Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:16]C)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2.B(Br)(Br)Br.O.[OH-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([OH:16])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2
Reactant: CCOC(=O)c1cc2cc(OC)cc(Cl)c2[nH]1
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1cc2cc(O)cc(Cl)c2[nH]1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
To a solution of ethyl 7-chloro-5-methoxyindole-2-carboxylate (82 mg, 0.323 mmol) in dichloromethane (5 ml) at −78° C. was added boron tribromide (1.07 ml of a 1.0M solution in DCM, 1.07 mmol) and the reaction stirred at −78° C. for 30 minutes then allowed to warm to ambient temperature overnight. Water was carefully added and the pH adjusted to pH 6-7 by addition of 2M sodium hydroxide. The mixture was extracted with ethyl acetate (2×50 ml), and the organic solution washed with brine, dried (MgSO4), filtered and evaporated to give ethyl 7-chloro-5-hydroxyindole-2-carboxylate (55 mg, 71%) as an orange solid.
Reaction SMILES: [C:1]([C:5]1[CH:19]=[CH:18][C:8]([O:9][CH2:10][C:11]([O:13]C(C)(C)C)=[O:12])=[CH:7][C:6]=1[F:20])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.O1CCCC1>C(Cl)Cl>[C:1]([C:5]1[CH:19]=[CH:18][C:8]([O:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][C:6]=1[F:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1ccc(C(C)(C)C)c(F)c1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)c1ccc(OCC(=O)O)cc1F
Yield: 89 %

Procedure:
A mixture of tert-butyl (4-tert-butyl-3-fluorophenoxy)acetate (630 mg, 2.2 mmol), trifluoroacetic acid (3.0 ml), tetrahydrofuran (3.0 ml) and methylene dichloride (3.0 ml) was treated in the same procedure described in Example 3(c) to furnish 443 mg of the title compound which was used for further reaction without purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH:35]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[CH3:18][C:14]1[CH:13]=[C:12]([C:10](=[O:11])[CH2:9][C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:34]3[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:44])([CH3:45])[CH3:46])=[O:41])[CH2:36][CH:35]=3)=[CH:3][CH:4]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH:17]=[CH:16][N:15]=1
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(Br)cc2)c2ccccc2C)ccn1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C(=O)C[C@H](c2ccc(C3=CCN(C(=O)OC(C)(C)C)CC3)cc2)c2ccccc2C)ccn1
Temperature: 85 °C
Yield: 96.6 %

Procedure:
A mixture of (R)-3-(4-bromophenyl)-1-(2-methylpyridin-4-yl)-3-o-tolylpropan-1-one (example 142, step 2; 300 mg, 761 μmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (353 mg, 1.14 mmol), [1,1′-bis(diphenyl-phosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (27.8 mg, 38.0 μmol) in 1,4-dioxane (7.5 mL), water (5 mL) and 2 M aq. sodium carbonate solution (1.14 mL, 2.28 mmol) was heated at 85° C. for 4 h, then after cooling partitioned between sat. aq. ammonium chloride solution and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and evaporated. Chromatography (SiO2; heptane-ethyl acetate gradient) produced the title compound (365 mg, 97%). White foam, MS (ESI+): m/z=497.4 ([M+H]+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1)([O-])=O.C([OH:13])C.[OH-].[Na+]>CN(C)C=O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[O:13])=[CH:6][CH:5]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Nc1ccc(C=O)cc1
Temperature: 80 °C
Yield: 71.9 %

Procedure:
To a 1-liter flask were added 66.7 g (0.487 mol) of p-nitrotoluene, 223 g of ethanol and 2.7 g (4.1% by weight of the p-nitrotoluene) of N,N-dimethylformamide to form a mixture which was dissolved, maintained at 80° C. and then incorporated dropwise over a period of time of 2 hours with an aqueous alkali solution prepared by adding 51.5 g of a 50% aqueous solution of sodium hydroxide to said aqueous solution of sodium polysulphide. After the end of the incorporation with the aqueous alkali solution, the whole mass was refluxed for an additional two hours thereby completing the reaction. The resulting reaction mixture was subjected to steam distillation to obtain 42.3 g (0.350 mol) of p-aminobenzaldehyde in purified form. The yield of the p-aminobenzaldehyde so obtained was 71.8%, based on the weight of p-nitrotoluene used.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([CH2:13][O:14][C:15]3[CH:25]=[CH:24][C:18]([O:19][CH2:20][C:21]([OH:23])=[O:22])=[C:17]([CH3:26])[CH:16]=3)[S:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[C:27]([O-])([O-])=O.[K+].[K+].[CH:33]1(Br)[CH2:37][CH2:36][CH2:35][CH2:34]1>CC(C)=O>[CH:33]1([O:1][C:2]2[CH:3]=[C:4]([C:8]3[N:9]=[C:10]([CH2:13][O:14][C:15]4[CH:25]=[CH:24][C:18]([O:19][CH2:20][C:21]([O:23][CH3:27])=[O:22])=[C:17]([CH3:26])[CH:16]=4)[S:11][CH:12]=3)[CH:5]=[CH:6][CH:7]=2)[CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: Cc1cc(OCc2nc(-c3cccc(O)c3)cs2)ccc1OCC(=O)O
Reactant: O=C([O-])[O-]
Reactant: BrC1CCCC1
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(OCc2nc(-c3cccc(OC4CCCC4)c3)cs2)cc1C

Procedure:
2-(4-((4-(3-hydroxyphenyl)thiazol-2-yl)methoxy)-2-methylphenoxy)acetic acid (20 mol, 0.052 mmol) is dissolved in acetone (4 mL). K2CO3 (21 mg, 0.156 mmol) is added, followed by cyclopentyl bromide (38 μL, 0.259 mmol) and the resulting mixture is heated to reflux for 18 h. The solvent is evaporated in vacuo to give crude methyl 2-(4-((4-(3-(cyclopentyloxy)phenyl)thiazol-2-yl)methoxy)-2-methylphenoxy)acetate, which is used in Step B without further purification.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]=[N:16][C:17]3[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][N:18]=3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH:29]1([Mg]Br)[CH2:31][CH2:30]1>O1CCCC1>[CH:29]1([N:16]([CH2:15][C:12]2[CH:13]=[CH:14][C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:27])[F:28])=[CH:8][CH:7]=3)=[CH:10][CH:11]=2)[C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][N:18]=2)[CH2:31][CH2:30]1
Reactant: Br[Mg]C1CC1
Reactant: COC(=O)c1ccc(N=Cc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)nc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(N(Cc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)C2CC2)nc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 19.5 %

Procedure:
To a 0° C. solution of methyl 6-((4′-(trifluoromethyl)biphenyl-4-yl)methyleneamino)nicotinate (600 mg, 1.56 mmol) in tetrahydrofuran (10 mL) was added cyclopropylmagnesium bromide (5 mL, 2N in THF, 8 mmol). The reaction was stirred at 0° C. for 1 hr, then warmed to room temperature and left stirring for 12 h. The reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate (3×15 mL). The combined organics were dried over sodium sulfate, filtered and concentrated. Purification by preparative TLC (5:1 petroleum ether:ethyl acetate) gave methyl 6-(cyclopropyl(4′-(trifluoromethyl)biphenyl-4-yl)methylamino)nicotinate (130 mg).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:17])([F:16])[F:15])[CH:8]=2)[N:5]=[C:4]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[C:3]=1[C:24]([OH:26])=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:60]1([CH:65]2[CH2:70][CH2:69][NH:68][CH2:67][CH2:66]2)[CH2:64][CH2:63][CH2:62][CH2:61]1>CN(C=O)C.CCOC(C)=O>[CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:16])([F:15])[F:17])[CH:8]=2)[N:5]=[C:4]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[C:3]=1[C:24]([N:68]1[CH2:69][CH2:70][CH:65]([N:60]2[CH2:64][CH2:63][CH2:62][CH2:61]2)[CH2:66][CH2:67]1)=[O:26]
Reactant: C1CCN(C2CCNCC2)C1
Reactant: Cc1c(C(=O)O)c(-c2ccncc2)nn1-c1cccc(OC(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(C(=O)N2CCC(N3CCCC3)CC2)c(-c2ccncc2)nn1-c1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
5-Methyl-3-pyridin-4-yl-1-(3-trifluoromethoxy-phenyl)-1H-pyrazole-4-carboxylic acid (76 mg, 0.21 mmol) in 2.5 ml DMF was treated with iPr2NEt (0.11 ml, 0.63 mmol) and HATU (79 mg, 0.21 mmol), then after 20 min a solution of 4-(1-pyrrolidinyl)piperidine (32 mg, 0.21 mmol) in 1.5 ml DMF was added. The reaction mixture was stirred 0.5 h at room temperature, diluted with EtOAc and washed with three portions of saturated solution of NaHCO3 and brine. The aqueous phases were extracted with EtOAc the combined organic layers were dried over magnesium sulfate and evaporated. A column chromatography (amino-phase silica gel, EtOAc:MeOH, 19:1) afforded the title compound as a foam (74 mg, 71%). MS: 500.0 (MH+).
Reaction SMILES: [F:1][CH:2]([F:11])[O:3][C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6].[N:12]([O-])=O.[Na+].C([O-])(=O)C.[Na+].[C:21]([CH2:24][C:25](=[O:27])[CH3:26])(=[O:23])[CH3:22]>C(O)(=O)C.Cl.O.C(O)C>[F:1][CH:2]([F:11])[O:3][C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH:6][N:12]=[C:24]([C:25](=[O:27])[CH3:26])[C:21](=[O:23])[CH3:22]
Reactant: O=N[O-]
Reactant: CC(=O)CC(C)=O
Reactant: Nc1ccccc1OC(F)F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CC(=O)C(=NNc1ccccc1OC(F)F)C(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
To a solution of 2-(difluoromethoxy)aniline (1000 mg, 6.25 mmol) in 15 mL of acetic acid and 2.5 mL of concentrated hydrochloride solution, sodium nitrite (518 mg, 7.50 mmol) in 4 mL of water was added dropwise at 0° C., and the mixture was stirred at 0° C. for 1 h. Then to the reaction mixture was added dropwise a solution of sodium acetate (1538 mg, 18.75 mmol) and acetylacetone (812 mg, 8.12 mmol) in 10 mL of ethanol and 6 mL of water. The mixture was stirred at room temperature overnight, filtered, washed with water, EtOH/H2O (1:1) and hexane, and dried to give 3-{[2-(difluoromethoxy)phenyl]hydrazono}pentane-2,4-dione (1590 mg, 94%).
Reaction SMILES: Cl.Cl.[NH:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)[NH2:4].C(O[CH:14]=[CH:15][C:16]#[N:17])C.N(C1C=NC=CC=1)N>>[NH2:17][C:16]1[CH:15]=[CH:14][N:3]([C:5]2[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=2)[N:4]=1
Reactant: NNc1cccnc1
Reactant: CCOC=CC#N
Agent: Cl
Product: Nc1ccn(-c2cccnc2)n1

Procedure:
In a typical reaction, 3-hydrazinopyridine.dihydrochloride and an anhydrous alcohol are introduced into a reaction vessel and the alkoxide base is gradually added. The mixture is stirred and the 3-ethoxyacrylonitrile is added. The mixture is stirred at about 80° C. until most of the 3-hydrazinopyridine has reacted. The mixture is allowed to cool and the excess base is neutralized with acid. The crude 3-(3-amino-1H-pyrazol-1-yl)pyridine (8a) is conveniently isolated and purified by standard techniques.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([OH:13])=[C:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]([CH2:20][CH2:21][CH3:22])=[CH:6]2.[H-].[Na+].F[C:26]1[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][CH:27]=1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][CH:27]=1)=[C:8]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:7]([CH2:20][CH2:21][CH3:22])=[CH:6]2
Reactant: O=Cc1ccc(F)cc1
Reactant: CCCc1cc2cc(OC)ccc2c(O)c1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1cc2cc(OC)ccc2c(Oc2ccc(C=O)cc2)c1-c1ccccc1
Yield: 89 %

Procedure:
6-(Methyloxy)-2-phenyl-3-propyl-1-naphthalenol (97) (0.54 g, 1.86 mmol) was treated with NaH in DMF followed by addition of 4-fluorobenzaldehyde to give 0.66 g (89%) of the title compound (98) as a light yellow foam. 1H NMR (400 MHz, CDCl3): δ 0.81 (t, J=7.3 Hz, 3H), 1.40-1.55 (m, 2H), 2.53 (t, J=7.7 Hz, 2H), 3.94 (s, 3H), 6.67 (d, J=8.7 Hz, 2H), 7.05 (dd, J1=9.0 Hz, J2=2.5 Hz, 1H), 7.08-7.14 (m, 2H), 7.18 (d, J=2.5 Hz, 1H), 7.19-7.25 (m, 3H), 7.58-7.64 (m, 3H), 7.67 (d, J=9.2 Hz, 1H), 9.79 (s, 1H). LCMS (ESI): m/z 397 (M+H)+.
Reaction SMILES: [OH-:1].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[Cl:13])[C:9](=O)[N:8]([C:15]1[CH:19]=[CH:18][S:17][C:16]=1[C:20]([NH2:22])=[O:21])[C:7]2=[O:23]>C1COCC1.CO>[Cl:13][C:12]1[C:4]([Cl:3])=[CH:5][C:6]([C:7]([OH:23])=[O:1])=[C:10]([C:9]2[NH:22][C:20](=[O:21])[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[N:8]=2)[CH:11]=1
Reactant: [OH-]
Reactant: NC(=O)c1sccc1N1C(=O)c2cc(Cl)c(Cl)cc2C1=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc(Cl)c(Cl)cc1-c1nc2ccsc2c(=O)[nH]1
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
3-aminothiophene-2-carboxamide was added to an acetic acid solution of 4,5-dichlorophthalic anhydride and stirred all night heated to reflux to give 3-(5,6-dichloro-1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl)thiophene-2-carboxamide. 1M NaOH aq was added to THF-MeOH solution of the obtained 3-(5,6-dichloro-1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl)thiophene-2-carboxamide and stirred for 2.5 hours at 80° C. to give 4,5-dichloro-2-(4-oxo-3,4-dihydrothieno[3,2-d]pyrimidine-2-yl)benzoic acid. Sulfuric acid was added to a MeOH-1,4-dioxane solution of the obtained 4,5-dichloro-2-(4-oxo-3,4-dihydrothieno[3,2-d]pyrimidine-2-yl)benzoic acid and stirred for three days at 70° C. to give methyl 4,5-dichloro-2-(4-oxo-3,4-dihydrothieno[3,2-d]pyrimidine-2-yl)benzoate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[NH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[N:10]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu]I.C1(C)C=CC=CC=1>[N:9]1[N:10]([C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)[CH:11]=[C:12]2[C:17]=1[CH:16]=[CH:15][CH:14]=[CH:13]2
Reactant: Oc1ccc(Br)cc1
Reactant: c1ccc2[nH]ncc2c1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Oc1ccc(-n2cc3ccccc3n2)cc1
Temperature: 25 °C
Yield: 19.6 %

Procedure:
4-Bromophenol (2.00 g, 11.6 mmol) was combined with 1H-indazole (1.64 g, 13.9 mmol), copper(I) iodide (110 mg, 0.578 mmol), potassium phosphate (5.15 g, 24.3 mmol), trans-dimethylcyclohexane-1,2-diamine (0.365 mL, 2.31 mmol), and toluene (10 mL). The reaction was refluxed for 21 hours, then cooled to room temperature and partitioned between ethyl acetate and water/ammonium hydroxide. The organic layer was washed with 0.5 N HCl and brine, dried over magnesium sulfate, filtered and concentrated. Purification by column chromatography (0-40% ethyl acetate in heptane) gave 4-(2H-indazol-2-yl)phenol (0.479 g, 20%) as a tan solid. 1H NMR (400 MHz, (CD3)2SO, δ): 9.84 (s, 1H), 8.90 (s, 1H), 7.86 (d, J=8.8 Hz, 2H), 7.74 (d, J=8.4 Hz, 1H), 7.68 (d, J=8.8 Hz, 1H), 7.22-7.33 (m, 1H), 7.03-7.12 (m, 1H), 6.94 (d, J=8.8 Hz, 2H). MS (M+1): 211.2.
Reaction SMILES: Br[CH2:2][C:3]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:4]=1[C:5]([O:7]CC)=O.[CH:17]([C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)([CH3:19])[CH3:18].C(N(CC)C(C)C)(C)C>C(O)C>[CH:17]([C:20]1[CH:26]=[CH:25][C:23]([N:24]2[CH2:2][C:3]3[C:4](=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=3)[C:5]2=[O:7])=[CH:22][CH:21]=1)([CH3:19])[CH3:18]
Reactant: CC(C)c1ccc(N)cc1
Reactant: CCOC(=O)c1cc([N+](=O)[O-])ccc1CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)c1ccc(N2Cc3ccc([N+](=O)[O-])cc3C2=O)cc1
Temperature: 110 °C
Yield: 75.1 %

Procedure:
A mixture of ethyl 2-(bromomethyl)-5-nitrobenzoate (1.88 g, 6.52 mmol), 4-isopropylaniline (1.11 mL, 7.83 mmol) and N,N-diisopropylethylamine (1.36 mL, 7.83 mmol) in ethanol (75 mL) was heated in a sealed tube at 110° C. overnight. After this time, the mixture was cooled to room temperature and the solid collected by filtration to afford 2-(4-isopropylphenyl)-6-nitroisoindolin-1-one (1.45 g, 75%) as a yellow solid: mp 225-227° C.; 1H NMR (300 MHz, CDCl3) δ 8.77 (d, J=2.0 Hz, 1H) 8.48 (dd, J=8.3, 2.1 Hz, 1H), 7.76-7.69 (m, 3H), 7.32 (d, J=8.6 Hz, 2H), 2.94 (sept, J=6.9 Hz, 1H), 1.28 (d, J=6.9 Hz, 6H); ESI MS m/z 297 [M+H]+.
Reaction SMILES: [S:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([NH2:21])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:8]([OH:10])=[O:9])(=[O:4])(=[O:3])[NH2:2].CO[CH:24]1[CH2:28][CH2:27][CH:26](OC)O1>C(O)(=O)C>[S:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([N:21]2[CH:24]=[CH:28][CH:27]=[CH:26]2)[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:8]([OH:10])=[O:9])(=[O:3])(=[O:4])[NH2:2]
Reactant: COC1CCC(OC)O1
Reactant: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1
Solvent: CC(=O)O
Product: NS(=O)(=O)c1cc(C(=O)O)cc(-n2cccc2)c1Oc1ccccc1

Procedure:
A mixture of 3-sulphamoyl-4-phenoxy-5-amino-benzoic acid (3.08 g=10 mmols); P. W. Feit, J. Med. Chem. 14,432 (1971), 2,5-dimethoxy-tetrahydrofurane (1.32 g=10 mmols) and 5 ml of glacial acetic acid is refluxed for 15 minutes in an oil bath and evaporated to dryness in vacuo and the residue is recrystallised from ethyl acetate; the compound melts at 209°-210° C.
Reaction SMILES: C[C:2]([CH3:4])=[O:3].[CH:5]([OH:8])([CH3:7])[CH3:6].[CH2:9]([O:11]CC)C>C(O)(=O)C.C(OCC)(=O)C.O>[C:2]([O:3][CH2:6][CH2:5][CH3:7])(=[O:11])[CH3:4].[C:5]([O:3][CH2:2][CH3:4])(=[O:8])[CH2:7][CH3:9]
Reactant: CC(C)O
Reactant: CCOCC
Reactant: CC(C)=O
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CCCOC(C)=O
Product: CCOC(=O)CC

Procedure:
The crude alcohol product typically will further comprise unreacted acetic acid and unreacted higher acid, depending on conversion, for example, in an amount of less than 90 wt. %, e.g., less than 80 wt. % or less than 70 wt. %. In terms of ranges, the unreacted acetic acid and unreacted higher acid is optionally present in amounts from 0 to 90 wt. %, e.g., from 5 wt. % to 80 wt. %, from 15 wt. % to 70 wt. %, from 20 wt. % to 70 wt. % or from 25 wt. % to 65 wt. %. Where acetone is included as a reactant, the crude alcohol product may comprise from 0.01 wt. % to 10 wt. % isopropanol, e.g., from 0.1 wt. % to 10 wt %, from 1 wt. % to 9 wt. % or from 3 wt. % to 7 wt. %. In other embodiments, the crude alcohol product comprises from 0.01 wt. % to 20 wt. % diethyl ether, e.g., from 0.1 wt. % to 10 wt. %, from 1 wt. % to 9 wt. % or from 3 wt. % to 7 wt. %. As water is formed in the reaction process, the crude alcohol product will generally comprise water, for example, in amounts ranging from 5 wt. % to 35 wt. %, e.g., from 10 wt. % to 30 wt. % or from 10 wt. % to 26 wt. %. Ethyl acetate and higher esters, e.g., propyl acetate or ethyl propionate, may also be produced during the hydrogenation of acetic acid and higher acids or through side reactions. In these embodiments, the crude alcohol product may comprise esters in an amount ranging from 0 to 20 wt. %, e.g., from 0 to 15 wt. %, from 1 to 12 wt. % or from 3 to 10 wt. %. Acetaldehyde may also be produced through side reactions. Higher esters, such as propyl acetate and ethyl propionate, may be present in an amount from 0.001 to 5 wt. %, e.g., from 0.01 to 3 wt. % or from 0.1 to 1 wt. %. In these embodiments, the crude alcohol product comprises acetaldehyde in amounts ranging from 0 to 10 wt. %, e.g., from 0 to 3 wt. %, from 0.1 to 3 wt. % or from 0.2 to 2 wt. %. In some embodiments, where propionic acid is included as a reactant, the n-propanol formed via hydrogenation may be present in the crude alcohol product in an amount ranging from 0.001 wt. % to 40 wt. %, e.g., from 0.01 wt. % 20 wt. %, from 0.04 wt. % to 20 wt. %, from 0.5 to 10 wt. %, from 1 to 8 wt. % or from 2 to 5 wt. %, or in other embodiments, in an amount ranging from 0.001 wt. % to 20 wt. %, e.g., from 0.001 wt. % to 15 wt. %, from 0.01 wt. % to 14 wt. %, from 0.13 wt. % to 13.2 wt. %, from 1.3 wt. % to 11.9 wt. %, or from 4 wt. % to 9.3 wt. %.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:13]2[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:12]=2[N:11]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:25][C:23]1[CH:22]=[CH:21][C:13]2[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:10]([C@@H:8]([NH2:7])[CH3:9])=[N:11][C:12]=2[CH:24]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2cc(F)ccc2n1-c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N)c1nc2cc(F)ccc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.1 %

Procedure:
To a solution of [(S)-1-(5-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tert-butyl ester (661 mg, 1.9 mmol) in DCM (9 mL) was added TFA (4.5 mL) and the mixture stirred at RT for 2 h. The volatiles were removed in vacuo and the resulting residue partitioned between DCM (20 mL) and a saturated aqueous solution of NaHCO3 (40 mL). The two phase system was stirred for 10 min, then the organic fraction was dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in DCM) to afford the title compound as a yellow oil (379 mg, 78%). LCMS (Method J): RT 1.77 min [M+H]+ 256.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@@H:12]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@H:11]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@@H:10]([CH2:38][O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[O:9]2)=[CH:4][C:3]=1[C:47]1([C:50]#N)[CH2:49][CH2:48]1.[OH-:52].[Na+].CCO.[OH2:57]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@@H:12]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@H:11]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@@H:10]([CH2:38][O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[O:9]2)=[CH:4][C:3]=1[C:47]1([C:50]([OH:57])=[O:52])[CH2:49][CH2:48]1
Reactant: [OH-]
Reactant: O
Reactant: N#CC1(c2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)CC1
Agent: [Na+]
Solvent: CCO
Product: O=C(O)C1(c2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)CC1
Temperature: 110 °C
Reaction time: 15 h
Yield: 99 %

Procedure:
To a solution of cyanide 42 (3.0 g, 4.25 mmol) in EtOH/H2O (20 mL/20 mL) was added NaOH (20.5 g, 423 mmol). The mixture was stirred at 110° C. for 15 hours. The mixture was cooled to room temperature and evaporated in vacuo to remove EtOH. The residue was diluted with H2O, cooled to 0° C. and acidified with c-HCl solution. The titled compound 43 was precipitated as a solid, dissolved with EtOAc and extracted. The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo to provide the titled compound 43 (2.89 g, 99%).
Reaction SMILES: [C:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16](O)[C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]#[N:21])=[CH:12][CH:11]=2)=[C:6]([CH3:28])[C:5]=1[OH:29])(=[O:3])[CH3:2].ClCCl.C(N(S(F)(F)[F:39])CC)C>O>[C:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]([F:39])[C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]#[N:21])=[CH:12][CH:11]=2)=[C:6]([CH3:28])[C:5]=1[OH:29])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(OCc2ccc(C(O)c3cccc(C#N)c3)cc2)c(C)c1O
Reactant: CCN(CC)S(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CC(=O)c1ccc(OCc2ccc(C(F)c3cccc(C#N)c3)cc2)c(C)c1O
Temperature: -78 °C
Yield: 79.6 %

Procedure:
A mixture of 3-{[4-(4-acetyl-3-hydroxy-2-methyl-phenoxymethyl)-phenyl]-hydroxy-methyl}-benzonitrile (0.5 g, 1.29 mmol) and dichloromethane (15 mL) is stirred at −78° C. Diethylaminosulfur trifluoride (0.2 mL, 1.48 mmol) is added and the reaction is warmed to room temperature and stirred 30 min. The mixture is cooled to 0° C. and diluted with water (50 mL). The layers are separated, and the aqueous layer is extracted with dichloromethane (3×50 mL). The organic layers are combined, dried on magnesium sulfate, filtered, and concentrated. The residue is purified via silica chromatography eluting with hexanes to 7:3 hexanes:ethyl acetate to give the title compound (400 mg, 80%) as a white solid. LCMS M+1 390.