Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]([CH:22]([CH3:24])[CH3:23])=[CH:6][CH:7]=[C:8]([CH3:21])[CH2:9][CH2:10][CH:11]=[C:12]([CH3:20])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:19])[CH2:17]O)[CH3:2].CC1C=C(C)N=C(C)C=1.[Cl-].[Li+].CS([Cl:41])(=O)=O>C(OCC)C.O.CN(C)C=O>[CH2:1]([O:3][C:4](=[O:25])[C:5]([CH:22]([CH3:24])[CH3:23])=[CH:6][CH:7]=[C:8]([CH3:21])[CH2:9][CH2:10][CH:11]=[C:12]([CH3:20])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:19])[CH2:17][Cl:41])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C(=CC=C(C)CCC=C(C)CCC=C(C)CO)C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: Cc1cc(C)nc(C)c1
Product: CCOC(=O)C(=CC=C(C)CCC=C(C)CCC=C(C)CCl)C(C)C
Reaction time: 5 h
Yield: 88 %

Procedure:
To a mixture of the hydroxyester compound which is 14-hydroxy-2-(1-methylethyl)-5,9,13-trimethyl-2,4,8,12-tetradecatetraenoic acid ethyl ester (71.0 mg, 0.20 mmol), S-collidine (26.7 mg, 0.22 mmol), lithium chloride (8.5 mg, 0.20 mmol) and dimethylformamide (1 ml) is added methanesulfonyl chloride (25.2 mg, 0.22 mmol) under nitrogen atmosphere while stirring on an ice-bath. The stirring is continued at the same temperature for 5 hours. After confirming disappearance of the starting compound, to the reaction mixture are added water and ethyl ether and the organic layer is separated. The organic layer is washed with water, dried (MgSO4) and concentrated. The resulting residue is chromatographed (n-hexane/ethyl acetate =10:1) on silica gel column to give the desired 14-chloro-2-(1-methylethyl)-5,9,13-trimethyl-2,4,8,12-tetradecatetraenoic acid ethyl ester (64.6 mg, 86%) from the desired fraction.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])[CH:6]=[CH:7][CH:8]=1.Br.CCOC(C)=O>CC(O)=O>[OH:2][C:3]1[CH:4]=[C:5]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C(=O)c2ccccc2)c1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(c1ccccc1)c1cccc(O)c1
Temperature: 90 °C
Reaction time: 18 h
Yield: 90.2 %

Procedure:
1458 g (6.9 mol) of (3-methoxyphenyl)(phenyl)methanone was dissolved in 2090 mL of AcOH. To the solution, 2320 ml (20.6 mol) of 48% HBr was added and the mixture was stirred at 90° C. for 18 hours. The reaction was monitored by TLC (AcOEt:hex 1:9). After reaction was completed the mixture was cooled down to RT and poured into ice with stirring. The precipitated solid was filtered, washed with water and dried yielding the title compound as a white solid (1234 g, 91%).
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][CH:6]1[C:14]2[CH:13]=[CH:12][S:11][C:10]=2[CH2:9][CH2:8][CH:7]1[CH2:15]C)=[O:4].CNC(NC1C2C=CSC=2CCC1CCC)=O.CNC(NC1C2C=CSC=2CCC1CCCC)=O>>[CH3:1][NH:2][C:3]([NH:5][CH:6]1[C:14]2[CH:13]=[CH:12][S:11][C:10]=2[CH2:9][CH2:8][CH:7]1[CH3:15])=[O:4]
Reactant: CCC1CCc2sccc2C1NC(=O)NC
Agent: CCCC1CCc2sccc2C1NC(=O)NC
Agent: CCCCC1CCc2sccc2C1NC(=O)NC
Product: CNC(=O)NC1c2ccsc2CCC1C

Procedure:
Similarly, alkylation of 4,5,6,7-tetrahydrobenzo[b]thiophen-4-one with ethyl iodide, propyl iodide, and butyl iodide affords the corresponding 5-alkyl ketones, which are converted in the above manner to 1-methyl-3-(5-ethyl-4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea, 1-methyl-3-(5-propyl-4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea, and 1-methyl-3-(5-butyl-4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea, respectively.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11]C)[CH:8]=[CH:7][C:5]=2[N:6]=1.B(Br)(Br)Br.O>ClCCl>[Br:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: COc1ccc2nc(Br)sc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Oc1ccc2nc(Br)sc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2-bromo-6-methoxybenzothiazole (0.67 g) in dry dichloromethane (30 ml) at ambient temperature under an atmosphere of nitrogen was added dropwise a solution of boron tribromide in dichloromethane (5.5 ml, 1M). The mixture was stirred for 2 hours at ambient temperature, stored for 2 days then poured into water. The organic phase was separated, washed with water, dried over magnesium sulphate then evaporated under reduced pressure to give 2-bromo-6-hydroxybenzothiazole as a pale pink solid, 0.60 g, m.p. 203-204° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([F:16])[CH:15]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.Cl[CH2:18][CH2:19][NH:20][C:21](=[O:25])[O:22][CH2:23][CH3:24].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([F:16])[CH:15]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:18][CH2:19][NH:20][C:21](=[O:25])[O:22][CH2:23][CH3:24])=[CH:10][CH:11]=1
Reactant: CCOC(=O)NCCCl
Reactant: Oc1ccc(Oc2cc(F)cc(F)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)NCCOc1ccc(Oc2cc(F)cc(F)c2)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 79.7 %

Procedure:
A mixture of 4-(3,5-difluorophenoxy)phenol (0.50 g), ethyl N-2-chloroethylcarbamate (0.375 g), potassium carbonate (0.621 g) and anhydrous dimethylformamide (10 ml) was stirred at 100° C. for 3 hours, followed by cooling to room temperature. Ice-water (50 ml) was poured to the resultant mixture, which was extracted with toluene (50 ml). The toluene extract was washed with water and dried over anhydrous sodium sulfate. The toluene extract was concentrated under reduced pressure to give an oily residue. The residue was purified by silica gel column chromatography to give 0.605 g of ethyl N-2-[4-(3,5-difluorophenoxy)phenoxy]ethylcarbamate as a colorless liquid. nD25.5 1.5305.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[C:6]([CH3:16])(OCC)(OCC)[O:7][CH2:8][CH3:9]>CC(O)=O>[CH2:6]([O:7][C:8](=[C:2]([C:1]#[N:5])[C:3]#[N:4])[CH3:9])[CH3:16]
Reactant: CCOC(C)(OCC)OCC
Reactant: N#CCC#N
Solvent: CC(=O)O
Product: CCOC(C)=C(C#N)C#N
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 86 %

Procedure:
A mixture of malononitrile (5.0 g, 76 mmol), (EtO)3CCH3 (14.8 g, 91 mmol) and CH3COOH (1 mL) was stirred at 80° C. for 45 min. Then the mixture was cooled to room temperature and filtered to give 2-(1-ethoxy-ethylidene)-malononitrile (8.9 g, yield 86%) as a yellow solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=[CH:10]2)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+].[OH:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>COCCOC.C(OCC)(=O)C.O>[OH:29][C:30]1[CH:35]=[CH:34][C:33]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=[CH:10]3)=[CH:32][CH:31]=1
Reactant: OB(O)c1ccc(O)cc1
Reactant: COC(=O)c1cccc2cc(OS(=O)(=O)C(F)(F)F)ccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1cccc2cc(-c3ccc(O)cc3)ccc12
Temperature: 25 °C
Yield: 88.3 %

Procedure:
A solution of methyl 6-{[(trifluoromethyl)sulfonyl]oxy}-1-naphthoate (271 g, 0.81 mol) (from multiple batches), tetrakis(triphenylphospine)palladium (0) (37.4 g, 0.032 mol), 2 M sodium carbonate solution (1.3 L) and 4-hydroxyphenyl boronic acid (134 g, 0.97 mol) in ethylene glycol dimethyl ether (1.5 L) was heated at 80° C. for 1.5 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (2 L) and water (2 L). The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered and concentrated to a dark semisolid residue. The crude material was purified by crystallization from dichloromethane-heptane to give 199 g of the product as a tan solid.
Reaction SMILES: Cl.[NH2:2][OH:3].C[O-].[Na+].[Cl:7][C:8]1[CH:9]=[C:10]([OH:18])[C:11](=[CH:16][CH:17]=1)[C:12](OC)=[O:13].Cl>CO>[Cl:7][C:8]1[CH:9]=[C:10]([OH:18])[C:11](=[CH:16][CH:17]=1)[C:12]([NH:2][OH:3])=[O:13]
Reactant: COC(=O)c1ccc(Cl)cc1O
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C(NO)c1ccc(Cl)cc1O

Procedure:
Hydroxylamine hydrochloride (20.65 g, 0.297 mol) is added to a mixture of sodium methoxide (53 g, 0.99 mol) in methanol while maintaining the temperature below 10° C. A mixture of methyl 4-chlorosalicylate (46.2 g, 0.248 mol) in methanol is then added to the reaction mixture and the resultant mixture is stirred at room temperature for 10 days, acidified with concentrated hydrochloric acid (pH3) and filtered to give the title product as an off-white solid which is identified by NMR spectral analyses.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([OH:11])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Br)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC1CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a clear solution of 5-bromo-1-indanone (1.0 g, 4.7 mmol) in MeOH (6 mL) was added NaBH4 (0.36 g, 9.5 mmol). The mixture was stirred at room temperature overnight. The mixture was concentrated to dryness and redissolved in water/EtOAc. The layers were separated and the EtOAc layer was dried with anhydrous Na2SO4 and concentrated to obtain 1.1, which was used directly in the next step. 1HNMR (DMSO-d6) δ 7.41 (s, 1H), 7.36 (d, 1H, J2=8.08 Hz), 7.26 (d, 1H, J1=7.99 Hz), 5.28 (d, 1H, J=5.90 Hz), 4.99 (q, 1H), 2.91 (m, 1H), 2.71 (m, 1H), 2.33 (m, 1H), 1.78 (m, 1H).
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([C:21]([O:23]C)=[O:22])[CH:7]=[C:8]2[C:13]=1[O:12][C:11]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[CH:10][C:9]2=[O:20].Cl>CO.C(Cl)Cl>[Br:3][C:4]1[CH:5]=[C:6]([C:21]([OH:23])=[O:22])[CH:7]=[C:8]2[C:13]=1[O:12][C:11]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[CH:10][C:9]2=[O:20]
Reactant: COC(=O)c1cc(Br)c2oc(N3CCOCC3)cc(=O)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: O=C(O)c1cc(Br)c2oc(N3CCOCC3)cc(=O)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.3 %

Procedure:
NaOH 2N (40.7 mL, 81.48 mmol) was added to methyl 8-bromo-2-morpholino-4-oxo-4H-chromene-6-carboxylate (10 g, 27.2 mmol) in a mixture of methanol (225 mL) and DCM (75 mL). The slurry was stirred at room temperature for 16 h. The solvents were evaporated, water (150 mL) was added to the slurry, the solution was cooled down to 0° C. and HCl 6N (15 mL, 89.6 mmol) solution was added dropwise to the reaction mixture until pH ˜3.4. The formed solid was collected by filtration, washed with water (3×50 mL), then toluene (3×50 mL) followed by Diethyl ether (3×50 mL), dried at 55° C. under vacuum over P2O5 to afford 8-bromo-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (9.47 g, 98%) as a beige solid. The crude product was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[CH2:6].C[N+]1([O-])CC[O:14]CC1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C@H:5]1[O:14][CH2:6]1
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=Cc1cccc(Cl)c1
Solvent: ClCCl
Product: Clc1cccc([C@@H]2CO2)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 86.3 %

Procedure:
A round-bottom flask equipped with a overhead stirrer was charged with 3-chlorostyrene (1.00 g, 7.22×10−3 mol), CH2Cl2 (78 mL), (R,R)-4 (0.349 g, 3.61×10−4 mol), and NMO (4.22 g, 3.62×10−2 mol). The solution was cooled to −78° C. before solid M-CPBA (2.51 g, 1.46×10−2 mol) was added in portions over 1.5 minutes. The reaction was monitored by GC. Upon completion (3 h), the reaction was quenched by the addition of a solution of dimethyl sulfide (6 mL) in CH2Cl2 (25 mL) precooled to −78° C. The solution was stirred for an additional 10 minutes at −78° C. before removal of the cold bath and addition of 2N NaOH (20 mL) and CH2Cl2 (20 mL). The phases were separated and the aqueous layer was washed with CH2Cl2 (2×50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Removal of the catalyst was effected by elution through a pad of SiO? (10 g) using pentane and CH2Cl2 (1:1). The eluent was concentrated in vacuo, and subsequent bulb-to-bulb distillation from CaH2 afforded (R)-3-chlorostyrene oxide (0.963 g, 86%) as a colorless liquid in 81% ee.
Reaction SMILES: ClC(OCC)=O.[CH2:7]([N:14]1[C@H:18]([C:19](OC)=[O:20])[C@H:17]([C:23](O)=[O:24])[N:16]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:15]1=[O:33])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>O1CCCC1>[CH2:26]([N:16]1[C@H:17]2[CH2:23][O:24][C:19](=[O:20])[C@H:18]2[N:14]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:15]1=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COC(=O)[C@@H]1[C@H](C(=O)O)N(Cc2ccccc2)C(=O)N1Cc1ccccc1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1OC[C@H]2[C@@H]1N(Cc1ccccc1)C(=O)N2Cc1ccccc1
Reaction time: 0.5 h
Yield: 64.6 %

Procedure:
A solution of ethyl chloroformate (0.54 g) in tetrahydrofuran (2 ml) was added dropwise to a mixture of (4R,5S)-1,3-dibenzyl-5-methoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid (mp., 149°-150° C., [α]36525 =-27.4° at c=1 in DMF, 1.84 g), triethylamine (0.51 g) and tetrahydrofuran (10 ml) at -5° C. The mixture was stirred at the same temperature for 30 minutes. Precipitated triethylamine hydrochloride was filtered off and the filtrate was added dropwise to a solution of sodium borohydride (0.24 g) in 90 % aqueous tetrahydrofuran (10 ml) at -15° C. After reacting, the mixture was acidified with diluted hydrochloric acid and extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by chromatography on silica gel column to give (3aS,6aR)-1,3-dibenzylhexahydro-1H-furo[3,4-d]imidazole-2,4-dione (1.04 g). M.P., 114°-117° C. [α]D20 =+59.0° (c=1, CHCl3).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].CCOCC>CC(C)=O.O>[CH2:11]([O:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCCc1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)=O
Solvent: O
Product: OCCc1ccc(OCc2ccccc2)cc1

Procedure:
A mixture of 4-hydroxyphenethyl alcohol (15.02 g), benzyl bromide (13.6 ml), and potassium carbonate (75.1 g) in acetone (250 ml) is heated at reflux for about 4 hours. The mixture is cooled and poured into ether and water. The organic layer is washed with water, 1N sodium hydroxide solution, brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give 4-benzyloxyphenethyl alcohol.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH:13]=O)=[N:4][CH:3]=1.[C:16]([O:20][C:21](=[O:29])[NH:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([CH3:19])([CH3:18])[CH3:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH2:13][N:26]2[CH2:25][CH2:24][CH:23]([NH:22][C:21](=[O:29])[O:20][C:16]([CH3:18])([CH3:17])[CH3:19])[CH2:28][CH2:27]2)=[N:4][CH:3]=1
Reactant: O=CCn1c(=O)ccc2ncc(F)cc21
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3ncc(F)cc32)CC1
Temperature: 25 °C
Reaction time: 7.5 h
Yield: 18.8 %

Procedure:
To a solution of 1.66 g of (7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde in 42 mL of chloroform, 1.61 g of tert-butyl(piperidin-4-yl)carbamate and 0.48 g of acetic acid were added, and the mixture was stirred at room temperature for 7.5 hours. To the reaction mixture, 2.56 g of sodium triacetoxyborohydride was added, and the mixture was stirred for 10 hours. Thereto was added a saturated aqueous sodium hydrogen carbonate solution, and the organic layer was separated. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Ethanol was added to the resultant residue, and the solid was filtered off to obtain 0.59 g of tert-butyl (1-(2-(7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([CH3:11])[C:3]=1[C@H:12]([OH:15])[CH2:13][OH:14].N1C=CC=CC=1.[C:22](Cl)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]>C(Cl)Cl>[C:22]([O:14][CH2:13][C@H:12]([C:3]1[C:4]([CH3:11])=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[Br:1])[OH:15])(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: Cc1cc([N+](=O)[O-])cc(Br)c1[C@H](O)CO
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc([N+](=O)[O-])cc(Br)c1[C@H](O)COC(=O)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a suspension of (S)-1-(2-bromo-6-methyl-4-nitrophenyl)ethane-1,2-diol (65D) (6.96 g, 25.22 mmol) in DCM (100 ml), was added pyridine (5 mL) at 0° C. To the solution was added pivaloyl chloride (PivCl) slowly at 0° C. The reaction mixture was stirred at 0° C. for 5 min, then raised to rt, stirred at rt for 5 h. The reaction mixture was washed by sat. NaHCO3, extracted by DCM, dry over MgSO4, filtered, purified by silica gel column, eluting by 0-40% EtOAc in Hexanes to give 9.13 g of 65E. The product taken on without full characterization.
Reaction SMILES: Br[C:2]1[CH:10]=[N:9][C:8]([Cl:11])=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[NH4+].[Cl-].[CH3:14][O-:15].[Na+]>>[CH3:14][O:15][C:2]1[CH:10]=[N:9][C:8]([Cl:11])=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2
Reactant: C[O-]
Reactant: Clc1ncc(Br)c2cc[nH]c12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: COc1cnc(Cl)c2[nH]ccc12
Temperature: 110 °C

Procedure:
A mixture of 4-bromo-7-chloro-6-azaindole (6 g), CuBr (3.7 g) and NaOMe (30 mL, 5% in MeOH) was heated at 110° C. for 24 hours in a sealed tube. After cooling to room temperature, the reaction mixture was added to saturated aqueous NH4Cl. The resulting aqueous solution was extracted with EtOAc (3×30 mL). The combined organic layer was dried over MgSO4, filtered and the filtrate was concentrated in vacuo to afford a residue, which was purified by using silica gel chromatography to give 1.8 g of 4-methoxy-7-chloro-6-azaindole, Precursor 2e.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[N:12](COCC[Si](C)(C)C)[CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[C:4]([C:26]2[CH2:31][CH2:30][C:29]([CH3:33])([CH3:32])[CH2:28][CH:27]=2)[CH:3]=1.CCO.C(O)(C(F)(F)F)=O.C(O)CC>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[NH:12][CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[C:4]([C:26]2[CH2:31][CH2:30][C:29]([CH3:33])([CH3:32])[CH2:28][CH:27]=2)[CH:3]=1
Reactant: CC1(C)CC=C(c2cc(Br)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Solvent: CCO
Solvent: CCCO
Solvent: ClCCl
Product: CC1(C)CC=C(c2cc(Br)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
To a solution of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid[4-bromo-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide (as prepared in the previous step, 350 mg, 0.661 mmol) in 5 mL of DCM (CH2Cl2) was added 0.15 mL of EtOH followed by 2.5 mL of TFA. After stirring at RT for 3 h, the mixture was treated with 10 mL of n-propanol and concentrated in vacuo. The residue was triturated with DCM to afford 253 mg (96%) of the title compound as a white solid. 1H-NMR (DMSO-d6; 400 MHz): δ 14.3 (s, 1H), 9.78 (s, 1H), 8.31 (s, 1H), 7.95 (d, 2H, J=8.6 Hz), 7.50 (dd, 2H, J=8.6, 2.3 Hz), 7.41 (d, 1H, J=2.3 Hz), 5.71 (m, 1H), 2.24 (m, 2H), 1.95 (m, 2H), 1.47 (m, 2H), 0.98 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C19H19BrN4O, 399.1 (M+H), found 399.1.
Reaction SMILES: [Li].[C:2]([C:6]#[CH:7])([CH3:5])([CH3:4])[CH3:3].[CH:8]([CH:10]=[CH2:11])=[O:9].C(O)(C)C>O1CCCC1>[CH3:3][C:2]([CH3:5])([CH3:4])[C:6]#[C:7][CH:8]([OH:9])[CH:10]=[CH2:11]
Reactant: C#CC(C)(C)C
Reactant: C=CC=O
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: C=CC(O)C#CC(C)(C)C
Temperature: 40 °C
Reaction time: 24 h
Yield: 73.9 %

Procedure:
Under a blanket of dry nitrogen, at 0° C., metallic lithium (0.667 gr., 0.096 mole) was added to a mixture of t-butylacetylene (9.94 gr., 0.121 mole) and tetrahydrofuran (75 ml). The mixture was heated to 40° C. for 5 hours and kept at room temperature for 24 hours. The lithium was almost completely consumed. A second amount of t-butylacetylene (9.94 gr., 0.121 mole) was added and the reaction mixture was stirred for 21 hours. The mixture was cooled to 0° C. and a solution of freshly distilled acrolein (6.634 gr., 0.118 mole) in tetrahydrofuran (10 ml) was added gradually during 30 minutes. The mixture was stirred at 0° C. for 30 minutes and then at room temperature for 3 hours. Isopropanol (6 ml) was added to quench the remaining lithium. The mixture was quenched using saturated ammonium chloride aqueous solution (30 ml) at 0° C. The pH was brought to 6 by 10% sulfuric acid (ca. 45 ml). The tetrahydrofuran and excess t-butylacetylene were evaporated and the mixture was extracted 3 times by dichloromethane (70 ml each time). The organic phase was washed with water (2×20 ml), dried and the solvent evaporated to give 10.2 gr. of an almost pure 6,6-dimethylhept-1-en-4-yn-3-ol (73.9% yield).
Reaction SMILES: [F:1][C:2]([C:12]([F:15])([F:14])[F:13])([C:8]([F:11])([F:10])[F:9])[CH2:3][CH:4](I)[CH2:5]O.Cl>[Zn].C(O)(=O)C>[F:1][C:2]([C:12]([F:13])([F:14])[F:15])([C:8]([F:9])([F:10])[F:11])[CH2:3][CH:4]=[CH2:5]
Reactant: OCC(I)CC(F)(C(F)(F)F)C(F)(F)F
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: C=CCC(F)(C(F)(F)F)C(F)(F)F
Temperature: 80 °C
Reaction time: 2 h

Procedure:
About 11 g of the RF-intermediate 4,5,5,5-tetra fluoro-4-(trifluoromethyl)-2-iodopentan-1-ol can be added to a glass pressure tube and about 13 grams of 30% (wt/wt) aqueous acetic acid can be added to the other tube to form a mixture. The mixture can be heated to about 80° C., and 4 grams of powdered zinc can be added slowly through a solid addition system. The mixture can be allowed to stir for an additional 2 hours before being cooled and adding 2 mL of 1.5 N HCl to phase separate the mixture. The organic layer can be decanted to give 3 grains of the RF-intermediate 4,5,5,5-tetrafluoro-4-(trifluoromethyl)pentan-1-ene which can be 75.14% (area percent by gas chromatography).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH:11][C:12](=O)[CH3:13])[CH:6]=[CH:7][CH:8]=1.[OH-].[K+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:7][CH:8]=1)[C:12]([CH3:13])=[N:11][CH2:10][CH2:9]2
Reactant: COc1cccc(CCNC(C)=O)c1
Agent: [K+]
Agent: [OH-]
Product: COc1ccc2c(c1)CCN=C2C
Temperature: 110 °C
Reaction time: 2 h
Yield: 93.4 %

Procedure:
A mixture soultion of polyphosphoric acid (61.4 ml, 0.66 mol) and phosphorouspentoxide(28.0 g, 0.2 mol) was heated to 90° C. N-(3-methoxyphenylethyl) acetamide (63.6 g, 0.33 mol) was added to the mixture solution and then stirred for 2 hours at 110° C. The reaction mixture was poured into ice water, adjusted to alkali with potassium hydroxide, and then extracted with ethyl ether. The extract was dried over anhydrous magnesium sulfate and concentrated under a reduces pressure. The resulting residue was purified by a silica gel column chromatography, using a solution of methanol and dichloromethane (1:20) as a eluent, to give 54.0 g of the titled compound.