Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([CH2:16][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:8]=1[N:9]1[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]1)[NH2:5].Cl[C:24]1[C:33]2[C:28](=[CH:29][C:30]([Cl:34])=[CH:31][CH:32]=2)[N:27]=[CH:26][CH:25]=1.Cl>C(#N)C>[Cl:34][C:30]1[CH:29]=[C:28]2[C:33]([C:24]([NH:5][C:4]3[CH:6]=[C:7]([CH2:16][N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[C:8]([N:9]4[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]4)=[C:2]([CH3:1])[CH:3]=3)=[CH:25][CH:26]=[N:27]2)=[CH:32][CH:31]=1
Reactant: Cc1cc(N)cc(CN2CCOCC2)c1N1CCN(C)CC1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Agent: Cl
Solvent: CC#N
Product: Cc1cc(Nc2ccnc3cc(Cl)ccc23)cc(CN2CCOCC2)c1N1CCN(C)CC1
Yield: 61.9 %

Procedure:
3-Methyl-4-(4-methylpiperazin-1-yl)-5-(morpholin-4-ylmethyl)aniline (79 mg, 0.26 mmol) and 4,7-dichloroquinoline (56 mg, 1.1 eq) were refluxed overnight in 5 mL of acetonitrile with 0.78 mL of HCl 1M. The reaction mixture was then evaporated and purified by flash chromatography (DCM/MeOH/NH4OH//9/1/0.1) to yield expected compound as a pale yellow solid (75 mg, 62% yield). m/z (ESI) 466.4 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[C:21]([C:28]([F:31])([F:30])[F:29])[CH:20]=1.N1C=CC=CC=1>C1COCC1>[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([N:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[O:24])=[C:21]([C:28]([F:29])([F:30])[F:31])[CH:20]=1
Reactant: COc1ccc(Nc2ccc(OC)cc2)cc1
Reactant: O=C(Cl)c1ccc(F)cc1C(F)(F)F
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1ccc(N(C(=O)c2ccc(F)cc2C(F)(F)F)c2ccc(OC)cc2)cc1
Temperature: 90 °C
Yield: 84.2 %

Procedure:
1 equivalent of bis-(4-methoxyphenyl)amine (1a) (0.73 g, 3.18 mmol) was mixed with 1.2 equivalents of 4-fluoro-2-trifluoromethylbenzoyl chloride (0.87 g, 3.82 mmol) and 6 equivalents of pyridine (1.51 g, 19.08 mmol) in a dry three-necked round-bottomed flask equipped with a magnetic stirring bar and a reflux condenser. The mixture was dissolved in anhydrous THF (20 mL) and heated to 90° C. for 20 hours. The reaction solution was cooled to room temperature and filtered. The solvent was removed under reduced pressure. The residue was purified by flash column chromatography using silica-gel with EtOAc/hexanes (3/7 v/v) to afford the pure corresponding benzamide compound as a colorless oil, 1.12 g, 84.2% yield. 1H NMR (CDCl3, 300 MHz) δ 7.34-7.26 (m, 4H), 7.09-7.01 (m, 3H), 6.91 (d, 2H, J=8.7 Hz), 6.87 (d, 2H, J=8.7 Hz), 3.80 (s, 3H), 3.71 (s, 3H). MS m/z 442.1 (M+Na)+.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:3]=1.P(Cl)(Cl)([Cl:23])=O.[OH-].[Na+]>CN(C)C=O>[Cl:23][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:3]=1
Reactant: O=[N+]([O-])c1ccc2nc(-c3ccccc3)cc(O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2nc(-c3ccccc3)cc(Cl)c2c1
Temperature: 70 °C
Yield: 101.2 %

Procedure:
4-Hydroxy-6-nitro-2-phenylquinoline (10.00 g, 38 mmol) was suspended in phosphorus oxychloride (POCl3) (57.58 g, 380 Mol) at 0° C. Dimethylformamide (DMF) (45 ml) was added dropwise and the resulting mixture heated at 70° C. for 5 hours. The reaction was cooled and then poured onto ice. The pH was adjusted to 6 with aqueous sodium hydroxide and the precipitate collected by vacuum filtration and dried in a vacuum oven to give 4-chloro-6-nitro-2-phenylquinoline (10.95 g, 102%) as a yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:36](=[O:38])[CH3:37])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[N:27][C:22]=4[CH2:21][O:20][C:19]4[CH:28]=[CH:29][C:30]([C:32](O)([CH3:34])[CH3:33])=[CH:31][C:18]3=4)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:36]([OH:38])[CH3:37])[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[N:27][C:22]=4[CH2:21][O:20][C:19]4[CH:28]=[CH:29][C:30]([C:32]([CH3:34])=[CH2:33])=[CH:31][C:18]3=4)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CC(=O)C1(c2ccc(Cl)cc2)CCN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C=C(C)c1ccc2c(c1)C(=CCCN1CCC(c3ccc(Cl)cc3)(C(C)O)CC1)c1cccnc1CO2
Temperature: 0 °C

Procedure:
The product of Example 457 (64 mg, 0.12 mmol) was dissolved in anhydrous methanol (2.5 mL) and the resulting solution cooled to 0° C. Sodium borohydride (37 mg, 1 mmol,) was added portionwise over 5 h. The reaction was quenched with water and concentrated. The crude product residue was purified by reverse phase HPLC (water, acetonitrile, formic acid gradient) to afford the titled compound (note elimination of tertiary benzylic alcohol). MS m/z: 515 (m+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[CH:20]([C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=1[S:32](=[O:35])(=[O:34])[NH2:33])([CH3:22])[CH3:21]>>[CH:20]([C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:19][C:3]2[CH:4]=[CH:5][C:6]([N:8]3[CH2:12][CH2:11][CH:10]([N:13]4[CH2:17][CH2:16][CH2:15][CH:14]4[CH3:18])[CH2:9]3)=[CH:7][C:2]=2[CH3:1])=[O:28])=[CH:25][C:24]=1[S:32](=[O:35])(=[O:34])[NH2:33])([CH3:22])[CH3:21]
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Reactant: CC(C)c1ccc(C(=O)O)cc1S(N)(=O)=O
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1ccc(C(C)C)c(S(N)(=O)=O)c1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 4-isopropyl-3-sulfamoyl-benzoic acid. MS: 485.3 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([CH:12]([CH3:14])[CH3:13])[C:6]2=O.C1COCC1.CO.[BH4-].[Na+]>O>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5]([CH:12]([CH3:14])[CH3:13])=[CH:6]2
Reactant: CC(C)C1Cc2c(Br)cccc2C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)C1=Cc2cccc(Br)c2C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 73.4 g (0.29 mol) of 4-bromo-2-isopropylindan-1-one in 530 ml of a mixture of THF-methanol (2:1, vol.), 22.0 g (0.58 mol) of NaBH4 was added in small portions while vigorously stirring for 2 h at 0° C. This mixture was stirred for 12 h at room temperature and then added to 600 ml of cold water. The organic layer was separated, the aqueous layer was extracted with 3×300 ml of methyl-tert-butyl ether. The combined organic fractions were dried over K2CO3 and then evaporated to dryness. The residue was dissolved in 1500 ml of toluene, and 2.0 g of p-TosOH was added. The resulting solution was refluxed for 2 h using a Dean-Stark trap to remove the water formed, and then it was passed through a short Silica Gel 60 column (40-63 um, d 100 mm, l 80 mm, eluent: hexanes). This column was additionally washed with 250 ml of toluene. The combined organic fractions were evaporated to dryness. The product was isolated by vacuum distillation (bp 128-132° C./4 mm Hg). Yield 57.8 g (84%).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4](Cl)[C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[OH-].[NH4+:23]>O>[NH2:23][C:4]1[C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=[C:2]([Br:1])[N:3]=1
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)nc2Cl)CC1
Agent: [OH-]
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)nc2N)CC1
Temperature: 120 °C
Reaction time: 12 h
Yield: 51 %

Procedure:
A 300 mL pressure vessel was charged with tert-butyl 4-(5-bromo-3-chloropyrazin-2-yl)piperazine-1-carboxylate (5.0 g, 13 mmol) and concentrated ammonium hydroxide (60 mL). The vessel was sealed and the reaction mixture was magnetically stirred at 120° C. for 12 h. After the reaction mixture was cooled to room temperature, the vessel was opened and the resulting mixture was poured into water (100 mL) and extracted with CH2Cl2 (50 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with 3% EtOAc in CH2Cl2 (containing 2% Et3N), to afford 2.4 g (51%) of the product as a white solid. MS m/z: 358 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:21][C:22](=[O:35])[CH2:23][CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34].FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[CH:4][C:3]=1[NH:21][C:22](=[O:35])[CH2:23][CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34]
Reactant: COc1ccccc1CCCCC(=O)Nc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1CCCCC(=O)Nc1cc(C2CCNCC2)ccc1F
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
Into a solution of tert-butyl 4-(4-fluoro-3-{[5-(2-methoxyphenyl)pentanoyl]amino}phenyl)-1-piperidinecarboxylate (48.4 mg, 0.100 mmol) in CH2Cl2 (2.0 mL) was added trifluoroacetic acid (114 mg, 1.0 mmol) at room temperature. The reaction mixture was stirred for 30 min and concentrated in vacuo. The residue was dissolved in CHCl3/i-PrOH (3:1, 10 mL) and was basified to pH 11 with 5% KOH solution. The organic layer was separated and the aqueous layer was extracted with CHCl3/i-PrOH (3:1, 3×10 mL). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford afford N-[2-fluoro-5-(4-piperidinyl)phenyl]-5-(2-methoxyphenyl)pentanamide (38.0 mg, 95%): 1H NMR (400 MHz, CD3OD) δ 8.30-8.12 (m, 1H), 7.64-7.41 (m, 1H), 7.24-7.07 (m, 2H), 7.06-6.92 (m, 1H), 6.92-6.74 (m, 3H), 3.80 (s, 3H), 3.25-3.06 (m, 2H), 2.80-2.49 (m, 5H), 2.48-2.24 (m, 3H), 1.89-1.71 (m, 4H), 1.71-1.46 (m, 4H); ESMS m/e: 385.2 (M+H)+.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[N:11]=[C:12]([N:15]=[C:16]([NH2:18])[NH2:17])[S:13][CH:14]=2)[N:9]=1.[CH2:19]([S:21](C(=N)OCC)(=[O:23])=[O:22])[CH3:20].[CH2:29]([N:31](CC)CC)C>CO>[NH2:17][C:16](=[N:15][C:12]1[S:13][CH:14]=[C:10]([C:8]2[N:9]=[C:5]([CH2:4][NH:3][CH:29]=[N:31][S:21]([CH2:19][CH3:20])(=[O:22])=[O:23])[S:6][CH:7]=2)[N:11]=1)[NH2:18]
Reactant: CCOC(=N)S(=O)(=O)CC
Reactant: NCc1nc(-c2csc(N=C(N)N)n2)cs1
Reactant: CCN(CC)CC
Agent: Cl
Solvent: CO
Product: CCS(=O)(=O)N=CNCc1nc(-c2csc(N=C(N)N)n2)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.7 %

Procedure:
A suspension of 4-(2-aminomethylthiazol-4-yl)-2-(diaminomethyleneamino)thiazole dihydrochloride (1.3 g), ethyl ethanesulfonylformimidate (0.8 g) and triethylamine (1.0 g) in methanol (20 ml) was stirred at room temperature for 8 hours. The solvent was removed under reduced pressure. The residue was chromatographed on a silica gel column eluting with a mixture of chloroform and methanol (10:1). Recrystallization from a mixture of N,N-dimethylformamide and water afforded 2-(diaminomethyleneamino)-4-(2-ethanesulfonyliminomethylaminomethylthiazol-4-yl)thiazole (0.53 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]#[N:10])=[C:4](Cl)[N:3]=1.C([N:14]([CH:18]([CH3:20])[CH3:19])C(C)C)C.[CH:21]1([NH2:24])[CH2:23][CH2:22]1>O1CCOCC1>[Cl:8][C:6]1[C:5]([C:9]#[N:10])=[C:4]([NH:24][CH:21]2[CH2:23][CH2:22]2)[N:3]=[C:2]([NH:14][CH:18]2[CH2:19][CH2:20]2)[N:7]=1
Reactant: NC1CC1
Reactant: N#Cc1c(Cl)nc(Cl)nc1Cl
Reactant: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#Cc1c(Cl)nc(NC2CC2)nc1NC1CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.2 %

Procedure:
To a solution of 500 mg (2.4 mmol) of 2,4,6-trichloro-5-cyano-pyrimidine in 30 ml of dioxane were added at room temperature 0.84 ml (4.8 mmol) of N-ethyl-diisopropylamine and 0.52 ml (7.2 mmol) of cyclopropylamine. The yellow reaction mixture was stirred at room temperature during 18 hours, then, for working-up, it was evaporated under reduced pressure. The residue obtained was then chromatographed on silica gel using a 3:1 mixture of dichloromethane and hexane as the eluent yielding 328 mg (1.3 mmol, 55% of theory) of 4-chloro-2,6-bis-cyclopropylamino-pyrimidine-5-carbonitrile as a yellow solid; MS: [M+H]+=249.
Reaction SMILES: [Na].[CH2:2]([O:4][C:5](=[O:17])[CH2:6][C:7]([NH:9][CH2:10][CH2:11][C:12]([O:14]CC)=O)=[O:8])C.O>CO.C1(C)C=CC=CC=1>[CH3:2][O:4][C:5]([CH:6]1[C:12](=[O:14])[CH2:11][CH2:10][NH:9][C:7]1=[O:8])=[O:17]
Reactant: CCOC(=O)CCNC(=O)CC(=O)OCC
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CO
Product: COC(=O)C1C(=O)CCNC1=O
Temperature: 25 °C
Yield: 88 %

Procedure:
A solution of β-alanine ethylester hydrochloride (13.8 g, 90 mmol) in dichloromethane (90 mL) and triethylamine (TEA, 13.8 mL, 99 mmol) was stirred at room temperature for 1 hour. More TEA (13.8 mL, 99 mmol) was added, the solution was cooled to 0° C. under stirring and ethylmalonylchloride (12.6 mL, 99 mmol) was added dropwise. After 1 hour at 0° C., the reaction mixture was stirred 1 hour at room temperature. A 15% aqueous solution of K2CO3 (90 mL) was added and the layers were separated. The organic phase was washed with 10% HCl (90 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was chromatographed on flash silica gel (450 g, eluant: ethyl acetate/n-hexane 2:1) to give N-(2-ethoxycarbonyl-ethyl)-malonamic acid ethyl ester as a yellow oil (15 g, 64.9 mmol, 72% yield). Sodium metal (610 mg, 26.6 mmol) was dissolved in dry MeOH (25 mL) at room temperature under stirring and inert atmosphere. After complete dissolution the mixture was stirred 10′ longer, then N-(2-ethoxycarbonyl-ethyl)-malonamic acid ethyl ester (6.15 g, 26.6 mmol) in dry toluene (150 mL) was added dropwise. After addition, the reaction mixture was stirred at 90° C. for 6 hours, cooled to room temperature, water (30 mL) was added and the layers were separated. The organic phase was washed with water (2×10 mL), the combined aqueous phases were acidified with 37% HCl and extracted thoroughly with a mixture of DCM/MeOH (5:1). After drying over Na2SO4 and concentration, 3-methoxycarbonylpiperidin-2,4-dione as a pink solid was obtained (4 g, 88% yield). 3-Methoxycarbonylpiperidin-2,4-dione (4 g, 23.4 mmol) was dissolved in acetonitrile containing 1% of water (250 mL) and refluxed for 4 hours. The reaction mixture was concentrated to give the title compound, as a yellow solid (2.4 g, 90% yield).
Reaction SMILES: [N:1]1([N:7]2[CH2:12][CH2:11][CH2:10][NH:9][C:8]2=[O:13])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([S:25]([CH2:28][C@@H:29]([OH:33])[C:30](O)=[O:31])(=[O:27])=[O:26])[CH:19]=[CH:18]2.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[Cl:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([S:25]([CH2:28][C@@H:29]([OH:33])[C:30]([N:4]1[CH2:3][CH2:2][N:1]([N:7]3[CH2:12][CH2:11][CH2:10][NH:9][C:8]3=[O:13])[CH2:6][CH2:5]1)=[O:31])(=[O:26])=[O:27])[CH:19]=[CH:18]2
Reactant: O=C(O)[C@H](O)CS(=O)(=O)c1ccc2cc(Cl)ccc2c1
Reactant: O=C1NCCCN1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C([C@H](O)CS(=O)(=O)c1ccc2cc(Cl)ccc2c1)N1CCN(N2CCCNC2=O)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 61 %

Procedure:
1-(Piperazin-1-yl)tetrahydropyrimidin-2(1H)-one obtained in Example 25b) (0.55 g), (2S)-3-[(6-chloronaphthalen-2-yl)sulfony]-2-hydroxypropionic acid (0.94 g) and HOBt (0.46 g) were dissolved in DMF (20 mL), WSC was added thereto, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and the residue was washed with an aqueous sodium bicarbonate solution, and extracted with dichloromethane. The extract was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate to ethyl acetate/methanol=5/1), and recrystallized from ethyl acetate-methanol to obtain the title compound (0.88 g, 61%) as a colorless powder.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:10])[CH2:8][NH2:9])([CH3:5])([CH3:4])[CH3:3].[N+:11]([C:14]1[CH:19]=[CH:18][C:17](F)=[CH:16][CH:15]=1)([O-:13])=[O:12].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[C:2]([O:6][C:7](=[O:10])[CH2:8][NH:9][C:17]1[CH:18]=[CH:19][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)CNc1ccc([N+](=O)[O-])cc1
Temperature: 90 °C
Yield: 81.3 %

Procedure:
A mixture of glycine tert-butyl ester hydrochloride (3.35 g, 20 mmol), 4-nitrofluorobenzene (2.82 g, 20 mmol) and potassium carbonate (4.2 g, 30 mmol) in DMSO (15 mL) was heated at 90° C. for 22 hr. The reaction mixture was allowed to cool to room temperature and then poured onto crushed ice. The precipitated yellow solid was filtered, washed with water and dried (Na2SO4) to give N-(4-nitrophenyl)glycine tert-butyl ester (4.1 g, 81%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10](NN)[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.C(OC)(=O)C(C)=O>CO>[C:14]1([C:7]2[C:6]3[CH:20]=[CH:2][CH:3]=[CH:4][C:5]=3[N:11]=[CH:10][CH2:9][N:8]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Agent: COC(=O)C(C)=O
Solvent: CO
Product: C1=Nc2ccccc2C(c2ccccc2)=NC1
Reaction time: 7 h

Procedure:
A mixture of 5.7 g. (0.02 mole) of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine, 3 ml. (0.04 mole) of methyl pyruvate and 50 ml. of methanol is stirred, under nitrogen, for 17 hours at room temperature, by which time the solid has dissolved. Three ml. more methyl pyruvate is added and the solution is allowed to stand for 7 hours more. After filtration and evaporation in vacuo (50° C./0.5 mm.) a brown gum is obtained which is chromatographed on silica gel and eluted with 1% methanol in chloroform. Evaporation of the combined fractions containing the product (as indicated by thin layer chromatography) gives a gum which is crystallized from a mixture of chloroform and ether. A yield of 3.5 g. (67%) of 7-chloro-2-[[1-methoxycarbonyl)ethylidene]hydrazino]-5-phenyl-3H-1,4-benzodiazepine is obtained as nearly white crystals of melting point 156°-157° C. Melt solvate indicates the product contained 1.95% CHCl3 even after prolonged drying in vacuo.
Reaction SMILES: C(C1SC2[C:11]3[S:14][C:15]4[C:19](CCCCCCCCCCCCCCCCC)=[C:18]([C:37]([O:39]CC)=[O:38])[S:17][C:16]=4[C:10]=3SC=2C=1CCCCCCCCCCCCCCCCC)(OCC)=O.[Li+].[OH-:60].C1[CH2:65][O:64]CC1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CO>[S:17]1[C:16]2[C:10]([C:65]([OH:64])=[O:60])=[CH:11][S:14][C:15]=2[CH:19]=[C:18]1[C:37]([OH:39])=[O:38]
Reactant: CCCCCCCCCCCCCCCCCc1c(C(=O)OCC)sc2c1sc1c3sc(C(=O)OCC)c(CCCCCCCCCCCCCCCCC)c3sc21
Reactant: [OH-]
Reactant: C1CCOC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Li+]
Solvent: CO
Product: O=C(O)c1cc2scc(C(=O)O)c2s1
Yield: 96 %

Procedure:
Ester deprotection (Step C) The 2,6-dicarboethoxy-3,7-diheptadecylthieno[3,2-b]thieno[2′,3′:4,5]thieno[2,3-d]thiophene (26.0 g, 30 mmol) product of Example 2, LiOH (2.9 g, 121 mmol in 29 mL water), THF (100 mL), MeOH (20 mL) and a catalytic amount (about 35 mg) of tetrabutylammonium bromide were combined in a round bottomed flask fitted with a condenser and heated at reflux overnight. Approximately 90% of the solvent was evaporated and the residue was acidified to pH 1 with concentrated hydrochloric acid to form a solid which was collected by filtration, washed thoroughly with water and methanol, and dried under vacuum to yield 3,7-diheptadecanyl thieno[3,2-b]thieno[2′:3′:4,5]thieno[2,3-d]thiophene-2,6-dicarboxylic acid (23.5 g, 96% yield). 1H NMR (D8-THF) δ 0.88 (6H, m), 1.20-1.50 (72H, m), 1.70-1.87 (4H, m), and 3.23 (4H, m).
Reaction SMILES: [CH3:1][CH:2]([O:6][CH2:7][CH:8]([O:12]C)[CH2:9]OC)[CH2:3][O:4]C.C(C(CCCCCCCCCC)CO)CCCCCCC>O>[CH3:9][CH:8]([OH:12])[CH2:7][O:6][CH:2]([CH2:3][OH:4])[CH3:1].[CH2:3]([OH:4])[CH:2]([OH:6])[CH3:1]
Reactant: COCC(C)OCC(COC)OC
Agent: CCCCCCCCCCC(CO)CCCCCCCC
Solvent: O
Product: CC(O)CO
Product: CC(O)COC(C)CO
Temperature: 70 °C

Procedure:
The hydroxypropylcellulose is dispersed in deionized water until complete swelling takes place. A solution of acetal dibenzylidene sorbitol, dipropyleneglycol, PEG 300 and propylene glycol is prepared, it is heated to 70° C. and then the propylenecarbonate is added, under stirring. The solution of PPG 27 glyceryl ether, Cosmacol ELI, 2-octyl dodecanol, perfume and preservative, previously prepared, is added to this solution, the temperature being maintained constant at 70° C.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[N:7]=[CH:6][CH:5]=1.[NH:18]1[CH2:23][CH2:22][CH:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:15][O:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][C:10]=1[O:16][CH3:17])[N:7]=[CH:6][CH:5]=[C:4]2[CH2:3][N:18]1[CH2:19][CH2:20][CH:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[CH2:22][CH2:23]1
Reactant: COc1cc2nccc(CCl)c2cc1OC
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc2nccc(CN3CCC(NC(=O)OC(C)(C)C)CC3)c2cc1OC
Temperature: 80 °C
Reaction time: 4 h
Yield: 94.9 %

Procedure:
4-(Chloromethyl)-6,7-dimethoxyquinoline hydrochloride (0.75 g, 2.74 mmol), tert-butyl piperidin-4-ylcarbamate (0.77 g, 3.84 mmol), and cesium carbonate (2.68 g, 8.23 mmol) were dissolved in DMF (14 mL) and heated to 80° C. while stirring. After 4 hours, the reaction was cooled, DMF was removed, and the compound was taken up in DCM (150 mL) and water (20 mL). The aqueous layer was extracted 2× with DCM (50 mL). The organics were washed with brine, dried with sodium sulfate, and concentrated to give the desired product tert-butyl 1-((6,7-dimethoxyquinolin-4-yl)methyl)piperidin-4-ylcarbamate (1.04 g, 2.60 mmol, 95% yield). MS (ESI pos. ion) m/z: 402.2 (MH+). Calc'd exact mass for C22H31N3O4: 401. 1HNMR (400 MHz, CDCl3): 8.64-8.65 (d, J=4.4 Hz, 1H), 7.58 (s, 1H), 7.42 (s, 1H), 7.23-7.24 (d, J=4.4 Hz, 1H), 4.57-4.59 (m, 1H), 4.03 (s, 3H), 4.01 (s, 3H), 3.83 (s, 2H), 2.82-2.85 (bd, J=11.6 Hz, 2H), 2.18-2.24 (bt, J=10.8 Hz, 2H), 1.92-1.95 (bd, J=12.4 Hz, 2H), 1.44 (s, 9H), 1.41-1.44 (m, 2H, overlapping).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:9]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10]2)[S:5][C:6]=1[CH:7]=O.[CH:15]1([NH:18][C:19]([C@@H:21]2[C@H:26]([NH:27][C:28]3[C:33]([Cl:34])=[CH:32][N:31]=[C:30]([NH2:35])[C:29]=3[NH2:36])[C@@H:25]3[CH2:37][C@H:22]2[CH:23]=[CH:24]3)=[O:20])[CH2:17][CH2:16]1.C([O-])(=O)C.[NH4+]>>[CH:15]1([NH:18][C:19]([C@@H:21]2[C@H:26]([NH:27][C:28]3[C:33]([Cl:34])=[CH:32][N:31]=[C:30]4[NH:35][C:7]([C:6]5[S:5][C:4]([N:9]6[CH2:13][CH2:12][C@@H:11]([OH:14])[CH2:10]6)=[N:3][C:2]=5[Cl:1])=[N:36][C:29]=34)[C@@H:25]3[CH2:37][C@H:22]2[CH:23]=[CH:24]3)=[O:20])[CH2:17][CH2:16]1
Reactant: O=Cc1sc(N2CCC(O)C2)nc1Cl
Reactant: Nc1ncc(Cl)c(N[C@H]2[C@@H](C(=O)NC3CC3)[C@@H]3C=C[C@H]2C3)c1N
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: O=C(NC1CC1)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4sc(N5CC[C@@H](O)C5)nc4Cl)nc23)[C@H]2C=C[C@@H]1C2
Yield: 11.1 %

Procedure:
In a similar fashion to Compound LXXXVII, 4-Chloro-2-(3-hydroxy-pyrrolidin-1-yl)-thiazole-5-carbaldehyde (174.40 mg, 0.74951 mmol), (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid cyclopropylamide (200 mg, 0.6 mmol), and Ammonium acetate (92.439 mg, 1.1992 mmol) were reacted to produce 36.26 mg (10%) of the title compound. (300 MHz, DMSO-d6) 12.68 (s, 1H), 8.30 (s, 1H), 7.94 (s, 1H), 6.93 (s, 1H), 6.38-6.30 (m, 2H), 4.99 (t, J=17 Hz, 8.5 Hz, 1H), 3.44 (m, 4H), 2.84 (s, 1H), 2.76 (s, 1H), 2.66 (m, 1H), 2.23 (d, J=8 Hz, 1H), 2.01 (m, 4H), 1.38 (d, J=8 Hz, 1H), 0.63 (m, 2H), 0.37 (m, 2H). MS=546 (M+H), HPLC: 2.35 min. (G Method)