Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:15][CH2:14][N:5]2[C:6]3[C:11]([C:12]([CH3:13])=[C:4]2[C:3]1=O)=[CH:10][CH:9]=[CH:8][CH:7]=3.Cl.[NH2:19][OH:20]>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:17])[CH2:15][CH2:14][N:5]2[C:6]3[C:11]([C:12]([CH3:13])=[C:4]2[C:3]1=[N:19][OH:20])=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: Cc1c2n(c3ccccc13)CCC(C)(C)C2=O
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: Cc1c2n(c3ccccc13)CCC(C)(C)C2=NO
Yield: 40.2 %

Procedure:
The title compound is prepared in an analogous manner to Step 1. A mixture of 6,7,8,9-tetrahydro-8,8,10-trimethylpyrido[1,2-a]indol-9-one (700 mg, 3.08 mmol, described in Example 1, Step 3), and hydroxylamine hydrochloride (420 mg, 6.04 mmol) was refluxed in pyridine (40 mL) for 21/2 hours. The reaction mixture was evaporated to dryness in vacuo and the residue suspended in water (20 mL). The insoluble components were extracted with ether (3×40 mL). The combined organic layer was washed with 5% hydrochloric acid, 10% sodium bicarbonate, and water. The separated organic layer was dried over MgSO4, filtered, and evaporated. The residue was chromatographed on silica gel (10 g). Elution with chloroform/hexane (1:1) afforded 300 mg (40%) of the title compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](I)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:10]([OH:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[CH:17]>[Cu]I.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:17]#[C:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][OH:18])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C#CCCCCCCO
Reactant: Clc1ccc(I)cc1Cl
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: OCCCCCCC#Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 3,4-dichloroiodobenzene (2.16 g), oct-7-yn-1-ol (1.20 g), tetrakis (triphenylphosphine)palladium (0) (0.185 g), copper (I) iodide (0.046 g) and triethylamine (15 ml) was stirred at room temperature for 16 h. The solid was filtered off and the filtrate evaporated under reduced pressure. The residual oil was dissolved in ethyl acetate (15 ml) and washed with water (10 ml), 2M hydrochloric acid (2×10 ml) and brine (10 ml). Drying over magnesium sulfate and removal of the solvent under reduced pressure gave an oil that was purified by flash chromatography on silica gel using dichloromethane as eluent. This gave 8-(3,4-dichlorophenyl)oct-7-yn-1-ol (1.89 g). 1H-NMR (CDCl3) δ 1.2-1.75 (8H, m), 2.40 (2H, t), 3.66 (2H, t), 7.19 (1H, dd), 7.35 (1H, d) and 7.47 (1H, dd).
Reaction SMILES: [Cl:1][CH2:2][C:3](=O)[CH3:4].[N:6]1([CH2:13][C:14]2[S:18][C:17]([C:19](=[S:21])[NH2:20])=[CH:16][CH:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[ClH:22]>C(O)C>[ClH:1].[ClH:22].[CH3:4][C:3]1[N:20]=[C:19]([C:17]2[S:18][C:14]([CH2:13][N:6]3[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]3)=[CH:15][CH:16]=2)[S:21][CH:2]=1
Reactant: NC(=S)c1ccc(CN2CCCCCC2)s1
Reactant: CC(=O)CCl
Agent: Cl
Solvent: CCO
Product: Cc1csc(-c2ccc(CN3CCCCCC3)s2)n1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
730 mg of chloroacetone was added to 30 ml of ethanol solution containing 2.0 g of 5-[(hexahydro-1H-azepin-1-yl)methyl]-2-thiophenecarbothioamide, and the mixture was stirred overnight at 80° C. The reaction solution was ice-cooled, adjusted to pH 1 by adding hydrochloric acid and then concentrated under a reduced pressure. The resulting residue was then recrystallized from acetonitrile to give 1.6 g of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.[CH3:18][C@H:19]([NH:28][CH3:29])[C@H:20]([OH:27])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1.Cl.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:29][N:28]([C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2[C:3]=1[N:11]=[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:9]=2)[CH:19]([CH3:18])[CH:20]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[OH:27]
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Reactant: CN[C@@H](C)[C@H](O)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1nc(N(C)C(C)C(O)c2ccccc2)c2nc(-c3ccccc3)cc-2[nH]1
Temperature: 120 °C
Reaction time: 20 h
Yield: 15.1 %

Procedure:
To a 5-mL, Wheaton vial were added 4-chloro-2-methyl-6-phenylpyrrolo[3,2-d]pyrimidine (Example 1 (e)) (100 mg, 0.41 mmol) and ephedrine hydrochloride (Aldrich Chemical Company) (410 mg, 2.1 mmol), followed by addition of a solution of potassium carbonate (0.71 g, 5.1 mmol) in water (2.5 mL). The reaction mixture was stirred at 120° C. for 20 h, allowed to cool to room temperature and extracted with CH2Cl2. The organic layer was dried over Na2SO4, concentrated in vacuo to give a brown residue, which was purified by flash chromatography on silica gel with 1:1 EtOAc/hexanes as eluant to give 23 mg (15%) of the title compound as a tan solid. 1H NMR (DMSO-d6; 400 MHz): d 1.21 (d, 3, J=6.8), 2.42 (s, 3), 3.21 (s, 3), 4.91 (m, 1), 5.02 (m, 1), 5.87 (br s, 1), 6.69 (s, 1), 7.18-7.85 (m, 10), 10.73 (br s, 1). MS m/z: 373 (M+1), 371 (M−1).
Reaction SMILES: Br[CH:2]1[C:19]2[C@:14]([CH3:21])([CH2:15][CH2:16][C:17](=[O:20])[CH:18]=2)[C@@H:13]2[C@H:4]([C@H:5]3[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C:8](=[O:22])[CH2:7][CH2:6]3)[CH2:3]1.[N-:23]=[N+:24]=[N-:25].[Na+].CO>CN(C)C=O>[N:23]([C:18]1[C:17](=[O:20])[CH2:16][CH2:15][C@@:14]2([CH3:21])[C:19]=1[CH2:2][CH2:3][C@@H:4]1[C@@H:13]2[CH2:12][CH2:11][C@@:9]2([CH3:10])[C@H:5]1[CH2:6][CH2:7][C:8]2=[O:22])=[N+:24]=[N-:25]
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@]12CCC(=O)C=C1C(Br)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: C[C@]12CCC(=O)C(N=[N+]=[N-])=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 48.3 %

Procedure:
To a stirred solution of 1.1 g of 6-bromoandrost-4-en-3,17-dione in 57.4 ml of dimethylformamide are added 0.250 g of sodium azide. The resulting mixture is heated at 30°-35° C. for 72 hours, cooled and worked up as described in the example 3. There are obtained 0.476 g of the title compound, m.p. (MeOH) 143°-144° C. (dec.);
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([CH3:7])[S:4][C:3]=1[C:8]([O:10]C)=O.Cl[C:13]1[N:18]=[CH:17][C:16]([C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:14]=1>CO>[CH3:7][C:5]1[S:4][C:3]2[C:8](=[O:10])[N:18]3[CH:17]=[C:16]([C:19]([O:21][CH3:22])=[O:20])[CH:15]=[CH:14][C:13]3=[N:1][C:2]=2[CH:6]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: COC(=O)c1sc(C)cc1N
Solvent: CO
Product: COC(=O)c1ccc2nc3cc(C)sc3c(=O)n2c1
Temperature: 180 °C

Procedure:
A mixture of 5 g (0.0292 mol) of 3-amino-5-methyl-2-thiophene-carboxylic acid, methyl ester (German Patent No. 1055007, Apr. 16, 1959) and 5 g (0.0292 mol) of 6-chloro-3-pyridinecarboxylic acid, methyl ester (Alfred Bader Chemical Company) is heated in an oil bath at 180° C. for thirty minutes. The mixture is cooled, dissolved in hot methanol, cooled and 1.2 g of 2-methyl-10-oxo-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carboxylic acid, methyl ester is collected; mp 215°-216° C. after recrystallization from methanol.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([Cl:21])=[CH:5][C:6]([F:20])=[C:7]([C:9]2[C:13]([Cl:14])=[C:12]([C:15]([F:18])([F:17])[F:16])[N:11]([CH3:19])[N:10]=2)[CH:8]=1.C([O-])(=[O:24])C.[Na+].O>CN(C=O)C>[Cl:21][C:4]1[CH:5]=[C:6]([F:20])[C:7]([C:9]2[C:13]([Cl:14])=[C:12]([C:15]([F:18])([F:17])[F:16])[N:11]([CH3:19])[N:10]=2)=[CH:8][C:3]=1[CH2:2][OH:24]
Reactant: CC(=O)[O-]
Reactant: Cn1nc(-c2cc(CBr)c(Cl)cc2F)c(Cl)c1C(F)(F)F
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nc(-c2cc(CO)c(Cl)cc2F)c(Cl)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.9 %

Procedure:
To a solution of 7.1 g (0.0175 mole) 3-[5-(bromomethyl)-4-chloro-2-fluorophenyl]-4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazole in 20 mL DMF was added 1.5 g (0.018 mole) sodium acetate. The mixture was stirred for 12 hours at 25° C. The mixture was poured into 100 mL cold water and the solid filtered and dried. The product was recrystallized from ethanol/-water to give 6.0 g (90%) of 2-chloro-5-(4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-4-fluorobenzenemethanol, acetate (ester), mp 90° C. The acetate was dissolved in 10 mL 1,4-dioxane and 10 mL water and 6.3 mL (0.0158 mole) 10% NaOH solution was added. After 30 minutes the solution was neutralized with concentrated HCl, filtered and the solid dried. The solid was recrystallized from ethanol/water to give 5.4 g (99%) of 2-chloro-5-[4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-4-fluorobenzenemethanol as a white solid; mp 103° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]=C=O)=[CH:14][CH:13]=1.O>[O-]CC.[Na+].CO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:18][C:15]2[CH:16]=[CH:17][C:12]([CH3:11])=[CH:13][CH:14]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: Cc1ccc(N=C=O)cc1
Reactant: Cc1ccc(C(=O)O)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1ccc(NC(=O)c2ccc(C)cc2)cc1
Temperature: 35 °C
Reaction time: 0.87 h

Procedure:
p-Methylbenzoic acid (95.31 grams, 0.70 mole), sodium ethoxide catalyst (0.2144 gram, 0.225% wt. of the p-methylbenzoic acid used) and N,N'-dimethylacetamide (575 grams) are added to a reactor equipped with a reflux condenser and stirred under a nitrogen atmosphere at 35° C. to provide a solution. p-Methylphenyl isocyanate (97.87 grams, 0.735 mole) is added over a two minute period inducing an exotherm to 40° C. At this time, heating of the reactor commences and a 160° C. temperature is achieved 52 minutes later. After three hours at the 160° C. reaction temperature, the reactor is cooled to 30° C. the the contents poured into deionized water (3.50 liters). A precipitated white crystalline product is recovered by filtration of the aqueous slurry then dried in a vacuum oven at 80° C. and 5 mm Hg for fifteen hours. The dry product and methanol (700 milliliters) are stirred together with heating to provide a solution at 63° C. After cooling the methanol solution to 4° C. for fourteen hours, a white crystalline product is filtered off and dried at 70° C. and 5 mm Hg in a vacuum oven to a constant weight of 135.6 grams. Fourier transform infrared spectrophotometric analysis of a potassium chloride pellet of the product confirms the product structure of 4,4'-dimethylbenzanilide (amide carbonyl absorbance at 1649 cm-1 and amide N--H stretching absorbance at 3349 and 3290 (shoulder) cm-1.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:26])[NH:11][C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])[N:15]=[CH:14][N:13]=1)=[O:4].[Li+].[OH-]>C1COCC1.O>[CH3:25][O:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:16]1[N:15]=[CH:14][N:13]=[C:12]([NH:11][C:10]([N:6]2[CH2:7][CH2:8][CH2:9][CH:5]2[C:3]([OH:4])=[O:2])=[O:26])[CH:17]=1
Reactant: COC(=O)C1CCCN1C(=O)Nc1cc(-c2ccccc2OC)ncn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccccc1-c1cc(NC(=O)N2CCCC2C(=O)O)ncn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-[6-(2-methoxy-phenyl)-pyrimidin-4-ylcarbamoyl]-pyrrolidine-2-carboxylic acid methyl ester (LX) (500 mg, 1.40 mmol) in a mixture of THF and water (1:1) was added a solution of LiOH (0.118 g, 2.80 mmol) in water at ice bath temperature over 10 min and then allowed to stir for two hours at room temperature. THF was evaporated and the aqueous solution was acidified with 2N HCl. This aqueous phase was then extracted with ethyl acetate (2×100 ml), the combined organic phases were washed with water and brine, dried over anhydrous sodium sulfate and concentrated in a vacuum rotavapor to afford 1-[6-(2-methoxy-phenyl)-pyrimidin-4-ylcarbamoyl]-pyrrolidine-2-carboxylic acid as a white solid. Yield: 210 mg, 43.8%.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:35]=[CH:34][C:20]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([CH3:33])([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:19][CH:18]=1>CN(C)C=O>[N:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[O:3][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:35]=[CH:34][C:20]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([CH3:33])([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:19][CH:18]=1
Reactant: CCOC(=O)C(C)(C)CCCCOc1ccc(OCCCCCBr)cc1
Reactant: Oc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)CCCCOc1ccc(OCCCCCOc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Into 5 ml of dry dimethylformamide containing 150 mg of sodium hydride (60% suspension in mineral oil) was added 292 mg of 2-hydroxypyridine. After stirring the mixture at room temperature for 15 minutes, 1.2 g of ethyl 6-[p-(5-bromopentyloxy)phenoxy]-2,2-dimethylhexanoate was added thereto. The mixture was stirred at room temperature for 12 hours, and thereafter the solvent was removed from the reaction solution under reduced pressure. The remaining oily substance was dissolved in chloroform, washed with water, and then dried over anhydrous magnesium sulfate. After drying, the solvent was distilled off under reduced pressure. The remaining oily substance was subjected to silica gel column chromatography and the product was eluted out using as an eluent chloroform-methanol (99:1). The solvent was distilled off from the eluate under reduced pressure to give the desired ethyl 6-[p-[5-(2-pyridyloxy)pentyloxy)phenoxy]-2,2-dimethylhexanoate as an oily substance (495 mg).
Reaction SMILES: C(=O)[CH2:2][CH2:3][CH:4]=[O:5].N1[CH2:14][CH2:13][CH2:12][C@H:8]1[C:9]([OH:11])=[O:10].C1COCC1.C>CC1OCCC1>[OH:10][CH:9]1[O:11][C@H:13]2[CH2:14][C:3]([CH:4]=[O:5])=[CH:2][C@H:12]2[CH2:8]1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=CCCC=O
Solvent: CC1CCCO1
Solvent: C1CCOC1
Product: O=CC1=C[C@H]2CC(O)O[C@H]2C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
The solution of succinaldehyde 8 from the first step (50.6 g, 0.588 mol) in 2-MeTHF was stirred at r.t. (S)-Proline (1.35 g, 11.8 mmol, 0.02 eq.) was added as a solid (Note: The reaction turns from a colourless suspension to a pink suspension over 10 min) and the reaction stirred at r.t. for 20 h. THF (294 ml) was added, followed by [Bn2NH2][OCOCF3] (3.67 g, 11.8 mmol, 0.02 eq.). The reaction was stirred for a further 20 h. Note: The reaction turns to a dark maroon suspension over 20 h. Activated charcoal (100 g) was added to the reaction and the volume of the reaction mixture was reduced by ½ under reduced pressure (˜300 mL). tert-Butyl methyl ether (TBME) (an equal volume to the volume of THF/2-MeTHF removed; 300 mL) was added slowly (over ˜15 mins) and with vigorous stirring of the mixture. Note: For the purposes of this example, slow addition of TBME helps to avoid the formation of oligomer aggregates. The mixture was stirred for 60 min before filtration of the resulting solids (through a sinter funnel; diameter: ˜10 cm). The solids were washed with 2-MeTHF (3×120 ml or until the product was not observed in the filtrate by TLC, 1:1 petroleum ether/EtOAc) and the filtrate was concentrated under reduced pressure. Note: For the purposes of this example, the filtrate should not be concentrated to complete dryness to help avoid solidifying the oligomers on the column, thereby clogging the column during the purification process. The material was purified by column chromatography (˜400 g silica), eluting with petroleum ether/EtOAc (8:2 to 5:5), to give the lactol 7 (as an approximately 2:1 mixture of diastereoisomers), as a brown oil.
Reaction SMILES: Br[CH2:2][CH2:3][S:4]([C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1)(=[O:6])=[O:5].[NH:15]1[CH:19]=[CH:18][CH:17]=[N:16]1>>[N:15]1([CH2:2][CH2:3][S:4]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH:19]=[CH:18][CH:17]=[N:16]1
Reactant: N#Cc1ccc(S(=O)(=O)CCBr)cc1
Reactant: c1cn[nH]c1
Product: N#Cc1ccc(S(=O)(=O)CCn2cccn2)cc1

Procedure:
250 mg of 4-(2-bromoethylsulfonyl)benzonitrile was used in Procedure P with pyrazole to yield 4-(2-(1H-pyrazole-1-yl)ethylsulfonyl)benzonitrile. 300 mg of 4-(2-(1H-pyrazole-1-yl)ethylsulfonyl)benzonitrile was reacted via Procedure T to give 4-(2-(1H-pyrazole-1-yl)ethylsulfonyl)benzoic acid. 75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(2-(1H-pyrazole-1-yl)ethylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield 4-(2-(1H-pyrazol-1-yl)ethylsulfonyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide. MS (Q1) 467.0 (M)+.
Reaction SMILES: C1(C)C=CC=CC=1.[NH2:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=1)/[CH:12]=[CH:13]/[C:14]1[S:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1.Br[CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>C(N(CC)CC)C>[CH2:33]([O:32][C:30]([CH2:29][CH2:28][CH2:27][NH:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=1)/[CH:12]=[CH:13]/[C:14]1[S:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1)=[O:31])[CH3:34]
Reactant: CCOC(=O)CCCBr
Reactant: Nc1cccc(/C=C/c2nc3ccccc3s2)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCNc1cccc(/C=C/c2nc3ccccc3s2)c1
Temperature: 100 °C
Reaction time: 20 h
Yield: 65.5 %

Procedure:
To 10 ml of toluene were added 1.0 g of 2-(trans-3-aminostyryl)benzothiazole, 0.78 g of ethyl 4-bromobutyrate and 0.4 g of triethylamine, and the mixture was stirred at 100° C. for 20 hours. After cooled to room temperature, the mixture was extracted with toluene, dried over anhydrous magnesium sulfate and then the solvent was evaporated under reduced pressure. The residue was purified through silica gel column chromatography by use of ethyl acetate-n-hexane to obtain 951 mg of the title compound (yield 66%).
Reaction SMILES: C[N:2](C)[C:3](=[N:5][C:6](=O)[C:7]1[CH:12]=[C:11]([CH2:13][CH3:14])[C:10]([O:15][CH3:16])=[N:9][C:8]=1[CH3:17])[CH3:4].[CH3:20][NH:21]N>C(O)(=O)C>[CH3:20][N:21]1[C:6]([C:7]2[C:8]([CH3:17])=[N:9][C:10]([O:15][CH3:16])=[C:11]([CH2:13][CH3:14])[CH:12]=2)=[N:5][C:3]([CH3:4])=[N:2]1
Reactant: CNN
Reactant: CCc1cc(C(=O)N=C(C)N(C)C)c(C)nc1OC
Solvent: CC(=O)O
Product: CCc1cc(-c2nc(C)nn2C)c(C)nc1OC
Temperature: 90 °C
Reaction time: 12 h
Yield: 57.3 %

Procedure:
In a round bottom flask under a nitrogen atmosphere N-(1-dimethylaminoethylidene)-5-ethyl-6-methoxy-2-methyl-nicotinamide (synthesized on 0.567 mmol scale) prepared in accordance with the procedures of Step 1, Example 19 is treated with glacial acetic acid (1 mL), followed by methylhydrazine (50 μL, 0.94 mmol). The resulting mixture is stirred at 90° C. for 12 hr. The reaction mixture is evaporated to dryness and the residue is purified by flash chromatography on a 5-gram silica gel cartridge by elution with dichloromethane:methanol (99:1). Fractions containing the product are combined, evaporated and re-purified by flash chromatography on a 5-gram silica gel cartridge by elution with dichloromethane:methanol (199:1). Fractions containing the product are combined and the solvent evaporated to give 3-(2,5-dimethyl-2H-1,2,4-triazol-3-yl)-5-ethyl-6-methoxy-2-methyl-pyridine (80 mg, 57% yield). MS: m/e 247 (M+H); 1H NMR (CDCl3, δ, ppm): 7.29 (1H, s), 3.98 (3H, s), 3.66 (3H, s), 2.58 (2H, q), 2.42 (3H, s), 2.31 (3H, s), 1.19 (3H, t).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][N:6]([C:11](=[O:31])[C@H:12]([CH2:24][CH2:25][CH2:26][NH:27][C:28](=[NH:30])[NH2:29])[N:13]([N+:21]([O-:23])=[O:22])C(OC(C)(C)C)=O)[CH2:7][CH2:8][O:9][CH3:10])[CH3:2].[ClH:33].C(OCC)(=O)C.C(OCC)C>C(OCC)(=O)C>[ClH:33].[CH2:1]([O:3][C:4](=[O:32])[CH2:5][N:6]([C:11](=[O:31])[C@H:12]([CH2:24][CH2:25][CH2:26][NH:27][C:28](=[NH:29])[NH2:30])[NH:13][N+:21]([O-:23])=[O:22])[CH2:7][CH2:8][O:9][CH3:10])[CH3:2]
Reactant: CCOC(=O)CN(CCOC)C(=O)[C@H](CCCNC(=N)N)N(C(=O)OC(C)(C)C)[N+](=O)[O-]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCOC(=O)CN(CCOC)C(=O)[C@H](CCCNC(=N)N)N[N+](=O)[O-]
Reaction time: 3 h

Procedure:
To a stirred solution of 29.8 g of NG -nitro-N2 -(tert-butoxycarbonyl)-L-arginyl-N-(2-methoxyethyl)glycine ethyl ester in 50 ml of ethyl acetate was added 80 ml of 10% dry HCl-ethyl acetate at 0° C. After 3 hours, to this solution was added 200 ml of dry ethyl ether to precipitate a viscous oily product. This was filtered and washed with dry ethyl ether to give 24.1 g of NG -nitro-L-arginyl-N-(2-methoxyethyl)glycine ethyl ester hydrochloride as an amorphous solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[CH:24]=[CH:23][CH:22]=[C:16]2[C:17]([NH:19][C:20](=[O:21])[C:15]=12)=[O:18].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>C(OCC)C>[N:25]1([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:24]=[CH:23][CH:22]=[C:16]3[C:17]([NH:19][C:20](=[O:21])[C:15]=23)=[O:18])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: C1COCCN1
Reactant: O=C1NC(=O)c2c(CCCCCCCCCCCCBr)cccc21
Solvent: CCOCC
Product: O=C1NC(=O)c2c(CCCCCCCCCCCCN3CCOCC3)cccc21

Procedure:
12-Bromododecylphthalimide (623 mg; 2.0 mmoles) and morpholine (0.35 ml; 4.0 mmoles) were dissolved in anhydrous ethyl ether (5 ml). Reaction times and process as per Example 1.
Reaction SMILES: [CH3:1][N:2]([CH3:35])[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[S:13]([NH:16][CH:17]([CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[C:18](O)=[O:19])(=[O:15])=[O:14].C(N(CC)CC)C.[CH2:43]([CH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)[CH3:44].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C)C=O>[CH3:35][N:2]([CH3:1])[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[S:13]([NH:16][CH:17]([C:18]([N:48]1[CH2:49][CH2:50][CH:45]([CH2:43][CH3:44])[CH2:46][CH2:47]1)=[O:19])[CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:26])[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=[O:15])=[O:14]
Reactant: CCC1CCNCC1
Reactant: CN(C)c1cccc2c(S(=O)(=O)NC(CCCNC(=O)OCc3ccccc3)C(=O)O)cccc12
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC1CCN(C(=O)C(CCCNC(=O)OCc2ccccc2)NS(=O)(=O)c2cccc3c(N(C)C)cccc23)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
To a cold (0° C.), nitrogen-blanketed mixture of 2d (48.90 g, 0.098 mol), triethylamine (25.0 mL, 0.18 mol) and 4-ethylpiperidine (20.0 g, 0.18 mol) in anhydrous dimethylformamide (160 mL) was added dropwise diphenylphosphoryl azide (21.1 mL, 0.098 mol). The mixture was stirred at about 0° C. for about 1 hour and at ambient temperature for about 2 hours before it was partitioned between ether (150 mL) and water (80 mL). The ethereal layer was separated and the aqueous layer was extracted four additional times with ether (80 mL). The combined ethereal extracts were then washed with saturated sodium bicarbonate solution and brine prior to drying (Na2SO4) and solvent concentration. Two identical reactions were performed in tandem. Purification of the combined residues by HPLC on silica gel (elution with 50% ethyl acetate in hexane) furnished 53.09 g (45%) of 3d as a yellow foam, m.p. 56°-62° C. (dec.); 1H NMR (CDCl3) δ 8.47 (d, 1H), 8.30 (t, 1H), 8.16 (d, 1H), 7.58 (m, 1H), 7.56-7.36 (m, 6H), 7.15 (d, 1H), 6.17-5.96 (dd, 1H), 5.10 (s, 2H), 4.75-4.62 (bm, 1H), 4.10-3.91 (bm, 2H), 3.42-3.30 (bm, 1H), 3.16-2.92 (bm, 2H), 2.85-2.83 (d, 6H), 2.68-2.41 (dt, 1H), 2.24-1.97 (m, 1H), 1.57-0.76 (m, 3 H), 0.16-0.08 (m, 1H); 13C NMR (CDCl3) ppm 168.50, 156.40, 151.62, 136.50, 135.00, 134.70, 130.56, 130.44, 129.80, 129.35, 129.18, 128.50, 128.41, 128.07, 128.00, 123.01, 122.93, 119.33, 115.58, 115.47, 66.60, 52.29, 52.19, 45.70, 45.43, 45.37, 45.13, 42.02, 42.21, 40.35, 40.18, 37.48, 37.34, 32.17, 31.92, 31.06, 30.79, 30.65, 29.67, 28.77, 28.58, 25.12, 11.08; IR (KBR, cm-1) 33,50 2975, 2975, 2950, 1725, 1650, 1550, 1475, 1350, 1275, 1180, 1160; MS m/z (MH+) 595.