Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4](=[C:9](OC)[CH3:10])[C:5]([O:7][CH3:8])=[O:6])(=O)[CH3:2].C(O)(=O)C.[CH:17]([NH2:19])=[NH:18].[CH3:20][C:21]([CH3:24])([O-:23])[CH3:22].[K+:25].Cl>C1COCC1.CO.CC(C)=O>[CH3:20][C:21]([CH3:24])([O-:23])[CH3:22].[K+:25].[CH3:2][C:1]1[C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:9]([CH3:10])[N:19]=[CH:17][N:18]=1
Reactant: N=CN
Reactant: COC(=O)C(C(C)=O)=C(C)OC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1c(C)ncnc1C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Methyl 2-acetyl-3-methoxy-2-butenoate (86 g), formamidine acetate (62.5 g), acetone (344 ml) and methyl alcohol (258 ml) were charged into a 2 L 3-necked, flask (fitted with addition funnel, condenser, agitator and nitrogen inlet). The reaction is blanketed with nitrogen, the agitator is started and the batch cooled to between −5 and 0° C. While the batch was cooling, a solution of potassium t-butoxide is prepared (67.4 g in THF, 258 ml) under nitrogen. When the batch reached the correct temperature, the potassium t-butoxide solution was charged slowly keeping the temperature below 5° C. The batch was allowed to warm to about 25° C. The reaction was complete after about 1.5 hours. Concentrated hydrochloric acid was added dropwise to bring the pH to 7. The batch was concentrated under vacuum until no more volatiles were collected. Methyl t-butylether (170 ml) and water (90 ml) were charged into the reaction. The batch was agitated for about 10 minutes and the layers were then separated. The lower aqueous layer was back extracted twice, each time with 170 ml methyl t-butylether. All the upper organic layers were combined and concentrated under vacuum to afford crude methyl 4,6-dimethylpyrimidine-5-carboxylate 103 gm as an oil. The product was purified by chromatography on a silica gel column eluting with heptane/ethyl acetate (7:3) followed by crystallization from heptane, m. p. 43–45° C., 1H NMR (CDCl3): δ2.53 (6H, s, CH3), δ3.96 (3H, s, OCH3), δ8.96 (1H, s, ArH). 13H CMR (CDCl3): δ167.97, δ164.71, δ158.23, δ53.05, δ23.18. HR-MS; Calculated for C7H9N2O2, m/z=153.0664. Found 153.0667.
Reaction SMILES: [CH:1]([N:4]=[C:5]=[N:6][CH:7]([CH3:9])[CH3:8])([CH3:3])[CH3:2].[CH2:10]([OH:28])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>>[CH2:10]([O:28][C:5](=[N:6][CH:7]([CH3:9])[CH3:8])[NH:4][CH:1]([CH3:3])[CH3:2])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CC(C)N=C=NC(C)C
Reactant: CCCCCCCC/C=C\CCCCCCCCO
Product: CCCCCCCC/C=C\CCCCCCCCOC(=NC(C)C)NC(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.7 %

Procedure:
A mixture of N,N'-diisopropylcarbodiimide (12.6 g, 0.1 mole), oleyl alcohol (26.8 g, 0.1 mole) and cuprous chloride (60 mg) is stirred at room temperature for 4 hours. Infrared analysis shows the reaction to be virtually complete. The reaction mixture is placed on a column of alumina (454 g) and eluted with methylene chloride to give 36.2 g of O-oleyl-N,N'-diisopropylisourea. The product is identified by mass spectrometry (molecular ion at m/e 394), infrared spectroscopy (the C=N band at 1660 cm-1) and nuclear magnetic resonance in deuterated chloroform; resonances are given in δ relative to tetramethylsilane: 0.9-2.2 (mutiplet 37 protons); 2.9-3.8 (multiplet 3 protons); 4.0 (triplet, 2 protons) 5.3 (multiplet, 2 protons).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:16]2[CH:21]=[CH:20][C:19](Br)=[CH:18][N:17]=2)([C:14]#[N:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(P(C(C)(C)C)C1C=CC2C(=CC=CC=2)C=1C1C2C(=CC=CC=2)C=CC=1)(C)(C)C.C(O[Na])(C)(C)C.C(=[NH:71])(C1C=CC=CC=1)C1C=CC=CC=1.O.NO.C([O-])(=O)C.[Na+].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:16]2[CH:21]=[CH:20][C:19]([NH2:71])=[CH:18][N:17]=2)([C:14]#[N:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccc(Br)cn2)CC1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)O[Na]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccc(N)cn2)CC1
Temperature: 120 °C
Reaction time: 7 h

Procedure:
To a suspension of 4-(5-bromopyridin-2-yl)-4-cyanopiperidine-1-carboxylic acid tert-butyl ester (7.1 g), palladium(II) acetate (554 mg), (±)-2-(di-tert-butylphosphino)-1,1′-binaphthyl (1.51 g), and tert-butoxysodium (2.79 g) in toluene (48 ml) was added benzophenone imine (3.42 ml), stirred at 120° C. for 7 hours, then ethanol (48 ml), hydroxylamine monohydrate (5.4 g), and sodium acetate (9.54 g) were added thereto at room temperature, and stirred for 3.5 hours. To the reaction solution was added water (48 ml), stirred, then an aqueous solution of sodium hydrogen carbonate was added thereto, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and then the solvent was evaporated in vacuo. The obtained residue was purified with basic silica gel chromatography (n-hexane/ethyl acetate) to give 4-(5-aminopyridin-2-yl)-4-cyanopiperidine-1-carboxylic acid tert-butyl ester (4.0 g) as a white solid. 1H-NMR (DMSO-d6) δ (ppm): 1.40 (9H, s), 1.82-1.89 (2H, m), 2.08 (2H, J=12.8 Hz), 3.00 (2H, brs), 4.04 (2H, J=12.8 Hz), 6.96 (1H, dd, J=8.7, 3.1 Hz), 7.21 (1H, d, J=8.2 Hz), 7.92 (1H, d, J=2.6 Hz).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([C:12]2[CH:34]=[CH:33][C:15]([O:16][C:17]3[CH:26]=[C:25]4[C:20]([CH:21]([C:27]([O:29]C)=[O:28])[CH2:22][CH2:23][O:24]4)=[CH:19][C:18]=3[C:31]#[N:32])=[CH:14][CH:13]=2)=[O:11])=[N:7][CH:8]=1.[OH-].[Na+].CO>C1COCC1.C(OCC)(=O)C.Cl>[F:36][C:2]([F:1])([F:35])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([C:12]2[CH:34]=[CH:33][C:15]([O:16][C:17]3[CH:26]=[C:25]4[C:20]([CH:21]([C:27]([OH:29])=[O:28])[CH2:22][CH2:23][O:24]4)=[CH:19][C:18]=3[C:31]#[N:32])=[CH:14][CH:13]=2)=[O:11])=[N:7][CH:8]=1
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4ccc(C(F)(F)F)cn4)cc3)c(C#N)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#Cc1cc2c(cc1Oc1ccc(C(=O)Nc3ccc(C(F)(F)F)cn3)cc1)OCCC2C(=O)O
Reaction time: 2 h
Yield: 23 %

Procedure:
Methyl 7-(4-((5-(trifluoromethyl)pyridin-2-yl)carbamoyl)phenoxy)-6-cyanochroman-4-carboxylate (9 mg, 0.018 mmol) was diluted with THF (500 μL) followed by the addition of sodium hydroxide (0.11 mL, 0.11 mmol) and methanol (100 μL). After stirring for 2 hours, the reaction was diluted with ethyl acetate and 1N HCl. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated. The material was purified using a reverse phase biotage 12iC18 column eluting with 0.1% TFA/5% ACN/95% water to 0.1% TFA/95% ACN/5% water to yield 7-(4-((5-(trifluoromethyl)pyridin-2-yl)carbamoyl)phenoxy)-6-cyanochroman-4-carboxylic acid (2.0 mg, 23% yield). MS (ESI)=484.0 (M+1).
Reaction SMILES: C([O:8][CH2:9][C:10](=[O:19])[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])C1C=CC=CC=1>CO.[Pd]>[OH:8][CH2:9][C:10](=[O:19])[CH2:11][C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13]
Reactant: CC(C)(C)OC(=O)CC(=O)COCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)CC(=O)CO
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 65 %

Procedure:
A mixture of 963 mg (5 mmol) of tert.-butyl 4-benzyloxyacetoacetate and 200 mg of palladium (10% on charcoal) in 50 ml of methanol was stirred at room temperature under a hydrogen atmosphere (1 atmosphere) for 1.5 hours. The catalyst was filtered off washed with a little methylene chloride. The filtrate solution was evaporated in vacuo and the residue was filtered through 3 g of neutral aluminum oxide (methylene chloride). The solvent was evaporated off in vacuo and the oil which remained was dried under a high vacuum. 567 mg (65% of tert.-butyl 4-hydroxyacetoacetate were obtained, and were used immediately for further reactions.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@H:21]([OH:23])[CH3:22])[CH2:12][C@@H:11]([O:31][Si](C(C)(C)C)(C)C)[CH2:10]1)(C(C)(C)C)(C)C.CC(C)([O-])C.[K+].C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1.[O:71]1[C@H:73]([CH:74]([CH3:76])[CH3:75])[CH2:72]1.[Si](O[C@@H]1[C@@]2(C)C(=CC=C3[C@@H]2CC[C@@]2(C)[C@H]3CC=C2[C@H](OC[C@H](O)C(C)C)C)C[C@@H](O[Si](C(C)(C)C)(C)C)C1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C1(C)C=CC=CC=1>[OH:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@H:21]([O:23][CH2:72][C@H:73]([OH:71])[CH:74]([CH3:76])[CH3:75])[CH3:22])[CH2:12][C@@H:11]([OH:31])[CH2:10]1
Reactant: CC(C)[C@@H]1CO1
Reactant: C[C@@H](O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C)(C)[O-]
Agent: CC(C)[C@@H](O)CO[C@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)[C@@H](O)CO[C@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 18.1 %

Procedure:
Using 1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-hydroxypregna-5,7,16-triene (69.7 mg, 0.125 mmol), potassium t-butoxide (170 mg, 1.52 mmol), dibenzo-18-crown-6 (22.0 mg, 0.0610 mmol), toluene (4 ml) and (R)-(−)-1,2-epoxy-3-methylbutane (0.13 ml, 1.24 mmol), alkylation reaction (109° C., 1 hour) and work up were performed by the same procedure as in Example 119, and then the residue was separated by preparative thin layer chromatography (0.5 mm×3, hexane:dichloromethane:ethyl acetate=45:5:2, developed three times) to give a fraction containing 1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-{2(R)-hydroxy-3-methylbutyloxy}pregna-5,7,16-triene (23.6 mg). An aliquot of 21.1 mg was deprotected with tetrahydrofuran (1 ml) and 1M tetra-n-butylammonium fluoride solution in tetrahydrofuran (0.2 ml) (reaction temperature 76° C., reaction period 13 hours) and worked up by the same procedure as in Example 119, and then the residue was purified by preparative thin layer chromatography (0.25 mm×1, dichloromethane:ethanol=15:1, developed twice) to give the title compound as a colorless oil (9.4 mg, 20%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:5][C:4]=1[OH:21].N(C(N(C)C)=O)=NC(N(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:54][CH2:55][NH:56]C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:5][C:4]=1[O:21][CH2:54][CH2:55][NH2:56]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: COc1cc2c(ccn2S(=O)(=O)c2ccccc2)cc1O
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2c(ccn2S(=O)(=O)c2ccccc2)cc1OCCN
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 110.7 %

Procedure:
To 6-methoxy-1-(phenylsulfonyl)-1H-indol-5-ol (Intermediate 15, 2.0 g, 6.6 mmol), 1,1′-azobis(N,N-dimethylformamide) (2.3 g, 13 mmol), triphenylphosphine (3.5 g, 13 mmol), tert-butyl N-(2-hydroxy-ethyl)carbamate (2.1 g, 13 mmol) and DCM (40 mL) were added. The mixture was heated at 150° C. for 20 minutes in a microwave heater. The reaction mixture was allowed to cool to room temperature and TFA (30 mL) was added. The reaction mixture was allowed to stir at room temperature for 30 minutes. The solvent was removed under reduced pressure and the crude material was purified by flash chromatography on silica gel using 5% MeOH in DCM as the eluent to afford the title compound (2.53 g) MS m/z 347 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:22][CH2:23][CH2:24][C:25]#[N:26]>CC#N>[C:25]([CH2:24][CH2:23][CH2:22][N:12]1[CH2:13][CH2:14][N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:10][CH2:11]1)#[N:26]
Reactant: COc1ccccc1N1CCNCC1
Reactant: N#CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccccc1N1CCN(CCCC#N)CC1
Yield: 75 %

Procedure:
A mixture of 2-methoxy-phenylpiperazine (8 g), K2CO3 (2.5 eq) and 4-bromobutyronitrile (1.05 eq) in CH3CN (150 mL) was refluxed for 10 h. After filtration and concentration in vacuo, the residue is taken up in AcOEt (1000 ml), washed with H2O, the organic layer is washed with aqueous HCl (50 mL, 1 M). Then the acid layer is washed with AcOEt (2×20 ml) and neutralized with aqueous NH3 (28% in H2O) until pH 11. Extraction is carried out with AcOEt, the organic layer is dried with Na2SO4 and concentrated in vacuo. The residual solid is crystallized in hexane to give the title compound (6.8 g, 75%, mp 74° C.). 1H NMR (200 MHz, CDCl3) δ 1.80-1.94 (m, 2H), 2.43-2.57 (m, 4H), 2.62-2.67 (m, 4H), 3.09 (m, 4H), 3.87 (s, 3H), 6.85-7.04. 13C NMR (50 MHz, CDCl3) δ 14.9, 22.7, 50.5, 53.2, 55.3, 56.3, 111.1, 118.1, 119.8, 120.9, 122.9, 141.1, 152.2.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][OH:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[O:13]=[S:14]1(=[O:37])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:16]([NH:23][C@@H:24]([CH2:29][C:30]2[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=2)[C:25]([O:27][CH3:28])=[O:26])=[N:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[O:13]=[S:14]1(=[O:37])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:16]([NH:23][C@@H:24]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([O:12][CH2:11][C:9]3[CH:8]=[CH:7][C:6]4[O:1][CH2:2][CH2:3][O:4][C:5]=4[CH:10]=3)=[CH:32][CH:31]=2)[C:25]([O:27][CH3:28])=[O:26])=[N:15]1
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC1=NS(=O)(=O)c2ccccc21
Reactant: OCc1ccc2c(c1)OCCO2
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccc(OCc2ccc3c(c2)OCCO3)cc1)NC1=NS(=O)(=O)c2ccccc21
Temperature: 5 °C

Procedure:
2,3-Dihydro-1,4-benzodioxin-6-ylmethanol (0.25 g, 1.5 mmol), methyl (2S)-2-[(1,1-dioxo-1,2-benzoisothiazol-3-yl)amino]-3-(4-hydroxyphenyl)-propionate (0.36 g, 1 mmol) and triphenylphosphine (0.79 g, 3 mmol) were dissolved in tetrahydrofuran (3 ml). After cooling to 5° C., DIAD (0.61 g, 3 mmol) was added to the reaction mixture. The reaction was then stirred at room temperature for 18–24 h. THF was evaporated to obtain crude title product.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[N:4][C:5](Br)=[CH:6][CH:7]=1.[F:10][CH:11]([F:14])[CH2:12][OH:13].CC(C)([O-])C.[K+].O>C1COCC1>[Br:1][C:2]1[C:3]([CH3:9])=[N:4][C:5]([O:13][CH2:12][CH:11]([F:14])[F:10])=[CH:6][CH:7]=1
Reactant: Cc1nc(Br)ccc1Br
Reactant: OCC(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(OCC(F)F)ccc1Br
Temperature: 70 °C
Reaction time: 12 h
Yield: 96.6 %

Procedure:
To a mixture of 3,6-dibromo-2-methylpyridine (2.00 g, 7.97 mmol) and 2,2-difluoroethanol (981 mg, 12.0 mmol) in THF (100 mL) is added potassium tert-butoxide (1.34 g, 12.0 mmol), and the mixture is stirred at 70° C. for 12 hours. After cooling to room temperature, the resulting mixture is poured to water (200 mL). The aqueous layer is extracted with ethyl acetate (200 mL×2). The organic layer is dried over sodium sulfate and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (8:1) to give 1.94 g (97% yield) of the title compound as colorless oil.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Cl.[CH3:12][CH2:13][O:14][CH2:15][CH3:16].C(OCC)=C>C(OCC)(=O)C>[CH2:13]([O:14][CH:15]([O:10][C:7]1[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=1)[CH3:16])[CH3:12]
Reactant: CC(C)c1ccc(O)cc1
Reactant: CCOCC
Agent: C=COCC
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(C)Oc1ccc(C(C)C)cc1

Procedure:
To 50 ml of dehydrated ethyl acetate (AcOEt) were added 5.0 g (36.7 mmol) of 4-isopropylphenol and 1.7 ml of hydrochloric acid/ether (HCl-Ether) solution (1.0 mol/L), and temperature of the reaction system was controlled to 40° C. Ethyl vinyl ether (7.9 g: 109.6 mmol) was added dropwise to the mixture, and the resultant mixture was stirred overnight. After the completion of the reaction, the reaction mixture was washed with an aqueous solution of sodium hydrogencarbonate, and washed with water to remove the solvent. Thus obtained mixture was purified by silica gel column chromatography (eluent: hexane) to provide 7.0 g (33.6 mmol) of 1-(1-ethoxy)ethoxy-4-isopropylbenzene.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]([C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[C:19]([Cl:27])[CH:18]=1)=[N:5][NH:6]S(C1C=CC(C)=CC=1)(=O)=O.C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3](=[O:28])[C:4]([C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[C:19]([Cl:27])[CH:18]=1)=[N+:5]=[N-:6]
Reactant: COC(=O)C(=NNS(=O)(=O)c1ccc(C)cc1)c1ccc(S(C)(=O)=O)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(=[N+]=[N-])c1ccc(S(C)(=O)=O)c(Cl)c1
Reaction time: 1 h
Yield: 39.9 %

Procedure:
A solution of (3-chloro-4-methanesulfonyl-phenyl)-(4-toluenesulfonyl-hydrazono)-acetic acid methyl ester (3.82 g, 8.5 mmol) and triethylamine (1.3 mL, 9.35 mmol) in dichloromethane (40 mL) was stirred at 25° C. After 1 h, the reaction was evaporated under reduced pressure and the resulting residue was purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 60/40 hexanes/ethyl acetate) to give (3-chloro-4-methanesulfonyl-phenyl)-diazo-acetic acid methyl ester (978 mg, 40% yield) as a bright yellowish orange solid, mp 102.7-106.5° C.; EI-HRMS m/e calcd for C10H9N2ClSO4 (M+) 287.9972, found 287.9979.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:32]=[C:6]2[N:7]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:8]([CH3:21])=[C:9]([C:19]#[N:20])[C@@H:10]([C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=3)[N:5]2[N:4]=1.[C:33](Cl)(=[O:37])[CH:34]([CH3:36])[CH3:35]>N1C=CC=CC=1>[C:19]([C:9]1[C@@H:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:5]2[N:4]=[C:3]([NH:2][C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[N:32]=[C:6]2[N:7]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:31])[F:30])[CH:23]=2)[C:8]=1[CH3:21])#[N:20]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N)nc2N1c1cccc(C(F)(F)F)c1
Reactant: CC(C)C(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NC(=O)C(C)C)nc2N1c1cccc(C(F)(F)F)c1
Reaction time: 12 h

Procedure:
Under an atmosphere of argon protective gas, (7R)-2-amino-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile hydrochloride (30 mg, 66 μmol) was dissolved in abs. pyridine (1.5 ml). At room temperature, isobutyryl chloride (21 mg, 107 μmol, 3 eq.) was added. After 12 h of stirring, analysis of the reaction by HPLC showed substantial conversion. The reaction mixture was concentrated under reduced pressure and directly purified by preparative HPLC (Gromsil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (24.5 mg, 76% of theory).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH2:9]([Sn](CCCC)(CCCC)C=C)[CH2:10]CC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:9]=[CH2:10])=[CH:4][N:3]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Fc1ccc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc(F)nc1

Procedure:
A mixture of 7.0 g (0.04 mole) 2-fluoro-5-bromopyridine, 15.3 g (0.048 mole) tributyl(vinyl)stannane, 2.5 g (0.002 mole) tetrakis(triphenylphosphine)palladium in 70 ml toluene was boiled with reflux during 16 hours. Toluene was evaporated with a 30 cm column. The residue was fractionated twice.
Reaction SMILES: [C:1]1([C@@:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([OH:11])[C:8]([OH:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[H][H]>CO.[Pd]>[CH2:15]1[CH2:14][CH2:13][CH:12]([C@@:7]([OH:11])([C:8]([OH:10])=[O:9])[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:17][CH2:16]1
Reactant: [H][H]
Reactant: O=C(O)[C@](O)(C1=CCCCC1)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=C(O)[C@@](O)(c1ccccc1)C1CCCCC1
Reaction time: 18 h
Yield: 90.2 %

Procedure:
To a solution of (S)-Cyclohexenyl phenyl glycolic acid (1.11 g, 4.78 mmol) in methanol (16 mL) was added 10% Pd/C (0.11 g). The reaction was subjected to 1 ATM of Hydrogen and was allowed to stir for 18 h. The reaction mixture was filtered through a plug of celite and concentrated in vacuo to provide 1.01 g of (S)-CHPGA (91%, 98.3% e.e.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:27])[CH2:9][CH2:10][CH:11]([C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[CH3:26])[O:12][CH2:13][C:14](OCC)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[Cl:25][C:23]1[CH:22]=[CH:21][C:20]([CH3:26])=[C:19]([CH:11]([O:12][CH2:13][CH2:14][OH:15])[CH2:10][CH2:9][N:8]([CH3:27])[C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])[CH:24]=1
Reactant: CCOC(=O)COC(CCN(C)C(=O)OC(C)(C)C)c1cc(Cl)ccc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(Cl)cc1C(CCN(C)C(=O)OC(C)(C)C)OCCO
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 55.9 %

Procedure:
To a solution of ethyl 2-(3-(tert-butoxycarbonyl(methyl)amino)-1-(5-chloro-2-methylphenyl) propoxy)acetate (800 mg, 2 mmol) in MeOH (16 mL) was added NaBH4 (305 mg, 8 mmol) in portions while the temperature was lower than 40° C. After addition, the mixture was stirred at room temperature for 2-3 h. The solvent was removed in vacuo to the residue, which was partitioned between water and ethyl acetate. The organic layer was washed with H2O and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified on silica gel chromatography to afford tert-butyl 3-(5-chloro-2-methylphenyl)-3-(2-hydroxyethoxy)propyl(methyl)carbamate (400 mg, 56%). 1H NMR (CDCl3, 400 MHz) δ 1.22 (m, 3H), 1.43 (m, 9H), 1.87 (m, 2H), 2.21 (s, 3H), 2.87 (s, 3H), 3.39 (m, 2H), 3.80 (m, 1H), 4.00 (m, 1H), 4.61 (m, 1H), 7.08 (m, 2H), 7.37 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:12][C:13]([F:16])([F:15])[F:14])[C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)C=O.[CH:17]([O:24][CH2:25][CH3:26])([O:21][CH2:22][CH3:23])OCC>CCCCCC>[Br:1][C:2]1[CH:3]=[C:4]([O:12][C:13]([F:14])([F:15])[F:16])[C:5]([O:10][CH3:11])=[C:6]([CH:17]([O:21][CH2:22][CH3:23])[O:24][CH2:25][CH3:26])[CH:9]=1
Reactant: CCOC(OCC)OCC
Reactant: COc1c(C=O)cc(Br)cc1OC(F)(F)F
Solvent: CCCCCC
Product: CCOC(OCC)c1cc(Br)cc(OC(F)(F)F)c1OC

Procedure:
5-bromo-2-methoxy-3-trifluoromethoxybenzaldehyde (5.22 g) was dissolved in n-hexane (15 mL) and triethyl orthoformate (4.4 mL), and Amberlyst-15 (522 mg) was added to the solution, and then the mixture was refluxed for 3 hours. The reaction solution was filtered, and then the solvent was distilled off under reduced pressure to obtain the title compound (6.19 g) as a brown oily substance.