Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[C:7]([O:10]/[N:11]=[C:12](/[C:16]1[N:17]=[C:18]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[S:19][CH:20]=1)\[C:13](O)=[O:14])([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:31][C@@H:32]1[C:39](=[O:40])[N:38]2[C@@H:33]1[S:34][CH2:35][C:36]([CH2:57][Cl:58])=[C:37]2[C:41]([O:43][CH:44]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42].P(Cl)(Cl)(=O)OC1C=CC=CC=1.CN1CCOCC1>ClCCl>[C:1]([O:5][C:6](=[O:29])[C:7]([O:10]/[N:11]=[C:12](/[C:16]1[N:17]=[C:18]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[S:19][CH:20]=1)\[C:13]([NH:31][C@@H:32]1[C:39](=[O:40])[N:38]2[C@@H:33]1[S:34][CH2:35][C:36]([CH2:57][Cl:58])=[C:37]2[C:41]([O:43][CH:44]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:42])=[O:14])([CH3:9])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)O)cs1
Agent: Cl
Agent: O=P(Cl)(Cl)Oc1ccccc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CCl)CS[C@H]23)cs1
Temperature: -40 °C
Reaction time: 2 h
Yield: 71.5 %

Procedure:
To a solution of (Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid (30.5 g, 71.0 mmol) and (6R,7R)-benzhydryl 7-amino-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate, hydrochloride (32.1 g, 71.0 mmol) in dichloromethane (500 mL), stirred under nitrogen at −30° C., was added neat phenyl phosphorodichloridate (12.93 mL, 85 mmol). The reaction mixture was cooled to −40° C. and N-methylmorpholine (23.42 mL, 213 mmol) was added dropwise over 30 min, and stirred for an additional 2 hours at −40° C. The reaction was then quenched by addition of 150 mL of a 10% aq. solution of citric acid, and the phases were separated. The organic phase was concentrated and the residue was then dissolved in 500 mL of ethyl acetate. The organic solution was washed with 100 mL of a 5% aq. sodium bicarbonate, 100 mL of brine, dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified on a 330 g silica gel column eluting with 0-80% ethyl acetate in hexanes to afford (6R,7R)-benzhydryl 7-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (42 g, 50.8 mmol, 71.6% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.42 (s, 9 H) 1.55 (s, 9 H) 1.63 (s, 3 H) 1.66 (s, 3 H) 3.52 (d, J=18.19 Hz, 1 H) 3.66 (d, J=18.19 Hz, 1 H) 4.43 (d, J=4.29 Hz, 2 H) 5.12 (d, J=5.05 Hz, 1 H) 6.08 (dd. J=8.84, 5.05 Hz, 1 H) 6.99 (s, 1 H) 7.30-7.49 (m, 12 H) 8.25 (d, J=8.84 Hz, 1 H). LCMS: (M+H)+: 826.5.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][N:10]=[C:9]3[N:18]([CH2:21][CH3:22])[N:19]=[CH:20][C:8]=23)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C.O>[CH:1]1([NH:6][C:7]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=[C:9]3[N:18]([CH2:21][CH3:22])[N:19]=[CH:20][C:8]=23)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1NC1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCn1ncc2c(NC3CCCC3)c(C(=O)O)cnc21
Temperature: 50 °C
Yield: 95.2 %

Procedure:
A solution of Intermediate 2 (2.2 g) in ethanol: water (95:5, 16.85 ml) was treated with sodium hydroxide (1.2 g) and heated at 50° C. for 16 h. The mixture was concentrated in vacuo and the residue re-dissolved in water (0.85 ml). The solution was acidified to pH4 using acetic acid and the resultant white precipitate was collected by filtration and dried under vacuum to afford Intermediate 3 (1.9 g). LCMS showed MH+=275; TRET=2.65 min
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[O:5][C:6]1[N:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=O.CN1CCOCC1.ClC(OCC(C)C)=O.[Cl:33][C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH2:36][NH2:37]>C(Cl)Cl.O>[Cl:33][C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH2:36][NH:37][C:8](=[O:10])[C:7]1[CH:11]=[CH:12][CH:13]=[N:14][C:6]=1[O:5][C:4]1[CH:15]=[CH:16][CH:17]=[C:2]([F:1])[CH:3]=1
Reactant: O=C(O)c1cccnc1Oc1cccc(F)c1
Reactant: NCc1ccccc1Cl
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: O
Product: O=C(NCc1ccccc1Cl)c1cccnc1Oc1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 71.3 %

Procedure:
To a stirred solution of 2-(3-Fluoro-phenoxy)-nicotinic acid (0.300 grams, 1.29 mmole) and NMM (0.144 grams, 1.41 mmole) in dry methylene chloride (15 ml) at −10° C. was added isobutyl chloroformate (0.193 grams, 1.41 mmole). After 20 minutes at −10° C. 2-chlorobenzylamine (0.219 grams, 1.55 mmole) was added and the mixture was allowed to warm to room temperature over night. The mixture was poured into water and extracted with ethyl acetate. The combined organics were washed with 1 N NaOH, water and brine, dried over MgSO4, filtered and concentrated to give a solid that was purified by chromatography on silica gel eluting with 30% ethyl acetate/hexane to give a white solid. Recrystalization from ethyl acetate/hexane gave a solid (0.328 g). M.P. 115-117° C.; Anal. calcd. for C19H14N2O2ClF: C, 63.96; H, 3.95; N, 7.85. Found: C, 64.04; H, 3.92; N, 7.85.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][CH:5]=1.[CH2:13](I)[CH3:14].CC(C)([O-])C.[K+].O>CN(C)C=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][CH2:13][CH3:14])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(CO)cc1
Reactant: CCI
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
4-(Hydroxymethyl)benzoic acid methyl ester (2.0 g) and ethyl iodide (3.8 g) were dissolved in N,N-dimethylformamide (60 mL), potassium tert-butoxide (2.8 g) was added under ice-cooling, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=10:1 to 5:1) to give the title compound (2.0 g) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.CC1(C)O[C:17](=[O:18])[CH2:16][C:14](=[O:15])[O:13]1>C1(C)C=CC=CC=1>[C:14]([CH2:16][C:17]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)=[O:18])([OH:15])=[O:13]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: Nc1ccc(C(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C(O)CC(=O)Nc1ccc(C(=O)O)cc1
Yield: 92.1 %

Procedure:
4-Aminobenzoic acid (0.50 g, 3.6 mmol) was added to a solution of Meldrum's acid (0.63 g, 4.4 mmol) in toluene (5.0 mL) and treated according to Procedure 1. 4-[(Carboxyacetyl)amino]benzoic acid (0.74 g, 91%) was obtained as a colourless solid; δH (400 MHz, DMSO-d6) 3.38 (br s, 2H, CH2), 7.68 (t, J2,3=J5,6=8.0 Hz, 1H, H2, H6), 7.89 (d, J2,3=J5,6=8.0, 1H, H3, H5), 10.44 (s, 1H, NH), 12.70 (br s, 1H, CO2H).
Reaction SMILES: [Cl-:1].[Mn+2:2].[Cl-:3].[CH2:4]([CH:22]1[CH2:36][NH:35][CH2:34][CH2:33][NH:32][CH2:31][CH2:30][NH:29][CH2:28][CH2:27][NH:26][CH2:25][CH2:24][NH:23]1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>CO>[Cl:1][C:22]1([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:36][NH:35][CH2:34][CH2:33][NH:32][CH2:31][CH2:30][NH:29][CH2:28][CH2:27][NH:26][CH2:25][CH2:24][N:23]1[Cl:3].[Mn+2:2]
Reactant: CCCCCCCCCCCCCCCCCCC1CNCCNCCNCCNCCN1
Reactant: [Cl-]
Agent: [Mn+2]
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCC1(Cl)CNCCNCCNCCNCCN1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a refluxing solution of anhydrous manganese(II) chloride (0.18 g, 1.4 mmol) in anhydrous methanol (50 ml) was added 2-octadecyl-1,4,7,10,13-pentaazacyclopentadecane prepared as in example 28I (0.65 g, 1.4 mmol). The resulting solution was refluxed under a dry nitrogen atmosphere for 2 h and then stirred at room temperature overnight. The solvent was removed in vacuo, the oily residue redissolved in hot THF (20 ml) and filtered. The solution was concentrated and hot ethyl ether was added with stirring to give 0.62 g (75% yield) of the product as a white solid: FAB mass spectrum (NBA) m/z (relative intensity) 556/558 [(M-Cl)+, 100/34]; Exact mass (M-Cl)+ : calcd., 557.3996; found, 557.4058 (C28H61N5MnCl).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:67])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47](OS(C3C=CC=CC=3[N+]([O-])=O)(=O)=O)[CH:46]([O:63][CH2:64][CH:65]=[CH2:66])[CH2:45]2)[CH:7]([CH3:68])[CH2:6][CH2:5][C:4]1=[O:69])[CH3:2].[N-:70]=[N+:71]=[N-:72].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:67])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([N:70]=[N+:71]=[N-:72])[CH:46]([O:63][CH2:64][CH:65]=[CH2:66])[CH2:45]2)[CH:7]([CH3:68])[CH2:6][CH2:5][C:4]1=[O:69])[CH3:2]
Reactant: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1OS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1N=[N+]=[N-]
Temperature: 70 °C
Yield: 45.2 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(4"-(o-nitrophenylsulfonyloxy)-3"-allyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (66 mg) in N,N-dimethyl formamide (1 ml) was added an excess of sodium azide (22 mg) and the mixture heated to 70° C. After 2.5 hours the reaction was cooled to room temperature, diluted with ethyl acetate, extracted from half-saturated ammonium chloride, and washed with brine. The combined organics were dried over sodium sulfate and purified by flash chromatography on silica gel (ethyl acetate:hexane (1:2)+1% methanol) to give the title compound (25 mg).
Reaction SMILES: [CH2:1]([N:4]([CH2:36][CH2:37][CH3:38])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:32][C:33]([OH:35])=[O:34])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]([CH2:26][C:27]2[NH:28][CH:29]=[CH:30][N:31]=2)[CH2:19][C:20]2[N:21]([CH3:25])[CH:22]=[CH:23][N:24]=2)=[CH:13][CH:12]=1)[CH2:2][CH3:3].C(Cl)(Cl)Cl.[CH2:43]([OH:49])[CH2:44][O:45][CH2:46][CH2:47]O>>[OH:49][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:34][C:33](=[O:35])[CH2:32][N:9]([CH2:8][CH2:7][CH2:6][CH2:5][N:4]([CH2:1][CH2:2][CH3:3])[CH2:36][CH2:37][CH3:38])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]([CH2:26][C:27]2[NH:28][CH:29]=[CH:30][N:31]=2)[CH2:19][C:20]2[N:21]([CH3:25])[CH:22]=[CH:23][N:24]=2)=[CH:13][CH:12]=1
Reactant: CCCN(CCC)CCCCN(CC(=O)O)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Reactant: OCCOCCO
Solvent: ClC(Cl)Cl
Product: CCCN(CCC)CCCCN(CC(=O)OCCOCCO)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Temperature: 80 °C
Reaction time: 72 h

Procedure:
The compound (424.0 mg) obtained in Example 65-1 was dissolved in diethylene glycol (8.0 ml) and the whole was stirred at 80° C. for 3 days. After completion of the reaction, the resultant was added with chloroform and washed with water, followed by drying with magnesium sulfate. The solvent was distilled off. The residue was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining a hydrochloride (280.2 mg) of the subject compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:23])=[C:5]([C:14]([O:21][CH3:22])=[C:15]([O:19][CH3:20])[C:16]=1[O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13].C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:36](O)=[O:37]>>[CH3:1][O:2][C:3]1[C:4]([CH3:23])=[C:5]([C:14]([O:21][CH3:22])=[C:15]([O:19][CH3:20])[C:16]=1[O:17][CH3:18])[CH2:6][C:7]1[C:8]([OH:13])=[C:9]([CH:10]=[CH:11][CH:12]=1)[CH:36]=[O:37]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1c(C)c(Cc2ccccc2O)c(OC)c(OC)c1OC
Agent: C1N2CN3CN1CN(C2)C3
Product: COc1c(C)c(Cc2cccc(C=O)c2O)c(OC)c(OC)c1OC
Temperature: 80 °C
Reaction time: 4 h
Yield: 27 %

Procedure:
2-(3,4,5,6-Tetramethoxy-2-methylbenzyl)phenol (8.64 g, 27.17 mmol) and hexamethylenetetramine (5.00 g, 35.67 mmol) were dissolved in trifluoroacetic acid (100 ml) followed by heating at 80° C. with stirring for 4 hours. After completion of the reaction, the solvent was evaporated therefrom, water (100 ml) was added to the resulting residue and the mixture was stirred for 30 minutes and extracted with methylene chloride. The extract was washed with water and dried, the solvent was evaporated therefrom and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give the title compound (2.50 g, 7.23 mmol, 27%).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([SH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([F:33])=[C:29]([F:32])[CH:30]=2)[N:25]=[CH:24][N:23]=1>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:22]3[C:31]4[C:26](=[CH:27][C:28]([F:33])=[C:29]([F:32])[CH:30]=4)[N:25]=[CH:24][N:23]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1cc2ncnc(Cl)c2cc1F
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(S)c2)no1
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc(Sc3ncnc4cc(F)c(F)cc34)c2)no1
Yield: 37 %

Procedure:
The title compound was prepared from 1-(5-tert-butylisoxazol-3-yl)-3-(3-mercaptophenyl)urea described in Example 44A (87 mg, 0.3 mmol) and 4-chloro-6,7-difluoroquinazoline (60 mg, 0.3 mmol) from Example 4A Step 2 as described in Example 46 to give 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6,7-difluoro quinazolin-4-ylthio)phenyl)urea (50 mg, 0.11 mmol, 37%). 1H NMR (300 MHz, DMSO-d6) δ 9.61 (s, 1H), 9.05 (s, 1H), 8.88 (s, 1H), 8.34 (dd, 1H), 8.09 (dd, 1H), 7.88 (s, 1H), 7.53 (d, 1H), 7.47 (t, 1H), 7.30 (d, 1H), 6.49 (s, 1H), 1.28 (s, 9H); LC-MS (ESI) m/z 478 (M+Na)+.
Reaction SMILES: [CH:1]1[C:12]2=[C:13]3[C:4](=[CH:5][CH:6]=[CH:7][C:8]3=[N:9][C:10]3[N:11]2[CH2:14][O:15][CH:16]=3)[CH2:3][CH:2]=1.[CH3:17][NH:18][CH3:19].C(COC)[O:21]C>>[CH3:17][N:18]([CH3:19])[C:14](=[O:21])[O:15][CH2:16][C:10]1[NH:9][C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:13]=2[C:12]([N:11]=1)=[CH:1][CH:2]=[CH:3]3
Reactant: COCCOC
Reactant: C1=CC2=c3c(cccc3=NC3=COCN32)C1
Reactant: CNC
Product: CN(C)C(=O)OCC1=Nc2cccc3cccc(c23)N1

Procedure:
A 10 g (0.44 mole) sample of 1H, 3H-oxazolo[3,4-a]perimidine, 3-one is dissolved in glyme at 30°, and the resulting solution is treated with excess 40% aqueous dimethylamine for 10 min. The mixture is then concentrated, dissolved in CHCl3, washed with water and dried. Further concentration gives an oil which is crystallized from ethyl acetate-cylcohexane and is then recrystallized from the same solvents twice to give the desired product, (2-perimidyl)methyl N,N-dimethylcarbamate, as yellow crystals, m.p. 161°-162° C.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([CH:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[O:10]1)([OH:8])=[O:7].[CH3:19]O>>[CH3:19][O:7][C:6]([CH:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[O:10]1)=[O:8]
Reactant: O=C(O)C1CCc2ccccc2O1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C1CCc2ccccc2O1
Yield: 96 %

Procedure:
14.2 ml of sulphuric acid (100% strength) are added to a solution of 70.34 g (0.39 mol) of 2-carboxychroman in 1400 ml of methanol and the whole is boiled under reflux for 4 hours. After cooling, the reaction mixture is concentrated by evaporation in vacuo and the residue is dissolved in diethyl ether and washed with water, cold saturated sodium hydrogen carbonate solution and again with water. The ethereal phase is dried over sodium sulphate and concentrated by evaporation in vacuo. 72.8 g (96%) of 2-methoxycarbonylchroman are obtained in the form of a pale yellow oil.
Reaction SMILES: [CH2:1]([Cl:4])[CH:2]=[CH2:3].[CH2:5]([SiH:8]([O:11][CH3:12])[O:9][CH3:10])[CH:6]=[CH2:7]>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[Cl:4][CH2:1][CH2:2][CH2:3][Si:8]([O:11][CH3:12])([O:9][CH3:10])[CH2:5][CH:6]=[CH2:7]
Reactant: C=CCCl
Reactant: C=CC[SiH](OC)OC
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Product: C=CC[Si](CCCCl)(OC)OC
Yield: 76643.8 %

Procedure:
Using the same apparatus and procedure described in EXAMPLE 1, 7.7 g (0.1 mol) of allylchloride and 60 μl of 1% chloroplatinic acid catalyst were added to the flask. Through the dropping funnel was added dropwise 6.6 g (0.05 mmol) of allyldimethoxysilane for 30 min. while refluxing. After confirming by gas chromatography to complete the reaction, the product was fractionally distilled under vacuum (59°-62° C./0.5 torr) to give 8.0 g (81%) of 7-chloro-4,4-dimethoxy-4-sila-1-heptene.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:16]=[CH:15][C:9]2[C:10](=[O:14])[CH:11]=[CH:12][O:13][C:8]=2[CH:7]=1.BrCCC[CH2:21][Cl:22].OC1C=CC2C(=O)C=COC=2C=1>>[Cl:22][CH2:21][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:16]=[CH:15][C:9]2[C:10](=[O:14])[CH:11]=[CH:12][O:13][C:8]=2[CH:7]=1
Reactant: ClCCCCBr
Reactant: O=c1ccoc2cc(OCCCCl)ccc12
Agent: O=c1ccoc2cc(O)ccc12
Product: O=c1ccoc2cc(OCCCCCl)ccc12

Procedure:
The title compound, mp 75°-78° C. was prepared as described above for 7-(3-chloropropoxy)-4H-1-benzopyran-4-one, starting from 1-bromo-4-chlorobutane and 7-hydroxy-4H-1-benzopyran-4-one.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7]([NH2:18])[N:6]=1)[CH:2]=[CH2:3].[CH2:19]([N:22]=[C:23]=[O:24])[CH2:20][CH3:21].C(N(CC)CC)C.O>C1COCC1>[CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7]([NH:18][C:23](=[O:24])[NH:22][CH2:19][CH2:20][CH3:21])[N:6]=1)[CH:2]=[CH2:3]
Reactant: CCCN=C=O
Reactant: C=CCNc1nc(N)nc2ccc([N+](=O)[O-])cc12
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCNc1nc(NC(=O)NCCC)nc2ccc([N+](=O)[O-])cc12
Yield: 80.5 %

Procedure:
After 200 mg (0.82 mmol) of 4-allylamino-2-amino-6-nitroquinazoline was dissolved in 10 ml of THF, 153 mg (1.80 mmol) of propylisocyanate and 0.13 ml (0.90 mmol) of triethylamine were added thereto, and then the reaction mixture was subjected to heating under reflux overnight. Water was added to the reaction solution, followed by extraction with ethyl acetate, washing with brine and drying over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 218 mg (80.5%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:43])[CH:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[C:27]3[C:26]4[C@@H:25]([CH2:28][CH:29]([NH:32][C:33](=[O:42])[O:34][CH2:35][C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[C:30]#[N:31])[CH2:24][CH2:23][C:22]=4[S:21][C:20]=3[N:19]=[CH:18][N:17]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:44][Li].O.OO>CO>[C:1]([O:5][C:6]([N:8]([CH3:43])[CH:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[C:27]3[C:26]4[C@@H:25]([CH2:28][C@H:29]([NH:32][C:33](=[O:42])[O:34][CH2:35][C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[C:30](=[O:44])[NH2:31])[CH2:24][CH2:23][C:22]=4[S:21][C:20]=3[N:19]=[CH:18][N:17]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:3])([CH3:4])[CH3:2].[C:1]([O:5][C:6]([N:8]([CH3:43])[CH:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[C:27]3[C:26]4[C@@H:25]([CH2:28][C@@H:29]([NH:32][C:33](=[O:42])[O:34][CH2:35][C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[C:30](=[O:44])[NH2:31])[CH2:24][CH2:23][C:22]=4[S:21][C:20]=3[N:19]=[CH:18][N:17]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(C#N)NC(=O)OCc2ccccc2)CC4)CC1
Reactant: [Li]O
Agent: OO
Solvent: O
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](C[C@@H](NC(=O)OCc2ccccc2)C(N)=O)CC4)CC1
Product: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](C[C@H](NC(=O)OCc2ccccc2)C(N)=O)CC4)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a 50-mL round-bottom flask containing a solution of benzyl N-[2-[(3R)-12-[(4-[[(tert-butoxy)carbonyl](methyl)amino]cyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2 (6),9,11-tetraen-3-yl]-1-cyano ethyl]carbamate (450 mg, 0.74 mmol, 1.00 equiv) in methanol (20 mL) was added LiOH.H2O (94 mg, 2.24 mmol, 3.00 equiv) and H2O2 (30%, 2 mL) at 0° C. The resulting solution was stirred for 2 h at 0° C. and quenched with saturated aqueous Na2SO3 and extracted with 3×50 mL of ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5-1:3) to afford the corresponding benzyl N-[(1S)-2-[(3R)-12-[(4-[[(tert-butoxy)carbonyl](methyl)amino]cyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2 (6),9,11-tetraen-3-yl]-1-carbamoylethyl]carbamate (167.3, 230 mg) as a white solid and benzyl N-[(1R)-2-[(3R)-12-[(4-[[(tert-butoxy)carbonyl](methyl)amino]cyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2 (6),9,11-tetraen-3-yl]-1-carbamoylethyl]carbamate (167.4, 90 mg) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH2:15][CH2:16][C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([C:27]([F:30])([F:29])[F:28])[CH:21]=3)=[O:18])[CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][NH2:40])=[CH:35][CH:34]=1>CS(C)=O.O>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:17](=[O:18])[CH2:16][CH2:15][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:40][CH2:39][C:36]4[CH:37]=[CH:38][C:33]([O:32][CH3:31])=[CH:34][CH:35]=4)[N:7]=3)[CH:10]=2)=[CH:21][C:22]=1[C:27]([F:30])([F:29])[F:28]
Reactant: O=C(CCc1cccc(Oc2ccnc(Cl)n2)c1)Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: COc1ccc(CN)cc1
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(CNc2nccc(Oc3cccc(CCC(=O)Nc4ccc(Cl)c(C(F)(F)F)c4)c3)n2)cc1
Temperature: 95 °C

Procedure:
To a solution of 3-{3-[(2-chloropyrimidin-4-yl)oxy]phenyl}-N-[4-chloro-3-(trifluoromethyl)phenyl]propanamide (0.200 g, 0.44 mmol) in DMSO (1 mL) were added 1-(4-methoxyphenyl)methanamine (0.056 mL, 0.44 mmol) and TEA (0.061 mL, 0.44 mmol). The reaction mixture was heated at 95° C. overnight and then cooled to rt, diluted with water and extracted with EtOAc. The combined organic solutions were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography to give A-224. 1H NMR (400 MHz, d6 DMSO) δ: 10.35 (s, 1H), 8.11-8.15 (m, 1H), 8.05-8.11 (m, 1H), 7.75-7.81 (m, 1H), 7.62 (d, 1H), 7.30-7.39 (m, 1H), 7.09-7.26 (m, 2H), 7.04-7.07 (m, 1H), 6.67-7.00 (m, 4H), 6.05 (d, 1H), 4.25-4.43 (br m, 1H), 3.96-4.10 (br m, 1H), 3.67 (s, 3H), 2.93 (t, 2H), and 2.67 (t, 2H). LCMS, FA: Rt=1.88 min, [MH+ 557.3].