Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH:7][CH2:8][CH2:9][NH2:10].[C:11](Cl)(=[O:15])[C:12]([CH3:14])=[CH2:13].[K+].[Br-]>ClCCl>[C:11]([C:2]([C:11](=[O:15])[C:12]([CH3:14])=[CH2:13])([CH2:3][NH:4][CH2:5][CH2:6][NH:7][CH2:8][CH2:9][NH2:10])[N:1]([C:11](=[O:15])[C:12]([CH3:14])=[CH2:13])[C:11](=[O:15])[C:12]([CH3:14])=[CH2:13])(=[O:15])[C:12]([CH3:14])=[CH2:13]
Reactant: C=C(C)C(=O)Cl
Reactant: NCCNCCNCCN
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Product: C=C(C)C(=O)N(C(=O)C(=C)C)C(CNCCNCCN)(C(=O)C(=C)C)C(=O)C(=C)C
Temperature: 25 °C

Procedure:
Triethylene tetramine (2.93 g, 0.02 moles) in dichloromethane (100 ml) was added drop wise over 6 hrs to a solution of methacryloyl chloride (8.32 g, 0.08 moles) in dichloromethane (40 ml), stirring vigorously at room temperature. The reaction was continued stirring at room temperature overnight and the suspension formed was filtered. The filtrate was extracted with NaOH (aq). The water was rotary evaporated and the residue was washed with acetone and filtered. The acetone filtrate was concentrated down and put through a silica gravity chromatography column with acetone as the elutant to obtain a white solid. The solid is recrystallized from diethyl ether to give white crystals, m.p. 168-170° C. 1H n.m.r. (D2O) δ, 5.71(19.7 Hz), 5.51 (7.8 Hz), 5.31(9.7 Hz), 5.06 (17.7 Hz), (8 H, d×4) C—CH2; 3.61 (6 H, m) N—CH2—CH2; 3.48(6 H, m) N—CH2—CH2; 1.96(4.1 Hz); 1.93(5.8 Hz); 1.91(6.0 Hz); 1.88(4.5 Hz), (12 H, d×4) CH3; 13C n.m.r. (D2O), δ 178.76, 178.70, 174.71, 174.61 (C=O); 142.19, 142.0, 141.71, 141.56 (C=CH2), 124.52, 124.19, 120.06, 119.60 (C=CH2); 22.30, 22.20, 20.48; (CH3), 50.33, 49.22, 46.45, 44.00, 40.22, 39.49 (N—CH2—CH2). MS: mz: 419.3 (MH+, 100%), 391.3(4), 266.2(10), 223.1(42); HRMS: found: 419.26695 C22H34N4O4 requires 418.5299. Elemental analysis: found: C, 62.97; H, 8.09; N, 13.31; C22H34N4O4 requires C, 63.13; H, 8.19; N, 13.39. I.R. (KBr) (CM−1) 3353, 1665, 1650, 1530, 1279.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([CH3:25])[CH:16]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]=1>>[CH3:14][C:12]1[CH:11]=[C:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([CH3:25])[CH:16]=2)[N:9]=[C:8]([C:4]2[CH:3]=[C:2]([C:30]3[CH:31]=[CH:32][C:27]([NH2:26])=[N:28][CH:29]=3)[CH:7]=[CH:6][CH:5]=2)[N:13]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)c(C)c2)nc(-c2cccc(Br)c2)n1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Cc1cc(-c2ccc(C(F)(F)F)c(C)c2)nc(-c2cccc(-c3ccc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-methyl-6-(3-methyl-4-trifluoromethyl-phenyl)-pyrimidine (example E.53) (0.11 g, 0.3 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.087 g, 0.4 mmol) according to the general procedure VI. Obtained as a light brown solid (0.028 g, 22%). MS (ISP) 421.1 [(M+H)+]; mp 153° C.
Reaction SMILES: [CH3:1][N:2]([CH3:4])O.[H-].[Na+].[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[N:17]3[C:18]([CH2:21]Cl)=[N:19][N:20]=[C:16]3[CH2:15][N:14]=[C:13]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[C:12]=2[CH:29]=1>CN(C)C=O>[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[N:17]3[C:18]([CH2:21][N:2]([CH3:4])[CH3:1])=[N:19][N:20]=[C:16]3[CH2:15][N:14]=[C:13]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[C:12]=2[CH:29]=1
Reactant: CN(C)O
Reactant: ClCc1nnc2n1-c1ccc(Br)cc1C(c1ccccn1)=NC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)Cc1nnc2n1-c1ccc(Br)cc1C(c1ccccn1)=NC2

Procedure:
In the manner given in Example 16, a solution of N,N-dimethylhydroxylamine in dimethylformamide is treated with sodium hydride suspended in mineral oil, and the mixture is treated with 8-bromo-1-(chloromethyl)-6-(2-pyridyl)-4H-s triazolo[4,3-a][1,4]benzodiazepine to give 8-bromo-1[(dimethylamino)methyl]-6-(2-pyridyl)-4H-s-triazolo [4,3-a][1,4]benzodiazepine, N1 -oxide.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][C:7]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11][C:8]=3[CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[C:23](Cl)(=O)[CH:24]([CH3:26])[CH3:25].C(N(CC)CC)C>ClC(Cl)C.CCOC(C)=O>[CH2:23]([N:1]1[C:10]2[C:5](=[CH:6][C:7]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11][C:8]=3[CH:9]=2)[CH2:4][CH2:3][CH2:2]1)[CH:24]([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCc2cc3c(cc2CC1)NCCC3
Reactant: CC(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: CC(C)CN1CCCc2cc3c(cc21)CCN(C(=O)OC(C)(C)C)CC3
Reaction time: 0.5 h

Procedure:
To a solution of 250 mg of t-butyl 1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate in 2.5 ml of dichloroethane were added 0.175 ml of isobutyryl chloride and 0.4 ml of triethylamine, followed by elevating the temperature to 60° C. and stirring for 30 minutes. The reaction mixture was diluted with EtOAc and washed with 1 M hydrochloric acid, water, a 1 M aqueous sodium hydroxide solution, and saturated brine, and the solvent was concentrated. To the resulting residue was added 2 ml of THF and 3.5 ml of a 1 M solution of a borane-THF complex in THF was added thereto in an ice-bath, followed by stirring at room temperature overnight. The reaction mixture was ice-cooled, and EtOH was added thereto, followed by stirring at room temperature for 30 minutes. The reaction mixture was concentrated and the resulting residue was purified by silica gel chromatography (elution solvent: HEX-EtOAc) to obtain 213 mg of t-butyl 1-isobutyl-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[CH:50]=[CH:49][C:48]([F:51])=[CH:47][C:46]=1[Cl:52]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[CH:50]=[CH:49][C:48]([F:51])=[CH:47][C:46]=3[Cl:52])[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Fc1ccc(CBr)c(Cl)c1
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(Cc3ccc(F)cc3Cl)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-(bromomethyl)-2-chloro-4-fluorobenzene and isolated as colorless gum (5.5 mg, 32%). MS (m/e): 425.4 (MH+).
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[CH2:15][C:16]1[O:20][C:19]([CH3:21])=[N:18][C:17]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O.O>[CH3:21][C:19]1[O:20][C:16]([CH2:15][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])=[C:17]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:18]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1nc(-c2ccccc2)c(CBr)o1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1oc(C)nc1-c1ccccc1)C(=O)OCC
Reaction time: 0.17 h
Yield: 66.2 %

Procedure:
60% Sodium hydride in oil (1.48 g) was added portionwise to a solution of diethyl malonate (11.7 g) in N,N-dimethylformamide (50 ml) and the mixture was stirred for 10 minutes. A solution of 5-bromomethyl-2-methyl-4-phenyloxazole (9.2 g) in N,N-dimethylformamide (20 ml) was added dropwise under ice-cooling. The mixture was stirred under ice-cooling for 30 minutes, diluted with water, and extracted with ethyl ether. The ethyl ether layer was washed with water and dried over anhydrous sodium sulfate. The solvent was then distilled off and the residue was purified by silica gel chromatography [silica gel: 120 g; eluent: hexane-ethyl ether (3:2)] to give an oil (8.0 g) of diethyl 2-(2-methyl-4-phenyl-5-oxazolylmethyl)malonate.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[C:8](I)=[N:9][N:10]([CH3:11])[C:5]2=[CH:4][CH:3]=1.Cl[C:14]1[CH:15]=CC2[C:18](=[C:20](I)[N:21]([CH3:23])N=2)[N:19]=1.CN1CCNCC1.N1CCC[C@H]1C(O)=O>[Cu]I>[Cl:1][C:2]1[N:7]=[C:6]2[C:8]([N:19]3[CH2:14][CH2:15][N:21]([CH3:23])[CH2:20][CH2:18]3)=[N:9][N:10]([CH3:11])[C:5]2=[CH:4][CH:3]=1
Reactant: Cn1nc2ccc(Cl)nc2c1I
Reactant: Cn1nc(I)c2nc(Cl)ccc21
Agent: [Cu]I
Agent: CN1CCNCC1
Agent: O=C(O)[C@@H]1CCCN1
Product: CN1CCN(c2nn(C)c3ccc(Cl)nc23)CC1
Temperature: 100 °C

Procedure:
To a solution of 5-chloro-3-iodo-1-methyl-1H-pyrazolo[4,3-b]pyridine (104 mg, 0.354 mmol, containing the isomer 5-chloro-3-iodo-2-methyl-2H-pyrazolo[4,3-b]pyridine (360 mg, 1.22 mmol) was added 1-methylpiperazine (184 mg, 1.84 mmol), CuI (70 mg, 0.368 mmol), L-proline (84 mg, 0.736 mmol). The reaction mixture was heated at 100° C. for 4 h. The reaction was cooled, washed by sat. NaHCO3, extracted with EtOAc, dried over MgSO4, filtered, concentrated and purified by silica gel column, eluting by 0-100% EtOAc in hexanes to give the product. LCMS-ESI+: calc'd for C12H16ClN5: 266.1 (M+H+); Found: 266.2 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:6]([CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[C:5]2[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1.[C:32](=O)([O-])[O-].[K+].[K+].ClC[C:40]1[O:44][C:43]([C:45]([O:47][CH2:48][CH3:49])=[O:46])=[CH:42][CH:41]=1.O>CN(C)C=O>[C:20]([O:19][C:18]([NH:17][CH2:16][C:6]1[C:7]([CH2:12][CH:13]([CH3:15])[CH3:14])=[N:8][C:9]2[C:4]([C:5]=1[C:25]1[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=1)=[CH:3][C:2]([O:1][CH2:32][C:41]1[CH:42]=[C:43]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[O:44][CH:40]=1)=[CH:11][CH:10]=2)=[O:24])([CH3:23])([CH3:21])[CH3:22]
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(O)cc23)cc1
Reactant: CCOC(=O)c1ccc(CCl)o1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(COc2ccc3nc(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c4ccc(C)cc4)c3c2)co1
Temperature: 25 °C
Reaction time: 6 h
Yield: 79 %

Procedure:
To a solution of tert-butyl {[6-hydroxy-2-isobutyl-4-(4-methylphenyl)quinolin-3-yl]methyl}carbamate (0.40 g, 0.95 mmol) in N,N-dimethylformamide (10 ml) were added potassium carbonate (0.28 g, 2.0 mmol) and ethyl 5-chloromethyl-2-furancarboxylate (0.38 g, 2.0 mmol) and the mixture was stirred at room temperature for 6 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give ethyl 4-({[3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl]oxy}methyl)-2-furoate (0.43 g, yield 80%) as pale-yellow crystals.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21](=O)[CH3:22])=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[CH3:25][O:26][NH2:27].C(N(CC)CC)C>CO>[CH3:25][O:26]/[N:27]=[C:21](/[C:18]1[N:17]=[C:16]2[N:12]([CH2:11][C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)[N:13]=[N:14][C:15]2=[N:20][CH:19]=1)\[CH3:22]
Reactant: CON
Reactant: CC(=O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CO/N=C(\C)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Temperature: 30 °C
Reaction time: 3 h
Yield: 75.7 %

Procedure:
To a solution of 1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone (6.3 mg, 0.021 mmol) in methanol (3 mL) was added O-methylhydroxylamine hydrochloride (16.7 mg, 0.20 mmol), followed by addition of triethyl amine to adjust the pH to 5-6. The reaction mixture was stirred at 30° C. for 3 h. The solvent was removed under reduced pressure and the residue was dissolved in DCM. The resulting solution was washed with NaHCO3 solution, water and brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by prep-HPLC to afford 5.3 mg (69%) of the title compound. 1H-NMR (400 MHz, CD3Cl) δ ppm 9.67 (s, 1H), 8.94 (m, 1H), 8.16 (t, 2H), 7.93 (d, 1H), 7.86 (dd, 1H), 7.53 (dd, 1H), 6.11 (s, 2H), 4.14 (s, 3H), 2.38 (s, 3H). LCMS (method A): [MH]+=334, tR=5.02 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8](I)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH:15][C:16](=[O:18])[CH3:17].C([Sn](CCCC)(CCCC)[C:25]1[O:26][CH2:27][CH2:28][CH:29]=1)CCC.CCN(CC)CC>O1CCOCC1.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>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([C:25]2[O:26][CH2:27][CH2:28][CH:29]=2)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH:15][C:16](=[O:18])[CH3:17]
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCCO1
Reactant: COC(=O)c1cc(I)c(C(F)(F)F)cc1NC(C)=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C2=CCCO2)c(C(F)(F)F)cc1NC(C)=O
Temperature: 25 °C
Yield: 85.9 %

Procedure:
To a solution of 2-acetylamino-5-iodo-4-trifluoromethyl-benzoic acid methyl ester (10 g, 25.8 mmol) in dioxane were added tributyl-(4,5-dihydro-furan-2-yl)-stannane (13.9 g, 38.7 mmol), (Ph3P)4Pd then Et3N (4.52 mL, 32.3 mmol). The reaction mixture was heated at reflux for 18 h to give a brown suspension that was allowed to cool to r.t. The reaction mixture was filtered through a sintered funnel and the filtrate was concentrated under in vacuo. The residue was purified by flash column chromatography (silica gel, 1:4 EtOAc/hexanes) to give the title compound (7.3 g, 86%) as beige crystals, m.p.: 120-125° C., API-ES: m/z 330 [M+H]+
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][NH:6][C:7]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH:15][C:16]([O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][NH:24]C(OC(C)(C)C)=O)=[O:17])=[O:8])[CH3:2].[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36]>ClCCl>[F:33][C:34]([F:39])([F:38])[C:35]([O-:37])=[O:36].[CH2:1]([O:3][C:4](=[O:32])[CH2:5][NH:6][C:7]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH:15][C:16]([O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][NH2:24])=[O:17])=[O:8])[CH3:2]
Reactant: O=C(O)C(F)(F)F
Reactant: CCOC(=O)CNC(=O)OCCOCCNC(=O)OCCOCCNC(=O)OC(C)(C)C
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)OCCOCCNC(=O)OCCOCCN
Product: O=C([O-])C(F)(F)F
Yield: 99.4 %

Procedure:
(2-{2-[2-(2-t-Butoxycarbonylaminoethoxy)ethoxycarbonylamino]ethoxy}ethoxycarbonylamino acetic acid ethyl ester (Compound 5, 13.2 g, 0.03 mol, 1 eq) was dissolved in dichloromethane (100 mL) and then stirred. After slowly adding trifluoroacetic acid (150 mL), the mixture was stirred at room temperature for 30 minutes. After removing the solvent, washing 2 times with diethyl ether followed by drying yielded trifluoroacetate of (2-{2-[2-(aminoethoxy)ethoxycarbonylamino]ethoxy}ethoxycarbonylamino)acetic acid ethyl ester (Compound 6, 14.3 g, 99.4%). The trifluoroacetate of (2-{2-[2-(aminoethoxy)ethoxycarbonylamino]ethoxy}ethoxycarbonylamino)acetic acid ethyl ester (Compound 6, 14.1 g, 0.029 mol, 1.5 eq) was dissolved in dichloromethane (200 mL). After sufficiently cooling in an ice bath, triethylamine (28 mL, 0.2 mol, 10 eq) was slowly added for neutralization. Then, previously synthesized 2-(2-(t-butoxycarbonylamino)ethoxy)ethyl 2-(2-((4-nitrophenoxy)carbonyloxy)ethoxy)ethyl carbamate (Compound 4, 10 g, 0.02 mol, 1 eq) was added. After slowly adding triethylamine (5.6 mL, 0.04 mol, 2 eq), the mixture was stirred at room temperature for 3 hours. Then, the reaction mixture was washed 3 times with 1 N HCl aqueous solution (250 mL). The organic layer was separated, dried with magnesium sulfate, and then concentrated. Purification by silica gel column chromatography yielded the target compound ethyl 38,38-dimethyl-4,12,20,28,36-pentaoxo-5,8,13,16,21,24,29,32,37-nonaoxa-3,11,19,27,65-pentaazanonatriacontan-1-oate (Compound 9, 10.2 g, 74%).
Reaction SMILES: C(S[CH:6]([C:10](=[O:15])CC(C)C)[CH:7](C)[CH3:8])C(=C)C.C(SC(C(=O)CC(C)C)C(C)C)C=CC.[CH2:31]([S:34][CH:35]([C:39](=[O:44])[CH2:40][CH:41]([CH3:43])[CH3:42])[CH:36]([CH3:38])[CH3:37])[CH:32]=[CH2:33]>>[CH2:32]([CH:31]([S:34][CH:35]([CH:36]([CH3:38])[CH3:37])[C:39]([CH2:40][CH:41]([CH3:43])[CH3:42])=[O:44])[C:10]([CH2:6][CH2:7][CH3:8])=[O:15])[CH3:33]
Reactant: C=C(C)CSC(C(=O)CC(C)C)C(C)C
Reactant: C=CCSC(C(=O)CC(C)C)C(C)C
Agent: CC=CCSC(C(=O)CC(C)C)C(C)C
Product: CCCC(=O)C(CC)SC(C(=O)CC(C)C)C(C)C

Procedure:
3-methyl-thio-4-heptanone; 3-propyl-thio-4-heptanone; 3-(methallylthio)-2,6-dimethyl-4-heptanone; 3-crotylthio-2,6-dimethyl-4-heptanone; and 3-allylthio-2,6-dimethyl-4-heptanone.
Reaction SMILES: [C:1]([CH2:9][C:10]#[N:11])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12](#[N:16])[CH2:13][C:14]#[N:15].C([O-])(=O)C.[NH4+].C(O)C>O.Cl>[C:2]1([C:1]([CH2:9][C:10]#[N:11])=[C:13]([C:12]#[N:16])[C:14]#[N:15])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCC#N
Reactant: N#CCC(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: N#CCC(=C(C#N)C#N)c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of benzoylacetonitrile (9.94 g, 0.0685 mole), malononitrile (11.3 g, 0.17 mole), ammonium acetate (5.4 g, 0.07 mole) and ethanol (100 mL) was heated at reflux for 1.5 hours. After cooling to room temperature, the reaction mixture was diluted with water (50 mL) and concentrated hydrochloric acid (7.5 mL) was added dropwise over 5 minutes. The resulting precipitate was collected by filtration and washed with water and ligroin. The yield was 10.0 g (76%), m.p. 92°-98° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[S].[CH2:11](N)[CH2:12][NH2:13]>>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[NH:13][CH2:12][CH2:11][N:6]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: N#Cc1cccc(Br)c1
Reactant: NCCN
Agent: [S]
Product: Brc1cccc(C2=NCCN2)c1

Procedure:
To a solution of 3-bromobenzonitrile (500 mg, 2.75 mmol) in ethylenediamine (3.5 mL) was added sulfur (44 mg, 1.4 mmol). The mixture was refluxed overnight then poured onto ice water, which caused the product to precipitate as a white solid. The product was isolated by vacuum filtration and dried in a vacuum oven (545 mg, 88%). 1H-NMR (CDCl3) δ 7.93 (t, J=1.7 Hz, 1H), 7.68 (ddd, J=7.8, 1.2, 1.2 Hz, 1H), 7.56 (dddd, J=7.8, 0.9, 0.9, 0.9 Hz, 1H), 7.26 (dd, J=10.5, 8.0 Hz, 1H), 3.78 (br s, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]=[C:9]([CH3:12])[C:8]([O:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[C:7]([CH3:21])[C:6]=2[C:5]([OH:22])=[CH:4][CH:3]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH3:34][O:35][C:36](=[O:39])[CH2:37]Br>ClCCl>[CH3:34][O:35][C:36](=[O:39])[CH2:37][O:22][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[C:11]2[C:6]=1[C:7]([CH3:21])=[C:8]([O:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:9]([CH3:12])=[N:10]2
Reactant: COC(=O)CBr
Reactant: Cc1nc2c(Cl)ccc(O)c2c(C)c1Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(Cl)c2nc(C)c(Oc3ccc(Cl)cc3)c(C)c12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 8-chloro-3-(4-chlorophenoxy)-2,4-dimethylquinolin-5-ol (0.16 g), N,N-dimethylformamide (3.0 mL), potassium carbonate (0.20 g) and bromoacetic acid methyl ester (0.88 g) was stirred at room temperature for 15 hours. The mixture was diluted with dichloromethane, washed with water and dried over magnesium sulfate. The solvent was removed under reduced pressure and purification of the residue by column chromatography on silica gel, eluting with a mixture of dichloromethane and ethyl acetate (1:0 to 5:1 by volume) gave title compound as an off-white solid, 0.20 g.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[S:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26]Cl>>[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][N:7]1[C:8]([S:9][C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]1=[O:18]
Reactant: CCc1c(Sc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: ClCc1ccccn1
Product: CCc1c(Sc2cc(C)cc(C)c2)n(Cc2ccccn2)c(=O)[nH]c1=O
Yield: 26.7 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenyl)thio-2,4-pyrimidinedione and 2-picolyl chloride were reacted by the same way with the example 1 to obtain the titled compound (98 mg, yield: 26.7%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([O:29][CH2:30][CH3:31])[C:17](N[C@H](C2C=CC=CC=2)CO)=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:33]>O.O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C@H:16]([O:29][CH2:30][CH3:31])[C:17]([OH:18])=[O:33])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCO[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)N[C@@H](CO)c1ccccc1
Reactant: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: O
Product: CCO[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O

Procedure:
3-(4-Benzyloxyphenyl)-(S)-2-ethoxy-N-(2-hydroxy-(R)-1-phenylethyl)propanoic amide (8.9 g; 21.22 mmole) was hydrolyzed with concentrated sulfuric acid (27 ml) in water (104 ml) and dioxane (104 ml) at 90° C. for 5 hours. The reaction mixture was poured onto water (220 ml) and extracted with ethyl acetate. The organic phase was washed with brine, dried (sodium sulfate) and the solvent was evaporated in vacuo to give 6.85 g of a mixture of 3-(4-benzyloxyphenyl)-2-(S)-ethoxypropanoic acid and (S)-2-ethoxy-3-(4-hydroxyphenyl)-propanoic acid, which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][OH:15])[O:11][C:10]2=[O:16])[CH:5]=[CH:6][C:7]=1[I:8].C(N(CC)C(C)C)(C)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][O:15][S:27]([CH3:26])(=[O:29])=[O:28])[O:11][C:10]2=[O:16])[CH:5]=[CH:6][C:7]=1[I:8]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1O[C@@H](CO)CN1c1ccc(I)c(F)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
A solution of (5R)-3-(3-fluoro-4-iodophenyl)-5-hydroxymethyl-oxazolidin-2-one (1019, 11.66 g, 34.6 mmol) in methylene chloride (CH2Cl2, 80 mL) was treated with N,N-diisopropylethylamine (Hunig's base, DIEA, 8.95 g, 12.1 mL, 69.2 mmol, 2.0 equiv) at 25° C., and the resulting mixture was cooled down to 0-5° C. before methanesulfonyl chloride (MsCl, 4.36 g, 2.95 mL, 38.1 mmol, 1.1 equiv) was dropwise introduced into the reaction mixture at 0-5° C. under N2. The resulting reaction mixture was subsequently stirred at 0-5° C. for 1 h under N2. When TLC and HPLC/MS showed that the reaction was complete, the reaction mixture was quenched with H2O (60 mL) and CH2Cl2 (60 mL). The two layers were separated, and the aqueous layer was extracted with CH2Cl2 (60 mL). The combined organic extracts were washed with H2O (2×60 mL) and saturated NaCl aqueous solution (40 mL), dried over MgSO4, and concentrated in vacuo. The residue was further dried in vacuo to afford the crude, (5R)-methanesulfonic acid 3-(3-fluoro-4-iodophenyl)-2-oxo-oxazolidin-5-ylmethyl ester (1020, 14.0 g, 14.36 g theoretical, 97.5%) as off-white powders, which was found to be essentially pure and was directly used in the subsequent reactions without further purifications. For 1020: 1H NMR (300 MHz, DMSO-d6) δ 3.26 (s, 3H, OSO2CH3), 3.83 (dd, 1H, J=6.4, 9.2 Hz), 4.19 (t, 1H, J=5.4 Hz), 4.44-4.54 (m, 2H), 5.01-5.06 (m, 1H), 7.22 (dd, 1H, J=2.4, 8.7 Hz), 7.56 (dd, 1H, J=2.4, 8.7 Hz), 7.84 (dd, 1H, J=7.5, 8.7 Hz); C11H11FIN5S, LCMS (EI) m/e 416 (M++H).