Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13](B3OC(C)(C)C(C)(C)O3)=[CH:12][CH:11]=2)=[O:9])[CH2:4][CH2:3]1.[C:25]1([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[CH:30]=[CH:29][C:28]([CH2:31][N:32]2[C:36]3[CH:37]=[C:38]([F:49])[C:39]([C:42]4[CH:47]=[CH:46][C:45](Br)=[CH:44][CH:43]=4)=[C:40]([F:41])[C:35]=3[N:34]=[C:33]2[O:50][CH:51]2[CH2:56][CH2:55][CH:54]([C:57]([O:59][CH2:60][CH3:61])=[O:58])[CH2:53][CH2:52]2)=[CH:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.O.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>[C:25]1([C:62]2[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=2)[CH:26]=[CH:27][C:28]([CH2:31][N:32]2[C:36]3[CH:37]=[C:38]([F:49])[C:39]([C:42]4[CH:43]=[CH:44][C:45]([C:13]5[CH:12]=[CH:11][C:10]([C:8]([N:5]6[CH2:4][CH2:3][CH:2]([OH:1])[CH2:7][CH2:6]6)=[O:9])=[CH:15][CH:14]=5)=[CH:46][CH:47]=4)=[C:40]([F:41])[C:35]=3[N:34]=[C:33]2[O:50][CH:51]2[CH2:52][CH2:53][CH:54]([C:57]([O:59][CH2:60][CH3:61])=[O:58])[CH2:55][CH2:56]2)=[CH:29][CH:30]=1
Reactant: CCOC(=O)C1CCC(Oc2nc3c(F)c(-c4ccc(Br)cc4)c(F)cc3n2Cc2ccc(-c3ccccc3)cc2)CC1
Reactant: CC1(C)OB(c2ccc(C(=O)N3CCC(O)CC3)cc2)OC1(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: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCC(Oc2nc3c(F)c(-c4ccc(-c5ccc(C(=O)N6CCC(O)CC6)cc5)cc4)c(F)cc3n2Cc2ccc(-c3ccccc3)cc2)CC1
Temperature: 120 °C

Procedure:
To a yellow solution of (4-hydroxypiperidin-1-yl)[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanone (0.147 g, 0.443 mmol), ethyl 4-{[1-(biphenyl-4-ylmethyl)-5-(4-bromophenyl)-4,6-difluoro-1H-benzimidazol-2-yl]oxy}cyclohexane-carboxylate (0.260 g, 0.403 mmol), and Pd(PPh3)4 (0.028 g, 0.024 mmol) was added 1 M K2CO3 (1.20 mL, 1.20 mmol) dropwise via syringe. The mixture was heated at 120° C. for 45 min, and then diluted with EtOAc and H2O. The aqueous layer was separated and further extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. Purification of the resulting residue by flash chromatography (100% EtOAc) afforded the desired compound as a ˜2:1 mixture of trans/cis isomers. The cis/trans isomers were separated via reverse phase Gilson™ HPLC (60-100% MeCN/H2O) to afford a faster eluting isomer A and a slower eluting isomer B as white solids.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5](=[O:35])[C@@H:6]([O:11][C@@H:12]([C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[CH2:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][O:33][CH3:34])[CH2:26]2)=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:7][CH:8]([CH3:10])[CH3:9])#[N:2].ClC1C=C(C=CC=1)C(OO)=[O:41].C([O-])(O)=O.[Na+]>ClCCl>[C:1]([CH2:3][NH:4][C:5](=[O:35])[C@@H:6]([O:11][C@@H:12]([C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[CH2:30][CH2:29][CH2:28][N+:27]([CH2:31][CH2:32][O:33][CH3:34])([O-:41])[CH2:26]2)=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:7][CH:8]([CH3:10])[CH3:9])#[N:2]
Reactant: COCCN1CCCC(c2ccc([C@H](O[C@@H](CC(C)C)C(=O)NCC#N)c3ccccc3)cc2)C1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COCC[N+]1([O-])CCCC(c2ccc([C@H](O[C@@H](CC(C)C)C(=O)NCC#N)c3ccccc3)cc2)C1
Reaction time: 0.08 h

Procedure:
To a solution of (2S)-N-(cyanomethyl)-2-{[(R)-{4-[1-(2-methoxyethyl)piperidin-3-yl]phenyl}(phenyl)methyl]oxy}-4-pentanamide from example 41 step 3 (390 mg, 0.81 mmol) in dichloromethane (12 mL) at 0° C. was added 77% quality 3-chloroperoxybenzoic acid (183 mg, 0.81 mmol). The mixture was stirred for 5 minutes and then 5% NaHCO3 solution (10 mL) was added with stirring. The dichloromethane layer was separated, dried (Na2SO4), filtered and concentrated. The residue was chromatographed on silica gel using 30% methanol in ethyl acetate as eluent to obtain the title compound as a foam.
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[CH:11][N:12]3[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[O:6][CH:7]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:44]>C(Cl)Cl>[Br:44][CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[CH:11][N:12]3[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[O:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)n1ccc2c(-c3nc(CO)co3)cccc21
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1ccc2c(-c3nc(CBr)co3)cccc21
Reaction time: 4 h
Yield: 100 %

Procedure:
To a solution of tert-butyl 4-[4-(hydroxymethyl)-1,3-oxazol-2-yl]-1H-indole-1-carboxylate (330 mg) and PPh3 (330 mg) in DCM (6.6 mL) was added portionwise carbon tetrabromide (418 mg) at ambient temperature and the mixture was stirred at the same temperature for 4 hours. The resulting mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography(n-hexane:EtOAc=5:1) to afford tert-butyl 4-[4-(bromomethyl)-1,3-oxazol-2-yl]-1H-indole-1-carboxylate (396 mg) as a white solid.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[CH:12]=2)[CH2:7]1.C1(OC)C=CC=CC=1.[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33]>>[F:35][C:34]([F:37])([F:36])[C:32]([OH:38])=[O:33].[N+:15]([C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[CH2:7][NH:6][CH2:14]2)([O-:17])=[O:16]
Reactant: COc1ccc(CN2Cc3ccc([N+](=O)[O-])cc3C2)c(OC)c1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1ccc2c(c1)CNC2
Temperature: 120 °C

Procedure:
2-(2,4-dimethoxy-benzyl)-5-nitro-2,3-dihydro-1H-isoindole (13 g) in TFA (18 ml) was treated with anisole (6 ml) then heated in a CEM microwave synthesiser at 120° C. (30 Watts) for 20 minutes (carried out batch wise, 6 times). The reaction mixture was evaporated in vacuo and the residue partitioned between DCM and water. The water layer was separated, washed with DCM (×3) then evaporated and re-evaporated with toluene/MeOH (×3) to give 9.8 g of 5-nitro-2,3-dihydro-1H-isoindole trifluoroacetic acid salt as a beige solid. 1H NMR (DMSO-d6) 9.85 (2H, br s), 8.32 (1H, d), 8.25 (1H, dd), 7.70 (1H, d), 4.68 (2H, s), 4.65 (2H, s).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[C:7]([CH:17]1[CH2:19][CH2:18]1)=[CH:6]2)#[N:2].[F:24][C:25]([F:36])([F:35])[C:26]1[CH:31]=[C:30]([C:32](O)=O)[CH:29]=[CH:28][N:27]=1>>[CH:17]1([C:7]2[N:8]([CH2:12][C:13]3[N:16]=[C:32]([C:30]4[CH:29]=[CH:28][N:27]=[C:26]([C:25]([F:36])([F:24])[F:35])[CH:31]=4)[O:15][N:14]=3)[C:9]3[C:5]([CH:6]=2)=[C:4]([C:20]([F:22])([F:23])[F:21])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)[CH2:19][CH2:18]1
Reactant: O=C(O)c1ccnc(C(F)(F)F)c1
Reactant: N#Cc1ccc2c(cc(C3CC3)n2CC(=N)NO)c1C(F)(F)F
Product: N#Cc1ccc2c(cc(C3CC3)n2Cc2noc(-c3ccnc(C(F)(F)F)c3)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 72 from 2-[5-cyano-2-cyclopropyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (Example 364A) and 2-(trifluoromethyl)-4-pyridinecarboxylic acid: MS (ES) m/z 478 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11]1[CH:15]=[C:14]([N:16]2[C:24]3[CH:23]=[C:22]([CH2:25][OH:26])[N:21]=[CH:20][C:19]=3[N:18]=[CH:17]2)[S:13][C:12]=1[C:27]([NH2:29])=[O:28])[CH3:9].[CH3:30][S:31](Cl)(=[O:33])=[O:32].C(N(CC)CC)C>ClCCl>[CH3:30][S:31]([O:26][CH2:25][C:22]1[N:21]=[CH:20][C:19]2[N:18]=[CH:17][N:16]([C:14]3[S:13][C:12]([C:27](=[O:28])[NH2:29])=[C:11]([O:10][C@@H:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Br:1])[CH3:9])[CH:15]=3)[C:24]=2[CH:23]=1)(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](Oc1cc(-n2cnc3cnc(CO)cc32)sc1C(N)=O)c1ccccc1Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](Oc1cc(-n2cnc3cnc(COS(C)(=O)=O)cc32)sc1C(N)=O)c1ccccc1Br

Procedure:
In a similar manner as described for example 49 (step 1), 357 mg of 3-[(1R)-1-(2-bromophenyl)ethoxy]-5-[6-(hydroxymethyl)-1H-imidazo[4,5-c]pyridin-1-yl]thiophene-2-carboxamide, 173 mg of methanesulfonyl chloride, and 153 mg of triethylamine in 7.5 ml dichloromethane give (1-{4-[(1R)-1-(2-bromophenyl)ethoxy]-5-carbamoyl-2-thienyl}-1H-imidazo[4,5-c]pyridin-6-yl)methyl methanesulfonate as crude material that is used for step 2 without further purification.
Reaction SMILES: Cl.C[O:3]C(=O)[C@H](CC1C=CC=CC=1)N.COC(=O)[C@H](CC1C=CC=CC=1)N[C:20]([CH2:22][C:23]1[N:27]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:35])[C:26]([CH2:36][CH2:37][CH2:38][CH3:39])=[N:25][CH:24]=1)=[O:21]>>[ClH:35].[CH2:36]([C:26]1[N:27]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:35])[C:23]([CH2:22][C:20]([OH:21])=[O:3])=[CH:24][N:25]=1)[CH2:37][CH2:38][CH3:39]
Reactant: CCCCc1ncc(CC(=O)N[C@@H](Cc2ccccc2)C(=O)OC)n1Cc1ccccc1Cl
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Product: CCCCc1ncc(CC(=O)O)n1Cc1ccccc1Cl

Procedure:
The procedure of Example 12 (ii-iii) was followed using L-phenylalanine methyl ester hydrochloride in place of glycine methyl ester hydrochloride. From 5.59 g (16.3 mmol) of 2-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]acetic acid hydrochloride, there was obtained 6.88 g (90%) of the intermediate N-[{2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-yl}methylcarbonyl]-L-phenylalanine methyl ester; mp 88°-90° C. (from ethanol/water). Hydrolysis of this ester provided the title compound in a 79% yield; mp 168°-170° C.; [α]25 (c=1, methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CCN(C(C)C)C(C)C>C(#N)C>[C:26]([N:15]1[CH2:16][CH2:17][N:12]([C:6]2([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)[C:5]3[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=3)[NH:8][C:7]2=[O:11])[CH2:13][CH2:14]1)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)N1CCNCC1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(c1ccccc1)N1CCN(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.7 %

Procedure:
The mixture of rac-6-chloro-3-(3-chloro-benzyl)-3-piperazin-1-yl-1,3-dihydro-indol-2-one (100 mg, 0.266 mmol), benzoyl chloride (37 mg, 0.266 mmol) and DIPEA (34 mg, 0.266 mmol) in acetonitrile (3 mL) was stirred at room temperature for overnight. Then the mixture was concentrated and the residue was purified with preparative HPLC to give 29 mg of rac-3-(4-benzoyl-piperazin-1-yl)-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one as a light orange solid. MS m/z 480 (M+H)+.
Reaction SMILES: [C:1]([NH:5][C:6]([C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][NH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:14]([O:21][C:22]([NH:24][C@@H:25]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C@@H:26]1[O:28][CH2:27]1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[CH2:14]([O:21][C:22]([NH:24][C@@H:25]([CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C@H:26]([OH:28])[CH2:27][N:9]1[CH2:10][CH2:11][CH2:12][CH2:13][C@H:8]1[C:6]([NH:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:23])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)NC(=O)[C@@H]1CCCCN1
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@H]1CO1)OCc1ccccc1
Solvent: CCO
Product: CC(C)(C)NC(=O)[C@@H]1CCCCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Yield: 91.5 %

Procedure:
2.576 g of N-tert.butyl-2(S)-piperidinecarboxamide and 4.158 g of 3(S)-(benzyloxyformamido)-1,2(S)-epoxy-4-phenylbutane in 70 ml of ethanol was heated at reflux for 16 hours. The solvent was removed by evaporation and the residue was dissolved in 100 ml of diethyl ether and treated with 10 g of activated magnesium silicate. The solvent was then removed by evaporation and there were obtained 6.16 g of 1-[3(S)-(benzyloxyformamido)-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-2(S)-piperidinecarboxamide as a colourless glass; MS: m/e 482 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:31])[C:10]([NH:12][CH2:13][C:14]1[S:18][C:17]([N:19]2[C:23]([C:24](O)=[O:25])=[CH:22][C:21]([C:27]([F:30])([F:29])[F:28])=[N:20]2)=[CH:16][CH:15]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:32][O:33][C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH2:36][NH2:37].O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[CH3:32][O:33][C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH2:36][NH:37][C:24]([C:23]1[N:19]([C:17]2[S:18][C:14]([CH2:13][NH:12][C:10](=[O:11])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])[CH3:31])=[CH:15][CH:16]=2)[N:20]=[C:21]([C:27]([F:29])([F:30])[F:28])[CH:22]=1)=[O:25]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCc1ccc(-n2nc(C(F)(F)F)cc2C(=O)O)s1
Reactant: COc1ccccc1CN
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccccc1CNC(=O)c1cc(C(F)(F)F)nn1-c1ccc(CNC(=O)[C@H](C)NC(=O)OC(C)(C)C)s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 24.2 %

Procedure:
To a stirred solution of 25 (0.059 g, 0.128 mmol) in pyridine (0.851 mL) at 0° C. was added 2-methoxybenzylamine (0.020 mL, 0.153 mmol) and followed by dropwise addition of POCl3 (0.013 mL, 0.140 mmol). The mixture was stirred for 30 min at 0° C., then for 1 h from 0° C. to 21° C., then for 16 h at room temperature. The mixture was quenched with water and extracted with ethyl acetate, washed with brine, dried (MgSO4) filtered and concentrated. The residue was purified by silica gel column chromatography with gradient of EtOAc (20-60%) in hexanes to afford 26e (18 mg, 24%) as a white solid. LRMS (ESI): calc. 581.2; found 604.3 (MNa)+.
Reaction SMILES: [Cl:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([CH:6]=O)=[C:4]([F:11])[CH:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C>[Cl:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([CH2:6][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:4]([F:11])[CH:3]=1
Reactant: C1COCCN1
Reactant: O=Cc1cc(F)c(Cl)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: Fc1cc(CN2CCOCC2)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 42.8 %

Procedure:
4-Chloro-2,5-difluorobenzaldehyde (1 g, 5.66 mmol), morpholine (0.490 ml, 5.66 mmol) and sodium triacetoxyborohydride (1.741 g, 8.21 mmol) were mixed in dichloroethane (17 ml). The mixture was stirred at ambient temperature under argon atmosphere for 3 days. NaHCO3 (aq., sat, 25 ml) was added. The mixture was extracted with dichloromethane (×3). The combined organic phase were dried over MgSO4 filtered and concentrated in vacuo to give 4-(4-chloro-2,5-difluorobenzyl)morpholine (0.600 g, 43%) as a liquid.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6]O)[CH2:2]1.C(N(CC)CC)C.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>C(Cl)Cl>[S:21]([CH2:6][CH:3]1[CH2:4][CH2:5][O:1][CH2:2]1)([C:18]1[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=1)(=[O:23])=[O:22]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)CC2CCOC2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (tetrahydrofuran-3-yl)methanol (1.0 g, 9.8 mmol) in CH2Cl2 (5 mL) and triethylamine (1.98 g, 19.6 mmol) was added p-toluenesulfonyl chloride (2.8 g, 14.7 mmol) in portions over 15 minutes. The mixture was stirred at ambient temperature for 12 hours and was quenched with 10 mL of saturated, aqueous NaHCO3. The layers were separated and the aqueous layer was extracted with CH2Cl2 (2×10 mL) The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the title compound. MS (DCI/NH3) m/z 257 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1.[CH3:13][N:14]([CH3:18])[C:15](Cl)=[S:16].C(N(CC)CC)C>O1CCOCC1>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:15](=[S:16])[N:14]([CH3:18])[CH3:13])[CH:6]=1
Reactant: COC(=O)Cc1cccc(O)c1
Reactant: CN(C)C(=S)Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)Cc1cccc(OC(=S)N(C)C)c1

Procedure:
A mixture of (3-Hydroxy-phenyl)-acetic acid methyl ester (5.5 g, 33.1 mmol), N,N-dimethyl thiocarbamoyl chloride (5.11 g, 41.38 mmol), triethylamine (9.2 mL, 66.2 mmol), N,N-dimethylamino pyridine (0.4 g, 3.31 mmol) and dioxane (50 mL) is stirred at reflux 18 hr. The mixture is concentrated, partioned between 1M aqueous hydrochloric acid (200 mL) and ethyl acetate (3×75 mL). The combined organic extracts are dried over anhydrous magnesium sulfate, filtered, concentrated, and purified via silica chromatography eluting the product with dichloromethane to afford the title compound as a brown oil, 6.8 g, 81%. MS M++1 254. The structure is confirmed by 1H NMR spectroscopy.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O-:16])[N:10]=[CH:9]2)C=CC=CC=1.[Na+].[Cl-].[CH:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][C:32]=1[CH3:41]>>[CH:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][C:32]=1[CH2:41][O:16][CH2:15][CH2:14][CH2:13][C:11]1[N:10]=[CH:9][NH:8][CH:12]=1
Reactant: Cc1ccc2ccccc2c1
Reactant: [O-]CCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Cl-]
Agent: [Na+]
Product: c1ccc2cc(COCCCc3c[nH]cn3)ccc2c1

Procedure:
5 mmol of sodium 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanolate and 5 mmol of 2-naphthylmethane chloride are treated as described in Example 5.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(=O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
To a solution of 3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (Compound 3a) (0.25 g; 1.24 mmol) in anhydrous dichloromethane (9.0 mL) at 0° C. was added 1,1,1-tris(actyloxy)-1,1-dihydro-1,2-benzodioxol-3-(1H)-one (1.58 g; 3.72 mmol). The mixture was allowed to stir at room temperature under nitrogen for 2 h, to which was then added additional 1,1,1-tris(actyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (0.5 g; 1.18 mmol). Upon stirring for 20 h at room temperature, the reaction mixture was partitioned between dichloromethane and brine. The organic layer was washed with brine, dried over Na2SO4, filtered, and the solvent evaporated in vacuo to yield a crude oil. The crude oil was purified via flash column chromatography, eluting with 40% ethyl acetate in hexanes, to yield Compound 3b as an oil (0.24 g; 97% yield). 1H NMR (400 MHz, CDCl3): δ 4.0 (2H, br s), 3.60-3.57 (2H, m), 2.49-2.45 (2H, m), 2.01-1.95 (1H, m), 1.46 (9H, s).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@:8]([C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([NH:24][C@H:25]([CH2:33][N:34]([CH3:44])[C:35]([O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])=[O:36])[CH2:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:23])[CH2:17]2)([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[CH:6][CH:7]=1.[C:45]([Cu])#[N:46]>CN(C=O)C>[C:45]([C:2]1[CH:3]=[C:4]([C@:8]([C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([NH:24][C@H:25]([CH2:33][N:34]([CH3:44])[C:35]([O:37][CH2:38][CH2:39][Si:40]([CH3:41])([CH3:42])[CH3:43])=[O:36])[CH2:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:23])[CH2:17]2)([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[CH:6][CH:7]=1)#[N:46]
Reactant: N#C[Cu]
Reactant: COCCCC[C@@](O)(c1cccc(Br)c1)[C@@H]1CCCN(C(=O)N[C@@H](CC2CCCCC2)CN(C)C(=O)OCC[Si](C)(C)C)C1
Solvent: CN(C)C=O
Product: COCCCC[C@@](O)(c1cccc(C#N)c1)[C@@H]1CCCN(C(=O)N[C@@H](CC2CCCCC2)CN(C)C(=O)OCC[Si](C)(C)C)C1
Temperature: 220 °C
Yield: 22 %

Procedure:
To a stirred mixture of (3R)-3-((S)-1-(3-bromophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-cyclohexyl-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-yl)piperidine-1-carboxamide (40.0 mg, 0.06 mmol) in DMF (0.5 mL), was added CuCN (excess), and the resulting solution was heated in a CEM microwave reactor at 220° C. for 20 min. The mixture was cooled to rt, and purified by preparative HPLC to give (3R)-3-((S)-1-(3-Cyanophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-cyclohexyl-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)-amino)propan-2-yl)piperidine-1-carboxamide (8.0 mg, 22%). MS m/z 665 (M+Na+).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:17])[C:7]1[CH:12]=[C:11]([CH2:13][Br:14])[CH:10]=[C:9]([CH2:15]Br)[CH:8]=1)[CH3:4].[CH3:18][O:19][CH2:20][CH2:21][OH:22]>>[CH2:3]([O:5][C:6](=[O:17])[C:7]1[CH:8]=[C:9]([CH2:15][O:22][CH2:21][CH2:20][O:19][CH3:18])[CH:10]=[C:11]([CH2:13][Br:14])[CH:12]=1)[CH3:4]
Reactant: CCOC(=O)c1cc(CBr)cc(CBr)c1
Reactant: COCCO
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1cc(CBr)cc(COCCOC)c1

Procedure:
Sodium hydride (0.357 g, 60% dispersion in oil) was added to 2methoxyethanol (10 ml) with stirring. After 10 minutes 3,5-bis[bromomethyl]benzoic acid ethyl ester (J. Chem. Soc. Chem. Commun. 1992, 22, 1647) (3 g) was added and the mixture stirred for 3 hours. The mixture was partitioned between ethyl acetate and water. The organic phase was dried (MgSO4) and evaporated. Purified by chromatography eluting with 20% ethyl acetate in isohexane. Yield 0.45 g.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[N:8][CH:7]=1>OS(O)(=O)=O.O>[Br:5][C:6]1[C:15]2[C:10](=[C:11]([N+:1]([O-:4])=[O:2])[CH:12]=[CH:13][CH:14]=2)[CH:9]=[N:8][CH:7]=1
Reactant: Brc1cncc2ccccc12
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1cccc2c(Br)cncc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under argon, at room temperature, 65% HNO3 (200 mmol, 13.85 ml) is added in small portions to a solution of 4-bromoisoquinoline (100 mmol, 21.24 g) in 36N H2SO4 (50 ml). The reaction mixture is stirred for 3 h at room temperature. It is cooled to 0° C. and is then diluted with water. A yellow precipitate forms. It is filtered. The pH of the filtrate is adjusted to pH 10 by slow addition of 5N NaOH. The white precipitate which appears is extracted with CH2Cl2. This organic solution is washed with brine, dried over Na2SO4 and then evaporated under vacuum. The residue is purified by eluting on silica gel with an AcOEt/petroleum ether mixture. The purified product is recrystallized from absolute ethanol (EtOH).
Reaction SMILES: [OH:1][CH:2]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[C:22](O)(=[O:34])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>>[C:22]([O:1][CH:2]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:3][C:4]([O:6][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:5])(=[O:34])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCCC(O)CC(=O)OC(C)(C)C
Reactant: CCCCCCCCCCCC(=O)O
Product: CCCCCCCCCCCC(=O)OC(CCCCCCCCCCC)CC(=O)OC(C)(C)C
Yield: 89.2 %

Procedure:
tert-Butyl 3-hydroxytetradecanoate (314 mg) was acylated by the acid chloride derived from dodecanoic acid (1 g) according to similar manner to that of Preparation 1-(2) to afford tert-butyl 3-dodecanoyloxytetradecanoate (450 mg).