solvent: O
Product: O=[N+]([O-])c1ccc2nc(-c3ccccc3)sc2c1
Temperature: 5 °C
Reaction time: 1.17 h

Procedure:
2-Phenylbenzothiazole (Aldrich, 63.89 g, 0.302 mol) is nitrated with 100% nitric acid (190 ml, 4.53 mol) at 5° C. The mixture is stirred at 5° C. for 70 minutes, quenched in ice-water and basified with 32% NaOH (pH=10). The product is filtered off and the solid obtained is suspended in water and filtered off. The product is recrystallized from isopropyl ether. Yield: 73.6 g (95%); Rf (8/2 petroleum ether/ethyl acetate): 0.76; m.p.: 178.9-181.3°; 1H-NMR (d6-DMSO): 9.16 (d, 1H); 8.35 (dd, 1H); 8.23 (d, 1H); 8.15 (dd, 1H) 7.58; (m, 4H).
Reaction SMILES: [ClH:1].[C:2]([O:6][C:7]([NH:9][C@H:10]([C:20]([NH:22][CH2:23][C:24]([NH:26][C@H:27]([C:35]([NH:37][C:38]1[CH:47]=[C:46]2[C:41]([C:42]([CH3:49])=[CH:43][C:44](=[O:48])[O:45]2)=[CH:40][CH:39]=1)=[O:36])[CH2:28][CH2:29][CH2:30][NH:31][C:32](=[NH:34])[NH2:33])=[O:25])=[O:21])[CH2:11][O:12]CC1C=CC=CC=1)=[O:8])([CH3:5])([CH3:4])[CH3:3].[H][H]>CO.[C].[Pd].C(O)(=O)C>[ClH:1].[C:2]([O:6][C:7]([NH:9][C@H:10]([C:20]([NH:22][CH2:23][C:24]([NH:26][C@H:27]([C:35]([NH:37][C:38]1[CH:47]=[C:46]2[C:41]([C:42]([CH3:49])=[CH:43][C:44](=[O:48])[O:45]2)=[CH:40][CH:39]=1)=[O:36])[CH2:28][CH2:29][CH2:30][NH:31][C:32](=[NH:33])[NH2:34])=[O:25])=[O:21])[CH2:11][OH:12])=[O:8])([CH3:5])([CH3:3])[CH3:4]
Reactant: [H][H]
Reactant: Cc1cc(=O)oc2cc(NC(=O)[C@H](CCCNC(=N)N)NC(=O)CNC(=O)[C@H](COCc3ccccc3)NC(=O)OC(C)(C)C)ccc12
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc(=O)oc2cc(NC(=O)[C@H](CCCNC(=N)N)NC(=O)CNC(=O)[C@H](CO)NC(=O)OC(C)(C)C)ccc12
Yield: 66.9 %

Procedure:
7-(Nα -tert-butyloxycarbonyl-O-benzyl-L-serylglycyl-L-arginyl)amino-4-methylcoumarin hydrochloric acid salt (120 mg, 0.28 mM) was dissolved in methyl alcohol (50 ml), and palladium-carbon catalyst (20 mg) was added. Through this mixture hydrogen gas was passed for 4 hours with stirring. The catalyst was removed by filtration and the filtrate was concentrted to yield a solid material. The residue was dissolved in acetic acid (10 ml) and lyophilized to give 7-(Nα-tert-butyloxycarbonyl-L-serylglycyl-L-arginyl)amino-4-methylcoumarin hydrochloric acid salt [X] (70 mg).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]3[C:15]([N:16]=2)=[CH:14][N:13]=[N:12][CH:11]=3)=[C:4]([O:17][CH3:18])[CH:3]=1.[CH2:19](I)[CH3:20]>>[CH3:18][O:17][C:4]1[CH:3]=[C:2]([S:1][CH2:19][CH3:20])[CH:7]=[CH:6][C:5]=1[C:8]1[NH:9][C:10]2[C:15]([N:16]=1)=[CH:14][N:13]=[N:12][CH:11]=2
Reactant: CCI
Reactant: COc1cc(S)ccc1-c1nc2cnncc2[nH]1
Product: CCSc1ccc(-c2nc3cnncc3[nH]2)c(OC)c1

Procedure:
In a manner similar to that of Example 12, conversion of 2-(4-mercapto-2-methoxyphenyl)-1,3,5,6-tetraazaindene into the Na salt and subsequent reaction with ethyl iodide gives 2-(2-methoxy-4-ethylthiophenyl)-1,3,5,6-tetraazaindene, m.p. 248°.
Reaction SMILES: Cl[CH2:2][CH:3]1[CH2:7][CH2:6][O:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].[CH2:14]([NH2:17])[CH2:15][NH2:16]>C(O)C>[O:5]1[CH2:6][CH2:7][CH:3]([CH2:2][NH:16][CH2:15][CH2:14][NH2:17])[CH2:4]1
Reactant: ClCC1CCOC1
Reactant: NCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: NCCNCC1CCOC1
Yield: 77 %

Procedure:
A mixture of 0.2 mol of 3-(chloromethyl)tetrahydrofuran, 200 ml of ethanol, 0.2 mol of potassium carbonate and 0.2 mol of ethylenediamine placed in a 500 ml of round-bottomed flask was refluxed for 24 hours, and then the solvent was removed. The obtained product was yellow oily liquid in 77% yield.
Reaction SMILES: C([O:3][C:4](=[O:29])[C:5](=[O:28])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14](=[O:27])[N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[CH:8][CH:7]=1)C.C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[O:27]=[C:14]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:17][CH2:16]1)[CH2:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([C:5](=[O:28])[C:4]([OH:29])=[O:3])=[CH:7][CH:8]=1
Reactant: CCOC(=O)C(=O)c1ccc(OCC(=O)N2CCN(c3ccccc3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(O)C(=O)c1ccc(OCC(=O)N2CCN(c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 46.1 %

Procedure:
4-[2-Oxo-2-(4-phenyl-1-piperazinyl)ethoxy]-alpha-oxobenzeneacetic acid ethyl ester (0.7 g) in methanol (40 mL) was treated with sodium carbonate (0.24 g) in water (6 mL), and the mixture was stirred at room temperature for 1.25 hours. After the methanol was evaporated under reduced pressure, water was added and the solution was acidified with 3N hydrochloric acid, then the aqueous layer was extracted with a dichloromethane-tetrahydrofuran mixture (1:1). The organic layer was dried (MgSO4), evaporated, and the residue was crystallized from acetone to furnish 0.3 g of 4-[2-oxo-2-(4-phenyl-1-piperazinyl)ethoxy]-alpha-oxobenzeneacetic acid, mp 188°-192 ° C.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18](=[O:32])[N:19]([CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[CH:20]=[N:21]2)=[CH:16][C:15]=1[O:33][CH3:34].[N:35]1[CH:40]=[CH:39][C:38]([CH2:41]O)=[CH:37][CH:36]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH3:34][O:33][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:14]=1[O:13][CH2:41][C:38]1[CH:39]=[CH:40][N:35]=[CH:36][CH:37]=1)[N:21]=[CH:20][N:19]([CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:28])([CH3:29])[CH3:30])[C:18]2=[O:32]
Reactant: OCc1ccncc1
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCc1ccncc1
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 85.6 %

Procedure:
Diethyl azodicarboxylate (348 mg, 2 mmol) was added dropwise to a suspension of 7-hydroxy-6-methoxy-3((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (457 mg, 1.5 mmol), (prepared as described for the starting material in Example 22), 4-pyridinemethanol (218 mg, 2 mmol), and triphenylphosphine (524 mg, 2 mmol) in methylene chloride (7 ml) at 5° C. The mixture was stirred for 10 minutes at 5° C. and then 1 hour at ambient temperature. The mixture was poured directly on to a silica column and eluted with methylene chloride/methanol (95/5) to give 6-methoxy-3-((pivaloyloxy)methyl)-7-(4-pyridylmethoxy)-3,4-dihydroquinazolin-4-one (510 mg, 85%).
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[N:8][C:9]([O:12][CH2:13][C:14]2[C:15]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=[O:5])C.[NH2:27][CH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[O:31]1[CH2:32][CH2:33][CH:28]([NH:27][C:4]([C:6]2[N:7]=[N:8][C:9]([O:12][CH2:13][C:14]3[C:15]([C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)=[N:16][O:17][C:18]=3[CH3:19])=[CH:10][CH:11]=2)=[O:5])[CH2:29][CH2:30]1
Reactant: CCOC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2C)nn1
Reactant: NC1CCOCC1
Product: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)NC2CCOCC2)nn1
Yield: 73 %

Procedure:
As described for example 59, 6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridazine-3-carboxylic acid ethyl ester (143 mg, 0.4 mmol) was converted, using 4-aminotetrahydropyran instead of aminomethylcyclopropane, to the title compound (120 mg, 73%) which was obtained as a white solid after recrystallization from heptane:ethyl acetate. MS: m/e=413.3 [M+H].
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][OH:15].[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]Br.[OH-].[Na+].[Br-].C([NH+](CCCC)CCCC)CCC>CCOCC>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][Br:16]
Reactant: BrCCCCCBr
Reactant: Cc1oc(-c2ccccc2)nc1CCO
Agent: CCCC[NH+](CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CCOCC
Product: Cc1oc(-c2ccccc2)nc1CCOCCCCCBr
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The mixture of 2-(5-methyl-2-phenyloxazol-4-yl)ethanol (2.03 g), 1,5-dibromopentane (4.09 ml), 50% NaOH (4.0 ml) and tributylammonium bromide (0.1 g) was stirred at room temperature overnight. The reaction mixture was dilluted with ether, washed by water and an aqueous saturated solution of sodium chloride sucessively, dried over anhydrous magnesium sulfate and concentrated. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=10:1→4:1) to obtain the title compound (3.45 g) having the following physical data.
Reaction SMILES: [CH2:1]([CH:8]([C:14](OCC)=[O:15])[C:9](OCC)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)C>[CH2:1]([CH:8]([CH2:9][OH:10])[CH2:14][OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cc1ccccc1)C(=O)OCC
Solvent: CCOCC
Product: OCC(CO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Diethyl benzylmalonate (100g.) was added dropwise to a stirred suspension of lithium aluminimum hydride (12g.) in anhydrous diethyl ether (300ml.) at 0° C. under argon. The reaction mixture was then stirred overnight at room temperature and worked up by the conventional procedure, described in J. Org. Chem. 1953, 18, 1190. Evaporation of the ether solution gave 2-benzylpropane-1,3-diol. Phosphorus tribromide (26ml.) was added dropwise to this diol (44g.), whilst stirring at 75° C. After the vigorous reaction had ceased, the temperature was raised to 100° C. and maintained at this temperature overnight. The cooled mixture was poured into ice water (500ml.) and extracted with diethyl ether (2 × 500ml.). The combined ether extracts were washed with aqueous sodium bicarbonate, then brine, dried over sodium sulphate and the ether was evaporated. Distillation of the crude product in vacuo gave 2-benzyl-1,3-dibromopropane b.p. 116°-121° C./1.0 mm. Hg.