Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.CC1C=CC=CC=1C.C(O)(=[O:22])C>>[C:1]([OH:6])(=[O:11])[C:2]1[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:4]([OH:22])=[O:5].[C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12
Reactant: CC(=O)O
Agent: O=C1OC(=O)c2ccccc21
Solvent: Cc1ccccc1C
Product: O=C(O)c1ccccc1C(=O)O

Procedure:
As an example, reference is made to the production of phthalic anhydride with acetic acid as solvent. During oxidation of o-xylene as feedstock, phthalic acid and phthalic anhydride are obtained as products in the liquid-phase reactor. Therefore, not only the binary crystallization curves of phthalic acid in acetic acid or phthalic anhydride in acetic acid are used, but also those of the ternary system phthalic acid/phthalic anhydride/in acetic acid. By using the process of the invention, phthalic acid and phthalic anhydride are obtained as pure solid products. The acetic acid obtained as byproduct is recirculated into the reactor as solvent.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([NH:6][CH:7]=[C:8]([C:14]([O:16]CC)=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:2]1>C1(OC2C=CC=CC=2)C=CC=CC=1>[OH:16][C:14]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:6]=[C:3]2[CH:4]=[CH:5][S:1][C:2]=12
Reactant: CCOC(=O)C(=CNc1ccsc1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2ccsc2c1O
Reaction time: 0.83 h
Yield: 58.8 %

Procedure:
A solution of diethyl 2-{[(thien-3-yl)amino]methylene}malonate (43.4 g, 0.16 mol) in diphenyl ether (200 mL) in a 500 mL round bottom (RB) flask was degassed by three cycles of evacuation and nitrogen purge. The solution was then heated rapidly with a heating mantle to reflux and stirred at that temperature for 50 minutes. The heating mantle was removed and the yellow to brown solution was then stirred for 3 hours and was allowed to stand at room temperature for 16 hours, during which time a copious ppt appeared. The mixture was diluted with diethyl ether (300 mL) before collecting the solid by vacuum filtration. The collected solid was washed thoroughly with ether and dried in vacuo, leaving a white solid (21 g). More solid precipitated after the filtrate standing at room temperature overnight (7 g).
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][N+:7]([O-:10])=[CH:6][CH:5]=1)([O-])=O.[O-:11][CH2:12][CH3:13].[Na+]>C(O)C>[CH2:12]([O:11][C:4]1[CH:9]=[CH:8][N+:7]([O-:10])=[CH:6][CH:5]=1)[CH3:13]
Reactant: CC[O-]
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1
Agent: [Na+]
Solvent: CCO
Product: CCOc1cc[n+]([O-])cc1
Temperature: 50 °C
Reaction time: 40 h
Yield: 99 %

Procedure:
4-nitropyridine-N-oxide (12 g) was dissolved in ethanol, sodium ethoxide (8.8 g) was added to the mixture, and the mixture was stirred for 40 hours at 50° C. After allowing the mixture to be cooled to room temperature, the precipitates were filtered, the solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 4-ethoxypyridine-N-oxide (11.8 g). To 4-ethoxypyridine-N-oxide (11.8 g) was added dimethyl sulfate (8.56 ml), and the mixture was stirred for 1 hour at 110° C. After diluting with methanol (180 ml), the mixture was heated to reflux for 1 hour, an aqueous solution (18 ml) of ammonium peroxodisulfate (20.6 g) was added dropwise to the solution under heat reflux, and the mixture was heated to reflux for 1 hour. After allowing the mixture to be cooled to room temperature, the solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give (4-ethoxy-2-pyridinyl)methanol (2.8 g).
Reaction SMILES: Cl[C:2]1[N:3]([CH3:32])[C:4](=[O:31])[C:5]2[N:6]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[C:7]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)=[N:8][C:9]=2[N:10]=1.[C:33]([O:37][CH2:38][CH3:39])(=[O:36])[CH2:34][OH:35].[H-].[Na+]>CN1CCCC1=O.C(OCC)(=O)C>[Cl:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[N:6]1[C:5]2[C:4](=[O:31])[N:3]([CH3:32])[C:2]([O:35][CH2:34][C:33]([O:37][CH2:38][CH3:39])=[O:36])=[N:10][C:9]=2[N:8]=[C:7]1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:13][CH2:12]1
Reactant: Cn1c(Cl)nc2nc(N3CCN(C(=O)OC(C)(C)C)CC3)n(-c3ccccc3Cl)c2c1=O
Reactant: CCOC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1nc2nc(N3CCN(C(=O)OC(C)(C)C)CC3)n(-c3ccccc3Cl)c2c(=O)n1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 210.3 %

Procedure:
10 mg of t-butyl 4-[2-chloro-7-(2-chlorophenyl)-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl]piperazine-1-carboxylate and 10 mg of ethyl glycolate were dissolved in 0.2 ml of N-methylpyrrolidone, and 10 mg of sodium hydride was added thereto. The mixture was stirred at room temperature for 2 hours. The reaction solution was dissolved in ethyl acetate, and the mixture was washed with 1N hydrochloric acid. Thus, 24 mg of t-butyl 4-[7-(2-chlorophenyl)-2-ethoxycarbonylmethoxy-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl]piperazine-1-carboxylate was obtained. 8 mg of this compound was dissolved in trifluoroacetic acid, and the mixture was concentrated. The residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 2.11 mg of the title compound.
Reaction SMILES: C(C1N=[C:7]([N:22]2C[CH2:26][O:25][CH2:24][CH2:23]2)[C:8]2N=NN(CC3C=CC=CC=3Cl)[C:9]=2N=1)(C)(C)C.[C:28]([C:32]1[N:33]=[C:34](Cl)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29].COC[C@@H]1CCCN1>>[C:28]([C:32]1[N:33]=[C:34]([N:22]2[CH2:7][CH2:8][CH2:9][C@H:23]2[CH2:24][O:25][CH3:26])[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: COC[C@@H]1CCCN1
Product: COC[C@@H]1CCCN1c1nc(C(C)(C)C)nc2c1nnn2Cc1ccccc1Cl

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (S)-2-(methoxymethyl)pyrrolidine and isolated as light-yellow gum (12.0 mg, 61%). MS(m/e): 415.4 (MH+).
Reaction SMILES: C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:15][O:16][C:17]([C:19]([CH3:42])([CH3:41])[CH2:20][C:21]1[CH:26]=[C:25]([CH3:27])[C:24]([C:28]2[NH:29][C:30]3[CH:36]=[C:35]([C:37](O)=[O:38])[CH:34]=[CH:33][C:31]=3[N:32]=2)=[C:23]([CH3:40])[CH:22]=1)=[O:18].[CH3:43][C:44]1[CH:53]=[CH:52][CH:51]=[CH:50][C:45]=1[C:46]([NH:48][NH2:49])=O.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>CN(C=O)C.CCOC(C)=O>[CH3:15][O:16][C:17](=[O:18])[C:19]([CH3:41])([CH3:42])[CH2:20][C:21]1[CH:22]=[C:23]([CH3:40])[C:24]([C:28]2[NH:29][C:30]3[CH:36]=[C:35]([C:37]4[O:38][C:46]([C:45]5[CH:50]=[CH:51][CH:52]=[CH:53][C:44]=5[CH3:43])=[N:48][N:49]=4)[CH:34]=[CH:33][C:31]=3[N:32]=2)=[C:25]([CH3:27])[CH:26]=1
Reactant: COC(=O)C(C)(C)Cc1cc(C)c(-c2nc3ccc(C(=O)O)cc3[nH]2)c(C)c1
Reactant: Cc1ccccc1C(=O)NN
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)Cc1cc(C)c(-c2nc3ccc(-c4nnc(-c5ccccc5C)o4)cc3[nH]2)c(C)c1

Procedure:
Add EDC (380 mg, 1.98 mmol) and HOBt (268 mg, 1.98 mmol) to a stirring solution of 2-[4-(2-methoxycarbonyl-2-methyl-propyl)-2,6-dimethyl-phenyl]-3H-benzoimidazole-5-carboxylic acid (626 mg, 1.65 mmol) and 2-methyl-benzoic acid hydrazide (248 mg, 1.65 mmol) in DMF (6 mL) under N2. Upon disappearance of the carboxylic acid by LC/MS, dilute the reaction with EtOAc (60 mL) and extract with water (20 mL) followed by brine (10 mL). Dry the organic phase over Na2SO4 and evaporate the solvent. Dissolve the residue in DMF (6 mL) and add Burgess reagent (1.18 g, 4.95 mmol). Heat the mixture my microwave irradiation to 150° C. for 15 min. Dilute the reaction with EtOAc (100 mL) and extract with water (25 mL). Extract the organic phase with saturated NaHCO3 (2×25 mL) followed by brine (20 mL). Dry the organic phase over Na2SO4 and evaporate the solvent. Purify the residue by silica gel chromatography (10-45% ACN/DCM) to afford the title compound as a yellow oil: (M+H)+ 495.3.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH3:22])[C:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C:10]=3[C:5]2=[CH:4][CH:3]=1.[CH2:23]([N:31]1[CH2:36][CH2:35][NH:34][C:33](=[O:37])[CH2:32]1)[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH3:22][N:8]1[C:6]2=[N:7][C:2]([N:34]3[CH2:35][CH2:36][N:31]([CH2:23][CH2:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:32][C:33]3=[O:37])=[CH:3][CH:4]=[C:5]2[C:10]2[CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14][C:9]1=2
Reactant: O=C1CN(CCc2ccccc2)CCN1
Reactant: Cn1c2c(c3ccc(Br)nc31)CN(C(=O)OC(C)(C)C)CC2
Product: Cn1c2c(c3ccc(N4CCN(CCc5ccccc5)CC4=O)nc31)CN(C(=O)OC(C)(C)C)CC2
Yield: 67.5 %

Procedure:
tert-Butyl 2-bromo-9-methyl-5,7,8,9-tetrahydro-6H-pyrido[3′,4′:4,5]pyrrolo[2,3-b]pyridine-6-carboxylate (86 mg, 0.23 mmol) and 4-phenethylpiperazin-2-one (56 mg, 0.27 mmol) were reacted according to Example 2 (step e) to provide the title compound (76 mg, 67%) as a yellow powder: ESI MS m/z 490 [M+H]+.
Reaction SMILES: [NH:1]([C:5]1[CH:11]=[CH:10][C:8]([OH:9])=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3].C([O-])([O-])=O.[K+].[K+].[CH3:18][CH2:19][O:20][C:21]([CH2:23]Br)=[O:22]>CC(C)=O>[CH2:19]([O:20][C:21](=[O:22])[CH2:23][O:9][C:8]1[CH:10]=[CH:11][C:5]([NH:1][C:2](=[O:3])[CH3:4])=[CH:6][CH:7]=1)[CH3:18]
Reactant: CCOC(=O)CBr
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc(NC(C)=O)cc1
Yield: 80.1 %

Procedure:
To a mixture of Paracetamol (300 grams, 1.984 mol), anhydrous K2CO3 (1.80 Kg, 7.814 mmol) in anhydrous acetone (3 liters) was added ethyl bromo acetate (452 grams, 2.7 mol) and refluxed for 16 hours. Acetone was distilled and water (5 liter) was added. Crude 59 was filtered, dried, and recrystallized from a mixture of toluene:Hexane (1:5) to give pure 59 (377 grams, 80%) as a white shining powder. The melting point was found to be 104.2-106.2° C.
Reaction SMILES: [F:1][C:2]1([F:20])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([C@:11]34[CH2:19][O:18][CH2:17][CH2:16][C@H:15]3[CH2:14][O:13][NH:12]4)[C:4]=2[O:3]1>C(O)(=O)C.[Zn]>[NH2:12][C@:11]1([C:10]2[C:4]3[O:3][C:2]([F:20])([F:1])[O:6][C:5]=3[CH:7]=[CH:8][CH:9]=2)[C@H:15]([CH2:14][OH:13])[CH2:16][CH2:17][O:18][CH2:19]1
Reactant: FC1(F)Oc2cccc([C@]34COCC[C@H]3CON4)c2O1
Agent: [Zn]
Solvent: CC(=O)O
Product: N[C@@]1(c2cccc3c2OC(F)(F)O3)COCC[C@H]1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
Zinc powder (2.01 g) was added to a solution of (±)-(3aR*,7aS*)-7a-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-hexahydropyrano[3,4-c]isoxazole (875 mg) in acetic acid (30 ml), and the mixture was stirred at room temperature overnight. The insoluble matter was removed by filtration through celite, and the solvent was evaporated under reduced pressure. Ice was added to the residue, followed by neutralization with a 5 N sodium hydroxide solution. The aqueous layer was extracted with dichloromethane, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (661 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11](=[O:16])[CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17](=O)([O:20]C)[O:18][CH3:19].[H-].[Na+].CO>C1CCCCC1.O>[CH3:19][O:18][C:17]([C:12]1[CH:13]2[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:9]([CH2:10][C:11]=1[OH:16])[CH2:15][CH2:14]2)=[O:20]
Reactant: COC(=O)OC
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=O)C2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: CO
Solvent: O
Product: COC(=O)C1=C(O)CC2CCC1N2C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 87.7 %

Procedure:
3-Oxo-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester from Step 1 (14.1 g, 62 mmol) was dissolved in cyclohexane (550 mL), to which was added dimethyl carbonate (12.4 g, 137 mmol), followed by sodium hydride (5.0 g, 125 mmol) and methanol (0.2 mL). The reaction mixture was stirred at reflux for 15 hours, then cooled to room temperature, and water (25 mL) was added. The reaction mixture was concentrated under reduced pressure to a volume of 50 mL, which was then partitioned between ethyl acetate and saturated aqueous ammonium chloride. The combined organic extracts were washed with water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, ethyl acetate/hexane) to provide 3-hydroxy-8-azabicyclo[3.2.1]oct-2-ene-2,8-dicarboxylic acid 8-tert-butyl ester 2-methyl ester as a light yellow oil (15.4 g, 87% yield).
Reaction SMILES: C([O:5][C:6](=[O:37])[C@H:7]([CH3:36])[NH:8][C:9](=[O:35])[C@H:10]([CH2:19][CH2:20][CH:21]([F:34])[CH:22]([C:31]([OH:33])=[O:32])[NH:23]C(OC(C)(C)C)=O)[NH:11]C(OC(C)(C)C)=O)(C)(C)C.O>CCOCC.Cl>[F:34][CH:21]([CH:22]([C:31]([OH:33])=[O:32])[NH2:23])[CH2:20][CH2:19][C@@H:10]([C:9]([NH:8][C@H:7]([C:6]([OH:37])=[O:5])[CH3:36])=[O:35])[NH2:11]
Reactant: C[C@H](NC(=O)[C@H](CCC(F)C(NC(=O)OC(C)(C)C)C(=O)O)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: C[C@H](NC(=O)[C@@H](N)CCC(F)C(N)C(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 96 h

Procedure:
The Nα,Nε -di-t-butoxycarbonyl-δ-fluoro-ε-carboxylysyl-L-alanine t-butyl ester prepared above (511 mg) is dissolved in ether saturated with HCl gas, and the mixture is stirred at room temperature for 4 days. The precipitate is collected and dissolved in 1N HCl. Evaporation gives a white foam which is dried carefully and is dissolved in ethanol. Upon addition of excess propylene oxide, the title compound crystallizes with 0.75 mmoles of HCl and 0.75 mmoles of water.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([C:24]([OH:26])=O)[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.C(Cl)CCl.[O:43]1[C:47]2=[CH:48][N:49]=[CH:50][CH:51]=[C:46]2[CH:45]([CH2:52][NH2:53])[CH2:44]1>C(Cl)Cl.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([C:24]([NH:53][CH2:52][CH:45]3[C:46]4[C:47](=[CH:48][N:49]=[CH:50][CH:51]=4)[O:43][CH2:44]3)=[O:26])[CH2:20][CH2:19]2)=[O:17])=[CH:27][CH:28]=1
Reactant: O=C(O)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(Cl)cc2)CC1
Reactant: NCC1COc2cnccc21
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NCC1COc2cnccc21)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-(1-(4-chlorobenzyl)-1H-indole-2-carbonyl)piperidine-4-carboxylic acid (317 mg, 0.799 mmol), 1-hydroxybenzotriazole (135 mg, 0.999 mmol), and EDC (191 mg, 0.999 mmol) were dissolved in 2.0 mL of DCM. The reaction was allowed to stir at room temperature for 10 minutes before adding (2,3-dihydrofuro[2,3-c]pyridin-3-yl)methanamine (100 mg, 0.666 mmol) as a DCM solution and Hunig'sBase (0.174 mL, 0.999 mmol). The reaction was allowed to stir at room temperature overnight. The reaction was diluted with water and ethyl acetate. The organic layer was washed with saturated sodium bicarbonate and saturated sodium chloride solution. It was dried over magnesium sulfate, filtered and concentrated. The crude material was triturated in ethyl acetate, filtered and concentrated to obtain white solid. (Yield: 176 mg, white solid) 1H-NMR (500 MHz, DMSO-d6) 8.13-8.04, 7.63, 7.55, 7.37-7.28, 7.22, 7.13-7.02, 6.72, 5.47, 4.59, 4.47-4.28, 4.13-3.85, 3.73-3.62, 3.17, 3.07-2.76, 2.41-2.31, 1.79-1.20
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:29][C@@H:30]([C@H:32]4[CH2:36][NH:35][C:34](=[O:37])[CH2:33]4)[CH3:31])=[N:10][C:11]([C:13]4[CH:18]=[CH:17][C:16]([N:19]5[CH2:24][CH2:23][N:22]([S:25]([CH3:28])(=[O:27])=[O:26])[CH2:21][CH2:20]5)=[CH:15][CH:14]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.C1(N2C3[C:46]([O:62][C@@H:63]([C@H]4CNC(=O)C4)C)=NC(C4C=CC(N5CCNCC5)=CC=4)=CC=3N=C2)CC1.O1CC(S(Cl)(=O)=O)C1>>[CH:1]1([N:4]2[C:8]3[C:9]([O:29][C@@H:30]([C@H:32]4[CH2:36][NH:35][C:34](=[O:37])[CH2:33]4)[CH3:31])=[N:10][C:11]([C:13]4[CH:18]=[CH:17][C:16]([N:19]5[CH2:24][CH2:23][N:22]([S:25]([CH:28]6[CH2:63][O:62][CH2:46]6)(=[O:26])=[O:27])[CH2:21][CH2:20]5)=[CH:15][CH:14]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1
Reactant: C[C@@H](Oc1nc(-c2ccc(N3CCNCC3)cc2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Reactant: C[C@@H](Oc1nc(-c2ccc(N3CCN(S(C)(=O)=O)CC3)cc2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Agent: O=S(=O)(Cl)C1COC1
Product: C[C@@H](Oc1nc(-c2ccc(N3CCN(S(=O)(=O)C4COC4)CC3)cc2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1

Procedure:
Following the procedure described for intermediate 3.45, starting from (R)-4-((R)-1-((3-cyclopropyl-6-(4-(piperazin-1-yl)phenyl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one (90 mg, 0.2 mmol) and oxetane-3-sulfonyl chloride (0.12 ml, 0.89 mmol) to provide 42.4 mg of (R)-4-((R)-1-((3-cyclopropyl-6-(4-(4-(oxetan-3-ylsulfonyl)piperazin-1-yl)phenyl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([NH:12][CH2:13][C:14]2[CH:22]=[C:21]3[C:17]([CH:18]=[CH:19][NH:20]3)=[CH:16][CH:15]=2)=[O:11])=[CH:6][C:5]=1[Cl:23].O.[OH-].[Li+]>O1CCCC1.CO.O>[Cl:23][C:5]1[CH:6]=[C:7]([C:10]([NH:12][CH2:13][C:14]2[CH:22]=[C:21]3[C:17]([CH:18]=[CH:19][NH:20]3)=[CH:16][CH:15]=2)=[O:11])[CH:8]=[CH:9][C:4]=1[C:3]([OH:24])=[O:2]
Reactant: COC(=O)c1ccc(C(=O)NCc2ccc3cc[nH]c3c2)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(NCc1ccc2cc[nH]c2c1)c1ccc(C(=O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 98 %

Procedure:
A solution of 2-chloro-4-[[[(1H-indol-6-yl)methyl]amino]carbonyl]benzoic acid methyl ester (Example 80; 2.00 g, 5.9 mmol) in tetrahydrofuran/methanol (1:1; 10 mL) was added to a solution of lithium hydroxide monohydrate (491 mg, 11.7 mmol) in water (5 mL). The solution was allowed to stir at room temperature for 72 h and then concentrated under reduced pressure to remove tetrahydrofuran and methanol. The remaining solution was diluted with water and acidified with 1N hydrochloric acid solution. The resulting mixture was extracted with ethyl acetate and the organic extracts were washed with brine, dried (MgSO4), filtered and concentrated to afford 2-chloro-4-[[[(1H-indol-6-yl)methyl]amino]carbonyl]benzoic acid (1.90 g, 99% yield) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[OH:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[OH:20])[CH:15]=[O:16].C(=O)([O-])[O-].[Cs+].[Cs+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[OH:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[O:20][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH:15]=[O:16]
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: COc1ccc(CCl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2ccc(C=O)cc2O)cc1
Reaction time: 48 h
Yield: 58.9 %

Procedure:
4-Methoxybenzylchloride (20.6 mL, 0.14 mol, 1.05 eq) was added to a stirred solution of 3,4-dihydroxybenzaldehyde (20 g, 0.15 mol, 1 eq), tetra-n-butylammonium iodide (44.6 g, 0.12 mol, 0.8 eq) and cesium carbonate (35.4 g, 0.11 mol, 0.75 eq) in N,N-dimethylformamide (200 mL). The reaction mixture was stirred for 2 days, and then concentrated in vacuo. The residual solution was diluted with ethyl acetate (200 mL) and washed with 0.5M HCl (400 mL), water (4×200 mL) and saturated sodium chloride solution (200 mL), then dried over sodium sulfate and evaporated in vacuo. This gave a gummy solid which was recrystallized from ethyl acetate and petroleum ether to give the product as a pale brown powder (21.29 g, 57%). 1H NMR (CDCl3) δ 9.84 (s, 1H, O═C—H), 5.80 (s, 1H, OH), 5.13 (s, 2H, CH2Ar), 3.85 (s, 3H, OCH3).
Reaction SMILES: S1C=CC=C1.CC(N(O)C(N)=[O:12])C#C.[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]2S[C:26]([C:28]#[C:29][CH:30]([N:32]([OH:36])[C:33]([NH2:35])=[O:34])[CH3:31])=[CH:25][CH:24]=2)=[CH:18][CH:17]=1>>[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]2[O:12][C:26](/[CH:28]=[CH:29]/[CH:30]([N:32]([OH:36])[C:33]([NH2:35])=[O:34])[CH3:31])=[CH:25][CH:24]=2)=[CH:18][CH:17]=1
Reactant: C#CC(C)N(O)C(N)=O
Reactant: CC(C#Cc1ccc(Cc2ccc(F)cc2)s1)N(O)C(N)=O
Solvent: c1ccsc1
Product: CC(/C=C/c1ccc(Cc2ccc(F)cc2)o1)N(O)C(N)=O

Procedure:
The desired compound is prepared according to the method of Example 2, except substituting furan for thiophene, and substituting N-(3-butyn-2-yl)N-hydroxyurea, prepared as in Example 3, step 2, for (R) N-(3-butyn-2-yl)N-hydroxyurea.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C@H:13]1[N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][C@@H:16]([CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[NH:34][C:35](=[O:55])[C@H:36]([CH:42]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[NH:37][C:38]([O:40][CH3:41])=[O:39])[O:15][CH2:14]1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(Cl)Cl.O>[CH:12]([C@H:13]1[N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:20])[CH2:17][C@@H:16]([CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[NH:34][C:35](=[O:55])[C@H:36]([CH:42]([C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[NH:37][C:38]([O:40][CH3:41])=[O:39])[O:15][CH2:14]1)=[O:11]
Reactant: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](CO)CO1)C(c1ccccc1)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](C=O)CO1)C(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of oxalyl chloride (5 eq) in DCM (0.3 M) at −78° C. was added a solution of DMSO (10 eq) in DCM (0.5M). The reaction mixture was stirred at −78° C. for 30 min. A solution of tert-butyl (2R,5R)-5-(hydroxymethyl)-2-[2-(2-{[N-(methoxycarbonyl)-β-phenyl-L-phenylalanyl]amino}phenyl)ethyl]morpholine-4-carboxylate (Example 185, step 10) (1 eq) in CH2Cl2 (0.2M) was added dropwise and stirred at −40° C. for 1.5 hours. It was then cooled to −78° C. and triethylamine (10 eq)) was added and the reaction mixture was stirred at 0° C. for 1 h. Water was added and the reaction mixture was warmed to rt for 30 min. The mixture was poured into aqueous sodium hydrogen carbonate and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with brine, dried with MgSO4 and concentrated under vacuum to afford the title compound as a yellow gum. The material was used in the subsequent step without further purification.