Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH:5]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18]Cl)=[CH:11][CH:10]=1)=[O:8])[CH3:2].[CH3:27][C@@H:28]1[CH2:32][CH2:31][CH2:30][NH2+:29]1.C1(S([O-])(=O)=O)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[CH2:1]([O:3][C:4](=[O:26])[CH:5]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][N:29]2[CH2:30][CH2:31][CH2:32][C@H:28]2[CH3:27])=[CH:11][CH:10]=1)=[O:8])[CH3:2]
Reactant: C[C@@H]1CCC[NH2+]1
Reactant: CCOC(=O)C(CC(=O)c1ccc(OCCCCl)cc1)c1ccccn1
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])c1ccccc1
Agent: [I-]
Solvent: CC#N
Product: CCOC(=O)C(CC(=O)c1ccc(OCCCN2CCC[C@H]2C)cc1)c1ccccn1
Yield: 30.6 %

Procedure:
In a 100 mL round bottom flask, 4-[4-(3-chloro-propoxy)-phenyl]-4-oxo-2-pyridin-2-yl-butyric acid ethyl ester (2.77 g, 7.4 mmol), benzenesulfonate (R)-2-methyl-pyrrolidinium (3.59 g, 14.7 mmol), potassium carbonate (4.07 g, 29.5 mmol), and potassium iodide (100 mg, 0.6 mmol) in acetonitrile (100 mL) was heated to reflux 14 h. The reaction was cooled and the solvent concentrated under vacuum. The slurry was partitioned between methylene chloride and water, and then washed with water 3 times. The organics were chromatographed through silica gel with methylene chloride/methanol (95:5) eluent. Ethereal HCl was added to make the bis HCl salt and produce 960 mg (28%) of an amorphous solid. MS m/z 425 (M+H).
Reaction SMILES: [CH:1]1[CH2:5][CH2:4][CH2:3][CH:2]=1.[C:6]1([PH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[CH:1]1([P:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1=CCCC1
Reactant: c1ccc(Pc2ccccc2)cc1
Product: c1ccc(P(c2ccccc2)C2CCCC2)cc1

Procedure:
A stirred mixture of 47.6 g (0.7 m) cyclopentene and 136.7 g (0.735 m) diphenyl phosphine in a quartz wessel was irradiated at 15° C. by a broad spectrum ultraviolet light for 17 days. A slow addition reaction took place. Gas chromatographic analysis indicated 60% conversion at the end of the reaction period. The reaction mixture was then fractionally distilled in vacuo to obtain the desired cyclopentyl diphenyl phoshine adduct as a colorless mobile liquid of bp. 138°-140° C. at 0.3 mm (As a by-product, tetraphenyl biphosphine, bp. 210°-212° C. at 0.15 mm, was obtained.)
Reaction SMILES: [CH3:1][N:2]([CH3:44])[C:3]([C:5]1[CH:6]=[C:7]([CH:41]=[CH:42][CH:43]=1)[O:8][C:9]1[N:14]=[C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([NH2:23])=[C:11]([O:24][C:25]2[CH:30]=[C:29]([C:31]#[N:32])[CH:28]=[CH:27][C:26]=2[O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:10]=1)=[O:4].[CH2:45]1COC[CH2:46]1.C(O)C>>[CH3:1][N:2]([CH3:44])[C:3]([C:5]1[CH:6]=[C:7]([CH:41]=[CH:42][CH:43]=1)[O:8][C:9]1[N:14]=[C:13]2[C:12]([N:23]=[C:45]([CH3:46])[N:15]2[CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:11]([O:24][C:25]2[CH:30]=[C:29]([C:31]#[N:32])[CH:28]=[CH:27][C:26]=2[O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[N:10]=1)=[O:4]
Reactant: CN(C)C(=O)c1cccc(Oc2nc(NCc3ccccc3)c(N)c(Oc3cc(C#N)ccc3OCc3ccccc3)n2)c1
Reactant: C1CCOC1
Solvent: CCO
Product: Cc1nc2c(Oc3cc(C#N)ccc3OCc3ccccc3)nc(Oc3cccc(C(=O)N(C)C)c3)nc2n1Cc1ccccc1
Temperature: 170 °C

Procedure:
2-(3-Dimethylaminocarbonylphenoxy)-4-(benzyl)amino-5-amino-6-(2-benzyloxy-5-cyanophenoxy)pyrimidine, a compound of formula (J), (0.26 g, 0.44 mmol), was treated with ethyl imidate hydrochloride (0.17 g, 1.3 mmol) in THF/ethanol at 80° C for 6 hours and then concentrated to an oil. The residue was heated in a sand bath under vacuum at 170° C. for 2.0 hours, cooled and filtered through a pad of silica, eluting with 5% methanol in methylene chloride. Evaporation of the volatiles afforded 0.20 g of 2-(3-dimethylaminocarbonylphenoxy)-6-(2-benzyloxy-5-cyanophenoxy)-8-methyl-9-benzylpurine, a compound of formula (L).
Reaction SMILES: [C:1]1([O:11][CH2:12][C:13]([NH:15][C@H:16]([C:21]([NH:23][C@H:24]([CH:33]=[O:34])[CH2:25][C:26](=NNC(N)=O)[OH:27])=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(O)(=[O:37])C.CO>C=O.O>[C:1]1([O:11][CH2:12][C:13]([NH:15][C@H:16]([C:21]([NH:23][C@H:24]([CH:33]=[O:34])[CH2:25][C:26]([OH:27])=[O:37])=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)O
Reactant: CC(C)C[C@H](NC(=O)COc1cccc2ccccc12)C(=O)N[C@H](C=O)CC(O)=NNC(N)=O
Agent: C=O
Solvent: O
Solvent: CO
Product: CC(C)C[C@H](NC(=O)COc1cccc2ccccc12)C(=O)N[C@H](C=O)CC(=O)O
Yield: 79 %

Procedure:
A solution of (3S)-3-[N-((1-naphthyloxy)acetyl)leucinyl]amino-4-oxobutanoic acid semicarbazone (0.320 g, 0.68 mmol) in 37% aqueous formaldehyde(1.0 mL)-acetic acid(1.0 mL)-methanol(3.0 mL) was stirred at room temperature under nitrogen for 3.5 hrs. The resulting solution was diluted with water and extracted with EtOAc. The extract was washed with water and saturated NaCl solution, dried over anhydrous Na2SO4 and evaporated to dryness. The residue was taken up in EtOAc, filtered through Celite and evaporated to dryness. The product was taken up in a small amount of dioxane, diluted with water, frozen and lyophilized to give the title compound (0.222 g, 79%) as a fluffy white solid. TLC(EtOAc-pyridine-AcOH—H2O; 60:20:5:10) Rf=0.65.
Reaction SMILES: [CH3:1][C:2]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[C:6]([OH:15])[C:5]=2[NH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:22](Br)[CH:23]=[CH2:24]>C1COCC1.CN1C(=O)CCC1>[CH2:24]([N:4]1[C:5]2[C:6]([OH:15])=[N:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]=2[C:2]([CH3:1])=[CH:3]1)[CH:23]=[CH2:22]
Reactant: Cc1c[nH]c2c(O)nc3ccccc3c12
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: C=CCn1cc(C)c2c3ccccc3nc(O)c21
Temperature: 40 °C
Reaction time: 12 h
Yield: 54.1 %

Procedure:
A solution of 1-methyl-3H-pyrrolo[2,3-c]quinolin-4-ol (1.2 g, 6.05 mmol) in a mixture of THF (30 mL) and NMP (60 mL) was treated with Cs2CO3 (2.95 g, 9.08 mmol). Allyl bromide (0.524 mL, 6.06 mmol) was added dropwise, and the resulting mixture was stirred at 40° C. for 12 h. The mixture was cooled and quenched with aqueous HCl (1 N) and EtOAc. The organic layer was separated, washed with aqueous HCl (1 N), brine, and dried over Na2SO4. Filtration and removal of the volatiles gave a residue that was triturated with Et2O to give the title compound (0.78 g, 54%) as a solid. LCMS (ES+) m/z 239 (M+H)+.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1)=[O:5].[Br:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1.C(C1C=CC=CC=1)(=O)C>O.C(O)C>[Br:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[CH:3][C:4]([C:6]2[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=2)=[O:5])=[CH:16][CH:15]=1
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: O=Cc1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)c1ccccc1
Solvent: O
Product: O=C(C=Cc1ccc(Br)cc1)c1ccc(Br)cc1
Reaction time: 8 h
Yield: 97 %

Procedure:
Sodium hydroxide (1.8 g, 45 mmol) and 4-bromoacetophenone (7.12 g, 36 mmol) were dissolved in water (18 mL) and ethanol (50 mL). 4-Bromo benzaldehyde (6.62 g, 36 mmol) dissolved in ethanol (20 mL) was added dropwise to the acetophenone solution. A slurry quickly formed, which was allowed to stir overnight. The slurry was filtered, was with water until the filtrate was neutral to pH paper, and dried at 100° C. for 12 hours. A light tan solid was obtained (12.8 g, 97% yield).
Reaction SMILES: Cl.[CH2:2]([N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[NH:9])[CH3:3].[CH3:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:12]=1[N:18]=[C:19]=[O:20].C(OCC)(=O)C>C1C=CC=CC=1>[CH3:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH3:10])[C:12]=1[NH:18][C:19]([N:9]=[C:5]1[CH2:6][CH2:7][CH2:8][N:4]1[CH2:2][CH3:3])=[O:20]
Reactant: CCN1CCCC1=N
Reactant: Cc1cccc(C)c1N=C=O
Agent: Cl
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CCN1CCCC1=NC(=O)Nc1c(C)cccc1C
Temperature: 25 °C

Procedure:
The hydrochloride of 1-ethyl-2-iminopyrrolidine (7.43 g.; 0.05 mole) is converted to free base (5.6 g.; 0.05 mole) in benzene in the usual manner. Then 7.35 g. (0.05 mole) of 2,6-dimethylphenylisocyanate, dissolved in anhydrous benzene, is added. The reaction mixture is stirred at room temperature for 1 3/4 hours and then the solvent is evaporated to dryness in vacuo to give an oily residue. Trituration with ethyl acetate and cooling produces a solid product, 1-(2,6-dimethylphenyl)-3-(1-ethyl-2-pyrrolidylidene)urea, m.p. = 120°-122° C. Recrystallization from acetone gives the pure product, m.p. - 121°-123° C.
Reaction SMILES: C(C1C=CC(C(NC2C=CC(C3C=C4C(CN([C@@H](C(C)C)C(O)=O)C4=O)=CC=3)=NC=2)=O)=CC=1)(C)(C)C.[Cl:37][C:38]1[CH:43]=[C:42]([NH:44][C:45](=[O:57])[C:46]2[CH:51]=[CH:50][C:49]([CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])=[CH:48][CH:47]=2)[CH:41]=[CH:40][C:39]=1[C:58]1[CH:66]=[C:65]2[C:61]([CH2:62][N:63]([C@@H:68]([CH:73]([CH3:75])[CH3:74])[C:69]([O:71]C)=[O:70])[C:64]2=[O:67])=[CH:60][CH:59]=1>>[Cl:37][C:38]1[CH:43]=[C:42]([NH:44][C:45](=[O:57])[C:46]2[CH:51]=[CH:50][C:49]([CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])=[CH:48][CH:47]=2)[CH:41]=[CH:40][C:39]=1[C:58]1[CH:66]=[C:65]2[C:61]([CH2:62][N:63]([C@@H:68]([CH:73]([CH3:74])[CH3:75])[C:69]([OH:71])=[O:70])[C:64]2=[O:67])=[CH:60][CH:59]=1
Reactant: CCCCCc1ccc(C(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)OC)C(C)C)C4)c(Cl)c2)cc1
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(C(C)(C)C)cc4)cn3)cc2C1=O
Product: CCCCCc1ccc(C(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)O)C(C)C)C4)c(Cl)c2)cc1
Yield: 72 %

Procedure:
The compound of example 486 was prepared analogous to the compound of example 404 by hydrolysis of the compound of example 485.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:28])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[NH:17][C:18]([C:20]2[S:21][C:22]([CH2:26][OH:27])=[CH:23][C:24]=2[Cl:25])=[O:19])=[CH:4][CH:3]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[NH:17][C:18]([C:20]2[S:21][C:22]([CH:26]=[O:27])=[CH:23][C:24]=2[Cl:25])=[O:19])=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc(Cl)cc1)c1cc(Cl)ccc1NC(=O)c1sc(CO)cc1Cl
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc(Cl)c(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cc2)s1
Reaction time: 20 h
Yield: 40.6 %

Procedure:
To a solution of N-(4-chlorophenyl)-2-[((5-hydroxymethyl-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide (0.085 g, 0.19 mmol) in DMF (6 mL) was added pyridinium dichromate (PDC) (0.25 g, 0.65 mmol) at ambient temperature. After stirring for 20 hours, water was added and the reaction mixture was extracted with methylene chloride. The combined extracts were dried over Na2SO4, filtered, concentrated in vacuo, and purified by flash chromatography on silica to afford 0.035 g of N-(4-chlorophenyl)-2-[((5-formyl-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide, as a pale yellow solid; NMR (DMSO-d6) 11.3 (s, 1), 10.8(s, 1), 9.9 (s, 1),8.3 (d, 1), 8.1 (s, 1), 7.9 (s, 1), 7.7 (d, 2), 7.6 (d, 1), 7.4 (d, 2) ppm.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:27])[CH2:15][CH2:16]/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)=[CH:4][CH:3]=1.[CH2:28]([O:30][C:31](=[O:51])[CH2:32][C:33]1([C:36]2[CH:41]=[CH:40][C:39](B3OC(C)(C)C(C)(C)O3)=[CH:38][CH:37]=2)[CH2:35][CH2:34]1)[CH3:29]>>[CH2:28]([O:30][C:31](=[O:51])[CH2:32][C:33]1([C:36]2[CH:41]=[CH:40][C:39]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:27])[CH2:15][CH2:16]/[CH:17]=[CH:18]/[C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=4)=[CH:4][CH:3]=3)=[CH:38][CH:37]=2)[CH2:35][CH2:34]1)[CH3:29]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)CC/C=C/c1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)CC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4onc(C)c4C(O)CC/C=C/c4ccc(Cl)c(Cl)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 110, Step 3, using (E)-1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-5-(3,4-dichloro-phenyl)-pent-4-en-1-ol and {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl}-acetic acid ethyl ester.
Reaction SMILES: [Ag:1].[C:2]([CH:5]([CH:7]([C:9]([O-:11])=[O:10])[OH:8])[OH:6])([O-:4])=[O:3].[Na+].[Na+].[N+]([O-])([O-])=O.[Ag+]>>[C:2]([CH:5]([CH:7]([C:9]([O-:11])=[O:10])[OH:8])[OH:6])([O-:4])=[O:3].[Ag+2:1]
Reactant: [Ag]
Agent: [Ag+]
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: O=[N+]([O-])[O-]
Product: [Ag+2]

Procedure:
This example illustrates the preparation of the silver coating solutionthat is used in Examples 4 and 5. 3 ml of a sodium tartrate solution (1 g tartaric acid disodium salt dihydrate (obtained from Aldrich) dissolved in20 ml distilled water) was added to 3 ml of a silver nitrate solution (10 gsilver nitrate dissolved in 10 ml distilled water) at 22° C. A whiteprecipitate of silver tartrate formed rapidly. Concentrated ammonium hydroxide, 28% ammonia (obtained from EM Science), was added dropwise to the solution until the silver tartrate dissolved completely to give a clear solution of ammonical silver tartarate with a pH of approximately 12.
Reaction SMILES: [CH:1]1[C:13]2[N:12]([CH2:14][C:15]#[C:16][C:17]#[C:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C1C2[N:35]([CH2:37]C#C)[C:34]3C(=CC=CC=3)C=2C=CC=1.C([OH:46])CCCC#C.Br[O-].[Na+]>>[CH3:34][NH:35][C:37]([O:23][CH2:22][CH3:21])=[O:46].[CH:10]1[C:11]2[N:12]([CH2:14][C:15]#[C:16][C:17]#[C:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: C#CCn1c2ccccc2c2ccccc21
Reactant: C#CCCCCO
Agent: OCCCCC#CC#CCn1c2ccccc2c2ccccc21
Agent: [Na+]
Agent: [O-]Br
Product: CCOC(=O)NC

Procedure:
For example, 9-(N-carbazolyl)-5, 7-nonadiyn -1-ol (5) is synthesized in about 80% yield by cross coupling of 3-(N-carbazolyl)-1-propyne (3) with 6-bromo-5-hexyn-1-ol (6), which, in turn, is synthesized from 5-hexyn-1-ol with sodium hypobromite. Reaction of (5) with methylisocyanate (7) gives 9-(N-carbazolyl)- 5,7-nonadiyn-1-ol methylurethane (8) in almost quantitative yield. ##STR12##
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=3)[CH2:12][CH2:11]2)=[N:2]1.C(N(CC)CC)C.[CH3:32][C:33]([CH3:38])([CH3:37])[C:34](Cl)=[O:35]>C1COCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][C:18]3[CH:19]=[CH:20][C:21]([NH:24][C:34](=[O:35])[C:33]([CH3:38])([CH3:37])[CH3:32])=[CH:22][CH:23]=3)[CH2:14][CH2:15]2)=[N:2]1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccc(CCN2CCN(c3nsc4ccccc34)CC2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1ccc(CCN2CCN(c3nsc4ccccc34)CC2)cc1
Yield: 92.3 %

Procedure:
4-[2-(4-1,2-Benzisothiazol-3-yl-piperazin-1-yl)-ethyl]-phenylamine (135 mg, 0.4 mmol) was dissolved in 5 ml THF and triethylamine was added (112 μL, 0.8 mmol). Trimethyl acetyl chloride (49.3 μL, 0.4 mmol) was added under stirring and the reaction stirred at room temperature overnight. The reaction mixture was concentrated under nitrogen and dissolved in 5 ml methylene chloride and then washed with water. The organic layer was concentrated and evaluated by LCMS. The mixture was purified by MPLC using a Biotage 40s prepacked silica gel cartridge eluting with 3% methanol in methylene chloride. N-{4-[2-(4-1,2-Benzisothiazol-3-yl-piperazin-1-yl)-ethyl]-phenyl}-2,2-dimethyl-propionamide (156 mg) was isolated in 98.2% purity @ 254 nm; LCMS (APCI): 423 [M+H]+
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N+:12]([O-])=O)=[C:7]([NH:15][CH3:16])[CH:6]=[CH:5]2.C(N(CC)CC)C.Cl.NC1C=CC2C(=CC=CC=2)C=1N.O.O.[C:39]([OH:44])(=O)[C:40](O)=[O:41]>C(O)C.Cl.[Pd]>[CH3:16][N:15]1[C:7]2[CH:6]=[CH:5][C:4]3[CH:3]=[CH:2][CH:11]=[CH:10][C:9]=3[C:8]=2[NH:12][C:40](=[O:41])[C:39]1=[O:44]
Reactant: O=C(O)C(=O)O
Reactant: CNc1ccc2cc(Br)ccc2c1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Agent: Nc1ccc2ccccc2c1N
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: Cn1c(=O)c(=O)[nH]c2c3ccccc3ccc21
Yield: 91.5 %

Procedure:
A suspension of 6-bromo-2-methylamino-1-nitronaphthalene (2.81 g, 10 mmol) and triethylamine (1.40 ml, 10 mmol) in 150 ml of 96% ethanol was hydrogenated at room temperature and atmospheric pressure in the presence of 5% palladium-on-carbon (500 mg) for 1 h. The solution was filtered directly into 50 ml of 4M hydrochloric acid under a nitrogen atmosphere. The acidic filtrate was evaporated to dryness and the solid diaminonaphthalene hydrochloride was refluxed with oxalic acid dihydrate (1.5 g, 11.9 mmol) in 25 ml of 4M hydrochloric acid without further purification. After reflux for 2 h the mixture was cooled, and the solid product was isolated by filtration and washed with water, ethanol and ether to give 2.07 g (92%) of the title compound. M.p. 332.7° C. (ethanol); IR (KBr): 1685 cm-1 ; 1H-NMR (DMSO-d6): 3.60 (s, 3H, CH3), 7.33-7.93 (m, 5H, ArH), 8.37-8.60 (m, 1H, ArH), 12.13 (broad s, 1H, NH); MS m/z: 226 (M+, 100%).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:9]([NH:10][C:11](=[O:37])[C@H:12]([CH2:33][CH:34]([CH3:36])[CH3:35])[NH:13][C:14](=[O:32])[C:15]2[CH:20]=[CH:19][C:18]([NH:21]C(OCC3C=CC=CC=3)=O)=[CH:17][CH:16]=2)[CH2:8][CH2:7][O:6]1)(=[O:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:4][C@H:5]1[C@@H:9]([NH:10][C:11](=[O:37])[C@H:12]([CH2:33][CH:34]([CH3:35])[CH3:36])[NH:13][C:14](=[O:32])[C:15]2[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=2)[CH2:8][CH2:7][O:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1OCC[C@@H]1NC(=O)[C@H](CC(C)C)NC(=O)c1ccc(NC(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: CC(=O)O[C@@H]1OCC[C@@H]1NC(=O)[C@H](CC(C)C)NC(=O)c1ccc(N)cc1
Yield: 82.7 %

Procedure:
In ethanol (100 ml) was dissolved (2S,3S)-2-acetoxy-3-[[N-[4-(N-benzyloxycarbonylamino)benzoyl]-(L)-leucyl]amino]tetrahydrofuran (1.0 g) and following addition of palladium-on-carbon (5%, 0.7 g), the catalytic hydrogenation was carried out at ambient temperature and atmospheric pressure. The catalyst was then filtered off and the filtrate was concentrated under reduced pressure to provide (2S,3S)-2-acetoxy-3-[[N-(4-aminobenzoyl)-(L)-leucyl]amino]tetrahydrofuran (chemical formula below) (0.61 g, 81%). As recrystallied from dichloromethane-isopropyl ether, colorless crystals, m.p. 148°-150° C. optical rotation [α]D -61.3° (C=0.29, CHCl3). ##STR68##
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[CH:7]=[C:8]([C:14]([CH3:16])=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10])([O-:3])=[O:2].[NH2:20]/[C:21](/[CH3:36])=[CH:22]\[C:23]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:24]>C(O)C>[CH3:36][C:21]1[NH:20][C:14]([CH3:16])=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:7]([C:6]2[CH:17]=[CH:18][CH:19]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:22]=1[C:23]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:24]
Reactant: CCCCCCCCCCOC(=O)/C=C(/C)N
Reactant: CCOC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(C)=O
Solvent: CCO
Product: CCCCCCCCCCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Reaction time: 18 h

Procedure:
A solution of 263 g (1 mol) of ethyl 2-(3-nitrobenzylidene)acetoacetate and 241 g (1 mol) of decyl 3-aminocrotonate in 2.4 liters of absolute ethanol was heated to boiling under nitrogen for 18 hours. The mixture was then filtered hot and the filtrate was evaporated in vacuo to about one half of the volume. The concentrated solution was cooled in ice, producing a thick mass of crystals. This was filtered off with suction, recrystallized from ethanol and, after washing with 0.5 liters of n-hexane, was dried in a vacuum oven at 60° C.
Reaction SMILES: [O-][N+:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[N:12]([CH2:15][CH2:16][O:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([N:24]([CH3:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:23])[CH:13]=[N:14][C:4]=2[CH:3]=1.ClC(Cl)(Cl)C([N:36]=C=O)=O>ClCCl>[NH2:36][C:3]1[C:4]2[N:14]=[CH:13][N:12]([CH2:15][CH2:16][O:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([N:24]([CH3:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:23])[C:5]=2[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=2[N:2]=1
Reactant: CN(C(=O)CCCCOCCn1cnc2c[n+]([O-])c3ccccc3c21)c1ccccc1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: ClCCl
Product: CN(C(=O)CCCCOCCn1cnc2c(N)nc3ccccc3c21)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Using the general method of Parts C and D of Example 11, 2-(1H-imidazo[4,5-c]quinolin-1-yl)ethanol (0.63 g, 2.9 mmol) and 5-bromo-N-methyl-N-phenylpentanamide (1.3 g, 4.8 mmol) were combined to provide 0.24 g of 5-[2-(5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]-N-methyl-N-phenylpentanamide as a colorless oil. The resulting N-oxide product was dissolved in dichloromethane and trichloroacetyl isocyanate (0.11 ml) was added dropwise. The reaction was stirred at room temperature for 2 hours and then the solvent was removed under vacuum. The resulting oil was dissolved in methanol and sodium methoxide (0.2 ml, 25% by weight in methanol) was slowly added. The reaction was maintained overnight and then concentrated under vacuum. Purification by flash column chromatography (silica gel, 9:1 ethyl acetate\methanol) provided 24 mg of 5-[2-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]-N-methyl-N-phenylpentanamide as a white solid.
Reaction SMILES: [ClH:1].[C:2](N)(=[NH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CC[O-].[Na+].[CH3:15][N:16]([CH2:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=1)[C:22]([NH:24][NH2:25])=O)[CH3:17].Cl.CCOCC>C(O)C>[ClH:1].[CH3:15][N:16]([CH3:17])[CH2:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:21]([C:22]2[N:9]=[C:2]([C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[NH:25][N:24]=2)[CH:20]=1
Reactant: CN(C)Cc1cccc(C(=O)NN)c1
Reactant: N=C(N)c1ccccc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: CN(C)Cc1cccc(-c2n[nH]c(-c3ccccc3)n2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27 %

Procedure:
To a stirred ethanolic suspension of benzamidine hydrochloride salt (235 mg, 1.5 mmol, 1.5 eq.), was added 1.2N NaOEt in ethanol (1.7 ml, 2 eq.) over 3 minutes, the mixture was further stirred for 30 min. at r.t. To this was added 3-dimethylaminomethyl-benzoic acid hydrazide (193 mg, 1 mmol) in ethanol at 20° C. and the mixture heated to reflux for 24 hrs. Upon cooling the product mixture was filtered, solvent evaporated and residue subjected to preparative reversed-phase HPLC purification using a YMC ODS-AQ column (20×50 mm) and a (0.1% trifluoroacetic acid) water-acetonitrile gradient (25 ml/min. flow rate). The pure fractions were concentrated and the product obtained was converted to the hydrochloride salt by addition of excess 2N HCl/ether solution (1.0 ml) followed by solvent evaporation and high vacuum drying to afford the title compound (84 mg, 0.27 mmol, 27% yield) as a yellow foam. MS: m/e=279.4 (M+H+).