Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[N:16]=[CH:15][N:14]([C:17]3[S:18][C:19]([C:29]([NH2:31])=[O:30])=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=4)[N:21]=3)[C:13]=2[CH:32]=1)C1C=CC=CC=1.ClCCl>O>[Cl:28][C:24]1[CH:23]=[C:22]([C:20]2[N:21]=[C:17]([N:14]3[C:13]4[CH:32]=[C:9]([OH:8])[CH:10]=[CH:11][C:12]=4[N:16]=[CH:15]3)[S:18][C:19]=2[C:29]([NH2:31])=[O:30])[CH:27]=[CH:26][CH:25]=1
Reactant: NC(=O)c1sc(-n2cnc3ccc(OCc4ccccc4)cc32)nc1-c1cccc(Cl)c1
Solvent: ClCCl
Solvent: O
Product: NC(=O)c1sc(-n2cnc3ccc(O)cc32)nc1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.7 %

Procedure:
To a mixture of 3.2 g (6.96 mmole) of 2-(6-benzyloxy-benzoimidazol-1-yl)-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid amide (I.25c) and 50 mL of dichloromethane at 0 degrees was added, dropwise, 5.86 mL (56 mmole) of boron trifluoride-dimethylsulfide complex. The mixture was stirred at ambient temperature for 1 hour and then 50 mL of water was added. The mixture was stirred vigorously for 1 hour. The precipitate was collected by filtration to give 2.6 g of 4-(3-chloro-phenyl)-2-(6-hydroxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid amide (I.25d) as an off-white solid.
Reaction SMILES: [C:1]1([C:7]2([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][C:14]3[C:9](=[C:10]([Cl:18])[C:11]([Cl:17])=[C:12]([OH:16])[CH:13]=3)[C:8]2=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][C:34]([O:36]CC)=[O:35].[OH-].[Na+].Cl>CN(C)C=O.O>[O:19]=[C:8]1[C:9]2[C:14](=[CH:13][C:12]([O:16][CH2:33][C:34]([OH:36])=[O:35])=[C:11]([Cl:17])[C:10]=2[Cl:18])[CH2:15][C:7]1([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)CBr
Reactant: O=C1c2c(cc(O)c(Cl)c2Cl)CC1(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)COc1cc2c(c(Cl)c1Cl)C(=O)C(c1ccccc1)(c1ccccc1)C2
Temperature: 90 °C

Procedure:
A stirred mixture of 2,2-diphenyl-5-hydroxy-6,7-dichloro-1-indanone (4.9 g., 0.0133 mole), potassium carbonate (3.68 g., 0.0266 mole) and ethyl bromoacetate (4.45 g., 0.0266 mole) in dimethylformamide (150 ml.) is warmed at 55°-60° C. for 3.5 hours, then treated with water (150 ml.)-10 N sodium hydroxide solution (7.5 ml., 0.075 mole) and heated at 90° C. for 1.5 hrs. The reaction mixture is added slowly to water (1 l.)-12 N hydrochloric acid (30 ml.) to precipitate 3.60 g. of (1-oxo-2,2-diphenyl-6,7-dichloro-5-indanyloxy)acetic acid which melts at 251°-252° C. after crystallization from first acetic acid, then nitromethane.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:10]=[CH:11][CH:12]=1)[NH:5][CH2:6][CH2:7][O:8][CH3:9].BrC1C(C)=C(N([CH2:26][C:27]2[CH:39]=[CH:38][C:30]([O:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[C:29]([CH3:40])[CH:28]=2)CCCC)C=CC=1>>[Br:1][C:2]1[C:3]([CH3:13])=[C:4]([N:5]([CH2:26][C:27]2[CH:39]=[CH:38][C:30]([O:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[C:29]([CH3:40])[CH:28]=2)[CH2:6][CH2:7][O:8][CH3:9])[CH:10]=[CH:11][CH:12]=1
Reactant: CCCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(Br)c1C
Reactant: COCCNc1cccc(Br)c1C
Product: CCOC(=O)COc1ccc(CN(CCOC)c2cccc(Br)c2C)cc1C

Procedure:
Prepared from 3-bromo-N-(2-methoxyethyl)-2-methylaniline using the procedure described for Intermediate 59.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][C:10]1[C:19](Br)=[C:18]2[C:13]([CH:14]=[CH:15][C:16]([O:21][CH3:22])=[N:17]2)=[N:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[CH2:1]([NH:8][C:19]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[N:17]=2)[N:12]=[CH:11][C:10]=1[Br:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: COc1ccc2ncc(Br)c(Br)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2ncc(Br)c(NCc3ccccc3)c2n1
Temperature: 120 °C
Reaction time: 2 h
Yield: 46.9 %

Procedure:
Benzylamine (67 mg, 0.63 mmol, 2.0 eq) is added at room temperature to a stirred solution of 7,8-dibromo-2-methoxy-[1,5]naphthyridine (100 mg, 0.31 mmol, 1.0 eq) in N,N-dimethylformamide (10 mL), followed by potassium carbonate (87 mg, 0.63 mmol, 2.0 eq). After 2 hours stirring at 120° C., solvent is removed and the residue is extracted with ethyl acetate (3×10 mL) and water (10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give the crude product that is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 5:1, v/v) to afford benzyl-(3-bromo-6-methoxy-[1,5]naphthyridin-4-yl)-amine as a light yellow solid (50 mg, 46% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH3:12])=[N+:7]([O-])[CH:8]=[CH:9][CH:10]=1)=[O:4].O=P(Cl)(Cl)[Cl:15]>>[Cl:15][CH2:12][C:6]1[N:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)c1ccc[n+]([O-])c1C
Reactant: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cccnc1CCl
Yield: 30.8 %

Procedure:
The crude 3-(methoxycarbonyl)-2-methylpyridine-1-oxide (35 g, 210 mmol) was added in small portion to POCl3 (300 g) at room temperature. After the addition, the reaction mixture was refluxed for 3 hours before it was concentrated in vacuo. The residue was poured into ice-water, neutralized with aq. NaHCO3 solution and extracted with AcOEt (125 mL×3). The combined organic layers were washed with brine, dried over anhy. NazSO4, filtered, and concentrated in vacuo to afford a crude product which was then purified by column chromatography to give title compound (12 g, yield 30%).
Reaction SMILES: N1C=CC=N1.[Cl:6][C:7]1[CH:12]=[C:11]([C:13]([OH:15])=O)[CH:10]=[CH:9][N:8]=1.S(Cl)([Cl:18])=O>N1C=CC=CC=1.C1(C)C=CC=CC=1>[Cl:6][C:7]1[CH:12]=[C:11]([C:13]([Cl:18])=[O:15])[CH:10]=[CH:9][N:8]=1
Reactant: O=C(O)c1ccnc(Cl)c1
Reactant: O=S(Cl)Cl
Agent: c1cn[nH]c1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ccnc(Cl)c1

Procedure:
Scheme III shows the synthesis of a pyrazole, compound 13, analogs of compound 5 in which the pyridine 10 ring bears a chlorine atom at position 2. 2-Chloropyridine-4-carboxylic acid, compound 9, is treated with thionyl chloride in a solvent such as toluene, and heated to reflux to give 2-chloropyridine-4-carboxylic acid chloride, compound 10, which is then converted to methyl 2-chloroisonicotinate, compound 11. Compound 11 is treated with a ketone 2 in the presence of a base such as sodium methoxide in a solvent such as tetrahydrofuran, at temperatures ranging from 25° C. up to reflux to provide a diketone, compound 12. Treatment of the diketone, compound 12, with an arylhydrazine derivative 4 in ethanol or other suitable solvent at a temperature ranging up to reflux, provides pyrazole compound 13. When R2 of ketone 2 is hydrido, then R2 of 13 is hydrido.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9](S(C(F)(F)F)(=O)=O)=[CH:8][CH:7]=1)([F:4])([F:3])[F:2].FC(F)(F)OC1C=CC(N)=CC=1>>[F:2][C:1]([F:3])([F:4])[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=S(=O)(c1ccc(OC(F)(F)F)cc1)C(F)(F)F
Agent: Nc1ccc(OC(F)(F)F)cc1
Product: FC(F)(F)Oc1ccccc1

Procedure:
Methods for the preparation of compounds of this type are already known in the art. For example, Chemical Abstracts 61-8217 describes the preparation of p-F3COC6H4SO2CF3. According to the described process, paratrifluoromethoxyaniline obtained by nitration of trifluoromethoxybenzene is subjected to diazotization in an aqueous HCl medium. The resultant product is treated first with EtOCS2K, then with potassium hydroxide, and finally with dimethyl sulfate to produce paratrifluoromethoxythioanisole. This product is chlorinated to give paratrifluoromethoxytrichloromethylthiobenzene. This compound is then treated with SbF3 to produce paratrifluoromethoxytrifluoromethylthiobenzene, which is converted to the desired product by chromic acid oxidation in acetic acid. Similarly known from Chemical Abstracts 87-134,266 h is the preparation of m-CF3SC6H4SO2CF3 by trifluoromethylation with CF3I of the corresponding thiol in liquid ammonia under ultraviolet irradiation.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:14]([CH2:22][C:23](OCC)=[O:24])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:14]([CH2:22][C:23]([NH:1][C:2]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:24])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1cc(Cl)ccc1N
Reactant: CCOC(=O)CC(=O)c1ccccc1
Product: CCOC(=O)c1cc(Cl)ccc1NC(=O)CC(=O)c1ccccc1
Yield: 49.1 %

Procedure:
To 6.0 grams of ethyl 2-amino-5-chlorobenzoate is added 6.4 grams of ethyl benzoylacetate, the mixture is heated at 180° to 190° C. for ten hours, cooled, crystals separated out therefrom are collected by filtration, and washed with methanol to give 5.1 grams of ethyl 2-benzoylacetylamino-5-chlorobenzoate, colorless needles. To 200 ml of ethanol is added 640 mg of metal sodium, then 4.8 grams of ethyl 2-benzoylacetylamino-5-chlorobenzoate is added thereto, the mixture is heated to reflux for two hours, cooled, poured into ice water, adjusted to pH 3 with 10% hydrochloric acid, crystals separated out therefrom are collected by filtration, and recystallized from dimethylformamide and methanol to give 1.9 grams of 3-benzoyl-6-chloro-4-hydroxy-2-quinoline, pale yellow needles, melting at above 300° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[CH2:10][CH2:11][CH2:12][C:13](=O)[C:14]=2[C:15]=1[OH:16])=[O:5])[CH3:2].Cl.[NH2:19][OH:20]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[CH2:10][CH2:11][CH2:12][C:13](=[N:19][OH:20])[C:14]=2[C:15]=1[OH:16])=[O:5])[CH3:2]
Reactant: NO
Reactant: CCOC(=O)c1cnc2c(c1O)C(=O)CCC2
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cnc2c(c1O)C(=NO)CCC2
Yield: 72.4 %

Procedure:
To 80 ml of ethyl alcohol were added 2.35 g of 4-hydroxy-5-oxo-5,6,7,8-tetrahydroquinoline-3-carboxylic acid ethyl ester and 0.69 g of hydroxylamine hydrochloride. The resulting reaction mixture was refluxed on an oil bath for 1 hour. After the ethyl alcohol was distilled off under reduced pressure, the residue was dissolved in dilute hydrochloric acid and the resulting solution was adjusted to pH 5.8 with 10% potassium carbonate. The crystals so precipitated were separated by filtration to obtain a yield of 1.8 g of the desired compound. This compound melted (and decomposed) at 245°-247° C. (uncorrected values). Its infrared absorption spectrum (KBr tablet) had absorption peaks at 3240, 3060, 2960, 2920, 1720, 1650, 1550, and 1185 cm-1, and its n.m.r. spectrum (CF3COOH, 60Mc, TMS) had signals at δ values of 1.50 (3H, t, J=7.5 Hz), 2.0-2.6 (2H, m), 3.0-3.5 (4H, m), 4.6 (2H, q, J=7.5 Hz), and 8.95 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9](=[O:12])[CH2:10]Br)=[CH:4][C:3]=1[Cl:13].[O:14]([CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][CH2:30][NH:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH:9]([CH2:10][N:31]([CH2:30][CH2:29][CH2:28][O:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][CH2:21][O:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[OH:12])=[CH:4][C:3]=1[Cl:13]
Reactant: c1ccc(CNCCCOCCOCCCOc2ccccc2)cc1
Reactant: Nc1c(Cl)cc(C(=O)CBr)cc1Cl
Solvent: C1CCOC1
Product: Nc1c(Cl)cc(C(O)CN(CCCOCCOCCCOc2ccccc2)Cc2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.9 %

Procedure:
1-[4-Amino-3,5-dichlorophenyl]-2-bromoethanone (0.95 g), N-[3-[2-(3-phenoxypropoxy)ethoxy]propyl]benzenemethanamine (1.15 g) and DEA (0.48 g) were stirred together in THF (35 ml) at room temperature under nitrogen for 7 h. The mixture was filtered and the filtrate evaporated in vacuo. The residue was dissolved in methanol (35 ml) and treated portionwise with sodium borohydride (0.34 g), at 0° C. under nitrogen, stirred at room temperature for 18 h, diluted with water (150 ml) and the solvent evaporated in vacuo. The residue was extracted with ethyl acetate (2×150 ml), dried and evaporated in vacuo to give an oil. Purification by FCC eluting with System H (95:5:1) gave the title compound (1.30 g) as an oil. T.l.c. (System H 90:10:1) Rf 0.39
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[Cl:11][C:12]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16]([Cl:23])[C:13]=1[CH2:14][OH:15].C(N(CC)CC)C>ClCCl.O>[Cl:11][C:12]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16]([Cl:23])[C:13]=1[CH:14]=[O:15]
Reactant: O=[N+]([O-])c1cc(Cl)c(CO)c(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=Cc1c(Cl)cc([N+](=O)[O-])cc1Cl
Reaction time: 0.5 h

Procedure:
A solution of dimethyl sulphoxide (1.2 cm3) in dichloromethane (5 cm3) was added dropwise to a stirred solution of oxalyl chloride (0.7 cm3, 8.0 mmol) in dichloromethane (12 cm3) at -60° C. under nitrogen. After 10 mins at -60° C. a solution of 2,6-dichloro-4-nitrobenzylalcohol (1.53 g, 6.9 mmol) in dichloromethane (10 cm3) was added dropwise and the stirred mixture kept at -60° C. for 0.5 h. Triethylamine (4.6 cm3, 33 mmol) was then added and the mixture was allowed to warm to room temperature at which stage water (35 cm3) was added. The heterogeneous mixture was separated and the aqueous phase extracted with dichloromethane (35 cm3). The combined organic fractions were extracted with hydrochloric acid (2M, 60 cm3), then water (60 cm3), saturated sodium carbonate solution (60 cm 3), and finally water (60 cm3) then dried and evaporated under reduced pressure to give 2,6-dichloro-4-nitrobenzaldehyde as a pure oil which slowly solidified.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:5]([N:9]=[C:10]([C:12]3([CH2:15][NH:16][C:17]([N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[O:18])[CH2:14][CH2:13]3)[N:11]=2)[CH:6]=[CH:7][CH:8]=1.[I:24]N1C(=O)CCC1=O.B(F)(F)F.[O-]S([O-])(=S)=O.[Na+].[Na+]>C([O-])(O)=O.[Na+]>[I:24][C:6]1[N:5]2[N:9]=[C:10]([C:12]3([CH2:15][NH:16][C:17]([N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[O:18])[CH2:14][CH2:13]3)[N:11]=[C:4]2[C:3]([O:2][CH3:1])=[CH:8][CH:7]=1
Reactant: COc1cccn2nc(C3(CNC(=O)N4CCCC4)CC3)nc12
Reactant: O=C1CCC(=O)N1I
Agent: FB(F)F
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Product: COc1ccc(I)n2nc(C3(CNC(=O)N4CCCC4)CC3)nc12
Reaction time: 24 h

Procedure:
Under an argon atmosphere Pyrrolidine-1-carboxylic acid [1-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-cyclopropylmethyl]-amide (0.085 g, 0.23 mmol) was mixed with N-iodosuccinimide (0.16 g, 0.69 mmol). BF3*2H2O (0.5 mL, 7.8 mmol) was added at 0° C. The dark suspension was stirred at rt for 4 h after which N-iodosuccinimide (0.08 g1) and BF3*2H2O (0.25 mLl) were added. The suspension was stirred for 24 h all together after which it was poured onto a 1:1 solution of saturated Na2S2O3 and saturated NaHCO3 (30 mL). The aqueous phase was extracted with DCM (×2) and the combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica using DCM:MeOH 97:3 as the eluent to afford Pyrrolidine-1-carboxylic acid [1-(5-iodo-8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-cyclopropylmethyl]-amide.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][C:26]=2[OH:28])[CH:21]=[CH:20][N:19]=1>>[F:15][C:14]([F:17])([F:16])[C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:5]=[CH:4][N:3]=[C:2]([O:28][C:26]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:27]=3[CH:18]=[N:19][CH:20]=[CH:21]4)[CH:7]=2)=[CH:9][CH:10]=1
Reactant: Oc1cccc2ccncc12
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)ncn2)cc1
Product: FC(F)(F)c1ccc(-c2cc(Oc3cccc4ccncc34)ncn2)cc1

Procedure:
The title compound was prepared from 4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine (Example 2(a), Method A) and isoquinolin-8-ol (MonomerChem) under the conditions of Example 6. Mp: 194–195° C. MS (ESI, pos. ion) m/z: 368.2 (M+1).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[C@@H:14]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:13][C@@H:12](O)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.C1C=CC(OP(OC2C=CC=CC=2)([N:64]=[N+:65]=[N-:66])=O)=CC=1>C1COCC1>[N:64]([C@H:12]1[CH2:13][C@H:14]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[C@H:10]([CH2:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:11]1)=[N+:65]=[N-:66]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C[C@@H](O)C[C@H]1COCc1ccccc1
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](N=[N+]=[N-])C[C@H]1COCc1ccccc1
Reaction time: 0.08 h
Yield: 62.7 %

Procedure:
To a solution of (1S,3S,4S)-3-[(benzyloxy)methyl]-4-{[tert-butyl(dimethyl)-silyl]oxy}cyclopentanol (138.9 mg, 0.0004127 mol) and PPh3 (118 mg, 0.000451 mol) in THF (2.7 mL) at 0° C. was slowly added DEAD (71.1 μL, 0.000451 mol). The reaction was stirred for 5 minutes, then diphenylphosphonic azide (97.4 μL, 0.000452 mol) was added dropwise. The mixture was stirred for one hour. The reaction was partitioned with water and EtOAc. The layers were separated and the aqueous extracted with EtOAc (2×). The combined organics were washed with brine (1×), dried (Na2SO4), filtered, and collected in vacuo. The residue was purified by flash chromatography (0 to 10% EtOAc/hexanes) to obtain 93.5 mg (63%) of the title compound.
Reaction SMILES: [I:1]/[CH:2]=[CH:3]/[CH2:4][CH:5]([O:10][Si](C)(C)C)[CH2:6][CH2:7][CH2:8][CH3:9].C1(C)C=CC=CC=1>C(O)(=O)C.O1CCCC1.O>[OH:10][CH:5]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4]/[CH:3]=[CH:2]/[I:1]
Reactant: CCCCC(C/C=C/I)O[Si](C)(C)C
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCCC(O)C/C=C/I

Procedure:
A 23 g portion of 1-iodo-4-trimethylsiloxy-trans-1-octene is dissolved in a mixture of 200 ml of glacial acetic acid, 100 ml of tetrahydrofuran, and 50 ml of water. After solution occurs, toluene is added and the mixture is evaporated. The resulting oil is chromatographed on silica gel with hexane progressively enriched in benzene followed by acetone to give 16 g of an oil, pmr spectrum (CDCl): 3.69 (m. CHOH) and 2.3 (s, OH).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13](Br)=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1CCCCC1.[CH2:24]([OH:29])[CH2:25][CH2:26][C:27]#[CH:28].Cl>[Cu]I>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:28]#[C:27][CH2:26][CH2:25][CH2:24][OH:29])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CCCCO
Reactant: CC(C)(C)OC(=O)N1CCc2cc(Br)ccc21
Agent: [Cu]I
Agent: Cl
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCc2cc(C#CCCCO)ccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 105.9 %

Procedure:
To 3.73 g (12.5 mmol) 5-Bromo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester in 25 ml piperidine 722 mg (0.63 mmol) tetrakis-(triphenylphosphine)-palladium and 120 mg (0.625 mmol) CuI were added. The solution was purged with argon and was heated to 80° C. over a period of 45 min, during which 0.9 ml (9.4 mmol) 4-pentynol were added. Additional 0.9 ml (9.4 mmol) 4-pentynol were added and the mixture was stirred for 2 h, poured into ice water and 2M HCl was added. The inorganic phase was extracted with ether, the combined organic phases were washed with water and dried over Na2SO4. Purification on silica gel with hexane/EtOAc 4:1 to 2:1 yielded 3.0 g (79%) 5-(5-Hydroxy-pent-1-ynyl)-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester as light brown solid, MS: 302 (MH+). (See also: Stara, Irena G.; Stary, Ivo; Kollarovic, Adrian; Teply, Filip; Saman, David; Fiedler, Pavel. Coupling reactions of halobenzenes with alkynes. The synthesis of phenylacetylenes and symmetrical or unsymmetrical 1,2-diphenylacetylenes. Collect. Czech. Chem. Commun. (1999), 64(4), 649-672)
Reaction SMILES: [BH4-].[Na+].C([O:5][C:6](=O)[CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[N:14]=2)[N:10]=[N:9]1)C>CO.O>[Br:19][C:15]1[N:14]=[C:13]([C:11]2[N:10]=[N:9][N:8]([CH2:7][CH2:6][OH:5])[CH:12]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)Cn1cc(-c2cccc(Br)n2)nn1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCCn1cc(-c2cccc(Br)n2)nn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of NaBH4 (60 mg, 1.58 mmol) in MeOH (3.0 mL) at room temperature was added ethyl[4-(6-bromopyridin-2-yl)-1H-1,2,3-triazol-1-yl]acetate (245 mg, 0.79 mmol) in MeOH (7.0 mL) The reaction was stirred at room temperature for 2 h. It was then diluted with water and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered, and evaporated. Flash chromatography (20-100% EtOAc/hexanes) afforded the title compound as a colorless gum.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:15][C:16](=[O:26])[CH2:17][O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:14].[Cl:27][C:28]1[CH:29]=[CH:30][C:31]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[C:32]([CH:37]=1)[C:33](OC)=[O:34]>C1COCC1>[Cl:27][C:28]1[CH:29]=[CH:30][C:31]([O:38][CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)=[C:32]([C:33](=[O:34])[CH:17]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:16]([O:15][CH2:13][CH3:14])=[O:26])[CH:37]=1
Reactant: COC(=O)c1cc(Cl)ccc1OCc1ccccc1
Reactant: CCOC(=O)COCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(OCc1ccccc1)C(=O)c1cc(Cl)ccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.8 %

Procedure:
In a flame-dried flask were placed dry THF (4 ml) and diisopropylamine (1.21 g, 0.012 mol). n-Butyllithium (1.55M in hexane, 7.7 ml, 0.012 mol) was added dropwise at -10° C. under argon. After stirring for 0.5 h at 0° C., a solution of ethylphenylmethoxyacetate (2.33 g, 0.012 mol) in dry THF (4 ml) was added dropwise at -78° C. After one h methyl 5-chloro-2-phenylmethoxybenzoate (2.21 g, 0.008 mol) in dry THF (4 ml) was added. Stirring was continued for an additional 2 h at -78° C. and the reaction mixture was quenched with 2 ml of EtOH at -20° C. The quenched mixture was poured into 50 ml of 10% aqueous HCl solution and extracted with ether. The ether layer was washed with water, dried (Na2SO4), filtered and concentrated under reduced pressure affording a light yellow oil. Purification by flash chromatography (silica gel) using toluene-CHCl3 (5:1) as eluent afforded 1.96 g (56%) of ethyl 5-chloro-β-oxo-α,2-bis(phenylmethoxy)benzenepropanoate as white crystals (EtOH): mp 64°-65° C.; IR (KBr) 1735 (ester) and 1685 (conjugated carbonyl) cm-1 ; NMR (CDCl3, 90 MHz) δ 1.16 (t, 3H, OCH2CH3) 4.13 (q, 2H, OCH2CH3), 4.55 (dd, 1H, OCH2Ph, JAB =12.6 Hz), 4.60 (dd, 1H, OCH2Ph, JAB =12.6 Hz), 5.07 (s, 2H, OCH2Ph), 5.28 (s, 1H, CHCO2Et), 6.85 (d, 1H, ArH, J=8.9 Hz), 7.05-7.50 (m, 11H, ArH), 7.64 (d, 1H, ArH, J=2.5 Hz). Anal calcd. for C25H23ClO5 : C, 68.41; H, 5.28; Cl, 8.07. Found: C, 68.14; H, 5.28; Cl, 8.09.
Reaction SMILES: [C:1]([C:3]1[CH:45]=[CH:44][C:6]2[N:7](COCC[Si](C)(C)C)[C:8]([CH:10]([C:17]3[C:25]([O:26][CH3:27])=[CH:24][C:23]([CH3:28])=[C:22]4[C:18]=3[CH:19]=[CH:20][N:21]4C(OC(C)(C)C)=O)[CH:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13])=[N:9][C:5]=2[CH:4]=1)#[N:2].C(C1C=CC2N=C(C(C3C(OC)=CC(C)=C4C=3C=CN4C(OC(C)(C)C)=O)C(C)C(OC)=O)N(COCC[Si](C)(C)C)C=2C=1)#N>>[C:1]([C:3]1[CH:45]=[CH:44][C:6]2[NH:7][C:8]([CH:10]([C:17]3[C:25]([O:26][CH3:27])=[CH:24][C:23]([CH3:28])=[C:22]4[C:18]=3[CH:19]=[CH:20][NH:21]4)[CH:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13])=[N:9][C:5]=2[CH:4]=1)#[N:2]
Reactant: COC(=O)C(C)C(c1c(OC)cc(C)c2c1ccn2C(=O)OC(C)(C)C)c1nc2cc(C#N)ccc2n1COCC[Si](C)(C)C
Agent: COC(=O)C(C)C(c1c(OC)cc(C)c2c1ccn2C(=O)OC(C)(C)C)c1nc2ccc(C#N)cc2n1COCC[Si](C)(C)C
Product: COC(=O)C(C)C(c1nc2cc(C#N)ccc2[nH]1)c1c(OC)cc(C)c2[nH]ccc12

Procedure:
The title compound was synthesized from (±)-tert-butyl 4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-3-methoxy-2-methyl-3-oxopropyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-3-methoxy-2-methyl-3-oxopropyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate as a single diastereomer (diastereomer A, tr=16.9 min from Example 147-A) following the procedure shown in Example 142-C. MS (ESI+) m/z 403.0 (M+H).