Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:26](O)=[O:27])=[C:8]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:14][CH:13]=2)[N:9]=1)(=[O:3])[CH3:2].[NH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl>CN(C)C=O>[C:1]([NH:4][C:5]1[S:6][C:7]([C:26]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])=[C:8]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:20])[O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[CH:14][CH:13]=2)[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(CCc2ccc(NC(=O)OC(C)(C)C)cc2)c(C(=O)O)s1
Reactant: Nc1ccccc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1nc(CCc2ccc(NC(=O)OC(C)(C)C)cc2)c(C(=O)Nc2ccccc2)s1
Temperature: 55 °C
Reaction time: 3 h

Procedure:
A mixture of 2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl)amino]phenyl}ethyl)-1,3-thiazole-5-carboxylic acid (80.mg), aniline (0.019 ml), benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (113 mg) and N,N-diisopropylethylamine (0.076 ml) in N,N-dimethylformamide (2 ml) was stirred at ambient temperature for 21 hours and at 55 ° C. for 3 hours. The reaction mixture was poured into 1N hydrochloric acid, and extracted with chloroform. The organic layer was washed with water, saturated sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residual solid was washed with ethyl ether to give tert-butyl 4-{2-[2-(acetylamino)-5-(anilinocarbonyl)-1,3-thiazol-4-yl]ethyl}phenylcarbamate (57.2 mg) as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:24]=[CH:23][C:20](C=O)=[CH:19][CH:18]=3)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:37]([O:42][CH3:43])([O:40][CH3:41])OC>CO>[Br:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:24]=[CH:23][C:20]([CH:37]([O:40][CH3:41])[O:42][CH3:43])=[CH:19][CH:18]=3)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: COC(OC)OC
Reactant: CC(C)Oc1ccc(-c2noc(-c3ccc(C=O)cc3)n2)cc1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COC(OC)c1ccc(-c2nc(-c3ccc(OC(C)C)c(Br)c3)no2)cc1
Yield: 96 %

Procedure:
4-(3-(3-bromo-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)benzaldehyde (0.551 g, 1.423 mmol), molecular sieve (4A, 8-12 mesh, 130 mg) and p-toluenesulfonic acid monohydrate (0.037 g, 0.195 mmol) were added in trimethyl orthoformate (4 ml, 36.2 mmol) and methanol (6 ml), the reaction mixture was heated at 80° C. for 16 hr. The solution was cooled, the reaction mixture was concentrated to afford grey solid, which was purified via silica gel chromatography (12 g, 20% EtOAc:Heptane) to afford 3-(3-bromo-4-isopropoxyphenyl)-5-(4-(dimethoxymethyl)phenyl)-1,2,4-oxadiazole (0.61 g, 1.366 mmol, 96% yield) as white solid.
Reaction SMILES: [F:1][C:2]1[CH:31]=[C:30]([N+:32]([O-])=O)[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH2:18][CH:19]3[CH2:27][CH:22]4[CH2:23][N:24]([CH3:26])[CH2:25][CH:21]4[CH2:20]3)=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1.CN(C=O)C>[Pd].CO>[F:1][C:2]1[CH:31]=[C:30]([NH2:32])[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH2:18][CH:19]3[CH2:20][CH:21]4[CH2:25][N:24]([CH3:26])[CH2:23][CH:22]4[CH2:27]3)=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1
Reactant: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1OCC1CC2CN(C)CC2C1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cc2c(Oc3ccc(N)cc3F)ccnc2cc1OCC1CC2CN(C)CC2C1

Procedure:
To a par hydrogenation reaction vessel was added 4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-7-(2-methyl-octahydro-cyclopenta[c]pyrrol-5-ylmethoxy)-quinoline (0.800 g, 1.6 mmol, 1.0 eq.), DMF (50 ml), EtoAc (50 ml), MeOH (50 ml), TEA (5 ml) and 10% Pd/C (200 mg). The vessel was placed on the par hydrogenator at 35 psi overnight. The Pd was filtered and the solvent removed to give 3-fluoro-4-[6-methoxy-7-(2-methyl-octahydro-cyclopenta[c]pyrrol-5-ylmethoxy)-quinolin-4-yloxy]-phenylamine as an off yellow solid (0.78 g, 99% yield). 1H NMR (400 MHz, CDCl3): 8.45 (d, 1H), 7.57 (s, 1H), 7.36 (s, 1H), 7.05 (t, 1H), 6.54 (m, 2H), 6.39 (d, 1H), 4.16 (d, 2H), 4.01 (s, 3H), 3.81 (m, 3H), 2.61 (m, 3H), 2.41 (m, 1H), 2.29 (s, 3H), 2.23 (m, 2H), 1.32 (m, 2H); MS (EI) for C25H28FN3O3: 438 (M+H+).
Reaction SMILES: CON(C)[C:4](=[O:18])[C@@H:5]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:6].[CH3:20][Mg]Br.C1COCC1.C1(C)C=CC=CC=1.O>C1COCC1>[O:18]=[C:4]([CH3:20])[C@@H:5]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH3:6]
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OCc1ccccc1
Reactant: C[Mg]Br
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(=O)[C@H](C)NC(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Under argon, 1000 mg of benzyl {(2S)-1-[methoxy(methyl)amino]-1-oxopropan-2-yl}carbamate (Example 148A, 3.8 mmol, 1 equivalent) were dissolved in 19.5 ml of THF and cooled to −78° C. At this temperature, 4 ml of 1.4 M methylmagnesium bromide solution in 1:3 THF/toluene (6 mmol, 1.5 equivalents) were added slowly. The mixture was stirred at −78° C. for 5 min and at RT for 1 h and allowed to stand at RT overnight. 0.27 ml of water was then added with ice cooling, and the mixture was concentrated. The residue was diluted with water and 1 N aqueous hydrochloric acid solution and extracted four times with ethyl acetate. The organic phase was washed with saturated aqueous sodium bicarbonate solution and with saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and concentrated. This gave 813 mg (88% of theory; purity 90%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C(=O)([O-])[O-].[K+].[K+].[C:15](Cl)(=[O:24])[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O.CC(C)=O>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:15](=[O:24])[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ccccc1F
Reactant: O=C(Cl)C=Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(C=Cc1ccccc1)Nc1ccccc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-fluoroaniline (25.0 g, 225 mmol) and potassium carbonate (47 g, 337 mmol) in water (112 mL) and acetone (45 mL) at 0° C. was added cinnamoyl chloride (37 g, 225 mmol, 1 eq) in acetone (45 mL) over 2 h. The reaction was stirred for 1 h @ 0° C., then quenched into 200 mL of ice-water. The white crystalline solid was filtered and washed with water. The solid was air dried for 2 h, then washed with 400 mL of hexanes. The solid was dried under vacuum overnight to afford product. 1 H NMR (400 MHz, CDCl3) δ ppm 8.49 (br t, J=7.8 Hz, 1H), 7.80 (d, J=15.3 Hz, 1H), 7.57 (m, 3H), 7.41 (m, 3H), 7.17 (m, 3H), 6.61 (d, J=15.6 Hz, 1H). Mass Spectrum (ESI) m/e=242.1 (M+1).
Reaction SMILES: [K+].[N:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[C:18]([O-:20])=[O:19])=[CH:4][CH:3]=1.CN(C=O)C.Cl[CH2:27][N:28]([CH3:39])[S:29]([C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=1)(=[O:31])=[O:30].O>C1COCC1>[CH3:27][N:28]([CH2:39][O:19][C:18]([C:10]1[NH:11][C:12]2[C:17]([C:9]=1[NH:8][C:5]1[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:20])[S:29]([C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=1)(=[O:30])=[O:31]
Reactant: O=C([O-])c1[nH]c2ccccc2c1Nc1ccncc1
Reactant: Cc1ccc(S(=O)(=O)N(C)CCl)cc1
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N(C)COC(=O)c2[nH]c3ccccc3c2Nc2ccncc2)cc1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 23.2 %

Procedure:
Under N2 at 60° C. dissolve 3-(4-pyridinylamino)-1H-indole-2-carboxylic acid potassium salt (2.0 g, 6.89mmol) in a mixture of anhydrous THF and DMF (60:10 mL Cool to −5° C. add piperidinomethyl polystyrene HL resin (NOVA #01-64-0212, 30 mg) and follow with a solution of N-chloromethyl-N-methyl-4-methylbenzenesulfonamide (1.9 g, 8.34 mmol) in anhydrous THF (10 mL) dropwise. After 30 min, add water (100 mL) and then extract with dichloromethane (3×50 mL). Combine organic layers, wash with NaHCO3 (sat), water, brine, dry with MgSO4 and then concentrate. Purify the residue on an ISCO RediSep 35-gram silicagel cartridge, eluting with 50% heptane/ethyl acetate, ethyl acetate and then 10% methanol/ethyl acetate. Combine product containing fractions and concentrate to a solid (1.1 g). Wash the solid with methanol/ether, and dry to give the title compound as a white solid (720 mg): TLC (silica gel, EtOAc/MeOH, 8:2), Rf=0.49, 1H NMR (DMSO-d6) δ 11.47 (1H, s), 8.32 (1H, s), 8.09 (2H, d, J=5.7 Hz), 7.63 (2H, d, J=8.3 Hz), 7.48 (1H, d, J=8.3 Hz), 7.34 (2H, m), 7.14 (3H, m), 6.52 (2H, d, J=6.0 Hz), 5.61 (2H, s), 2.83 (3H, s), 2.05 (3H, s).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])([CH2:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[CH2:17][CH2:16][CH2:15]2)[CH2:7][C:8]([OH:10])=O)=[O:5])[CH3:2].[NH:26]1[CH2:31][CH2:30][CH:29]([N:32]2[CH2:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[NH:34][C:33]2=[O:42])[CH2:28][CH2:27]1>>[CH2:17]1[C:18]2[C:19](=[CH:20][C:12]([CH2:11][C:6]([CH2:7][C:8](=[O:10])[N:26]3[CH2:27][CH2:28][CH:29]([N:32]4[CH2:41][C:40]5[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=5)[NH:34][C:33]4=[O:42])[CH2:30][CH2:31]3)([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:13][CH:14]=2)[CH2:15][CH2:16]1
Reactant: CCOC(=O)C(CC(=O)O)(Cc1ccc2c(c1)CCC2)C(=O)OCC
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Product: CCOC(=O)C(CC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1)(Cc1ccc2c(c1)CCC2)C(=O)OCC

Procedure:
Prepared analogously to Example 76c) from 3,3-bis-ethoxycarbonyl-4-indan-5-yl-butanoic acid and 3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]([C:14]([O:16]CC)=[O:15])[C:7]2=[O:19].O.Cl>CCO>[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]([C:14]([OH:16])=[O:15])[C:7]2=[O:19]
Reactant: CCOC(=O)c1c[nH]c2ccc(Br)cc2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1c[nH]c2ccc(Br)cc2c1=O
Temperature: 75 °C
Reaction time: 1.5 h
Yield: 95.7 %

Procedure:
2N Sodium hydroxide (506 mL, 1011.43 mmol) was added to a stirred suspension of ethyl 6-bromo-4-oxo-1H-quinoline-3-carboxylate (59.9 g, 202.29 mmol) in EtOH (590 mL) and the resulting solution stirred at 75° C. for 1.5 h. Water was added and the mixture cooled to 0° C. The pH of the solution was adjusted to 3 using hydrochloric acid and the precipitate collected by filtration. The solid was washed with water, EtOH/water (1:1) then Et2O before being dried to afford the desired material (51.9 g, 96%) as a beige solid. NMR Spectrum: 1H NMR (500 MHz, DMSO-d6) δ 7.80 (1H, d), 8.05 (1H, d), 8.37 (1H, s), 8.93 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=270.
Reaction SMILES: Br[CH2:2][C:3]1[S:7][CH:6]=[N:5][C:4]=1[C:8](=[O:10])[CH3:9].[SH:11][C:12]1[N:17]=[C:16]([OH:18])[CH:15]=[C:14]([C:19]([F:22])([F:21])[F:20])[N:13]=1.C(N(CC)CC)C>C(O)C>[C:8]([C:4]1[N:5]=[CH:6][S:7][C:3]=1[CH2:2][S:11][C:12]1[N:17]=[C:16]([OH:18])[CH:15]=[C:14]([C:19]([F:22])([F:20])[F:21])[N:13]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1ncsc1CBr
Reactant: Oc1cc(C(F)(F)F)nc(S)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(=O)c1ncsc1CSc1nc(O)cc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 34.4 %

Procedure:
To a mixture of 1-[5-(bromomethyl)-1,3-thiazol-4-yl]ethan-1-one (615 mg, 2.8 mmol) and 2-sulfanyl-6-(trifluoromethyl)pyrimidin-4-ol (255 mg, 1.3 mmol) in absolute ethanol (25 mL) at 0° C. was added triethylamine (725 μL, 5.2 mmol). The mixture was stirred at room temperature for 4 hours. The mixture was evaporated, and the solid residue was treated with diethyl ether (50 mL). The solid salts were removed by filtration. The filtrate was recovered and evaporated. The crude product was purified by flash chromatography (0-10% MeOH/CH2Cl2 and 0-5% MeOH/CH2Cl2), affording 2-{[(4-acetyl-1,3-thiazol-5-yl)methyl]sulfanyl}-6-(trifluoromethyl)pyrimidin-4-ol (150 mg, 34%); 1H NMR (500 MHz, DMSO-d6): δ 2.71 (s, 3H), 4.82 (s, 2H), 6.58 (s, 1H), 8.99 (s, 1H); M+336.
Reaction SMILES: C[O:2][C:3]([CH2:5][C:6]1[CH:29]=[CH:28][C:9]([O:10][CH2:11][C@@H:12]2[CH2:27][N:15]3[CH2:16][CH2:17][N:18]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][N:21]=4)[CH2:19][C@@H:14]3[CH2:13]2)=[CH:8][CH:7]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[OH:2][CH2:3][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:10][CH2:11][C@@H:12]2[CH2:27][N:15]3[CH2:16][CH2:17][N:18]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][N:21]=4)[CH2:19][C@@H:14]3[CH2:13]2)=[CH:28][CH:29]=1
Reactant: COC(=O)Cc1ccc(OC[C@H]2C[C@H]3CN(c4ccc(Cl)cn4)CCN3C2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCCc1ccc(OC[C@H]2C[C@H]3CN(c4ccc(Cl)cn4)CCN3C2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 101.6 %

Procedure:
A solution of 0.15 g (0.33 mmol) of (7S,8aS)-7-(4-((methoxycarbonyl)methyl)phenoxy)methyl-2-(5-chloropyridin-2-yl)-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine (Example 13d) in 15 mL of anhydrous ethyl ether was added dropwise to an ice-cold suspension of 0.027 g (0.65 mmol) of lithium aluminum hydride in 15 mL of anhydrous ethyl ether and the mixture stirred for 30 min. The reaction was carefully quenched at 0° C. with 0.027 mL of water, 0.027 mL of 15% sodium hydroxide, and 0.081 mL of water. The precipiate which formed was filtered through Celite, the filtrate concentrated in vacuo, and purification of the residue by flash silica gel chromatography with 95:5 chloroform:methanol gave 0.13 g (95%) of the title compound. mp (.HCl) 199°-202° C. HRMS calcd for C21H27ClN3 O2 (MH+): 388.1792, found: 388.1807.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][CH:7]=[CH:6][CH:5]=[CH:4][N:3]1[CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[N:12]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:11]([CH3:24])([CH3:23])[CH2:10]1.[CH3:25][N:26]1[C:31](C)([CH3:32])[CH2:30]C(O)[CH2:28][C:27]1([CH3:36])[CH3:35].[NH2-].[Li+]>C1(C)C(C)=CC=CC=1>[O:1]=[C:2]1[CH2:8][CH:7]=[CH:6][CH:5]=[CH:4][N:3]1[CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[N:12]([CH2:17][C:18]([O:20][CH:21]2[CH2:28][C:27]([CH3:36])([CH3:35])[N:26]([CH3:25])[C:31]([CH3:32])([CH3:30])[CH2:22]2)=[O:19])[C:11]([CH3:23])([CH3:24])[CH2:10]1
Reactant: CCOC(=O)CN1C(C)(C)CC(N2C=CC=CCC2=O)CC1(C)C
Reactant: CN1C(C)(C)CC(O)CC1(C)C
Agent: [Li+]
Agent: [NH2-]
Solvent: Cc1ccccc1C
Product: CN1C(C)(C)CC(OC(=O)CN2C(C)(C)CC(N3C=CC=CCC3=O)CC2(C)C)CC1(C)C
Reaction time: 5 h

Procedure:
A solution of 7.5 g (0.022 mole) of ethyl 4-(2-oxo-1-azepinyl)-2,2,6,6-tetramethylpiperidin-1-ylacetate and 4.2 g (0.024 mole) of 1,2,2,6,6-pentamethylpiperidin-4-ol in 50 ml of xylene is heated for one hour at 120° C. in the presence of 0.1 g of lithium amide esterification catalyst. The xylene-ethanol azeotropic mixture is slowly distilled off using an oil bath held at 150° C. to heat the reaction vessel. After five hours, four drops of acetic acid is added to the reaction mixture and the xylene solvent is removed by distillation.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH2:2][CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5].[OH-].[K+].[CH2:12]1[O:14][CH2:13]1>>[C:1]([O:9][CH2:12][CH2:13][OH:14])(=[O:8])[CH2:2][CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)CCC(=O)O
Reactant: C1CO1
Agent: [K+]
Agent: [OH-]
Product: CC(C)(C)CCC(=O)OCCO
Temperature: 25 °C

Procedure:
To a 1 liter glass flask is added one mole of neoheptanoic acid and 1 gm of potassium hydroxide (solid), to provide the base catalyst for the subsequent ethoxylation reaction. Gaseous nitrogen is introduced to purge oxygen from the flask. A conventional bubbler device provided with NUJOL® oil is provided in the nitrogen gas feed line to the reaction flask. Gases discharged from the reaction flask are passed through a second such bubbler device. With continuous nitrogen flow through the flask, the temperature of the neo-acid/base mixture is raised to 150° C. at a rate of about 10° C./min. by means of a heating mantle. Thereafter, gaseous nitrogen flow is stopped and is replaced with gaseous ethylene oxide which is permitted to bubble through the neo-acid mixture. Periodic withdrawal of samples of the reaction mixture are made which are titrated to determine the level of residual neo-acid. The addition of ethylene oxide is controlled such that substantially all of the ethylene oxide introduced is reacted, thereby avoiding gaseous throughput through the gas withdrawal line of the reaction vessel. The adsorption of the ethylene oxide is also controlled such that there is no substantial rise in temperature of the reaction vessel due to any reaction exotherm. When it is determined that the proper amount of ethylene oxide has been added (via titration, as described above), the flow of ethylene oxide is terminated, and the reaction vessel is again purged with gaseous nitrogen and allowed to cool to room temperature. (An excess of ethylene oxide should be avoided). The crude product is then washed with water until the washwater is determined to be neutral. The monoethyoxylate thereby obtained is distilled at a pressure of 100 mmHg.
Reaction SMILES: C([O:5][C:6](=[O:32])[C:7]1[CH:12]=[CH:11][C:10]([C:13]([N:15]2[C:23]3[C:18](=[CH:19][C:20]([C:24]#[N:25])=[CH:21][CH:22]=3)[CH:17]=[C:16]2[C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[O:14])=[CH:9][CH:8]=1)(C)(C)C>C(O)(C(F)(F)F)=O>[C:24]([C:20]1[CH:19]=[C:18]2[C:23](=[CH:22][CH:21]=1)[N:15]([C:13]([C:10]1[CH:9]=[CH:8][C:7]([C:6]([OH:32])=[O:5])=[CH:12][CH:11]=1)=[O:14])[C:16]([C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)=[CH:17]2)#[N:25]
Reactant: CC(C)(C)OC(=O)c1ccc(C(=O)n2c(-c3cccnc3)cc3cc(C#N)ccc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc2c(c1)cc(-c1cccnc1)n2C(=O)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(5-Cyano-2-pyridin-3-yl-indole-1-carbonyl)-benzoic acid tert-butyl ester (100 mg) is dissolved in TFA (3 mL) and stirred at ambient temperature for 1 h. The solvent is removed in vacuo and the residue is triturated with diethyl ether twice. The residue is purified by reverse phase HPLC with Sunfire C18 and a gradient of acetonitrile in 0.1% aqueous TFA to afford 4-(5-cyano-2-pyridin-3-yl-indole-1-carbonyl)-benzoic acid as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm (TFA salt) 7.24 (s, 1H), 7.28 (dd, J=7.9, 4.9 Hz, 1H), 7.73-7.77 (m, 4H), 7.81 (dt, J=8.1, 1.9, 1.8 Hz, 1H), 7.87-7.91 (m, 2H), 8.32 (t, J=1.1 Hz, 1H), 8.41 (dd, J=4.9, 1.6 Hz, 1H), 8.63-8.65 (m, 1H), 13.40 (br. s., 1H). HRMS (ESI) m/z 366.0868 [(M+H)+ Calcd for C22H14N3O3: 366.0879].
Reaction SMILES: [Br-].[F:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][CH2:8][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:5][CH:4]=1.CC(C)([O-])C.[K+].[CH2:36]([CH:41]1[CH2:46][CH2:45][CH:44]([CH:47]2[CH2:52][CH2:51][CH:50]([CH2:53][CH:54]=O)[CH2:49][CH2:48]2)[CH2:43][CH2:42]1)[CH2:37][CH2:38][CH2:39][CH3:40].CCOCC>C1COCC1>[F:2][C:3]1[CH:4]=[CH:5][C:6](/[CH:7]=[CH:8]\[CH2:54][CH2:53][CH:50]2[CH2:51][CH2:52][CH:47]([CH:44]3[CH2:43][CH2:42][CH:41]([CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:46][CH2:45]3)[CH2:48][CH2:49]2)=[CH:28][CH:29]=1
Reactant: Fc1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCCC1CCC(C2CCC(CC=O)CC2)CC1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCC1CCC(C2CCC(CC/C=C\c3ccc(F)cc3)CC2)CC1
Yield: 57.8 %

Procedure:
4-fluorophenethyltriphenylphosphoniumbromide (4.2 g, 9 mmol) was dried and then dissolved in THF (10 ml), followed by stirring under ice cooling, adding potassium-t-butoxide (1.0 g, 9 mmol) slowly to the obtained reaction solution, stirring at room temperature for 2 hours after the completion of dropping, adding a THF (50 ml) solution of 4-(4-pentylcyclohexyl)-cyclohexylacetoaldehyde (2.7 g, 9.7 mmol) and further stirring for 5 hours, adding ether after the completion of reaction, filtering off the obtained white crystals deposited, concentrating the filtrate under reduced pressure, and purifying the obtained brown oil by means of silica gel column chromatography, to obtain a mixture (2.0 g, 5.2 mmol) of 1-(4-fluorophenyl)-4-(4-(4-pentylcyclohexyl)cyclohexyl)-2Z-butene with its E-isomer.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][N+:11]([O-])=O)=[CH:5][CH:4]=1>CO.[Ni]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][NH2:11])=[CH:7][CH:8]=1
Reactant: COc1ccc(C(C[N+](=O)[O-])c2ccccc2)cc1
Agent: [Ni]
Solvent: CO
Product: COc1ccc(C(CN)c2ccccc2)cc1
Reaction time: 8 h
Yield: 93.4 %

Procedure:
To prewashed (3× water, 3×MeOH) RaNi (0.40 g) in MeOH (10 mL) was added 1-methoxy-4-(2-nitro-1-phenylethyl)benzene (0.188 g, 0.73 mmol), then shaken under H2 atmosphere (35 psi) in Parr shaker overnight. The reaction was filtered through Celite, washed with MeOH. The filtrate was concentrated to afford the product (155 mg, 94%) as a solid: 1H NMR (400 MHz, CDCl3) δ ppm 7.11-7.36 (7H, m), 6.79-6.89 (2H, m), 4.21 1H, (t, J=7.45 Hz), 3.76 (3H, s), 3.24 (2H, d, J=8.84 Hz).
Reaction SMILES: Br[CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:12]#[N:13])=[CH:7][CH:8]=2)[C:3]1=O.Cl.[NH:16]1[CH:20]=[C:19]([CH2:21][C:22]([NH2:24])=[S:23])[N:18]=[CH:17]1>>[C:12]([C:6]1[CH:5]=[C:4]2[C:9]([CH2:10][CH2:11][C:2]3[S:23][C:22]([CH2:21][C:19]4[N:18]=[CH:17][NH:16][CH:20]=4)=[N:24][C:3]=32)=[CH:8][CH:7]=1)#[N:13]
Reactant: NC(=S)Cc1c[nH]cn1
Reactant: N#Cc1ccc2c(c1)C(=O)C(Br)CC2
Agent: Cl
Product: N#Cc1ccc2c(c1)-c1nc(Cc3c[nH]cn3)sc1CC2

Procedure:
Starting compounds: 2-bromo-7-cyano-1-tetralone, 4-imidazolylthioacetamide hydrochloride
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]([OH:16])[C@H:14]([OH:17])[CH2:13][S:12]1.[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][NH2:23]>C(O)C>[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][NH:23][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@H:15]([OH:16])[C@H:14]([OH:17])[CH2:13][S:12]1
Reactant: NCc1cccc(F)c1
Reactant: O[C@H]1[C@H](O)CS[C@H]1n1cnc2c(Cl)ncnc21
Solvent: CCO
Product: O[C@@H]1[C@H](O)CS[C@H]1n1cnc2c(NCc3cccc(F)c3)ncnc21
Yield: 82 %

Procedure:
(2R,3S,4S)-2-(6-chloro-9H-purin-9-yl)tetrahydrothiophen-3,4-diol (1 equivalent), prepared in Step 2, and 3-fluorobenzylamine (1.5 equivalents) were dissolved in ethanol (5 ml) at room temperature for 2-3 hrs with stirring. The reaction mixture was concentrated in a vacuum and the concentrate was purified through silica gel column chromatography using a mixture of dichloromethane:methanol (20:1, v/v) as an elution solvent to afford the object compound (0.11 g, 82%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:19]#[C:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:4]([C:8]2([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C([O-])(=[O:28])C.[Li+]>C(O)(C(F)(F)F)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[C:3](/[C:19](/[OH:28])=[CH:20]/[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:4]([C:8]2([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C#Cc1c(Cl)cccc1C1(C(=O)OCC)CCOCC1
Reactant: CC(=O)[O-]
Agent: [Pd+2]
Agent: [Li+]
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)/C=C(\O)c1c(Cl)cccc1C1(C(=O)OCC)CCOCC1
Temperature: 25 °C
Yield: 39.2 %

Procedure:
A mixture of ethyl 4-(3-chloro-2-(3-ethoxy-3-oxoprop-1-ynyl)phenyl)-tetrahydro-2H-pyran-4-carboxylate (0.5 g, 1 mmol) in 1.5 mL TFA was stirred at room temperature and treated with lithium acetate (0.09 g, 1 mmol) and palladium(II) acetate (0.02 g, 0.07 mmol). The resulting solution was stirred at room temperature for 2 hours and concentrated. The residue was diluted with 100 mL EtOAc, washed with water (3×20 mL), 20 mL saturated NaCl, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by column chromatography (10-20% EtOAc/hexane) to give 0.15 g of the product as a yellow oil. MS m/e: (M+H)+ 383.