Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH:15][C:16]([CH2:18][CH2:19][C@@H:20]([NH:28]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:17])=[N+:2]=[N-:3].C(NCC)C>C(Cl)Cl>[NH2:28][C@H:20]([CH2:19][CH2:18][C:16](=[O:17])[NH:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][N:1]=[N+:2]=[N-:3])[C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22]
Reactant: CC(C)(C)OC(=O)[C@@H](CCC(=O)NCCOCCOCCOCCN=[N+]=[N-])NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: CCNCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@H](N)CCC(=O)NCCOCCOCCOCCN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
Compound 103 (2.7 g, 4.3 mmol) was dissolved in 30 ml methylene chloride and 30 ml diethylamine was added. The reaction mixture was stirred at room temperature for 2 h, and then concentrated to an oil under reduced pressure. The residue was dissolved with diethyl ether and ethyl acetate (ca. 50 ml ea.) and extracted with 10% citric acid. The aqueous layer was neutralized to pH13 with 10N NaOH and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give 1.6 g of a brown oil, 4.0 mmol, 92% (compound 104).
Reaction SMILES: F[C:2]1C=CC(COC2C=C(C)N(C3C=C(C=CC=3C)C(O)=O)C(=O)C=2)=C(CNC(OC)=O)C=1.Br[C:35]1[C:36](=[O:68])[N:37]([C:58]2[CH:59]=[C:60]([CH:64]=[CH:65][C:66]=2[CH3:67])[C:61]([OH:63])=[O:62])[C:38]([CH3:57])=[CH:39][C:40]=1[O:41][CH2:42][C:43]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:44]=1[CH2:50][NH:51][C:52]([O:54][CH2:55][CH3:56])=[O:53]>>[CH2:55]([O:54][C:52]([NH:51][CH2:50][C:44]1[CH:45]=[C:46]([F:49])[CH:47]=[CH:48][C:43]=1[CH2:42][O:41][C:40]1[CH:39]=[C:38]([CH3:57])[N:37]([C:58]2[CH:59]=[C:60]([CH:64]=[CH:65][C:66]=2[CH3:67])[C:61]([O:63][CH3:2])=[O:62])[C:36](=[O:68])[CH:35]=1)=[O:53])[CH3:56]
Reactant: COC(=O)NCc1cc(F)ccc1COc1cc(C)n(-c2cc(C(=O)O)ccc2C)c(=O)c1
Reactant: CCOC(=O)NCc1cc(F)ccc1COc1cc(C)n(-c2cc(C(=O)O)ccc2C)c(=O)c1Br
Product: CCOC(=O)NCc1cc(F)ccc1COc1cc(C)n(-c2cc(C(=O)OC)ccc2C)c(=O)c1

Procedure:
Prepared using a procedure similar to that used in the preparation of 3-[4-[(4-fluoro-2-{[(methoxycarbonyl)amino]methyl}benzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoic acid. 1H NMR (CD3OD/400 MHz) δ 8.03 (m, 1H), 7.74 (s, 1H), 7.48 (m, 2H), 7.11 (m, 1H), 7.03 (m, 1H), 6.21 (s, 1H), 6.08 (s, 1H), 5.18 (s, 2H), 4.38 (s, 2H), 4.08 (q, 2H, J=7.2 Hz), 2.11 (s, 3H), 1.90 (s, 3H), 1.23 (t, 3H, J=7.2 Hz). ES HRMS m/z 469.1738 (M+H calculated for C25H26FN2O6 requires 469.1769). Step 3: Preparation of 3-[3-bromo-4-[(2-{[(ethoxycarbonyl)amino]methyl}-4-fluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].OS(O)(=O)=O.[CH3:17]O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([O:8][CH3:17])=[O:7]
Reactant: COc1cccc(C(=O)O)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(OC)c1
Reaction time: 8 h
Yield: 96 %

Procedure:
A solution of 3-methoxybenzoic acid (20 g, 131.58 mmol, 1.00 equiv) in MeOH (100 mL) and H2SO4 (13 g, 130.00 mmol, 1.00 equiv, 98%) was allowed to react, with stirring in a 250-mL round-bottom flask, overnight under reflux. The reaction was quenched by the addition of 100 mL of water/ice, extracted with 3×100 mL of dichloromethane, and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum yielding 21 g (96%) of methyl 3-methoxybenzoate as yellow oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10](=[O:16])[N:9]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:8]=2[S:7][C:6]=1[CH2:21][C:22]1[C:23]([CH3:28])=[N:24][NH:25][C:26]=1[CH3:27])=[O:4].[OH-].[Na+:30]>C1COCC1.O.CO>[Na+:30].[CH3:27][C:26]1[C:22]([CH2:21][C:6]2[S:7][C:8]3[N:9]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:10](=[O:16])[N:11]([CH3:15])[C:12](=[O:14])[C:13]=3[C:5]=2[C:3]([O-:4])=[O:2])=[C:23]([CH3:28])[NH:24][N:25]=1
Reactant: COC(=O)c1c(Cc2c(C)n[nH]c2C)sc2c1c(=O)n(C)c(=O)n2CC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1n[nH]c(C)c1Cc1sc2c(c1C(=O)[O-])c(=O)n(C)c(=O)n2CC(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Prepared from a solution of the product of step e) (19.0 g) and sodium hydroxide (2.52 g) in THF (400 ml), water (35 ml) and methanol (60 ml). After stirring at ambient temperature for 24 hours the precipitate was filtered off and washed with cold THF to give the sub-title compound as a white solid (17.2 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[C:10](=[O:14])[CH2:11][CH2:12][CH:13]=1.CC(C)(O)[C:17]#[N:18].C(=O)([O-])[O-].[Na+].[Na+]>CO>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]1[C:10](=[O:14])[CH2:11][CH2:12][CH:13]1[C:17]#[N:18]
Reactant: O=C1CCC=C1CCCCCCCO
Reactant: CC(C)(O)C#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: N#CC1CCC(=O)C1CCCCCCCO
Yield: 68.8 %

Procedure:
A mixture of 2-(7-hydroxyheptyl)cyclopent-2-en-1-one (17 g.), acetone cyanohydrin (8.5 g.), 6% aqueous sodium carbonate (8 ml.) and methanol (50 ml.) was stirred and heated under reflux for 4 hours. Methanol was removed in vacuo, water (100 ml.) was added and the mixture was extracted with diethyl ether and the extract dried over magnesium sulphate. The solvent was removed by evaporation, and the residue was distilled under reduced pressure to give 2-(7-hydroxyheptyl)-3-oxocyclopentanecarbonitrile (13.3 g.), b.p. 144°-182° C./0.15 mm.Hg, nD25 1.4795.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:18][C:19]2[C:20]([N+:37]([O-])=O)=[C:21]([CH:34]=[CH:35][CH:36]=2)[O:22][C:23]2[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:24]=2[C:25]([O:27][CH3:28])=[O:26])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1>CO.[Ni]>[NH2:37][C:20]1[C:19]([NH:18][CH:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:36][CH:35]=[CH:34][C:21]=1[O:22][C:23]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)c1ccc(F)cc1Oc1cccc(NC(c2ccc(OC)cc2)c2ccc(OC)cc2)c1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: COC(=O)c1ccc(F)cc1Oc1cccc(NC(c2ccc(OC)cc2)c2ccc(OC)cc2)c1N

Procedure:
A solution of EXAMPLE 368B (1.1 g) in methanol was hydrogenated over Raney Ni, at 60 psi of H2 at room temperature. The filtered solution was concentrated to give the title compound.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:23])[C@H:6]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:2]=[CH2:3].Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=1)=[O:26].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[CH2:1]([O:4][C:5](=[O:23])[C@H:6]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][C:25]([O:27][C:28]2[CH:29]=[CH:30][C:31]([N+:34]([O-:36])=[O:35])=[CH:32][CH:33]=2)=[O:26])=[CH:20][CH:21]=1)[NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:2]=[CH2:3]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: C=CCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
36.7 g (114.3 mmol) N-Boc-L-tyrosine allyl ester, 23.0 g (114.3 mmol) 4-nitrophenyl chloroformate, 17.5 ml (125.7 mmol) triethylamine and 1.40 g (11.4 mmol) 4-dimethylamino pyridine were combined in 1000 ml dichloromethane and stirred at room temperature for 2 h. The reaction mixture was extracted with approx. 500 ml water and with approx. 250 ml brine and dried over approx. 100 g sodium sulfate. The solvent was removed by rotary evaporation (approx. 40° C., approx. 200 mbar, approx. 30 min.) and the product was dissolved in warm diethyl ether and crystallized over night at 4° C. The crystals were filtered of, washed with cold diethyl ether and dried in high vacuum (approx. 0.1 mbar, 18 h). The yield was 29.86 g, (59.6 mmol, 52% of theory) of the desired product.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=O.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:19])([CH3:16])([CH3:15])[CH3:14].CO>C(Cl)Cl>[CH3:1][O:30][C:29](=[O:31])[CH2:28][CH2:27][CH2:26][CH:21]1[CH2:22][CH2:23][CH2:24][CH2:25][N:20]1[C:18]([O:17][C:13]([CH3:16])([CH3:14])[CH3:15])=[O:19]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CCCC(=O)O
Solvent: ClCCl
Solvent: CO
Product: COC(=O)CCCC1CCCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
1,1′-Carbonyldiimidazole (23.3 g, 143.7 mmol) was added to a solution of 4-(1-tert-butoxycarbonyl)piperidin-2-yl)butanoic acid (2) (26 g, 95.8 mmol) in methylene chloride. The reaction mixture was stirred at room temperature for 1 h. Methanol (19.4 ml, 479 mmol) was then added and the reaction mixture was stirred overnight. The complete reaction was checked by means of TLC. When the reaction was complete, the reaction mixture was washed 3× with sat. NH4Cl solution (aqueous) and 2× with sat. NaCl solution. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to obtain tert-butyl 2-(4-methoxy-4-oxobutyl)piperidine-1-carboxylate (3) (25.67 g, 94%).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[NH:23]1[CH2:27][C@H:26]([OH:28])[C@@H:25]([OH:29])[CH2:24]1>>[Br:1][C:2]1[C:3]([N:23]2[CH2:27][C@H:26]([OH:28])[C@@H:25]([OH:29])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(Br)c1
Reactant: O[C@H]1CNC[C@@H]1O
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2C[C@H](O)[C@@H](O)C2)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 6.1 using 5-bromo-6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide (Stage 22.2) and (3S,4S)-pyrrolidine-3,4-diol to afford an off-white solid. UPLC-MS (Condition 3) tR=0.98 min, m/z=477.9 [M+H]+, m/z=475.8 [M−H]−; 1H NMR (400 MHz, DMSO-d6) δ ppm 3.55 (d, J=11.13 Hz, 2H) 3.91-4.09 (m, 4H) 5.18 (d, J=2.81 Hz, 2H) 7.34 (d, J=9.05 Hz, 2H) 7.80-7.93 (m, 2H) 8.34 (d, J=1.96 Hz, 1H) 8.67 (d, J=1.96 Hz, 1H) 10.24 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9](O)[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8].P(Br)(Br)[Br:13]>CCCCCCC.CCOCC.N1C=CC=CC=1>[Br:13][CH:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH3:10]
Reactant: CC(O)c1ccc(Cl)c(Cl)c1
Reactant: BrP(Br)Br
Solvent: CCOCC
Solvent: CCCCCCC
Solvent: c1ccncc1
Product: CC(Br)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 170.4 %

Procedure:
To a solution of 1-(3,4-dichlorophenyl)ethanol (0.87 g, 4.55 mmol)in n-heptane (5.00 mL) and Et2O (0.500 mL) at 0° C. was added pyridine (1 drop) and phosphorous tribromide (0.214 mL, 2.277 mmol). The reaction mixture was warmed to RT and stirred for 2 h. The reaction was diluted with ether, washed with water (1×), saturated NaHCO3 (1×), and brine (1×). The organic layer was dried over magnesium sulfate, filtered, and concentrated to give 4-(1-bromoethyl)-1,2-dichlorobenzene (0.985 g, 3.88 mmol, 85% yield). m/z (ESI) 249.0 (M+H)+.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[C:7]([CH:11]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[N:24]4[CH:25]=[CH:26][CH:27]=[C:28]([CH:29]([F:31])[F:30])[C:23]4=[N:22][CH:21]=3)[C:17]([C:32]#[N:33])=[CH:16][N:15]=2)[CH3:12])[CH:8]=[CH:9][CH:10]=1)=[N+]=[N-].[H][H]>C(O)C.[C].[Pd]>[NH2:1][CH2:4][C:5]1[CH:6]=[C:7]([CH:11]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[N:24]4[CH:25]=[CH:26][CH:27]=[C:28]([CH:29]([F:30])[F:31])[C:23]4=[N:22][CH:21]=3)[C:17]([C:32]#[N:33])=[CH:16][N:15]=2)[CH3:12])[CH:8]=[CH:9][CH:10]=1
Reactant: [H][H]
Reactant: CC(Nc1ncc(C#N)c(-c2cnc3c(C(F)F)cccn23)n1)c1cccc(CN=[N+]=[N-])c1
Agent: [Pd]
Solvent: CCO
Product: CC(Nc1ncc(C#N)c(-c2cnc3c(C(F)F)cccn23)n1)c1cccc(CN)c1
Yield: 92.8 %

Procedure:
87 mg of the 2-({1-[3-(azidomethyl)phenyl)ethyl}amino)-4-[8-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-5-carbonitrile [102-1] was dissolved in 3 mL of ethanol, then 50 mg of 10% palladiumcarbon catalyst was added, and stirred overnight at room temperature in a hydrogen atmosphere. The insolubles were filtered through celite, the filtrate was concentrated under reduced pressure, and 76 mg of 2-({1-[3-(aminomethyl)phenyl)ethyl}amino)-4-[8-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-5-carbonitrile [102-2] was obtained as a yellow solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12])=O.[NH2:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([Br:21])=[CH:16][N:15]=1.O>C(O)C>[Br:21][C:17]1[CH:18]=[C:19]([CH3:20])[C:14]2[N:15]([CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[O:11][CH3:12])[N:13]=2)[CH:16]=1
Reactant: Cc1cc(Br)cnc1N
Reactant: COc1ccccc1C(=O)CBr
Solvent: O
Solvent: CCO
Product: COc1ccccc1-c1cn2cc(Br)cc(C)c2n1
Temperature: 80 °C
Yield: 54.1 %

Procedure:
A mixture of 2-bromo-2′-methoxyacetophenone (0.500 g, 2.183 mmol) and 2-amino-5-bromo-3-methylpyridine (0.408 g, 2.183 mmol) in ethanol (8 mL) was heated to 80° C. for 16 hours in a pressure vessel. A yellow thick precipitate formed. Water was added and the solid was extracted with ethyl acetate (some DCM and MeOH were added to help in the dissolution). The organic extracts were then washed with brine, dried over Na2SO4, filtered and concentrated and the residue was purified by silica gel chromatography (Biotage SNAP 100 g, 10 to 20% ethyl acetate in hexanes) to give 220 (0.375 g, 1.182 mmol, 54.2% yield) as a white solid. LRMS (ESI): calc. 316.02 found 317.1 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:16](Cl)(Cl)=[S:17]>O1CCOCC1.O>[CH3:9][S:8][C:6]1[CH:7]=[C:2]([N:1]=[C:16]=[S:17])[C:3]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:5]=1
Reactant: S=C(Cl)Cl
Reactant: CSc1ccc(-c2ccccc2)c(N)c1
Solvent: C1COCCO1
Solvent: O
Product: CSc1ccc(-c2ccccc2)c(N=C=S)c1

Procedure:
Reaction of 2-amino-4-methylthiobiphenyl (10.8 g) with thiophosgene (4.6 ml) in a mixture of dioxan (10 ml) and water (200 ml) at 10° C. and then at ambient temperature for 15 hours yielded 4-methylthio-2-biphenylylisothiocyanate as a yellow oil.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(N(CC)CC)C>C(Cl)Cl>[CH:12]([C@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:11]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C=O
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 80.6 %

Procedure:
Oxalyl chloride (9.0 mL, 100 mmol) was added to a solution of DMSO (10.5 mL, 150 mmol) in 80 mL of CH2Cl2 at −78° C., under a nitrogen atmosphere. The solution was stirred for 20 min at −78° C., tert-butyl (2R)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (9.9 g, 49 mmol) was added, and the resultant solution stirred at −78° C. for 20 min. Triethylamine (28 mL, 200 mmol) was added to the reaction solution, the dry ice-acetone bath was removed, and the resultant solution was allowed to stir for two hours, slowly warming to ambient temperature. The reaction solution was quenched with brine, the phases were separated, and the organic phase was washed with 1 M KH2PO4 and saturated NaHCO3. The organic solution was then dried over Na2SO4, filtered, and concentrated to an orange oil. This oil was then dissolved in heptane, filtered through a plug of silica gel eluting with heptane, and the filtrate was concentrated to yield tert-butyl (2R)-2-formylpyrrolidine-1-carboxylate (7.87 g).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:36]([CH3:37])=[CH:35][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:32]=[CH:31][C:22]([CH2:23][CH:24]5[S:28][C:27](=[O:29])[NH:26][C:25]5=[O:30])=[CH:21][CH:20]=4)[N:14]([CH3:33])[C:13]=3[CH:34]=2)=[CH:6][C:5]=1[CH3:38].[F:39][C:40]([F:51])([F:50])[C:41]1[CH:46]=[CH:45][C:44]([N:47]=[C:48]=[O:49])=[CH:43][CH:42]=1.C(N(CC)CC)C>O1CCCC1>[O:29]=[C:27]1[NH:26][C:25](=[O:30])[CH:24]([CH2:23][C:22]2[CH:21]=[CH:20][C:19]([O:18][CH2:17][C:15]3[N:14]([CH3:33])[C:13]4[CH:34]=[C:9]([O:8][C:7]5[CH:6]=[C:5]([CH3:38])[C:4]([NH:3][C:48]([NH:47][C:44]6[CH:43]=[CH:42][C:41]([C:40]([F:39])([F:50])[F:51])=[CH:46][CH:45]=6)=[O:49])=[C:36]([CH3:37])[CH:35]=5)[CH:10]=[CH:11][C:12]=4[N:16]=3)=[CH:32][CH:31]=2)[S:28]1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: Cc1cc(Oc2ccc3nc(COc4ccc(CC5SC(=O)NC5=O)cc4)n(C)c3c2)cc(C)c1N
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(Oc2ccc3nc(COc4ccc(CC5SC(=O)NC5=O)cc4)n(C)c3c2)cc(C)c1NC(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 40 h
Yield: 74.5 %

Procedure:
A mixture of 5-[4-[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (288 mg), α,α,α-trifluoro-p-tolyl isocyanate (112 mg), triethylamine (121 mg) and anhydrous tetrahydrofuran (10 ml) was stirred at room temperature for 40 hours. The reaction mixture was concentrated and diluted with water. The precipitate was isolated by filtration and washed with water and ethyl acetate to afford the title compound (257 mg, mp 206-208° C.).
Reaction SMILES: [C:1]([NH:5][S:6]([CH2:9][CH2:10][CH2:11][CH2:12][OH:13])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:14](OC(=O)C)(=[O:16])[CH3:15]>N1C=CC=CC=1>[C:1]([NH:5][S:6]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14](=[O:16])[CH3:15])(=[O:7])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NS(=O)(=O)CCCCO
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCCCCS(=O)(=O)NC(C)(C)C
Reaction time: 1 h

Procedure:
A crude product (1.17 g) of N-tert-butyl-4-hydroxybutane-sulfonamide was dissolved in pyridine (3.0 ml) and acetic anhydride (1.5 ml) was added, and the mixture was left standing at room temperature for 1 hr. The reaction mixture was concentrated to dryness under reduced pressure and the residue was partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was washed once with water and once with saturated brine, dried over magnesium sulfate and concentrated to dryness under reduced pressure to give N-tert-butyl-4-acetoxybutanesulfonamide (425 mg) as a pale-yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:50])[CH2:7][C@H:8]([NH:24][C:25]([C@@H:27]1[CH2:32][CH2:31][CH2:30][N:29]([C:33](=[O:49])[CH2:34][CH2:35][CH:36]2[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]2)[CH2:28]1)=[O:26])[C:9]1[CH:10]=[N:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH:14]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:57][C:58]1[CH:63]=[CH:62][C:61]([S:64]([O:67][CH2:68][CH2:69]OS(C2C=CC(C)=CC=2)(=O)=O)(=[O:66])=[O:65])=[CH:60][CH:59]=1>CN(C)C=O>[C:1]([O:5][C:6](=[O:50])[CH2:7][C@H:8]([NH:24][C:25]([C@@H:27]1[CH2:32][CH2:31][CH2:30][N:29]([C:33](=[O:49])[CH2:34][CH2:35][CH:36]2[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]2)[CH2:28]1)=[O:26])[C:9]1[CH:10]=[N:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:69][CH2:68][O:67][S:64]([C:61]3[CH:62]=[CH:63][C:58]([CH3:57])=[CH:59][CH:60]=3)(=[O:66])=[O:65])=[CH:19][CH:18]=2)[CH:14]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1ccc(S(=O)(=O)OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(CCc2ccc(O)cc2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)OCCOc2ccc(CCc3cncc([C@H](CC(=O)OC(C)(C)C)NC(=O)[C@@H]4CCCN(C(=O)CCC5CCN(C(=O)OC(C)(C)C)CC5)C4)c3)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.8 %

Procedure:
Tert-butyl 4-{3-[(3R)-3-{[(1S)-3-tert-butoxy-1-{5-[(4-hydroxyphenyl)ethyl]pyridin-3-yl}-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (67 mg, 0.10 mmol) was dissolved in N,N-dimethylformamide (9.7 mL). Cesium carbonate (79 mg, 0.24 mmol) and ethane-1,2-diyl bis(4-methylbenzenesulfonate) (54 mg, 0.15 mmol) were added. The mixture was stirred at room temperature for 4 hours, quenched by addition of saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined extracts were washed with brine and dried over sodium sulfate. The solution was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (ethyl acetate in hexane 20% to 100% followed by dioxane in ethyl acetate 0 to 60%) to yield 64 mg of tert-butyl 4-{3-[(3R)-3-{[(1S)-3-tert-butoxy-1-(5-{2-[4-(2-{[(4-methylphenyl)sulfonyl]oxy}ethoxy)phenyl]ethyl}pyridin-3-yl)-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:25][CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:25][CH:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:21])=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1onc(-c2cccc(Cl)c2)c1COc1ccc(C(=O)O)cn1
Reactant: NC1CCOCC1
Product: Cc1onc(-c2cccc(Cl)c2)c1COc1ccc(C(=O)NC2CCOCC2)cn1
Yield: 89 %

Procedure:
As described for example 98b, 6-[3-(3-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (69 mg, 0.2 mmol) was converted, using 4-aminotetrahydropyran instead of 2,2,2-trifluoroethylamine, to the title compound (76 mg, 89%) which was obtained as a white solid. MS: m/e=428.5 [M+H]+.
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:15])[C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH2:21]1[O:23][CH2:22]1.O1CCOCC1>O1CCCC1>[OH:23][CH2:22][CH2:21][C:14]1[CH:13]=[N:12][CH:11]=[CH:10][C:9]=1[C:8]([NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:15]
Reactant: O=C(Nc1ccccc1)c1ccncc1
Reactant: C1CO1
Agent: [Li]CCCC
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1)c1ccncc1CCO
Temperature: 25 °C
Yield: 43 %

Procedure:
To a solution of N-phenylisonicotinamide (1.98 g, 10 mmol) in tetrahydrofuran (40 ml) at -78° C. was added a solution of n-butyllithium (1.6M in hexanes; 13.5 ml, 21.6 mmol) and the resulting red solution stirrred for 40 minutes before addition of a solution of ethylene oxide in dioxane (3.56M; 3.0 ml, 11 mmol). After allowing the mixture to warm to room temperature over 21/2 hours, the reaction was quenched by addition of methanol (8 ml). The solvent was evaporated and the residue partitioned between ethyl acetate (70 ml) and water (25 ml). The organic layer was washed with saturated brine (25 ml), dried (MgSO4) and evaporated. The residue was chromatographed on silica eluting with 10% methanol/dichloromethane to afford the title compound as a solid (1.05 g, 43%); δH (CDCl3) 3.07 (2H, t, J 5.6 Hz, ArCH2 CH2OH), 3.70 (1H, br s, OH), 4.10 (2H, t, J 5.6 Hz, ArCH2 CH2OH), 7.15-7.19 (1H, m, ArH), 7.35-7.39 (2H, m, ArH), 7.49 (1H, d, J 5.2 Hz, ArH), 7.69-7.71 (2H, m, ArH), 8.44-8.48 (2H, m, ArH), 9.77 (1H, s, NH).