Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:51]([O:54][C@@H:55]1[C@@H:61]([O:62][C:63](=[O:65])[CH3:64])[C@H:60]([O:66][C:67](=[O:69])[CH3:68])[CH2:59][S:58][CH:56]1O)(=[O:53])[CH3:52]>C1COCC1>[CH3:3][C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH:56]3[S:58][CH2:59][C@@H:60]([O:66][C:67](=[O:69])[CH3:68])[C@H:61]([O:62][C:63](=[O:65])[CH3:64])[C@H:55]3[O:54][C:51](=[O:53])[CH3:52])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1ccc2cc(O)ccc21
Reactant: CC(=O)O[C@H]1[C@H](OC(C)=O)CSC(O)[C@@H]1OC(C)=O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)O[C@H]1[C@H](OC(C)=O)CSC(Oc2ccc3c(ccn3C(=O)OC(C)(C)C)c2)[C@@H]1OC(C)=O
Temperature: 45 °C
Reaction time: 3 h
Yield: 11 %

Procedure:
A solution of 1.75 g (7.51 mM) of 5-hydroxy-1H-indole-1-carboxylic acid tert-butyl ester in 25 ml of THF, 2.73 g (13.5 mM) of diisopropylazodicarboxylate and 3.54 g (13.5 mM) of triphenylphosphine are added to a solution of 2.85 g (9.75 mM) of 2,3,4-tri-O-acetyl-5-thio-D-xylopyranose in 50 ml of THF. The reaction mixture is stirred at 45° C. for 3 hours and then concentrated under reduced pressure. The evaporation residue is dissolved in ethyl acetate and the organic phase is washed with a 1N solution of sodium hydroxide, and then with a concentrated aqueous solution of ammonium chloride. The organic phase is subsequently dried over magnesium sulfate and concentrated under reduced pressure. The evaporation residue is purified by C18-grafted silica chromatography, elution being carried out with an acetonitrile/water mixture (7/3; v/v). The desired product is obtained in the form of a pale yellow solid with a yield of 11%.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([N:11]([CH2:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]([OH:28])=O)[S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH3:22])(=[O:14])=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CN1CCOCC1.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1>CN(C=O)C>[CH2:4]([CH:3]1[CH2:2][NH:1][C:26](=[O:28])[C:25]2[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=2[CH2:23][N:11]1[S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH3:22])(=[O:14])=[O:13])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COc1ccccc1S(=O)(=O)N(Cc1ccccc1C(=O)O)C(CN)Cc1ccccc1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COc1ccccc1S(=O)(=O)N1Cc2ccccc2C(=O)NCC1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91.6 %

Procedure:
To a solution of compound 2f (45 mg, 0.1 mmol) in dry DMF (15 mL) was added 4-methylmorpholine (33 mg, 0.32 mmol). The mixture was stirred at rt for 10 min and DPPA (41 mg, 0.15 mmol) was added. This resulting mixture was stirred at rt for 24 h and then concentrated in vacuo to remove the solvent. The residue was dissolved in EA (10 mL), washed with saturated aqueous NH4Cl and brine, dried over anhydrous Na2SO4. Concentration in vacuo and purification by prep-TLC gave compound 2g as a white solid (40 mg, 91% yield). 1H-NMR (400 MHz, CDCl3) δ 8.03 (dd, 1H, J=8.0, 1.6 Hz), 7.47-6.99 (m, 11H), 6.86 (d, 1H, J=8.0 Hz), 6.15 (m, 1H), 5.02 (d, J=15.6 Hz, 1H), 4.22 (d, J=15.6 Hz, 1H), 4.18 (m, 1H), 3.76 (s, 3H), 3.20 (dd, J=15.2, 8.8 Hz, 1H), 3.02-2.88 (m, 2H), 2.39 (d, J=8.8 Hz, 1H). MS (ESI+) m/z: 437 [M+H]+, 459 [M+Na]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:11]([CH3:13])([CH3:12])[CH2:10][C:9]1=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-:15].[Li+]>O1CCCC1.CCOCC.O>[C:1]([O:5][C:6]([NH:8][C:11]([CH3:13])([CH3:12])[CH2:10][C:9]([OH:14])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N1C(=O)CC1(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(CC(=O)O)NC(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 87 %

Procedure:
A 3 L, 3-neck round bottom flask equipped with a magnetic stirrer, thermometer, nitrogen bubbler and addition funnel was charged with 180.3 g (0.89 mol) of N-(t-butoxycarbonyl)-4,4-dimethylazetidin-2-one dissolved in 1 L of tetrahydrofuran. The solution was cooled to 0°-5° C. and treated dropwise with 890 mL of 1.0M aqueous lithium hydroxide over 30 minutes. The reaction mixture was stirred at 0°-5° C. for 2 hours then diluted with 1 L of ether and 1 L of water. The layers were allowed to separate and the aqueous layer reextracted with an additional 1 L of ether. The aqueous layer was acidified by the addition of 1 L of saturated aqueous sodium bisulfate, then extracted with 1×1 L and 2×500 mL of ether. The combined organic layer and ether extracts were washed with 500 mL of saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated under vacuum to 173 g of a yellow oil that solidified upon standing. The material was slurried with warm hexane then filtered and dried under high vacuum to afford 168.5 g (0.775 mol,87%) of product as a white solid. 1H NMR (200 MHz,CDCl3): 1.39 (s,6H), 1.44 (s,9H), 2.72(s,2H). FAB-MS: calculated for C10H19NO4 217; found 218 (M+H,54%).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:13]([NH2:15])=O)[C:11](O)=[C:6]2[CH:5]=[N:4]1)[CH3:2].S(Cl)([Cl:18])=O>>[Cl:18][C:11]1[C:10]([C:13]#[N:15])=[CH:9][N:8]=[C:7]2[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][C:6]=12
Reactant: O=S(Cl)Cl
Reactant: CCn1ncc2c(O)c(C(N)=O)cnc21
Product: CCn1ncc2c(Cl)c(C#N)cnc21

Procedure:
10.3 g. of 1-ethyl-4-hydroxy-1H-pyrazolo-[3,4-b]pyridine-5-carboxamide (0.05 mol.) and 125ml. of thionyl chloride are refluxed for 3.5 hours. After cooling, the thionyl chloride is removed in vacuo and the residue is extracted twice with 400ml. of refluxing hexane. The combined extracts are treated with charcoal, filtered and evaporated. The product, 4-chloro-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile, is recrystallized from a small amount of hexane, yield 2.9 g. (28%), m.p. 100°-102°.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH2:23][C@@H:24]5[CH2:28][CH2:27][CH2:26][NH:25]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.Br[CH2:37][C:38]([NH2:40])=[O:39]>>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH2:23][C@@H:24]5[CH2:28][CH2:27][CH2:26][N:25]5[CH2:37][C:38]([NH2:40])=[O:39])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:33])[F:34])[CH:3]=1
Reactant: NC(=O)CBr
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1C[C@@H]1CCCN1
Product: NC(=O)CN1CCC[C@H]1CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
2-[(2S)-2-{[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]methyl}pyrrolidin-1-yl]acetamide was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(2S)-pyrrolidin-2-ylmethyl]-1,3-thiazolidine-2,4-dione (Example 145) and 2-bromoacetamide following General Procedure H.
Reaction SMILES: C1(C[O:8][C:9](=[O:31])[CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:19]=2[N:18]([C:20](=[O:29])[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C:17](=[O:30])[CH2:16]3)C=CC=CC=1.[H][H]>O1CCCC1.[Pd]>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([C:20]([N:18]2[C:19]3[C:15](=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:10][C:9]([OH:31])=[O:8])[CH2:16][C:17]2=[O:30])=[O:29])=[CH:22][CH:23]=1
Reactant: COc1ccc(C(=O)N2C(=O)Cc3cccc(CC(=O)OCc4ccccc4)c32)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)N2C(=O)Cc3cccc(CC(=O)O)c32)cc1

Procedure:
A solution of 29.5 g (0.1 mole) 2,3-dihydro-1-(4-methoxybenzoyl)-2-oxo-1H-indole-7-acetic acid phenylmethyl ester in tetrahydrofuran is reduced with hydrogen over 2 g of 20% Pd/C catalyst. After the theoretically calculated amount of hydrogen has been consumed, the solution is filtered through filter aid. The filtrate is concentrated at reduced pressure and the oily residue is triturated with anhydrous diethyl ether to yield 2,3-dihydro-1-(4-methoxybenzoyl)-2-oxo-1H-indole-7-acetic acid.
Reaction SMILES: [CH3:1][C:2]([CH3:35])([CH3:34])[CH2:3][O:4][S:5]([C:8]1[CH:9]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([C@:21]3([CH3:33])[C:27]([F:29])([F:28])[C:26]([CH3:31])([CH3:30])[O:25][CH2:24][C:23](=O)[NH:22]3)[CH:15]=2)[CH:11]=[CH:12][CH:13]=1)(=[O:7])=[O:6].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:45])=CC=1>O1CCOCC1>[CH3:1][C:2]([CH3:34])([CH3:35])[CH2:3][O:4][S:5]([C:8]1[CH:9]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([C@:21]3([CH3:33])[C:27]([F:28])([F:29])[C:26]([CH3:31])([CH3:30])[O:25][CH2:24][C:23](=[S:45])[NH:22]3)[CH:15]=2)[CH:11]=[CH:12][CH:13]=1)(=[O:6])=[O:7]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)COS(=O)(=O)c1cccc(-c2ccc(F)c([C@@]3(C)NC(=O)COC(C)(C)C3(F)F)c2)c1
Solvent: C1COCCO1
Product: CC(C)(C)COS(=O)(=O)c1cccc(-c2ccc(F)c([C@@]3(C)NC(=S)COC(C)(C)C3(F)F)c2)c1
Yield: 90 %

Procedure:
The reaction of 3′-((R)-6,6-difluoro-5,7,7-trimethyl-3-oxo-[1,4]oxazepan-5-yl)-4′-fluoro-biphenyl-3-sulfonic acid 2,2-dimethyl-propyl ester (124 mg, 241 μmol with Lawesson's reagent (97.7 mg, 241 μmol) in 1,4-dioxane (10 ml) yielded the 3′-((R)-6,6-difluoro-5,7,7-trimethyl-3-thioxo-[1,4]oxazepan-5-yl)-4′-fluoro-biphenyl-3-sulfonic acid 2,2-dimethyl-propyl ester (115 mg, 90%) as a white foam. MS (ISP): m/z=530.2 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([F:32])[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:18]([CH2:30][CH3:31])=[CH:19][C:20]([CH:27]4[CH2:29][CH2:28]4)=[C:21]([CH:26]=3)[C:22](OC)=[O:23])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].O.[NH2:34][NH2:35]>C(O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([F:32])[CH2:10][CH2:11][N:12]([C:15]([C:17]3[C:18]([CH2:30][CH3:31])=[CH:19][C:20]([CH:27]4[CH2:28][CH2:29]4)=[C:21]([CH:26]=3)[C:22]([NH:34][NH2:35])=[O:23])=[O:16])[CH2:13][CH2:14]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CCc1cc(C2CC2)c(C(=O)OC)cc1C(=O)N1CCC(F)(c2ccc(C#N)cc2)CC1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCc1cc(C2CC2)c(C(=O)NN)cc1C(=O)N1CCC(F)(c2ccc(C#N)cc2)CC1
Temperature: 80 °C
Reaction time: 15 h
Yield: 75 %

Procedure:
To a solution of methyl 5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclopropyl-4-ethylbenzoate (compound 226.7, 200 mg, 0.460 mmol, 1.00 equiv) in ethanol (15 mL) was added hydrazine hydrate (80%, 5 mL). The resulting solution was stirred at 80° C. for 15 h. After cooling to ambient temperature, the reaction was quenched with 50 mL of water, then extracted with 3×50 mL of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to yield 150 mg (75%) of 5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclopropyl-4-ethylbenzohydrazide as a colorless oil.
Reaction SMILES: Cl.[NH2:2][OH:3].[C:4]([C:7]1[CH:8]=[C:9]([NH:13][C:14](=[O:37])[NH:15][CH2:16][C:17]([N:19]2[CH:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:29][CH2:28][CH:20]2[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:18])[CH:10]=[CH:11][CH:12]=1)(=O)[CH3:5]>O.CO.N1C=CC=CC=1>[OH:3]/[N:2]=[C:4](/[C:7]1[CH:8]=[C:9]([NH:13][C:14](=[O:37])[NH:15][CH2:16][C:17]([N:19]2[CH:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:29][CH2:28][CH:20]2[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:18])[CH:10]=[CH:11][CH:12]=1)\[CH3:5]
Reactant: CC(=O)c1cccc(NC(=O)NCC(=O)N2C(C(=O)OC(C)(C)C)CCC2c2ccccc2)c1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CO
Product: C/C(=N\O)c1cccc(NC(=O)NCC(=O)N2C(C(=O)OC(C)(C)C)CCC2c2ccccc2)c1
Yield: 35.5 %

Procedure:
0.5 g of hydroxylamine hydrochloride in solution in 6 cm3 of water is added to a solution of 3 g of tert-butyl (2RS,5SR)-1-{2-[3-(3-acetylphenyl)ureido]acetyl}-5-phenylprolinate in 12 cm3 of methanol and 6 cm3 of pyridine. The reaction mixture is heated under reflux for 2 hours. After evaporation of the solvents under reduced pressure at a temperature in the vicinity of 45° C., the residue is taken up in 100 cm3 of ethyl acetate and the organic phase is washed with 3 times 50 cm3 of water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure. The crude product obtained is purified by chromatography on silica [eluent: dichloromethane/methanol (95/5 by volume)]. The fractions containing the expected product are combined and concentrated to dryness under reduced pressure at a temperature in the vicinity of 40° C. After recrystallization in acetonitrile, 1.1 g of tert-butyl (E)-(2RS,5SR)-1-{2-{3-[3-(1-hydroxyiminoethyl)phenyl]ureido}acetyl}-5-phenylprolinate, melting at 118° C., are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4](I)[CH:3]=1.[C:10]1([C:16]#[CH:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[NH:8][C:16]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[CH:17]2
Reactant: C#Cc1ccccc1
Reactant: Nc1ccc(Br)cc1I
Product: Brc1ccc2[nH]c(-c3ccccc3)cc2c1
Yield: 60 %

Procedure:
The general procedure was used to convert 4-bromo-2-iodobenzenamine and phenylacetylene to the title product. Purification by flash chromatography gave the analytically pure product as a white solid, 60% yield. 1H NMR (300 MHz, DMSO) δ 11.77 (s, 1H), 7.88-7.85 (d, J=7.4, 2H), 7.72 (s, 1H), 7.50-7.45 (t, J=7.5, 2H), 7.39-7.35 (m, 2H), 7.23-7.20 (dd, J=8.5, 1.8, 1H), 6.89 (s, 1H). 13C NMR (75 MHz, DMSO) δ 139.06, 135.69, 131.54, 130.41, 128.88, 127.78, 125.09, 123.89, 122.04, 113.15, 111.78, 98.16. Anal. Calcd. for C14H10BrN: C, 61.79; H, 3.70; Br, 29.36; N, 5.15. Found C, 61.60; H, 3.74; N, 5.02.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:8])[CH2:6][CH3:7].[CH3:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:12]=1[OH:18]>C(Cl)Cl>[C:5]([O:18][C:12]1[C:13]([CH3:17])=[CH:14][C:15]([C:5](=[O:8])[CH2:6][CH3:7])=[CH:16][C:11]=1[CH3:10])(=[O:8])[CH2:6][CH3:7]
Reactant: CCC(=O)Cl
Reactant: Cc1cccc(C)c1O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCC(=O)Oc1c(C)cc(C(=O)CC)cc1C
Reaction time: 2 h
Yield: 170.5 %

Procedure:
To a mixture of aluminum chloride (32.0 g, 24 mmol) in methylene chloride (100 mL) was added propionyl chloride (3.56 mL, 40.95 mmol) all at once followed by 2,6-dimethylphenol (5.0 g, 40.93 mmol in 25 mL of methylene chloride) over 5 min. After stirring 1 h at ambient temperature a second equivalent of propionyl chloride was added (3.56 mL). The reaction was stirred 2 h more and then carefully quenched with water. The mixture was extracted with ether (3×) and the combined organic phase was washed with aqueous bicarbonate and brine; then it was dried over magnesium sulfate and concentrated to give 8.18 g (85%) of 2,6-dimethyl-4-propionylphenyl propionate as a waxy tan solid which had: NMR δ 7.68 (s, 2 H), 2.95 (q, J=7.3 Hz, 2 H), 2.65 (q, J=7.5 Hz, 2 H), 2.19 (s, 6 H), 1.32 (t, J=7.6 Hz, 3 H), 1.20 (t, J=7.3 Hz, 3 H). This product also contained some minor impurities in the NMR spectrum but was found suitable for use without further purification.
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.C([O-])([O-])=O.[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[NH4+].[Cl-]>CN(C=O)C.CCOCC>[CH2:17]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:10][CH:2]1[CH3:1])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC1Cc2ccccc2N1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC1Cc2ccccc2N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.5 %

Procedure:
To a solution of 1 g (7.5 mmol) of 2-methyl-2,3-dihydro-1H-indole in anhydrous DMF were added 1.03 g (7.5 mmol) of K2CO3 and then dropwise 0.97 mL (8.0 mmol) of benzylbromide. The mixture was stirred at RT for 3hrs and then distributed between Et2O and a saturated aqueous solution of NH4Cl. The combined organic phases were dried over Na2SO4 and evaporated to yield 1.7 g (quantitative) of crude 1-benzyl-2-methyl-2,3-dihydro-1H-indole, light blue oil, MS: 224 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:31](C)[C:32](=O)OC(C)(C)C)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:30])[C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:19][CH:18]=2)=[CH:11][N:10]=1>C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:3]=[C:4]([NH:31][CH3:32])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]([NH:15][C:16](=[O:30])[C:17]2[CH:18]=[CH:19][C:20]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:21][CH:22]=2)=[CH:13][CH:14]=1
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(Oc2ccc(NC(=O)c3ccc(Oc4ccccc4)cc3)cn2)c(F)c1
Solvent: O=C(O)C(F)(F)F
Product: CNc1ccc(Oc2ccc(NC(=O)c3ccc(Oc4ccccc4)cc3)cn2)c(F)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 67.5 %

Procedure:
tert-Butyl [3-fluoro-4-({5-[(4-phenoxybenzoyl)amino]pyridin-2-yl}oxy)phenyl]-methylcarbamate (0.53 g) was dissolved in TFA (4 mL) and stirred at room temperature for 5 min. The mixture was evaporated under reduced pressure and the residue was dissolved in AcOEt. Ice cold 5 M NaOH was added to adjust the pH to 12, and the mixture was extracted with AcOEt. The organic layer was washed with water and saturated aqueous NaCl, dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was dissolved in Et2O, and the solution was stirred for 1 day. The resulting precipitate was collected and washed with Et2O to give the title compound as a white powder (0.29 g).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:42])[N:5]([CH2:12][C:13]([O:15][C@H:16]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH:34]([F:36])[F:35])=[C:29]([O:37][CH2:38][CH:39]3[CH2:41][CH2:40]3)[CH:28]=1)[CH2:17][C:18]1[C:23]([Cl:24])=[CH:22][N+:21]([O-:25])=[CH:20][C:19]=1[Cl:26])=[O:14])[C:6]2=[O:11].[CH3:43][O:44][CH2:45][C:46](Cl)=[O:47]>CN(C=O)C.CN(C1C=CN=CC=1)C>[Cl:24][C:23]1[CH:22]=[N+:21]([O-:25])[CH:20]=[C:19]([Cl:26])[C:18]=1[CH2:17][C@@H:16]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH:34]([F:35])[F:36])=[C:29]([O:37][CH2:38][CH:39]2[CH2:40][CH2:41]2)[CH:28]=1)[O:15][C:13](=[O:14])[CH2:12][N:5]1[C:4](=[O:42])[C:3]2[C:7](=[CH:8][CH:9]=[CH:10][C:2]=2[NH:1][C:46](=[O:47])[CH2:45][O:44][CH3:43])[C:6]1=[O:11]
Reactant: Nc1cccc2c1C(=O)N(CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC3CC3)c1)C2=O
Reactant: COCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: COCC(=O)Nc1cccc2c1C(=O)N(CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC3CC3)c1)C2=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 67.5 %

Procedure:
(S)-4-(2-(2-(4-amino-1,3-dioxoisoindolin-2-yl)acetoxy)-2-(3-(cyclopropylmethoxy)-4 (difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (20.0 mg; 0.032 mmol) was dissolved in DMF (2 ml) and cooled down to 0° C. in a ice bath. 2-methoxyacetyl chloride (20.0 mg; 0.184 mmol) and DMAP (0.048 mmol; 5.89 mg) were added to the reaction solution that was stirred a 0° C. for 2 hours. After that time, the reaction was quenched with aqueous HCl (1M) (20 ml) and extracted with EtOAc (20 ml). The organic phase was further washed with HCl (1M) (3×20 ml), dried over Na2SO4 and the solvent removed under reduced pressure to afford the titled compound (15.0 mg; 67% yield). 1H NMR (400 MHz, acetone) δ ppm 10.33-10.47 (m, 1H), 8.80-8.93 (m, 1H), 8.22 (s, 2H), 7.83-7.95 (m, 1H), 7.57-7.67 (m, 1H), 7.16-7.24 (m, 2H), 7.04-7.11 (m, 1H), 6.94 (t, J=75.00 Hz, 1H), 6.13-6.22 (m, 1H), 4.46 (s, 2H), 4.14 (d, J=3.09 Hz, 2H), 3.91-4.06 (m, 2H), 3.65 (s, 3H), 3.49-3.58 (m, 1H), 3.26-3.38 (m, 1H), 1.17-1.39 (m, 1H), 0.54-0.69 (m, 2H), 0.36-0.48 (m, 2H). MS/ESI+ [MH]+=694.1.
Reaction SMILES: [H-].[Na+].FC(F)(F)[C:5]([NH:7][S:8]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH2:15][CH2:14]2)(=[O:10])=[O:9])=O.C[N:23]([CH3:26])[CH:24]=[O:25]>>[C:11]1([C@H:26]2[CH2:5][N:7]([S:8]([C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[NH:16][CH2:15][CH2:14]4)(=[O:10])=[O:9])[C:24](=[O:25])[NH:23]2)[CH:12]=[CH:13][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(NS(=O)(=O)c1ccc2c(c1)CCN2)C(F)(F)F
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: O=C1N[C@@H](c2ccccc2)CN1S(=O)(=O)c1ccc2c(c1)CCN2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 68 %

Procedure:
Sodium hydride (60% oily, 475 mg, 11.88 mmol) was suspended in 15 ml of dimethylformamide and cooled down to 0° C. To the suspension was added N-trifluoroacetyl-indoline-5-sulfonamide (0.832 g, 2.97 mmol) prepared in Preparation 7 in several portions, and then the mixture was stirred at 0° C. for 10 min. Then, (S)-2-N-phenoxycarbonylamino-2-phenylethylmethanesulfonate (1.0 g, 2.97 mmol) prepared in Preparation 6 was added thereto. The reaction mixture was stirred at 0° C. for 3 hours and further stirred at room temperature for 1 hour. After confirming the completion of reaction by TLC, the reaction mixture was poured into 30 ml of ice. The resulting precipitate was collected and dried to afford 0.72 g of the title compound.
Reaction SMILES: [OH:1][CH:2]1[CH2:9][N:8]2[C:4](=[N:5][C:6]3[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:7]=32)[CH2:3]1.[H-].[Na+].S(OC)(O[CH3:23])(=O)=O>O1CCCC1.O>[CH3:23][O:1][CH:2]1[CH2:9][N:8]2[C:4](=[N:5][C:6]3[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:7]=32)[CH2:3]1
Reactant: COS(=O)(=O)OC
Reactant: O=[N+]([O-])c1ccc2c(c1)nc1n2CC(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC1Cc2nc3cc([N+](=O)[O-])ccc3n2C1
Yield: 23.4 %

Procedure:
A solution of 0.28 g (1.28 mmol) of 2,3-dihydro-2-hydroxy-6-nitro-1H-pyrrolo[1,2-a]benzimidazole (step IX-2 of Example IX) in 5 ml of tetrahydrofuran is added to a suspension, stirred under argon at 20° C., of 0.2 g (5 mmol) of sodium hydride at 60% in 10 ml of tetrahydrofuran. After stirring for fifteen minutes, 0.24 ml (2.5 mmol) of dimethyl sulphate is added. The reaction mixture is stirred at 20° C. for 12 hours and then poured in 100 ml of water and extracted three times with 50 ml of ethyl acetate. The organic phases are combined, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulphate and concentrated under reduced pressure. The residue obtained is purified by silica column chromatography, elution being carried out with a mixture of dichloromethane and methanol. 70 mg of the expected product are thus isolated in the form of a foam.