Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2](Cl)(Cl)[C@@H:3]1[O:8][C:7](=[O:9])[C@@H:6]([CH3:10])[C@H:5]([CH3:11])[O:4]1.S(=O)(=O)(O)O.[CH3:19]C(O)C>O>[CH3:10][C@@H:6]([C@@H:5]([OH:4])[CH3:11])[C:7]([O:8][CH:3]([CH3:19])[CH3:2])=[O:9]
Reactant: C[C@@H]1O[C@H](C(Cl)(Cl)Cl)OC(=O)[C@H]1C
Reactant: CC(C)O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)OC(=O)[C@@H](C)[C@H](C)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 1.0 g of (2S, 5S, 6S)-2-trichloromethyl-5,6-dimethyl-1,3-dioxan-4-one obtained by procedure similar to Example 1-(7) were added 0.1 ml of concentrated sulfuric acid and 10 ml of 2-propanol, stirred at room temperature for one hour, and 20 ml of water was added followed by ether extraction. The ether phase was dried over anhydrous sodium sulfate and the residue was subjected to distillation to give 0.4 g of isopropyl (2S, 3S)-2-methyl-3-hydroxybutanoate of the following formula. ##STR51##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22](OCC)=[O:23])=[CH:17][CH:16]=3)[CH:11]=[C:10]([CH:27]3[CH2:29][CH2:28]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][OH:23])=[CH:17][CH:16]=3)[CH:11]=[C:10]([CH:27]3[CH2:29][CH2:28]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1ccc(Nc2cc(-c3cccc(Cl)c3)nc(C3CC3)c2)cc1
Solvent: C1CCOC1
Product: OCCc1ccc(Nc2cc(-c3cccc(Cl)c3)nc(C3CC3)c2)cc1
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 79.3 %

Procedure:
A 25-mL round bottom flask was charged with ethyl 2-(4-((2-(3-chlorophenyl)-6-cyclopropylpyridin-4-yl)amino)phenyl)acetate (0.152 g, 0.37 mmol) and THF (6 mL) at rt. Borane-dimethylsulfide complex (0.106 mL, 1.12 mmol) was added and the resulting solution was stirred at 50° C. for 2.5 h until the starting material was consumed (monitored by LCMS analysis). The reaction was quenched with methanol then treated with 2N aqueous HCl (5 drops) and concentrated under reduced pressure. The residue was diluted with methanol and then concentrated under reduced pressure. The residue was treated with saturated sodium bicarbonate (0.1 mL) and then purified by column chromatography on silica using hexanes/ethyl acetate (10:0 to 0:10) as the eluent to afford 2-(4-((2-(3-chlorophenyl)-6-cyclopropylpyridin-4-yl)amino)phenyl)ethanol (0.107 g, 78%) as a colorless oil. MW=364.87. 1H NMR (CDCl3, 500 MHz) δ 7.94-7.92 (m, 1H), 7.81-7.76 (m, 1H), 7.35-7.30 (m, 2H), 7.27-7.23 (m, 2H), 7.18-7.14 (m, 2H), 6.99 (d, J=2.0 Hz, 1H), 6.65 (d, J=2.0 Hz, 1H), 5.94 (s, 1H), 3.90 (q, J=6.0 Hz, 2H), 2.88 (t, J=1.5 Hz, 2H), 1.99-1.92 (m, 1H), 1.40 (t, J=2.0 Hz, 1H), 1.12-1.07 (m, 2H), 0.96-0.90 (m, 2H); ESI MS m/z 365 [M+H]+. Treatment with 1.25M HCl in methanol (0.70 mL, 0.88 mmol) afforded the title compound (0.105 g, 90%) as a light yellow solid. MW=401.33. M.p. 125-128° C. 1H NMR (DMSO-d6, 500 MHz) δ 13.57 (br s, 1H), 10.50 (br s, 1H), 7.95-7.93 (m, 1H), 7.77-7.73 (m, 1H), 7.72-7.66 (m, 1H), 7.65-7.59 (m, 1H), 7.34-7.29 (m, 2H), 7.28-7.24 (m, 2H), 7.07 (s, 1H), 6.58 (br s, 1H), 3.63 (t, J=7.0 Hz, 2H), 2.74 (t, J=7.0 Hz, 2H), 2.40-2.29 (m, 1H), 1.22 (s, 2H), 1.05-0.96 (m, 2H); APCI MS m/z 365 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[CH:11][C:4]=1[O:5][CH2:6][CH2:7][N:8]=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[CH:11][C:4]=1[O:5][CH2:6][CH2:7][NH2:8]
Reactant: COc1cc(F)c(F)cc1OCCN=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(F)c(F)cc1OCCN
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
A solution of 2-(2-methoxy-4,5-difluoro-phenoxy)-ethylazide (0.69 g, 3.46 mmol) and triphenylphosphine (1.27 g, 4.84 mmol) in tetrahydrofuran (15 ml) containing water (0.08 ml) was stirred at room temperature overnight. The solvent was removed under vacuum. Chromatography with ethyl acetate removed triphenylphosphine oxide, followed elution with ethyl acetate-methanol-ammonium hydroxide 8.5:1.5:0.5, afforded 0.53 g of product as a white solid: mp 44-46° C.; MS EI m/e 203 (M+).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>CN(C)C=O>[N:22]1([C:2]2[N:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: COC(=O)c1cnc(Cl)cc1C(F)(F)F
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(N2CCCC2)cc1C(F)(F)F

Procedure:
A mixture of 2.5 g (10.43 mmol) of methyl 6-chloro-4-trifluoromethylnicotinate, of 2.88 g (20.87 mmol) of potassium carbonate and of 2.61 ml (31.3 mmol) of pyrrolidine in 90 ml of dimethylformamide is heated at 100° C. for 3 hours. The reaction mixture is subsequently concentrated under reduced pressure and then taken up in 100 ml of water. A precipitate is recovered by filtration and is washed with 150 ml of water. After drying under reduced pressure, 2.5 g of the expected product are isolated.
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:6][N:5]=1)([CH3:3])[CH3:2].[H-].[Na+].Cl[CH2:18][C:19]1[CH:38]=[CH:37][C:22]([CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]([O:35]C)=[O:34])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1.Cl>CO.O1CCCC1.[OH-].[Na+].O.CN(C)C=O>[CH:1]([C:4]1[N:5]([CH2:18][C:19]2[CH:38]=[CH:37][C:22]([CH2:23][O:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[N:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:8]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cc(-c2ccccc2)[nH]n1
Reactant: COC(=O)CCc1ccc(OCc2ccc(CCl)cc2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1cc(-c2ccccc2)nn1Cc1ccc(COc2ccc(CCC(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.9 %

Procedure:
A mixture of 3-isopropyl-5-phenyl-1H-pyrazole (186 mg, 1.0 mmol), sodium hydride (60% in oil, 40 mg, 1.0 mmol) and N,N-dimethylformamide (5 mL) was stirred at room temperature for 1 hr. Methyl 3-(4-{[4-(chloromethyl)benzyl]oxy)phenyl)propanoate (318 mg, 1.00 mmol) was added to the reaction mixture at room temperature, and the mixture was further stirred for 1 hr. The reaction mixture was poured into 1 N hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried using a Presep Dehydration tube (Manufactured by Wako Pure Chemical Industries, Ltd.), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1-1:1) to give a yellow oil. The yellow oil was dissolved in a mixed solvent of methanol (3 mL) and tetrahydrofuran (3 mL), and 1 N aqueous sodium hydroxide solution (2 mL) was added. The mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with water, neutralized with 1 N hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was dried using a Presep Dehydration tube (Manufactured by Wako Pure Chemical Industries, Ltd.), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1-1:4) to give the title compound (254 mg, yield 56%, 2 steps) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:20])[C:15]([F:19])([F:18])[CH:16]=[CH2:17])=[CH:4][CH:3]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:20])[C:15]([F:18])([F:19])/[CH:16]=[CH:17]/[C:25]2[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=2)=[CH:6][CH:7]=1
Reactant: C=CC(F)(F)C(O)c1c(C)noc1-c1ccc(Br)cc1
Reactant: Fc1ccc(I)cc1
Product: Cc1noc(-c2ccc(Br)cc2)c1C(O)C(F)(F)/C=C/c1ccc(F)cc1

Procedure:
Prepared according to the procedure described in Example 39, Step 1, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-2,2-difluoro-but-3-en-1-ol and 1-fluoro-4-iodo-benzene.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Al+3].[Cl-].[Cl-].[Cl-].[Cl:15][C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=1[O:23][CH3:24].Cl>ClCCCl>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](=[O:5])[C:20]1[CH:19]=[CH:18][C:17]([O:23][CH3:24])=[C:16]([Cl:15])[C:21]=1[Cl:22]
Reactant: COc1cccc(Cl)c1Cl
Reactant: O=C(Cl)c1ccccc1F
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1ccc(C(=O)c2ccccc2F)c(Cl)c1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 31.55 g of o-fluorobenzoyl chloride in 100 ml 1,2-dichloroethane, 26.54 g of AlCl3 was added over a 30 minute period. A solution of 32 g of 2,3-dichloroanisole in 50 ml of 1,2-dichloroethane was added dropwise. There was an evolution of gas and the temperature rose to 35°. The mixture was stirred 2 hours and then poured overa mixture of 100 ml concentrated HCl and 100 ml ice. The organic solvent was evaporated in vacuo and the mixture extracted with ether. The ether extract was washed with 10% K2CO3, washed withwater, and dried over Na2SO4, and the ether was evaporated to give a solid. Recrystallization of the solid from the ether-hexane mixturegave 38.69 g (70%) of 2'-fluoro-4-methoxy-2,3-dichlorobenzophenone, m.p. 74°-77°.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:14]2[CH:18]=[CH:17][O:16][N:15]=2)[CH2:9][C:10]([O:12]C)=[O:11])=[CH:4][CH:3]=1.[CH3:19][O:20]/[N:21]=[C:22](/[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)\[CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31]O)=[CH:27][CH:26]=1>>[CH3:19][O:20]/[N:21]=[C:22](/[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)\[CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][O:1][C:2]2[CH:7]=[CH:6][C:5]([CH:8]([C:14]3[CH:18]=[CH:17][O:16][N:15]=3)[CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=2)=[CH:27][CH:26]=1
Reactant: CO/N=C(\COc1ccc(CO)cc1)c1ccccc1
Reactant: COC(=O)CC(c1ccc(O)cc1)c1ccon1
Product: CO/N=C(\COc1ccc(COc2ccc(C(CC(=O)O)c3ccon3)cc2)cc1)c1ccccc1

Procedure:
Compound 17 was prepared by using methyl 3-(4-hydroxyphenyl)-3-(1,2-oxazol-3-yl)propanoate and (4-{[(2Z)-2-(Methoxyimino)-2-phenylethyl]oxy}phenyl) methanol by following the procedure described in Scheme 11.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH2:11]O.[Cl-].[Na+].[BrH:15]>C(OCC)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH2:11][Br:15]
Reactant: COc1cccc(OC)c1CO
Reactant: Br
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Product: COc1cccc(OC)c1CBr
Temperature: 25 °C
Reaction time: 1 h

Procedure:
After a mixture of 5.7 grams (0.034 mole) of 2,6-dimethoxyphenylmethanol in 40 mL of concentrated hydrobromic acid was stirred at ambient temperature for about one hour, the reaction mixture was taken up in diethyl ether. Solid sodium chloride was added to the mixture to obtain a phase separation. The organic layer was separated and concentrated under reduced pressure, yielding about 4.7 grams of 2,6-dimethoxyphenylmethyl bromide. This compound was used immediately in the next reaction.
Reaction SMILES: CCN(C(C)C)C(C)C.[N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N:16]2[CH:20]=[C:19]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[N:18]=[N:17]2)[CH:11]=1.NC1C=NC=CC=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[F:57][C:58]1[CH:70]=[CH:69][C:61]([O:62][CH:63]2[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]2)=[CH:60][C:59]=1[C:71]([F:74])([F:73])[F:72]>CN(C=O)C>[F:57][C:58]1[CH:70]=[CH:69][C:61]([O:62][CH:63]2[CH2:68][CH2:67][N:66]([C:25](=[O:27])[CH2:24][NH:23][C:21]([C:19]3[N:18]=[N:17][N:16]([C:12]4[CH:11]=[N:10][CH:15]=[CH:14][CH:13]=4)[CH:20]=3)=[O:22])[CH2:65][CH2:64]2)=[CH:60][C:59]=1[C:71]([F:74])([F:72])[F:73]
Reactant: Fc1ccc(OC2CCNCC2)cc1C(F)(F)F
Reactant: O=C(O)CNC(=O)c1cn(-c2cccnc2)nn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Nc1cccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCC(Oc2ccc(F)c(C(F)(F)F)c2)CC1)c1cn(-c2cccnc2)nn1
Reaction time: 0.03 h
Yield: 20 %

Procedure:
DIPEA (97 mg, 0.75 mmol) was added to a stirred solution of [(1-pyridin-3-yl-1H-[1,2,3]triazole-4-carbonyl)-amino]-acetic acid (prepared by the method used for the synthesis of Intermediate 64, starting from 3-aminopyridine, and subsequently, application of Step 3 of the General Scheme) (62 mg, 0.25 mmol) in DMF (2 mL) followed by HOBt (35 mg, 0.26 mmol) and EDCI (50 mg, 0.26 mmol). After 2 minutes of stirring, 4-(4-fluoro-3-trifluoromethyl-phenoxy)-piperidine hydrochloride (prepared by the method used for the synthesis of Intermediate 15) (75 mg, 0.25 mmol) was added and the resulting mixture was stirred at room temperature overnight. The reaction mixture was partitioned between cold water and ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (using silica gel 60-120 and 40% EtOAc in hexane as eluent) afforded 24 mg (20% Yield) of 1-pyridin-3-yl-1H-[1,2,3]triazole-4-carboxylic acid {2-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 493, 95.48%. 1H NMR (300 MHz, DMSO-d6): δ 9.43 (s, 1H), 9.2 (m, 1H), 8.75 (m, 1H), 8.5 (m, 1H), 8.4 (m, 1H), 7.7 (m, 1H), 7.4 (m, 3H), 4.75 (m, 1H), 4.3 (m, 2H), 3.9 (m, 1H), 3.7 (m, 1H), 3.5 (m, 2H), 2.0 (m, 2H), 1.6 (m, 2H).
Reaction SMILES: B([O-])O[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C=CCCCCCC.B1C2CCCC1CCC2.[OH-].[Na+].[C:31]([O:35][C:36]([N:38]1[C:46]2[C:41](=[CH:42][CH:43]=[C:44](Br)[CH:45]=2)[C:40]([CH2:48][OH:49])=[CH:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]>C1COCC1>[C:31]([O:35][C:36]([N:38]1[C:46]2[C:41](=[CH:42][CH:43]=[C:44]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH:45]=2)[C:40]([CH2:48][OH:49])=[CH:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)n1cc(CO)c2ccc(Br)cc21
Reactant: CCCCCCCCOB[O-]
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: C=CCCCCCC
Solvent: C1CCOC1
Product: CCCCCCCCc1ccc2c(CO)cn(C(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An octyl boronate intermediate is generated by adding 1-octene (1.38 g, 14.1 mmol) to a solution of 9-BBN in THF (28.3 mL of a 0.5 M solution, 14.1 mmol). The reaction mixture is stirred at room temperature overnight. An aqueous solution of sodium hydroxide (5.0 mL of a 3.0 M solution) is added, followed by the addition of compound 25 (3.10 g, 10.0 mmol) and Pd[P(Ph)3]4 (0.310 g, 0.270 mmol). The reaction is brought to reflux and maintained for 12 hours under an inert atmosphere. The reaction is cooled, filtered, concentrated in vacuo and the residue purified using silica gel chromatography with hexane/ethyl acetate (75:25) as solvent.
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[OH:5][N:6]1[CH:10]=[CH:9][CH:8]=[N:7]1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.ClCCl>[CH2:1]([O:5][N:6]1[CH:10]=[CH:9][CH:8]=[N:7]1)[C:2]#[CH:3]
Reactant: On1cccn1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: C#CCOn1cccn1
Reaction time: 12 h
Yield: 68.8 %

Procedure:
21.3 g of propargyl bromide are added to 15 g of 1-hydroxypyrazole and 15 g of sodium carbonate in 200 g of acetonitrile at 25° C., while stirring. Stirring is continued for 12 hours, after which the mixture is filtered under suction, the residue is washed with 100 g of acetonitrile, and the combined liquids are evaporated down in a rotary evaporator at 40° C. and under 20 mbar. The residue obtained in this procedure is dissolved in 200 g of dichloromethane, the solution is extracted 3 times with a total of 200 g of saturated aqueous sodium bicarbonate solution, and the organic phase is dried with magnesium sulfate and evaporated down. 15 g (70% of theory) of 1-pyrazolyl propargyl ether are obtained as an oil (H1 -NMR, δ in ppm: 2.6, t, 1H; 4.9, d, 2H; 6.2, m, 1H; 7.4, m, 2H). This substance is Example 10 in the Table below.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([CH2:14][O:15][C:16]2[C:24]3[N:23]=[C:22]([O:25][CH3:26])[N:21]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[C:20]=3[CH:19]=[CH:18][CH:17]=2)[C:8]=1[Cl:34])[CH3:6])=[O:4].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:59][C:60]([O:63][C:64]([N:66]1[CH2:70][C@@H:69]([C:71](O)=[O:72])[CH2:68][CH2:67]1)=[O:65])([CH3:62])[CH3:61].C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[Cl:34][C:8]1[C:9]([CH2:14][O:15][C:16]2[C:24]3[N:23]=[C:22]([O:25][CH3:26])[N:21]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[C:20]=3[CH:19]=[CH:18][CH:17]=2)=[C:10]([Cl:13])[CH:11]=[CH:12][C:7]=1[N:5]([CH3:6])[C:3](=[O:4])[CH2:2][NH:1][C:71]([C@H:69]1[CH2:68][CH2:67][N:66]([C:64]([O:63][C:60]([CH3:62])([CH3:61])[CH3:59])=[O:65])[CH2:70]1)=[O:72]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C(=O)O)C1
Reactant: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)cccc2n1Cc1ccccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)[C@H]4CCN(C(=O)OC(C)(C)C)C4)c3Cl)cccc2n1Cc1ccccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-amino-N-(2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)-N-methylacetamide (2.00 g, 4 mmol) in anhydrous DMF (12 ml) was treated with HBTU (2.12 g, 5.6 mmol), (S)-1-N-boc-β-proline (0.95 g, 4.4 mmol) and diisopropylethyl amine (2.09 mL, 12 mmol) with stirring at room temperature overnight. To the reaction was added ethyl acetate (200 mL) and the mixture was washed with aqueous saturated sodium bicarbonate (100 mL×3). The organic layer was dried over magnesium sulfate, filtered and evaporated to a tan solid, 2.43 g that was purified by chromatography (silica gel, ethyl acetate and methanol gradient) to afford (S)-tert-butyl 3-(2-((2,4-dichloro-3-((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yloxy)methyl)phenyl)(methyl)amino)-2-oxoethylcarbamoyl)pyrrolidine-1-carboxylate (34) as a tan solid, 1.68 g (60%), that had one peak by LC/MS (+ESI) m/z 697 (M++1) and 711 (M++1) (both ions in the same LC peak), and was pure by 1HNMR (400 MHz, CDCl3) δ 8.60 (m, 1H), 7.60 (m, 1H), 7.48 (m, 1H), 7.28 (m, 1H), 7.19 (m, 1H), 7.04 (m, 1H), 6.93 (m, 1H), 6.81 (m, 2H), 6.50 (m, 1H), 5.67 (s, 2H), 5.28 (s, 2H), 4.22 (s, 3H), 3.81 (m, 1H), 3.50 (m, 4H), 3.25 (m, 4H), 2.91 (m, 1H), 2.08 (m, 3H), 1.44 (s, 9H). 13CNMR (100 MHz, CDCl3) δ 168.2, 156.8, 156.1, 154.3, 149.6, 149.0, 138.4, 138.1, 137.0, 136.5, 135.8, 135.4, 130.1, 129.8, 122.6, 121.7, 120.8, 107.4, 103.1, 79.3, 67.1, 64.3, 60.4, 57.5, 48.6, 47.7, 41.9, 35.9, 30.7, 28.5, 21.0, 19.1, 14.2, 13.7. LN-15495-57.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH2:11]([O:13][CH:14]([O:17][CH2:18][CH3:19])[CH2:15]Br)[CH3:12].C(=O)(O)[O-].[Na+]>C(O)C>[CH:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][CH2:15][CH:14]([O:17][CH2:18][CH3:19])[O:13][CH2:11][CH3:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(N)cc1
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(CNc1ccc(C(C)C)cc1)OCC
Temperature: 25 °C
Yield: 90.9 %

Procedure:
A solution of 4-isopropylaniline (7.6 mL, 56 mmol), 2-bromoacetaldehyde diethyl acetal (5.5 mL, 36 mmol) and sodium bicarbonate (4.8 g, 57 mmol) in ethanol (60 mL) was stirred at reflux for 3 days under argon. After cooling to room temperature, the ethanol was removed in vacuo and the product was partitioned between ether and water, washed sequentially with water and brine, and dried over sodium sulfate. After removal of the solvent in vacuo, flash chromatography (silica, 10% ethyl acetate in hexanes) yielded 4-isopropyl-N-(2,2-diethoxyethyl) aniline (8.23 g, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][C:6]([CH:12]=[CH:13][CH2:14][OH:15])=[CH:5]2.[Na+].[Cl-]>CCOCC.O=[Mn]=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][C:6]([CH:12]=[CH:13][CH:14]=[O:15])=[CH:5]2
Reactant: OCC=Cc1cc2cc(Cl)c(Cl)cc2[nH]1
Agent: O=[Mn]=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Product: O=CC=Cc1cc2cc(Cl)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 48 h
Yield: 84 %

Procedure:
To a solution of (E) 3-(5,6-dichloro-2-indolyl)-2-propen-1-ol (13.8 g, 57.0 mmol) in Et2O (450 ml), activated MnO2 (35 g) and NaCl (35 g) were added. The reaction mixture was stirred for two days at RT, filtered on a Celite pad, washed with Et2O and dried over MgSO4 to afford (11.5 g, 47.9 mmol, yield 84.1%) of pure title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][S:12]([CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=2[Cl:26])(=[O:14])=[O:13])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].C(N(CC)C(C)C)(C)C.[Cl:36][CH:37]([Cl:47])[CH2:38]OS(C(F)(F)F)(=O)=O>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[C:10]([N:11]([S:12]([CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:23])[F:24])[CH:19]=[CH:18][C:17]=2[Cl:26])(=[O:13])=[O:14])[CH2:38][CH:37]([Cl:47])[Cl:36])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: O=S(=O)(OCC(Cl)Cl)C(F)(F)F
Reactant: COC(=O)c1nccnc1NS(=O)(=O)Cc1cc(C(F)(F)F)ccc1Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1nccnc1N(CC(Cl)Cl)S(=O)(=O)Cc1cc(C(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 29 %

Procedure:
To a solution of 3-(2-chloro-5-trifluoromethyl-phenylmethanesulfonylamino)-pyrazine-2-carboxylic acid methyl ester (Example 2.1) (0.5 g) in acetonitrile (5 ml) was added N,N-diisopropylethylamine (“Hunig's base”) (0.71 ml) at ambient temperature. The mixture was stirred for 5 minutes at ambient temperature before dropwise addition of 2,2-dichloroethyltrifluoromethanesulfonate (0.603 g) at ambient temperature. The reaction mixture was stirred at ambient temperature for 20 hours. The reaction mixture was concentrated and the residue purified by column chromatography on silica gel (eluent: iso-hexane/ethyl acetate 4:1) to give 3-[(2-chloro-5-trifluoromethyl-phenylmethanesulfonyl)-(2,2-dichloro-ethyl)-amino]-pyrazine-2-carboxylic acid methyl ester as a white solid (0.179 g). 1H-NMR (400 MHz, CDCl3): 8.61 (d, 1H), 8.51 (d, 1H), 7.73 (s, 1H), 7.53-7.59 (m, 2H), 5.99-6.02 (m, 1H), 4.71 (s, 2H), 4.58 (d, 2H), 4.02 (s, 3H) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:19]([NH2:20])=[C:18](Br)[C:17]([Cl:22])=[C:16]([C:23]([F:26])([F:25])[F:24])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si]([SiH]([Si](C)(C)C)[Si](C)(C)C)(C)C.N(C(C)(C)C#N)=NC(C)(C)C#N.O>C1(C)C=CC=CC=1.N(C(C)(C)C#N)=NC(C)(C)C#N>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:19]([NH2:20])=[CH:18][C:17]([Cl:22])=[C:16]([C:23]([F:24])([F:25])[F:26])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C(F)(F)F)c(Cl)c(Br)c2N)CC1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: C[Si](C)(C)[SiH]([Si](C)(C)C)[Si](C)(C)C
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(c2nc(C(F)(F)F)c(Cl)cc2N)CC1
Temperature: 85 °C
Yield: 96.6 %

Procedure:
A solution of the compound obtained in Step B (0.2 g), tris(trimethylsilyl)-silane (0.16 ml), and 2,2′-azobis(2-methylpropionitrile) (10 mg) in toluene (10 ml) was stirred at 85° C. for 2 hours under a nitrogen atmosphere. More tris(trimethylsilyl)silane (0.3 ml) and more 2,2′-azobis(2-methylpropionitrile) (5 mg) were then added and the reaction mixture was heated to 85° C. for 16 hours. The reaction mixture was cooled to ambient temperature, poured into water, extracted with ethyl acetate, dried over sodium sulfate and then concentrated in vacuo. Chromatography on silica gel (eluent: hexane/ethyl acetate 1:1) afforded 3-amino-5-chloro-6-trifluoromethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (0.160 g) as a solid. MS (ES+) 324/326 (M-isoprene); 1H NMR (400 MHz, CDCl3) 1.48 (s, 9H), 1.84 (m, 4H), 2.78 (m, 1H), 2.88 (m, 2H), 4.25 (m, 2H), 4.42 (s, 2H), 7.46 (s, 1H).