Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]([CH3:14])[CH:11]2[O:15][C:16]([CH3:19])([CH3:18])[O:17][CH:10]2[CH2:9]1)[C:2]1C=CC=C[CH:3]=1.C1[O:23][C@@H]1C.C(N(CC)CC)C>C(O)C>[CH3:18][C:16]1([CH3:19])[O:17][CH:10]2[CH2:9][N:8]([CH2:1][CH:2]([OH:23])[CH3:3])[CH2:13][CH:12]([CH3:14])[CH:11]2[O:15]1
Reactant: CC1CN(Cc2ccccc2)CC2OC(C)(C)OC12
Reactant: C[C@@H]1CO1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(O)CN1CC(C)C2OC(C)(C)OC2C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
40 (175 mg, 1 mmol), (R)-(+)-propylenoxide (297 mg, 5.1 mmol), and triethylamine (285 ul, 2 mmol) are dissolved in 3 ml of ethanol and stirred at room temperature for 5 h. After evaporation the residue is dissolved in ethyl acetate, washed subsequently with 1N NaOH and brine, dried over sodium sulphate and evaporated. The crude product, 214 mg of a yellow oil, is purified by Flash-chromatography (silica gel, dichloromethane/methanol/ammonia 95:5:0.5).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[K+].[C:6](OO)(C)(C)[CH3:7].[CH3:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]C=C>C(O)(=O)C>[CH2:12]([CH:2]1[CH2:7][CH2:6][O:4][C:1]1=[O:3])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: C=CCCCCCC
Reactant: CC(=O)[O-]
Reactant: CC(C)(C)OO
Agent: [K+]
Solvent: CC(=O)O
Product: CCCCCCC1CCOC1=O
Temperature: 115 °C
Yield: 65 %

Procedure:
A stock solution was prepared by heating at 115° C. 500 milliliters of acetic acid, 150 grams of potassium acetate, and 245 grams of manganous acetate tetrahydrate, Mn(OCOCH3)2.4H2O. A 50-milliliter aliquot of the stock solution was added to 2 milliliters of a 0.312 molar solution of tertiary butyl hydroperoxide in acetic acid. The solution also contained 400 microliters of octene-1. After heating, a hexyl gamma-butyrolactone was obtained with a 65% yield based on the tertiary butyl hydroperoxide.
Reaction SMILES: O[C:2]1[C:3]2[N:4]([C:12]([C:15]([F:18])([F:17])[F:16])=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.P(Cl)(Cl)([Cl:21])=O.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:21][C:2]1[C:3]2[N:4]([C:12]([C:15]([F:18])([F:17])[F:16])=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Oc1nc2ccccc2n2c(C(F)(F)F)nnc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: FC(F)(F)c1nnc2c(Cl)nc3ccccc3n12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
In a flame-dried reaction flask under a dry nitrogen atmosphere, there were placed 3.0 g. (0.0118 mole) of 4-hydroxy-1-trifluoromethyl-[1,2,4]triazolo[4,3-a]quinoxaline and 30 ml. of phosphorous oxychloride in 2.38 g. (0.0236 mole) of triethylamine (3.3 ml.). The reaction mixture was then heated at 100° C. for a period of approximately 16 hours (i.e., overnight). Upon completion of this step, the spent mixture was cooled to room temperature, concentrated in vacuo and then partitioned between ice, water and ethanol, followed by extraction with ethyl acetate. The latter extract was next washed with saturated brine and dried over anhydrous magnesium sulfate. After removal of the drying agent by means of filtration and the solvent by means of evaporation under reduced pressure, there was obtained a residue which was subsequently dissolved in hot chloroform and filtered. The latter filtrate was then allowed to stand overnight at room temperature and filtered again. The final filtrate was then concentrated in vacuo to ultimately afford 1.4 g. of 4-chloro-1-trifluoromethyl-[1,2,4]triazolo[4,3-a]quinoxaline in the form of a brownish-colored solid.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[O:5][CH:6]=[CH:7][C:8]=1[C:9]([O:11][CH3:12])=[O:10].S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCOCC1>[Br:1][C:6]1[O:5][C:4]([CH3:3])=[C:8]([C:9]([O:11][CH3:12])=[O:10])[CH:7]=1
Reactant: BrBr
Reactant: COC(=O)c1ccoc1C
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1cc(Br)oc1C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Bromine (2.0 ml) was added drop-wise to a mixture of methyl 2-methyl-3-furancarboxylate (5.0 g) in 1,4-dioxane (35 ml) stirred at 0° C. Stirring was continued at 0° C. for 2 hours and then at ambient temperature for 18 hours. Saturated aqueous sodium thiosulfate was added to the reaction mixture which was then extracted with ethyl acetate. The organic layer was dried with brine and over magnesium sulfate. The product isolated after evaporation of the solvent was further purified by flash column chromatography using cyclohexane:ethyl acetate (19:1) as eluent to give the title compound as a yellow oil.
Reaction SMILES: [NH2:1][CH:2]1[C:21](=[O:22])[N:4]2[C:5]([C:18]([OH:20])=[O:19])=[C:6]([CH2:9][S:10][C:11]3[S:12][C:13]([CH2:16][OH:17])=[N:14][N:15]=3)[CH2:7][S:8][C@H:3]12.[C:23](=O)(O)[O-].[Na+].C[S:29][CH2:30][C:31](O)=O>O.CC(C)=O.S(Cl)(Cl)=O>[CH3:23][CH2:31][C:30]([NH:1][CH:2]1[C:21](=[O:22])[N:4]2[C:5]([C:18]([OH:20])=[O:19])=[C:6]([CH2:9][S:10][C:11]3[S:12][C:13]([CH2:16][OH:17])=[N:14][N:15]=3)[CH2:7][S:8][C@H:3]12)=[S:29]
Reactant: O=C([O-])O
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(CO)s3)CS[C@H]12
Reactant: CSCC(=O)O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: O=S(Cl)Cl
Product: CCC(=S)NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(CO)s3)CS[C@H]12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
7-Amino-3-(5-hydroxymethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (1.8 g.) was dissolved in a mixture of water (40 ml.), acetone (40 ml.) and sodium bicarbonate (1.26 g.). On the other hand, 2-(methylthio)acetic acid (1.06 g.) was dissolved in a solution (5 ml.) of thionyl chloride. The solution was stirred at room temperature for 30 minutes, and then at 40°-50° C for 5 minutes. The excess of thionyl chloride was distilled off under reduced pressure. Thus obtained 2-(methylthio) acetyl chloride was dissolved in dried acetone (5 ml.). The acetone solution was added dropwise to the solution obtained above at 0°-5° C for 15 minutes. The mixture was stirred at the same temperature for an hour, and then at room temperature for an hour. From the reaction mixture, the acetone was distilled off under reduced pressure. The residue was washed with ethyl acetate, and then ethyl acetate (200 ml.) was added to the residue. The solution was adjusted to pH 1.5 with 10% hydrochloric acid, and the ethyl acetate layer was separated out. The remaining aqueous layer was extracted with ethyl acetate (100 ml.) four times. The ethyl acetate extracts were put together, washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate, and then the solvent was evaporated under reduced pressure to give 7-methylthio acetamido-3-(5-hydroxymethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (1.91 g.) m.p. 134°-139° C (dec.).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[C:8]([CH3:11])([CH3:10])[CH3:9].[F:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[C:16]([NH:18][NH2:19])=O.Cl.C(N(CC)CC)C>O1CCOCC1>[Cl:1][C:2]1[C:7]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:6][C:5]2[N:4]([C:16]([C:15]3[CH:20]=[CH:21][CH:22]=[CH:23][C:14]=3[F:13])=[N:18][N:19]=2)[N:3]=1
Reactant: NNC(=O)c1ccccc1F
Reactant: CC(C)(C)c1cc(Cl)nnc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)(C)c1cc2nnc(-c3ccccc3F)n2nc1Cl
Yield: 43.8 %

Procedure:
A mixture of 3,6-dichloro-4-(1,1-dimethylethyl)pyridazine (20 g, 0.097 mol), 2-fluorobenzhydrazide (22.6 g, 0.145 mol) and triethylamine hydrochloride (20 g, 0.0145 mol) in dioxan (1.2 l) was stirred and heated at reflux under a stream of nitrogen for 4 days. Upon cooling the volatiles were removed in vacuo and the residue was triturated with dichloromethane (200 ml), filtered and concentrated under vacuum. The residue was purified by chromatography on silica gel eluting with 0%→25% ethyl acetate/dichloromethane to give the title compound (12.95 g. 44%) as a white solid. Data for the title compound: 1H NMR (360 MHz, CDCl3) δ1.57 (9H, s), 7.26-7.35 (2H, m), 7.53-7.60 (1H, m), 7.89-7.93 (1H, m), 8.17 (1H, s); MS (ES+) m/e 305 [MH]+, 307 [MH]+.
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[C:9]([CH:15]=O)[C:10](=[O:14])[O:11]2)=[CH:6][CH:5]=1)[CH3:2].[C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N+:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[C:29]([S:34]([O-:37])(=[O:36])=[O:35])[CH:28]=1)([OH:21])=[O:20].[CH3:38][N+:39]([CH2:42][C:43]([OH:45])=[O:44])([CH3:41])[CH3:40]>CO.O>[C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N+:27]1[CH:32]=[CH:31][C:30](/[CH:33]=[CH:15]/[C:9]2[C:10](=[O:14])[O:11][C:12]3[C:7]([CH:8]=2)=[CH:6][CH:5]=[C:4]([N:3]([CH2:17][CH3:18])[CH2:1][CH3:2])[CH:13]=3)=[C:29]([S:34]([O-:37])(=[O:36])=[O:35])[CH:28]=1)([OH:21])=[O:20].[CH3:38][N+:39]([CH2:42][C:43]([OH:45])=[O:44])([CH3:41])[CH3:40]
Reactant: CCN(CC)c1ccc2cc(C=O)c(=O)oc2c1
Reactant: Cc1cc[n+](CCCCCC(=O)O)cc1S(=O)(=O)[O-]
Agent: C[N+](C)(C)CC(=O)O
Solvent: CO
Solvent: O
Product: CCN(CC)c1ccc2cc(/C=C/c3cc[n+](CCCCCC(=O)O)cc3S(=O)(=O)[O-])c(=O)oc2c1

Procedure:
0.2 mmol 7-diethylamino-2-oxo-2H-chromene-3-carbaldehyde and 0.2 mmol 1-(5-carboxy-pentyl)-3-sulfonato-4-methyl-pyridinium betaine are converted according to the general directions above. Column chromatography: SiO2 (RP18), eluent: methanol/water.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[S:12](Cl)(=[O:14])=[O:13].[NH2:16][CH2:17][CH:18]1[CH2:22][CH2:21][CH2:20][N:19]1[CH2:23][CH3:24].C(N(CC)CC)C>>[CH2:23]([N:19]1[CH2:20][CH2:21][CH2:22][CH:18]1[CH2:17][NH:16][S:12]([C:3]1[C:4]([Cl:11])=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[Cl:1])(=[O:14])=[O:13])[CH3:24]
Reactant: CCN1CCCC1CN
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1Cl
Solvent: CCN(CC)CC
Product: CCN1CCCC1CNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1Cl

Procedure:
Following the general procedure for sulfonamide formation outlined in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (2.0 g, 6.88 mmol), 2-aminomethyl- 1-ethyl-pyrolidine (882 mg, 6.88 mmol) and triethylamine(1.92 mL, 13.76 mmol) were reacted. The crude product (2.64 g) was carried on to the next step without purification. LC-MS (m/z) 382.0 (M+).
Reaction SMILES: [CH:1]([C:3]1[S:4][C:5]([CH3:8])=[CH:6][CH:7]=1)=[O:2].[CH:9]([O-])([O-])[O:10]C.[C:14]1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH3:14][O:2][CH:1]([O:10][CH3:9])[C:3]1[S:4][C:5]([CH3:8])=[CH:6][CH:7]=1
Reactant: Cc1ccc(C=O)s1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COC([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(OC)c1ccc(C)s1
Yield: 78.5 %

Procedure:
A mixture of 2-formyl-5-methylthiophene (12.6 g, 0.1 mol), methyl orthoformate (31.8 g) and a catalytic amount of p-toluene-sulfonic acid in toluene (120 ml) was refluxed for 6 hours. To the cooled reaction mixture was added ethyl acetate and washed with water twice. The organic layer was dried over magnesium sulfate. Removal of the solvent gave a brownish oil, which was purified by distillation under reduced pressure to afford 2-dimethoxymethyl-5-methylthiophene (13.54 g, 78.5% yield) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[N:8]=[CH:7][NH:6][C:5]2=[O:13].OS(O)(=O)=O.[N+:19]([O-])([OH:21])=[O:20]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N+:19]([O-:21])=[O:20])[C:11]=1[CH3:12])[N:8]=[CH:7][NH:6][C:5]2=[O:13]
Reactant: Cc1cc2nc[nH]c(=O)c2cc1Br
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1c(Br)cc2c(=O)[nH]cnc2c1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
6-Bromo-7-methylquinazolin-4(3H)-one (1.0 g, 4.2 mmol) was added to H2SO4 (98%, 15 mL) and the mixture was stirred at it until dissolution was complete. The mixture was cooled to 0° C. and then nitric acid (fuming) (0.26 g, 4.2 mmol) was added dropwise at 0° C. and stirred for 10 min, and then stirred at it for 5 h. The mixture was poured onto ice (300 g) and extracted with EtOAc (3×80 mL). The combined organic layers were washed with brine (100 mL), dried over MgSO4 and concentrated in vacuo. The product was recrystallized from MeOH (˜15 mL). MS (ESI, pos. ion) m/z: 284 [M+H]+
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[Cl:13][CH2:14][CH2:15][CH2:16][CH:17](P(OCC)(OCC)=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19].[OH-].[Li+].O>O1CCCC1.C(O)C>[Cl:13][CH2:14][CH2:15][CH2:16][C:17](=[CH:5][C:4]1[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=1[C:2]([F:12])([F:11])[F:1])[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)C(CCCCl)P(=O)(OCC)OCC
Reactant: O=Cc1ccccc1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(=Cc1ccccc1C(F)(F)F)CCCCl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(Trifluoromethyl)benzaldehyde (1 g) and ethyl 5-chloro-2-(diethoxyphosphoryl)pentanoate (CAS No. 870843-20-2, 2.1 g) were dissolved in a mixed solvent of tetrahydrofuran (30 mL) and ethanol (10 mL). Lithium hydroxide (412 mg) was added and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resulting organic layer was washed with brine and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration, and then the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain a geometric isomer mixture of the title compound (1.4 g).
Reaction SMILES: C(=O)(O)[O-].[Na+].[CH2:6]([O:13][C:14]1[CH:23]=[C:22]([CH:24]2[CH2:27][CH2:26][CH2:25]2)[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Br:28]Br>ClCCl>[CH2:6]([O:13][C:14]1[CH:23]=[C:22]([CH:24]2[CH2:27][CH2:26][CH2:25]2)[C:21]([Br:28])=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COC(=O)c1ccc(C2CCC2)cc1OCc1ccccc1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1cc(Br)c(C2CCC2)cc1OCc1ccccc1
Temperature: 10 °C
Reaction time: 1 h

Procedure:
Sodium bicarbonate (7.51 g) was added to a mixture of methyl 2-(benzyloxy)-4-cyclobutylbenzoate (14 g) and dichloromethane, then a dichloromethane (25 mL) solution of bromine (3.17 mL) was slowly added thereto at 10° C., and the mixture was stirred at the same temperature as above for 1 hour. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bisulfite and saturated saline and then dried over anhydrous sodium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (12.2 g).
Reaction SMILES: [CH:1]([O:4][CH:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@H:7]([CH2:22]SC(C)C)[CH2:6]1)([CH3:3])[CH3:2].O[O:28][S:29]([O-:31])=O.[K+].CCOC(C)=O.[CH3:39][CH:40](O)[CH3:41]>O>[CH:1]([O:4][CH:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@H:7]([CH2:22][S:29]([CH:40]([CH3:41])[CH3:39])(=[O:31])=[O:28])[CH2:6]1)([CH3:3])[CH3:2]
Reactant: CC(C)OC1CC[C@H](NC(=O)OCc2ccccc2)[C@H](CSC(C)C)C1
Reactant: O=S([O-])OO
Reactant: CC(C)O
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)OC1CC[C@H](NC(=O)OCc2ccccc2)[C@H](CS(=O)(=O)C(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A sample of benzyl (1S,2R)-4-isopropoxy-2-(isopropylthiomethyl)cyclohexylcarbamate (27.59 mMol) was dissolved in iPrOH (200 mL) prior to the addition of Oxone® (33.92 g, 55.18 mMol) as a solution in 300 mL of water. The reaction was stirred at rt overnight. Partitoned between EtOAc and water. Aqueous layer was re-extracted with EtOAc and combined organic layer was washed with brine and dried (MgSO4). Filtered, concentrated and flash chromatographed to yield benzyl (1S,2R)-4-isopropoxy-2-(isopropylsulfonylmethyl)cyclohexylcarbamate as a clear oil (7.73 g, 68% over steps 5 and 6). MS found: (M+H)+=412.35.
Reaction SMILES: [O:1]([CH2:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][Si](C=[N+]=[N-])(C)C.[BrH:19]>CC#N.CCCCCC.C(O)(=O)C>[Br:19][CH2:12][C:9](=[O:10])[CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)COc1ccccc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Br
Solvent: CCCCCC
Solvent: CC(=O)O
Solvent: CC#N
Product: O=C(CBr)COc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6.c (0.050 mmol) of phenoxyacetyl chloride in 250 μL of anhyd MeCN in a 1-dram short vial (Wheaton Glass) was added 50 μL (0.100 mmol) of a 2 M solution of trimethylsilyldiazomethane in hexane and the vial capped with a PTFE-lined cap. After stirring 1 h at room temperature on a vortex shaker, the mixture was cooled (0° C.) and 21 μL (0.105 mmol) of 30 wt % HBr in acetic acid was added dropwise (gas evolution). After vortexing for 10 min, the mixture was concentrated in vacuo on a vacuum centrifuge concentrator (Speed-Vac, Savant Instruments, Inc.) to provide an amber-colored oil which was used directly in the following step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3([O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1.[CH3:31]OC(=O)CC1C=CC(I)=CC=1>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3([O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:20][CH2:21]3)=[C:15]([CH3:31])[CH:14]=2)=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(I)cc1
Reactant: COC(=O)Cc1ccc(C#Cc2ccc(C3(OCc4ccccc4)CC3)cc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(C#Cc2ccc(C3(OCc4ccccc4)CC3)c(C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.5 %

Procedure:
Using General Procedure F; 1-ethynyl-4-(1-benzyloxycyclopropyl)-3-methyl-benzene (Intermediate 76, 90.0 mg, 0.34 mmol) and methyl-(4-iodophenyl)-acetate (Reagent B, 95.0 mg, 0.34 mmol) in triethylamine (5 mL) was treated with copper(I)iodide (22.0 mg, 0.11 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (80 mg, 0.11 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-4% EtOAc—hexanes) afforded 90.0 mg (71%) of the title compound as a pale-yellow oil.
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:5]=[CH:6][C:7]2[C@@:13]3([CH3:19])[N:14]=[C:15]([NH2:18])[S:16][CH2:17][C@H:12]3[CH2:11][O:10][C:8]=2[CH:9]=1.[OH-].[Na+].O.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[Br:1][C:5]1[C:4]([F:3])=[CH:9][C:8]2[O:10][CH2:11][C@@H:12]3[CH2:17][S:16][C:15]([NH2:18])=[N:14][C@:13]3([CH3:19])[C:7]=2[CH:6]=1
Reactant: BrBr
Reactant: C[C@]12N=C(N)SC[C@H]1COc1cc(F)ccc12
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: C[C@]12N=C(N)SC[C@H]1COc1cc(F)c(Br)cc12
Reaction time: 0.5 h
Yield: 63.5 %

Procedure:
Bromine (0.20 mL, 3.80 mmol) was added dropwise to a solution of rel-(4aR,10bS)-8-fluoro-10b-methyl-4,4a,5,10b-tetrahydrochromeno[4,3-d][1,3]thiazin-2-amine from step F6 (644 mg, 2.55 mmol), in acetic acid (20 mL) at rt. The mixture was stirred for 30 min. The reaction was poured onto ice. The slurry was made pH 3 upon slow addition of 50% NaOH/water. The aqueous mixture was made basic pH 7-8 by the addition of solid sodium bicarbonate. The aqueous layers were extracted with EtOAc. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified using silica gel column chromatography (0.25%-10% MeOH/CHCl3) to afford rel-(4aR,10bS)-9-bromo-8-fluoro-10b-methyl-4,4a,5,10b-tetrahydrochromeno[4,3-d][1,3]thiazin-2-amine (667 mg, 1.62 mmol, 64% yield) as a viscous oil. LCMS (M+H)+=333.02. 1H NMR (500 MHz, methanol-d4) δ 7.73 (d, J=7.5 Hz, 1H), 6.79 (d, J=9.8 Hz, 1H), 4.53 (dd, J=11.9, 2.9 Hz, 1H), 4.30 (dd, J=12.0, 6.0 Hz, 1H), 3.50 (dd, J=13.7, 3.9 Hz, 1H), 3.23 (dd, J=13.6, 8.1 Hz, 1H), 2.64 (dtd, J=10.0, 3.9, 3.0 Hz, 1H), 1.80 (s, 3H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[NH:13][N:12]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[N:10]=1)[CH3:2].[H-].[Na+].[H][H].[CH2:26]([O:28][C:29](Cl)=[O:30])[CH3:27]>O1CCCC1.C(OCC)C>[C:29]([N:13]1[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH2:1][CH3:2])=[N:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)=[N:12]1)([O:28][CH2:26][CH3:27])=[O:30]
Reactant: CCc1ccccc1-c1nc(-c2cccc(OC)c2)n[nH]1
Reactant: [H][H]
Reactant: CCOC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)n1nc(-c2cccc(OC)c2)nc1-c1ccccc1CC
Reaction time: 8 h

Procedure:
To a solution of 5.58 g (0.02 mole) of 5-(2-ethylphenyl)-3-(3-methoxyphenyl)-1H-1,2,4-triazole in 50 ml of anhydrous tetrahydrofuran, 0.66 g (0.02 mole) of an 80% oily suspension of sodium hydride were added. After the hydrogen development had ceased, a solution of 2 ml. (0.02 mole) of ethylchlorocarbonate in 20 ml of anhydrous tetrahydrofuran was added dropwise under stirring and the temperature was kept at 15°-20° C. Stirring was continued for 2,5 hours then, after adding 200 ml of anhydrous diethyl ether, the reaction mixture was filtered under vacuum and the filtrate brought to pH 3 by means of hydrogen chloride. The little amount of unreacted starting triazole which precipitated as the hydrochloride was filtered under vacuum, the filtrate was added with solid sodium bicarbonate and the resulting mixture stirred five minutes. After filtering the inorganic salts, the solution was concentrated to about 30 ml and kept overnight at about -10° C. 3.65 Grams of the compound of the title were obtained. M.p. 80°-82° C. Δ δ=-0.30.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:19])(O)[CH3:17])[C:10]=2[C:9]2[N:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.S(Cl)([Cl:26])=O>C(Cl)Cl.C(O)C>[ClH:26].[CH2:22]([O:21][CH2:20][C:13]1[N:14]2[C:10]3[C:9]4[N:8]([C:16]([CH3:19])([CH3:17])[CH2:15]2)[CH2:7][CH2:6][CH2:5][C:4]=4[N:3]=[C:2]([NH2:1])[C:11]=3[N:12]=1)[CH3:23]
Reactant: CCOCc1nc2c(N)nc3cccnc3c2n1CC(C)(C)O
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCO
Product: CCOCc1nc2c(N)nc3c4c2n1CC(C)(C)N4CCC3
Product: Cl
Reaction time: 0.5 h

Procedure:
A solution of 1-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-2-methylpropan-2-ol (500 mg, 1.59 mmol) dissolved in 15 mL of anhydrous CH2Cl2 was treated with thionyl chloride (232 mL, 3.18 mmol). After 30 minutes, the reaction mixture was concentrated under reduced pressure. The resulting material was concentrated from ethanol and then dissolved in 15 mL of TFA. The mixture was placed in pressure flask and treated with 250 mg of PtO2. The mixture was then shaken under H2 at 50 PSI (3.4×105 Pa) for 3 hours. The reaction mixture was filtered through a pad of CELITE filter agent. The pad was rinsed with CH2Cl2 and 2-propanol and the combined filtrates were concentrated under reduced pressure to give a syrup. The syrup was dissolved in 50 mL of hot ethanol and crystals formed upon cooling. The crystals were isolated by filtration and were then partitioned between dilute NH4OH solution (25 mL) and CH2Cl2 (25 mL). The organic portion was washed with additional dilute NH4OH solution (2×), H2O and brine. The organic portion was concentrated to give a syrup. Crystallization from HCl in ethanol gave the title compound as a yellow powder, m.p. 222-227° C. 1H NMR (300 MHz, DMSO-d6) δ 7.87 (s, 2H), 4.74 (s, 2H), 4.18 (s, 2H), 3.50 (q, J=7.0 Hz, 2H), 3.06 (t, J=5.1 Hz, 2H), 2.71 (t, J=6.2 Hz, 2H), 2.08 (m, 2H), 1.17 (s, 6H), 1.14 (t, J=7.0 Hz, 3H); 13C NMR (125 MHz, DMSO-d6) δ 150.5, 143.9, 132.8, 121.3, 119.5, 119.3, 65.4, 63.7, 54.5, 54.4, 22.1, 20.9, 20.7, 14.8; MS (ESI) m/z 302 (M+H)30; Anal. calcd for C16H23N5O.HCl: C, 56.88; H, 7.16; N, 20.73; Cl, 10.51. Found: C, 56.61; H, 8.09; N, 20.51; Cl, 10.88.