Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([Cl:32])[C:5]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:23][C@H:22]([CH2:24][O:25][CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][O:27]4)[C@@H:14]([O:15][CH:16]4[CH2:21][CH2:20][CH2:19][CH2:18][O:17]4)[C@@H:12]3O)[C:6]=2[N:7]=1.C(N(S(F)(F)[F:39])CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.N1C=CC=CC=1>[NH2:1][C:2]1[N:3]=[C:4]([Cl:32])[C:5]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:23][C@H:22]([CH2:24][O:25][CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][O:27]4)[C@@H:14]([O:15][CH:16]4[CH2:21][CH2:20][CH2:19][CH2:18][O:17]4)[C@H:12]3[F:39])[C:6]=2[N:7]=1
Reactant: Nc1nc(Cl)c2ccn([C@@H]3O[C@H](COC4CCCCO4)[C@@H](OC4CCCCO4)[C@@H]3O)c2n1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Nc1nc(Cl)c2ccn([C@@H]3O[C@H](COC4CCCCO4)[C@@H](OC4CCCCO4)[C@H]3F)c2n1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of the compound from Step G (0.24 g, 0.51 mmol) in CH2Cl2 (5 mL) and pyridine (0.8 mL) at −60° C. was added diethylaminosulfur trifluoride (DAST; 0.27 mL) dropwise under Ar. The solution was stirred at −60° C. for 0.5 h, at 0° C. overnight and at room temperature for 3h. The mixture was diluted with CH2Cl2 (25 mL) and poured into saturated aqueous NaHCO3 (15 mL). The organic layer was washed with water (10 mL), dried (Na2SO4) and evaporated. The residue was purified on a silica gel column with a solvent system of hexanes/EtOAc: 5/1 to give the title compound (45 mg) as a pale yellow foam.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:52]([CH3:54])[CH3:53])[C:7]([N:9]1[CH2:13][C@@H:12]([CH2:14][O:15][CH3:16])[CH2:11][C@H:10]1[C:17]1[NH:18][C:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]4[NH:38][C:37]([C@@H:39]5[CH2:43][C@H:42]([CH3:44])[CH2:41][N:40]5C(OC(C)(C)C)=O)=[N:36][CH:35]=4)=[CH:30][CH:29]=3)=[CH:24][CH:23]=2)=[CH:20][N:21]=1)=[O:8])=[O:4].Cl.[C:56]([O:60][C:61]([NH:63][C@H:64]([C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1)[C:65]([OH:67])=O)=[O:62])([CH3:59])([CH3:58])[CH3:57].CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O.CN(C=O)C.CO>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:52]([CH3:54])[CH3:53])[C:7]([N:9]1[CH2:13][C@@H:12]([CH2:14][O:15][CH3:16])[CH2:11][C@H:10]1[C:17]1[NH:18][C:19]([C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]4[NH:38][C:37]([C@@H:39]5[CH2:43][C@H:42]([CH3:44])[CH2:41][N:40]5[C:65](=[O:67])[C@H:64]([NH:63][C:61](=[O:62])[O:60][C:56]([CH3:57])([CH3:58])[CH3:59])[C:68]5[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=5)=[N:36][CH:35]=4)=[CH:30][CH:29]=3)=[CH:26][CH:27]=2)=[CH:20][N:21]=1)=[O:8])=[O:4]
Reactant: COC[C@H]1C[C@@H](c2ncc(-c3ccc(-c4ccc(-c5cnc([C@@H]6C[C@H](C)CN6C(=O)OC(C)(C)C)[nH]5)cc4)cc3)[nH]2)N(C(=O)[C@@H](NC(=O)OC)C(C)C)C1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccccc1
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COC[C@H]1C[C@@H](c2ncc(-c3ccc(-c4ccc(-c5cnc([C@@H]6C[C@H](C)CN6C(=O)[C@H](NC(=O)OC(C)(C)C)c6ccccc6)[nH]5)cc4)cc3)[nH]2)N(C(=O)[C@@H](NC(=O)OC)C(C)C)C1
Reaction time: 2 h
Yield: 73.7 %

Procedure:
(2S,4S)-tert-butyl 2-(5-(4′-(2-((2S,4S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate (342 mg, 0.46 mmol) was dissolved in DCM (4 mL), MeOH (1 mL) and HCl (4 M in dioxane, 1 mL) was added. The reaction mixture was stirred over night and then concentrated under reduced pressure. The crude residue was treated with (R)-2-(tert-butoxycarbonylamino)-2-phenylacetic acid (116 mg, 0.46 mmol), COMU (220 mg, 0.64 mmol) and DMF (5 mL), then DIPEA (0.4 mL, 2.31 mmol) was added dropwise. After 2 h, the mixture was diluted with EtOAc and washed successively with saturated aqueous NaHCO3 and brine. The organics were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (0% to 30% MeOH/EtOAc) to afford tert-butyl (R)-2-((2S,4S)-2-(5-(4′-(2-((2S,4S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)-4-methylpyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate (296 mg, 74%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Si](C=[N+]=[N-])(C)(C)[CH3:16].C(O)(=O)C>C(Cl)Cl.CO>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C:12]([O:14][CH3:16])=[O:13])=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CS(=O)(=O)c1ccc(CC(=O)O)cc1
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)Cc1ccc(S(C)(=O)=O)cc1
Reaction time: 0.25 h

Procedure:
Combined 2-(4-(methylsulfonyl)phenyl)acetic acid (1 g, 4.67 mmol) in DCM (15 mL) and MeOH (5 mL) and slowly added TMS-diazomethane (2 M in hexanes) (3.50 mL, 7.00 mmol) and the solution was stirred at 20° C. for 3 h. The reaction was quenched with acetic acid (0.134 mL, 2.334 mmol), let stir for 15 min, then concentrated in vacuo to give the title compound which was used without further purification. MS m/z 229 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[C:12](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:12][C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:5][CH2:6][C:2]1=[O:1]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C1CCCC1=O
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CCOC(=O)C1(C)CCCC1=O
Yield: 99.4 %

Procedure:
Under vigorously agitation, 20.3 g of ethyl 2-oxocyclopentane carboxylate was added to 53.8 g of fine powdery anhydrous potassium carbonate, and after stirring for several minutes, to the mixture was added 90 ml of acetone. The reaction mixture was further stirred for 15 to 30 minutes at room temperature, then to the mixture was dropwise added 36.9 g of methyl iodide. Upon the completion of the addition, the reaction mixture was heated for reflux for 1 hour. The solvent was removed under reduced pressure, and the solid residue was washed with diethyl ether. The washing liquor was collected and washed with water. After removing the solvent, 22.0 g of pale yellow liquid was obtained. The liquid was distilled under reduced pressure, and 20.9 g of colorless liquid as a distillate cut of 131-133° C./39 mmHg was collected. Yield: 94.6%.
Reaction SMILES: S=[C:2]1[CH2:6][S:5][C:4](=[O:7])[NH:3]1.[CH3:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH2:15]>C(O)C>[CH3:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH:15][C:2]1[CH2:6][S:5][C:4](=[O:7])[N:3]=1
Reactant: O=C1NC(=S)CS1
Reactant: COCCOCCN
Solvent: CCO
Product: COCCOCCNC1=NC(=O)SC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 84.4 %

Procedure:
To a solution of 4-thioxo-1,3-thiazolidin-2-one (2.24 g) in ethanol (20 mL) was added 2-(2-methoxyethoxy)ethanamine (2.5 g), and the mixture was stirred at room temperature for 5 hr. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (3.1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:23][CH2:24][C:25]#[CH:26])[C:9]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([O:21][CH3:22])[CH:15]=2)=[O:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:33](Cl)[C:34]#[CH:35].O>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:23][CH2:24][C:25]#[CH:26])[C:9]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:35][C:34]#[CH:33])=[C:16]([O:21][CH3:22])[CH:15]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: C#CCCl
Reactant: C#CCOC(C(=O)NCCc1ccc(O)c(OC)c1)c1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: O
Solvent: Cc1ccccc1
Product: C#CCOc1ccc(CCNC(=O)C(OCC#C)c2ccc(Cl)cc2)cc1OC
Temperature: 90 °C
Yield: 76.5 %

Procedure:
To a solution of 1 mol 2-(4-Chloro-phenyl)-N-[2-(4-hydroxy-3-methoxy-phenyl)-ethyl]-2-prop-2-ynyloxyacetamide in 500 ml toluene, 207 g potassium carbonate (1.5 mole) and 10 g tetrabutylammonium bromide are added. The mixture is heated to 90° C. and 1.4 mole propargyl chloride as a 35% solution in toluene is added over 30 minutes. After 3 hours the conversion of 2-(4-Chloro-phenyl)-N-[2-(4-hydroxy-3-methoxy-phenyl)-ethyl]-2-prop-2-ynyloxyacetamide is complete. To dissolve the salts 500 ml water are added and separated from the toluene product phase. The toluene is completely evaporated at 80° C./20 mbar and replaced by methanol. The product 2-(4-Chloro-phenyl)-N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-2-prop-2-ynyloxyacetamide is crystallized from solution by cooling down to 0° C., filtered and washed with 200 ml methanol of 0° C. The product is dried at 50° C. under vacuum. 315 g of 2-(4-Chloro-phenyl)-N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-2-prop-2-ynyloxyacetamide are obtained with a LC purity of 98%. Melting point=94-96° C.
Reaction SMILES: O[CH2:2][CH:3]1[N:9]2[C:10](=[O:13])[O:11][N:12]=[C:8]2[CH2:7][CH2:6][CH2:5][CH2:4]1.C(Br)(Br)(Br)[Br:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:15][CH2:2][CH:3]1[N:9]2[C:10](=[O:13])[O:11][N:12]=[C:8]2[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: BrC(Br)(Br)Br
Reactant: O=c1onc2n1C(CO)CCCC2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=c1onc2n1C(CBr)CCCC2
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of the product of Example 5 in dichloromethane was added carbon tetrabromide (460 mg, 1.3 mmol). This solution was cooled in an ice bath and stirred for 5 minutes. Triphenylphosphine (437 mg, 1.6 mmol) was added to the solution and stirring was continued for 5 minutes at 0° C. before allowing it to warm slowly to room temperature. The solvent was removed under reduced pressure. The residue was placed on a filter and washed three times with ether. The filtrate solvent was then removed under reduced pressure to yield the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([Cl:19])[C:16]=3[F:18])[C:11]([S:20][C:21]3[C:22]([F:32])=[C:23]([CH:29]=[CH:30][CH:31]=3)[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:10]2[CH:33]2[CH2:35][CH2:34]2)[CH:6]=[N:5]1.CCN(CC)CC.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[N-:55]=[C:56]=[O:57].N>C1COCC1.O>[Cl:19][C:15]1[C:16]([F:18])=[C:17]2[C:12]([C:11]([S:20][C:21]3[C:22]([F:32])=[C:23]([CH:29]=[CH:30][CH:31]=3)[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:10]([CH:33]3[CH2:35][CH2:34]3)[N:9]2[C:7]2[CH:6]=[N:5][N:4]([CH2:3][CH2:2][NH:1][C:56]([NH2:55])=[O:57])[CH:8]=2)=[CH:13][CH:14]=1
Reactant: [N-]=C=O
Reactant: CCOC(=O)c1cccc(Sc2c(C3CC3)n(-c3cnn(CCN)c3)c3c(F)c(Cl)ccc23)c1F
Agent: N
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)c1cccc(Sc2c(C3CC3)n(-c3cnn(CCNC(N)=O)c3)c3c(F)c(Cl)ccc23)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
To a stirred solution of indole 1 (Example 14, Step 2; 80 mg, 0.15 mmol) in THF (5 mL) under inert atmosphere were added Et3N (0.04 mL, 0.31 mmol) and triphosgene (18.3 mg, 0.06 mmol) at 0° C., stirred for 1 h, warmed to RT and stirred for 2 h. To this solution of crude isocyanate was passed ammonia gas at −78° C. for 10 min; warmed to 0° C. and stirred for 1 hr. The mixture was diluted with water and extracted with EtOAc (2×20 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to obtain the crude. This was purified by triturating with Et2O (2×5 mL) and dried under reduced pressure to afford 2 (30 mg, 34%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.19 (s, 1H), 7.82 (s, 1H), 7.60 (t, J=7.2 Hz, 1H), 7.22-7.11 (m, 3H), 6.84 (t, J=7.2 Hz, 1H), 6.04-6.03 (m, 1H), 5.53 (br s, 2H), 4.33 (q, 2H), 4.21 (t, J=6.0 Hz, 2H), 3.43 (t, J=6.0 Hz, 2H), 1.84-1.78 (m, 1H), 1.32 (t, J=7.2 Hz, 3H), 0.92-0.91 (m, 2H), 0.87-0.85 (m, 2H); MS: m/z 560.6 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[CH2:4][CH2:3]1.C(O[CH:17](OCC)[N:18]([CH3:20])[CH3:19])C>>[CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[C:4](=[CH:17][N:18]([CH3:20])[CH3:19])[CH2:3]1
Reactant: CC1(C)CCC(=O)c2ccccc21
Reactant: CCOC(OCC)N(C)C
Product: CN(C)C=C1CC(C)(C)c2ccccc2C1=O

Procedure:
The 3,4-dihydro-4,4-dimethyl-2-(dimethylaminomethylene)-1-(2H)-naphthalenone starting material was prepared from 4,4-dimethyl-1-tetralone (3.48 g, 20 mmol) and N,N-dimethylformamide diethyl acetal (10.5 ml, 60 mmol) to give the desired compund as bright yellkow crystals (3.53 g). δH (CDCl3) 8.05 (1H, ddd, J 7.7, 1.5, 0.5 Hz), 7.78 (1H, s), 7.42 (1H, m), 7.33-7.25 (2H,m), 3.12 (6H, s), 2.80 (2H, s) and 1.33 (6H, s).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH2:12]([C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1)[CH3:13]>>[CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:18][C:17]2[CH:19]=[CH:20][C:14]([CH2:12][CH3:13])=[CH:15][CH:16]=2)=[CH:5][CH:4]=1
Reactant: CCc1ccc(N)cc1
Reactant: CN(C)c1ccc(C=O)cc1
Product: CCc1ccc(NCc2ccc(N(C)C)cc2)cc1
Yield: 62.8 %

Procedure:
By the reaction and treatment in the same manner as in Preparation Example 1 using 4-dimethylaminobenzaldehyde (10 g) and 4-ethylaniline (8.12 g) as starting materials, [(4-dimethylaminophenyl)methyl](4-ethylphenyl)amine (10.7 g) was obtained. melting point: 64–66° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C@H:12]([NH:26]C(OCC1C=CC=CC=1)=O)[C:13](=[O:25])[NH:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2)([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O.CO.[Pd]>[C:1]([O:5][C:6](=[O:37])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C@H:12]([NH2:26])[C:13](=[O:25])[NH:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)Nc1ccc2ncccc2c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CCCCC[C@H](N)C(=O)Nc1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirring solution of (7S)-7-benzyloxycarbonylamino-7-(quinolin-6-ylcarbamoyl)-heptanoic acid tert-butyl ester (11.0 g, 21.8 mmol) in EtOAc and MeOH was added 10% Pd/C. The reaction was charged with H2, degassed and refilled with hydrogen three times. The slurry was stirred at RT for 2 h at balloon pressure, then filtered through a plug of Celite, and solvent was removed under reduced pressure. The hydrogenolysis of the ester yielded 8.0 g (99%) of a thick oil solid after 19 h. 1H NMR (CDCl3) δ 8.9–7.3 (7H, m), 3.96 (1H, m), 2.31 (2H, t), 2.0–1.2 (17H, m). MS (ESI): (MH+) 372.2.
Reaction SMILES: [CH3:1][N:2]([CH2:17][C@H:18]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=1)[CH2:19][CH:20]=C)[C:3](=[O:16])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1.C[N+]1([O-])CC[O:34]CC1.S([O-])([O-])(=O)=S.[Na+].[Na+].I([O-])(=O)(=O)=O.[Na+]>[Os](=O)(=O)(=O)=O.CO.ClCCl.O1CCCC1.O.CC(C)=O.C(O)(C)(C)C.O>[CH3:1][N:2]([CH2:17][C@H:18]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=1)[CH2:19][CH:20]=[O:34])[C:3](=[O:16])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CC[C@H](CN(C)C(=O)c1cc(OC)c(OC)c(OC)c1)c1ccc(Cl)c(Cl)c1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Solvent: CC(C)=O
Product: COc1cc(C(=O)N(C)C[C@@H](CC=O)c2ccc(Cl)c(Cl)c2)cc(OC)c1OC
Reaction time: 2 h

Procedure:
Combine (S)-N-methyl-N-(2-(3,4-dichlorophenyl)pent-4-enyl)-3,4,5-trimethoxybenzamide (1.39 g, 3.17 mmol), acetone/t-butanol/water (2/1/1, 32 mL), and a solution of N-methylmorpholine N-oxide (0.89 g 50% in water, 1.2). Add a solution of osmium tetraoxide (1.2 g, 4% in water, 0.06 mmol). After 2 hours, evaporate in vacuo to remove most of the acetone and partition the evaporated reaction mixture between dichloromethane and an aqueous 10% solution of sodium thiosulfate. Separate the layers, extract the organic layer with brine, dry over MgSO4, filter, and evaporate in vacuo to give a residue: Rf=0.26 (sliica gel, 6% methanol/dichloromethane). Combine the residue and tetrahydrofuran/water (4/1 40 mL). Add sodium meta-periodate (0.81 g, 3.8 mmol). After 1.5 hours, filter the reaction mixture, rinse the solids with tetrahydrofuran, and evaporate the filtrate to remove most of the tetrahydrofuran. Dilute the evaporated reaction mixture with dichlromethane. Extract with water, dry over MgSO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 1% methanol/dichloromethane to give the title compound.
Reaction SMILES: C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH2:36]([O:43][C:44]1[CH:45]=[CH:46][CH:47]=[C:48]2[C:52]=1[NH:51][C:50]([C:53]([NH:55][CH2:56][CH2:57][S:58]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=O)=[CH:49]2)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>ClCCl>[CH2:36]([O:43][C:44]1[CH:45]=[CH:46][CH:47]=[C:48]2[C:52]=1[NH:51][C:50]([C:53]1[S:58][CH2:57][CH2:56][N:55]=1)=[CH:49]2)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1)c1cc2cccc(OCc3ccccc3)c2[nH]1
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(COc2cccc3cc(C4=NCCS4)[nH]c23)cc1
Reaction time: 0.17 h
Yield: 26.5 %

Procedure:
To a solution of triphenylphosphine oxide (4.70 g) in dichloromethane (20 mL) was slowly added trifluoromethanesulfonic anhydride (1.42 mL) at 0° C. The mixture was stirred for 10 min, and 7-(benzyloxy)-N-[2-(tritylthio)ethyl]-1H-indole-2-carboxamide (1.60 g) was added. The reaction mixture was stirred at room temperature for 3 hr and concentrated. Saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography and the title compound (0.23 g, yield 27%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:20→1:2, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point 129-130° C.
Reaction SMILES: [N:1]1([C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:24][C:25]3[C:30]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:29][N:28]=[C:27]([N:36]([CH2:39][CH3:40])[CH2:37][CH3:38])[N:26]=3)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:11][CH:10]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[CH2:47](Cl)[C:48]#[CH:49]>CC(C)=O>[N:1]1([C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:24][C:25]3[C:30]([N:31]([CH2:49][C:48]#[CH:47])[S:32]([CH3:35])(=[O:34])=[O:33])=[CH:29][N:28]=[C:27]([N:36]([CH2:37][CH3:38])[CH2:39][CH3:40])[N:26]=3)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:11][CH:10]=2)=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C#CCCl
Reactant: CCN(CC)c1ncc(NS(C)(=O)=O)c(N[C@@H](Cc2ccc(OC(=O)N3CCCC3)cc2)C(=O)OC(C)(C)C)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCN(c1cnc(N(CC)CC)nc1N[C@@H](Cc1ccc(OC(=O)N2CCCC2)cc1)C(=O)OC(C)(C)C)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.1 %

Procedure:
Compound 11 (0.20 g, 0.35 mmol), K2CO3 (0.073 g, 0.53 mmol), and acetone (3 mL) were placed in a sealed tube and stirred at room temperature for one hour. Propargyl chloride (0.26 mL, 3.5 mmol) was added and the reaction was sealed and heated at reflux for 48 hours. The reaction mixture was concentrated in vacuo and the residue taken up in ethyl acetate. The solution was washed with water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to yield crude product as an orange film. The residue was purified by flash chromatography (1:1 ethyl acetate/hexanes) to yield 0.11 g (51%) of compound 12 as a transparent film.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:3]=1[C:4](Cl)=[N:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([Cl:12])[C:7]=1F.NC(N)=[S:22].N1C=CC=CC=1.C(N(CC)CC)C>C(O)(C)C>[Cl:12][C:8]1[C:7]2[S:22][C:4]([C:3]3[C:15]([F:19])=[CH:16][CH:17]=[CH:18][C:2]=3[Cl:1])=[N:5][C:6]=2[CH:11]=[CH:10][N:9]=1
Reactant: NC(N)=S
Reactant: Fc1cccc(Cl)c1C(Cl)=Nc1ccnc(Cl)c1F
Solvent: CC(C)O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: Fc1cccc(Cl)c1-c1nc2ccnc(Cl)c2s1
Temperature: 25 °C
Yield: 86.9 %

Procedure:
A mixture of 2-chloro-N-(2-chloro-3-fluoro-pyridin-4-yl)-6-fluorobenzimidoyl chloride (80 mg, 0.25 mmol), thiourea (76 mg, 1.0 mmol) and pyridine (82 μL, 1.0 mmol) in anhydrous isopropanol (1.5 mL) was heated under reflux, under nitrogen, for 3.5 hours. The reaction mixture was allowed to cool to ambient temperature and then triethylamine (1 mL) was added. The resultant mixture was heated under reflux for a further 1 hour then cooled to ambient temperature. The mixture was concentrated to dryness under reduced pressure and the residue was triturated with DCM, filtered and left to air dry. The crude product was purified by silica gel flash chromatography (0-10% EtOAc in cyclohexane) to give the desired compound as a white solid (65 mg, 86% yield). 1H NMR (400 MHz, CDCl3): δ 8.52 (d, J=5.6 Hz, 1H), 7.99 (d, J=5.6 Hz, 1H), 7.50 (td, J=8.3, 5.8 Hz, 1H), 7.41 (dt, J=8.2, 1.1 Hz, 1H), 7.21 (ddd, J=9.0, 8.4, 1.1 Hz, 1H). LCMS (Method C): RT=3.90 min, m/z: 299 [M+H+].
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:34])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([N:21]3[CH2:29][C:28]4[C:23](=[CH:24][CH:25]=[C:26]([S:30]([NH2:33])(=[O:32])=[O:31])[CH:27]=4)[CH2:22]3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH2:35]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)[CH2:36][CH2:37][CH3:38]>>[CH2:35]([N:39]1[CH2:44][CH2:43][N:42]([C:1](=[NH:2])[C:3]2[CH:4]=[C:5]([NH:9][C:10](=[O:34])[NH:11][C:12]3[CH:17]=[CH:16][C:15]([S:18]([N:21]4[CH2:29][C:28]5[C:23](=[CH:24][CH:25]=[C:26]([S:30]([NH2:33])(=[O:32])=[O:31])[CH:27]=5)[CH2:22]4)(=[O:20])=[O:19])=[CH:14][CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[CH2:41][CH2:40]1)[CH2:36][CH2:37][CH3:38]
Reactant: CCCCN1CCNCC1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)N3Cc4ccc(S(N)(=O)=O)cc4C3)cc2)c1
Product: CCCCN1CCN(C(=N)c2cccc(NC(=O)Nc3ccc(S(=O)(=O)N4Cc5ccc(S(N)(=O)=O)cc5C4)cc3)c2)CC1
Yield: 12 %

Procedure:
The title compound was prepared from 2-(4-(3-(3-cyanophenyl)ureido)phenylsulfonyl)isoindoline-5-sulfonamide following procedure C and using 3 equivalents of n-butylpiperazine as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: [CH3:1][CH:2]1[O:10][C:5]2([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])[O:6][CH:7]([CH3:9])[CH2:8][N:4]2[CH2:3]1.C(N(CC)CC)C.[C:24](Cl)(=[O:28])[C:25]([CH3:27])=[CH2:26]>C(Cl)(Cl)Cl>[CH3:1][CH:2]1[O:10][C:5]2([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:24](=[O:28])[C:25]([CH3:27])=[CH2:26])[O:6][CH:7]([CH3:9])[CH2:8][N:4]2[CH2:3]1
Reactant: C=C(C)C(=O)Cl
Reactant: CC1CN2CC(C)OC2(CCCCCO)O1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C=C(C)C(=O)OCCCCCC12OC(C)CN1CC(C)O2
Temperature: 0 °C
Yield: 462 %

Procedure:
In an oven dried 100 mL round-bottom flask equipped with a pressure equalizing addition funnel and a reflux condenser were added 5-(2,6-Dimethyl-tetrahydro-oxazolo[2,3-b]oxazol-7a-yl)-pentan-1-ol (22.9 g, 0.01 mol) followed by chloroform 50 mL and triethylamine 12.12 g, 0.12 mol). The reaction content was cooled to 0° C. under nitrogen. While stirring a solution of methacryloyl chloride (11.44 g, 0.11 mol) in chloroform was added slowly. After completion of the acid chloride the reaction was stirred one hour at 0° C., then allowed to warmed to room temperature and then stirred over night at room temperature. The triethylamine salt was filter off through Celite® (World Minerals, Santa Barbara, Calif.), the filtrate concentrate at reduced pressure. NMR (proton) showed this material to be the desired material contaminated with triethyl amine salt. This material was then washed with hexanes (2×125 ml), the hexanes washes combined concentrated giving 13.74 g of product.