Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[C:11]2[CH2:12][CH2:13]O[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])[C:4]=2[NH:3]1.[CH2:21]([O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[C:31]([CH3:36])[CH:30]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)COCCO.O>[CH3:36][C:31]1[CH:30]=[C:29]([O:28][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:35]=[CH:34][C:32]=1[N:33]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])[C:4]=3[N:3]=[C:2]([NH:3][CH2:4][CH2:5][OH:15])[C:11]=2[CH2:12][CH2:13]1
Reactant: Cc1cc(OCc2ccccc2)ccc1N
Reactant: O=c1[nH]c2c(OCC(F)(F)F)cccc2c2c1CCO2
Solvent: OCCOCCO
Solvent: O
Product: Cc1cc(OCc2ccccc2)ccc1N1CCc2c(NCCO)nc3c(OCC(F)(F)F)cccc3c21
Temperature: 250 °C
Yield: 86 %

Procedure:
4-Oxo-6-β,β,β-trifluoroethoxy-2,3,4,5-tetrahydrofuro[3,2-c]quinoline(5.7 g, 20.0 mmol) was dissolved in diethylene glycol(70 ml) and crude 4-benzyloxy-2-methyl aniline(5.6 g, 26.0 mmol) was added. The reaction mixture was refluxed at 250° C. for 15 hours. The reaction mixture was dissolved in water, extracted with dichloromethane, and the organic layer was washed with water for 3 times. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography(ethyl acetate:dichloromethane=1:1) to obtain 4.5 g of desired compound as solid in 47% of yield.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([NH:17][C:18]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[O:19])[S:9][C:10]=1[C:11](=[O:16])N(OC)C.[CH3:26][Mg]Br.[Cl-].[NH4+]>C1COCC1>[C:11]([C:10]1[S:9][C:8]([NH:17][C:18]([C:20]2[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=2)=[O:19])=[N:7][C:6]=1[C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)(=[O:16])[CH3:26]
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1sc(NC(=O)c2ccncc2)nc1-c1ccco1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)c1sc(NC(=O)c2ccncc2)nc1-c1ccco1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 68.9 %

Procedure:
Compound 98 (1.01 g, 2.82 mmol) was suspended in THF (20 mL), and a 0.93 mol/L solution of methylmagnesium bromide (12.0 mL, 11.2 mmol) in THF was added thereto under ice-cooling, followed by stirring at room temperature for 2.5 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the precipitated solid was collected by filtration to afford the entitled Compound 377 (609 mg, 69%) as a pale yellow solid.
Reaction SMILES: [CH2:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)[CH2:2][CH3:3].O=S(Cl)Cl.[CH2:17]([C:22]1[CH:27]=[CH:26][C:25]([C:28]2[N:29]=[CH:30][C:31](O)=[N:32][CH:33]=2)=[CH:24][CH:23]=1)[CH2:18][CH2:19][CH2:20][CH3:21]>N1C=CC=CC=1>[CH2:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:10][C:31]2[CH:30]=[N:29][C:28]([C:25]3[CH:26]=[CH:27][C:22]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:23][CH:24]=3)=[CH:33][N:32]=2)=[O:9])=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCCCc1ccc(-c2cnc(O)cn2)cc1
Reactant: CCCc1ccc(C(=O)O)cc1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CCCCCc1ccc(-c2cnc(OC(=O)c3ccc(CCC)cc3)cn2)cc1
Reaction time: 2 h

Procedure:
16.4 g of 4-propyl benzoic acid are boiled for hour with 24 g of SOCl2, which is followed by evaporating, dissolving the acid chloride obtained in 150 ml of toluene, adding 8 ml of pyridine and 24.2 g of 5-(4-pentylphenyl)-2-pyrazinol (obtainable analogously to Japanese Preliminary Published Application 144,770/84) and boiling for 2 hours. Cooling down and customary working up gives 5-(4-pentylphenyl)-pyrazin-2-yl 4-propylbenzoate.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1C1C=CC(O)=CC=1>O1CCCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Oc1ccc(-c2nc3ccccc3o2)cc1
Solvent: C1CCOC1
Product: c1ccc2ocnc2c1
Temperature: 30 °C
Reaction time: 18 h

Procedure:
Into a stirred solution of 0.5 g (2.4 mmol) of 4-(2-Benzoxazolyl)-phenol prepared as described in example 1 of in 10 ml of tetrahydrofurane and a few drops of dibutyltindilaurate catalyst, was added 0.6 g (2.52 mmol) of ICTEOS under nitrogen atmosphere. The mixture was stirred for 18 h at 30° C. After removal of the solvent, the product was precipitated with hexane, filtrated and dried to yield 0.99 g (90%) of (4-(3-(triethoxysilyl)propyl]-amino]carbonyl]oxy])phenyl)-benzoxazole. M.p. 141-142° C.; UV (ethanol) 304 nm (24′630).
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[NH2:7][C:8]1[CH:9]=[C:10]([C:14]2[CH:24]=[CH:23][C:17]3[N:18]([CH3:22])[C:19](=[O:21])[S:20][C:16]=3[CH:15]=2)[CH:11]=[N:12][CH:13]=1>N1C=CC=CC=1>[CH3:22][N:18]1[C:17]2[CH:23]=[CH:24][C:14]([C:10]3[CH:9]=[C:8]([NH:7][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH:13]=[N:12][CH:11]=3)=[CH:15][C:16]=2[S:20][C:19]1=[O:21]
Reactant: CCS(=O)(=O)Cl
Reactant: Cn1c(=O)sc2cc(-c3cncc(N)c3)ccc21
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1cncc(-c2ccc3c(c2)sc(=O)n3C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.2 %

Procedure:
General sulfonylation procedure: EtSO2Cl (51.4 mg, 0.4 mmol) was added dropwise to a solution of 6-(5-aminopyridin-3-yl)-3-methylbenzo[d]thiazol-2(3H)-one (Example 50: 28 mg, 0.1 mmol) in pyridine (2 mL) at 0° C. The resulting mixture was slowly warmed up to room temperature and stirred for additional 3 hrs at this temperature. After concentration, the residue was purified by flash column (MeOH/CH2Cl2, v/v, 1-3%) and yielded yellow solid (20 mg), MS (ESI) m/z 350.4 (M±H)+. 1H NMR (400 MHz, MeOD) δ ppm 1.35 (t, J=7.4 Hz, 3H), 3.22 (q, J=7.4 Hz, 2H), 3.51 (q, 3H), 7.38 (d, J=8 Hz, 1H), 7.68 (d, J=8 Hz, 1H), 7.87 (s, 1H), 7.95 (s, 1H), 8.40 (s, 1H), 8.58 (s, 1H).
Reaction SMILES: [CH3:1][C@H:2]([CH2:7][CH2:8][CH2:9][C@H:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:3][CH2:4][CH2:5]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:37]Br.O>CN(C)C=O.CCCCCC>[Br:37][CH2:5][CH2:4][CH2:3][C@H:2]([CH3:1])[CH2:7][CH2:8][CH2:9][C@H:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15]
Reactant: BrBr
Reactant: CC(C)CCC[C@@H](C)CCC[C@@H](C)CCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: O
Product: CC(C)CCC[C@@H](C)CCC[C@@H](C)CCCBr
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 9.6 g (39.6 mmol) of (4R,8R)-4,8,12-trimethyltridecanol in 30 mL of anhydrous N,N-dimethylformamide was added 10.7 g (40.84 mmol) of triphenylphosphine. The solution was stirred in an acetone-ice bath (-10° C.) while 2.1 mL (41 mmol) of bromine was added dropwise. The temperature rose to 5° C. The reaction mixture was stirred at room temperature for 1 hr then poured into 100 mL of water and 150 mL of hexane. After filtration, the layers were separated and the aqueous phase was extracted with 2×150 mL of hexane. The hexane layers were washed with saturated NaHCO3 solution, dried (MgSO4), filtered through a plug of silica gel, and concentrated in vacuo. Kugelrohr distillation (150°-160° C. bath temperature, 1 mm Hg) of the residue gave 2 fractions: 5.15 g of 95.8% GC purity and 3.55 g of 97.9% GC purity (72.2% yield). Redistribution of the larger fraction gave (4R,8R)-1-bromo-4,8,12-trimethyltridecane as a colorless liquid bp 120° C. (0.15 mm) having a GC purity of 97.9%; [a]25D-3.01° (c 2.09, hexane).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[OH:14].B.C1COCC1>C1COCC1>[NH2:11][CH2:10][C:9]1[CH:12]=[CH:13][C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[C:7]([OH:14])[CH:8]=1
Reactant: N#Cc1ccc(-c2ccco2)c(O)c1
Agent: B
Solvent: C1CCOC1
Product: NCc1ccc(-c2ccco2)c(O)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 32.7 %

Procedure:
To a solution of 4-Furan-2-yl-3-hydroxy-benzonitrile (180 mg, 0.97 mmol) in THF (5 mL) is added BH3.THF (5 mL, 1 M solution in THF, 5 mmol) under N2. The mixture is then allowed to stir at room temperature for 24 hours. The reaction is then quenched with 6N HCl. THF is then removed and the aqueous layer is then neutralized with ammonium hydroxide to pH 9. The mixture is then extracted with CHCl3/MeOH (9:1). The organic layer dried and evaporated and the residue is chromatographed to provide the desired product (60 mg, 33%). MS (ESI): 190 (M+1)+1.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][O:8][C:7]([C@H:10]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH3:11])=[N:6]1)=[O:4].C1CCN2C(=NCCC2)CC1.BrC(Cl)(Cl)Cl>ClCCl>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([C@H:10]([NH:12][C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[CH3:11])[O:8][CH:9]=1)=[O:4]
Reactant: COC(=O)C1COC([C@@H](C)NC(=O)OC(C)(C)C)=N1
Solvent: ClC(Cl)(Cl)Br
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1coc([C@@H](C)NC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 47.7 %

Procedure:
In a round-bottomed flask, 2-((R)-1-tert-butoxycarbonylamino-ethyl)-4,5-dihydro-oxazole-4-carboxylic acid methyl ester (337 mg, 1.18 mmol) was dissolved in dichloromethane (11 ml). The solution was cooled to −16° C. (NaCl/ice bath) and DBU (0.35 ml, 2.32 mmol) was added. After 5 min, bromotrichloromethane (0.13 ml, 1.33 mmol) was added and the reaction mixture was allowed slowly to warm to room temperature and stirred for 4 days. The reaction was quenched with 0.1 M aqueous HCl and extracted with EtOAc (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with EtOAc/hexanes (gradient 0-30% EtOAc) to afford 152 mg (48%) of 2-((R)-1-tert-butoxycarbonylamino-ethyl)-oxazole-4-carboxylic acid methyl ester as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([Cl:10])[C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.Cl[C:12](Cl)([O:14]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[Br:1][C:2]1[N:3]=[C:4]([Cl:10])[C:5]2[N:6]([C:12](=[O:14])[NH:9][N:8]=2)[CH:7]=1
Reactant: NNc1ncc(Br)nc1Cl
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: O=c1[nH]nc2c(Cl)nc(Br)cn12

Procedure:
A solution of 2.50 g of the product of Step C in THF (60 mL) was stirred as 3.32 g of triphosgene was added in portions to provide a tan suspension. A homogeneous solution was obtained after 30 min. and the excess phosgene was destroyed by the careful addition of water and the mixture was extracted with EtOAc. The organic extracts were washed with sat. sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated to afford 6-bromo-8-chloro-2H-[1,2,4]triazolo[4,3-a]pyrazin-3-one as a light yellow solid. MS (M+H−)=280.1.
Reaction SMILES: [Br:1][CH2:2][C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:7]([NH:19][CH:20]=[O:21])[CH:6]=1)[OH:4].N1C=CN=C1.[Si:27](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].C([Si](Cl)(C)C)CCC>CN(C)C=O.C(OC(C)C)(=O)C>[CH2:12]([O:11][C:8]1[CH:9]=[CH:10][C:5]([C@@H:3]([O:4][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH2:2][Br:1])=[CH:6][C:7]=1[NH:19][CH:20]=[O:21])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=CNc1cc([C@@H](O)CBr)ccc1OCc1ccccc1
Agent: CCCC[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CC(=O)OC(C)C
Product: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c(NC=O)c1
Reaction time: 72 h
Yield: 67.9 %

Procedure:
(R)-2-Bromo-1-(3-formamido-4-benzyloxyphenyl)ethanol (9.9 g, 28 mmol) was dissolved in dimethylformamide (36 mL). Imidazole (2.3 g, 34 mmol) and tert-butyldimethylsilyl chloride (4.7 g, 31 mmol) were added. The solution was stirred under nitrogen atmosphere for 72 h. Additional imidazole (0.39 g, 5.7 mmol) and tent-butyldimethylsilyl chloride (0.64 g, 4.3 mmol) were added and the reaction was stirred for an additional 20 h. The reaction mixture was then diluted with a mixture of isopropyl acetate (53 mL) and hexanes (27 mL) and transferred to a separatory funnel. The organic layer was washed twice with a mixture of water (27 mL) and saturated aqueous sodium chloride (27 mL) followed by a final wash with saturated aqueous sodium chloride (27 mL). The organic layer was dried over sodium sulfate. Silica gel (23.6 g) and hexanes (27 mL) were added and the suspension was stirred for 10 min. The solids were removed by filtration and the filtrate concentrated under vacuum. The residue was crystallized from hexanes (45 mL) to afford 8.85 g (19 mmol, 68%) of the title compound as a solid. MS m/z: [M+H+] calcd for C22H30NO3SiBr 464.1; found 464.2.
Reaction SMILES: FC1C=C(F)C=CC=1NC1C=CC(C(C2C=C(N3C=C(CCO)N=N3)C=CC=2C)=O)=C(C)C=1.Br[C:35]1[CH:40]=[CH:39][C:38]([C:41]([C:43]2[CH:48]=[C:47]([N:49]3[CH:53]=[C:52]([CH2:54][CH2:55][OH:56])[N:51]=[N:50]3)[CH:46]=[CH:45][C:44]=2[CH3:57])=[O:42])=[C:37]([CH3:58])[CH:36]=1.[Cl:59][C:60]1[CH:61]=[C:62]([NH2:67])[CH:63]=[CH:64][C:65]=1[Cl:66]>>[Cl:59][C:60]1[CH:61]=[C:62]([NH:67][C:35]2[CH:40]=[CH:39][C:38]([C:41]([C:43]3[CH:48]=[C:47]([N:49]4[CH:53]=[C:52]([CH2:54][CH2:55][OH:56])[N:51]=[N:50]4)[CH:46]=[CH:45][C:44]=3[CH3:57])=[O:42])=[C:37]([CH3:58])[CH:36]=2)[CH:63]=[CH:64][C:65]=1[Cl:66]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: Cc1cc(Br)ccc1C(=O)c1cc(-n2cc(CCO)nn2)ccc1C
Agent: Cc1cc(Nc2ccc(F)cc2F)ccc1C(=O)c1cc(-n2cc(CCO)nn2)ccc1C
Product: Cc1cc(Nc2ccc(Cl)c(Cl)c2)ccc1C(=O)c1cc(-n2cc(CCO)nn2)ccc1C

Procedure:
The reaction was carried out similarly as described in the preparation of compound 148, using compound 452 (0.13 mmol) and 3,4-dichloro-phenylamine (0.13 mmol). The crude product was purified by continuous gradient flash chromatography using MeOH/DCM/petroleum ether (40-60) 0:50:50, 0:100:0 and 5:95:0 as the eluent to afford the title compound as yellow solid. 13C NMR (DMSO-d6) δ 196.4, 146.4, 145.6, 142.0, 141.9, 141.6, 135.3, 134.9, 134.3, 132.1, 131.5, 131.0, 127.6, 122.5, 120.6, 120.5, 119.7, 118.6, 118.4, 112.2, 60.1, 29.1, 21.8, 18.8
Reaction SMILES: C[O:2][C:3](=[O:32])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24](=[O:31])[N:25]([CH3:30])[CH:26]=[CH:27][C:28]=2[CH3:29])=[CH:19][CH:18]=1)[NH:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])=[O:7].[OH-].[Na+]>C(O)C>[Cl:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([CH3:14])[C:8]=1[C:6]([NH:5][C@H:4]([C:3]([OH:32])=[O:2])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24](=[O:31])[N:25]([CH3:30])[CH:26]=[CH:27][C:28]=2[CH3:29])=[CH:19][CH:18]=1)=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc(-c2c(C)ccn(C)c2=O)cc1)NC(=O)c1c(C)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(Cl)c1C(=O)N[C@@H](Cc1ccc(-c2c(C)ccn(C)c2=O)cc1)C(=O)O
Temperature: 42.5 °C
Reaction time: 2 h
Yield: 85.4 %

Procedure:
To a suspension of N-[(2-chloro-6-methylphenyl)carbonyl]-4-(1,4-dimethyl-2-oxo-3-pyridinyl)-L-phenylalanine methyl ester (22 mg, 0.048 mmol) in ethanol (1 mL) was added 1N aqueous sodium hydroxide solution (0.5 mL) at room temperature. The resulting solution was heated to 40-45° C. and stirred for 2 h. Then, the ethanol was removed under vacuum and the residue was diluted with water (25 mL). The aqueous solution was washed with diethyl ether (25 mL) to remove any neutral impurities. The aqueous layer was acidified with 1.0 N HCl and the product was extracted into ethyl acetate (2×25 mL). The combined extracts were washed with brine solution (50 mL) and were dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration afforded 18 mg (86% yield) of N-[(2-chloro-6-methylphenyl)carbonyl]-4-(1,4-dimethyl-2-oxo-3-pyridinyl)-L-phenylalanine as an amorphous white solid. ES-HRMS m/e calcd for C24H23ClN2O4 (M+H) 439.1419. found 439.1425.
Reaction SMILES: [N:1]([C:4]1[C:12]([CH2:13]/[CH:14]=[C:15](\[CH3:22])/[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:11]([O:23][CH3:24])[C:10]([CH3:25])=[C:9]2[C:5]=1[C:6](=[O:26])[O:7][CH2:8]2)=[C:2]=[O:3].[CH3:27][OH:28]>>[CH3:27][O:28][C:2]([NH:1][C:4]1[C:12]([CH2:13]/[CH:14]=[C:15](\[CH3:22])/[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:11]([O:23][CH3:24])[C:10]([CH3:25])=[C:9]2[C:5]=1[C:6](=[O:26])[O:7][CH2:8]2)=[O:3]
Reactant: COC(=O)CC/C(C)=C/Cc1c(N=C=O)c2c(c(C)c1OC)COC2=O
Reactant: CO
Product: COC(=O)CC/C(C)=C/Cc1c(NC(=O)OC)c2c(c(C)c1OC)COC2=O

Procedure:
A solution of methyl (E)-6-(1,3-dihydro-4-isocyanato-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate (1.0 g) in 10 ml methanol was heated to reflux for 4 hours and then evaporated to dryness. The residue was recrystallized from acetone/hexane to give 0.41 g of methyl (E)-6-(1,3-dihydro-4-methoxycarbonylamino-6-methoxy-7-methyl-3- oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate. The ester (0.35g) and 0.05 g of LiOH-H2O in 9 ml 2:1 MeoH-H2O was heated at reflux for 4hours. The mixture was acidified, extracted with ethyl acetate, and the organic layer was dried over MgSO4. The organic layer was concentrated and the residue was further purified by silica gel chromatography (eluant 60:40:2 hexaneethyl acetate:acetic acid) to give 0.21 g of (E)-6-(1,3-dihydro-4- methoxycarbonylamino-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl. 4-hexenoic acid, mp 155°-158° C.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][C:6]([C:9]1[NH:10][C:11](=[O:21])[C:12]([OH:20])=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:14]=1)([CH3:8])[CH3:7].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[OH:20][C:12]1[C:11](=[O:21])[N:10]2[CH2:2][CH2:3][O:4][CH2:5][C:6]([CH3:8])([CH3:7])[C:9]2=[N:14][C:13]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)c1nc(C(C)(C)COCCCl)[nH]c(=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc2n(c(=O)c1O)CCOCC2(C)C
Temperature: 75 °C
Reaction time: 16 h
Yield: 77.4 %

Procedure:
Ethyl 2-(1-(2-chloroethoxy)-2-methylpropan-2-yl)-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate (1.75 g, 5.49 mmol) was dissolved in 30 mL DMF under N2 and treated with K2CO3 (2.27 g, 16.5 mmol). This was warmed at 70-80° C. with stirring for 16 h. The DMF was evaporated at reduced pressure and the residue was dissolved in water and washed with Et2O. The aqueous layer was acidified with dil HCl and extracted with CH2Cl2. After drying (MgSO4), filtration and concentration a solid was obtained. Trituration from 1:1 Et2O/hexanes gave the title compound (1.2 g, 77%) as white solid. 1H NMR (300 MHz, CDCl3) δ: 1.35-1.45 (m, 9H), 3.58 (s, 2H), 3.60-4.10 (m, 1H), 4.41 (q, J=6.95 Hz, 2H), 4.30-4.82 (m, 2H), 10.42 (s, 1H). LC/MS (M+H): 283.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:6]([SH:8])[CH:7]=1.[C:13]1([S:19]([C:22]2[CH:27]=[CH:26][C:25](F)=[C:24]([F:29])[CH:23]=2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:6]([S:8][C:25]2[CH:26]=[CH:27][C:22]([S:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)(=[O:21])=[O:20])=[CH:23][C:24]=2[F:29])[CH:7]=1
Reactant: O=S(=O)(c1ccccc1)c1ccc(F)c(F)c1
Reactant: O=C(O)Cc1cc(S)cc(Cl)c1
Product: O=C(O)Cc1cc(Cl)cc(Sc2ccc(S(=O)(=O)c3ccccc3)cc2F)c1

Procedure:
The title compound was prepared as described in example 1 step vi) but instead using the product from example 71 step (i) and the product from example 24 step (i).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([OH:8])=[C:6]([C:9]([C:11]2[C:12](=[O:30])[N:13]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:15][CH:16]=2)=[O:10])[CH:5]=[N:4]1)[CH3:2].C(N(CC)CC)C.[C:38]1([CH3:48])[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[CH:40][CH:39]=1.[Cl-].[NH4+]>C(#N)C>[CH2:1]([N:3]1[C:7]([O:8][S:44]([C:41]2[CH:42]=[CH:43][C:38]([CH3:48])=[CH:39][CH:40]=2)(=[O:46])=[O:45])=[C:6]([C:9]([C:11]2[C:12](=[O:30])[N:13]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:15][CH:16]=2)=[O:10])[CH:5]=[N:4]1)[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCn1ncc(C(=O)c2cnc(-c3ccccc3)n(Cc3ccccc3)c2=O)c1O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCn1ncc(C(=O)c2cnc(-c3ccccc3)n(Cc3ccccc3)c2=O)c1OS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of 5-[(1-ethyl-5-hydroxy-1H-pyrazol-4-yl)carbonyl]-2-phenyl-3-(phenylmethyl)-4(3H)-pyrimidinone (i.e. the product from Example 3, Step B) (300 mg, 0.75 mmol) in acetonitrile (10 mL) was added triethylamine (116 mg, 1.12 mmol), followed by p-toluenesulfonyl chloride (171 mg, 0.90 mmol), and the reaction mixture was stirred at room temperature for 72 h. Saturated aqueous ammonium chloride solution was added to the mixture, and the aqueous layer was extracted with dichloromethane. The organic layer was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by column chromatography eluting with 50% ethyl acetate in hexanes to afford the title product, a compound of the present invention, as a white solid (160 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][CH:10]2[CH2:15][CH:14]3[N:16](C(OC(C)(C)C)=O)[CH:11]2[CH2:12][CH2:13]3)[N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:8][C:6]1[CH:7]=[C:2]([CH3:1])[N:3]=[C:4]([NH:9][CH:10]2[CH2:15][CH:14]3[NH:16][CH:11]2[CH2:12][CH2:13]3)[N:5]=1
Reactant: Cc1cc(C)nc(NC2CC3CCC2N3C(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C)nc(NC2CC3CCC2N3)n1

Procedure:
To the title compound of step A (125 mg, 0.4 mmol) in DCM (3 mL) was added TFA (3 mL). After starting material was consumed, the reaction was concentrated, neutralized with 5% Na2CO3 and extracted with DCM. The combined organics were dried (Na2SO4) to give the title compound that was used in subsequent reactions without further purification. MS (ESI) mass calcd. for C12H18N4, 218.2; m/z found 219.2 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)#[N:2].Cl.[NH2:13][C:14]1[S:15][C:16]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:17]([CH3:19])[N:18]=1>N1C=CC=CC=1>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:13][C:14]2[S:15][C:16]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:17]([CH3:19])[N:18]=2)=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)c1sc(N)nc1C
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1sc(NC(=O)c2ccc(C#N)cc2)nc1C
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 82.6 %

Procedure:
A mixture of 4-cyanobenzoyl chloride (166.5 g), ethyl 2-amino-4-methylthiazole-5-carboxylate hydrochloride (224.0 g) and pyridine (2000 ml) was stirred at room temperature for 70 minutes. The precipitated crystals were collected by filtration, and washed with 3% hydrochloric acid and water to give ethyl 2-(4-cyanobenzoylamino)-4-methylthiazole-5-carboxylate (262.0 g).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[NH:8][C:7]([C:15]1[S:16][CH2:17][C@@H:18]([CH2:20][O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[N:19]=1)=[CH:6]2.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.CN(C=O)C>CS(C)=O>[N:28]1([CH2:2][C:3]2[CH:4]=[C:5]3[C:9](=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=2)[NH:8][C:7]([C:15]2[S:16][CH2:17][C@@H:18]([CH2:20][O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[N:19]=2)=[CH:6]3)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1
Reactant: C1COCCN1
Reactant: CC(C)(C)C(=O)OC[C@@H]1CSC(c2cc3cc(CCl)cc([N+](=O)[O-])c3[nH]2)=N1
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OC[C@@H]1CSC(c2cc3cc(CN4CCOCC4)cc([N+](=O)[O-])c3[nH]2)=N1

Procedure:
2,2-Dimethyl-propionic acid [(R)-2-(5-chloromethyl-7-nitro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]methyl ester prepared in Preparation 41 and morpholine were reacted according to the same procedure as Preparation 92 except that DMF was used as the solvent instead of DMSO to give the title compound.
Reaction SMILES: [F:1][C:2]([F:11])([CH3:10])/[CH:3]=[CH:4]/[C:5]([O:7]CC)=[O:6].[OH-].[Na+].Cl>C(O)C>[F:1][C:2]([F:11])([CH3:10])/[CH:3]=[CH:4]/[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)/C=C/C(C)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(F)(F)/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product of step C was dissolved in ethanol (24 ml), 4M NaOH was added (12 ml) and the mixture was stirred at room temperature for two hours. The mixture was acidified with 1M HCl and extracted with ethyl acetate. The organic extract was dried over magnesium sulfate, the solvent was removed under reduced pressure. 2.67 g of a colourless oil were obtained. MS(ESI) m/z=135.0 [M-1]−.