Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:6][CH:7]([CH3:11])[CH2:8][CH2:9][OH:10])[CH2:2][CH2:3][CH2:4][CH3:5].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.[OH-].[Na+].Cl>C1C=CC=CC=1.N1C=CC=CC=1>[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18]([O:10][CH2:9][CH2:8][CH:7]([O:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH3:11])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: CCCCCOC(C)CCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCCCCOC(C)CCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 35 %

Procedure:
5.0 g of 3-pentyloxybutanol, 3.98 g of p-toluenesulfonyl chloride, 1.65 g of pyridine, and 8 ml of benzene were charged in a 30 ml-reaction vessel and, under N2 stream, stirred for 23 hours at room temperature. Then, into the reaction mixture, 6.3 ml of hot conc. NaOH aqueous solution was added and stirred for 5 min. The mixture was poured in 280 ml of cold 10%-hydrochloric acid solution and extracted with hexane. The hexane layer was washed successively with cold 5%-hydrochloric acid solution, saturated NaCO3 aqueous solution and water and dried with anhydrous MgSO4, followed by distilling-off of the solvent to 6.0 g of a crude product, which was purified by alumina column chromatography (hexane) to obtain 2.3 g of 3-pentyloxybutyl p-toluenesulfonate.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([B:25]3[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]3)=[CH:21][CH:20]=2)=[CH:17][N:18]=1)=O)(C)(C)C.C(OCC)C>O1CCOCC1.ClCCl>[ClH:1].[NH:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([B:25]3[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]3)=[CH:21][CH:20]=2)=[CH:17][N:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC1(C)OB(c2ccc(-c3cnc([C@@H]4CCCN4)[nH]3)cc2)OC1(C)C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
A solution of hydrogen chloride in 1,4-dioxane (4 N, 75 mL) was added to a solution of (S)-2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (7.0 g, 15.9 mmol) in dichloromethane (50 mL). Gas evolution was observed. After 30 minutes, a solid formed. After 1.5 hours, the resulting solid was isolated by filtration with diethyl ether washing. Any residual solvent was removed under reduced pressure to provide (S)-2-pyrrolidin-2-yl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazole hydrochloride (5.6 g, 95%) as an off-white solid.
Reaction SMILES: [SH2:1].[NH2:2][CH:3]([P:16]([O:20][CH3:21])([O:18][CH3:19])=[O:17])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)=[O:5].[CH:22]#N>CO>[CH:22]([NH:2][CH:3]([P:16]([O:20][CH3:21])([O:18][CH3:19])=[O:17])[C:4]([O:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1)=[O:5])=[S:1]
Reactant: C#N
Reactant: COc1ccc(COC(=O)C(N)P(=O)(OC)OC)cc1
Reactant: S
Solvent: CO
Product: COc1ccc(COC(=O)C(NC=S)P(=O)(OC)OC)cc1
Reaction time: 8 h

Procedure:
Hydrogen sulfide (0.75 g) is passed into a cold (ice-bath) solution of p-methoxybenzyl α-amino-dimethylphosphonoacetate (6.06 g) in anhydrous methanol (5 ml). Hydrogen cyanide (0.53 g) is added and the ice-bath is removed. After standing overnight, the reaction mixture is added to water (50 ml) and extracted with ether (3 × 20 ml). The combined extracts are dried with magnesium sulfate, filtered, and evaporated in vacuo to dryness. The residue is chromatographed on silicon gel, affording p-methoxybenzyl α-thioformamido-dimethylphosphonoacetate.
Reaction SMILES: [Cl:1][C:2]1[N:18]=[CH:17][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]([NH2:16])=[O:15])[N:7]=3.CO[CH:21](OC)[N:22]([CH3:24])[CH3:23]>C1(C)C=CC=CC=1>[CH3:21][N:22]([CH3:24])[CH:23]=[N:16][C:14]([C:8]1[N:7]=[C:6]2[N:10]([CH2:11][CH2:12][O:13][C:4]3[CH:3]=[C:2]([Cl:1])[N:18]=[CH:17][C:5]=32)[CH:9]=1)=[O:15]
Reactant: COC(OC)N(C)C
Reactant: NC(=O)c1cn2c(n1)-c1cnc(Cl)cc1OCC2
Solvent: Cc1ccccc1
Product: CN(C)C=NC(=O)c1cn2c(n1)-c1cnc(Cl)cc1OCC2
Temperature: 95 °C

Procedure:
To a solution of 8-Chloro-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulene-2-carboxylic acid amide (2.40 g, 0.00907 mol) in Toluene (40 mL) was added 1,1-Dimethoxy-N,N-dimethylmethanamine (4.82 mL, 0.0363 mol). The flask was sealed and heated to 95° C. for 8 h. The reaction was deemed complete by TLC. The solvent was removed in vacuo to give 8-Chloro-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulene-2-carboxylic acid 1-dimethylamino-methylideneamide which was used crude. MS(ESI+) 320.1
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][NH:6][C:7]1[C:12]([NH:13][C:14](=O)[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)=[CH:11][CH:10]=[CH:9][N:8]=1)C.C(O)CO.[OH-].[K+]>O>[Cl:22][C:17]1[CH:16]=[C:15]([C:14]2[N:6]([CH2:5][C:4]([OH:3])=[O:24])[C:7]3=[N:8][CH:9]=[CH:10][CH:11]=[C:12]3[N:13]=2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: CCOC(=O)CNc1ncccc1NC(=O)c1ccc(Cl)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: O=C(O)Cn1c(-c2ccc(Cl)c(Cl)c2)nc2cccnc21

Procedure:
A mixture of N-[3-[(3,4-dichlorobenzoyl)amino]-2-pyridinyl]glycine ethyl ester (33 g, 0.09 mole) and 167 ml of ethylene glycol was heated at reflux for 11/2 hr. After cooling, potassium hydroxide (8.4 g) in 40 ml of water was added and the reaction mixture was heated at reflux for 1 hr. The solution was filtered to remove yellow insoluble precipitate, the filtrate was diluted with 650 ml of water, and acidified with ethanolic hydrogen chloride. The solid, which formed, was collected by filtration, washed with water, and dried under high vacuum first at 50° C. overnight, then at 70° C. for 21/2 days to give 25.3 g (98%), mp 248°-49° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC(=O)[NH:14][C@H:15]([C:19](=[O:21])[NH2:20])[CH2:16][C:17]#[CH:18])(C)(C)C>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[NH2:14][C@@H:15]([CH2:16][C:17]#[CH:18])[C:19]([NH2:20])=[O:21]
Reactant: O=C(O)C(F)(F)F
Reactant: C#CC[C@H](NC(=O)OC(C)(C)C)C(N)=O
Solvent: ClCCl
Product: C#CC[C@H](N)C(N)=O
Product: O=C([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
Trifluoroacetic acid (3 ml) was added to a solution of ((S)-1-carbamoylbut-3-ynyl)carbamic acid tert-butyl ester (138 mg, 0.65 mmol) in dichloromethane (3 ml). The reaction mixture was stirred for 1.25 h at room temperature. The solvent was removed in vacuo. The residue was dissolved in dichloromethane (40 ml) and the solvent was removed in vacuo. The latter procedure was repeated twice to give crude trifluoroacetate salt of (S)-2-aminopent-4-ynoic acid amide, which was used for the following experiments.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:24])[C:13]2[CH:18]=[CH:17][C:16]([C:19]3[NH:20][CH:21]=[CH:22][N:23]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl.O.Cl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:24])[C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:20]([S:33]([CH3:32])(=[O:35])=[O:34])[CH:21]=[CH:22][N:23]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)c1ccc(NC(=O)c2ccc(-c3ncc[nH]3)cc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(NC(=O)c2ccc(-c3nccn3S(C)(=O)=O)cc2)cc1
Reaction time: 0.67 h

Procedure:
The product from Example 6 (71.4 mg, 0.224 mmol) and triethylamine (62 μL, 0.44 mmol) in CH2Cl2 (2 mL) at 0° C. were treated with methanesulfonyl chloride (21 μL, 0.27 mmol). The solution was stirred for 40 minutes, allowed to warm over 15 minutes, diluted with water (3 mL) and 1 N HCl (0.5 mL), and extracted with CH2Cl2 (3×4 mL). The extracts were combined, dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (60% ethyl acetate in hexanes) to provide the title compound. 1H NMR (300 MHz, CDCl3) δ 7.96 (d, 2H), 7.85 (m, 3H), 7.57 (m, 3H), 7.41 (d, 2H), 7.22 (d, 1H), 3.02 (s, 3H), 1.33 (s, 9H); MS (m/z) 398.
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][C:17]=2[NH:22][C:23]([C:25]2[N:26]=[C:27](Br)[S:28][C:29]=2[NH:30]C(=O)OC(C)(C)C)=[O:24])[CH2:12][CH2:11]1)=O)CCC.[CH:39]([C:42]1[CH:43]=[C:44](B(O)O)[CH:45]=[CH:46][CH:47]=1)([CH3:41])[CH3:40]>>[NH2:30][C:29]1[S:28][C:27]([C:46]2[CH:45]=[CH:44][CH:43]=[C:42]([CH:39]([CH3:41])[CH3:40])[CH:47]=2)=[N:26][C:25]=1[C:23]([NH:22][C:17]1[CH:18]=[N:19][N:20]([CH3:21])[C:16]=1[N:13]1[CH2:14][CH2:15][CH:10]([CH2:9][NH2:8])[CH2:11][CH2:12]1)=[O:24]
Reactant: CCCCOC(=O)NCC1CCN(c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2C)CC1
Reactant: CC(C)c1cccc(B(O)O)c1
Product: CC(C)c1cccc(-c2nc(C(=O)Nc3cnn(C)c3N3CCC(CN)CC3)c(N)s2)c1

Procedure:
Following Example 278, Suzuki coupling of tert-butyl 4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamate and 3-isopropylbenzeneboronic acid gave 301 as the mono-formate salt as a red gum (38 mg, 41% over two steps). 1H NMR (400 MHz, d6-DMSO with D2O) δ 8.35 (s, 1H), 7.70 (s, 1H), 7.58 (d, J=7.7 Hz, 1H), 7.37 (t, J=7.7 Hz, 1H), 7.32-7.25 (m, 2H), 3.62 (s, 3H), 3.10 (d, J=11.5 Hz, 2H), 3.04-2.88 (m, 3H), 2.72 (d, J=6.9 Hz, 2H), 1.73 (d, J=12.6 Hz, 2H), 1.64-1.58 (m, 1H), 1.34-1.24 (m, 2H), 1.22 (d, J=6.9 Hz, 6H). LCMS (ES+) m/z 454 (M+1)
Reaction SMILES: C([O-])([O-])OCC.C(OC(=O)C)(=O)C.C(O[CH:17]=[C:18]([C:24](=[O:35])[C:25]1[C:30]([F:31])=[CH:29][C:28]([F:32])=[C:27]([F:33])[C:26]=1[F:34])[C:19]([O:21][CH2:22][CH3:23])=[O:20])C.[CH:36]1([NH2:39])[CH2:38][CH2:37]1>>[CH:36]1([NH:39][CH:17]=[C:18]([C:24](=[O:35])[C:25]2[C:30]([F:31])=[CH:29][C:28]([F:32])=[C:27]([F:33])[C:26]=2[F:34])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:38][CH2:37]1
Reactant: CCOC=C(C(=O)OCC)C(=O)c1c(F)cc(F)c(F)c1F
Reactant: NC1CC1
Agent: CCOC([O-])[O-]
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1c(F)cc(F)c(F)c1F

Procedure:
The resulting compound (28.4 g) was treated with ethyl orthoformate and acetic anhydride to convert it into ethyl 3-ethoxy-2-(2',3',4',6'-tetrafluorobenzoyl)acrylate and this compound was then treated with cyclopropylamine to give 32.8 g of ethyl 3 -cyclopropylamino-2-(2',3',4',6'-tetrafluorobenzoyl)acrylate. m.p. 107°-108° C.
Reaction SMILES: BrC1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[CH3:9][C:10]([CH3:12])=[O:11].[CH2:13]1COCC1>>[CH3:8][C:5]1[CH:6]=[CH:7][C:9]([C:10]([OH:11])([CH3:13])[CH3:12])=[CH:3][CH:4]=1
Reactant: Cc1ccc(Br)cc1
Reactant: C1CCOC1
Reactant: CC(C)=O
Product: Cc1ccc(C(C)(C)O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a clean RB flask, fitted with reflux condenser Mg (3.5 g, 0.1462 mol) was taken and added THF (125 ml) followed by slow addition of 4-bromo toluene (25 g, 0.1462 mol) for about 1 hr. The reaction mixture was then stirred at room temperature for about 3 h. Then into this slowly added acetone (10.7 mL, 0.1462 mol) and stirred at room temperature for about 2 hrs. After completion of the reaction as indicated by TLC, reaction mixture was then cooled to 0° C. and quenched with Sat ammonium chloride solution (30 ml) and extracted with ethyl acetate. Combined organic layer was dried over Na2SO4 and conc. Under reduced pressure to get the crude product (8-hydroxy p-cymene, 18.2 g).
Reaction SMILES: [CH:1]1([CH2:6][C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH2:11]([O:15][C:16](=[O:20])[C@H:17]([CH3:19])[NH2:18])[CH:12]([CH3:14])[CH3:13]>>[CH2:11]([O:15][C:16](=[O:20])[C@H:17]([CH3:19])[NH:18][C:7](=[O:9])[CH2:6][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)[CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)COC(=O)[C@H](C)N
Reactant: O=C(O)CC1CCCC1
Agent: Cl
Product: CC(C)COC(=O)[C@H](C)NC(=O)CC1CCCC1

Procedure:
Following General Procedure BB above, and using cyclopentylacetic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example BB above), the title compound was prepared as a solid having a melting point of 62° C.-64° C. The reaction was monitored by tlc on silica gel (Rf=0.37 in 1:3 EtOAc:hexane) and purification was by extraction with Et2O followed by washes with aqueous K2CO3 and aqueous HCl.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH2:11][OH:12].C(N(CC)CC)C.O>ClCCl>[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH2:11][O:12][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: OCc1cccs1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1cccs1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methanesulphonyl chloride (6.2 mL, 0.0797 mol) is added dropwise to a solution of thiophene-2-methanol (7.0 g, 0.0613 mol) and triethyl amine (12.8 mL, 0.0920 mol) in dichloromethane (70 mL) at 0-5° C. The reaction mixture is allowed to stir at room temperature for 30 min. Demineralized water (25 mL) is added to the reaction mixture and the organic layer is separated. The aqueous layer is extracted with dichloromethane (1×25 mL). Combined organic layer is dried over anhydrous sodium sulfate. Removal of solvent under reduced pressure gives methanesulfonic acid thiophen-2-ylmethyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[C:7]([CH3:13])[C:6]([CH3:14])=[C:5]2[OH:15].[H-].[Na+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C)C=O>[CH2:18]([O:15][C:5]1[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=[C:2]([Br:1])[CH:3]=2)[N:8]=[C:7]([CH3:13])[C:6]=1[CH3:14])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: Cc1nc2c(C)cc(Br)cc2c(O)c1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2c(C)cc(Br)cc2c(OCc2ccccc2)c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
26.6 Grams of 6-bromo-4-hydroxy-2,3,8-trimethylquinoline synthesized in the same way as that described in Example 1 was suspended in 70 ml of dimethylformamide, to which 4.4 g of 60% sodium hydride was added under cooling with ice and then the mixture was stirred at room temperature for 30 minutes. 19 Grams of benzyl bromide was added dropwise to the reaction mixture under cooling with ice and the mixture was allowed to react at room temperature overnight. After 50 ml of water was added, the reaction mixture was extracted with ethyl acetate and the organic layer was washed with a saturated brine and dried over anhydrous sodium sulfate overnight. After the solvent was evaporated under reduced pressure, the resultant crude product was purified by column chromatography on silica gel (WAKOGEL® C-200) eluting with n-hexane/ethyl acetate (6:1) to obtain 24.3 g of 4-benzyloxy-6-bromo-2,3,8-trimethylquinoline.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12]([O-])([O-])=O.[K+].[K+].[OH-].[K+].Cl>CC(C)=O.CO.CI>[CH3:12][O:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1ccc(C(=O)O)c(O)c1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CC(C)=O
Solvent: CI
Product: COc1cc(C)ccc1C(=O)O
Temperature: 25 °C
Yield: 24462.6 %

Procedure:
To a solution of 2-hydroxy-4-methylbenzoic acid (25 g, 0.164 mol) in acetone (350 mL) was added K2CO3 (68 g, 0.492 mmol) followed by MeI (41 mL, 0.656 mmol) and the reaction mixture heated at reflux for 48 hrs. After cooling to r.t. the reaction mixture was filtered and the filtrate was evaporated to give the crude methyl 2-methoxy-4-methylbenzoate. KOH (11.3 g, 1.2 eq) was dissolved in MeOH (300 mL) and the crude ester was added to the mixture and the solution heated at reflux 48 hrs. After cooling the reaction mixture was acidified with aq. HCl (1N) and extracted with ethyl acteate. The organic layer was washed with brine, dried over MgSO4, filtered and evaporated. The residue was triturated with Ethyl acetate/Hexane to give 20 g of 2-methoxy-4-methylbenzoic acid as a cream white solid (85% yield)
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:43])[C:10]1[C:15]([OH:16])=[CH:14][CH:13]=[C:12]([C:17]2[C:18]([N:37]([CH3:42])[S:38]([CH3:41])(=[O:40])=[O:39])=[CH:19][C:20]3[O:24][C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)=[C:22]([C:32](=[O:35])[NH:33][CH3:34])[C:21]=3[CH:36]=2)[N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:44]([O-])([O-])=O.[Cs+].[Cs+].ClCI>CN(C=O)C>[CH2:1]([N:8]1[C:9](=[O:43])[C:10]2[N:11]=[C:12]([C:17]3[C:18]([N:37]([CH3:42])[S:38]([CH3:41])(=[O:40])=[O:39])=[CH:19][C:20]4[O:24][C:23]([C:25]5[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=5)=[C:22]([C:32]([NH:33][CH3:34])=[O:35])[C:21]=4[CH:36]=3)[CH:13]=[CH:14][C:15]=2[O:16][CH2:44]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(O)c(C(=O)NCc4ccccc4)n3)cc12
Reactant: O=C([O-])[O-]
Agent: ClCI
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)C(=O)N(Cc3ccccc3)CO4)cc12
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 19.1 %

Procedure:
To a solution of N-benzyl-6-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)-3-hydroxypicolinamide (100 mg, 0.17 mmol) and Cs2CO3 (117 mg, 0.33 mmol) in DMF (20 mL) was added chloroiodomethane (47 mg, 0.25 mmol) dropwise at 110° C. under N2. The mixture was stirred at 110° C. for 0.5 hour. Then the mixture was concentrated and extracted with EtOAc. The combined organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by prep-TLC (DCM:CH3OH=20:1) to afford the product of 5-(3-benzyl-4-oxo-3,4-dihydro-2H-pyrido[2,3-e][1,3]oxazin-6-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (20 mg, yield: 19.6%). 1H-NMR (CDCl3, 400 MHz) δ 7.88˜7.90 (m, 3H), 7.72˜7.74 (m, 1H), 7.55 (s, 1H), 7.34˜7.39 (m, 5H), 7.25˜7.28 (m, 1H), 7.14 (t, J=7.2 Hz, 2H), 6.87 (br s, 1H), 5.19 (s, 2H), 4.76 (s, 2H), 3.14 (s, 3H), 2.93˜2.94 (m, 6H). MS (M+H)+: 615.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1.[Li]CCCC.[CH3:23][C:24](N(C)C)=[O:25].Cl>O1CCCC1.CCCCCC.O>[Si:11]([O:10][CH2:9][CH2:8][C:4]1[CH:3]=[C:2]([C:24](=[O:25])[CH3:23])[CH:7]=[CH:6][CH:5]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)OCCc1cccc(Br)c1
Reactant: CC(=O)N(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(=O)c1cccc(CCO[Si](C)(C)C(C)(C)C)c1
Reaction time: 0.5 h

Procedure:
To a solution of 1.6 g of [2-(3-bromophenyl)ethoxy](tert-butyl)dimethylsilane in tetrahydrofuran (20 ml) was added n-BuLi in hexane (1.57M, 3.88 ml) at −70° C., then the reaction mixture was stirred at same temperature for 30 min. To the solution was added dimethylacetamide (1.42 ml) drop wise at the same temperature. The mixture was stirred for another 1 hour. To the reaction mixture were added water and 8 ml of 1N HCl under ice-cooling. The mixture was stirred for 1 hour, then extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography with n-hexane and ethyl acetate (20/1–10/1) as an eluent to give 1-[3-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)phenyl]ethanone (350 mg) as colorless oil.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:14]#[CH:15])=[CH:4][C:5]2[C:6]([CH3:13])([CH3:12])[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.Br[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1>>[CH3:1][C:2]1[C:3]([C:14]#[C:15][C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)=[CH:4][C:5]2[C:6]([CH3:12])([CH3:13])[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: C#Cc1cc2c(cc1C)CCCC2(C)C
Reactant: N#Cc1ccc(Br)cc1
Product: Cc1cc2c(cc1C#Cc1ccc(C#N)cc1)C(C)(C)CCC2

Procedure:
Using a process similar to that described in Example 1c, 4.4 g (22 millimoles) of (5,6,7,8-tetrahydro-3,8,8-trimethylnaphth-2-yl)-ethyne and 2.7 g (15 millimoles) of 4-bromobenzonitrile were converted to the title compound. 1.3 g (29%) of product of melting point 128°-130° C. were obtained after recrystallization from ethanol.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C:14](=[CH:15][C:16](=[O:24])[CH2:17][CH2:18]1)[N:13]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:12]3)([O:3]C)=[O:2].O.O[Li].O.OS([O-])(=O)=O.[Na+]>O1CCOCC1>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C:14](=[CH:15][C:16](=[O:24])[CH2:17][CH2:18]1)[N:13]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:12]3)([OH:3])=[O:2]
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CN(C(=O)OC(C)(C)C)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=S(=O)([O-])O
Agent: [Li]O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@H]2[C@@H]3CC[C@H](C(=O)O)[C@@]3(C)CC[C@@H]2[C@@]2(C)CCC(=O)C=C12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 17β-carbomethoxy-6-t-butoxycarbonyl-6-azaandrost-4-en-3-one (15.4 g, 36 mmol), from part E, in dioxane (150 mL) and water (100 mL) is treated with LiOH.H2O (3.31 g, 79 mmol) and stirred overnight in a water bath. The reaction is poured into saturated aqueous NaHSO4 (150 mL), extracted with methylene chloride (3×100 mL), extracts washed with saturated aqueous NaCl, dried over MgSO4 and concentrated to a volume of 100 mL. At this point crystals begin to form and 2:1 hexanes/ethyl acetate (50 mL) is added, the mixture triturated, cooled to room temperature and 17β-carboxy-6-t-butoxycarbonyl-6-azaandrost-4-en-3-one collected as a fluffy white powder; yield: 9.44 g (63%); m.p. 215°-216° C. Anal. Calcd. for C24H35NO5.1/4H2O; C, 68.30; H, 8.48; N, 3.32. Found: C, 68.45; H, 8.41; N, 3.28.
Reaction SMILES: C(Cl)CCl.[CH2:5]([O:12][N:13]1[C:19](=[O:20])[N:18]2[CH2:21][C@H:14]1[CH2:15][CH2:16][C@H:17]2[C:22]([OH:24])=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C1C=CC2N(O)N=NC=2C=1.O[NH:36][C:37](=[NH:43])[C:38]([O:40][CH2:41][CH3:42])=[O:39]>CN(C=O)C>[CH2:5]([O:12][N:13]1[C:19](=[O:20])[N:18]2[CH2:21][C@H:14]1[CH2:15][CH2:16][C@H:17]2[C:22]1[O:24][N:43]=[C:37]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[N:36]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CCOC(=O)C(=N)NO
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1noc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.6 %

Procedure:
EDC (0.916 g, 4.78 mmol) was added to a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (1.2 g, 4.34 mmol) and HOBt (0.732 g, 4.78 mmol) in DMF (12 mL) at rt. The mixture was stirred at rt for 0.5 h, then ethyl 2-(hydroxyamino)-2-iminoacetate (0.689 g, 5.21 mmol) was added and the mixture was stirred for another 0.5 h at rt. The reaction mixture was then heated to 100° C. under microwave for 80 minutes. The solvent was removed under vacuum and the residue was purified by silica gel column chromatography (0 to 5% MeOH/DCM) to afford ethyl 5-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octan-2-yl)-1,2,4-oxadiazole-3-carboxylate (0.85 g, 53%). ESI-MS (EI+, m/z): 373.4.