Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH2:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]2[C:28]([OH:30])=[O:29])[CH:18]=[CH:19][CH:20]=1.[C:31]1([C:37]([CH:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)O)=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl>CN(C)C1C=CN=CC=1.ClCCl.C(OCC)(=O)C>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH2:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]2[C:28]([O:30][CH:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:37](=[O:38])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:29])[CH:18]=[CH:19][CH:20]=1
Reactant: O=C(c1ccccc1)C(O)c1ccccc1
Reactant: COc1cccc(CC2CCCCC2C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cccc(CC2CCCCC2C(=O)OC(C(=O)c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.1 %

Procedure:
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (501 mg) was added to a stirred solution of 2-[(3-methoxyphenyl)methyl]cyclohexanecarboxylic acid (500 mg), benzoin (427 mg), and 4-dimethylaminopyridine (12.2 mg) in dichloromethane (10 ml) under ice cooling. The resulting mixture was stirred at the same temperature for 2 hours and at room temperature for 1 hour, and then a mixture of ethyl acetate and 1N hydrochloric acid was added thereto. The organic layer was separated, washed successively with 1N hydrochloric acid, sodium bicarbonate aqueous solution and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was chromatographed over silica gel using n-hexane--toluene as an eluent to afford 2-oxo-1,2-diphenylethyl 2-[(3-methoxyphenyl)-methyl]cyclohexanecarboxylate (455 mg) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([SH:10])[NH:9][C:5]=2[CH:4]=1.[OH-].[Na+].Br[CH2:18][C:19]1[C:24]([O:25][CH3:26])=[C:23]([O:27][CH3:28])[CH:22]=[CH:21][N:20]=1>CO>[CH3:26][O:25][C:24]1[C:19]([CH2:18][S:10][C:8]2[NH:9][C:5]3[CH:4]=[C:3]([C:2]([F:13])([F:1])[F:14])[CH:12]=[CH:11][C:6]=3[N:7]=2)=[N:20][CH:21]=[CH:22][C:23]=1[O:27][CH3:28]
Reactant: COc1ccnc(CBr)c1OC
Reactant: FC(F)(F)c1ccc2nc(S)[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccnc(CSc2nc3ccc(C(F)(F)F)cc3[nH]2)c1OC
Reaction time: 1 h
Yield: 16.6 %

Procedure:
To a solution of 5-trifluoromethyl-2-mercaptobenzimidazole (1.10 g), 1N-sodium hydroxide (7.2 ml), and methanol (5 ml) was added a solution of 2-bromomethyl-3,4-dimethoxypyridine (1.3 g) in methanol (35 ml) at room temperature over 10 minutes. The mixture was stirred for one hour, concentrated, and extracted with chloroform. The organic layer was washed with 1N-sodium hydroxide and then with water, dried, and evaporated. The residue was purified by column chromatography on silica gel (chloroform-ethyl acetate-acetone (1:1:0.1)) and recrestallized from chloroform-isopropyl ether, to give 2-[(3,4-dimethoxypyrid-2-yl)methylthio]-5-trifluoromethylbenzimidazole (310 mg) as white crystals.
Reaction SMILES: C([Si](C)(C)OC(CCCCCCCC(O)=O)CCCCCCCC(O)=O)(C)(C)C.[Si]([O:37][CH:38]([CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][C:65]([O:67][CH2:68]/[CH:69]=[CH:70]\[CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH3:76])=[O:66])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][C:46]([O:48][CH2:49]/[CH:50]=[CH:51]\[CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])=[O:47])(C(C)(C)C)(C)C>C1(C)C=CC=CC=1.C(Cl)Cl>[OH:37][CH:38]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][C:46]([O:48][CH2:49]/[CH:50]=[CH:51]\[CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])=[O:47])[CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][C:65]([O:67][CH2:68]/[CH:69]=[CH:70]\[CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH3:76])=[O:66]
Reactant: CCCCCC/C=C\COC(=O)CCCCCCCC(CCCCCCCC(=O)OC/C=C\CCCCCC)O[Si](C)(C)C(C)(C)C
Agent: CC(C)(C)[Si](C)(C)OC(CCCCCCCC(=O)O)CCCCCCCC(=O)O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCCCC/C=C\COC(=O)CCCCCCCC(O)CCCCCCCC(=O)OC/C=C\CCCCCC
Temperature: 70 °C
Yield: 55.8 %

Procedure:
To a solution of compound 7 (2.0 g, 12.8 mmol) in toluene (40 mL) and CH2Cl2 (18 mL) and was added 8 (3.96 g, 11.8 mmol). The mixture was heated at 70° C. overnight. Column chromatography gave pure compound 9 (1.40 g, 6.59 mmol, 51%) as a colorless oil.
Reaction SMILES: [Li]CCCC.[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.[NH2:12][C:13]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:14]=1[C:15](O)=[O:16].[NH4+].[Cl-]>CCCCCC.CCOCC>[NH2:12][C:13]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:14]=1[C:15]([C:8]1[N:7]([CH3:6])[CH:11]=[CH:10][N:9]=1)=[O:16]
Reactant: Nc1ccc(Cl)cc1C(=O)O
Reactant: Cn1ccnc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCCCCC
Product: Cn1ccnc1C(=O)c1cc(Cl)ccc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 12.6 %

Procedure:
To a solution of nBuLi (0.0730 mol) in hexane was added N-methyl imidazole (0.0608 mol) drop wise at -40° C. over 30 min under a nitrogen atmosphere. The resulting yellow solution was stirred for a further 3 hr at rt, and then refluxed for 1 h. 2-amino-5-chlorobenzoic acid (1.74 g, 0.01014 mole) in dry ether (60 ml) was then added to the reaction mixture. The reaction mixture was stirred overnight at rt. To the reaction mixture was added saturated NH4Cl solution and the resulting mixture extracted with ethyl acetate (2×150 ml). The combined organic layers were dried over Na2SO4. After removal of solvent, the residue was purified by the flash chromatography using ethyl acetate/hexane (1:4) as eluent. Crystallization of the product from Et2O/hexane mixture gave 300 mg (13.7%) of product as yellow solid.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[NH:4][C:3]1=[O:14].[C:15]1([CH3:24])[CH:20]=[CH:19][CH:18]=[C:17]([N:21]=[C:22]=[O:23])[CH:16]=1.C(OC(C)C)(C)C>CN(C)C=O>[C:15]1([CH3:24])[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22](=[O:23])[NH:1][CH:2]2[C:8](=[O:9])[NH:7][C:6]3[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=3[NH:4][C:3]2=[O:14])[CH:16]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: NC1C(=O)Nc2ccccc2NC1=O
Solvent: CC(C)OC(C)C
Solvent: CN(C)C=O
Product: Cc1cccc(NC(=O)NC2C(=O)Nc3ccccc3NC2=O)c1
Reaction time: 1 h
Yield: 99.8 %

Procedure:
A mixture of 3-amino-1H-1,5-benzodiazepine-2,4(3H,5H)-dione (1.761 g, 9.21 mmol) and m-tolylisocyanate (1.31 g, 10.13 mmol) in dimethylformamide (17 ml) is stirred for 1 hr under ice-cooling. To the reaction mixture is added diisopropyl ether (50 ml) and the resultant crystalline precipitates are filtered off to obtain Compound 5 (2.98 g; yield, 99%). M.p. >300° C.
Reaction SMILES: [NH:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]3C[C:10]=3[CH:11]=2)[C:6](O)=[C:5](O)[N:4]=1)[NH2:2].[CH:16]([O-])([O-:20])[O:17]CC.[CH2:22](O)CCC>>[CH2:16]1[O:20][C:10]2[CH:11]=[C:12]3[C:7]([CH:6]=[CH:5][N:4]4[CH:22]=[N:2][N:1]=[C:3]43)=[CH:8][C:9]=2[O:17]1
Reactant: CCOC([O-])[O-]
Reactant: CCCCO
Reactant: NNc1nc(O)c(O)c2cc3c(cc12)C3
Product: c1cn2cnnc2c2cc3c(cc12)OCO3
Yield: 71 %

Procedure:
1-Hydrazino-6,7-methylenedioxylisoquinoline (25 g.) and 10 ml. of ethyl orthoformate were allowed to reflux for five hours in 70 ml. of 1-butanol.Evaporation of the solvent in vacuo and recrystallization from toluene provided the product in a yield of 71%; m.p. 267°-269°C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH3:25])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.C(N(CC)CC)C.[C:34](Cl)(=[O:36])[CH3:35]>C(Cl)Cl.O>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]([C:34](=[O:36])[CH3:35])[CH3:25])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: CC(=O)Cl
Reactant: CNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(C)C(C)=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To (6-methoxy-2′-methylaminomethyl-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester (0.114 g, 0.31 mmol) and triethylamine (0.05 mL, 0.34 mmol) in CH2Cl2 (1.2 mL) was added acetyl chloride (0.02 mL, 0.34 mmol), and the reaction was stirred at room temperature for 1 hour. Once no starting material was seen by analytical LCMS, the mixture was diluted with CH2Cl2 and H2O, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was purified by silica gel chromatography (0-100% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:8])=[N:4][NH:5][C:6]=1[Br:7].CC(C)=O.C(=O)([O-])[O-].[K+].[K+].Br[CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>CCCCCC>[Br:7][C:6]1[C:2]([Br:1])=[C:3]([CH3:8])[N:4]([CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:5]=1
Reactant: CCOC(=O)C(C)Br
Reactant: Cc1n[nH]c(Br)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CC(C)=O
Product: CCOC(=O)C(C)n1nc(Br)c(Br)c1C
Reaction time: 0.25 h
Yield: 75 %

Procedure:
A reaction mixture consisting of a solution of 13.7 g. (0.057 mole) 4,5 -dibromo-3-methylpyrazole in 200 ml. acetone and 15.7 g. (0.114 mole) anhydrous potassium carbonate was heated at the reflux temperature with continuous stirring for 15 minutes. After cooling, 10.4 g. (0.06 mole) ethyl 2-bromopropionate was added. This reaction mixture was then heated at the reflux temperature for 2.5 hours. It was cooled and filtered. The acetone was then removed by evaporation under reduced pressure, and the residue thus obtained was dissolved in hot hexane. After chilling in a refrigerator the crystals that had formed were collected on a filter. There was thus obtained 14.5 g. (75% yield) of ethyl 3,4 -dibromo-α, 5-dimethylpyrazole-1-acetate having a melting point at 61° to 62° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]([C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:32])[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([C:30]#[N:31])([CH3:29])[CH3:28])[CH:22]=2)=[CH:15][C:14]=1[OH:33])#[N:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:30]([C:27]([C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[C:20]([NH:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]#[N:12])=[C:14]([O:33][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH:15]=1)=[O:32])([CH3:29])[CH3:28])#[N:31]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(C#N)c(O)c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(C#N)c(Oc3ccc([N+](=O)[O-])cn3)c2)c1
Temperature: 80 °C
Reaction time: 20 h
Yield: 24.3 %

Procedure:
To a solution of 2-chloro-5-nitropyridine (1.06 g, 6.68 mmol) and N-(4-cyano-3-hydroxyphenyl)-3-(1-cyano-1-methylethyl)benzamide (2.0 g, 6.55 mmol) in N,N-dimethylformamide (15 mL) was added potassium carbonate (1.35 g, 9.82 mmol), and the mixture was stirred at 80° C. for 20 hr. The reaction mixture was cooled to room temperature, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate (300 mL), washed with water (150 mL) and saturated brine (150 mL×2), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20→40/60), and further purified by basic silica gel column chromatography (hexane/ethyl acetate=70/30→0/100). The obtained solution was concentrated under reduced pressure to give the title compound (0.68 g, 24%) as a pale-yellow oil.
Reaction SMILES: [CH2:1]([C:8]1[C:12]2[CH:13]=[C:14]([CH3:18])[CH:15]=[C:16]([Br:17])[C:11]=2[O:10][C:9]=1[CH:19]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[NH4+:22].II>C1COCC1>[CH2:1]([C:8]1[C:12]2[CH:13]=[C:14]([CH3:18])[CH:15]=[C:16]([Br:17])[C:11]=2[O:10][C:9]=1[C:19]#[N:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: Cc1cc(Br)c2oc(C=O)c(Cc3ccccc3)c2c1
Agent: II
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(Br)c2oc(C#N)c(Cc3ccccc3)c2c1
Reaction time: 8 h
Yield: 97 %

Procedure:
3-Benzyl-7-bromo-5-methyl-benzofuran-2-carbaldehyde (2.61 gm, 7.93 mmol) was added to a mixture of THF (10 ml) and concentrated ammonium hydroxide (80 ml). Iodine (2.2 g, 8.67 mmol) was added and the grey slurry was stirred overnight. Additional THF (20 ml), ammonium hydroxide (20 ml), and iodine (0.2 g, 0.8 mmol) were added, and the mixture stirred for 30 minutes. The reaction mixture was quenched by addition of aqueous 10% sodium thiosulfate (20 ml) and brine (20 ml). The mixture was extracted with diethy ether, and the combined organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 3-benzyl-7-bromo-5-methyl-benzofuran-2-carbonitrile (2.5 g, 97% yield). (M+H)+ 327.
Reaction SMILES: [C:1]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([OH:49])=O)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(N(CC)CC)C.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[OH:68][CH2:69][C@@H:70]([C@@H:72]([C@@H:74]([CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][CH2:88][CH3:89])[OH:75])[OH:73])[NH2:71]>C(Cl)(Cl)Cl>[C:1]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([NH:71][C@H:70]([C@@H:72]([C@@H:74]([CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][CH2:88][CH3:89])[OH:75])[OH:73])[CH2:69][OH:68])=[O:49])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OCCCCCCCCCCCCCCCCCCCCCCCCCCC(=O)O
Reactant: CCCCCCCCCCCCCC[C@@H](O)[C@@H](O)[C@@H](N)CO
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCCCCCCCCCCCCCCCCCCCCCCCCCCC(=O)N[C@@H](CO)[C@H](O)[C@H](O)CCCCCCCCCCCCCC
Reaction time: 2 h
Yield: 29.6 %

Procedure:
A solution of 27-oleoyloxy-heptacosanoic acid (2 g; 2.89 mmoles) in chloroform (30 ml) and triethylamine (1.6 ml; 11.5 mmoles) was added in 30 minutes to a stirred solution of 0.5 grams of p-toluenesulphonyl chloride (0.5 g; 2.6 mmoles) in chloroform (40 ml) under nitrogen while keeping the temperature at 50° C. After stirring for 1 hour at 50° C. phytosphingosine (0.8 g; 2.52 mmoles) was added and stirring was continued for 2 hours at 50° C. After cooling the mixture was washed with 50 ml of 0.5N hydrochloric acid, 50 ml of water and brine respectively. The organic layer was evaporated in vacuum and the residue was crystallized from 50 ml of warm 2-propanol under nitrogen giving 2.03 grams of the impure title compound. Purification over 40 grams of silica gel (Flash 30-60 μm) with chloroform/methanol=9/1 and subsequent crystallization from 40 ml of hot isopropanol gave 0.74 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]1[CH:13]=[N:14][N:15]3[C:20]([N:21]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])=[CH:19][C:18]([CH:38]=C)=[N:17][C:16]=13)=[CH:5]2.CC([OH:44])(C)C.N1C(C)=CC=CC=1C.[O-]S([O-])(=S)=O.[Na+].[Na+]>O=[Os](=O)(=O)=O.O.C(Cl)Cl>[CH3:27][Si:26]([CH3:29])([CH3:28])[CH2:25][CH2:24][O:23][CH2:22][N:21]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:35])([CH3:36])[CH3:37])[C:20]1[N:15]2[N:14]=[CH:13][C:12]([C:6]3[CH:7]=[N:8][C:9]4[C:4]([CH:5]=3)=[CH:3][C:2]([F:1])=[CH:11][CH:10]=4)=[C:16]2[N:17]=[C:18]([CH:38]=[O:44])[CH:19]=1
Reactant: C=Cc1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n2ncc(-c3cnc4ccc(F)cc4c3)c2n1
Reactant: CC(C)(C)O
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: O
Solvent: ClCCl
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C=O)nc2c(-c3cnc4ccc(F)cc4c3)cnn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 2200 %

Procedure:
To 3-(6-fluoroquinolin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)-5-vinylpyrazolo[1,5-a]pyrimidin-7-amine (1.3 g, 2.2 mmol) in 1,4-doixane (20 mL) was added 2.5 wt % OsO4 in t-BuOH (4.9 g, 0.1 mmol), 2,6-lutidine (1.1 mL, 9.0 mmol) and H2O (3 mL) and the resulting mixture was stirred at room temperature for 1 hour. NaIO4 (1.9 g, 8.9 mmol) was then added and stirring at room temperature was continued for 16 hours. LC/MS analysis at this time showed no starting material or diol intermediate present and confirmed full conversion to product. Saturated Na2S2O3 solution (30 mL) was added and the mixture stirred for 10 minutes. The reaction was transferred to a separatory funnel with CH2Cl2 (30 mL) and H2O (30 mL) and organics were extracted with CH2Cl2 (4×40 mL), dried (Na2SO4) and concentrated in vacuo to give 7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-fluoroquinolin-3-yl)pyrazolo[1,5-a]pyrimidine-5-carbaldehyde as a brown solid (1.3 g, 2.2 mmol, 100%). LC/MS: 2.92 mins, m/z=568.3 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[C@@H:7]([NH2:24])[CH2:8][NH:9][C:10](=[O:23])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:33]([NH:36][C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1)(=[O:35])[CH3:34]>CN(C)C=O>[C:1]([O:5][C:6](=[O:25])[C@@H:7]([NH:24][S:43]([C:40]1[CH:39]=[CH:38][C:37]([NH:36][C:33](=[O:35])[CH3:34])=[CH:42][CH:41]=1)(=[O:45])=[O:44])[CH2:8][NH:9][C:10](=[O:23])[C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:16]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)CCc1ccc(C(=O)NC[C@H](N)C(=O)OC(C)(C)C)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CCc1ccc(C(=O)NC[C@H](NS(=O)(=O)c2ccc(NC(C)=O)cc2)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.123 g (0.35 mmol) of (2S)-2-amino-3-(4-(2-methoxycarbonyl-ethyl)-benzoylamino)-propionic acid tert-butyl ester was dissolved in 2 ml of dimethylformamide and treated with 0.196 ml (1.4 mmol) of triethylamine and 0.164 g (0.7 mmol) of 4-acetylamino-benzenesulfonyl chloride. The solution was stirred for 4 hours at room temperature. The solvent was removed in vacuo, the residue was dissolved in dichloromethane and the solution was washed three times with water. The organic phase was dried with sodium sulfate, filtered and the solvent was removed in vacuo. The residue was chromatographed on silica gel eluting with n-heptane/ethyl acetate (1/2). Yield 90 mg. MS (ES+): m/e=548 (M+H+).
Reaction SMILES: Cl[CH:2]([C:4]1[O:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)=[N:7][N:8]=1)[CH3:3].[C:16]([O:23][CH3:24])(=[O:22])[CH2:17][C:18]([O:20][CH3:21])=[O:19].C1CCN2C(=NCCC2)CC1>C(#N)C.ClCCl>[CH3:21][O:20][C:18](=[O:19])[CH:17]([CH:2]([C:4]1[O:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)=[N:7][N:8]=1)[CH3:3])[C:16]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)CC(=O)OC
Reactant: CC(Cl)c1nnc(-c2cccc(Cl)c2)o1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COC(=O)C(C(=O)OC)C(C)c1nnc(-c2cccc(Cl)c2)o1
Yield: 77.5 %

Procedure:
2-(1-Chloro-ethyl)-5-(3-chloro-phenyl)-[1,3,4]oxadiazole (331 mg, 1.36 mmol) was mixed with dimethyl malonate (360 mg, 2/76 mmol) and DBU (207 mg, 1.36 mmol) in acetonitrile (3 ml) at 70° C. overnight. The reaction mixture was dilute with dichloromethane and washed with water. The organic layer was dried and concentrated. The residue was purified with 5˜20% ethyl acetate in hexanes to give 357 mg (74.3%) 2-{1-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-ethyl}-malonic acid dimethyl ester as white solid. 1H-NMR(CDCl3) d(ppm): 8.03 (s, 1H), 7.95 (d, 1H), 7.53 (d, 1H), 7.47 (t, 1H), 4.06 (d, 1H), 3.95 (m, 1H), 3.84 (s, 3H), 3.74 (s, 3H) and 1.51 (d, 3H). Step 2: 3-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-butyric acid methyl ester: 2-{1-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-ethyl}-malonic acid dimethyl ester (352.8 mg, 1.0 mmol) was mixed with sodium chloride (76.3 mg, 1.3 mmol) and a drop of water in DMSO (1.5 ml) at 175° C. for an h. The reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was washed with water and concentrated. The residue was purified with column chromatography with 10˜20% ethyl acetate in hexanes to give 215 mg (76.8%) 3-[5-(3-chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-butyric acid methyl ester as clear oil.
Reaction SMILES: [Si:1]([N:8]1[CH:11]([CH2:12][CH:13]([OH:25])[CH2:14][C:15]([O:17]CC2C=CC=CC=2)=[O:16])[CH2:10][C:9]1=[O:26])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>[Pd].C(O)C>[Si:1]([N:8]1[CH:11]([CH2:12][CH:13]([OH:25])[CH2:14][C:15]([OH:17])=[O:16])[CH2:10][C:9]1=[O:26])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)CC1CC(O)CC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)N1C(=O)CC1CC(O)CC(=O)O
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
A mixture of crude N-(t-butyldimethylsilyl)-4-(3-benzyloxycarbonyl-2-Hydroxypropyl)-azetidin-2-one (13.46 g, 35.6 mmol), 10% palladium on charcoal, and ethanol (200 ml) is hydrogenated at 40 psi for 30 mins. The mixture is filtered and the filtrate is evaporated under vacuum and stripped with toluene to give N-(t-butyldimethylsilyl)-4-(3-carboxy-2-hydroxypropyl)-azetidin-2-one (9.51 g) as an off-white solid: IR (neat film from Me2CO) 3200 (br), 1735, and 1700 (shifts to 1590 with Et3N) cm-1 ; NMR (Me2CO--d6) δ 0.25 (s, 6, 2CH3), 0.98 (s, 9, C(CH3)3) 1.17-2.33 (m, 2, CH--C CH2 --CH), 2.50 (d, 2, J=6.5, CH2CO2), 2.50-3.40 (m, 2, H3 and H3β), 3.97 (m, 2, H4 and CHOH); MS on bistrimethylsilyl derivative m/e 431 (M+), 416(M+-57) and 332 (374-42).
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[CH3:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]([C:27]([OH:31])([C:29]#[CH:30])[CH3:28])[CH:22]=1>>[F:19][C:3]1[C:2]([C:30]#[C:29][C:27]([OH:31])([C:23]2[CH:22]=[C:21]([CH3:20])[CH:26]=[CH:25][N:24]=2)[CH3:28])=[CH:18][C:6]2[C:7]3[N:8]([CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: C#CC(C)(O)c1cc(C)ccn1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Product: Cc1ccnc(C(C)(O)C#Cc2cc3c(cc2F)OCCn2cc(C(N)=O)nc2-3)c1
Yield: 10 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 2-(4-methylpyridin-2-yl)but-3-yn-2-ol (WO2009/158011A1) to give the titled compound as a white solid (39 mg, 10%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][CH:4]=[N:3]1.C([Li])CCC.[C:12](=[O:14])=[O:13]>C1COCC1.CCCCCC>[CH3:1][N:2]1[C:6]([C:12]([OH:14])=[O:13])=[N:5][CH:4]=[N:3]1
Reactant: Cn1cncn1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cn1ncnc1C(=O)O
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 88.4 %

Procedure:
1-Methyl-1H-1,2,4-triazole (1.19 g) was dissolved in THF (15 ml) and cooled to −78° C. under nitrogen. A 1.6M solution of butyllithium in hexane (9.4 ml) was added dropwise. The solution was stirred for 1.5 h at −78° C., then the solution was treated with solid carbon dioxide (2 g). After 30 min at −78° C. the solution was allowed to warm to RT and stirred overnight. The reaction was quenched with water (1 ml) and the solvent was decanted off. To the residue was added ethyl acetate (20 ml) and water (20 ml). The solvent was removed in vacuo and the residue was dried in a vacuum oven for 1 day (50° C.) to give the title compound (1.61 g) as a white solid.