Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[N:6]([CH3:28])[C:7](=[O:27])[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.CC(C)([O-])C.[K+].[F:37][C:38]([F:48])([F:47])[C:39]1[CH:46]=[CH:45][C:42]([CH2:43]Br)=[CH:41][CH:40]=1>O1CCCC1>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[N:6]([CH3:28])[C:7](=[O:27])[CH:8]([CH2:43][C:42]3[CH:41]=[CH:40][C:39]([C:38]([F:37])([F:47])[F:48])=[CH:46][CH:45]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: COc1ccc(COc2ccc(C3=NCC(=O)N(C)c4ccc(Cl)cc43)cc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(COc2ccc(C3=NC(Cc4ccc(C(F)(F)F)cc4)C(=O)N(C)c4ccc(Cl)cc43)cc2)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 48 %

Procedure:
(Z)-7-Chloro-5-(4-(4-methoxybenzyloxy)phenyl)-1-methyl-1H-benzo[e][1,4]diazepin-2(3H)-one (75 mg, 0.18 mmol) was dissolved in tetrahydrofuran (4 mL), and the solution was cooled to −78° C. under a nitrogen atmosphere. A 1 M solution of potassium tert-butoxide in tetrahydrofuran (267 μL, 0.267 mmol) was added dropwise, and the solution was stirred for 10 minutes. 4-(trifluoromethyl)benzyl bromide (64 mg, 0.267 mmol, solution in 1 mL tetrahydrofuran) was then added dropwise, and the cooling bath was then removed. The reaction was stirred at room temperature for 2 hours, and it was then quenched with water, and the mixture was portioned between water and ethyl acetate. The aqueous portion was extracted into ethyl acetate again, and the combined organic extracts were dried over sodium sulfate, and then concentrated, and purified by chromatography (gradient; 9:1 hexanes:ethyl acetate to 6:4 hexanes:ethyl acetate, then isocratic) yielding the product as a clear residue (50 mg, 49%).
Reaction SMILES: [Br:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:5]([CH:6]=O)=[C:4]([N:13]2[CH2:18][CH:17]([CH3:19])[O:16][CH:15]([CH3:20])[CH2:14]2)[CH:3]=1.[NH:21]1[C:28](=[O:29])[CH2:27][C:25](=[O:26])[NH:24][C:22]1=[O:23]>C(O)(C)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([CH2:6][C:27]3([CH:14]4[CH:15]([CH3:20])[O:16][CH:17]([CH3:19])[CH2:18][N:13]42)[C:25](=[O:26])[NH:24][C:22](=[O:23])[NH:21][C:28]3=[O:29])=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11]
Reactant: O=C1CC(=O)NC(=O)N1
Reactant: CC1CN(c2cc(Br)c([N+](=O)[O-])cc2C=O)CC(C)O1
Solvent: CC(C)O
Product: CC1CN2c3cc(Br)c([N+](=O)[O-])cc3CC3(C(=O)NC(=O)NC3=O)C2C(C)O1
Temperature: 85 °C
Reaction time: 2.5 h
Yield: 39.2 %

Procedure:
A mixture of 4-bromo-2-(2,6-dimethylmorpholin-4-yl)-5-nitrobenzaldehyde (from Step 2) (989 mg, 2.88 mmol) and barbituric acid (369 mg, 2.88 mmol) in isopropanol (15 mL) is sealed in a 20 mL scintillation vial and shaken at 85° C. for 2.5 hours. The product is adsorbed onto silica gel and purified by silica gel chromatography using a gradient from 20% EtOAc in CH2Cl2 to 25% EtOAc in CH2Cl2 as eluent. Product is isolated and dried (20 Torr, 100° C.) to give 512 mg of yellow solid. 1H NMR (DMSO-d6) δ 11.90, 11.62, 7.79, 7.36, 4.32, 3.87, 3.47–3.63, 2.94, 2.81, 1.15, 0.94.
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13](Br)[N:14]=2)[N:9]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:8]=1)=[O:6])([CH3:3])[CH3:2].[C:25]([SiH2:29][O:30][C:31]([CH3:56])([CH3:55])[C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[N:37]([CH3:41])[N:36]=[C:35]2[Sn](CCCC)(CCCC)CCCC)([CH3:28])([CH3:27])[CH3:26]>CN(C=O)C.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.[Cu]I>[CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:35]3[C:34]4[C:38](=[CH:39][CH:40]=[C:32]([C:31]([CH3:56])([CH3:55])[O:30][SiH2:29][C:25]([CH3:27])([CH3:26])[CH3:28])[CH:33]=4)[N:37]([CH3:41])[N:36]=3)[N:14]=2)[N:9]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:8]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2ccc(C(C)(C)O[SiH2]C(C)(C)C)cc12
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4ccc(C(C)(C)O[SiH2]C(C)(C)C)cc34)nc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
In a round-bottomed flask, 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid isopropylamide (300 mg, 0.73 mmol) and 5-(tert-butyl-dimethyl-silanyloxymethyl)-1-methyl-3-tributylstannanyl-1H-indazole (Example 273, 665 mg, 0.82 mmol) were dissolved in DMF (4.8 ml). The reaction mixture was evacuated and backfilled with argon then tetrakis(triphenylphosphine)palladium (0) (42 mg, 0.036 mmol) and copper (I) iodide (28 mg, 0.147 mmol) were added. The reaction mixture was stirred at 80° C. overnight then cooled to room temperature, quenched with water and diluted with petroleum ether. The resulting suspension was filtered and the solids washed with water, petroleum ether and a minimal amount of diethyl ether then dried under high vacuum to afford 426 mg (92%) of 2-[5-(tert-butyldimethyl-silanyloxymethyl)-1-methyl-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid isopropylamide as a brown powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[NH:8][N:7]=1)[CH3:2].CC(C)([O-])C.[K+].Cl[CH2:25][CH2:26][C:27]#[N:28].Cl>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[N:8]([CH2:25][CH2:26][C:27]#[N:28])[N:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1n[nH]c(=O)c2ccccc12
Reactant: N#CCCCl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1nn(CCC#N)c(=O)c2ccccc12
Reaction time: 0.5 h

Procedure:
To a solution of ethyl-4-oxo-3-H-phthalazin-1-ylacetate (10.91 g) and dry potassium t-butoxide (5.90 g) in dimethylformamide (50 ml) was added 3-chloropropionitrile (4.92 g) and the resulting solution was stirred for 30 minutes. The solution was then poured onto ice-water (300 ml); sufficient 10% HCl was added to adjust the pH of the resulting mixture to about 4.0 and the precipitated solid was collected and crystallized from methanol (yield: 7.64 g; m.p. 125°-126° C.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([Br:17])[C:14]=1[O:15][CH3:16])[CH2:5][C@:6]([CH3:11])([C:8]([OH:10])=[O:9])[NH2:7].F[C:19](F)(F)C(O)=O.Br.C=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([Br:17])[C:14]=1[O:15][CH3:16])[CH2:19][NH:7][C@@:6]([CH3:11])([C:8]([OH:10])=[O:9])[CH2:5]2
Reactant: O=C(O)C(F)(F)F
Reactant: COc1c(Br)cc(C[C@@](C)(N)C(=O)O)cc1Br
Agent: Br
Agent: C=O
Product: COc1c(Br)cc2c(c1Br)CN[C@@](C)(C(=O)O)C2
Temperature: 75 °C
Reaction time: 17 h

Procedure:
Compound 2.5 (4.8 mmol) was added to trifluoroacetic acid (5 mL). HBr (33% in acetic acid, 0.9 mL, 4.8 mmol) was added dropwise to the reaction mixture under nitrogen atmosphere. Upon the addition of the acid, formaldehyde (8.64 mmol, 260 mg, 0.7 mL) was added dropwise and the mixture stirred at 70-80° C. for 17 h. The reaction mixture was cooled, dried and concentrated. APCI MS 378 (M+1). The product was used in the next step.
Reaction SMILES: C[Si]([CH:5]=[N+:6]=[N-:7])(C)C.C([N:10]([CH2:13][CH3:14])[CH2:11][CH3:12])C.Cl.[Cl-].[O:17]1C[CH2:20][CH2:19][CH:18]1CC#N>CCCCCC>[N+:6](=[CH:5][C:18]([C:19]1[C:13]([CH3:14])=[N:10][CH:11]=[CH:12][CH:20]=1)=[O:17])=[N-:7]
Reactant: CCN(CC)CC
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: N#CCC1CCCO1
Agent: Cl
Agent: [Cl-]
Solvent: CCCCCC
Product: Cc1ncccc1C(=O)C=[N+]=[N-]
Reaction time: 7 h

Procedure:
To a mixture of 10% trimethylsilyldiazomethane in hexane (4.2 ml) and triethylamine (527 mg) in tetrahydrofuranacetonitrile chloride hydrochloride (500 mg) in an ice water bath. The mixture was stirred for 7 hours in an ice water bath and allowed to stand for 18 hours at 0° C., then evaporated in vacuo. Saturated aqueous sodium bicarbonate solution was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over magnesium sulfate. Evaporation of the solvent gave crude 3-diazoacetyl-2-methylpyridine as an yellow oil.
Reaction SMILES: [IH:1].C1O[C:5]2([CH2:10][CH2:9][C:8]([C:14]3[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=3)([N:11]([CH3:13])[CH3:12])[CH2:7][CH2:6]2)[O:4]C1.I.C1OC2(CCC(C3C=CC=CC=3C)(N(C)C)CC2)OC1>>[IH:1].[C:16]1([CH3:20])[CH:17]=[CH:18][CH:19]=[C:14]([C:8]2([N:11]([CH3:13])[CH3:12])[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]2)[CH:15]=1
Reactant: Cc1cccc(C2(N(C)C)CCC3(CC2)OCCO3)c1
Agent: Cc1ccccc1C1(N(C)C)CCC2(CC1)OCCO2
Agent: I
Product: Cc1cccc(C2(N(C)C)CCC(=O)CC2)c1
Yield: 75 %

Procedure:
Following the procedure of Example 16, but sutstituting 4-(m-tolyl)-4-dimethylaminocyclohexanone ethylene ketal hydroiodide for the 4-(o-tolyl)-4-dimethylaminocyclohexanone ethylene ketal hydroiodide there is obtained the 4-(m-tolyl)-4-dimethylaminocyclohexanone hydroiodide salt in 75% yield after recrystallization from methylene chloride:ethyl acetate; m.p. 172°-174.5° C.
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[C:14]([NH:17][C:18]3[C:19]4[N:20]([CH:25]=[CH:26][N:27]=4)[CH:21]=[C:22]([Br:24])[N:23]=3)[CH:15]=[CH:16][C:11]=2[N:10]=[CH:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[N:10]1[C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[C:19]4[N:20]([CH:25]=[CH:26][N:27]=4)[CH:21]=[C:22]([Br:24])[N:23]=3)=[CH:13][C:12]=2[NH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)n1cnc2ccc(Nc3nc(Br)cn4ccnc34)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Brc1cn2ccnc2c(Nc2ccc3nc[nH]c3c2)n1

Procedure:
A quantity of 0.23 g (1 mmole) of 6-Amino-benzoimidazole-1-carboxylic acid tert-butyl ester is treated with 0.27 g (1 mmole) of 6,8-Dibromo-imidazo[1,2-a]pyrazine in acetonitrile with 3 eq. of K2CO3 at reflux for 16 hrs. The reaction mixture is cooled partitioned between ethyl acetate and water, the organic extracts are dried over anhydrous MgSO4 and evaporated in vacuo to afford 6-(6-Bromo-imidazo[1,2-a]pyrazin-8-ylamino)-benzoimidazole-1-carboxylic acid tert-butyl ester. 6-(6-Bromo-imidazo[1,2-a]pyrazin-8-ylamino)-benzoimidazole-1-carboxylic acid tert-butyl ester is treated with an excess of TFA in dichloromethane at room temperature for 2 hrs. The reaction solution is evaporated in vacuo and partitioned between saturated Na2CO3 and ethyl acetate, the organic extracts are dried over anhydrous MgSO4 and evaporated in vacuo to afford (3H-Benzoimidazol-5-yl)-(6-bromo-imidazo[1,2-a]pyrazin-8-yl)-amine.
Reaction SMILES: C1C(=O)N([Cl:8])C(=O)C1.C(O)(=O)C.[CH2:13]([NH:15][C:16](=[O:18])[O-:17])[CH3:14].[CH:19]1([CH2:22][O:23][C:24]2[CH:25]=[CH:26][C:27]3[CH:28]([CH3:36])[CH:29]4[CH2:33][NH:32][CH2:31][CH:30]4[C:34]=3[CH:35]=2)[CH2:21][CH2:20]1>ClCCCl>[CH2:13]([NH:15][C:16](=[O:17])[O-:18])[CH3:14].[CH:19]1([CH2:22][O:23][C:24]2[C:25]([Cl:8])=[CH:26][C:27]3[CH:28]([CH3:36])[CH:29]4[CH2:33][NH:32][CH2:31][CH:30]4[C:34]=3[CH:35]=2)[CH2:20][CH2:21]1
Reactant: CC1c2ccc(OCC3CC3)cc2C2CNCC12
Reactant: O=C1CCC(=O)N1Cl
Agent: CCNC(=O)[O-]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC1c2cc(Cl)c(OCC3CC3)cc2C2CNCC12
Temperature: 70 °C
Reaction time: 3 h

Procedure:
NCS (38 mg, 0.28 mmol) and acetic acid (1 mL) were added to a solution of N-ethylcarbamate-5-cyclopropylmethoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (89 mg, 0.28 mmol) in DCE (2 mL), and the reaction solution was stirred for 3 hours at 70° C. The reaction was quenched with H2O and the solution filtered through an Extrelut column. The column was washed with CH2Cl2, and the filtrate was concentrated. The subtitle compound was obtained without further purification. MS calculated for C19H24ClNO3+H: 350, observed: 350.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[C:11]([NH2:13])=[O:12].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.O>N1C=CC=CC=1>[C:11]([C:3]1[CH:4]=[C:5]([C:6](=[O:7])[NH2:8])[CH:9]=[CH:10][C:2]=1[NH:1][S:20]([C:17]1[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=1)(=[O:22])=[O:21])(=[O:12])[NH2:13]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NC(=O)c1ccc(N)c(C(N)=O)c1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ccc(C(N)=O)cc2C(N)=O)cc1
Temperature: 25 °C
Yield: 51 %

Procedure:
To a solution of 4-aminoisophthalamide (1.00 g (5.58 mmol) in pyridine (10.0 ml), p-toluenesulfonyl chloride (1.06 g (5.58 mmol) was added with stirring at room temperature. After 3 hours' stirring at room temperature, water was added to the reaction mixture to separate crystals. The crystals were filtered and washed with water and ethyl acetate to give 0.94 g (51%) of 2′,4′-dicarbamoyl-p-toluenesulfonanilide as white crystals.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13](OCCCO)[CH:12]=2)[S:6]1(=[O:23])=[O:22])([CH3:4])([CH3:3])[CH3:2].[OH:24][C:25]1[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[C:26]=1[C:27]([O:29][CH3:30])=[O:28].[C:36]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:41]=CC=C[CH:37]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH3:30][O:29][C:27](=[O:28])[C:26]1[C:25]([OH:24])=[CH:34][CH:33]=[CH:32][C:31]=1[O:35][CH2:37][CH2:36][CH2:41][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:7]2[S:6](=[O:22])(=[O:23])[N:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:9](=[O:10])[CH:8]=2)[CH:12]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)N1C(=O)C=C(c2cccc(OCCCO)c2)S1(=O)=O
Reactant: COC(=O)c1c(O)cccc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: C1CCOC1
Product: COC(=O)c1c(O)cccc1OCCCc1cccc(C2=CC(=O)N(C(C)(C)C)S2(=O)=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4.08-C (0.21 g, 0.6 mmol), methyl 2,6-dihydroxybenzoate (0.13 g, 0.8 mmol), and triphenylphosphine (0.22 g, 0.8 mmol) in tetrahydrofuran (1.5 mL) was treated with diisopropyl azodicarboxylate (0.18 mL, 0.9 mmol) dropwise at 0° C. The reaction mixture was stirred at 25° C. for 2 h. The reaction mixture was concentrated to give a crude residue which was purified using flash column chromatography (100% hexane to 25% ethyl acetate/hexane) to yield 4.08-D as a white solid (0.18 g, 60%). 1H NMR (500 MHz, CDCl3): δ 11.47 (s, 1H), 7.42 (dd, J=8.3, 8.3 Hz, 1H), 7.34–7.31 (m, 3H), 7.11–7.08 (m, 1H), 6.62 (s, 1H), 6.60 (dd, J=8.3, 1.0 Hz, 1H), 6.43 (dd, J=8.3, 1.0 Hz, 1H), 4.27–4.25 (m, 2H), 4.21–4.19 (m, 2H), 3.91 (s, 3H), 2.33–2.30 (m, 2H), 1.73 (s, 9H); LCMS found for C24H27NO8SNa (M+Na)+: m/z=512.
Reaction SMILES: C1(N2CC[O:9]CC2)CCCC=1.[C:12]([C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:23]=1)[CH:19]=O)([CH3:15])([CH3:14])[CH3:13].Cl.[CH:29]1[CH:34]=[CH:33][CH:32]=[CH:31]C=1>>[C:12]([C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:23]=1)[CH:19]=[C:31]1[CH2:32][CH2:33][CH2:34][C:29]1=[O:9])([CH3:15])([CH3:14])[CH3:13]
Reactant: C1=C(N2CCOCC2)CCC1
Reactant: c1ccccc1
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1
Agent: Cl
Product: CC(C)(C)c1cc(C=C2CCCC2=O)cc(C(C)(C)C)c1
Temperature: 30 °C
Reaction time: 2 h
Yield: 86.9 %

Procedure:
With reflux device installed, 36.8 g (0.24 mol) of N-cyclopentenyl morpholine, 0.20 mol of 3,5-di(t-butyl)-benzaldehyde and 200 mL benzene were added to a round bottom flask and heated under reflux for 20 h. The resulting solution was cooled to 30° C. and slowly stirred while 62 mL of hydrochloric acid (6 mol/L) was added. After stirring for 2 h at room temperature, the benzene layer was separated and washed with water to neutral, and dried over anhydrous sodium sulfate overnight. Then the mixture was filtered to remove anhydrous sodium sulfate and benzene was recovered by evaporation under reduced pressure. The residue was cooled and solidified, then recrystallized in cyclohexane/ethanol to yield a light yellow flaky crystal product with a yield of 86.9%.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([OH:20])[CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:8]=[C:7]1[CH3:19].CI.[CH3:23]CCCCC>O1CCCC1.O>[CH3:23][O:20][CH:4]([CH3:3])[CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:8]=[C:7]1[CH3:19]
Reactant: Cc1nc2cnc3ccccc3c2n1CC(C)O
Reactant: CCCCCC
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Solvent: O
Product: COC(C)Cn1c(C)nc2cnc3ccccc3c21

Procedure:
Sodium hydride (1 g of 60% ) was added to a suspension of 5 g (0.021 mole) of α,2-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol in 100 mL of tetrahydrofuran. The resulting mixture was stirred for an hour. Methyl iodide (1.55 mL; 0.025 mole) was added and the reaction mixture was stirred for an hour. The reaction mixture was diluted with water then extracted three times with ethyl acetate. The ethyl acetate extracts were combined, dried over magnesium sulfate then concentrated under vacuum to provide 4.9 g of crude product as a brown oil. The oil was refluxed for one hour with 250 mL of hexane then filtered. The filtrate was cooled and the resulting precipitate was collected and dried to provide 2.4 g of a sticky light yellow powder. A sample was recrystallized from ether to provide 1-(2-methoxypropyl)-2-methyl-1H-imidazo[4,5c]quinoline as a white crystalline solid, m.p. 55°-57° C. The structure was confirmed by nuclear magnetic resonance spectroscopy.
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:18]3[C@H:21]([S:22][CH2:23][C:24]=2[CH2:25][S:26][C:27]2[S:37][C:30]4=[N:31][C:32]([CH3:36])=[CH:33][C:34](=[O:35])[N:29]4[N:28]=2)[C@H:20]([NH:38][C:39](=[O:87])/[C:40](/[C:62]2[N:63]=[C:64]([NH:67]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[S:65][CH:66]=2)=[N:41]\[O:42][C:43](=[O:61])[C:44]2[CH:49]=[C:48]([O:50][C:51](=[O:54])[CH2:52][Cl:53])[C:47]([O:55][C:56](=[O:59])[CH2:57][Cl:58])=[CH:46][C:45]=2[CH3:60])[C:19]3=[O:88])=[O:16])C2C=CC=CC=2)C=CC=CC=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>ClC(Cl)C>[NH2:67][C:64]1[S:65][CH:66]=[C:62](/[C:40](=[N:41]/[O:42][C:43](=[O:61])[C:44]2[CH:49]=[C:48]([O:50][C:51](=[O:54])[CH2:52][Cl:53])[C:47]([O:55][C:56](=[O:59])[CH2:57][Cl:58])=[CH:46][C:45]=2[CH3:60])/[C:39]([NH:38][C@@H:20]2[C:19](=[O:88])[N:18]3[C@@H:21]2[S:22][CH2:23][C:24]([CH2:25][S:26][C:27]2[S:37][C:30]4=[N:31][C:32]([CH3:36])=[CH:33][C:34](=[O:35])[N:29]4[N:28]=2)=[C:17]3[C:15]([OH:16])=[O:14])=[O:87])[N:63]=1
Reactant: Cc1cc(=O)n2nc(SCC3=C(C(=O)OC(c4ccccc4)c4ccccc4)N4C(=O)[C@@H](NC(=O)/C(=N\OC(=O)c5cc(OC(=O)CCl)c(OC(=O)CCl)cc5C)c5csc(NC(c6ccccc6)(c6ccccc6)c6ccccc6)n5)[C@H]4SC3)sc2n1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(Cl)Cl
Solvent: COc1ccccc1
Product: Cc1cc(=O)n2nc(SCC3=C(C(=O)O)N4C(=O)[C@@H](NC(=O)/C(=N\OC(=O)c5cc(OC(=O)CCl)c(OC(=O)CCl)cc5C)c5csc(N)n5)[C@H]4SC3)sc2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 93.3 %

Procedure:
To a solution of the product obtained in Step 5 (0.47 g) in dichloroethane (3.5 ml) were added anisole (0.23 ml) and trifluoroacetic acid (0.47 ml) under ice cooling, and the resulting solution was stirred at room temperature for five hours. After removing the solvent under reduced pressure, the residue was crystallized with ether, giving 0.3 g of the objective compound (as trifluoroacetic acid salt).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:11]([NH:13][C:14]2[S:15][C:16]([S:19]C#N)=[CH:17][N:18]=2)=[O:12])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].SC[C@@H]([C@@H](CS)O)O.[CH2:36]([N:38]([CH2:42][CH3:43])[CH2:39][CH2:40]S)[CH3:37]>>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([N:10]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:11]([NH:13][C:14]2[S:15][C:16]([S:19][CH2:37][CH2:36][N:38]([CH2:42][CH3:43])[CH2:39][CH3:40])=[CH:17][N:18]=2)=[O:12])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(N(C(=O)Nc2ncc(SC#N)s2)C2CCCCC2)CC1
Reactant: CCN(CC)CCS
Agent: O[C@H](CS)[C@@H](O)CS
Product: CCN(CC)CCSc1cnc(NC(=O)N(C2CCCCC2)C2CCN(C(C)=O)CC2)s1

Procedure:
Prepared as described in general procedures (H) and (I) using 1-(1-acetyl-piperidin-4-yl)-1-cyclohexyl-3-(5-thiocyanato-thiazol-2-yl)-urea, dithioerythritol and 2-diethylamino-ethanethiol
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[CH:12]([N:16]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]([OH:31])=[O:30])[CH2:24][CH2:23][N:22]([CH2:32][C:33]([OH:35])=[O:34])[CH2:21][CH2:20][N:19]([CH2:36][C:37]([OH:39])=[O:38])[CH2:18][CH2:17]1)[C:13]([OH:15])=[O:14].[H][H]>O.[Pt]=O>[NH4+:9].[NH4+:9].[NH4+:9].[NH4+:9].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[CH:12]([N:16]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]([O-:31])=[O:30])[CH2:24][CH2:23][N:22]([CH2:32][C:33]([O-:35])=[O:34])[CH2:21][CH2:20][N:19]([CH2:36][C:37]([O-:39])=[O:38])[CH2:18][CH2:17]1)[C:13]([O-:15])=[O:14]
Reactant: [H][H]
Reactant: COc1ccc([N+](=O)[O-])cc1C(C(=O)O)N1CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC1
Agent: O=[Pt]
Solvent: O
Product: COc1ccc(N)cc1C(C(=O)[O-])N1CCN(CC(=O)[O-])CCN(CC(=O)[O-])CCN(CC(=O)[O-])CC1
Product: [NH4+]
Yield: 420.2 %

Procedure:
To a solution of α-(2-methoxy-5-nitrophenyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (157 mg) (prepared by the procedure of Example 11) in water (20 ml) was added platinum oxide (20 mg). This mixture was hydrogenated (1 atmosphere hydrogen) for 1 hour at room temperature. After filtration, the material was further purified by chromatography (silica gel, Solvent System 5) to yield the title compound (141 mg) as an off-white solid, and characterized by:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][NH:6]1.C(N(CC)CC)C.[C:18](Cl)(=[O:21])[CH:19]=[CH2:20].C(OCC)C>C(Cl)Cl>[O:21]=[C:18]([N:6]1[CH2:7][CH2:8][CH2:9][CH:5]1[C:4]([O:3][CH3:2])=[O:10])[CH:19]=[CH2:20]
Reactant: C=CC(=O)Cl
Reactant: COC(=O)[C@@H]1CCCN1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=CC(=O)N1CCCC1C(=O)OC
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
L-Proline methyl ester hydrochloride (8.27 g, 0.05 mole) was dissolved in 250 ml of methylene chloride and triethylamine (40 ml, 0.28 mole) added thereto. The solution was filtered to remove the precipitate and cooled to 5° C. Over a period of 30 minutes, a solution of acryloyl chloride (4.52 g, 0.05 mole) was added to the cooled solution, the reaction allowed to warm to room temperature and stirred for 12 hours. Ethyl ether (100 ml) was then added to the solution and the resulting white solid filtered. An additional 200 ml of ethyl ether was added and a small amount of tan solid filtered out. The solvents were evaporated, and the resulting oil chromatographed on silica to isolate the product. The product was dried in vacuo at room temperature for 72 hours. The structure was confirmed by NMR.
Reaction SMILES: Cl.C([N:9]1[C:17]2[N:16]3[N:18]=[C:19]([CH3:30])[C:20]([C:21]4[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=4[CH3:29])=[C:15]3[N:14]=[C:13]([CH3:31])[C:12]=2[CH2:11][CH2:10]1)C1C=CC=CC=1.O.C(O)C>[H][H].[C].[Pd]>[C:26]1([CH3:27])[CH:25]=[C:24]([CH3:28])[CH:23]=[C:22]([CH3:29])[C:21]=1[C:20]1[C:19]([CH3:30])=[N:18][N:16]2[C:17]3[NH:9][CH2:10][CH2:11][C:12]=3[C:13]([CH3:31])=[N:14][C:15]=12
Reactant: [H][H]
Reactant: Cc1cc(C)c(-c2c(C)nn3c4c(c(C)nc23)CCN4Cc2ccccc2)c(C)c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1cc(C)c(-c2c(C)nn3c4c(c(C)nc23)CCN4)c(C)c1
Yield: 71.6 %

Procedure:
Concentrated hydrochloric acid (1 mL) was added to a mixture of 8-benzyl-3-mesityl-2,5-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine (4.7 g) which is a free compound of the compound prepared in Example 26, water-containing 5% palladium carbon (3.0 g) and ethanol (300 mL), followed by stirring at room temperature for two days in hydrogen atmosphere. After filtering through Celite, the filtrate was evaporated, which was neutralized with an aqueous solution of sodium bicarbonate. The resulting solid was filtered, and dissolved in a mixed solution of dichloromethane, methanol and ethyl acetate. After filtering off the insoluble matter, the mixture was purified by silica gel column chromatography (10-67% ethyl acetate/hexane), to give the title compound as white crystals (2.6 g). 1.0 g of a raw material was recovered.