Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:6]2[N:7]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[CH:10][C:5]2=[N:4][N:3]=1.[CH2:25]([NH:27][C:28]1([C:33]([NH2:35])=[O:34])[CH2:32][CH2:31][NH:30][CH2:29]1)[CH3:26]>C(O)CO>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:8]1[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:10][C:5]2[N:6]([C:2]([N:30]3[CH2:31][CH2:32][C:28]([NH:27][CH2:25][CH3:26])([C:33]([NH2:35])=[O:34])[CH2:29]3)=[N:3][N:4]=2)[N:7]=1
Reactant: CCNC1(C(N)=O)CCNC1
Reactant: Clc1ccc(-c2cc3nnc(Cl)n3nc2-c2ccccc2Cl)cc1
Solvent: OCCO
Product: CCNC1(C(N)=O)CCN(c2nnc3cc(-c4ccc(Cl)cc4)c(-c4ccccc4Cl)nn23)C1
Temperature: 110 °C
Reaction time: 2 h
Yield: 26.9 %

Procedure:
A suspension of 3-chloro-6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazine (113 mg, 0.3 mmol) and 3-(ethylamino)pyrrolidine-3-carboxamide (94 mg, 0.6 mmol) in ethylene glycol (2 mL) was stirred at 110° C. for 2 h. Analysis by HPLC/MS indicated the reaction was not complete. Additional 3-(ethylamino)pyrrolidine-3-carboxamide (47 mg, 0.3 mmol) was added. The reaction continued at 110° C. for 1 h more. After cooling to room temperature, the reaction mixture was loaded onto a silica gel cartridge (12 g), eluted with a gradient of MeOH (0-6%) in CH2Cl2 to obtain 40 mg of desired product with 90% purity. The product was further purified using reverse phase preparative HPLC (Conditions: Phenomenex Luna 5μ C18 21.2×100 mm; Eluted with 40% to 90% B, 8 min gradient, 90% B hold for 3 min, (A=90% H2O, 10% MeOH, 0.1% trifluoroacetic acid and B=10% H2O, 90% MeOH, 0.1% trifluoroacetic acid); Flow rate at 20 mL/min, UV detection at 220 nm) to yield the product as a TFA salt. The product was dissolved in EtOAc, washed with saturated aqueous NaHCO3, water, saturated aqueous NaCl, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was lyophilized in acetonitrile to afford 30 mg (20%) of the title compound as a yellow powder. HPLC/MS (method A): retention time=2.75 min, (M+H)+=496.2. 1H NMR (CDCl3, 400 MHz): δ 7.81 (s, 1H), 7.28-7.38 (m, 4H), 7.19-7.26 (m, 2H), 7.01-7.07 (m, 2H), 5.39 (s, 1H), 4.00-4.15 (m, 5H), 2.54-2.65 (m, 3H), 2.12 (m, 1H), 1.40-1.55 (m, 1H), 1.10 (t, J=7.09 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[O:19][C:7]([CH:8]=[C:9]2[N:13]=[C:12]3[CH:14]=[CH:15][CH:16]=[C:17]([NH2:18])[C:11]3=[N:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:20][C:21]1[CH:22]=[C:23]([N:28]=[C:29]=[O:30])[CH:24]=[CH:25][C:26]=1[Cl:27]>C(Cl)(Cl)Cl.CN(C)C=O>[Cl:20][C:21]1[CH:22]=[C:23]([NH:28][C:29]([N:13]2[C:12]3[CH:14]=[CH:15][CH:16]=[C:17]([NH2:18])[C:11]=3[NH:10][C:9]2=[CH:8][C:7]2[O:19][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[O:30])[CH:24]=[CH:25][C:26]=1[Cl:27]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: Nc1cccc2c1=NC(=Cc1ccc([N+](=O)[O-])o1)N=2
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Nc1cccc2c1NC(=Cc1ccc([N+](=O)[O-])o1)N2C(=O)Nc1ccc(Cl)c(Cl)c1
Yield: 78.4 %

Procedure:
51.2 g (0.2 moles) 2-(5-nitro-furfurylidene)-amino-benzimidazole are stirred in a mixture of 120 ml of chloroform and 80 ml of dimethylformamide, whereupon 37.6 g (0.2 moles) of powdered 3.4-dichlorophenyl-isocyanate are added. The crystalline reaction mixture is stirred at room temperature for 7 hours while a mixture of 40 ml of dimethylformamide and 60 ml of chloroform are added. The precipitated crystals are filtered off, washed with 100 ml of chloroform and dried in vacuo at 40° C. to 60° C. Thus 70 g of 1-(3',4'-dichlorophenyl-carbamoyl)-2-(5-nitro-furfurylidene)-amino-benzimidazole are obtained. Mp.: 202°-204° C.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:8][CH3:9])[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>C(Cl)Cl>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:2][CH:3]([CH2:8][CH3:9])[C:4]([O:6][CH3:7])=[O:5])(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: CCC(N)C(=O)OC
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(NS(=O)(=O)c1ccc(Cl)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 2-aminobutanoate hydrochloride 56 (25 g, 0.163 mol) was suspended in CH2Cl2 (100 mL) and triethylamine (50 mL) and 4-chlorobenzenesulfonyl chloride (37.8 g, 1.1 eq) were added to the mixture. The mixture was stirred at room temperature overnight. Diluted with 200 mL of CH2Cl2 and washed with water (3×50 mL), sat. NaHCO3 (2×50 mL), brine (50 mL) and dried (MgSO4). The solvent was removed by rotary evaporation to give the product 57 as a yellow oil. LCMS 292.0 (M+H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][N:6]1[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][C:10](=[O:11])[NH:9][C:7]1=[S:8].[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(OCC)(=O)C>N1C=CC=CC=1>[C:20]([O:1][CH2:2][CH2:3][O:4][CH2:5][N:6]1[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][C:10](=[O:11])[NH:9][C:7]1=[S:8])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=c1cc(-c2ccccc2)n(COCCO)c(=S)[nH]1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(OCCOCn1c(-c2ccccc2)cc(=O)[nH]c1=S)c1ccccc1
Yield: 88.9 %

Procedure:
An amount of 294 mg (1 mmol) of 1-[(2-hydroxyethoxy)methyl]-6-phenylthiouracil was dissolved in 5 ml pyridine. To this solution 0.17 ml (1.5 mmol) of benzoyl chloride was added and the reaction mixture was allowed to react at room temperature for 2 hours. After the reaction, it was distributed between ethyl acetate and aqueous layers, and the said ethyl acetate layer then concentrated to dryness. The residue was crystallized from toluene to obtain 340 mg of 1-[(2-benzoyloxyethoxy)methyl]-6-phenylthiouracil (Yield: 85%). This was then suspended in 5 ml of toluene, and to this solution 449 mg (1.11 mmol) of 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4 diphosphetane-2,4-disulfide was added and the reaction mixture was allowed to react at 100° C. for 3 hours. After the reaction, the reaction mixture was distributed between ethyl acetate and aqueous layers, the ethyl actate layer concentrated to dryness. The residue was dissolved in 2 ml of tetrahydrofuran and 5 ml of ethanol. To this solution 2.25 ml of 1N sodium hydroxide aqueous solution was added and the reaction mixture was allowed to react at room temperature for 1 hour. It was then neutralized with hydrochloric acid, and concentrated to dryness. The residue was distributed between ethyl acetate and aqueous layers, and the said ethyl acetate layer was then concentrated to dryness. The resultant was dissolved in a small amount of chloroform, adsorbed on a silica gel column and eluted with 2.5% methanol/chloroform. The eluate was concentrated and dried to obtain a residue, which was crystallized from toluene to obtain 141 mg of the target compound (Yield: 53%).
Reaction SMILES: [CH2:1]([O:3][P:4](Cl)([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5])[CH3:2].[NH2:17][C@H:18]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]([CH2:25][C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[C:19]1=[O:36]>>[CH2:1]([O:3][P:4]([NH:17][C@H:18]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]([CH2:25][C:26]([O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:27])[C:19]1=[O:36])([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5])[CH3:2]
Reactant: N[C@H]1CCCCN(CC(=O)OCc2ccccc2)C1=O
Reactant: CCOP(=O)(Cl)CCCCc1ccccc1
Product: CCOP(=O)(CCCCc1ccccc1)N[C@H]1CCCCN(CC(=O)OCc2ccccc2)C1=O

Procedure:
Ethoxy(4-phenylbutyl)phosphinyl chloride is reacted with (S)-3-amino-2-oxo-hexahydro-1H-azepine-1-acetic acid, phenylmethyl ester according to the procedure of Example 2(e) to give (S)-hexahydro-3-[[ethoxy(4-phenylbutyl)phosphinyl]amino]-2-oxo-1H-azepine-1-acetic acid, phenylmethyl ester.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([NH:11][C:12]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][C:13]=2[C:14]([NH:16][CH2:17][C:18]2[CH:26]=[CH:25][C:21]3[O:22][CH2:23][O:24][C:20]=3[CH:19]=2)=[O:15])[CH2:7][CH2:6]1)=[O:4].CO.[OH-].[Na+].Cl>O1CCCC1>[C:3]([CH:5]1[CH2:6][CH2:7][CH:8]([NH:11][C:12]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][C:13]=2[C:14]([NH:16][CH2:17][C:18]2[CH:26]=[CH:25][C:21]3[O:22][CH2:23][O:24][C:20]=3[CH:19]=2)=[O:15])[CH2:9][CH2:10]1)([OH:4])=[O:2]
Reactant: COC(=O)C1CCC(Nc2ccc([N+](=O)[O-])cc2C(=O)NCc2ccc3c(c2)OCO3)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(NCc1ccc2c(c1)OCO2)c1cc([N+](=O)[O-])ccc1NC1CCC(C(=O)O)CC1
Temperature: 60 °C
Yield: 97 %

Procedure:
A mixture of 2-[4-(methoxycarbonyl)cyclohexylamino]-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (269 mg), methanol (10 mL), tetrahydrofuran (10 mL) and 1N-sodium hydroxide solution (5 mL) was stirred for an hour at 60° C. The mixture was acidified with 1N-hydrochloric acid to pH 4 and the organic solvent was removed by evaporation. The aqueous layer was diluted with water and extracted with chloroform. The extract was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with diisopropyl ether to give 2-(4-carboxycyclohexylamino)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide as yellow powders (253 mg).
Reaction SMILES: Cl[C:2]1[C:3](=[O:19])[N:4]([CH2:15][CH2:16][O:17][CH3:18])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH:21]1[NH2:29]>>[CH2:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH:21]1[NH:29][C:2]1[C:3](=[O:19])[N:4]([CH2:15][CH2:16][O:17][CH3:18])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NC1Cc2ccccc2C1
Reactant: COCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Product: COCCN1C(=O)C(NC2Cc3ccccc3C2)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 4-chloro-2-(2-methoxyethyl)-5-phenylisothiazol-3(2H)-one 1,1-dioxide and indan-2-amine in a similar manner as described for Example 1. 1H NMR (400 MHz, CD3CN): δ 7.65-7.60 (m, 2H), 7.55-7.50 (m, 3H), 7.13-7.11 (m, 4H), 5.90 (d, 1H), 4.06-3.98 (m, 1H), 3.83 (t, 2H), 3.67 (t, 2H), 3.38 (s, 3H), 2.84-2.81 (m, 4H); Mass Spectrum: M+H+ 399.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].C(Cl)(=O)C.[CH:9]([O:11][CH2:12][CH3:13])=[CH2:10]>>[C:1]([O:4][CH:9]([O:11][CH2:12][CH3:13])[CH3:10])(=[O:3])[CH3:2]
Reactant: C=COCC
Reactant: CC(=O)O
Solvent: CC(=O)Cl
Product: CCOC(C)OC(C)=O
Temperature: 30 °C
Reaction time: 1 h

Procedure:
Into a 500 ml reaction flask, equipped with stirrer, cooling bath, thermometer, addition funnel and nitrogen blanket apparatus, is added 60 ml of acetic acid (1.1 moles) and 0.1 ml of acetyl chloride. Dropwise over a period of one hour, while maintaining the reaction mass at 30° C., is added 100 ml (1.0 moles) of ethyl vinyl ether. At the end of the addition of said ethyl vinyl ether, the reaction mass is stirred for a period of twelve hours, while maintaining the temperature thereof at 30° C.
Reaction SMILES: [N:1]1([C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]3[CH:18]=[N:19][C:20]([C:21]([OH:23])=O)=[C:10]3[CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.CN.C(P(=O)([O-])OCC)#N.Br.Br[CH2:36][CH2:37][NH2:38]>ClCCl>[O:23]1[CH2:36][CH2:37][N:38]=[C:21]1[C:20]1[N:19]=[CH:18][N:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:8]([C:6]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[O:7])[CH2:9][C:10]=12
Reactant: NCCBr
Reactant: O=C(O)c1ncn2c1CN(C(=O)N1CCCC1)c1ccccc1-2
Agent: Br
Agent: CCOP(=O)([O-])C#N
Agent: CN
Solvent: ClCCl
Product: O=C(N1CCCC1)N1Cc2c(C3=NCCO3)ncn2-c2ccccc21
Reaction time: 0.67 h

Procedure:
To a mixture of 4,5-dihydro-5-[(pyrrolidino)carbonyl]imidazo[1,5-a]quinoxaline-3-carboxylic acid (I, EXAMPLE 322, 1.03 g) and 25 ml of dichloromethane cooled at 0° in an ice bath are added 1.15 ml of Methylamine and 0.650 ml) of ethyl cyanophosphonate, followed immediately by 0.811 g of 2-bromoethylamine hydrobromide. The ice bath is then removed and the reaction is stirred for 40 min. Aqueous sodium bicarbonate is then added. The mixture is stirred for 10 min and then partitioned with dichloromethane. The organic layers are dried over sodium sulfate and concentrated. The resulting mixture is stirred in 20 ml of THF and 3.3 ml of 1M potassium tert-butoxide is added dropwise over 2-3 min and the reaction is stirred an additional 10 min, at which time the reaction mixture is partitioned between ethyl acetate, water, and saline. The organic layers are dried over magnesium sulfate and concentrated. The crude product is chromatographed on silica gel (300 ml) eluting with methanol/methylene chloride (4/96), the appropriate fractions are pooled and concentrated to give the title compound, mp 217°-220°; MS (m/z) at 337; IR (mineral oil) 1651, 1512, 1416, 1357, 1396 cm-1 ; NMR (CDCl3) 1.81, 3.27, 4.05, 4.42, 4.99, 7.11-7.18, 7.26, 7.51, 8.03 δ.
Reaction SMILES: Br[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH2:3]1.[CH:12]1([NH2:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C1C=CC=CC=1>[CH:12]1([NH:18][CH:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4](=[O:11])[CH2:3]2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C1CC(Br)c2ccccc21
Reactant: NC1CCCCC1
Solvent: c1ccccc1
Product: O=C1CC(NC2CCCCC2)c2ccccc21
Yield: 83.5 %

Procedure:
3-Bromo-2,3-dihydro-1H-inden-1-one (100 mg, 475 μmol) and cyclohexylamine (94 mg, 951 μmol) were dissolved in 2 mL of dry benzene and stirred under N2 until precipitation ceased (˜15 min). The cyclohexylamine•HBr was removed by filtration. The filtrate was applied to a flash SiO2 column that was developed with 8:1 hexanes-EtOAc to give the title compound as a clear oil (91 mg, 84% yield).
Reaction SMILES: [N:1]1([C:8]2[N:12]3[CH:13]=[C:14]([O:17][C@H:18]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[C@@H:21]([NH2:28])[CH2:20][CH2:19]4)[CH:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClC(Cl)(Cl)C[O:32][C:33](=O)[NH:34][C:35]1[N:36]([C:44]2[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=2)[N:37]=[C:38]([C:40]([CH3:43])([CH3:42])[CH3:41])[CH:39]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[N:1]1([C:8]2[N:12]3[CH:13]=[C:14]([O:17][C@H:18]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[C@@H:21]([NH:28][C:33]([NH:34][C:35]5[N:36]([C:44]6[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=6)[N:37]=[C:38]([C:40]([CH3:43])([CH3:42])[CH3:41])[CH:39]=5)=[O:32])[CH2:20][CH2:19]4)[CH:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: N[C@H]1CC[C@@H](Oc2ccc3nnc(N4CCCCCC4)n3c2)c2ccccc21
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCCC5)n4c3)c3ccccc32)cc1
Yield: 10 %

Procedure:
A solution of Intermediate 67b (173 mg, 0.458 mmol) and (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 186 mg, 0.458 mmol) in 1,4-dioxane (3 mL) and DIPEA (122 μL, 0.700 mmol) was stirred at 95° C. for 3.5 h. The cooled mixture was concentrated in vacuo. The residue was purified by FCC, using 0-14% [2M NH3 in MeOH] in DCM. Further purification by FCC, using 0-10% MeOH in DCM, gave impure product. This was further purified by HPLC (C18X-select column, 30-98% MeCN in H2O, 0.1% HCO2H) to give impure product. Further purified by HPLC (XBridge column, 35-98% MeCN in H2O, 0.1% NH4OH) to give an off-white powder after freeze-drying (50 mg). This material was further purified by MDAP (Method 7) to give the title compound as a white solid (28 mg, 10%). LCMS (Method 5): Rt 4.77 min, m/z 633.2 [MH+]. 1H NMR (400 MHz, d5-DMSO): 1.27 (9H, s), 1.64-1.71 (4H, m), 1.74-1.97 (6H, m), 1.99-2.18 (2H, m), 2.36 (3H, s), 3.38-3.43 (4H, m, under water signal), 4.77-4.85 (1H, m), 5.47 (1H, t, J 4.3), 6.32 (1H, s), 7.07-7.14 (2H, m), 7.25-7.40 (8H, m), 7.55-7.59 (2H, m), 8.06 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:38]=[CH:37][C:5]([CH:6]=[CH:7][C:8]([NH:10][CH2:11][C:12]([N:14]([C:16]2[C:17]([Cl:36])=[C:18]([C:32]([Cl:35])=[CH:33][CH:34]=2)[CH2:19][O:20][C:21]2[CH:22]=[CH:23][CH:24]=[C:25]3[C:30]=2[N:29]=[C:28]([CH3:31])[CH:27]=[CH:26]3)[CH3:15])=[O:13])=[O:9])=[CH:4][C:3]=1[CH3:39].C(N(CC)CC)C.[CH3:47][S:48](Cl)(=[O:50])=[O:49]>ClCCl>[Cl:36][C:17]1[C:16]([N:14]([C:12](=[O:13])[CH2:11][NH:10][C:8](=[O:9])[CH:7]=[CH:6][C:5]2[CH:37]=[CH:38][C:2]([NH:1][S:48]([CH3:47])(=[O:50])=[O:49])=[C:3]([CH3:39])[CH:4]=2)[CH3:15])=[CH:34][CH:33]=[C:32]([Cl:35])[C:18]=1[CH2:19][O:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:30]=1[N:29]=[C:28]([CH3:31])[CH:27]=[CH:26]2
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(N)c(C)c4)c3Cl)c2n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(NS(C)(=O)=O)c(C)c4)c3Cl)c2n1
Reaction time: 1 h

Procedure:
To a solution of 8-[3-[N-(4-amino-3-methylcinnamoylglycyl)-N-methylamino]-2,6-dichlorobenzyloxy]-2-methylquinoline (200 mg) and triethylamine (35.9 mg) in dichloromethane was dropwise added methanesulfonyl chloride (0.03 ml) at 0° C. under nitrogen atmosphere, and the mixture was stirred for 1 hour at the same temperature. Methanesulfonyl chloride (0.03 ml) and triethylamine (36 mg) were further added thereto, and the mixture was stirred for 1 hour at the same temperature. The solvent was removed in vacuo, and the residue was dissolved in methanol. To the solution was added 1N sodium hydroxide solution (0.5 ml), and the mixture was stirred for 3 hours at ambient temperature and concentrated. To the residue were added dichloromethane and water, the organic layer was washed with water, saturated sodium bicarbonate solution and brine, dried and concentrated in vacuo. The residue was purified by preparative thin-layer chromatography (dichloromethane:methanol=15:1, V/V) to give 8-[2,6-dichloro-3-[N-(4-methanesulfonamido-3-methylcinnamoylglycyl)-N-methylamino]benzyloxy]-2-methylquinoline (185 mg) as an amorphous powder.
Reaction SMILES: I.[NH2:2][C:3]1[C:4]([C:11]([NH:13][C:14](=[NH:17])SC)=[O:12])=[N:5][C:6]([Cl:10])=[C:7]([NH2:9])[N:8]=1.C(N(CC)CC)C.[C:25]([O:29][C:30](=[O:48])[NH:31][CH2:32][CH2:33][C:34](=[O:47])[NH:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][CH2:44][CH2:45][NH2:46])=[CH:38][CH:37]=1)([CH3:28])([CH3:27])[CH3:26]>C(O)C>[C:25]([O:29][C:30](=[O:48])[NH:31][CH2:32][CH2:33][C:34](=[O:47])[NH:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][CH2:44][CH2:45][NH:46][C:14]([NH2:17])=[N:13][C:11]([C:4]2[C:3]([NH2:2])=[N:8][C:7]([NH2:9])=[C:6]([Cl:10])[N:5]=2)=[O:12])=[CH:38][CH:37]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)NCCC(=O)Nc1ccc(CCCCN)cc1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Agent: I
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCC(=O)Nc1ccc(CCCCNC(N)=NC(=O)c2nc(Cl)c(N)nc2N)cc1
Temperature: 65 °C
Reaction time: 3 h
Yield: 78.9 %

Procedure:
1-(3,5-Diamino-6-chloropyrazine-2-carbonyl)-2-methylisothiourea hydriodide (0.32 g, 0.82 mmol) and triethylamine (0.42 mL) were added to a solution of {2-[4-(4-amino-butyl)phenylcarbamoyl]ethyl}carbamic acid tert-butyl ester 340 (0.25 g, 0.74 mmol) in ethanol (6 mL). The reaction mixture was stirred at 65° C. for 3 hours, and cooled to room temperature. The solvent was evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 10:1:0.1 to 5:1:0.1, v/v chloroform/methanol/concentrated ammonium hydroxide). The product was washed with water (2×25 mL) and dried in a vacuum oven overnight to provide 350 (0.32 g, 78%) as a yellow solid. 1H NMR (300 MHz, CD3OD) δ 1.44 (s, 9H), 1.69 (m, 4H), 2.57 (t, 2H), 2.66 (t, 2H), 3.27 (t, 2H), 3.40 (m, 2H), 7.15 (d, 2H), 7.47 (d, 2H).
Reaction SMILES: COP([CH2:7][C:8](=[O:16])[C:9]([F:15])([F:14])[CH2:10][CH2:11][CH2:12][CH3:13])(=O)OC.[OH-].[Na+].[C:19]([O:22][C@@H:23]1[C@H:27]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C@@H:26]([CH:38]=O)[C@H:25]([O:40][CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43][O:42]2)[CH2:24]1)(=[O:21])[CH3:20].O>COC(C)(C)C>[C:19]([O:22][C@@H:23]1[C@H:27]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C@@H:26](/[CH:38]=[CH:7]/[C:8](=[O:16])[C:9]([F:14])([F:15])[CH2:10][CH2:11][CH2:12][CH3:13])[C@H:25]([O:40][CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43][O:42]2)[CH2:24]1)(=[O:21])[CH3:20]
Reactant: COC(=O)CCCCCC[C@@H]1[C@@H](C=O)[C@H](OC2CCCCO2)C[C@@H]1OC(C)=O
Reactant: CCCCC(F)(F)C(=O)CP(=O)(OC)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COC(C)(C)C
Product: CCCCC(F)(F)C(=O)/C=C/[C@@H]1[C@@H](CCCCCCC(=O)OC)[C@@H](OC(C)=O)C[C@H]1OC1CCCCO1
Temperature: 25 °C
Reaction time: 1.2 h
Yield: 84.7 %

Procedure:
To a solution of dimethyl (3,3-difluoro-2-oxoheptyl)phosphonate (1) (1.109 g, 4.295 mmol) in t-butyl methyl ether (17 ml), sodium hydroxide (0.164 g, 4.10 mmol) was added and the mixture was stirred for approximately 1.2 hours at room temperature. A solution of methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-formyl-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (2) (0.955 g, 2.40 mmol) in t-butyl methyl ether (3 ml), and water (0.32 ml) were added thereto, and the mixed solution was heat refluxed for approximately 48 hours. After cooling to room temperature, water (5.6 ml) was added to the solution and stirred, and then, let to stand and separated into two layers. The aqueous layer was extracted twice with ethyl acetate (4 ml). The organic layers were combined, sequentially washed with 3% aqueous sodium chloride (6 ml) and saturated aqueous sodium chloride (6 ml), and then dried with anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (Fuji Silysia BW-300SP: 33 g; ethyl acetate:hexane=1:4) to give methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-((E)-4,4-difluoro-3-oxo-1-octenyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (3) (1.079 g; 2.033 mmol; yield: 84.8%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[N:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[C:10]=1[CH:11]=[CH:12][O:13]C)=[O:5])[CH3:2].OS(O)(=O)=O.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)[N:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[C:10]=1[CH2:11][CH:12]=[O:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(-c2ccc(Cl)cc2)n(-c2ccccc2Cl)c1C=COC
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1nc(-c2ccc(Cl)cc2)n(-c2ccccc2Cl)c1CC=O
Temperature: 25 °C

Procedure:
A solution of 2-(4-chloro-phenyl)-1-(2-chloro-phenyl)-5-(2-methoxy-vinyl)-1H-imidazole-4-carboxylic acid ethyl ester I-5g (275 mg, 0.659 mmol) and H2SO4 (200 μl) in 5:1 THF/H2O (18 ml) was heated at 70° C. for 3 hours. The reaction mixture was cooled to room temperature and treated with 1M K2CO3 until the pH of the reaction mixture was ˜6. The aqueous solution was extracted with CH2Cl2 and the combined organic extracts were washed with sat'd aq. NaCl, dried, and concentrated in vacuo to give a mixture of the starting material and product (I-5h): +APCI MS (M+1) 403.3
Reaction SMILES: [CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][C:3]=2[O:2]1.[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]([O:19][CH2:20][CH3:21])=[O:18]>[Cl-].[Zn+2].[Cl-].C(=S)=S>[CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH2:6][C:16]3[O:12][C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:14][CH:15]=3)=[CH:4][C:3]=2[O:2]1
Reactant: CCOC(=O)c1ccco1
Reactant: BrCc1ccc2c(c1)OCO2
Agent: [Cl-]
Agent: [Zn+2]
Solvent: S=C=S
Product: CCOC(=O)c1ccc(Cc2ccc3c(c2)OCO3)o1
Temperature: 25 °C

Procedure:
A solution of 60 g. of 3,4-methylenedioxybenzyl bromide in 200 ml. of carbon disulfide was slowly added over a period of 45 minutes to a solution of 260 g. of ethyl 2-furoate and 20 g. of zinc chloride in 600 ml. of carbon disulfide held at 31 10° C. The reaction mixture was allowed to warm to room temperature, filtered, extracted with water and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was removed and the residue distilled to give 27 g. of ethyl 5-(3,4-methylenedioxybenzyl)-2-furoate, b.p. 162°-166° C. (0.5 mm), which crystallized to a solid, m.p. 67°-68° C.