Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:14]=[C:13]([C:15]([O:17]CC)=[O:16])[N:12]=[C:11]2[C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:21]=2[F:27])[CH:7]=[CH:8][CH:9]=1)[CH3:2].[OH-].[Na+].Cl>O1CCCC1.O.CO>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[N:12]=[C:11]2[C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:21]=2[F:27])[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOC(=O)c1cn(-c2cccc(OCC)c2)c(-c2ccc(C)cc2F)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1cccc(-n2cc(C(=O)O)nc2-c2ccc(C)cc2F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.81 g (2.2 mmol) of ethyl 1-(3-ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazole-4-carboxylate in 10 mL of tetrahydrofuran, 5 mL of water and 5 mL of methanol was added 1.0 mL (5.0 mmol) of 5.0 M NaOH solution. The reaction mixture was stirred at ambient temperature overnight. Hydrochloric acid (2.0 M) was then added to neutralize the reaction mixture. After removal of the organic solvents in vacuo, dichloromethane (20 mL) was added and the organic layer was separated. The aqueous layer was extracted with dichloromethane (10 mL), and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to yield the title compound as a yellow foam. LC/MS 341.1 (M+1).
Reaction SMILES: [C:1]([Sn](I)(Cl)Cl)([F:4])([F:3])[F:2].[CH:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CN(C)C=O>[C:10]1([CH:9]([C:1]([F:4])([F:3])[F:2])[OH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccccc1
Reactant: FC(F)(F)[Sn](Cl)(Cl)I
Solvent: CN(C)C=O
Product: OC(c1ccccc1)C(F)(F)F

Procedure:
In Example 20, by using tin chloride instead of zinc powder, trifluoromethyl was caused to react with trifluoromethyl iodide (SnCl2), as in the case of the Example 20, and CF3SnCl2I was obtained. Consecutively, as in the case of the Example 20, CF3SnCl2I was put into a flask together with benzaldehyde and dimethylformamide, and subjected to reaction under the action of ultrasonic waves, and the product extracted from an oil layer generated was hydrolyzed, thereby phenyltrifluoromethylcarbinol was obtained.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].C[Al](C)C.[CH3:9][C:10]1[O:14][N:13]=[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]=1[CH2:21][CH2:22][C:23]1[S:24][C:25]([C:28](O)=[O:29])=[CH:26][N:27]=1>O1CCOCC1.C1(C)C=CC=CC=1>[CH:1]([NH:4][C:28]([C:25]1[S:24][C:23]([CH2:22][CH2:21][C:11]2[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:13][O:14][C:10]=2[CH3:9])=[N:27][CH:26]=1)=[O:29])([CH3:3])[CH3:2]
Reactant: Cc1onc(-c2ccccc2)c1CCc1ncc(C(=O)O)s1
Reactant: CC(C)N
Agent: C[Al](C)C
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: Cc1onc(-c2ccccc2)c1CCc1ncc(C(=O)NC(C)C)s1
Temperature: 90 °C
Reaction time: 1 h
Yield: 68.6 %

Procedure:
To a stirred solution of isopropylamine (75 mg, 1.27 mmol) in dioxane (5 mL) under argon and at room temperature was added trimethylaluminium (0.6 mL of a 2M solution in toluene, 1.2 ml). After 1 h, a solution of 2-[2-(5-methyl-3-phenyl-isoxazol-4-yl)-ethyl]-thiazole-5-carboxylic acid (100 mg, 0.32 mmol) in dioxane (5 mL) was added and the reaction mixture warmed to 90° C. After 3 h, the reaction mixture was cooled, quenched with ice water and extracted with dichloromethane. The combined extracts were washed with Seignette's salt solution then dried, filtered, and concentrated. Purification by chromatography (silica, 0 to 3% methanol in dichloromethane) gave the title compound (78 mg, 69%) as a pale yellow oil. MS: m/e=356.1 [M+H]+.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:8]([O:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([C:22]4[NH:23][C:24]5[C:25]([N:30]=4)=[N:26][CH:27]=[CH:28][CH:29]=5)=[O:21])=[CH:16][CH:15]=3)=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1>C1COCC1.[OH-].[Pd+2].[OH-]>[NH:23]1[C:24]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[N:30]=[C:22]1[CH:20]([C:17]1[CH:18]=[CH:19][C:14]([O:13][C:8]2[C:7]([CH:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:15][CH:16]=1)[OH:21]
Reactant: O=C(c1ccc(Oc2ncccc2C2=CCOCC2)cc1)c1nc2ncccc2[nH]1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: OC(c1ccc(Oc2ncccc2C2CCOCC2)cc1)c1nc2ncccc2[nH]1

Procedure:
To a round bottomed flask was added (4-(3-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yloxy)phenyl)(1H-imidazo[4,5-b]pyridin-2-yl)methanone (0.3642 g, 0.914 mmol) in THF (3.05 mL). Palladium hydroxide (0.032 g, 0.046 mmol) was added. The round bottomed flask was flushed with N2(g) followed by vacuum repeating the process three times. A balloon of H2(g) was then added to the reaction. Upon completion, reaction was filtered. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage pre-packed silica gel column (40S), eluting with a gradient of 0.5% to 10% MeOH in DCM, to provide (1H-imidazo[4,5-b]pyridin-2-yl)(4-(3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yloxy)phenyl)methanol. MS (ESI, pos. ion) m/z: 403.0 (M+1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[N:20][OH:21])[C:7]1[CH:19]=[CH:18][C:10]([O:11][C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=[O:14])=[CH:9][CH:8]=1.CN(C)C=O>[O-]CC.[Na+].C(O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[N:20][O:21][CH2:19][CH2:7][CH2:8][CH3:9])[C:7]1[CH:19]=[CH:18][C:10]([O:11][C:12]([CH3:17])([CH3:16])[C:13]([O:15][CH2:6][CH2:2][CH2:3][CH3:4])=[O:14])=[CH:9][CH:8]=1
Reactant: CC(C)(Oc1ccc(C(=NO)c2cccs2)cc1)C(=O)O
Agent: CC[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CCCCON=C(c1ccc(OC(C)(C)C(=O)OCCCC)cc1)c1cccs1
Reaction time: 3 h

Procedure:
2-[4-(2-Thienyl-hydroxyiminomethyl)-phenoxy]-2-methyl propionic acid (6.7 g) is dissolved in a sodium ethoxide solution in ethanol (100 ml; prepared from 1.3 g sodium), and the solution is then refluxed for 1 hour, after which dimethylformamide (75 ml) is added thereto and the ethanol is evaporated off. Butyl bromide (9 g) is added to the solution at 80° C. and the mixture is stirred for 3 hours, after which the solvent is evaporated under reduced pressure. Water and chloroform are then added to the resulting material. After stirring the mixture, the chloroform phase is decanted off and is then washed with an aqueous alkaline solution. After drying, the solvent is evaporated off and the desired ester is isolated as an oil consisting of an admixture of equivalent amounts of both stereoisomers Z/E. nd22 =1.545.
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:11]([NH2:12])[CH2:10][CH2:9][C:4]2([O:8][CH2:7][CH2:6][O:5]2)[CH2:3]1.[O:13]=[C:14](N1CCOC1=O)[CH2:15][CH2:16][CH:17]=O>>[CH3:1][C@H:2]1[C@@H:11]([N:12]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:13])[CH2:10][CH2:9][C:4]2([O:5][CH2:6][CH2:7][O:8]2)[CH2:3]1
Reactant: C[C@@H]1CC2(CC[C@@H]1N)OCCO2
Reactant: O=CCCC(=O)N1CCOC1=O
Product: C[C@@H]1CC2(CC[C@@H]1N1CCCC1=O)OCCO2
Yield: 77.6 %

Procedure:
Using the method in Example 167 and reagents cis-7-methyl-1,4-dioxa-spiro[4.5]dec-8-ylamine (Preparation 44) (2.3 g, 13.4 mmol) and 4-oxo-4-(2-oxo-oxazolidin-3-yl)-butyraldehyde (2.3 g, 13.43 mmol) yields 2.49 g (77%) of the title compound as a white solid. 1H NMR (CDCl3) δ 4.05-4.12 (m, 1H), 3.81-3.93 (m, 4H), 3.44 (t, 2H), 2.23-2.35 (m, 3H), 1.51-1.98 (m, 8H), 0.94 (d, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:28])=[C:4]([C:8]2[C:20]3[C:19]4[C:14](=[CH:15][C:16]([CH:21]([OH:24])[CH2:22][OH:23])=[CH:17][CH:18]=4)[NH:13][C:12]=3[C:11]([C:25]([NH2:27])=[O:26])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:29][C:30]1[CH:31]=[CH:32][C:33]([C:36](O)=[O:37])=[N:34][CH:35]=1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>C(#N)C.C1COCC1>[OH:24][CH:21]([C:16]1[CH:15]=[C:14]2[C:19]([C:20]3[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:36](=[O:37])[C:33]5[CH:32]=[CH:31][C:30]([F:29])=[CH:35][N:34]=5)[C:3]=4[CH3:28])=[CH:9][CH:10]=[C:11]([C:25]([NH2:27])=[O:26])[C:12]=3[NH:13]2)=[CH:18][CH:17]=1)[CH2:22][OH:23]
Reactant: Cc1c(N)cccc1-c1ccc(C(N)=O)c2[nH]c3cc(C(O)CO)ccc3c12
Reactant: O=C(O)c1ccc(F)cn1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CC#N
Solvent: C1CCOC1
Product: Cc1c(NC(=O)c2ccc(F)cn2)cccc1-c1ccc(C(N)=O)c2[nH]c3cc(C(O)CO)ccc3c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.5 %

Procedure:
A solution of 4-(3-amino-2-methylphenyl)-7-(1,2-dihydroxyethyl)-9H-carbazole-1-carboxamide (Example 70-4, 28 mg, 0.075 mmol), 5-fluoropicolinic acid (15.8 mg, 0.112 mmol), HOAT (18.3 mg, 0.134 mmol), and EDC (28.6 mg, 0.149 mmol) in acetonitrile-THF (2:1, 3 mL) was treated with DIEA (0.039 mL, 0.224 mmol) and stirred at rt overnight. The mixture was concentrated and purified by preparative HPLC. The residue from concentration of the appropriate effluent fractions was partitioned between NaHCO3 (aq) and EtOAc, and the organic phase was washed with brine, dried and concentrated to provide 7-(1,2-dihydroxyethyl)-4-(3-(5-fluoropicolinamido)-2-methylphenyl)-9H-carbazole-1-carboxamide as an off-white solid (20 mg, 53%). 1H NMR (400 MHz, DMSO-d6) δ 11.47 (1H, s), 10.38 (1H, s), 8.74 (1H, d, J=2.6 Hz), 8.28 (1H, dd, J=8.8, 4.8 Hz), 8.10-8.23 (1H, m), 7.95-8.04 (2H, m), 7.87-7.93 (1H, m), 7.72 (1H, s), 7.46-7.52 (1H, m), 7.43 (1H, t, J=7.6 Hz), 7.18 (1H, d, J=6.6 Hz), 6.97 (1H, d, J=7.7 Hz), 6.82-6.92 (2H, m), 5.22 (1H, t, J=3.5 Hz), 4.66-4.72 (1H, m), 4.56-4.64 (1H, m), 3.44 (2H, t, J=6.1 Hz), 1.97 (3H, s). Mass spectrum m/z 521.3 (M+Na)+.
Reaction SMILES: N1C2C(=CC=CC=2)C(CCO)=C1.C(C1C=CC=C2C=1NC=C2CCO)C.COC1C=C2C(C(CCO)=CN2)=CC=1.C1(COC2C=C3C(=CC=2)NC=C3CCO)C=CC=CC=1.C([C:63]1[CH:64]=[CH:65][CH:66]=[C:67]2[C:71]=1[NH:70][C:69]1[C:72]([CH2:77][NH:78][C:79](=[O:81])[CH3:80])([CH3:76])[O:73][CH2:74][CH2:75][C:68]2=1)C.COC1C=C2C(C3CCOC(CNC(=O)C)(C)C=3N2)=CC=1.C1(COC2C=C3C(=CC=2)NC2C(CNC(=O)C)(C)OCCC3=2)C=CC=CC=1>>[CH3:76][C:72]1([CH2:77][NH:78][C:79](=[O:81])[CH3:80])[C:69]2[NH:70][C:71]3[C:67]([C:68]=2[CH2:75][CH2:74][O:73]1)=[CH:66][CH:65]=[CH:64][CH:63]=3
Reactant: CCc1cccc2c3c([nH]c12)C(C)(CNC(C)=O)OCC3
Agent: CC(=O)NCC1(C)OCCc2c1[nH]c1ccc(OCc3ccccc3)cc21
Agent: CCc1cccc2c(CCO)c[nH]c12
Agent: COc1ccc2c(CCO)c[nH]c2c1
Product: CC(=O)NCC1(C)OCCc2c1[nH]c1ccccc21

Procedure:
In the same manner but replacing indole-3-ethanol with an equivalent amount of 7-ethylindole-3-ethanol, 6-methoxyindole-3-ethanol or 5-phenylmethoxy-indole-3-ethanol, the following compounds of formula IIa are obtained, respectively: N-[(8-ethyl-1,3,4,9-tetrahydro-1-methylpyrano[3,4-b]indol-1-yl)methyl]-acetamide, N-[(7-methoxy-1,3,4,9-tetrahydro-1-methylpyrano-[3,4-b]indol-1-yl)methyl]-acetamide and N-[(6-phenylmethoxy-1,3,4,9-tetrahydro-1-methylpyrano[3,4-b]indol-1-yl)methyl]-acetamide.
Reaction SMILES: C([NH:20][C:21]1[S:22][CH:23]=[C:24]([CH:26]=[C:27]2[S:31][C:30](=[O:32])[NH:29][C:28]2=[O:33])[N:25]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[ClH:34]>O1CCOCC1>[ClH:34].[NH2:20][C:21]1[S:22][CH:23]=[C:24]([CH:26]=[C:27]2[S:31][C:30](=[O:32])[NH:29][C:28]2=[O:33])[N:25]=1
Reactant: O=C1NC(=O)C(=Cc2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)S1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1nc(C=C2SC(=O)NC2=O)cs1

Procedure:
Following a procedure similar to that described in Example 21, the desired compound was prepared from 1.4 g of 5-(2-tritylaminothiazole-4-ylmethylene)thiazolidine-2,4-dione and 25 ml of a 4N dioxane solution of hydrogen chloride. The resulting product was a pale brown powder having the following physical properties.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:13]O)[CH:2]=1.S(Cl)(Cl)=O.[N-:19]=[N+:20]=[N-:21].[Na+]>>[N:19]([CH2:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: OCc1ccccc1-c1cccnc1
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: [N-]=[N+]=NCc1ccccc1-c1cccnc1

Procedure:
The product of Example 119A, thionyl chloride and sodium azide were processed according to the method of Example 115A to provide the product. MS (ESI+) m/z 211 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2].[Cl:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:26]4[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=4)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2]
Reactant: COc1ccc(-c2nc3cc(Br)ccc3o2)cc1[N+](=O)[O-]
Reactant: OB(O)c1ccc(Cl)cc1
Product: COc1ccc(-c2nc3cc(-c4ccc(Cl)cc4)ccc3o2)cc1[N+](=O)[O-]

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and 4-chlorophenylboronic acid (134 mg, 0.85 mmol) the subtitle compound was obtained (148 mg, 68%). 1H NMR (CDCl3) δ 8.74(s, 1H), 8.45(dd, 1H), 7.90(d, 1H), 7.64(d, 1H), 7.55(d, 3H), 7.44(d, 2H), 7.26(d, 1H), 4.07(s, 3H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][C:10]2[CH:9]=[C:8]([O:12][C:13]3[CH:18]=[CH:17][N:16]=[C:15]([C:19]([NH:21][CH3:22])=[O:20])[CH:14]=3)[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.[F:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[C:27](O)=[O:28].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CC(N(C)C)=O.CC(N(C)C)=O.CN1C(=O)CCC1.O>[F:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[C:27]([NH:1][CH:2]1[CH2:11][C:10]2[CH:9]=[C:8]([O:12][C:13]3[CH:18]=[CH:17][N:16]=[C:15]([C:19]([NH:21][CH3:22])=[O:20])[CH:14]=3)[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1)=[O:28]
Reactant: CNC(=O)c1cc(Oc2ccc3c(c2)CC(N)CC3)ccn1
Reactant: COc1ccc(C(=O)O)cc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CNC(=O)c1cc(Oc2ccc3c(c2)CC(NC(=O)c2ccc(OC)c(F)c2)CC3)ccn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 70.1 %

Procedure:
To a stirred solution of 4-[(7-amino-5,6,7,8-tetrahydronaphthalen-2-yl)oxy]-N-methylpyridine-2-carboxamide (25 mg) in DMA (1 mL) were added 3-fluoro-4-methoxybenzoic acid (16 mg, 0.094 mmol), DIPEA (26 μL), and a solution of TBTU (41 mg, 0.128 mmol) in DMA:NMP (1:1 v/v, 1 mL). The reaction mixture was allowed to stir at rt for 24 h. Water was added and the mixture was extracted with DCM. The organic solution was concentrated and purified by reverse phase HPLC to give 4-({7-[(3-fluoro-4-methoxybenzoyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}oxy)-N-methylpyridine-2-carboxamide (26.5 mg, 70%). LCMS: (AA) ES+450.5.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH2:9]S(C)=O)=[C:4]([NH:14][CH3:15])[CH:3]=1.C(O)C>C(O)(=O)C.[Zn]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH3:9])=[C:4]([NH:14][CH3:15])[CH:3]=1
Reactant: CNc1cc(F)ccc1C(=O)CS(C)=O
Agent: [Zn]
Solvent: CCO
Solvent: CC(=O)O
Product: CNc1cc(F)ccc1C(C)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1-(4-fluoro-2-methylaminophenyl)-2-methylsulphinylethanone (161.0 g), prepared in a similar manner to that described in Example 1, in acetic acid (770 ml) was added to a stirred mixture of zinc dust (228.2 g), acetic acid (210 ml) and ethanol (392 ml) at 80° over 1 hour. The mixture was stirred at 80° for a further 2 hours and then allowed to cool to ambient temperature. The combined filtrates obtained after filtration and washing the residue with dichloromethane (400 ml) were concentrated by distillation until the temperature of the remaining mixture reached 132° and then cooled to ambient temperature. Water (1 1) and dichloromethane (330 ml) were added sequentially, the mixture stirred for 10 minutes and the layers then separated. The aqueous phase was extracted with further dichloromethane (2×200 ml), the organic extracts combined, then washed with aqueous sodium hydroxide solution (5M; 200 ml) and evaporated in vacuo. Distillation in vacuo (b.p. 74°, 0.4 mm Hg) of the residue gave 4'-fluoro-2'-(methylamino)acetophenone, m.p. 52°-53°.
Reaction SMILES: Cl.C[O:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][C@H:8]([CH3:14])[NH:9]2.[BrH:15].BrC>>[BrH:15].[CH3:14][C@H:8]1[CH2:7][CH2:6][C:5]2[C:4]([OH:3])=[CH:13][CH:12]=[CH:11][C:10]=2[NH:9]1
Reactant: COc1cccc2c1CC[C@H](C)N2
Agent: Br
Agent: CBr
Agent: Cl
Product: C[C@H]1CCc2c(O)cccc2N1
Temperature: 100 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
A 500-mL round bottomed flask equipped with a heating mantle and an overhead stirrer was charged with (S)-5-methoxy-2-methyl-1,2,3,4-tetrahydroquinoline hydrochloride (20 g, 94 mmol) followed by hydrobromic acid (48%, 154 mL, 1361 mmol). The mixture was heated to 100° C., and the reaction readily proceeded with loss of bromomethane through an uncooled reflux condenser. After 1 h, solids precipitated from the solution. The reaction was complete after 10 h at 100° C. and allowed to cool to ambient temperature while stirring overnight. The reaction mixture was placed in an ice bath and stirred for 2 h at 0-5° C. The resulting white slurry was filtered and the pot and solids were washed with 20 mL of ice cold water. The filter cake was dried on a Buchner funnel under nitrogen blanket to afford (S)-2-methyl-1,2,3,4-tetrahydroquinolin-5-ol hydrobromide (21.71 g, 95%) as a white powder. MS (ES, m/z): 164 [M+H]+
Reaction SMILES: C(N)(=N)C1C=CC=CC=1.[CH3:10][C@H:11]1[CH2:94]O[C@@:14]2(O[C@H:17]3[C@@H:19](O)[C@H:20]4[C@@H:25]5[CH2:26][CH2:27][C@H:28]6[CH2:33][C@@H:32]([O:34][C@@H]7O[C@H](CO)[C@H](O[C@@H]8O[C@H](CO)C(O)[C@H](O[C@@H]9OC[C@@H](O)[C@H](O)[C@H]9O)[C@H]8O[C@@H]8O[C@H](CO)[C@H](O)[C@H](O[C@@H]9O[C@H](CO)[C@@H](O)[C@H](O)[C@H]9O)[C@H]8O)[C@H](O)[C@H]7O)[C@H:31](O)[CH2:30][C@:29]6([CH3:89])[C@H:24]5[CH2:23][CH2:22][C@:21]4([CH3:90])[C@H:16]3[C@@H:15]2[CH3:92])[CH2:13][CH2:12]1>P([O-])([O-])([O-])=O>[CH3:94][CH:11]([CH2:12][CH2:13][CH2:14][C@H:15]([C@@H:16]1[C@:21]2([CH3:90])[C@H:20]([C@H:25]3[C@H:24]([CH2:23][CH2:22]2)[C@:29]2([CH3:89])[C:28]([CH2:33][C@H:32]([CH2:31][CH2:30]2)[OH:34])=[CH:27][CH2:26]3)[CH2:19][CH2:17]1)[CH3:92])[CH3:10]
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1[C@@H](O)[C@H]3[C@@H]4CC[C@H]5C[C@@H](O[C@@H]6O[C@H](CO)[C@H](O[C@@H]7O[C@H](CO)C(O)[C@H](O[C@@H]8OC[C@@H](O)[C@H](O)[C@H]8O)[C@H]7O[C@@H]7O[C@H](CO)[C@H](O)[C@H](O[C@@H]8O[C@H](CO)[C@@H](O)[C@H](O)[C@H]8O)[C@H]7O)[C@H](O)[C@H]6O)[C@H](O)C[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Agent: N=C(N)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
Human pancreas was received at autopsy. About 30 g of tissue in 10 mM phosphate, pH 6.0, 50 mM benzamidine, 0.5% digitonin were homogenized with a polytron, centrifugally pelleted (48,000× g, 30 min.) and the supernatant collected. The supernatant was centrifugally pelleted (100,000× g, 60 min.) again and the second supernatant was passed through glass wool and dialized overnight against 50 mM benzamidine, 10 mM phosphate, pH 6.8. The dialysate was loaded onto a hydroxylapatite column (2.6×10 cm) equilibrated with 50 mM benzamidine, 10 mM phosphate, pH 6.8. The column was washed with identical buffer, then developed with a linear gradient of 50 mM to 350 mM phosphate, pH 6.8, 50 mM benzamidine. The cholesterol esterase activity eluted at a conductivity of 20-22 mS/cm. These fractions were pooled and loaded onto an AcA34 column (Bio-Rad Laboratories, Inc., 2200 Wright Avenue, Richmond, Calif. 94804) (2.6×90 cm) equilibrated with 500 mM NaCl, 10 mM phosphate, pH 6.0. The fraction emerging at an apparent molecular weight of 350 kDa contained cholesterol esterase activity and was dialyzed against 10 mM phosphate, pH 6.0.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([CH3:7])=[N:4][C:3]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].F[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21].O.[OH-].[Li+]>CS(C)=O>[CH2:11]([O:10][C:8]([C:3]1[N:4]=[C:5]([CH3:7])[S:6][C:2]=1[NH:1][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21])=[O:9])[CH3:12]
Reactant: CCOC(=O)c1nc(C)sc1N
Reactant: O=[N+]([O-])c1ccccc1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1nc(C)sc1Nc1ccccc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
Add a solution of ethyl 5-amino-2-methylthiazole-4-carboxylate (120 g; 645 mmol) and 2-fluoronitrobenzene (68 mL; 645 mmol) in dimethylsulphoxide (1 L) to a 2 L 3-necked RB flask equipped with reflux condenser, thermometer, mechanical stirrer. Add lithium hydroxide monohydrate (54 g; 1290 mmol) to the solution and heat at 50° C. for 3 hours under nitrogen. Cool the purple solution and pour onto ice/water, allow to stir for one hour, filter and wash with water, dry at 50° C. under reduced pressure to give 190 g (96%) as an orange solid: mass spectrum (m/e): 308 (M+1); 1HNMR(300 MHz, DMSO, ppm): 1.25 (tr, 3H), 2.56 (s, 3H), 4.25 (q, 2H), 7.20 (m, 1H), 7.78 (m, 2H), 8.20 (d, 1H), 11.42 (s, 1H, NH). 13CNMR(75 MHz, DMSO, ppm): 24.4, 29.2, 71.2, 127.8, 132.5, 132.8, 137.8, 146.5, 147.0, 147.5, 160.2, 161.5, 173.7. Formula: C13H13N3O4S.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16](=[O:39])[NH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27](B3OC(C)(C)C(C)(C)O3)=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:41][O:42][C:43](=[O:68])[NH:44][CH:45]([C:49]([N:51]1[CH2:55][CH2:54][CH2:53][CH:52]1[C:56]1[NH:57][C:58]([C:61]2[CH:66]=[CH:65][C:64](Br)=[CH:63][CH:62]=2)=[CH:59][N:60]=1)=[O:50])[CH:46]([CH3:48])[CH3:47].C(=O)([O-])[O-].[K+].[K+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:40])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16](=[O:39])[NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:25]=[CH:26][C:27]([C:64]3[CH:65]=[CH:66][C:61]([C:58]4[NH:57][C:56]([CH:52]5[CH2:53][CH2:54][CH2:55][N:51]5[C:49](=[O:50])[CH:45]([NH:44][C:43]([O:42][CH3:41])=[O:68])[CH:46]([CH3:48])[CH3:47])=[N:60][CH:59]=4)=[CH:62][CH:63]=3)=[CH:28][CH:29]=2)=[CH:22][CH:23]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)N1CCCC1C(=O)Nc1ccc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC(=O)NC(C(=O)N1CCCC1C(=O)Nc1ccc(-c2ccc(-c3ccc(-c4cnc(C5CCCN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)cc1)C(C)C
Temperature: 85 °C
Yield: 27.3 %

Procedure:
(2-Methyl-1-{2-[4′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-4-ylcarbamoyl]-pyrrolidine-1-carbonyl}-propyl)-carbamic acid methyl ester (102 mg, 0.227 mmol), (1-{2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (125 mg, 0.227 mmol), Pd(PPh3)4 (13 mg, 0.0114 mmol) and a 2 M aqueous solution of potassium carbonate (0.227 mL, 0.454 mmol) were degassed in 1,2-dimethoxyethane (2 mL) for 15 min. The stirred suspension was heated to 85° C. for 4 hours then concentrated, brought up in DMF/water and purified by reverse phase preparative HPLC to provide {1-[2-(4″-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-[1,1′; 4′,1″]terphenyl-4-ylcarbamoyl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (49 mg, 27%). (DMSO-d6, 400 MHz) 11.78 (s, 1H), 10.14 (s, 1H), 7.82-7.67 (m, 11H), 7.52 (d, J=1.8 Hz, 1H), 7.34-7.28 (m, 2H), 5.08 (m, 1H), 4.49 (m, 1H), 4.05 (m, 2H), 3.81 (m, 3H), 3.64 (m, 1H), 3.54 (s, 3H), 3.53 (s, 3H), 2.17-1.88 (m, 10H), 0.97-0.85 (m, 12H); MS (ESI) m/z 792 [M+H]+.