Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([NH:23][C:24]2[CH:25]=[C:26]([C:36]([F:39])([F:38])[F:37])[CH:27]=[C:28]([N:30]3[CH:34]=[N:33][C:32]([CH3:35])=[CH:31]3)[CH:29]=2)=[O:22])=[CH:6][C:7]=1[NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[N:19][CH:20]=2)[N:14]=1.[Cl:40][C:41]1[CH:51]=[CH:50][CH:49]=[CH:48][C:42]=1[CH:43]([OH:47])[C:44]([OH:46])=[O:45]>C(OC)(C)(C)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([NH:23][C:24]2[CH:25]=[C:26]([C:36]([F:38])([F:39])[F:37])[CH:27]=[C:28]([N:30]3[CH:34]=[N:33][C:32]([CH3:35])=[CH:31]3)[CH:29]=2)=[O:22])=[CH:6][C:7]=1[NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[N:19][CH:20]=2)[N:14]=1.[Cl:40][C:41]1[CH:51]=[CH:50][CH:49]=[CH:48][C:42]=1[CH:43]([OH:47])[C:44]([O-:46])=[O:45]
Reactant: O=C(O)C(O)c1ccccc1Cl
Agent: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(Nc4nccc(-c5cccnc5)n4)c3)cc(C(F)(F)F)c2)cn1
Solvent: COC(C)(C)C
Product: O=C([O-])C(O)c1ccccc1Cl
Temperature: 5 °C
Reaction time: 4 h

Procedure:
Nilotinib base (0.300 g, 0.57 mmol) was dissolved in TFE (2 mL) at 40° C. to obtain a mixture. The mixture was stirred and added to a solution of 2-chloromandelic acid (0.106 g, 0.57 mmol) in TFE (1 mL) at 40° C. Stirring of the resulting clear solution was continued for about 4 h at 40° C. and the solution was subsequently cooled to 5° C. The mixture was kept at 5° C. overnight and then methyl tert-butyl ether (MTBE) (1.5 v/v) was added to the mixture at room temperature, leading to precipitation. The precipitate was filtered to give a white solid of Nilotinib 2-chloromandelate form I.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Si](C)(C)C)(=O)=O.[F-].[Cs+].C([O:23][P:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)C.C(#N)C>CCOC(C)=O>[C:7]1([P:24](=[O:23])([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOP(c1ccccc1)c1ccccc1
Reactant: C[Si](C)(C)c1ccccc1OS(=O)(=O)C(F)(F)F
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
2-(trimethylsilyl)phenyl trifluoromethanesulfonate (25 mg, 0.083 mmol), Cesium Fluoride (70 mg, 0.461 mmol), Ethoxydiphenylphosphane (78 mg, 0.33 mmol), Acetonitrile (1 ml): Reaction Time: 16 h; Rf: 0.3 (1:3 EtOAc:Pet Ether); White Solid; 17.5 mg, 75%; 1H NMR (400 MHz, CDCl3, TMS) δ 7.74-7.63 (m, 6H), 7.59-7.51 (m, 3H), 7.50-7.40 (m, 6H); 13C NMR (100 MHz, CDCl3, TMS) δ 132.5 (d, J=104.0 Hz), 132.1 (d, J=10.0 Hz), 131.9 (d, J=2.3 Hz); 128.5 (d, J=12.4 Hz); 31P NMR (162 MHz, CDCl3) δ 29.2; Mass (M+Na)+ 301; Known Compound, Lit. K. Prokop, D. Goldberg, J. Am. Chem. Soc. 2012, 134, 8014.
Reaction SMILES: Cl([O-])(=O)(=O)=O.[CH2:6]([C:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][N+:16]([CH2:19][CH2:20][CH2:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[CH:15][CH:14]=2)[NH:10][N:9]=1)[CH3:7].[BH4-].[Na+]>CO>[CH2:6]([C:8]1[CH:12]=[C:11]([C:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][CH:22]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[OH:30])[CH2:15][CH:14]=2)[NH:10][N:9]=1)[CH3:7]
Reactant: CCc1cc(-c2cc[n+](CCCC(=O)c3ccc(F)cc3)cc2)[nH]n1
Agent: [BH4-]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CO
Product: CCc1cc(C2=CCN(CCCC(O)c3ccc(F)cc3)CC2)[nH]n1
Temperature: 0 °C

Procedure:
To a 2.2 g. portion of 4-(3-ethyl-5-pyrazolyl)-1-(3-p-fluorobenzoylpropyl)pyridinium perchlorate, prepared as described in Example 2, in 100 ml. of methanol is added portionwise with stirring 2.2 g. of sodium borohydride. The mixture is stirred for 2 hours and then poured into ice water causing formation of a white solid which was collected and recrystallized from methanol, m.p. 140.5°-141.5°C.
Reaction SMILES: CC1(C)S[C@@H]2[C@H:7](NC(C(C(O)=O)C3C=CC=CC=3)=O)[C:8](=[O:9])N2[C@H]1C(O)=O.[CH2:27]1[C@H:32](N)[C@@H:31]([O:34][C@H:35]2O[C@H](CN)[C@@H](O)[C@H](O)[C@H]2O)[C@H:30]([OH:46])[C@@H:29]([O:47][C@H:48]2O[C@H](CO)[C@@H](O)[C@H](N)[C@H]2O)[C@@H:28]1N>>[CH3:7][C:8]([C:27]1[CH:28]=[C:29]([O:47][CH3:48])[C:30]([OH:46])=[C:31]([O:34][CH3:35])[CH:32]=1)=[O:9]
Reactant: NC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O[C@H]3O[C@H](CO)[C@@H](O)[C@H](N)[C@H]3O)[C@H](N)C[C@@H]2N)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)C(C(=O)O)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Product: COc1cc(C(C)=O)cc(OC)c1O

Procedure:
After four weeks, the segments were transferred to BS-48 regeneration medium containing 200 mg/L carbenicillin and 25 mg/L kanamycin.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.Cl.CN(C)[CH2:15][CH2:16][CH2:17][N:18]=C=NCC.C1(N)CC1.O>CN(C)C=O>[CH:17]1([NH:18][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([CH3:11])=[C:2]([I:1])[CH:3]=2)[CH2:15][CH2:16]1
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1ccc(C(=O)O)cc1I
Agent: Cl
Agent: NC1CC1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1I
Yield: 98 %

Procedure:
A solution of 3-iodo-4-methylbenzoic acid (10.5 g, 40 mmol), 1-(3-dimethlaminopropyl)-3-ethylcarbodiimide hydrochloride (9.2 g, 48 mmol) and cyclopropylamine (2.6 g, 45.6 mmol) in N,N-dimethylformamide (70 ml) was stirred at room temperature for 4 h. Water (250 mL) was added. The solution was extracted with ethyl acetate (200 mL×2), washed with saturated K2CO3 solution (200 mL) and water (200 mL). Organic layer was dried over Na2SO4 and evaporated under reduced pressure to give the desired product (11.8 g, 98%).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[Cl:5][C:6]1[CH:7]=[C:8]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[O:9][CH:10]([C:12]1[S:16][C:15]([NH2:17])=[N:14][N:13]=1)[CH3:11]>C(OCC)(=O)C>[Cl:5][C:6]1[CH:7]=[C:8]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[O:9][CH:10]([C:12]1[S:16][C:15]([N:17]=[C:1]=[O:2])=[N:14][N:13]=1)[CH3:11]
Reactant: CC(Oc1cc(Cl)cc(Cl)c1)c1nnc(N)s1
Reactant: O=C(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(Oc1cc(Cl)cc(Cl)c1)c1nnc(N=C=O)s1
Reaction time: 64 h

Procedure:
A 500 milliliter, 3-neck flask equipped with a magnetic stirrer, thermometer, dry ice condenser/drying tube and inlet from a phosgene (COCl2) tank via a calibrated rotameter was charged with 50 milliliters of ethyl acetate saturated with phosgene at 20° C. (approximately 0.5 mole of phosgene). An additional 50 milliliters of ethylacetate was added, and 7.9 grams of 5-[1-(3,5-dichorophenoxy)ethyl]-2-amino-1,3,4-thiadiazole, (prepared above) in 30 milliliters of ethyl acetate was added. The resulting solution was stirred for 64 hours, and then purged with nitrogen until no COCl2 was detected. The solution was filtered and then topped at 70° C. in a roto-vac to form 10.0 grams of a viscous yellow oil of 5-[1-(3,5-dichlorophenoxy)ethyl]-1,3,4-thiadiazol-2-yl isocyanate dimer.
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9]C)=O)(=O)[CH2:2][CH2:3][CH3:4].C(O)(=O)C.[NH2:15][NH2:16]>C(O)C>[CH2:2]([C:1]1[CH2:6][C:7](=[O:9])[NH:16][N:15]=1)[CH2:3][CH3:4]
Reactant: NN
Reactant: CCCC(=O)CC(=O)OC
Solvent: CCO
Solvent: CC(=O)O
Product: CCCC1=NNC(=O)C1
Reaction time: 2 h

Procedure:
Methyl butyrylacetate (4 g, 27.7 mmol) was stirred in ethanol and acetic acid (10:1, 8:0.8 mL) and treated with hydrazine (1.05 mL, 33.3 mmol). After 2 hrs, the resulting solid was filtered off and washed with a minimum amount of acetonitrile to yield 3-propyl-1H-pyrazol-5(4H)-one. Then, the 3-propyl-1H-pyrazol-5(4H)-one (4.68 g, 11.8 mmol) and 4-chloroquinoline N-oxide (1.5 g, 11.8 mmol) were stirred in acetic anhydride (20 mL) at ambient temperature for 30-40 minutes. The reaction mixture was concentrated, and the resulting solid filtered off, washed with a minimum amount of methanol, and treated with hydrazine (0.84 mL, 26.7 mmol) in methanol (12 mL) to yield Example 23 as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.97 (t, J=7.33 Hz, 3H) 1.66-1.76 (m, 2H) 3.02 (t, J=7.07 Hz, 2H) 7.62 (t, J=7.58 Hz, 1H) 7.80 (t, J=7.71 Hz, 1H) 7.93 (d, J=8.34 Hz, 1H) 8.10 (d, J=8.34 Hz, 2H); ESI-MS: m/z calc'd for C15H14ClN3O 287.74. found 288.2 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:34])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:24]=[C:23]([CH2:25][CH3:26])[C:22]3[CH:21]([N:27]([CH:29]4[CH2:31][CH2:30]4)[CH3:28])[CH2:20][CH2:19][C:18]([CH3:33])([CH3:32])[C:17]=3[CH:16]=2)=[CH:9][CH:8]=1)([CH3:6])[CH3:5].[OH-].[K+].[Cl-].[NH4+]>CO.O1CCCC1>[CH:29]1([N:27]([CH3:28])[CH:21]2[CH2:20][CH2:19][C:18]([CH3:32])([CH3:33])[C:17]3[CH:16]=[C:15]([C:14]#[C:13][C:10]4[CH:9]=[CH:8][C:7]([C:4]([CH3:6])([CH3:5])[C:3]([OH:34])=[O:2])=[CH:12][CH:11]=4)[CH:24]=[C:23]([CH2:25][CH3:26])[C:22]2=3)[CH2:30][CH2:31]1
Reactant: CCc1cc(C#Cc2ccc(C(C)(C)C(=O)OC)cc2)cc2c1C(N(C)C1CC1)CCC2(C)C
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1cc(C#Cc2ccc(C(C)(C)C(=O)O)cc2)cc2c1C(N(C)C1CC1)CCC2(C)C
Temperature: 80 °C
Yield: 68.2 %

Procedure:
A solution of 2-{4-[5-(cyclopropyl-methyl-amino)-4-ethyl-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-2-methyl-propionic acid methyl ester (Intermediate 182, 0.035 g, 0.076 mmol) in methanol (3 mL) and tetrahydrofuran (2 mL) was treated with 3M potassium hydroxide (2 mL, 4 mmol) and the resulting reaction mixture was heated at 80° C. for 2 days. The reaction mixture was neutralized with ammonium chloride and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford a residue that was purified by preparative reverse phase HPLC to afford the title product (0.023 g, 69%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][C:11](=O)[CH3:12])[CH:5]=[CH:6][CH:7]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[F:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[C:11]([CH3:12])=[N:10][CH2:9][CH2:8]2
Reactant: CC(=O)NCCc1cccc(F)c1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CC1=NCCc2cc(F)ccc21

Procedure:
In close analogy to the procedure described above, N-[2-(3-fluoro-phenyl)-ethyl]-acetamide is reacted with phosphorus pentoxide to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1F.[CH3:11][C@H:12]([OH:16])[CH2:13][CH:14]=[CH2:15].[H-].[Na+]>C1COCC1.CCOCC>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:16][C@H:12]([CH2:13][CH:14]=[CH2:15])[CH3:11]
Reactant: N#Cc1ccc(Br)c(F)c1
Reactant: C=CC[C@H](C)O
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CC[C@H](C)Oc1cc(C#N)ccc1Br
Reaction time: 5 h
Yield: 70.6 %

Procedure:
To a solution of 4-bromo-3-fluorobenzonitrile (1.0 g, 5.00 mmol, 1 equiv) and (S)-pent-4-en-2-ol (0.52 g, 6.00 mmol, 1.2 equiv) in THF (25 mL) was added NaH (0.24 g of a 60% suspension in mineral oil, 6.00 mmol, 1.2 equiv). Slow gas evolution with considerable foaming observed. After 5 h, dilute with ether then wash with water and brine. The ether layer was dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash column chromatography (0-10% EtOAc in hexane) to provide the product as a colorless oil (0.94 g, 71%). 1H NMR (400 MHz, CDCl3) δ 7.69-7.62 (m, 1H), 7.15-7.08 (m, 2H), 5.89 (ddt, J=17.1, 10.1, 7.2 Hz, 1H), 5.23-5.12 (m, 2H), 4.54-4.42 (m, 1H), 2.61-2.51 (m, 1H), 2.51-2.40 (m, 1H), 1.39 (d, J=6.0 Hz, 3H).
Reaction SMILES: [C:1]([O:4][CH2:5][CH3:6])(=[O:3])[CH3:2].[C:7]1(C)[CH:12]=[CH:11]C=[CH:9][CH:8]=1.C1(C)C(C)=CC=CC=1.C(C1C=CC=CC=1)C>C(Cl)Cl>[CH2:5]1[C:6]2[C:9](=[CH:8][CH:7]=[CH:12][CH:11]=2)[CH2:2][C:1](=[O:3])[O:4]1
Reactant: Cc1ccccc1
Reactant: CCOC(C)=O
Solvent: CCc1ccccc1
Solvent: ClCCl
Solvent: Cc1ccccc1C
Product: O=C1Cc2ccccc2CO1

Procedure:
After the reaction, recovery of isochromanones can be carried out by concentration of reaction mixture or extraction with an organic solvent such as ethyl acetate, toluene, xylene, ethylbenzene, or methylene chloride. When the reaction mixture is separated into two layers, i.e., a water layer and a product layer, depending on the target isochromanones, it is possible to separate and remove the water layer. In particular, when the product is 3-isochromanone, the product layer is liquid at 85° C. or higher, so that solubility in water is low and the target compound can be recovered by separation operation. Further, distillation and purification under reduced pressure can give rise to highly pure 3-isochromanone.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21](I)[C:16]2=[CH:15][N:14]=1.[OH:23][C@@H:24]1[CH2:29][CH2:28][C@H:27]([N:30]2[CH2:38][C:37]3[C:32](=[CH:33][CH:34]=[C:35](B4OC(C)(C)C(C)(C)O4)[CH:36]=3)[C:31]2=[O:48])[CH2:26][CH2:25]1>>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21]([C:35]3[CH:36]=[C:37]4[C:32](=[CH:33][CH:34]=3)[C:31](=[O:48])[N:30]([C@H:27]3[CH2:26][CH2:25][C@@H:24]([OH:23])[CH2:29][CH2:28]3)[CH2:38]4)[C:16]2=[CH:15][N:14]=1
Reactant: COc1cc(OC)c(F)c(-c2ncc3c(I)n[nH]c3n2)c1F
Reactant: CC1(C)OB(c2ccc3c(c2)CN([C@H]2CC[C@@H](O)CC2)C3=O)OC1(C)C
Product: COc1cc(OC)c(F)c(-c2ncc3c(-c4ccc5c(c4)CN([C@H]4CC[C@@H](O)CC4)C5=O)n[nH]c3n2)c1F

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 4, Step 2 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine and 2-(cis-4-hydroxycyclohexyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one. LCMS (M+H)+=522.1.
Reaction SMILES: I/[C:2](/[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1)=[CH:3]\[CH2:4][S:5][C:6]1[CH:18]=[CH:17][C:9]([O:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:8]([CH3:19])[CH:7]=1.[S:30]1[C:34]([Sn](CCCC)(CCCC)CCCC)=[CH:33][C:32]2[CH:48]=[CH:49][CH:50]=[CH:51][C:31]1=2.C(Cl)(Cl)Cl.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C1CCCCC1.[F-].[K+]>CN(C)C=O.C(OCC)(=O)C>[S:30]1[C:34](/[C:2](/[C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)=[CH:3]\[CH2:4][S:5][C:6]2[CH:18]=[CH:17][C:9]([O:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:8]([CH3:19])[CH:7]=2)=[CH:33][C:32]2[CH:48]=[CH:49][CH:50]=[CH:51][C:31]1=2
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2ccccc2s1
Reactant: CCOC(=O)COc1ccc(SC/C=C(\I)c2ccc(C(F)(F)F)cc2)cc1C
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)COc1ccc(SC/C=C(/c2ccc(C(F)(F)F)cc2)c2cc3ccccc3s2)cc1C
Temperature: 60 °C
Reaction time: 5 h
Yield: 77.4 %

Procedure:
To a solution of ethyl (Z)-[4-[3-iodo-3-(4-trifluoromethylphenyl)allylsulfanyl]-2-methylphenoxy]acetate (407.1 mg, 0.759 mmol; example 29, step D-E) and (benzo[b]thiophen-2-yl)-tributyltin (327.2 mg, 0.773 mmol, prepared according to Morimoto et al.: J. Med. Chem. 44, 3355 (2001)) in dry N,N-dimethylformamide (3 mL) Pd2(dba)3.CHCl3 (24.1 mg, 0.023 mmol) was added. Traces of moisture and oxygen were removed and 0.20M solution of tri(tert.butyl)phosphine in cyclohexane (0.49 mL, 0.098 mmol) was added under atmosphere of nitrogen and the whole mixture was stirred at 60° C. for 5 h. The dark solution was poured into 10% aqueous solution of potassium fluoride (20 mL) and subsequently ethyl acetate (30 mL) was added. The layers were separated, the aqueous layer was washed with ethyl acetate (2×15 mL) and the collected organic layers were washed with brine (10 mL), 10% solution of potassium fluoride (20 mL), water (20 mL) and brine (20 mL). The organic solution was dried with anhydrous sodium sulfate and its evaporation gave an oil that was purified by column chromatography (silica gel Fluka 60, hexane/ethyl acetate 9:1) yielding 318.6 mg of the ester. Yield: 318.6 mg (76%).
Reaction SMILES: S(=O)(=O)(O)O.O.[C:7]([OH:16])(=[O:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13].[CH3:17]O>>[C:7]([O:16][CH3:17])(=[O:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13].[C:7]([OH:16])(=[O:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13]
Reactant: CO
Agent: CC(C)CCCCC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)CCCCC(C)C

Procedure:
The sulfuric acid is employed in an amount sufficient to both catalyze the reaction and to serve as a dehydrating agent or desiccant for the by-product water. Accordingly, the sulfuric acid should be employed in an amount greater than about 0.05 moles per mole of carboxylic acid to be esterified and preferably above 0.1 moles and of sulfuric acid per mole of carboxylic acid, which is sufficient to both catalyze the dehydrate the water. Most desirably, from about 0.1 to about 0.5 moles of sulfuric acid and most preferably about 0.2 moles will be employed per mol of carboxylic acid. The reaction is carried out at elevated temperatures, conveniently reflux conditions. With methanol as the alcohol and a carboxylic acid having from about 6 to about 22 carbon atoms a temperature will be on the order of about 70° to about 100° C. However, temperatures on the order at about 40° to about 120° C. and more preferably 60° to about 80° C. will be employed. The specific temperature employed will be determined however by the specific alcohol employed and specific carboxylic acid to be esterified. In the laboratory reflux periods of about 1 to 2 hours were sufficient to provide yields of methyl isooctanoate in the methanol esterification of isooctanoic acid employing about 1.5 to about 2 moles of methanol per mole of isooctanoic acid which provided the ester of greater than 99% purity. In contrast, in reactions not using an excess of sulfuric acid (only a catalytic amount) time periods of reflux of about 10 hours or more were required to provide about an 80% yield of ester of lower purity even with a seven molar excess of methanol. Again, the reaction period will depend on the specific alcohol employed and specific acid to be esterified. Generally reaction periods will not need to exceed about 4 hours and the reaction will be complete (about 90% yield) usually within 1 to about 3 hours employing the preferred levels of carboxylic acid, alcohol and sulfuric acid. After completion of the esterification the sulfuric acid layer is removed and any unesterified acid is removed as the sodium salt by an alkaline aqueous wash. The ester may be dried by azeotropic distillation with an aliphatic hydrocarbon solvent such as heptane. The unreacted carboxylic acid in the aqueous alkaline wash can be recovered by acidification with an acid, preferably spent sulfuric acid, from the esterification step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](Cl)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[OH-].[OH-].[C:14]([C:17]1[CH:18]=[C:19]([B+2])[CH:20]=[CH:21][CH:22]=1)(=[O:16])[CH3:15].[F-].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>[C:14]([C:17]1[CH:22]=[C:21]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=2)[CH:20]=[CH:19][CH:18]=1)(=[O:16])[CH3:15]
Reactant: COc1cc(Cl)cc(OC)c1
Reactant: [B+2]c1cccc(C(C)=O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Product: COc1cc(OC)cc(-c2cccc(C(C)=O)c2)c1
Temperature: 25 °C
Yield: 90.5 %

Procedure:
An oven dried Schlenk tube was evacuated and backfilled with argon and charged with palladium acetate (2.2 mg, 0.01 mmol, 1.0 mol %), 2-(di-tert-butylphosphino)biphenyl (6.0 mg, 0.020 mmol, 2.0 mol %), 3,5-dimethoxyphenyl chloride (173 mg, 1.0 mmol), 3-acetylphenylboron dihydroxide (246 mg, 1.5 mmol), and potassium fluoride (174 mg, 3.0 mmol). The tube was evacuated and backfilled with argon, and THF (1 mL) was added through a rubber septum. The reaction mixture was stirred at room temperature until the starting aryl chloride had been completely consumed as judged by GC analysis. The reaction mixture was then diluted with ethyl acetate (30 mL) and poured into a separatory funnel. The mixture was washed with 2.0 M NaOH (20 mL). The organic layer was washed with brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude material was purified by flash chromatography on silica gel to afford 232 mg (91%) of the title compound.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH:13]([CH3:20])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])(=O)=O)=CC=1.[OH:22][C:23]1[CH:31]=[CH:30][C:26]2[CH2:27][CH2:28][O:29][C:25]=2[CH:24]=1>>[CH3:20][CH:13]([CH2:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])[CH2:12][CH2:11][O:22][C:23]1[CH:31]=[CH:30][C:26]2[CH2:27][CH2:28][O:29][C:25]=2[CH:24]=1
Reactant: CC(C)=CCCC(C)CCOS(=O)(=O)c1ccc(C)cc1
Reactant: Oc1ccc2c(c1)OCC2
Product: CC(C)=CCCC(C)CCOc1ccc2c(c1)OCC2

Procedure:
3,7-dimethyl-6-octenyl p-toluenesulfonate and 6-hydroxy-2,3-dihydrobenzofuran are reacted to produce 6-[(3,7-dimethyl-6-octenyl)-oxy]-2,3-dihydrobenzofuran of boiling point 126°-128° C./0.001 mmHg; nD20 = 1.5223; and 3,7-dimethyl-6-octenyl p-toluenesulfonate and 6-hydroxy-3-methyl-2,3-dihydrobenzofuran are reacted to produce 6-[(3,7-dimethyl-6-octenyl)-oxy]-3-methyl-2,3-dihydrobenzofuran of boiling point (bulb-tube) 130° C./0.14 mmHg; nD20 = 1.5150.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:3]=1.[Cl:18][C:19]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:20]=1[NH2:21]>>[Cl:18][C:19]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:20]=1[NH:21][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccncc2)n1
Reactant: Nc1cc(O)ccc1Cl
Product: Oc1ccc(Cl)c(Nc2cc(C(F)(F)F)nc(-c3ccncc3)n2)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 2-chloro-5-hydroxyaniline (42 mg, 0.290 mmol) similar to Example 108 and isolated as a brown solid (3 mg, 4%). 1H NMR (CDCl3): 8.68 (dd, J=1.8, 4.5 Hz, 2H), 8.13 (dd, J=1.8, 4.2 Hz, 2H), 7.99 (d, J=2.7 Hz, 1H), 7.34 (s, 1H), 7.33 (d, J=8.7 Hz, 1H), 6.98 (s, 1H), 6.73 (dd, J=2.7, 8.7 Hz, 1H).
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([CH:27]=O)=[CH:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH3:32][CH2:33][CH:34]([NH2:37])[CH2:35][CH3:36].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CS(C)=O.C(O)(=O)C>[CH2:33]([CH:34]([NH:37][CH2:27][C:24]1[CH:23]=[CH:22][C:21]([C:18]2[CH:19]=[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:9]2[CH2:10][CH2:11][N:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH2:7][CH2:8]2)=[CH:26][CH:25]=1)[CH2:35][CH3:36])[CH3:32]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(C=O)cc4)cc23)CC1
Reactant: CCC(N)CC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CCC(CC)NCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cc1
Reaction time: 2 h
Yield: 75.1 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formylphenyl)-1H-indole-7-carboxamide (40 mg, 0.09 mmol) in DMSO (900 μL) and acetic acid (2 drops) was added 3-pentanamine (108 μL, 1.08 mmol). After 2 h, sodium triacetoxyborohydride (172 mg, 0.81 mmol) was added. Reaction mixture was stirred overnight. Compound was purified by Gilson Preparatory HPLC to afford 34.5 mg of the title compound (74%).
Reaction SMILES: [Li+].[OH-].[C:3]([O:7][C:8]([NH:10][C@@H:11]([CH2:16][C:17]1[CH:18]=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=1)[C:12]([O:14]C)=[O:13])=[O:9])([CH3:6])([CH3:5])[CH3:4]>>[C:3]([O:7][C:8]([NH:10][C@@H:11]([CH2:16][C:17]1[CH:18]=[N:19][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:21][CH:22]=1)[C:12]([OH:14])=[O:13])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)[C@H](Cc1ccc(C(F)(F)F)nc1)NC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(F)(F)F)nc1)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
To a LiOH solution (1.0 M in 1:1:1 water:MeOH:THF, 75 mL) was added (S)-methyl 2-(tert-butoxycarbonylamino)-3-(6-(trifluoromethyl)pyridin-3-yl)propanoate (3.8 g, 10.9 mmol). The reaction was stirred at room temperature for 30 minutes. The organic solvent in the reaction mixture was evaporated. The residue was diluted with EtOAc, washed with saturated ammonium chloride (2×100 mL), and dried over sodium sulfate. The solvent was removed to provide the product as a white solid (2.4 g, 66%). LCMS (API-ES) m/z (%): 335.0 (100%, M+H+).