Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][CH2:4][C:5]([O:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>C1(C)C=CC=CC=1>[CH:8]1([O:7][C:5]2[S:29][C:2]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:3][CH:4]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=C(CCC(=O)c1ccccc1)OC1CCCCC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: c1ccc(-c2ccc(OC3CCCCC3)s2)cc1

Procedure:
In a 500 mL round-bottomed flask under argon was added cyclohexyl 4-oxo-4-phenylbutanoate (2 g, 7.68 mmol) and Lawesson reagent (3.73 g, 9.22 mmol) in anhydrous toluene (125 mL) to give a white suspension. The mixture was heated to reflux whereby the lawesson's reagent dissolved. The mixture was refluxed for ˜24 h at which point the mixture was cooled and filtered. The filtrate was concentrated and placed on a short column of SiO2 and flashed with CH2Cl2:Hex 1:3 yielding a white solid (1.4 g) which was 2-(cyclohexyloxy)-5-phenylthiophene (70%)
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:36]=[C:24]4[C:25]([C:29]5[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=5)=[CH:26][CH:27]=[CH:28][N:23]4[N:22]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[F:35][C:32]1[CH:33]=[CH:34][C:29]([C:25]2[C:24]3[N:23]([N:22]=[C:21]([NH:20][C:17]4[CH:18]=[CH:19][C:14]([CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)=[CH:15][CH:16]=4)[N:36]=3)[CH:28]=[CH:27][CH:26]=2)=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3nc4c(-c5ccc(F)cc5)cccn4n3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(-c2cccn3nc(Nc4ccc(C5CCNCC5)cc4)nc23)cc1

Procedure:
[8-(4-fluoro-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-yl]-(4-piperidin-4-yl-phenyl)-amine was prepared from 4-{4-[8-(4-fluoro-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-ylamino]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester and trifluoroacetic acid (0.500 mL) in a manner analogous to Example 312 to give product (0.112 g). MP=244-247° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.62 (s, 1H), 8.79 (d, 1H), 8.22 (m, 2H), 7.82 (d, 1H), 7.60 (d, 2H), 7.35 (m, 2H), 7.12 (m, 3H), 3.00 (m, 2H), 2.55 (m, 3H), 2.20 br m, 1H), 1.65 (m, 2H), 1.45 (m, 2H). MS=388 (MH)+.
Reaction SMILES: CS([C:5]1[N:6]=[CH:7][C:8]2[C:17]3[CH:16]=[CH:15][C:14]([C:18]([O:20]C)=[O:19])=[CH:13][C:12]=3[N:11]=[C:10]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:9]=2[N:29]=1)(=O)=O.Cl.CN.C[CH2:34][N:35](C(C)C)C(C)C.[Li+].[OH-]>CN(C=O)C.O.CO.C1COCC1>[CH3:34][NH:35][C:5]1[N:6]=[CH:7][C:8]2[C:17]3[CH:16]=[CH:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][C:12]=3[N:11]=[C:10]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:9]=2[N:29]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)c1ccc2c(c1)nc(Nc1ccccc1)c1nc(S(C)(=O)=O)ncc12
Agent: CN
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: CNc1ncc2c(n1)c(Nc1ccccc1)nc1cc(C(=O)O)ccc12
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 74 %

Procedure:
In a closed vial, methyl 3-(methylsulfonyl)-5-(phenylamino)pyrimido[4,5-c]quinoline-8-carboxylate (1.0 eq, 62 mg, 0.152 mmol) was mixed with Methylamine hydrochloride (100 mg), DIEA (260 ul) in DMF (1 ml). The mixture was stirred at 60° C. for 40 min. Addition of water induced precipitation of methyl 3-(methylamino)-5-(phenylamino)pyrimido[4,5-c]quinoline-8-carboxylate which was isolated by filtration. This material was suspended in a 1:1:1 mixture of THF, MeOH and water (4 ml), and vigorously stirred at 60° C. in the presence of LiOH (200 mg) for 1.5 hours. Water aqueous HCl were added and to reach pH=1. The solid was filtered, dried and triturated in AcOEt/hexanes to provide 3-(methylamino)-5-(phenylamino)pyrimido[4,5-c]quinoline-8-carboxylic acid as a yellow solid (40 mg, 74% yield). LCMS (ES): >95% pure, m/z 346 [M+1]+.
Reaction SMILES: Cl.Cl.[N:3]1([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:22]=[C:21]3[C:16]([CH2:17][CH2:18][NH:19][CH2:20]3)=[CH:15][CH:14]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.CCN(CC)CC.[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37](Cl)(=[O:39])=[O:38]>>[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37]([N:19]1[CH2:18][CH2:17][C:16]2[C:21](=[CH:22][C:13]([O:12][CH2:11][CH2:10][CH2:9][N:3]3[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]3)=[CH:14][CH:15]=2)[CH2:20]1)(=[O:39])=[O:38]
Reactant: c1cc2c(cc1OCCCN1CCCCC1)CNCC2
Reactant: O=S(=O)(Cl)c1ccccc1F
Agent: Cl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccccc1F)N1CCc2ccc(OCCCN3CCCCC3)cc2C1

Procedure:
2-(2-Fluoro-benzenesulfonyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline is prepared from 7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline dihydrochloride (104 mg, 0.3 mmol), NEt3 (0.14 mL, 1.1 mmol), and 2-fluorobenzenesulfonyl chloride (80 mg, 0.41 mmol) via a procedure substantially analogous to Procedure F except that an additional SCX column purification step is performed to give the free base product (85 mg, 66% yld) as an amber oil. MS (ES+) 433.2(M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:4][OH:5])[CH3:3].C(N(CC)CC)C.Cl[S:14]([C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[C:19]([CH3:27])=[CH:20][N:21]=[CH:22]2)(=[O:16])=[O:15]>C(Cl)Cl.O>[CH3:27][C:19]1[C:18]2[C:23](=[CH:24][CH:25]=[CH:26][C:17]=2[S:14]([NH:1][C@H:2]([CH3:3])[CH2:4][OH:5])(=[O:16])=[O:15])[CH:22]=[N:21][CH:20]=1
Reactant: C[C@@H](N)CO
Reactant: Cc1cncc2cccc(S(=O)(=O)Cl)c12
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cncc2cccc(S(=O)(=O)N[C@H](C)CO)c12
Reaction time: 2 h
Yield: 80.4 %

Procedure:
To a solution of 1.0 g of D-alaninol in 50 ml of methylene chloride was added 2.02 g of triethylamine, and after addition of 3.22 g of 5-chlorosulfonyl-4-methylisoquinoline under ice-cooling, the mixture was stirred for 2 hours. This reaction mixture was diluted with water and extracted with methylene chloride and the extract was dried and concentrated. The residue was purified by silica gel column chromatography (chloroform/methanol=30/1) to provide 3.0 g of (R)-2-[(4-methyl-5-isoquinolinyl)sulfonyl amino]-1-propanol (white crystals).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13](=[O:20])[NH:14][CH2:15][CH2:16][CH2:17][O:18][CH3:19])=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22].CO.[Si](C=[N+]=[N-])(C)(C)[CH3:29].C(O)(=O)C>C(Cl)Cl>[CH3:29][O:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13](=[O:20])[NH:14][CH2:15][CH2:16][CH2:17][O:18][CH3:19])=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CCOC(=O)c1cnn(-c2ccc(C(=O)NCCCOC)cn2)c1O
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)c1cnn(-c2ccc(C(=O)NCCCOC)cn2)c1OC
Temperature: 20 °C
Reaction time: 0.33 h
Yield: 87 %

Procedure:
Combined ethyl 5-hydroxy-1-(5-((3-methoxypropyl)carbamoyl)pyridin-2-yl)-1H-pyrazole-4-carboxylate (2.2 g, 6.32 mmol), MeOH (5 mL), and DCM (50 mL) and added 2.0 M TMS-diazomethane in hexanes (4.42 mL, 8.84 mmol) (over about 10 minutes) and stirred at 20° C. for 20 min. The reaction was then quenched with acetic acid (0.145 mL, 2.53 mmol) and concentrated in vacuo to give a residue which was purified on an 80 g silica gel column eluted with 10 to 100% EtOAc in hexanes to give the title compound (2.0 g, 87% yield) as a white solid. MS m/z 363 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.30 (t, J=7.1 Hz, 3H) 1.78 (quin, J=6.6 Hz, 2H) 3.25 (s, 3H) 3.30-3.37 (m, 2H) 3.39 (t, J=6.3 Hz, 2H) 4.14 (s, 3H) 4.27 (q, J=7.1 Hz, 2H) 7.79 (dd, J=8.5, 0.6 Hz, 1H) 8.03 (s, 1H) 8.39 (dd, J=8.5, 2.4 Hz, 1H) 8.76 (t, J=5.6 Hz, 1H) 8.98 (dd, J=2.4, 0.6 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7](C(=O)C(N)=O)=[C:8]([CH3:19])[N:9]2CC2C=CC=CC=2)=[CH:5][CH:4]=1.C(OC(NC1C=C(OC)C=CC=1CC(=O)C)=O)(C)(C)C>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([CH3:19])[NH:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(C(=O)C(N)=O)c(C)n(Cc3ccccc3)c2c1
Agent: COc1ccc(CC(C)=O)c(NC(=O)OC(C)(C)C)c1
Product: COc1ccc2cc(C)[nH]c2c1
Yield: 61 %

Procedure:
6-Methoxy-2-methyl-1-(phenylmethyl)-1H-indole-3-glyoxylic acid amide. Using the method in Example 9, Part C, 13.7 g 49 mmol) of 1-[2-(tert-butoxycarbonylamino)-4-methoxyphenyl]-2-propanone was reacted with 20 mL of trifluoroacetic and the produce chromatographed on silica eluting with 20% EtOAc/hexane. There was obtained 4.8 g (61% yield) of crude 6-methoxy-2-methyl-1H-indole. By the method in Example 6, Part A, this material (30 mmol) was treated with 1.2 g (30 mmol) of 60% NaH/mineral oil and 3.6 mL of benzyl bromide in DMF to give after chromatography on silica (eluting with 25% EtOAc/hexane) 4.77 g (63% yield) of 6-methoxy-2-methyl-1-(phenylmethyl)-1H-indole. By the method in Example 16, Part C, 1.97 g (8 mmol) of 6-methoxy-2-methyl-1-(phenylmethyl)-1H-indole was reacted with 0.73 mL (8.4 mmol) of oxalyl chloride and then ammonia to give 0.875 g (34% yield) of 6-methoxy-2-methyl-1-(phenylmethyl)-1H-indole-3-glyoxylic acid amide from EtOAc, mp, 230-234° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[N:15]([CH2:16][CH:17]=O)[CH:14]=[N:13][C:12]=3[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.[OH-].[Na+]>CC(O)=O>[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([CH2:17][CH2:16][N:15]2[C:11]([C:9]3[S:8][C:4]4[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=4[CH:10]=3)=[C:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:13]=[CH:14]2)[CH2:28][CH2:27]1
Reactant: CN1CCNCC1
Reactant: Nc1ncnc2sc(-c3c(-c4ccccc4)ncn3CC=O)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CN1CCN(CCn2cnc(-c3ccccc3)c2-c2cc3c(N)ncnc3s2)CC1
Reaction time: 8 h
Yield: 28 %

Procedure:
[5-(4-Aminothieno[2,3-d]pyrimidin-6-yl)-4-phenyl-1H-imidazol-1-yl]acetaldehyde (Intermediate 74) (100 mg) and N-methyl piperazine (100 μL) were stirred in AcOH (1 mL) for 15 minutes. Na(AcO)3BH (70 mg) was added and the reaction allowed to stir overnight. The reaction was made basic with 2M NaOH (50 mL) and then the product extracted with DCM (3×50 mL). The organics were washed with water (30 mL), brine (30 mL), dried (MgSO4) and concentrated in vacuo. The product was purified by flash chromatography on silica eluting with DCM:7N NH3 in MeOH. (95:5) to afford the title compound as a solid (32 mg, 28%);
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][S:9]([NH:12][CH2:13][CH2:14][OH:15])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[C:18]=1Br.C([O-])([O-])=O.[K+].[K+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:15][CH2:14][CH2:13][NH:12][S:9]([CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:18]2[C:17]([Cl:16])=[CH:22][C:21]([Cl:23])=[CH:20][C:19]=2[Cl:24])[CH:3]=1)(=[O:11])=[O:10]
Reactant: Clc1cc(Cl)c(Br)c(Cl)c1
Reactant: Nc1cccc(CS(=O)(=O)NCCO)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=S(=O)(Cc1cccc(Nc2c(Cl)cc(Cl)cc2Cl)c1)NCCO
Temperature: 150 °C
Reaction time: 1 h
Yield: 5 %

Procedure:
To a stirred solution of C-(3-Aminophenyl)-N-(2-hydroxyethyl)-methanesulfonamide (200 mg, 0.87 mmol), 1,3,5-trichloro-2-bromobenzene (283 mg, 1.09 mmol), K2CO3 (300 mg, 2.17 mmol) and XantPhos (50 mg, 0.09 mmol) in 1,4-dioxane (2 ml) under nitrogen in a microwave tube was added Pd2dba3 (40 mg, 0.04 mmol) in one portion and the tube sealed. The reaction was heated with stirring in a microwave at 150° C. for 60 minutes. The reaction was cooled before filtering through celite. The crude reaction mixture was part-purified by column chromatography eluting with ethyl acetate:hexane and the concentrated fractions further purified by preparative chromatography under acidic conditions to afford the named product (17.8 mg, 5%); 6H (400 MHz, DMSO) 8.00 (1H, s), 7.76 (2H, s), 7.12 (1H, t), 6.99 (1H, t), 6.76 (1H, d), 6.62 (1H, s), 6.48 (1H, d), 4.69 (1H, brs), 4.21 (2H, s), 3.39 (2H, m) and 2.93 (2H, q); LCMS Rt=3.83 min, m/z (ES−) 409 (M−H).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][C:8]1([CH:13]2[CH2:18][CH2:17][CH:16]([NH2:19])[CH2:15][CH2:14]2)[O:12][CH2:11][CH2:10][O:9]1.[C:20](Cl)([O:22][CH2:23][CH:24]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21]>O.O1CCOCC1>[CH:35]1[C:36]2[CH:24]([CH2:23][O:22][C:20](=[O:21])[NH:19][CH:16]3[CH2:17][CH2:18][CH:13]([C:8]4([CH3:7])[O:9][CH2:10][CH2:11][O:12]4)[CH2:14][CH2:15]3)[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:31]=2[CH:32]=[CH:33][CH:34]=1
Reactant: CC1(C2CCC(N)CC2)OCCO1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC1(C2CCC(NC(=O)OCC3c4ccccc4-c4ccccc43)CC2)OCCO1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A solution of 12.72 g (120 mmol) of sodium carbonate is placed in 120 mL of water and combined with a solution of 7.00 g (38 mmol) of 4-(2-methyl-[1,3]dioxolan-2-yl)cyclohexylamine (cis/trans mixture) in 50 g of dioxane. After cooling to 0° C., a solution of 10.09 g (39 mmol) of Fmoc-chloride in 100 g of dioxane is added dropwise within 0.2 hours. The reaction mixture is stirred for 16 hours with the cooling removed. Then the mixture is poured onto water and extracted with ethyl acetate. The organic phase is washed with water, dried, and evaporated to dryness. The residue is purified by chromatography. Yield: 13.10 g (85%) cis/trans ratio 4:1; NMR: LH201618.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:11]([NH:13][C@@H:14]([C:20]([NH:22][CH2:23][C:24]([N:26]([CH2:43][CH3:44])[C@H:27]([C:35]([NH:37][NH:38][C:39]([CH2:41][CH3:42])=[O:40])=[O:36])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:25])=[O:21])[CH2:15][CH2:16][S:17]([CH3:19])=[O:18])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O.N[C@H](C(O)=O)CCSC.N[C@H](C(O)=O)CC1C=CC(O)=CC=1>>[NH2:1][C@H:2]([C:11]([NH:13][C@@H:14]([C:20]([NH:22][CH2:23][C:24]([N:26]([CH2:43][CH3:44])[C@H:27]([C:35]([NH:37][NH:38][C:39]([CH2:41][CH3:42])=[O:40])=[O:36])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:25])=[O:21])[CH2:15][CH2:16][S:17]([CH3:19])=[O:18])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1
Reactant: CCC(=O)NNC(=O)[C@H](Cc1ccccc1)N(CC)C(=O)CNC(=O)[C@@H](CCS(C)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Agent: CSCC[C@H](N)C(=O)O
Agent: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)NNC(=O)[C@H](Cc1ccccc1)N(CC)C(=O)CNC(=O)[C@@H](CCS(C)=O)NC(=O)[C@@H](N)Cc1ccc(O)cc1
Reaction time: 0.17 h

Procedure:
To 0.50 g of BOC-Tyr-(D)-Met(O)-Gly-EtPhe-NHNHCOCH2CH3 were added 0.5 ml of anisole and 5 ml of TFA, and the mixture was shaken for 10 minutes. The solvent was distilled off, and ether was added to recover by filtration the product in the form of powder. The product was subjected to ion exchange on Amberlite IRA 410 (acetic acid type), and then poured on a column (2.2×120 cm) of Cephadex LH-20. The elution was conducted with 0.1 N acetic acid, and the fractions of 300 to 350 ml were collected and lyophilized. Yield: 0.35 g [α]D24 +18.5° (c=0.49, MeOH), Rf2, 0.24. Amino Acid analysis (4% thioglycolic acid/6 N hydrochloric acid hydrolysis): Gly 1.00(1), Met 1.05(1), Tyr 0.97(1).
Reaction SMILES: C([N+](CC)(CC)CC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.CN(C)C=O.[CH3:26][O:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=[O:33])=[CH:30][CH:29]=1.[C:36](Cl)([Cl:39])([Cl:38])[Cl:37]>C(Cl)(Cl)Cl>[Cl:37][C:36]([CH:32]([C:31]1[CH:34]=[CH:35][C:28]([O:27][CH3:26])=[CH:29][CH:30]=1)[OH:33])([Cl:39])[Cl:38]
Reactant: ClC(Cl)(Cl)Cl
Reactant: COc1ccc(C=O)cc1
Agent: CC[N+](CC)(CC)CC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(O)C(Cl)(Cl)Cl)cc1
Yield: 94.5 %

Procedure:
A 10 g quantity of tetraethyl ammonium salt of p-toluenesulfonic acid was dissolved in 60 ml of dimethylformamide containing 0.1 mole of chloroform. The solution was placed in a cathode chamber and in an anode chamber. Further 13.6 g (0.1 mole) of p-methoxybenzaldehyde and 0.01 mole of carbon tetrachloride was introduced into the cathode chamber. A glass filter was used as a diaphragm. Electrolysis was conducted at a constant current of 0.1 A. After current (2 F/mole) was passed, the reaction liquid was withdrawn from the cathode chamber. The carbon tetrachloride and chloroform were distilled off and the residue was extracted with methylene chloride. The methylene chloride was distilled off from the extract and the residue was distilled in a vacuum, giving trichloromethyl-4-methoxyphenyl carbinol. Yield 94.5%, b.p. 122°-124° C./1 mmHg.
Reaction SMILES: [CH:1]([C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[CH3:17])=[CH:5][CH:4]=1)=[CH2:2].[CH2:20]=[O:21]>N1C=CC=CC=1>[CH:1]([C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[CH2:17][CH2:20][OH:21])=[CH:5][CH:4]=1)=[CH2:2]
Reactant: C=Cc1ccc(Cn2c(C)nc3ccccc32)cc1
Reactant: C=O
Solvent: c1ccncc1
Product: C=Cc1ccc(Cn2c(CCO)nc3ccccc32)cc1
Temperature: 95 °C
Reaction time: 24 h

Procedure:
Next, 1-(4-vinylbenzyl)-2-(2-hydroxyethyl)benzimidazole was prepared. A mixture of 1-(4-vinylbenzyl)-2-methylbenzimidazole (20.0 g, 81 mmol), formaldehyde (320 mmol as 26.1 g of the 37% aqueous solution), and 25 g of pyridine were stirred magnetically and heated to 95° C. The mixture became homogeneous within minutes. After 24 h, the mixture was cooled to ambient and concentrated at reduced pressure to deposit a tan oil. The product was purified by flash chromatography (silica gel, 75% dichloromethane/25% ether), followed by recrystallization from a mixture of 100 mL of methanol plus 40 mL of water. The product was obtained as 9.1 g (41%) of an off-white solid. 1H NMR (CDCl3) δ 2.97 (t, J=5.5, 2H), 4.12 (t, J=5.5, 2H),4.1 (br s, 1H), 5.24 (d, J=10.8, 1H), 5.30 (s, 2H), 5.71 (d, J=17.6, 1H), 6.7 (m, 1H), 7.00 (d, J=8.1, 2H), 7.2 (m,3H) 7.34 (d, J= 8.2, 2H), 7.73 (m, 1H). ES−MS m/e 279+ (M+1).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14](=O)[CH2:15][CH2:16][C:17]([OH:19])=O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.O.[NH2:22][NH2:23]>C(O)C>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]3[CH2:15][CH2:16][C:17](=[O:19])[NH:22][N:23]=3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(O)CCC(=O)/C=C/c1ccc(-n2ccnc2)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: O=C1CCC(C=Cc2ccc(-n3ccnc3)cc2)=NN1

Procedure:
A solution of 2 g of (E)-6-[4-(1H-imidazol-1-yl)phenyl]-4-oxo-5-hexenoic acid in 60 ml of ethanol containing 0.5 g of 80% hydrazine hydrate is heated to reflux for three hours. The solution is concentrated to a small volume (ca 10 ml) and filtered. The residue is crystallized from THF/methanol to give 0.6 g of the 4,5-dihydro-pyridazinone, mp 230°-231° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[C:11]([C:18]([F:21])([F:20])[F:19])=[N:10]2)=[CH:5][CH:4]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C:23]1=[O:28]>>[F:19][C:18]([F:21])([F:20])[C:11]1[C:12]2[CH2:13][CH2:14][CH2:15][CH2:16][C:17]=2[N:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:28])=[CH:4][CH:5]=2)[N:10]=1
Reactant: O=C1CCCCN1
Reactant: FC(F)(F)c1nn(-c2ccc(CCl)cc2)c2c1CCCC2
Product: O=C1CCCCN1Cc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1

Procedure:
The title compound was prepared from 1-[4-(chloromethyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole and 2-piperidinone using a similar procedure to that described for Description 15.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[I:12]N1C(=O)CCC1=O.C(=O)([O-])[O-].[Na+].[Na+]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([I:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C1CCC(=O)N1I
Reactant: O=C(O)c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(O)c1cc(I)c(F)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.6 %

Procedure:
2,4-Difluorobenzoic acid 10 (45.0 g, 285 mmol) was dissolved in concentrated sulfuric acid (360 mL) at 0° C. and N-iodosuccinimide (NIS, 64 g, 284 mmol) was added in portions at 0° C. The mixture was allowed to warm to room temperature (rt) and stirred 4 hours (h). The mixture was poured into ice water (approximately 1000 mL) and 10% aqueous sodium carbonate solution (80 mL) was added. After the mixture was stirred for 0.5 h, the precipitate was filtered, washed with water (approximately 2000 mL), then dried at 50° C. in a convection oven for 2 days to provide 76.3 g (94%) of 11 as a gray solid.
Reaction SMILES: [CH3:1][C:2]1[C:8](=[O:9])[NH:7][C:5](=[O:6])[N:4]([C@@H:10]2[O:14][C@H:13]([CH2:15][OH:16])[C@@H:12]([N:17]=[N+:18]=[N-:19])[CH2:11]2)[CH:3]=1.C[O-].[Na+].BrC[C:25]([O:27][CH2:28][CH3:29])=[O:26].O>CN1C(=O)N(C)CCC1>[C:25]([N:7]1[C:8](=[O:9])[C:2]([CH3:1])=[CH:3][N:4]([C@@H:10]2[O:14][C@H:13]([CH2:15][OH:16])[C@@H:12]([N:17]=[N+:18]=[N-:19])[CH2:11]2)[C:5]1=[O:6])([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CCOC(=O)CBr
Reactant: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCN(C)C1=O
Product: CCOC(=O)n1c(=O)c(C)cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 267 mg AZT in 1 ml DMPU was treated with 500 ul of sodium methoxide solution (4.4 M NaOMe, in MeOH) and 250 ul of ethyl bromoacetate and stirred 30 minutes at room temperature. Another 500 ul NaOMe solution and 250 ul ethyl bromoacetate were added and the mixture was heated 1 hour at 60° C. in a water bath. The resulting suspension was diluted with 15 ml deionized water and extracted with EtOAc. The organic phase was washed, first with 5% NaHCO3 then saturated NaCl solution, concentrated under reduced pressure and chromatographed by preparative TLC on silica gel-F 2000 um using the solvent system CHCl3 /MeOH/HOAc (95+5+0.5). Three bands were visualized with UV (254 nm) and were eluted separately with MeOH. Fraction A (Rf =0.19) was identified as AZT by TLC and UV spectrum by comparison with an authentic AZT reference. It was also immunologically active in an AZT assay by FPIA. Fractions B (Rf =0.37) and C (Rf =0.57) had similar UV spectra, resembling that of 3-methylthymidine. Fraction B was immunologically active (approximately 110% "cross-reactivity" relative to AZT in an AZT assay by FPIA). Fraction C was immunologically inactive. Fraction B was therefore evaporated to dryness and saved.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:15]=[CH:16]/[C:17](=[NH:21])OCC)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Cl.[C:23]1([C@H:29]([CH3:34])[C:30]([NH:32][NH2:33])=O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(OCC)(=O)C.O>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:15]=[CH:16]/[C:17]2[NH:21][C:30]([C@H:29]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH3:34])=[N:32][N:33]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: CCOC(=N)/C=C/c1ccc(-n2cnc(C)c2)c(OC)c1
Reactant: C[C@H](C(=O)NN)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: COc1cc(/C=C/c2nnc([C@@H](C)c3ccccc3)[nH]2)ccc1-n1cnc(C)c1
Temperature: 75 °C
Reaction time: 19 h
Yield: 33.3 %

Procedure:
A solution of ethyl (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylimidate (30 mg) and TEA (35 ul) in ethanol (0.5 ml) was added to a solution of (S)-2-phenylpropionic acid hydrazide monohydrochloride (37 mg) and TEA (35 uL) in ethanol (0.5 mL), and the reaction solution was stirred at 75° C. for 19 hours. The reaction solution was left to cool to room temperature. Then, ethyl acetate and water were added to the reaction solution, and the organic layer was separated. The organic layer washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-ethanol system) to obtain 13.5 mg of the title compound with positive optical rotation. The property values of the compound are as follows.