Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC(N1CCCC1C1NC(C2C=CC(C3C=CC4C(=CC=C(C5NC(C6CCCN6C(=O)C(NC(OC)=O)C(C)C)=NC=5)C=4)C=3)=CC=2)=CN=1)=O)(C)(C)[CH3:2].[C:55]([O:59][C:60]([N:62]1[CH2:66][CH2:65][CH2:64][CH:63]1[C:67]1[NH:68][C:69]([C:72]2[CH:77]=[CH:76][C:75](Br)=[CH:74][CH:73]=2)=[CH:70][N:71]=1)=[O:61])([CH3:58])([CH3:57])[CH3:56].C(OC(N1CCCC1C1NC(C2C=CC3C(=CC=C(B4OC(C)(C)C(C)(C)O4)C=3)C=2)=CN=1)=O)(C)(C)C.[CH3:115][O:116][C:117](=[O:154])[NH:118][CH:119]([C:123]([N:125]1[CH2:129][CH2:128][CH2:127][CH:126]1[C:130]1[NH:131][C:132]([C:135]2[CH:144]=[CH:143][C:142]3[C:137](=CC=[C:140](B4OC(C)(C)C(C)(C)O4)[CH:141]=3)[CH:136]=2)=[CH:133][N:134]=1)=[O:124])[CH:120]([CH3:122])[CH3:121]>>[C:55]([O:59][C:60]([N:62]1[CH2:66][CH2:65][CH2:64][CH:63]1[C:67]1[NH:68][C:69]([C:72]2[CH:77]=[CH:76][C:75]3[C:74](=[CH:1][CH:2]=[C:141]([C:142]4[CH:143]=[CH:144][C:135]([C:132]5[NH:131][C:130]([CH:126]6[CH2:127][CH2:128][CH2:129][N:125]6[C:123](=[O:124])[CH:119]([NH:118][C:117]([O:116][CH3:115])=[O:154])[CH:120]([CH3:122])[CH3:121])=[N:134][CH:133]=5)=[CH:136][CH:137]=4)[CH:140]=3)[CH:73]=2)=[CH:70][N:71]=1)=[O:61])([CH3:58])([CH3:57])[CH3:56]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(B4OC(C)(C)C(C)(C)O4)ccc3c2)[nH]1)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(Br)cc2)[nH]1
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6C(=O)OC(C)(C)C)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Agent: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc3cc(B4OC(C)(C)C(C)(C)O4)ccc3c2)[nH]1
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)OC(C)(C)C)[nH]5)ccc4c3)cc2)[nH]1)C(C)C

Procedure:
2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester was prepared following the procedure for 2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester, substituting (1-{2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester for 2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester and 2-{5-[6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester for [2-Methyl-1-(2-{5-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester. LCMS-ESI+: calc'd for C42H49N7O5: 731.4 (M+); Found: 732.9 (M+H+).
Reaction SMILES: [C:1]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11]2)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:18](OC(=O)C)(=[O:20])[CH3:19].[CH3:25][CH2:26][O:27][C:28](OCC)(OCC)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl.CO>[C:18]([N:13]1[C:14]2[C:10](=[CH:9][C:8]([C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:16][CH:15]=2)[C:11](=[C:28]([O:27][CH2:26][CH3:25])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:12]1=[O:17])(=[O:20])[CH3:19]
Reactant: CCOC(OCC)(OCC)c1ccccc1
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCC(=O)c1ccc2c(c1)CC(=O)N2
Solvent: ClCCl
Solvent: CO
Product: CCCCCC(=O)c1ccc2c(c1)C(=C(OCC)c1ccccc1)C(=O)N2C(C)=O

Procedure:
Prepared from 5-hexanoyl-2-indolinone, acetic anhydride and triethyl orthobenzoate Rf=0.72 (methylene chloride/methanol 30:1)
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].N1C=CC=CC=1.[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1.O>ClCCl>[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH:8][C:7]2[CH:9]=[CH:10][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[O:23])=[CH:20][CH:19]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc([N+](=O)[O-])cc1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 91.3 %

Procedure:
To a stirred suspension of 19.83 gm (143.56 mMol) 4-nitroaniline in 150 mL dichloromethane and 12.9 mL (159.5 mMol) pyridine at 0° C. were slowly added 24.5 gm (154.8 mMol) 4-fluorobenzoyl chloride. The reaction mixture was then stirred for 15 minutes at 0° C., at which time the reaction mixture became homogeneous, and then for an hour at room temperature. To this mixture were then added 100 mL water and the solid which formed was collected by filtration. The filter cake was washed with hexane (80 mL) followed by water (100 mL) and it was then dried under vacuum at 60° C. to give 34.1 gm (91%) N-(4-fluorobenzoyl)-4-nitroaniline.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH:6]=[CH:7][C:8]1=[N:9][CH2:10][CH2:11][N:12]([CH3:20])[C:13]2[CH:18]=[CH:17][C:16](N)=[CH:15][C:14]1=2.[N:25]1C=CC=[CH:27][CH:26]=1.CS(Cl)(=O)=[O:33]>ClCCl>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH:6]=[CH:7][C:8]1=[N:9][CH2:10][CH2:11][N:12]([CH3:20])[C:13]2[CH:18]=[CH:17][C:16]([CH2:27][C:26]([NH2:25])=[O:33])=[CH:15][C:14]1=2
Reactant: c1ccncc1
Reactant: CN1CCN=C(C=Cc2ccc(Cl)c(Cl)c2)c2cc(N)ccc21
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: CN1CCN=C(C=Cc2ccc(Cl)c(Cl)c2)c2cc(CC(N)=O)ccc21
Reaction time: 1 h

Procedure:
To a solution of 100 mg, 0.219 mmol) of (E)-5-(3,4-dichlorostyryl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-7-amine hydrochloride in 3 ml of dichloromethane was added 0.073 ml, 0.9 mmol) of pyridine, and 0.018 ml, (0.231 mmol) of methanesulphonyl chloride. The solution was stirred for 1 hour, concentrated under reduced pressure and the residue partitioned between brine and dichloromethane. The organic phase was dried over magnesium sulphate, filtered and evaporated, The residue was chromatographed on silica gel using first dichloromethane/methanol (98:2) and then dichloromethane/methanol (97:3) for the elution. There was obtained (E)-5-(3,4-dichlorostyryl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-7-acetamide hydrochloride as a brown solid MS: m/e 424.1 [M+H]+.
Reaction SMILES: Br[C:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2S[C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:20]([Cu])#[N:21].CN(C)C=O.[NH4+].[OH-]>C(Cl)(Cl)Cl.N1C=CC=CC=1>[O:9]=[C:8]1[C:2]([C:20]#[N:21])=[C:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]2[C:6](=[CH:5][CH:13]=[CH:12][CH:11]=2)[NH:7]1
Reactant: O=C1Nc2ccccc2SC(c2ccccc2)=C1Br
Reactant: N#C[Cu]
Agent: [NH4+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: N#Cc1c(-c2ccccc2)c2ccccc2[nH]c1=O
Temperature: 0 °C
Yield: 29.8 %

Procedure:
A stirred mixture of 10 g (0.030 mole) of 3-bromo-2-phenyl-1,5-benzothiazepin-4(5H)-one from part A, 10 g (0.11 mole) of CuCN, and 75 ml of dimethylformamide is treated with 1 ml of pyridine, heated, and the resulting dark solution refluxed for 2 hours. After cooling, the reaction mixture is poured into a vigorously stirred mixture of 600 ml of ice-water, 600 ml of concentrated NH4OH, and 300 ml of CHCl3. Stirring is continued until essentially 2 clear layers are obtained. The layers are separated and the blue aqueous NH4OH layer is extracted with additional CHCl3 (4×150 ml). The combined organic layers are washed with 10% NH4OH (2×150 ml), then with 150 ml of H2O, dried (MgSO4), and the solvent evaporated (finally at 1 mm. pressure to remove dimethylformamide) to give 5.9 g of a reddish, partly solid residue. The latter is crystallized from 60 ml of MeCN to give 2.2 g (30%) of a pale yellow solid, m.p. 263°-265°(dec.).
Reaction SMILES: [H-].[Na+].[CH2:3]1[O:13][C:6]2([CH2:11][CH2:10][C:9](=O)[CH2:8][CH2:7]2)[O:5][CH2:4]1.[OH2:14].[CH2:15]1[CH2:19][O:18][CH2:17][CH2:16]1>>[CH2:17]([O:18][C:19]([CH:15]=[C:9]1[CH2:10][CH2:11][C:6]2([O:13][CH2:3][CH2:4][O:5]2)[CH2:7][CH2:8]1)=[O:14])[CH3:16]
Reactant: O
Reactant: C1CCOC1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C=C1CCC2(CC1)OCCO2
Reaction time: 0.5 h

Procedure:
Triethylphosphonoacetate (146 mL, 0.74 mol) is added to a suspension of NaH (60% in oil, 29.5 g, 0.74 mol) in THF (2500 mL) at 0-5° C., and the mixture is stirred for 30 min at the same temperature. To the mixture is added dropwise 1,4-cyclohexanedione monoethylene acetal (100 g, 0.64 mol) in THF (700 mL) at 0-5° C. and stirring is continued for 1 hour at the same temperature. After addition of H2O (1500 mL), the mixture is extracted with EtOAc (3000 mL). The water layer is extracted with EtOAc (1500 mL×2) and combined organic layer is washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to afford 8-ethoxycarbonylmethylidene-1,4-dioxaspiro[4.5]decane (172.9 g) as a colorless oil. The crude product is used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:16]([O:19][CH2:20][CH2:21]Br)(=[O:18])[CH3:17]>CN(C=O)C>[CH2:20]([O:19][C:16](=[O:18])[CH2:17][O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[CH3:9])[CH3:21]
Reactant: CC(=O)OCCBr
Reactant: Cc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(Br)cc1C
Temperature: 25 °C
Reaction time: 20 h
Yield: 102.7 %

Procedure:
A mixture of 4-bromo-2-methylphenol (10.0 g, 53.5 mmol) and 325 mesh potassium carbonate (11.08 g, 80.2 mmol) in DMF (100 mL) is treated dropwise with bromoethyl acetate (10.71 g, 64.1 mmol) and then stirred for about 20 hours at room temperature under N2. The reaction is filtered, and the filtrate is acidified with 1 N HCl. The mixture is then diluted with water and extracted with Et2O. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using 5/1 hexanes/ethyl acetate to afford about 15.01 g (100%) of the titled compound. Rf=0.33 (4/1 hexanes/EtOAc). 1H NMR (400 MHz, CDCl3).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:13]2[N:14]=[CH:15][N:16]([CH2:17][C:18]([CH3:21])([OH:20])[CH3:19])[C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=1.[CH:22]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH2:23]>O1CCCC1>[Cl:3][C:4]1[C:13]2[N:14]=[CH:15][N:16]([CH2:17][C:18]([CH3:21])([O:20][CH2:23][CH2:22][S:24]([CH3:27])(=[O:26])=[O:25])[CH3:19])[C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=1
Reactant: C=CS(C)(=O)=O
Reactant: CC(C)(O)Cn1cnc2c(Cl)nc3ccccc3c21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(Cn1cnc2c(Cl)nc3ccccc3c21)OCCS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Sodium hydride (60% dispersion in mineral oil, 58 mg, 1.45 mmol) was added to a stirred solution of 1-(4-chloro-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (described in U.S. Pat. No. 4,689,338 Example 189, Part D, 4.00 g, 14.5 mmol) in tetrahydrofuran (58 mL). After 5 minutes, methyl vinyl sulfone (3.10 g, 29.0 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 17 hours. The volatiles were removed under reduced pressure and the resulting oil was purified by flash chromatography (silica gel, eluted with 5% methanol in dichloromethane) to yield 4.3 g of 4-chloro-1-{2-methyl-2-[2-(methylsulfonyl)ethoxy]propyl}-1H-imidazo[4,5-c]quinoline as a foam.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[NH2:19][C:20]1[CH:42]=[CH:41][C:23]([C:24]([N:26]2[CH2:32][C:31]3[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=3[CH2:29][C:28]3[CH:37]=[CH:38][CH:39]=[CH:40][C:27]2=3)=[O:25])=[CH:22][CH:21]=1>O>[CH:37]1[C:28]2[CH2:29][C:30]3[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=3[CH2:32][N:26]([C:24]([C:23]3[CH:22]=[CH:21][C:20]([NH:19][C:4](=[O:5])[C:3]4[CH:7]=[CH:8][CH:9]=[C:10]([Cl:11])[C:2]=4[Cl:1])=[CH:42][CH:41]=3)=[O:25])[C:27]=2[CH:40]=[CH:39][CH:38]=1
Reactant: O=C(Cl)c1cccc(Cl)c1Cl
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1)c1cccc(Cl)c1Cl
Reaction time: 2 h
Yield: 65.7 %

Procedure:
A mixture of 301.6 mg of 2,3-dichlorobenzoyl chloride and 145 mg of triethylamine is stirred while 314 mg of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine is added. Stirring is continued for 2 hours. Water is added and the organic layer washed with 1N HCl, water, 1M NaHCO3 and water then dried over Na2SO4. The organic layer is passed through a pad of hydrous magnesium silicate and hexane added to the filtrate at the boil to give 0.32 g of the desired product as a crystalline solid, m.p. 225°-230° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][NH:28][CH2:29][C:30]([O:32]CC)=[O:31])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+]>O1CCCC1.C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][NH:28][CH2:29][C:30]([OH:32])=[O:31])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CCOC(=O)CNCc1cn(C)c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CNCC(=O)O)cn(C)c34)no2)cc1Cl
Temperature: 20 °C
Reaction time: 8 h
Yield: 56.3 %

Procedure:
To a solution of ethyl N-{[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]methyl}glycinate (D77) (283 mg) in tetrahydrofuran (5 mL) and ethanol (5 mL) stirred at 20° C. was added a solution of sodium hydroxide (40 mg) in water (5 mL) in one charge. The reaction mixture was stirred at 20° C. overnight. The reaction mixture was concentrated to about 5 mL and then H2SO4 (0.1 M) solution was added dropwise until no further white precipitate was formed. The solid was filtered and washed with EtOAc. The solid was collected and then was suspended in methanol (5 mL). The mixture was acidified with HCl (1 M) solution to pH around 1 to form a clear solution. After most of the solvent was evaporated off, the residue was freeze-dried to afford N-{[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]methyl}glycine (E56) (150 mg) as a hydrochloride salt. δH (DMSO-d6, 400 MHz): 1.37 (6H, d), 3.72 (3H, s), 3.85 (2H, s), 4.39 (2H, s), 4.87-4.93 (1H, m), 7.30 (1H, t), 7.47 (1H, d), 7.52 (1H, d), 7.62 (1H, s), 8.05 (1H, s), 8.14 (1H, dd), 8.21 (1H, d), 9.23 (1H, br s). MS (ES): C23H23ClN4O4 requires 454; found 380.1 (M—NHCH2COOH+).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([CH3:14])[CH2:8][N:7]([CH2:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:38]=[CH:37][C:26]([C:27]([NH:29][CH:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[O:28])=[CH:25][C:24]=1[O:39][CH3:40].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[CH:16]1([CH2:15][N:7]2[CH2:8][CH:9]([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[CH:38]=[CH:37][C:26]([C:27]([NH:29][CH:30]5[CH2:31][CH2:32][N:33]([CH3:36])[CH2:34][CH2:35]5)=[O:28])=[CH:25][C:24]=4[O:39][CH3:40])=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CC1CN(CC2CCCC2)c2nc(Cl)ncc2N(C)C1=O
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)O
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(CC1CCCC1)CC(C)C(=O)N2C
Yield: 56 %

Procedure:
A solution of 0.050 g (0.00016 mole) of (rac)-2-chloro-9-cyclopentylmethyl-5,7-dimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-55), 0.050 g (0.00016 mole) of 4-amino-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide, 0.047 g (0.00016 mole) of p-toluenesulfonic acid monohydrate and 4.0 mL of 2-propanol was heated at 180 degrees for 2 hours in a microwave reactor. The reaction mixture was concentrated under reduced pressure. The residue was diluted with dichloromethane and washed twice with saturated sodium bicarbonate solution. The aqueous phases were extracted with dichloromethane. The combined organic phases were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with dichloromethane-methanol (100:0-75:25) to give 0.048 g of (rac)-4-(9-cyclopentylmethyl-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diaze-pin-2-ylamino)-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-55) as white powder. HRMS (ES+) m/z Calcd for C29H41N7O3+H [(M+H)+]: 536.3344. Found: 536.3344.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][C@@H:27]([CH2:38][O:39][CH3:40])[C:28]([NH:30][C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][N:32]=1)=[O:29])(C(C)(C)C)(C)C.CCOC(C)=O>C1COCC1>[CH3:31][CH2:36][CH2:35][CH:34]([CH3:37])[CH3:33].[OH:26][C@@H:27]([CH2:38][O:39][CH3:40])[C:28]([NH:30][C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][N:32]=1)=[O:29]
Reactant: COC[C@H](O[Si](C)(C)C(C)(C)C)C(=O)Nc1ccc(C)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC(C)C
Product: COC[C@H](O)C(=O)Nc1ccc(C)cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of tetrabutylammonium fluoride (1M in THF) (8.63 mL, 8.63 mmol) was added in one portion to a stirred solution of (S)-2-(tert-butyldimethylsilyloxy)-3-methoxy-N-(5-methylpyridin-2-yl)propanamide C4d (1.4 g, 4.31 mmol) in THF (20 mL). The resulting solution was stirred at ambient temperature for 4 hours. The reaction mixture was concentrated, diluted with EtOAc (50 mL) and washed sequentially with water (20 mL) and saturated brine (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product as an oil. Trituration with 1:1 isohexane:EtOAc afforded (S)-2-hydroxy-3-methoxy-N-(5-methylpyridin-2-yl)propanamide (340 mg). The residue was purified by flash silica chromatography with EtOAc to afford a second batch of (S)-2-hydroxy-3-methoxy-N-(5-methylpyridin-2-yl)propanamide (220 mg).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[B:6]([OH:8])[OH:7].[C:9]([O:13][C:14]1[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=1)([CH3:12])([CH3:11])[CH3:10]>>[S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[C:9]([O:13][C:14]1[CH:19]=[CH:18][C:17]([B:6]([OH:8])[OH:7])=[CH:16][CH:15]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)Oc1ccc(Br)cc1
Reactant: OB(O)c1cccs1
Product: CC(C)(C)Oc1ccc(B(O)O)cc1
Product: c1ccsc1

Procedure:
3-(4-Benzyloxy)phenoxy!benzo b!thiophene-2-boronic acid was reacted with 4-(-tertbutoxy)bromobenzene according to the conditions described above for 2-iodo-3-(4-benzyloxy)phenoxy!benzo b!thiophene and 4-(tertbutoxy)phenyl boronic acid to give 2-(4-tertbutyloxyphenyl)-3-(4-benzyloxy)phenoxy!benzo b!thiophene in 81% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:40]=[CH:39][C:12]([C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:34][CH2:35][CH2:36][CH2:37][OH:38])[C:24](=[O:33])[C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[CH:18][CH:17]=2)=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(=O)(O)[O-].[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.CC(=O)OCC>[CH2:1]([O:8][C:9]1[CH:40]=[CH:39][C:12]([C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:34][CH2:35][CH2:36][CH:37]=[O:38])[C:24](=[O:33])[C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)=[CH:18][CH:17]=2)=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1ccc(C(=O)Oc2ccc(CN(CCCCO)C(=O)c3ccc(OC)cc3)cc2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCCCCCOc1ccc(C(=O)Oc2ccc(CN(CCCC=O)C(=O)c3ccc(OC)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Prepared from compound 87: To a stirring solution of 4-((N-(4-hydroxybutyl)-4-methoxybenzamido)methyl)phenyl 4-(heptyloxy)benzoate 87 (258 mg, 0.484 mmol) in DCM was added sodium bicarbonate (81 mg, 0.968 mmol) and Dess-Martin periodinane (308 mg, 0.726 mmol). The reaction mixture was stirred at room temperature for 2 h. The crude reaction was diluted with EA followed by NaHCO3 and aq. NaS2O3. The biphasic mixture was stirred overnight at room temperature. The organic phase was separated, washed with NaHCO3, dried over MgSO4, and concentrated to yield 264 mg of crude 4-((4-methoxy-N-(4-oxobutyl)benzamido)methyl)phenyl 4-(heptyloxy)benzoate INT-8. LCMS-ESI (m/z) calculated for C33H39NO6: 545; found 546 [M+H]+, tR=3.14 min (Method 3).
Reaction SMILES: C(O[C:4]([C:6]1[N:7]([NH2:26])[CH:8]=[C:9]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=2[CH3:25])[C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:5])C.[CH2:27]([O:29][CH:30]([O:37]CC)[CH2:31][C:32](OCC)=O)[CH3:28].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1CCN2C(=NCCC2)CC1>CN(C=O)C.O>[CH2:27]([O:29][C:30]([C:31]1[C:4](=[O:5])[C:6]2[N:7]([CH:8]=[C:9]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=3[CH3:25])[C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:26][CH:32]=1)=[O:37])[CH3:28]
Reactant: CCOC(=O)CC(OCC)OCC
Reactant: CCOC(=O)c1c(-c2ccccc2)c(Cc2cccc(F)c2C)cn1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1c[nH]n2cc(Cc3cccc(F)c3C)c(-c3ccccc3)c2c1=O
Temperature: 90 °C
Reaction time: 0.75 h
Yield: 75.2 %

Procedure:
To a solution of the compound of step 5 (6.290 g, 17.85 mmol) in 180 ml of anhydrous DMF under nitrogen were added ethyl 3,3-diethoxy-propanoate (10.42 ml, 53.55 mmol) and p-toluenesulfonic acid hydrate (0.509 g, 2.68 mmol), and the solution was heated at 90° C. for 1.5 h. After cooling to 60° C., DBU (13.32 ml, 89.24 mmol) was added dropwise and the mixture was stirred for 45 min at 60° C. The solution was then cooled to room temperature, water (600 ml) was added and the solution was extracted four times with EA (200 ml). The combined organic phases were washed with 0.5 N hydrochloric acid (300 ml) and brine (300 ml), dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. The residue was triturated several times with cyclohexane and dried in vacuo at 50° C. 5.43 g of the title compound were obtained as a brown solid melting at 176-177° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([NH:9][NH2:10])=[O:8])=[CH:5][CH:4]=1)[CH3:2].C(O)(=O)C.[CH:17](=O)[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CO>[C:20]1([CH2:19][CH2:18][CH:17]=[N:10][NH:9][C:7](=[O:8])[C:6]2[CH:11]=[CH:12][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCc1ccc(C(=O)NN)cc1
Reactant: O=CCCc1ccccc1
Solvent: CO
Solvent: CC(=O)O
Product: CCc1ccc(C(=O)NN=CCCc2ccccc2)cc1

Procedure:
4-ethyl-benzoic acid hydrazide (10 g, 60.9 mmoles) was dissolved in 32 mL of methanol. Acetic acid (1 mL) was added, the mixture was brought to reflux, and hydrocinnamaldehyde (5.77 g, 67 mmoles) was then slowly added. The reaction mixture was refluxed for 10 h and monitored by TLC. The precipitates were collected via filtration and washed with hexanes. 4-Ethyl-benzoic acid (3-phenyl-propylidene)-hydrazide was obtained as a white solid (9.34 g, 54.7% yield). Rf=0.36 (1:1 EtOAc:n-hexane); 1H NMR (400 MHz, CDCl3) δ 8.87 (s, 1H), 7.72-7.24 (m, 10H), 2.87 (t, J=15.2 Hz, 2H), 2.79-2.57 (m, 4H), 1.24 (t, J=8 Hz, 3H).
Reaction SMILES: C(N(CC)CC)C.[CH:8]([O:10][CH2:11][C:12]#[C:13][CH2:14][OH:15])=[O:9].[CH3:16][S:17](Cl)(=[O:19])=[O:18].C(=O)(O)[O-].[Na+]>C(=O)(OC)OC>[CH3:16][S:17]([O:15][CH2:14][C:13]#[C:12][CH2:11][O:10][CH:8]=[O:9])(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: O=COCC#CCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: COC(=O)OC
Product: CS(=O)(=O)OCC#CCOC=O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 97.9 %

Procedure:
41.5 g (0.409 mol) of triethylamine was added to 300 ml of dimethyl carbonate solution of 44.0 g (0.386 mol) of 4-formyloxy-2-butyn-1-ol, and cooled to 0° C. 46.9 g (0.409 mol) of methanesulfonyl chloride was dropwise added to the solution while the inner temperature was controlled to be not higher than 15° C. After the addition, this was stirred at 25° C. for 1.5 hours, the reaction mixture was poured into an aqueous saturated sodium bicarbonate solution, the aqueous layer was separated, and the organic layer was concentrated to give 72.6 g (yield 98%) 4-formyloxy-2-butyn-1-yl methanesulfonate. For use in the battery test, this was purified through silica gel column chromatography.