Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]=[C:10]=S.C([O:14][C:15](=[O:24])[C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([NH2:23])[CH:17]=1)C.CC(C)N=C=NC(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:22][C:19]2[CH:20]=[CH:21][C:16]([C:15]([OH:24])=[O:14])=[CH:17][C:18]=2[N:23]=1
Reactant: S=C=Nc1c(Cl)cccc1Cl
Reactant: CCOC(=O)c1ccc(N)c(N)c1
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1ccc2[nH]c(Nc3c(Cl)cccc3Cl)nc2c1
Reaction time: 2 h

Procedure:
A mixture of 1,3-dichloro-2-isothiocyanato-benzene (5.66 g, 27.8 mmol) and 3,4-diamino-benzoic acid ethyl ester (5.00 g, 27.8 mmol) in 40 mL DMF was stirred for 2 h. DIC (4.40 mL, 28.2 mmol) was added and stirred overnight at ambient temperature. The mixture was stirred for 30 min at 80° C., diluted with water and concentrated i.vac. The residue was taken up in ethanol and 60 mL 1 M aq. NaOH was added and stirred overnight at reflux. Ethanol was evaporated and the aq. phase was filtered. The filtrate was acidified with formic acid, cooled, filtered and dried.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@H:16]([OH:17])[C@@H:15]([CH2:18][O:19][C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:14][C@H:11]([O:12][CH3:13])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:39]1([CH3:49])[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[CH:41][CH:40]=1>N1C=CC=CC=1>[CH2:1]([O:8][C@@H:9]1[C@H:16]([O:17][S:45]([C:42]2[CH:43]=[CH:44][C:39]([CH3:49])=[CH:40][CH:41]=2)(=[O:47])=[O:46])[C@@H:15]([CH2:18][O:19][C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[O:14][C@H:11]([O:12][CH3:13])[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CO[C@@H]1C[C@H](OCc2ccccc2)[C@H](O)[C@@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)O1
Solvent: c1ccncc1
Product: CO[C@@H]1C[C@H](OCc2ccccc2)[C@H](OS(=O)(=O)c2ccc(C)cc2)[C@@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
Methyl 3-O-benzyl-6-O-trityl-2-deoxy-α-D-ribo-hexopyranoside (13.3 g; 26.05 mmoles) was dissolved in dry pyridine (41 ml) and cooled in an ice bath under nitrogen. p-Toluenesulfonyl chloride (9.93 g, 52.09 mmoles) was added all at once and the reaction was stirred at room temperature under nitrogen overnight. The reaction was partitioned between ether and water. The ether layer was extracted four times with water, dried (K2CO3, anhyd), and the solvent evaporated in veluting with methylene chloride until excess p-toluenesulfonyl chloride had been eluted. Elution was continued with 2% (by volume) acetone in methylene chloride. Fractions containing the product were collected and evaporated to dryness to leave 15.5 g of methyl 3-O-benzyl-4-O-tosyl-6-O-trityl-2-deoxy-α-D-ribo-hexopyranoside as a glassy gum, [α]D25 =66.24 (C, 1.0, CHCL3)
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.[CH3:10][S:11]([NH2:14])(=[O:13])=[O:12].N12CCCN=C1CCCCC2>O1CCCC1>[Br:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:14][S:11]([CH3:10])(=[O:13])=[O:12])=[O:9])[N:6]=1
Reactant: O=C(O)c1csc(Br)n1
Reactant: CS(N)(=O)=O
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CS(=O)(=O)NC(=O)c1csc(Br)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.1 %

Procedure:
2-Bromo-1,3-thiazole-4-carboxylic acid (0.8 g, 3.85 mmol) was initially charged in tetrahydrofuran (10 ml). N,N′-Carbonyldiimidazole (0.94 g, 5.77 mmol) was added and the reaction mixture was heated under reflux for 1 h. Methanesulphonamide (0.55 g, 5.77 mmol) was added and, after 10 min, 1,8-diazabicyclo[5.4.0]undec-7-ene (0.88 g, 5.77 mmol). The reaction mixture was stirred at room temperature for 16 h and then the solvent was removed under reduced pressure. The residue was taken up in water and acidified with hydrochloric acid. The precipitated product was filtered off with suction. The aqueous phase was extracted with dichloromethane; the organic phase was dried over sodium sulphate and filtered, and the solvent was removed under reduced pressure. This gave a total of 1.0 g (89% of theory) of 2-bromo-N-(methylsulphonyl)-1,3-thiazole-4-carboxamide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:15](N)([NH2:18])(=[O:17])=[O:16]>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([S:15](=[O:17])(=[O:16])[NH2:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: NS(N)(=O)=O
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCCN(S(N)(=O)=O)CC1

Procedure:
To a solution of 1,4-Diazepane-1-carboxylic acid tert-butyl ester (3.16 g) in dioxane (40 ml) was added sulfamide (4.0 g) and the reaction mixture was then heated at reflux for 18 h. The reaction mixture was then reduced in vacuo and the residue partitioned between EtOAc (100 ml) and H2O (100 ml). The organics were separated and the aqueous layer was re-extracted with EtOAc (2×100 ml). Organics were combined, dried (MgSO4) and reduced in vacuo to give the subtitle compound as a white solid. Yield: 4.27 g
Reaction SMILES: C(OC([N:6]1[CH2:10][CH2:9][CH:8]([C:11]2[C:15]3[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=3[O:13][N:12]=2)[CH2:7]1)=O)=C.[ClH:21]>C(O)(C)C>[ClH:21].[F:20][C:18]1[CH:17]=[CH:16][C:15]2[C:11]([CH:8]3[CH2:9][CH2:10][NH:6][CH2:7]3)=[N:12][O:13][C:14]=2[CH:19]=1
Reactant: C=COC(=O)N1CCC(c2noc3cc(F)ccc23)C1
Agent: Cl
Solvent: CC(C)O
Product: Fc1ccc2c(C3CCNC3)noc2c1
Temperature: 0 °C

Procedure:
A mixture of 3-(6-fluoro-1,2-benzisoxazol-3-yl)-1-pyrrolidinylcarboxylic acid ethenyl ester (5.1 g, 18.4 mmol, hydrochloric acid (5 ml), and isopropyl alcohol (50 ml) was heated at reflux for 3.5 hours. At the end of the reaction, the solvent was reduced to about 30 ml on a rotary evaporator and the mixture was cooled to 0° C. for 2 hours. The crystals were collected by filtration and rinsed with cold isopropyl alcohol. The 6-fluoro-3-(3-pyrrolidinyl)-1,2-benzisoxazole hydrochloride product weighed 3.09 g (69%), m.p.=225°-227° C.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[OH-].[Na+].[CH3:13][CH:14]1[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]1.Cl[O-].[Na+]>C(OCC)(=O)C.O>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[S:1][N:16]1[CH2:17][CH2:18][CH2:19][CH:14]([CH3:13])[CH2:15]1
Reactant: CC1CCCNC1
Reactant: Sc1nc2ccccc2s1
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CC1CCCN(Sc2nc3ccccc3s2)C1
Reaction time: 2 h
Yield: 95.5 %

Procedure:
In a 500 ml volume flask, there are charged 2-mercaptobenzothiazole (UV absorption spectrum: 329 mμ) (41.28 g), sodium hydroxide (10 g) and water (180 ml), and the resultant mixture is stirred to form a solution. After the addition of 3-methylpiperidine (27.2 g) to the resulting solution, a 15 % by volume aqueous solution of sodium hypochlorite (138.5 ml) is dropwise added thereto in 2 hours, during which the inner temperature is kept below 70° C. The reaction mixture is allowed to stand at the same temperature for 1 hour and then shaken with ethyl acetate (150 ml). The ethyl acetate extract is washed with water and distilled under reduced pressure to give 1-(2-benzothiazolylthio)-3-methyl-piperidine (62.3 g).
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]([C:10]2[C:14]([S:15][CH3:16])=[C:13]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[N:12]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=3[Cl:31])[N:11]=2)=[N:8][N:9]=1)([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:40])C=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([C:5]1[O:6][C:7]([C:10]2[C:14]([S:15]([CH3:16])=[O:40])=[C:13]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)[N:12]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=3[Cl:31])[N:11]=2)=[N:8][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1c(-c2nnc(C(C)(C)C)o2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)c1c(-c2nnc(C(C)(C)C)o2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.4 %

Procedure:
To a solution of 2-tert-Butyl-5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-(methylthio)-1H-pyrazol-3-yl)-1,3,4-oxadiazole (Ia-1) (150 mg, 0.30 mmol) in CH2Cl2 (5 mL) was added m-CPBA (77% Max, 74 mg, 0.33 mmol). The reaction mixture was stirred for 1 hr at room temperature. Saturated NaHCO3 was added to the reaction mixture, and the organic extract was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was subjected to silica gel column chromatography (eluent: hexane/EtOAc=½) to obtain 100 mg (65%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[C@H:4]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[NH:5][C:6](=[O:30])[C@H:7]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH:8][C:9](=[O:22])[CH2:10][NH:11]C(OCC1C=CC=CC=1)=O>[Pd].C(O)(=O)C>[CH3:1][O:2][C:3](=[O:38])[C@H:4]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[NH:5][C:6](=[O:30])[C@H:7]([CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[NH:8][C:9](=[O:22])[CH2:10][NH2:11]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)CN

Procedure:
A mixture of benzyloxycarbonyl-glycyl-phenylalanyl-phenylalanine methyl ester (1.5 g, 2.9 mmoles described in Example 1) and 5% palladium on carbon (0.15 g) in acetic acid 140 ml) is rapidly stirred under an atmosphere of hydrogen until the benzyloxycarbonyl group is removed. The mixture is filtered and the filtrate is evaporated. The residue is triturated with ether to give a precipitate of glycyl-phenylalanyl-phenylalanine methyl ester. A solution of benzyloxycarbonly-(N6 -t-butoxycarbonyl)-lysine p-nitrophenyl ester [1.36 g, 2.7 mmoles, described by E. Sandrin and R. A. Boissonas, Helv. Chem. Acta. 46, 1637 (1963)] in dimethylformamide (20 ml) is added dropwise to a cooled solution of the above compound (1.2 g, 217 mmoles) and N-ethylmorpholine (1.35 ml, 2.7 mmoles). The reaction mixture is stirred overnight at room temperature and evaporated. The residue is dissolved in methanol (4 ml) and diethyl ether is added. The precipitate is crystallized from ethyl acetate-petroleum ether (30°-60° C.) to obtain the title compound, mp 139°-142° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([OH:6])[CH2:2]1.[C:7]([O:11][C:12]([N:14]1[CH2:17][CH:16]([C:18](O)=[O:19])[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].Cl.CN(C)CCCN=C=NCC>ClCCl>[C:7]([O:11][C:12]([N:14]1[CH2:17][CH:16]([C:18]([N:1]2[CH2:5][CH2:4][C@H:3]([OH:6])[CH2:2]2)=[O:19])[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: O[C@H]1CCNC1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(C(=O)N2CC[C@H](O)C2)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 80.6 %

Procedure:
(S)-Pyrrolidin-3-ol (0.276 g, 3.17 mmol) was added to a mixture of azetidine-1,3-dicarboxylic acid mono-tert-butyl ester (0.4 g, 2.11 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.61 g, 3.17 mmol) in dichloromethane (7 mL). The resulting reaction mixture was stirred at RT under nitrogen atmosphere for 48 h. The mixture was diluted with DCM (10 mL) and washed with water (1×15 mL), 10% aqueous citric acid solution (2×15 mL) and brine (2×15 mL), and dried over sodium sulphate. The solvents were reduced in vacuo to afford the title compound as colourless oil (0.46 g, 81%). 1H NMR (400 MHz, CDCl3): δ 4.55-4.48 (1 H, m), 4.17 (2 H, s), 4.05-4.04 (2 H, m), 3.50-3.47 (5 H, m), 2.01-2.00 (2 H, m), 1.43 (9 H, d, J=0.96 Hz).
Reaction SMILES: [CH3:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6](=[O:18])[C:5]([C:19]([OH:21])=[O:20])=[CH:4][CH:3]=1.[I-:22].[Na+].[N+]([O-])(O)=O>C(O)(=O)C>[I:22][C:3]1[CH:4]=[C:5]([C:19]([OH:21])=[O:20])[C:6](=[O:18])[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:16])([F:17])[F:15])[CH:9]=2)[C:2]=1[CH3:1]
Reactant: [I-]
Reactant: Cc1ccc(C(=O)O)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: [Na+]
Solvent: O=[N+]([O-])O
Solvent: CC(=O)O
Product: Cc1c(I)cc(C(=O)O)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 50 °C
Yield: 68 %

Procedure:
To 6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylic acid (28.6 kg, 1 mol eq, limiting reagent) was added sodium iodide (15.1 kg, 1.05 mol eq) and acetic acid (200.2 L, 7 rel vol). 90% Nitric acid (20.1 kg, 3.0 mol eq) was added dropwise. The reaction was heated to 50° C. and stirred until an HPLC assay showed reaction to be complete. The reaction was cooled and stirred. The precipitated product was collected by filtration, washed with water (171.6 L, 6 rel vol) and dried to constant weight to yield the title compound (19.2 kg, 45.4 mol, 68%); 1H NMR (CDCl3): δ 2.36 (s, 3H); 7.42 (d, 1H, J=8.1 Hz); 7.50 (s, 1H); 7.78 (t, 1H, J=7.8 Hz); 7.85 (d, 1H, J=7.9 Hz); 8.86 (s, 1H); 13.44 (s, 1H) ppm; LCMS: m/z 424.0 (MH+).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:5]=12.[C:12]([O-])(=[O:14])C.[Na+].C=O.C([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C>[OH:14][CH2:12][C:3]1[N:4]2[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:5]2=[N:1][CH:2]=1
Reactant: CC(=O)[O-]
Reactant: N#Cc1ccc2nccn2c1
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: N#Cc1ccc2ncc(CO)n2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 80.8 %

Procedure:
To a solution of imidazo[1,2-a]pyridine-6-carbonitrile (7-1) (1.43 g, 10 mmol) in 3 mL of acetic acid were added sodium acetate (3.03 g, 37 mmol) and then formaldehyde (6 mL, 37% in water). The reaction mixture was stirred at 100° C. overnight. After cooled to room temperature, the mixture was adjusted to pH>7 with aqueous Na2CO3. The precipitate was collected to afford the title compound (1.4 g). MS (m/z): 174.0 (M+H)+
Reaction SMILES: [CH2:1]([NH2:6])[CH2:2][CH2:3][CH2:4][CH3:5].[CH:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH:7](=[N:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCCCCN
Reactant: O=Cc1ccccc1
Product: CCCCCN=Cc1ccccc1

Procedure:
condensing N-pentylamine with benzaldehyde to produce the N-benzylidene-N-pentylamine of formula II
Reaction SMILES: [CH3:1][N:2]([C:17]([NH:19][C@H:20]([C:24]([NH:26][C@H:27]([C@@H:35]([OH:72])[C@@H:36]([OH:71])[C@@H:37]([NH:45][C:46](=[O:70])[C@H:47]([CH:67]([CH3:69])[CH3:68])[NH:48][C:49]([N:51]([CH2:53][C:54]1[N:55]=[C:56]([NH:59]C(OC(C)(C)C)=O)[S:57][CH:58]=1)[CH3:52])=[O:50])[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:25])[CH:21]([CH3:23])[CH3:22])=[O:18])[CH2:3][C:4]1[N:5]=[C:6]([NH:9]C(OC(C)(C)C)=O)[S:7][CH:8]=1.CO>C(Cl)(Cl)Cl>[CH3:52][N:51]([C:49]([NH:48][C@H:47]([C:46]([NH:45][C@H:37]([C@@H:36]([OH:71])[C@@H:35]([OH:72])[C@@H:27]([NH:26][C:24](=[O:25])[C@H:20]([CH:21]([CH3:22])[CH3:23])[NH:19][C:17]([N:2]([CH2:3][C:4]1[N:5]=[C:6]([NH2:9])[S:7][CH:8]=1)[CH3:1])=[O:18])[CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)=[O:70])[CH:67]([CH3:69])[CH3:68])=[O:50])[CH2:53][C:54]1[N:55]=[C:56]([NH2:59])[S:57][CH:58]=1
Reactant: CC(C)[C@H](NC(=O)N(C)Cc1csc(NC(=O)OC(C)(C)C)n1)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)N(C)Cc1csc(NC(=O)OC(C)(C)C)n1)C(C)C
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)[C@H](NC(=O)N(C)Cc1csc(N)n1)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)N(C)Cc1csc(N)n1)C(C)C

Procedure:
Using the procedure of Example 58B but replacing the resultant compound of Example 58A with the resultant compound of Example 93 provided, after silica gel chromatography using first 5% then 10% methanol in chloroform followed by 2% isopropylamino/10% methanol in chloroform, 53 mg (38%) of the desired compound (Rf 0.15, 10% methanol in chloroform) as a white solid, m.p. 130°-134° C. Mass spectrum: (M+1)+ =837.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:10]([C:11]=1[CH3:12])=[CH:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][CH:6]=2)[CH3:2].[H-].[Na+].Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1>CN(C)C=O>[CH2:1]([C:3]1[N:4]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:5]2[C:10]([C:11]=1[CH3:12])=[CH:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][CH:6]=2)[CH3:2]
Reactant: Fc1ccc(CBr)cc1
Reactant: CCOC(=O)c1ccc2[nH]c(CC)c(C)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2c(c1)c(C)c(CC)n2Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 500 mg portion of ethyl 2-ethyl-3-methyl-1H-indole-5-carboxylate was dissolved in 10 ml of N,N-dimethylformamide, and 113 mg of sodium hydride (55% dispersion in oil) was added under ice-cooling, followed by stirring at room temperature for 30 minutes. Then, 490 mg of 1-(bromomethyl)-4-fluorobenzene was added under ice-cooling, followed by stirring at room temperature for 2 hours. After evaporation of the solvent under a reduced pressure, the residue was diluted with ethyl acetate and washed with water and saturated brine. After drying the organic layer with anhydrous sodium sulfate, the solvent was evaporated under a reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:20 to 1:0) to obtain 587 mg of ethyl 2-ethyl-1-(4-fluorobenzyl)-3-methyl-1H-indole-5-carboxylate as a pale brown oily material.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]([C:10]1[N:11]([CH2:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=O)[C:12]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[CH:14][C:13]=2[N:22]=1)[CH2:8][CH3:9].Cl.[CH3:31][NH:32][O:33][CH3:34].CN(C)C=O>ClCCl>[CH3:34][O:33][N:32]([CH3:31])[C:27](=[O:29])[CH2:26][CH2:25][CH2:24][CH2:23][N:11]1[C:12]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[CH:14][C:13]=2[N:22]=[C:10]1[CH2:7][CH2:8][CH3:9]
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCCC(=O)O
Reactant: CNOC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCc1nc2cnc3ccccc3c2n1CCCCC(=O)N(C)OC
Reaction time: 1 h
Yield: 92.9 %

Procedure:
Oxalyl chloride (2.62 mL, 30.1 mmol) was added to a solution of 5-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)pentanoic acid (5.21 g, 16.7 mmol) in dichloromethane (50 mL) at room temperature. The reaction was stirred for 1 hour, then the volatiles were removed under reduced pressure. Dichloromethane (50 mL) was added to the residue, followed by N,O-dimethylhydroxylamine hydrochloride (3.26 g, 33.5 mmol) and N,N-dimethylformamide (2 mL). The reaction mixture was stirred at room temperature overnight, then was concentrated under reduced pressure. The residue was diluted with dichloromethane and an ammonium hydroxide solution. The mixture was transferred to a separatory funnel and the layers were separated. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford 5.5 g of crude N-methoxy-N-methyl-5-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)pentanamide as a brown oil that was used without purification in the next step.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)=[CH:4][CH:3]=1.[CH3:25][N:26]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[N:27]1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1>[CH3:25][N:26]1[CH:30]=[C:29]([C:2]2[CH:3]=[CH:4][C:5]([C:8]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[C:9]3[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:11]([CH3:17])([CH3:18])[CH2:10]3)=[CH:6][CH:7]=2)[CH:28]=[N:27]1
Reactant: CC1(C)CC(=C(c2ccccc2)c2ccc(Br)cc2)CC(C)(C)C1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1cc(-c2ccc(C(=C3CC(C)(C)CC(C)(C)C3)c3ccccc3)cc2)cn1
Yield: 88.4 %

Procedure:
The procedure described for 22 (Example 11) was employed using 16 (192 mg, 0.5 mmol), Pd(Ph3P)4 (58 mg, 0.05 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (208 mg, 1.0 mmol), 2N aqueous Na2CO3 (0.5 mL, 1.0 mmol), and THF (3 mL). The reaction mixture was refluxed for 12 h. Aqueous work-up followed by flash column chromatography afforded 170 mg (88%) of the title product 23 as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 7.73 (s, 1H), 7.56 (s, 1H), 7.37 (d, J=8.0 Hz, 2H), 7.26 (d, J=8.8 Hz, 2H), 7.20-7.16 (m, 4H), 3.92 (s, 3H), 2.02 (s, 2H), 1.97 (s, 2H), 1.29 (s, 2H), 0.95 (s, 6H), 0.93 (s, 6H). LCMS (APCI): m/z 385 (M+H)+.
Reaction SMILES: Cl.[O:2]=[CH:3][C@H:4]([C@H:6]([C@H:8]([CH2:10][OH:11])[OH:9])[OH:7])[OH:5].[CH3:12]O>>[CH3:12][O:2][CH:3]1[O:9][C@@H:8]([CH2:10][OH:11])[C@H:6]([OH:7])[C@@H:4]1[OH:5]
Reactant: CO
Reactant: O=C[C@@H](O)[C@@H](O)[C@@H](O)CO
Agent: Cl
Product: COC1O[C@@H](CO)[C@H](O)[C@@H]1O
Reaction time: 2.5 h

Procedure:
A cold solution of dry hydrogen chloride (4;4 g, 0.12 mmol) in methanol (100 mL) was slowly added to the solution of L-(+)-ribose 1 (50 g, 0.33 mole in methanol (1000 mL) at room temperature. After addition, the solution was stirred for 2.5 h and quenched with pyridine (100 mL). The mixture was stirred for 10 min and the solvent was evaporated. The residue was dissolved in pyridine (100 mL) and the resulting solution was concentrated to dryness to give 1-O-methyl-L-ribofuranose 2 as a pale-yellow syrup.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C@H:11]([CH2:20][NH:21][CH2:22][CH3:23])[CH2:12][C:13]([O:15][C:16](C)(C)C)=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]>CO.Cl.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C@H:11]([CH2:20][NH:21][CH2:22][CH3:23])[CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CCNC[C@H](CC(=O)OC(C)(C)C)Nc1ccc(C#N)c(Cl)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCNC[C@H](CC(=O)OC)Nc1ccc(C#N)c(Cl)c1
Temperature: 60 °C

Procedure:
The 1,1-dimethylethyl (3S)-3-[(3-chloro-4-cyanophenyl)amino]-4-(ethylamino)butanoate from the previous step was dissolved in a mixture of MeOH (150 mL) and 4N HCl/dioxane (20 mL) and heated to 60° C. for 3 h. The solvents were concentrated to a slurry, Et2O (200 mL) was added, the solid filtered, washed well with Et2O to give the titled compound (4.0 g).