Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([CH3:18])=[CH:16][CH:15]=[C:14]1[CH3:19].[Cl:20][C:21]([Cl:25])([F:24])[S:22]Cl>ClCCl>[Cl:12][C:4]1[CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:13]1[C:14]([CH3:19])=[CH:15][C:16]([S:22][C:21]([Cl:25])([Cl:20])[F:24])=[C:17]1[CH3:18]
Reactant: FC(Cl)(Cl)SCl
Reactant: Cc1ccc(C)n1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Solvent: ClCCl
Product: Cc1cc(SC(F)(Cl)Cl)c(C)n1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 0 °C
Yield: 89.6 %

Procedure:
To a cooled (0° C.) solution of 3.00 g (9.74 mmoles) of the 1-(2,6-dichloro-4-trifluoromethylphenyl)-2,5-dimethylpyrrole prepared above in 60 mL of dichloromethane was added dropwise 1.03 mL (1.67 g, 9.86 mmoles) of dichlorofluoromethanesulfenyl chloride in 5 mL of dichloromethane solution. The mixture was maintained at 0° C. for 3 hours and then washed with a saturated aqueous solution of NaHCO3. Removal of solvent under reduced pressure afforded a black off which was chromatographed on silica gel with a 1% EtOAc in hexane eluent to give 3.85 g (90%) of 1-(2,6-dichloro-4-trifluoromethylphenyl)-2,5-dimethyl-3-(dichlorofluoromethylthio)pyrrole as a yellow off: 1H NMR (CDCl3): δ2.00 (s, 3H), 2.10 (s, 3H), 6.27 (s, 1H), 7.80 (s, 2H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][CH:3]=1.[F:11][C:12]([F:22])([F:21])[O:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.CC([O-])(C)C.[K+].[H][H]>[Pd]>[F:11][C:12]([F:21])([F:22])[O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:2]2[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=2)=[CH:16][CH:15]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: [H][H]
Reactant: Oc1ccc(OC(F)(F)F)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: Nc1ccc(Oc2ccc(OC(F)(F)F)cc2)cc1

Procedure:
Reaction of 4-fluoro-nitrobenzene with 4-trifluoromethoxyphenol in the presence of KOtBu as described in Example 74A, followed by reduction of the nitro group (hydrogen, 10% Pd/C) gave 4-(4-trifluoromethoxyphenoxy)-aniline. The aniline (4.58 g, 17 mmol) was dissolved in conc. HCl (3.1 mL) and ice (4.5 g) cooled to −5 C., then treated with a solution of NaNO2 (1.17 g, 17 mmol) in water (7mL) which was added dropwise. The cold soltion was added to an aqueous (7 mL) solution of potassium xanthate (5.46 g, 34 mmol) and the resulting mixture was heated at 70 C for 2 h, then allowed to cool to rt and partitioned between EtOAc and water. The organic extract was dried (MgSO4), filt ered and concentrated to give the title compound
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])/[CH:5]=[CH:6]/[CH:7]1[CH:14]2[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:16][CH:8]1[CH2:9]3)[CH2:13]2)[CH3:2].C(OC(=O)/C=C\C1C2CC3CC(CC1C3)C2)C.[H][H]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH2:6][CH:7]1[CH:8]2[CH2:9][CH:10]3[CH2:11][CH:12]([CH2:13][CH:14]1[CH2:15]3)[CH2:16]2)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)/C=C/C1C2CC3CC(C2)CC1C3
Agent: [Pd]
Agent: CCOC(=O)/C=C\C1C2CC3CC(C2)CC1C3
Solvent: CCOC(C)=O
Product: CCOC(=O)CCC1C2CC3CC(C2)CC1C3

Procedure:
The mixture of (E)-3-tricyclo[3.3.1.1-3,7]dec-2-yl-2-propenoic acid ethyl ester and (Z)-3-tricyclo[3.3.1.1-3,7]dec-2-yl-2-propenoic acid ethyl ester (0.018 mol, 4.23 g), dissolved in ethyl acetate (500 mL) was hydrogenated over 10% Pd/C catalyst (450 mg), (1 atm H2) with vigorous stirring until the uptake of hydrogen ceased (1 h). The reaction mixture was filtered through a pad of celite, and the filtrate dried (Na2SO4) and concentrated in vacuo to provide tricyclo[3.3.1.1-3,7]decane-2-propanoic acid ethyl ester as a colorless oil.
Reaction SMILES: C[O:2][C:3](=[O:24])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH:14]([O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[CH2:13][CH2:12][CH:11]1[CH:22]=[O:23].[OH-].[Na+]>CO>[CH:22]([CH:11]1[CH2:12][CH2:13][CH:14]([O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[CH:10]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:24])=[O:2])=[O:23]
Reactant: COC(=O)CCCCCCC1C(C=O)CCC1OC1CCCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=CC1CCC(OC2CCCCO2)C1CCCCCCC(=O)O
Temperature: 40 °C
Reaction time: 18 h

Procedure:
To a solution of 2-formyl-5-(tetrahydropyran-2-yloxy)cyclopentaneheptanoic acid methyl ester (23.64 g), described by J. Bagli and T. Bogri, Tetrahedron Letters, 3815 (1972), see also U.S. Pat. No. 3,773,795 issued Nov. 20, 1973, in methanol (20 ml) is added 10% NaOH (33.5 ml). The reaction mixture is stirred under a nitrogen atmosphere at 40° C (bath temperature) for 18 hr. The mixture is cooled and the methanol is evaporated from the mixture. The residue is taken up in ether and the resulting mixture is washed with a small amount of water. The aqueous layer is acidified with acetic acid and extracted with ether. The ether extract is washed with water, dried and concentrated to yield the title compound, νmax film 2700, 1712, 1125 and 1025 cm-1.
Reaction SMILES: CC(O)(C(C)=C)C.Cl[C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([O:14]O)=[O:13].S([O-])([O-])=O.[Na+].[Na+].O>C(Cl)(Cl)Cl>[C:12]([OH:14])(=[O:13])[C:11]1[CH:16]=[CH:17][CH:18]=[CH:9][CH:10]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: C=C(C)C(C)(C)O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 46.7 g of 2,3-dimethyl-3-buten-2-ol in 602 ml of chloroform was cooled to 0°-5° in a dry ice-acetone bath. To this was added dropwise, during 4 hours, a solution of 96.5 g of m-chloroperoxybenzoic acid (113.5 g of 85%) in 966 ml of chloroform. The reaction mixture temperature was maintained at 0°-5° throughout the addition. Upon complete addition, the reaction mixture was allowed to warm to ambient temperature where it was stirred for 18 hours. To the reaction mixture was slowly added a solution of 11.8 g of sodium sulfite in a minimum amount of water. The reaction mixture was tested for peroxides using wet acidic sodium iodide-starch paper; there were no peroxides present. Concentration of the reaction mixture to below one-half the original volume resulted in precipitation of benzoic acid from the reaction mixture. The benzoic acid was removed by filtration. The concentration, precipitation, and filtration was repeated several time until at the last concentration only a small amount of precipitated benzoic acid was collected. There remained 16.6 g of residual yellow liquid, from which on standing a white solid crystallized. The liquid portion was decanted off and the solid was washed with diethyl ether. The ether wash was added to the liquid portion. The white solid had a melting point of 116°-118° and decomposed explosively at 170°-180°. The liquid portion was distilled using a Vigreux column, to give 9.32 g of 2-[(1-hydroxy-1- methyl)ethyl]-2-methyloxirane bp 35°-65°/15-20 mm. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: C(O[C:4]([NH:6]/[C:7](/[C:14]([F:17])([F:16])[F:15])=[CH:8]\[C:9]([O:11]CC)=O)=[O:5])C.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]2[S:26][N:25]=[C:24]([C:27]3[CH:28]=[C:29]([CH3:35])[C:30]([O:33][CH3:34])=[CH:31][CH:32]=3)[C:23]=2[CH:36]=1.N12CCCN=C1CCCCC2>C1(C)C(C)=CC=CC=1>[CH3:34][O:33][C:30]1[C:29]([CH3:35])=[CH:28][C:27]([C:24]2[C:23]3[CH:36]=[C:19]([N:18]4[C:9](=[O:11])[CH:8]=[C:7]([C:14]([F:15])([F:16])[F:17])[NH:6][C:4]4=[O:5])[CH:20]=[CH:21][C:22]=3[S:26][N:25]=2)=[CH:32][CH:31]=1
Reactant: COc1ccc(-c2nsc3ccc(N)cc23)cc1C
Reactant: CCOC(=O)/C=C(\NC(=O)OCC)C(F)(F)F
Solvent: Cc1ccccc1C
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(-c2nsc3ccc(-n4c(=O)cc(C(F)(F)F)[nH]c4=O)cc23)cc1C
Yield: 72 %

Procedure:
A mixture of ethyl 3-[(ethoxycarbonyl)amino]-4,4,4-trifluorocrotonate, (Z)-(2.04 g, 8 mmol), 5-amino-3-(6-methoxy-m-tolyl)-1,2-benzisothiazole (2.59 g, 9.6 mmol) and 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU, 1.46 g, 9.6 mmol) in xylene (15 mL) is heated at 110° C. for 6 hours, cooled, and quenched with ethyl acetate and water. The resultant mixture is extracted with ethyl acetate. The organic extracts are combined, washed with aqueous 2 N hydrochloric acid, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain a foam. Flash chromatography of the foam using silica gel and a 3:7 ethyl acetate/hexanes solution gives the title product as a solid (2.5 g, 72% yield) which is identified by 1H and 19F NMR spectral analyses.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH2:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][NH:13]1>>[ClH:1].[CH2:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][N:13]1[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: Clc1ccnc2ccccc12
Product: Cl
Product: c1ccc2c(c1)CCN(c1ccnc3ccccc13)C2

Procedure:
The title compound, m.p. 200° C., and MS: m/e=260 (M+), was prepared from 4-chloro-quinoline and 1,2,3,4-tetrahydroisoquinoline
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:22]=[CH:21][C:11]([C:12]([NH:14][C@H:15]3[C@H:19]([OH:20])[CH2:18][NH:17][CH2:16]3)=[O:13])=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl[C:24]1[CH:33]=[N:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=1.C(O)CCC.O>C(N(CC)CC)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:22]=[CH:21][C:11]([C:12]([NH:14][C@H:15]3[C@H:19]([OH:20])[CH2:18][N:17]([C:24]4[CH:33]=[N:32][C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:25]=4)[CH2:16]3)=[O:13])=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cnc2ccccc2n1
Reactant: O=C(N[C@@H]1CNC[C@H]1O)c1ccc(-c2cccc(F)c2)nc1
Solvent: CCCCO
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(N[C@@H]1CN(c2cnc3ccccc3n2)C[C@H]1O)c1ccc(-c2cccc(F)c2)nc1
Temperature: 90 °C
Yield: 79 %

Procedure:
To a vial was added trans-6-(3-fluorophenyl)-N-[4-hydroxypyrrolidin-3-yl]nicotinamide (40 mg, 0.12 mmol 2-chloroquinoxaline (29.2 mg, 0.18 mmol), n-butanol, water and triethylamine (0.3 mL of each). The reaction mixture was heated to 90° C. overnight and then cooled to room temperature and the solvent removed. The residue was taken up in DMSO and purified by RP-HPLC to give the desired product, trans-6-(3-fluorophenyl)-N-[4-hydroxy-1-quinoxalin-2-ylpyrrolidin-3-yl]nicotinamide (40 mg, 79%). HRMS (M+H) expected 430.1679, observed 430.1793
Reaction SMILES: Br.[CH2:2]([N:5]1[CH:9]=[C:8]([CH3:10])[S:7][C:6]1=[NH:11])[CH:3]=[CH2:4].[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([O:22][CH3:23])=[C:17]([CH:21]=1)[C:18](Cl)=[O:19]>>[CH2:2]([N:5]1[CH:9]=[C:8]([CH3:10])[S:7]/[C:6]/1=[N:11]\[C:18](=[O:19])[C:17]1[CH:21]=[C:13]([Cl:12])[CH:14]=[CH:15][C:16]=1[O:22][CH3:23])[CH:3]=[CH2:4]
Reactant: C=CCn1cc(C)sc1=N
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Agent: Br
Product: C=CCn1cc(C)s/c1=N\C(=O)c1cc(Cl)ccc1OC

Procedure:
A mixture of Example 232A (0.5 g) and 5-chloro-2-methoxybenzoylchloride (0.57 g) were processed according to the method of Example 227B to afford the title compound. 1H NMR (300 MHz, dimethylsulfoxide-d6) δ ppm 2.28 (d, J=1.4 Hz, 3H), 3.78 (s, 3H), 4.77 (d, 2H), 5.13 (dq, J=16.9, 1.3 Hz, 1H), 5.24 (dq, J=10.5, 1.4 Hz, 2H), 5.94-6.07 (m, 1H), 7.11 (d, 1H), 7.23 (q, J=1.4 Hz, 1H), 7.43 (dd, 1H), 7.68 (d, 1H); MS (ESI+) m/z 323 (M+H)+.
Reaction SMILES: [C:1]([C:3]1([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)#N.[OH-:17].[K+].C(O)C[OH:21]>O>[C:1]([C:3]1([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)([OH:21])=[O:17]
Reactant: N#CC1(c2ccc(Cl)cc2)CCC(=O)CC1
Reactant: [OH-]
Reactant: OCCO
Agent: [K+]
Solvent: O
Product: O=C1CCC(C(=O)O)(c2ccc(Cl)cc2)CC1
Yield: 82.2 %

Procedure:
A mixture of 21.87 g. (0.079 mole) of 4-cyano-4-(4-chlorophenyl)cyclohexanone, ethylene ketal (prepared in Example 19) and 22 g. of potassium hydroxide in 220 ml. of ethylene glycol is heated at reflux for about 16 hours. The resulting solution is allowed to cool, diluted with water and washed with ether. The aqueous layer is covered with ether and then cautiously acidified. The aqueous layer is extracted with two additional portions of ether and the extracts combined. The extracts are evaporated to dryness and the solid remaining is recrystallized from a mixture of ethylene chloride and Skellysolve B to give 19.26 g. (82.2% yield) of 4-carboxy-4-(4-chlorophenyl)cyclohexanone, ethylene ketal, having a melting point of 162.5° to 164.5°C.
Reaction SMILES: O1CCCC1.C1(C)C=CC=CC=1.[C:13]1([Mg]Br)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:21][C:22](=[O:26])[C:23](=[O:25])[CH3:24]>C1COCC1.C1(C)C=CC=CC=1>[OH:26][C:22]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:21])[C:23](=[O:25])[CH3:24]
Reactant: Br[Mg]c1ccccc1
Reactant: CC(=O)C(C)=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(=O)C(C)(O)c1ccccc1
Yield: 68 %

Procedure:
The process can also be run in mixtures of tetrahydrofuran and toluene, thereby making the process more economical. When 1.1 equivalent of phenylmagnesium bromide (1.9M in 50% THF/PhMe) was added to 2,3-butanedione in 50% THF/PhMe, crude product was isolated in 82.4% yield (Run 10, Table IV) after work-up. Short path vacuum distillation gave 3-hydroxy-3-phenylbutan-2-one in 68% yield. Alternatively, preparation of phenylmagnesium bromide in 38% THF/PhMe, followed by reaction with 2,3-butanedione in 38% THF/PhMe afforded 3-hydroxy-3-phenylbutan-2-one in 66.4% yield (Run 11, Table IV) after work-up and distillation. Similarly phenylmagnessium bromide in 25% THR/PheMe reacted with 2,3-butanedione in 25% THF/PheMe yielded 3-hydroxy-3-phenylbutan-2-one in 56.9% yield after work-up and distillation.
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:9]=[C:10]([C:13]([OH:15])=O)[S:11][CH:12]=2)[N:4]([CH3:16])[N:3]=1.[NH2:17][C@@H:18]([CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:9]=[C:10]([C:13]([NH:17][C@H:18]([CH2:19][N:20]3[C:28](=[O:29])[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21]3=[O:30])[CH2:31][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[O:15])[S:11][CH:12]=2)[N:4]([CH3:16])[N:3]=1
Reactant: Cc1c(Cl)nn(C)c1-c1csc(C(=O)O)c1
Reactant: N[C@@H](CC1CCCCC1)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(Cl)nn(C)c1-c1csc(C(=O)N[C@@H](CC2CCCCC2)CN2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 113 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(3-chloro-1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (150 mg, 0.58 mmol) [prepared according to the procedure of Example 176], 2-[(2S)-2-amino-3-cyclohexylpropyl]-1H-isoindole-1,3(2H)-dione (176 mg, 0.54 mmol) [prepared according to the procedure of Preparation 6, except substituting 3-cyclohexyl-N-{[(1,1-dimethylethyl)oxy]carbonyl}-L-alanine (5 g, 18.4 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (336 mg, 0.72 mmol) in chloroform (6 mL). DIEA (520 μL, 2.98 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (336 mg, 0.61 mmol, quant.): LC-MS (ES) m/z=526 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=2[CH3:17])[C:11]([OH:13])=[O:12])=[C:5]([CH3:7])[N:6]=1.IC1NC([CH:24]2C[CH2:27][O:26][CH2:25]2)=NC=1C.IC1NC(C)=NC=1C>>[CH3:17][C:16]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=1[C:4]1[NH:3][C:2]([CH:1]2[CH2:24][CH2:25][O:26][CH2:27]2)=[N:6][C:5]=1[CH3:7]
Reactant: Cc1nc(C2CCOC2)[nH]c1I
Reactant: Cc1nc(C)c(-c2cc(C(=O)O)ccc2C)[nH]1
Agent: Cc1nc(C)c(I)[nH]1
Product: Cc1ccc(C(=O)O)cc1-c1[nH]c(C2CCOC2)nc1C

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 5.7, except 5-iodo-4-methyl-2-(tetrahydrofuran-3-yl)-1H-imidazole (compound 171.1) was used in place of 5-iodo-2,4-dimethyl-1H-imidazole (compound 5.5).
Reaction SMILES: Br[C:2]1[S:3][C:4]([Br:7])=[CH:5][N:6]=1.[N:8]1([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C(N(CC)CC)C>O1CCCC1>[C:17]([O:16][C:14]([N:8]1[CH2:13][CH2:12][N:11]([C:2]2[S:3][C:4]([Br:7])=[CH:5][N:6]=2)[CH2:10][CH2:9]1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: Brc1cnc(Br)s1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)s2)CC1
Temperature: 160 °C
Yield: 68 %

Procedure:
A mixture of 24.7 mmol 2,5-dibromothiazole, 49.4 mmol tert-butyl 1-piperazinecarboxylate and 74.1 mmol triethylamine in 24 ml tetrahydrofuran in a sealed tube was heated at 160° C. for 30 min under microwave irradiation. The reaction mixture was concentrated and the residue was purified by chromatography (SiO2, ethyl acetate/heptane) to afford the title compound as a white crystalline solid (yield 68%). MS (m/e): 350.2 ({81Br}M+H+, 100%), 348.2 ({79Br}M+H+, 98%).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[CH3:11][NH:12][O:13][CH3:14].CCN(CC)CC.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(Cl)Cl>[CH3:14][O:13][N:12]([CH3:11])[C:8]([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[N:7]=1)=[O:10]
Reactant: O=C(O)c1cccc(F)n1
Reactant: CNOC
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1cccc(F)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.6 %

Procedure:
To a cooled mixture of 6-fluoro picolinic acid (1.19 g, 8.43 mmol), N,O-dimethylhydroxylamine (860 mg, 8.82 mmol) and Et3N (3.27 mL, 23.52 mmol) in CH2Cl2 (10 mL) was added 1-propane phosphonic acid cyclic anhydride (4.49 mL, 7.05 mmol; 50 wt % solution in EtOAc) dropwise and stirred at room temperature for 3 h. The reaction mixture was filtered, washed with CH2Cl2 (2×10 mL), evaporated to dryness, and subjected to column chromatography (SiO2, 40% EtOAc-hexanes) to obtain 6-fluoro-pyridine-2-carboxylic acid methoxy-methyl-amide (1.19 g) in 73% yield. ESMS m/z (relative intensity): 185 (M+H)+ (100).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[C:8]([CH3:14])[CH:9]=[C:10]([CH3:13])[CH:11]=2)[CH:6]([CH2:15][CH2:16][O:17]C(=O)C)[CH2:5]1)(=[O:3])[CH3:2].[OH-].[Na+]>C(Cl)(Cl)Cl.CO.O>[C:1]([N:4]1[C:12]2[C:7](=[C:8]([CH3:14])[CH:9]=[C:10]([CH3:13])[CH:11]=2)[CH:6]([CH2:15][CH2:16][OH:17])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCC1CN(C(C)=O)c2cc(C)cc(C)c21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CC(CCO)c2c(C)cc(C)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.8 %

Procedure:
1-Acetyl-3-(2-acetoxyethyl)-4,6-dimethylindoline (2.0 g) was dissolved in a mixture of CHCl3 /MeOH=1/1 (25 ml), and a solution of NaOH (1.5 g) in water (5 ml) was added, which was followed by stirring at room temperature for 1 hr. The solvent was evaporated under reduced pressure. CHCl3 (100 ml) was added, and the mixture was washed with water and dried over anhydrous sodium sulfate. CHCl3 was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CHCl3 /MeOH=50/1-10/1) to give 1.2 g of 1-acetyl-3-(2-hydroxyethyl)-4,6-dimethylindoline.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([C@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[C:15]([OH:17])=[O:16])=[O:8])=[CH:3][CH:2]=1>[OH-].[Na+]>[N:1]1[CH:6]=[CH:5][C:4]([C:7]([C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[C:15]([OH:17])=[O:16])=[O:8])=[CH:3][CH:2]=1
Reactant: O=C(c1ccncc1)[C@H]1CCCC[C@H]1C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)[C@H]1CCCC[C@H]1C(=O)c1ccncc1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
Cis-2-(4-pyridylcarbonyl)cyclohexanecarboxylic acid was dissolved in 10% sodium hydroxide (300 mL) and stirred at 20° C. for 16 h. The aqueous solution was extracted with diethyl ether (200 mL) and then acidified to pH=4 by addition of 6 M hydrochloric acid. The resulting precipitate was collected and recrystallized from hot water, to give (1S,2R)-2-(4-pyridylcarbonyl)-cyclohexanecarboxylic acid, as a white solid (4.8 g, 40% from cis-1,2-cyclohexanedicarboxylic anhydride).
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:13])[C@H:4]([O:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:5].[F:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[Mg]Br.[Cl-].[NH4+].O>C1COCC1.C(#N)C>[Cl:1][CH2:2][C:3]([C:18]1[CH:17]=[CH:16][C:15]([F:14])=[CH:20][C:19]=1[F:21])([OH:13])[CH:4]([O:6][C:7](=[O:12])[C:8]([CH3:9])([CH3:11])[CH3:10])[CH3:5]
Reactant: Fc1ccc([Mg]Br)c(F)c1
Reactant: C[C@@H](OC(=O)C(C)(C)C)C(=O)CCl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(OC(=O)C(C)(C)C)C(O)(CCl)c1ccc(F)cc1F
Reaction time: 0.08 h
Yield: 15 %

Procedure:
A solution of 0.41 g (2.0 mmol) of (R)-1-chloro-3-pivaloyloxybutan-2-one in 5 mL of THF was cooled to 0° C., and 3.2 mL (2.2 mmol) of a 0.69 M solution of 2,4-difluorophenylmagnesium bromide prepared by the same method as that in Example 3 was added dropwise thereto over a period of 5 minutes. After the completion of the dropwise addition, stirring was continued for another 1 hour, and 10 mL of a saturated aqueous solution of ammonium chloride was added to stop the reaction. Furthermore, 10 mL of water was added, and extraction was performed with ethyl acetate (20 mL×2). After drying over anhydrous sodium sulfate, concentration was performed under reduced pressure to obtain a crude product. A quantitative analysis was performed by HPLC. Thereby, the title compound was obtained in a yield of 15% ((2S,3R)/(2R,3R)=92/8) (HPLC, column: YMC-A302 manufactured by YMC Co. Ltd., mobile phase: acetonitrile/20 mM (potassium) phosphate buffer solution (pH=2.5)=6/4, flow rate: 1.0 mL/min, column temperature: 30° C., detector: UV 210 nm, retention time: 10 minutes (2S,3R) and 8 minutes (2R,3R)). 1H-NMR (400 MHz, CDCl3) δ: 1.05 (d, 3H, J=6.3 Hz), 1.25 (s, 9H), 3.86 (d, 1H, J=11.5 Hz), 4.19 (d, 1H, 11.5 Hz), 5.38 (q, 1H, J=6.3 Hz), 6.77-6.80 (m, 1H), 6.91-6.93 (m, 1H), 7.69-7.71 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][CH2:4][CH2:5]O.[CH2:9]([N:11](CC)CC)C.CS(Cl)(=O)=O.CCCCC>CCOCC>[F:1][C:2]([F:8])([F:7])[CH2:3][CH2:4][CH2:5][C:9]#[N:11]
Reactant: OCCCC(F)(F)F
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: CCOCC
Solvent: CCCCC
Product: N#CCCCC(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirring solution of 6.40 g (50.3 mM) 4,4,4-trifluorobutanol, prepared in Example 45d, and 7.71 ml (55.3 mM) triethylamine in 1.50 ml Et2O at 0° C. under N2, was added 4.28 ml (55.3 mM) methanesulfonyl chloride dropwise. A white precipitate formed and was stirred 60 minutes at 0° C. An equal volume of pentane was added and the reaction mixture was filtered through celite, followed by concentration on a rotary evaporator without heat. The crude mesylate was mixed with 8.19 g (126 mM) KCN and catalytic KI in 150 ml dimethysulfoxide at rt. The reaction mixture was then heated to 80° C. for 3 hours, turning deep orange and gelling. After cooling, the orange gel was poured into 100 ml of stirring H2O, extracted into Et2O, washed with saturated NaCl, dried over MgSO4, filtered and volatiles distilled. The crude liquid residue was 5.12 g (75%).