Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH:22]([O:25][CH3:26])[O:23][CH3:24])=[CH:15][CH:14]=1)[CH:8]=[CH:7]2.[C:27]([O:33][C@@H:34]1[C@@H:39]([O:40][C:41](=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43])[C@H:38]([O:47][C:48](=[O:53])[C:49]([CH3:52])([CH3:51])[CH3:50])[C@@H:37]([CH2:54][O:55][C:56](=[O:61])[C:57]([CH3:60])([CH3:59])[CH3:58])[O:36][C@@H:35]1Br)(=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29].[OH-].[Na+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)C1C=CC=CC=1.C(Cl)Cl>[CH3:24][O:23][CH:22]([O:25][CH3:26])[CH2:21][CH2:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][CH2:11][N:9]2[C:10]3[C:6](=[CH:5][CH:4]=[CH:3][C:2]=3[O:1][C@@H:35]3[O:36][C@H:37]([CH2:54][O:55][C:56](=[O:61])[C:57]([CH3:60])([CH3:59])[CH3:58])[C@@H:38]([O:47][C:48](=[O:53])[C:49]([CH3:50])([CH3:51])[CH3:52])[C@H:39]([O:40][C:41](=[O:46])[C:42]([CH3:43])([CH3:44])[CH3:45])[C@H:34]3[O:33][C:27](=[O:32])[C:28]([CH3:31])([CH3:29])[CH3:30])[CH:7]=[CH:8]2)=[CH:14][CH:15]=1
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@H](Br)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Reactant: COC(CCOc1ccc(CCn2ccc3cccc(O)c32)cc1)OC
Agent: CCCC[N+](CCCC)(CCCC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(CCOc1ccc(CCn2ccc3cccc(O[C@@H]4O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]4OC(=O)C(C)(C)C)c32)cc1)OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 27.8 %

Procedure:
To a mixture of 7-hydroxy-1-{2-[4-(3,3-dimethoxy-propoxy)phenyl]ethyl}-1H-indole (1.57 g), 2,3,4,6-tetra-O-pivaloyl-α-D-glucopyranosyl bromide (2.56 g) and benzyltri-(n-butyl)ammonium chloride (1.38 g) in methylene chloride (15 mL) was added 5 mol/L aqueous sodium hydroxide solution (2.7 mL), and the mixture was stirred at room temperature for 2 days. The reaction mixture was purified by column chromatography on aminopropylated silica gel (eluent: n-hexane/ethyl acetate=1/1), and purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=6/1-4/1) to give 1-{2-[4-(3,3-dimethoxypropoxy)phenyl]ethyl}-7-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-indole (1.05 g). This material was dissolved in acetone (12 mL). To the solution were added water (6 mL) and oxalic acid dihydrate, and the mixture was heated for reflux for 2 hours. To the reaction mixture was added piperazine (0.64 g), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The ethyl acetate solution was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1), and purified by column chromatography on aminopropylated silica gel (n-hexane/ethyl acetate=4/1-3/1-2/1) to give the title compound (0.31 g).
Reaction SMILES: [S:1]([Cl:5])(Cl)(=[O:3])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:25]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:30]=[CH:29][C:28](S(O)(=O)=O)=[CH:27][CH:26]=1.C(N(CC)CC)C>C(Cl)Cl>[C:25]1([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:30]=[CH:29][C:28]([S:1]([Cl:5])(=[O:3])=[O:2])=[CH:27][CH:26]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: O=S(=O)(O)c1ccc(-c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 45.1 %

Procedure:
Sulfuryl chloride (392 μl, 4.74 mmol) was added dropwise to a 0° C. suspension of triphenylphosphine-resin (1.58 g) in methylene chloride (10 ml). A solution of 4-biphenylsulfonic acid (400 mg, 1.58 mmol) and triethylamine (220 μl) in methylene chloride (5 ml) was added. The mixture was stirred at room temperature for 6 hours and stored at 5° C. for 3 days. This was filtered and the filtrate was evaporated. The residue was coevaporated with toluene twice to give the crude product as a white solid. Purification of the crude product by chromatography (silica, methylene chloride) gave 180 mg of the title product as a white solid.
Reaction SMILES: [CH2:1]([CH:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([CH2:27][CH3:28])=[N:19][N:20]3[CH:23]3[CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:30][C:31](=O)[CH2:32][C:33]1[CH:34]=[N:35][NH:36][CH:37]=1>>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([CH2:27][CH3:28])=[N:19][N:20]3[CH:23]3[CH2:24][CH2:25][CH2:26]3)=[CH:16][CH:15]=2)[CH2:11][CH2:12][N:13]1[C:31](=[O:30])[CH2:32][C:33]1[CH:34]=[N:35][NH:36][CH:37]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1nn(C2CCC2)c2cc(N3CCNC(Cc4ccccc4)C3)ccc12
Reactant: COC(=O)Cc1cn[nH]c1
Product: CCc1nn(C2CCC2)c2cc(N3CCN(C(=O)Cc4cn[nH]c4)[C@@H](Cc4ccccc4)C3)ccc12
Yield: 13 %

Procedure:
Prepared by the method outlined for Example 275 using 6-(3-benzyl-piperazin-1-yl)-1-cyclobutyl-3-ethyl-1H-indazole (185 mg, 0.494 mmol) and (1H-pyrazol-4-yl)-acetic acid methyl ester (148 mg, 1.06 mmol) with heating for 5 days to afford product as a colorless solid (31 mg, 13%). LC/MS (Method B) 3.70 min, [M+1]+ 483.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=[C:9]1[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]1.OS(O)(=O)=O>O>[CH2:18]([O:17][C:15]([CH:12]1[CH2:13][CH2:14][C:9]([C:4]2[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=2)([C:4]2[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=2)[CH2:10][CH2:11]1)=[O:16])[CH3:19]
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: Oc1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)C1CCC(c2ccc(O)cc2)(c2ccc(O)cc2)CC1
Temperature: 0 °C
Yield: 50.5 %

Procedure:
Phenol (1.1 g, 11.8 mmol) was diluted with water (0.53 mL) and cooled to 0° C. with stirring. Ethyl 4-oxocyclohexanecarboxylate (0.94 mL, 5.87 mmol) was added followed by dropwise addition of concentrated H2SO4 (2.11 g). After 10 min the mixture was warmed to room temperature and allowed to stir for 4 hr. The mixture was then diluted with water and the product extracted with EtOAc (2×). The organic layer was washed with water, brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by chromatography (silica gel, 2:1 Hexane/EtOAc) to give 1.01 g (51%) of 4,4-bis(4-hydroxyphenyl)cyclohexane carboxylic acid ethyl ester.
Reaction SMILES: Cl.[CH:2]([N:15]1[CH2:18][CH2:17][CH:16]1[CH2:19][OH:20])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C>CS(C)=O>[CH:2]([N:15]1[CH2:18][CH2:17][CH:16]1[CH:19]=[O:20])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: OCC1CCN1C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=CC1CCN1C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred mixture of 9.0 g of 1-benzhydrylazetidine-2-methanol hydrochloride, 26.1 ml of triethylamine and 60 ml of dimethylsulfoxide were added dropwise a solution of 14.9 g pyridine-sulfur trioxide complex in 60 ml of dimethylsulfoxide. The mixture was stirred at room temperature for 30 minutes, after which it was poured into ice water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, followed by removal of the solvent by distillation. The residue was recrystallized from n-hexane to yield 1-benzhydrylazetidine-2-carbaldehyde as colorless crystals melting at 88°-89° C.
Reaction SMILES: [F:1][C:2]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])=[CH:7][C:6]=1[C:17]1[CH:22]=[C:21]([C:23]#[C:24][Si](C)(C)C)[C:20](=[O:29])[N:19]([CH3:30])[CH:18]=1.C([O-])([O-])=O.[K+].[K+].O>CCO>[F:1][C:2]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][S:12]([CH2:15][CH3:16])(=[O:13])=[O:14])=[CH:7][C:6]=1[C:17]1[CH:22]=[C:21]([C:23]#[CH:24])[C:20](=[O:29])[N:19]([CH3:30])[CH:18]=1
Reactant: CCS(=O)(=O)Nc1ccc(Oc2ccc(F)cc2F)c(-c2cc(C#C[Si](C)(C)C)c(=O)n(C)c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: C#Cc1cc(-c2cc(NS(=O)(=O)CC)ccc2Oc2ccc(F)cc2F)cn(C)c1=O
Temperature: 20 °C
Reaction time: 12 h
Yield: 56.8 %

Procedure:
To a mixture of N-[4-(2,4-difluorophenoxy)-3-[1-methyl-6-oxo-5-(2-trimethylsilylethynyl)pyridin-3-yl]phenyl]ethanesulfonamide (100 mg, 0.19 mmol) in EtOH (10 mL) was added K2CO3 (157 mg, 1.14 mmol). The reaction was stirred at 20° C. for 12 h and poured into H2O (30 mL) and extracted with DCM (20 mL×3). The organic phase was washed with brine (20 mL), dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by prep-HPLC to afford the title compound (48 mg, 56%) as an off-white solid. 1H NMR (CDCl3, 400 MHz): δ 7.90 (d, J=2.4 Hz, 1H), 7.69 (d, J=2.4 Hz, 1H), 7.26 (d, J=2.8 Hz, 1H), 7.14-7.11 (m, 1H), 7.01-6.94 (m, 2H), 6.89-6.86 (m, 1H), 6.77 (d, J=8.8 Hz, 1H), 6.55 (s, 1H), 3.67 (s, 3H), 3.34 (s, 1H), 3.14 (q, J=7.2 Hz, 2H), 1.42 (t, J=7.2 Hz, 3H). LCMS (M+H)+=445.
Reaction SMILES: [Na].Br[C:3]1[CH:4]=[N:5][CH:6]=[N:7][CH:8]=1.[CH2:9]([OH:11])[CH3:10]>>[CH2:9]([O:11][C:3]1[CH:4]=[N:5][CH:6]=[N:7][CH:8]=1)[CH3:10]
Reactant: Brc1cncnc1
Reactant: CCO
Agent: [Na]
Product: CCOc1cncnc1
Reaction time: 60 h
Yield: 25.6 %

Procedure:
Sodium (2.89 g. 125.8 mmol) was dissolved in ethanol (110 mL) and 5-bromopyrimidine (10.0 g, 62.9 mmol) added. The reaction was heated at 120° in an autoclave for 17 h and then allowed to stand at 23° for 60 h. The ethanol was removed under reduced pressure and water (5 mL) added to the concentrate. The aqueous phase was extracted with CH2Cl2 (4×100 mL). The combined organic extracts were washed with saturated NaCI solution, dried with anhydrous K2CO3, filtered, and concentrated under reduced pressure. Silica gel chromatography (Hexane/EtOAc; 70:30) of the concentrate yielded 5-ethoxypyrimidine (2.00 g, 25.6%).
Reaction SMILES: C1(O[C:8](=[O:24])[NH:9][C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)C=CC=CC=1.[CH3:25][O:26][C:27](=[O:51])[CH2:28][CH2:29][NH:30][C:31](=[O:50])[C:32]1[CH:37]=[CH:36][C:35]([CH2:38][NH:39][CH:40]2[CH2:45][CH2:44][CH:43]([C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:42][CH2:41]2)=[CH:34][CH:33]=1.FC(F)(F)C([O-])=O.C(N(CC)CC)C>ClCCl.C1(C)C=CC=CC=1>[CH3:25][O:26][C:27](=[O:51])[CH2:28][CH2:29][NH:30][C:31](=[O:50])[C:32]1[CH:37]=[CH:36][C:35]([CH2:38][N:39]([CH:40]2[CH2:41][CH2:42][CH:43]([C:46]([CH3:47])([CH3:48])[CH3:49])[CH2:44][CH2:45]2)[C:8]([NH:9][C:10]2[CH:15]=[C:14]([C:16]([F:18])([F:19])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:21])[F:22])[CH:11]=2)=[O:24])=[CH:34][CH:33]=1
Reactant: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Oc1ccccc1
Reactant: COC(=O)CCNC(=O)c1ccc(CNC2CCC(C(C)(C)C)CC2)cc1
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)CCNC(=O)c1ccc(CN(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C2CCC(C(C)(C)C)CC2)cc1
Yield: 67 %

Procedure:
The above carbamic acid phenyl ester (1.0 g, 2.9 mmol) was mixed with 3-{4-[(4-tert-butyl-cyclohexylamino)methyl]benzoylamino}propionic acid methyl ester, trifluoroacetate (1.07 g, 2.9 mmol), prepared as described above and triethylamine (1.2 mL, 8.6 mmol) in dichloromethane (55 mL) and the resulting mixture was refluxed for 4 hours. The cooled reaction mixture was diluted with toluene (50 mL) and washed with water (3×50 mL) and a mixture of water and saturated aqueous sodium chloride (1:1, 3×100 mL), dried (MgSO4) and concentrated in vacuo to afford 1.2 g (67%) of 3-{4-[3-(3,5-bis-trifluoromethylphenyl)-1-(4-tert-butyl-cyclohexyl)ureidomethyl]benzoylamino}propionic acid methyl ester as a solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2.[OH-].[Na+].Cl[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26](=[O:29])[CH:27]=[CH2:28])=[O:19].Cl.C([O-])(=O)C=C.Cl>CN(C=O)C.O>[C:26]([O:25][CH2:24][CH2:23][CH2:22][CH2:21][O:20][C:18]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2)=[O:19])(=[O:29])[CH:27]=[CH2:28]
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Reactant: C=CC(=O)OCCCCOC(=O)Cl
Agent: C=CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CC(=O)OCCCCOC(=O)Oc1ccc2cc(C(=O)O)ccc2c1

Procedure:
The pH of a solution of 100 g (0.53 mol) of 6-hydroxy-2-naphthoic acid in a solvent mixture of 600 ml of water and 500 ml of DMF was adjusted to 10 with 10 percent sodium hydroxide solution at 0° C. 132 g (0.61 mol) of 4-acryloyloxybutyl chloroformate (prepared according to WO 97/00600 A2) was subsequently added dropwise over a period of 2 h, in the course of which the temperature was kept between 0 and 5° C. and the pH at 10 (±0.2 pH unit) by means of 10 percent sodium hydroxide solution. The resulting solution was subsequently diluted with 3 l of water/ice mixture and the pH was adjusted to 5 with concentrated hydrochloric acid. The resulting suspension was filtered, the resulting filtercake was washed with 3 l of water and, after drying, 165.8 g (87% of theory based on the pure acrylate derivative) of a beige-colored powder were obtained, which comprises the compound NAPA shown above and the corresponding acrylate/HCl adduct.
Reaction SMILES: [Br:1]Br.[C:3]([O:9][C:10]1[CH:11]=[C:12]([C:23](=[O:25])[CH3:24])[CH:13]=[CH:14][C:15]=1[O:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5].C(OC(C)(C)C)(=O)C.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)(Cl)Cl>[Br:1][CH2:24][C:23]([C:12]1[CH:13]=[CH:14][C:15]([O:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[C:10]([O:9][C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5])[CH:11]=1)=[O:25]
Reactant: CC(=O)c1ccc(OC(=O)C(C)(C)C)c(OC(=O)C(C)(C)C)c1
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)OC(C)(C)C
Product: CC(C)(C)C(=O)Oc1ccc(C(=O)CBr)cc1OC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of bromine (3.15 ml., 0.061 mole) in chloroform (50 ml.) was added dropwise at room temperature to a stirred solution of 3',4'-bis(pivaloyloxy)acetophenone (19.5 g., 0.016 mole) and t-butyl acetate (8.2 ml., 0.06 mole) in chloroform (150 ml.) containing a catalytic amount of anhydrous aluminium chloride (0.2 g.). The reaction mixture was stirred at room temperature for 1 hour after the addition was complete, chromatographic silica gel (75 g.) was then added and the mixture evaporated in vacuo. The residual solid was added to the top of a column of dry chromatographic silica-gel (1 kg., previously deactivated by addition of 10% w/w water and then equilibrated with 10% v/w of a 5% v/v solution of ethyl acetate in toluene). The column was developed by elution with a 5% v/v solution (1.1 l.) of ethyl acetate in toluene. The column was then eluted with ethyl acetate (2×500 ml.) and the fractions collected were monitored by thin layer chromatography (TLC) (on silica plates developed in a 50% v/v mixture of ethyl acetate and toluene). The later fractions were combined and evaporated to give 2-bromo-3',4'-bis(pivaloyloxy)acetophenone as an oil (14.2 g.) which rapidly crystallised to give a solid of m.p. 64°-66° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:18][C@H:19]1[C@H:24]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:23]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@@:22]([C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[C:45]([CH2:50][C:51]3[CH:56]=[CH:55][C:54]([O:57][CH2:58][C:59]([F:62])([F:61])[F:60])=[CH:53][CH:52]=3)[CH:44]=2)([O:41][CH3:42])[O:21][C@@H:20]1[CH2:63][OH:64])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH2:11]([O:18][C@H:19]1[C@H:24]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:23]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@@:22]([C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[C:45]([CH2:50][C:51]3[CH:52]=[CH:53][C:54]([O:57][CH2:58][C:59]([F:61])([F:62])[F:60])=[CH:55][CH:56]=3)[CH:44]=2)([O:41][CH3:42])[O:21][C@@H:20]1[CH:63]=[O:64])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCC(F)(F)F)cc3)c2)O[C@H](CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCC(F)(F)F)cc3)c2)O[C@H](C=O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 96.7 %

Procedure:
Oxalyl chloride (0.16 mL, 1.87 mmol) was dissolved in 5 mL dichloromethane and cooled to −78° C., followed by dropwise addition of dimethyl sulfoxide (0.2 mL, 2.88 mmol) in dichloromethane (3 mL). The reaction mixture was stirred for 15 minutes, before 10 mL solution of [(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(2,2,2-trifluoroethoxy)phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methanol 7h (1.10 g, 1.44 mmol) in dichloromethane were added and stirred for 40 minutes. Then the reaction mixture was warmed and stirred for 3 hours at room temperature after triethylamine (1.0 mL, 7.21 mmol) was dropwise added. Thereafter, the reaction mixture was partitioned after 5 mL 1 M hydrochloric acid were added, the aqueous phase was extracted with ethyl acetate (10 mL×2) and the organic extracts were combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(2,2,2-trifluoroethoxy)phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde 7i (1.06 g, yellow grease), which was used directly in the next step without purification.
Reaction SMILES: [CH3:1][C:2]1[S:23][C:5]2=[N:6][C:7]([CH3:22])=[C:8]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:9]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)=[C:4]2[CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:34]1[CH2:38]OC[CH2:35]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[S:23][C:5]2=[N:6][C:7]([CH3:22])=[C:8]([CH:17]([CH2:35][CH2:34][CH3:38])[C:18]([O:20][CH3:21])=[O:19])[C:9]([C:10]3[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=3)=[C:4]2[CH:3]=1
Reactant: C1CCOC1
Reactant: COC(=O)Cc1c(C)nc2sc(C)cc2c1-c1ccc(C)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCCI
Product: CCCC(C(=O)OC)c1c(C)nc2sc(C)cc2c1-c1ccc(C)cc1
Yield: 65.4 %

Procedure:
This compound was prepared according to the procedure C from methyl 2-(2,6-dimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)acetate (0.188 g; 0.578 mmol), LHMDS 1N in THF (0.650 mL; 0.650 mmol), 1-iodopropane (0.092 mL; 0.943 mmol) in DMF (8 mL) for 4 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-15%) in heptane furnished 0.139 g (65%) of the title compound as a yellow oil.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:17]([CH2:18][C:19]([OH:21])=O)[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=2)=[CH:5][CH:4]=1.Cl.Cl.[CH3:24][N:25]([CH3:33])[C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1.C(N(CC)CC)C>CN(C)C=O.O>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:17]([CH2:18][C:19]([NH:32][C:29]3[CH:30]=[CH:31][C:26]([N:25]([CH3:33])[CH3:24])=[CH:27][CH:28]=3)=[O:21])[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=2)=[CH:7][CH:8]=1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: CN(C)c1ccc(N)cc1
Agent: Cl
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CN(C)c1ccc(NC(=O)Cn2c(-c3ccc(Cl)cc3)nc3cccnc32)cc1
Temperature: 60 °C
Yield: 12.7 %

Procedure:
Under a nitrogen atmosphere, oxlyl chloride (2.21 g, 0.0174 mole) was added slowly dropwise to a stirred and cooled (0°-10° C.) suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0174 mole) in 50 ml of dimethylformamide. After the addition was complete, the reaction solution was heated at 60° C. for 5 hrs. This acylchloride solution was added dropwise to a stirred and cooled (<10° C.) suspension of N,N-dimethyl-1,4-phenylenediamine dihydrochloride (3.64 g, 0.0174 mole),triethylamine (5.27 g, 0.052 mole), and 75 ml of dimethylformamide. The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into 1800 ml of water and refrigerated overnight. The solid was collected by filtration and dried. The solid was recrystallized twice from isopropyl alcohol, collected by filtration, washed with water, and dried under high vacuum at 98° C. overnight to give 0.9 g (12.7%) of crystals, mp 245°-246.5° C.
Reaction SMILES: [CH:1]1([N:4]2[CH:8]=[C:7]([NH:9]C(=O)OC(C)(C)C)[N:6]=[CH:5]2)[CH2:3][CH2:2]1.Cl>CO>[CH:1]1([N:4]2[CH:8]=[C:7]([NH2:9])[N:6]=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)Nc1cn(C2CC2)cn1
Agent: Cl
Solvent: CO
Product: Nc1cn(C2CC2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
A solution of 237D (0.60 gm, 2.3 mmole) in a 5.0 N solution of HCl in methanol was left stirring at room temperature for 1 hr. This was applied onto a Phenomenex Strata-X-C 33 um cation mixed-mode polymer, flushed with methanol, and the product was eluted with a 2 N solution of ammonia in methanol. Removal of the solvents left 237E, (0.20 gm; 59% yield). 1H NMR (500 MHz, CDCl3) δ 0.87 (m, 4H) 3.21 (s, 1H) 6.27 (s, 1H) 7.16 (br s, 1H).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:16]([NH:18][C@H:19]([C:32]([NH:34][C@H:35]([C:43]([NH:45][CH2:46][C:47]([OH:49])=[O:48])=[O:44])[CH2:36][CH2:37][CH2:38][NH:39][C:40](=[NH:42])[NH2:41])=[O:33])[CH2:20][CH2:21][C:22](=[O:31])[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:17])[CH2:11][CH2:12][C:13](=[O:15])[NH2:14])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].CC(OC([NH:57][C@H:58]([C:61](OCC1C=CC([N+]([O-])=O)=CC=1)=[O:62])[CH2:59][OH:60])=O)(C)C>FC(F)(F)C([O-])=O>[NH2:57][C@H:58]([C:59]([NH:1][C@H:2]([C:7]([NH:9][C@H:10]([C:16]([NH:18][C@H:19]([C:32]([NH:34][C@H:35]([C:43]([NH:45][CH2:46][C:47]([OH:49])=[O:48])=[O:44])[CH2:36][CH2:37][CH2:38][NH:39][C:40](=[NH:41])[NH2:42])=[O:33])[CH2:20][CH2:21][C:22](=[O:31])[O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:17])[CH2:11][CH2:12][C:13](=[O:15])[NH2:14])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5])=[O:60])[CH2:61][OH:62]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: N=C(N)NCCC[C@H](NC(=O)[C@H](CCC(=O)OCc1ccccc1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CC(N)=O)C(=O)NCC(=O)O
Agent: O=C([O-])C(F)(F)F
Product: N=C(N)NCCC[C@H](NC(=O)[C@H](CCC(=O)OCc1ccccc1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CO)C(=O)NCC(=O)O

Procedure:
Likewise under the conditions of Example II-2 and from 806 g of H-Asn-Gln-Glu(OBzl)-Arg-Gly-OH and 366 g of Boc-Ser-ONb, the product is obtained, monitored by NMR and TLC with a yield of 688 g (77%) and in trifluoroacetate form.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[C:14](=[O:19])[CH2:13]2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:9][CH:10]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[C:14](=[O:19])[CH2:13]2)[CH2:11]1
Reactant: CN1CCN(C2CN(C(=O)OC(C)(C)C)C2)CC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCN(C2CNC2)CC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
A mixture of 3-(4-methyl-3-oxopiperazin-1-yl)azetidine-1-carboxylic acid tert-butyl ester (211 mg, 0.78 mmol) and TFA (2 mL) in DCM (4 mL) was stirred at room temperature for 2 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording 4-Azetidin-3-yl-1-methylpiperazin-2-one as a white solid (125 mg, 95%). 1H NMR (CDCl3, 300 MHz): δ 3.63 (m, 4H); 3.37-3.27 (m, 3H); 3.03 (s, 2H); 2.96 (s, 3H); 2.58 (t, J=5.6 Hz, 2H); 2.13-1.97 (m, 1H).