Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(#N)C.C([O:7][C@@H:8]1[CH:13]=[CH:12][C@@:11]([OH:20])([C:14]#[C:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH2:10][O:9]1)(=O)C>O>[OH:9][CH2:10][C:11]1([C:14]#[C:15][Si:16]([CH3:17])([CH3:18])[CH3:19])[O:20][C@@H:8]([OH:7])[CH:13]=[CH:12]1
Reactant: CC(=O)O[C@@H]1C=C[C@@](O)(C#C[Si](C)(C)C)CO1
Solvent: CC#N
Solvent: O
Product: C[Si](C)(C)C#CC1(CO)C=C[C@H](O)O1
Temperature: 40 °C
Reaction time: 15 h
Yield: 93.3 %

Procedure:
570 mL of an acetonitrile solution containing 190 g of Compound 5 was heated to 40° C., to which 760 mL of an aqueous solution containing 19 g Lipase PS Amano SD was added and the resultant was agitated for 15 hours while maintaining the temperature at 40° C. After confirming the end of the reaction by thin-layer chromatography, the resultant was left to cool at room temperature, added with water and subjected to extraction with ethyl acetate. The organic layer was concentrated to obtain 148 g of a mixture of Compounds 9 and 10 as a clear brown oily product (crude yield: 93.8%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:19]3=[N:20][C:21](S(C)=O)=[N:22][CH:23]=[C:18]3[CH2:17][N:16]([C:27]3[C:32]([F:33])=[C:31]([O:34][CH3:35])[CH:30]=[C:29]([O:36][CH3:37])[C:28]=3[F:38])[C:15]2=[O:39])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:40]>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:19]3=[N:20][C:21]([NH2:40])=[N:22][CH:23]=[C:18]3[CH2:17][N:16]([C:27]3[C:32]([F:33])=[C:31]([O:34][CH3:35])[CH:30]=[C:29]([O:36][CH3:37])[C:28]=3[F:38])[C:15]2=[O:39])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(OC)c(F)c(N2Cc3cnc(S(C)=O)nc3N(C3CCN(C(=O)OC(C)(C)C)CC3)C2=O)c1F
Reactant: N
Solvent: C1COCCO1
Product: COc1cc(OC)c(F)c(N2Cc3cnc(N)nc3N(C3CCN(C(=O)OC(C)(C)C)CC3)C2=O)c1F
Yield: 81 %

Procedure:
4-[3-(2,6-Difluoro-3,5-dimethoxy-phenyl)-7-methylsulfinyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (419 mg, 0.738 mmol) and liquid ammonia (20 mL) in dioxane (20 mL) were stirred in a sealed tube at room temperature for 24 hours. The solvent was removed under reduced pressure. The resulting residue was purified via flash chromatography eluting with a gradient of ethyl acetate:hexanes (2:1 to 5:1) to give 312 mg (81%) of the title compound: MS (APCI) 421.1, 465.2, 521.2.
Reaction SMILES: CC(C)([O-:4])C.[K+].[C:7]([N:10]1[CH2:22][CH2:21][C:20]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:23][CH3:24])[CH:18]=3)[NH:13][C:12]=2[C:11]1([CH3:26])[CH3:25])(=[O:9])[CH3:8].C(OCC)(=O)C.CO>CN(C=O)C>[C:7]([N:10]1[CH2:22][C:21]2[C:20](=[O:4])[C:19]3[CH:18]=[C:17]([O:23][CH3:24])[CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[C:11]1([CH3:26])[CH3:25])(=[O:9])[CH3:8]
Reactant: COc1ccc2[nH]c3c(c2c1)CCN(C(C)=O)C3(C)C
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc2[nH]c3c(c(=O)c2c1)CN(C(C)=O)C3(C)C
Reaction time: 8 h

Procedure:
Potassium tert-butoxide (269 mg; 2.39 mmol) is added to a solution of 2-acetyl-1,1-dimethyl-6-methoxy-1,2,3,4-tetrahydro-β-carboline (164 mg; 0.60 mmol) in DMF (15 ml). The mixture is stirred under an oxygen atmosphere overnight. A 1/1 ethyl acetate/methanol mixture (10 ml) is then added. After evaporating the solvent and washing the solid, 2-acetyl-3,3-dimethyl-7-methoxy-9-oxo-1,3,4,9-tetrahydropyrrolo[3,4-b]quinoline is obtained (38 mg; 22%)
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[Br:9][C:10]1[CH:11]=[CH:12][C:13]([O:20][CH3:21])=[C:14]([S:16](Cl)(=[O:18])=[O:17])[CH:15]=1>>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([O:20][CH3:21])=[C:14]([S:16]([NH:1][C:2]2[O:6][N:5]=[C:4]([CH3:7])[C:3]=2[Br:8])(=[O:17])=[O:18])[CH:15]=1
Reactant: COc1ccc(Br)cc1S(=O)(=O)Cl
Reactant: Cc1noc(N)c1Br
Product: COc1ccc(Br)cc1S(=O)(=O)Nc1onc(C)c1Br
Yield: 61 %

Procedure:
5-Bromo-2-methoxy-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 5-bromo-2-methoxybenzenesulfonyl chloride according to the procedures described in Example 5. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 92°-195° C., yield 61%.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.C(Br)C1C=CC=CC=1.[CH3:18][C:19]1[CH:23]=[C:22]([N:24]2[C:28](=[O:29])[NH:27][N:26]=[CH:25]2)[S:21][C:20]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31]>>[CH2:6]([N:27]1[C:28](=[O:29])[N:24]([C:22]2[S:21][C:20]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:19]([CH3:18])[CH:23]=2)[CH:25]=[N:26]1)[C:5]1[CH:8]=[CH:9][CH:2]=[CH:3][CH:4]=1
Reactant: CCOC(=O)c1sc(-n2cn[nH]c2=O)cc1C
Reactant: Fc1ccc(CBr)cc1
Agent: BrCc1ccccc1
Product: CCOC(=O)c1sc(-n2cnn(Cc3ccccc3)c2=O)cc1C
Yield: 82 %

Procedure:
Following the procedure as described in Example 29, making variations as required to replace 4-fluorobenzyl bromide with benzyl bromide to react with ethyl 3-methyl-5-(5-oxo-1H-1,2,4-triazol-4(5H)-yl)thiophene-2-carboxylate, the title compound was obtained as a yellowish solid in 82% yield: 1H NMR (300 MHz, CDCl3) δ 7.72 (s, 1H), 7.43-7.31 (m, 5H), 6.94 (s, 1H), 5.01 (s, 2H), 4.32 (q, J=7.1 Hz, 2H), 2.54 (s, 3H), 1.36 (t, J=7.1 Hz, 3H); MS (ES+) m/z 344.2 (M+1).
Reaction SMILES: [NH2:1][C:2]([CH3:16])([CH2:5][N:6]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([Cl:15])[CH:11]=[CH:12]2)=[N:7]1)[C:3]#[N:4].[F:17][C:18]([F:29])([F:28])[C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[S:24])=[CH:21][CH:20]=1>>[Cl:15][C:10]1[CH:11]=[CH:12][C:13]2[C:8]([CH:9]=1)=[N:7][N:6]([CH2:5][C:2]([NH:1][C:23](=[S:24])[C:22]1[CH:21]=[CH:20][C:19]([C:18]([F:17])([F:28])[F:29])=[CH:27][CH:26]=1)([C:3]#[N:4])[CH3:16])[CH:14]=2
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Reactant: CC(N)(C#N)Cn1cc2ccc(Cl)cc2n1
Product: CC(C#N)(Cn1cc2ccc(Cl)cc2n1)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(6-chloro-2H-indazol-2-yl)-2-methylpropionitrile (20 mg, described in Example 132) and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (37 mg, 98%). MS (ES): M/Z [M+H]=439. 1H NMR: (400 MHz, CHLOROFORM-d): 1.95 (s, 3H), 4.81 (d, 1H), 4.89 (d, 1H), 7.12 (dd, J=9.0, 1.6 Hz, 1H), 7.65 (d, J=9.0, 1H), 7.69 (s, 1H), 7.78 (d, J=8.3 Hz, 2H), 7.89 (d, J=8.3 Hz, 2H), 8.18 (s, 1H) and 8.58 (s, 1H). 19F NMR (376 MHz, CHLOROFORM-d): −42.2 (s, 3F).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[CH3:13][NH2:14]>O1CCCC1.C(OCC)(=O)C>[CH3:13][NH:14][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: CN
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNC(=O)c1cccc([N+](=O)[O-])c1
Reaction time: 2 h

Procedure:
In a dry flask 3-nitrobenzoyl chloride (7.00 g, 37.7 mmol) was dissolved in tetrahydrofuran (300 mL) and methylamine (41.5 mL of a 2.0 M solution in tetrahydrofuran, 82.9 mmol) was added. The reaction mixture was stirred for 2 hours. The reaction mixture was diluted with ethyl acetate (500 mL) and extracted with water three times (100 mL). The organic layer was dried with sodium sulfate, filtered, and concentrated in vacuo. The crude solid (6.38 g, 94%) was used with further purification. 1H NMR (300 MHz, CDCl3), δ: 8.84 (bs, 1H), 8.67 (m, 1H), 8.37 (dd, J=8, J′=2, 1H), 8.28 (d, J=7, 1H), 7.78 (dd, J=8, J′=7, 1H), 2.83 (m, 3H). MS (ESI), m+/z: (M+H)+=181.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:6][CH:7]=1.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC(=O)C>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:2]2[N:3]=[N:4][C:5]([N:8]3[CH:12]=[CH:11][N:10]=[CH:9]3)=[CH:6][CH:7]=2)=[CH:16][CH:15]=1
Reactant: Oc1ccc(Br)cc1
Reactant: Clc1ccc(-n2ccnc2)nn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Brc1ccc(Oc2ccc(-n3ccnc3)nn2)cc1

Procedure:
A mixture of 4.5 parts of 3-chloro-6-(1H-imidazol-1-yl)pyridazine, 3.2 parts of 4-bromophenol, 4.2 parts of sodium carbonate and 80 parts of 2-propanone was stirred and refluxed over weekend. The reaction mixture was evaporated and the residue was taken up in water and 2.2'-oxybispropane. The layers were separated. The organic phase was dried, filtered and evapoated. The residue was crystallized from 2-propanol, yielding 3.5 parts of 3-(4-bromophenoxy)-6-(1H-imidazol-1-yl)pyridazine; mp. 168.4° C. (compound 6).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]([O:17][CH3:18])=[C:15]([O:19][CH3:20])[CH:14]=[CH:13][C:4]=1[CH2:5][S:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[CH2:21](Br)[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[C:39]([O-:46])(=[O:45])/[CH:40]=[CH:41]/[C:42]([O-:44])=[O:43]>CC#N.C(O)C>[C:39]([OH:46])(=[O:45])/[CH:40]=[CH:41]/[C:42]([OH:44])=[O:43].[CH3:1][O:2][C:3]1[C:16]([O:17][CH3:18])=[C:15]([O:19][CH3:20])[CH:14]=[CH:13][C:4]=1[CH2:5][S:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:21][CH:22]=[CH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:9][CH2:8]1
Reactant: COc1ccc(CSC2CCNCC2)c(OC)c1OC
Reactant: O=C([O-])/C=C/C(=O)[O-]
Reactant: BrCC=Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCO
Solvent: CC#N
Product: COc1ccc(CSC2CCN(CC=Cc3ccccc3)CC2)c(OC)c1OC
Product: O=C(O)/C=C/C(=O)O

Procedure:
A mixture of 10 g of 4-(2,3,4-trimethoxybenzylthio)piperidine and 6.62 g of cinnamyl bromide in 300 ml of CH3CN is heated under reflux for 15 hours in the presence of 4.64 g of potassium carbonate and 0.5 g of potassium iodide. The salt is then filtered off and the filtrate is evaporated under reduced pressure. The residue is taken up in CH2Cl2 --H2O and, after decantation, the ichloromethane phase is dried over Na2SO4 and evaporated under reduced pressure. The resulting residue (15 g) is purified by chromatography on 600 g of silica with a toluene-methanol (95-5) system, yielding 10 g of crude base, which is converted into the fumarate in an ethanol medium. 7 g of 4-(2,3,4-trimethoxybenzylthio)-1-cinnamylpiperidine fumarate are obtained in the form of white crystals which melt at 129° C.
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:5]([CH2:6][NH:7][C:8]([NH2:10])=[O:9])[NH:4][C:3]1=[O:11].C(=O)(O)[O-].[Na+].Cl.[Cl:18][CH2:19][C:20]([NH:22][C:23]1[S:24][CH:25]=[C:26](/[C:28](=[N:32]/[O:33][C:34]([CH3:49])([C:36]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=2)=[O:37])[CH3:35])/[C:29](Cl)=[O:30])[N:27]=1)=[O:21]>O.O1CCCC1>[Cl:18][CH2:19][C:20]([NH:22][C:23]1[S:24][CH:25]=[C:26](/[C:28](=[N:32]/[O:33][C:34]([CH3:49])([C:36]([O:38][CH2:39][C:40]2[CH:41]=[CH:42][C:43]([N+:46]([O-:48])=[O:47])=[CH:44][CH:45]=2)=[O:37])[CH3:35])/[C:29]([NH:1][C@H:2]2[C@@H:5]([CH2:6][NH:7][C:8]([NH2:10])=[O:9])[NH:4][C:3]2=[O:11])=[O:30])[N:27]=1)=[O:21]
Reactant: NC(=O)NC[C@H]1NC(=O)[C@H]1N
Reactant: CC(C)(O/N=C(\C(=O)Cl)c1csc(NC(=O)CCl)n1)C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N[C@@H]1CNC(N)=O)c1csc(NC(=O)CCl)n1)C(=O)OCc1ccc([N+](=O)[O-])cc1
Yield: 66.4 %

Procedure:
A 350 mg portion of the thus-obtained cis-3-amino-4-ureidomethyl-2-azetidinone (433 mg) is dissolved in a mixture of 25 ml of water and 25 ml of tetrahydrofuran and, under ice-cooling and stirring, 628 mg of sodium bicarbonate is added. Then, 1.43 g of 2-(2-chloroacetamido-4-thiazolyl)-2-(Z)-[1-methyl-1-(p-nitrobenzyloxycarbonyl)ethoxyimino]acetyl chloride hydrochloride is added and the mixture is stirred at room temperature for 2 hours. The tetrahydrofuran is distilled off under reduced pressure, 50 ml of water is added to the residue, and the mixture is stirred. The crystalline precipitate is collected by filtration, washed with aqueous sodium bicarbonate, water and hexane in that order, and dried to give 1.1 g of cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-(Z)-[1-methyl-1-(p-nitrobenzyloxycarbonyl)ethoxyimino]acetamido]-4-ureidomethyl-2-azetidinone as colorless crystals.
Reaction SMILES: [C:1]([S:4][C@H:5]1[CH2:9][N:8]([S:10]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)(=[O:12])=[O:11])[C@H:7](C(O)=O)[CH2:6]1)(=[O:3])[CH3:2].CN1CC[O:30]CC1.[B-](F)(F)(F)F.CN(C(ON1C(=O)C=CC=C1)=[N+](C)C)C.[CH3:53][O:54][C:55](=[O:69])[C:56]1[CH:61]=[CH:60][C:59]([N:62]([CH3:68])[C:63](=[O:67])[CH2:64][NH:65][CH3:66])=[CH:58][CH:57]=1>C(Cl)Cl>[CH3:53][O:54][C:55](=[O:69])[C:56]1[CH:57]=[CH:58][C:59]([N:62]([C:63](=[O:67])[CH2:64][NH:65][C:66]([C@@H:7]2[CH2:6][C@@H:5]([S:4][C:1](=[O:3])[CH3:2])[CH2:9][N:8]2[S:10]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)(=[O:12])=[O:11])=[O:30])[CH3:68])=[CH:60][CH:61]=1
Reactant: CC(=O)S[C@@H]1C[C@@H](C(=O)O)N(S(=O)(=O)c2ccc3ccccc3c2)C1
Reactant: CNCC(=O)N(C)c1ccc(C(=O)OC)cc1
Reactant: CN1CCOCC1
Agent: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(N(C)C(=O)CNC(=O)[C@@H]2C[C@@H](SC(C)=O)CN2S(=O)(=O)c2ccc3ccccc3c2)cc1
Temperature: 25 °C
Yield: 99.8 %

Procedure:
(al) 150 mg (0.4 mmol) (2S,4R)-4-Acetylsulfanyl-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid in 10 ml CH2Cl2 were treated with 49 μl (0.43 mmol, 1.1 eq) 4-methyl morpholine, 142 mg (0.47 mmol, 1.2 eq) TPTU and 140 mg (0.59 mmol, 1.5 eq) 4-(methyl-methylaminoacetyl-amino)-benzoic acid methyl ester. The solution was stirred at RT over night. The mixture was concentrated and purified by flash chromatography yielding 233 mg (98%) (2S,4R)-4-[[[[4-Acetylsulfanyl-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carbonyl]-amino]-acetyl]-methyl-amino]-benzoic acid methyl ester as white foam, MS: 598 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Br:8].[CH3:9][O:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[Br:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:15]1[CH:14]=[CH:13][CH:12]=[C:11]([O:10][CH3:9])[CH:16]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: Brc1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cccc(-c2ccccc2Br)c1
Reaction time: 12 h
Yield: 69.7 %

Procedure:
20.0 g (85.52 mmol) of 1,2-dibromobenzene, 11.70 g (76.97 mmol) of 3-methoxyphenylboronic acid, 0.99 g (0.86 mmol) of Pd(PPh3)4, and 18.13 g (171.04 mmol) of sodium carbonate were put, suspended in 300 ml of toluene and 100 ml of ethanol, and refluxed and agitated for 12 hours. After the reaction was finished, extraction was performed by dichloromethane, filtering was performed by silica gel, and the column was used at a ratio of hexane:MC=4:1 (v/v) to obtain 14.12 g of 2-bromo-3′-methoxybiphenyl that was the target compound (yield 63%).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N+:27]([O-:29])=[O:28].O.[NH2:32][NH2:33]>CN(C=O)C>[N+:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH2:20][C:19]1[C:3]2[C:4](=[O:18])[N:5]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:33][N:32]=1)([O-:29])=[O:28]
Reactant: NN
Reactant: O=C(Cc1ccccc1[N+](=O)[O-])c1c(O)c2cccnc2n(-c2ccccc2)c1=O
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2c(Cc3ccccc3[N+](=O)[O-])n[nH]c2c2cccnc2n1-c1ccccc1
Yield: 85.1 %

Procedure:
To a suspension of 4-hydroxy-3-[1-oxo-2-(2-nitrophenyl)ethyl]-1-phenyl-1,8-naphthyridin-2 (1H)-one (643 mg, 1.60 mmol, prepared in Synthetic Example 20) in DMF (16 ml) was added hydrazine monohydrate (80%, 230 μl, 5.74 mmol, 3.6 eq.), and the mixture was treated in the same manner as in Example 24 to give 3-(2-nitrobenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (541 mg, 85%).
Reaction SMILES: [SH:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][N:3]=1.[CH2:13]([NH:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16]>C(O)C>[C:7]1([C:5]2[NH:4][N:3]=[C:2]([S-:1])[N:6]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1.[CH2:13]([NH2+:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCNCCCC
Reactant: Sc1n[nH]c(-c2ccccc2)n1
Solvent: CCO
Product: CCCC[NH2+]CCCC
Product: [S-]c1n[nH]c(-c2ccccc2)n1
Temperature: 23 °C
Yield: 61 %

Procedure:
A mixture of 17.7 parts of 3-mercapto-5-phenyl-1,2,4-triazole, 12.9 parts of di-n-butylamine and 50 parts by volume of ethyl alcohol was heated at reflux temperature for one and a half hours. On cooling to 23° C., the product precipitated and this was filtered, washed with ethyl alcohol and dried, yielding 61 percent of N,N-di-n-butylammonium 5-phenyl-1,2,4-triazole-3-thiolate which had a melting point of 133°-137° C. and the following elemental analysis:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[NH:5][C:6]=1[C:7]([OH:9])=O.CCN(C(C)C)C(C)C.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.[NH2:47][C@@H:48]([CH3:64])[CH2:49][N:50]1[CH:54]=[CH:53][C:52]([C:55]2[CH:62]=[CH:61][C:58]([C:59]#[N:60])=[C:57]([Cl:63])[CH:56]=2)=[N:51]1>CN(C=O)C.O>[Cl:63][C:57]1[CH:56]=[C:55]([C:52]2[CH:53]=[CH:54][N:50]([CH2:49][C@@H:48]([NH:47][C:7]([C:6]3[NH:5][C:4]([C:10]4[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=4)=[N:3][C:2]=3[CH3:1])=[O:9])[CH3:64])[N:51]=2)[CH:62]=[CH:61][C:58]=1[C:59]#[N:60]
Reactant: Cc1nc(-c2cccnc2)[nH]c1C(=O)O
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-c2cccnc2)[nH]c1C(=O)N[C@@H](C)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
4-methyl-2-(pyridin-3-yl)-1H-imidazole-5-carboxylic acid (78 mg; 0.384 mmol) and DIPEA (0.20 ml, 1.151 mmol) were dissolved in 5 ml of dry DMF. HOBt hydrate (88 mg; 0.575 mmol) and EDCI (110 mg; 0.575 mmol) were added at RT. Solid (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (100 mg; 0.384 mmol) was added in one portion and the reaction was stirred for 2 h at 60° C. temperature and stirred at RT overnight. Water (40 ml) was added and the mixture was allowed to stir 1 h at RT. The precipitated product was filtered, dried in vacuum at 40° C. for 12 h, to give the title compound 136 mg. 1H-NMR (400 MHz; d6-DMSO): δ 1.12 (d, 3H), 2.49 (s, 3H), 4.40 (m, 3H), 6.97 (d, 1H), 7.48 (m, 1H), 7.88 (m, 2H), 8.02 (m, 2H), 8.07 (d, 1H), 8.21 (m, 1H), 8.58 (m, 1H), 9.13 (d, 1H), 12.85 (s, 1H).
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14](C)[CH2:13][CH2:12]3)=[N:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26].C1(C)C=CC=CC=1>O>[C:28]1([O:27][C:25]([N:14]2[CH2:13][CH2:12][CH:11]([C:8]3[C:7]4[C:2]([F:1])=[CH:3][CH:4]=[CH:5][C:6]=4[O:10][N:9]=3)[CH2:16][CH2:15]2)=[O:26])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CN1CCC(c2noc3cccc(F)c23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(Oc1ccccc1)N1CCC(c2noc3cccc(F)c23)CC1
Yield: 63.3 %

Procedure:
A mixture of 1.74 g of 4-fluoro-3-(1-methyl-4-piperidyl)-1,2-benzisoxazole, 1.25 g of potassium carbonate, 1.40 g of phenyl chloroformate and 50.0 ml of toluene was stirred under reflux for 8.0 hrs. The mixture was poured into water and the toluene layer was separated, dried over anhydrous magnesium sulfate and the solvent was removed in vacuo to yield an oil. The oil was purified by passing through a silica gel column (20:1), using 1% methanol in dichloromethane as the eluent. The eluent was evaporated and the residue solidified when scratched to yield a solid. The solid was recrystallized from petroleum-ether (bp 30°-60°) to yield 1.6 g (65%) of product, mp 108°-110°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:25]=[C:24]([O:26][C@H:27]3[C@H:31]4[O:32][CH2:33][C@@H:34]([OH:35])[C@H:30]4[O:29][CH2:28]3)[N:23]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=1.Br[C:45]1[CH:50]=[CH:49][C:48]([N:51]=[S:52]([CH3:56])([NH:54][CH3:55])=[O:53])=[CH:47][CH:46]=1>>[OH:35][C@H:34]1[C@H:30]2[O:29][CH2:28][C@@H:27]([O:26][C:24]3[N:23]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:41])[CH3:42])[C:5]4=[N:6][C:7]([C:8]5[CH:13]=[CH:12][C:11]([C:45]6[CH:46]=[CH:47][C:48]([N:51]=[S:52]([CH3:56])([NH:54][CH3:55])=[O:53])=[CH:49][CH:50]=6)=[CH:10][CH:9]=5)=[C:2]([Cl:1])[CH:3]=[C:4]4[N:25]=3)[C@H:31]2[O:32][CH2:33]1
Reactant: CC1(C)OB(c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O)n4COCC[Si](C)(C)C)cc2)OC1(C)C
Reactant: CNS(C)(=O)=Nc1ccc(Br)cc1
Product: CNS(C)(=O)=Nc1ccc(-c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O)n4COCC[Si](C)(C)C)cc2)cc1

Procedure:
The title compound is prepared from (3R,3aR,6R,6aR)-6-(6-chloro-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-b]pyridin-2-yloxy)hexahydrofuro[3,2-b]furan-3-ol and N′-(4-bromophenyl)-N-methyl-methanesulfonimidamide following a procedure analogous to that described for Intermediate 3 (Step 3). LC (method 1): tR=1.07 min; Mass spectrum (ESI+): m/z=686 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](/[C:15](/[CH3:40])=[CH:16]/[C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([CH3:26])[CH:21]=[C:20]2[CH2:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][C:29]=1[O:38][CH3:39])=[O:14])(C)(C)C>C(Cl)Cl>[C:13](/[C:15](/[CH3:40])=[CH:16]/[C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([CH3:26])[CH:21]=[C:20]2[CH2:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][C:29]=1[O:38][CH3:39])([OH:14])=[O:12]
Reactant: COC(=O)c1ccc(Cc2cn(C)c3ccc(/C=C(\C)C(=O)OC(C)(C)C)cc23)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(Cc2cn(C)c3ccc(/C=C(\C)C(=O)O)cc23)c(OC)c1
Reaction time: 1.5 h
Yield: 75 %

Procedure:
Trifluoroacetic acid (50 ml) was added to a solution of methyl E-4-[5-[2-(t-butoxycarbonyl)-1-propenyl]-1-methylindol-3-ylmethyl]-3-methoxybenzoate (6.4 g) in a small volume of methylene chloride (10 ml) cooled in an ice-bath. After 1.5 hr, the solution was evaporated (at approximately room temperature), and the residue was crystallized from methanol to give methyl E-4-[5-(2-carboxy-1-propenyl)-1-methylindol-3-ylmethyl]-3-methoxybenzoate (4.2 g, 75%) as a white powder: mp 182°-183°; partial NMR (250 MHz, DMSO-d6): 2.03(s, 3H, CCH3), 3.75(s, 3H), 3.83(s, 3H), 3.90(s, 3H), 4.06(s, 2H, ArCH2Ar').
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:14]=[CH:15][C:16]=1[CH:17]([CH3:19])[CH3:18])[C:8]([NH:10][C:11]([NH2:13])=[NH:12])=[O:9])(=[O:4])=[O:3].[C:20]([O-:23])([O-])=O.[K+].[K+].C(Cl)Cl.CO>CN(C=O)C>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:14]=[CH:15][C:16]=1[CH:17]([CH3:19])[CH3:18])[C:8]([NH:10][C:11](=[NH:13])[NH:12][C:20](=[O:23])[C:7]1[CH:14]=[CH:15][C:16]([CH:17]([CH3:18])[CH3:19])=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=1)=[O:9])(=[O:3])=[O:4]
Reactant: CC(C)c1ccc(C(=O)NC(=N)N)cc1S(C)(=O)=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)c1ccc(C(=O)NC(=N)NC(=O)c2ccc(C(C)C)c(S(C)(=O)=O)c2)cc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The acid chloride 1 a) and 3.9 g of 3-methylsulfonyl-4-i-propylbenzoylguanidine are dissolved in 50 ml of DMF, and 3.4 g of K2CO3 are then added. The mixture is stirred at RT for 4 h and then left to stand overnight. The solution is subsequently concentrated and the residue stirred up in 200 ml of water. The solid is filtered off and washed with 100 ml of water. This solid is then dissolved in 100 ml of EA and washed 1× with 10 ml of 1N HCl and then 1× with 50 ml of NaCl solution. Drying takes place over Na2SO4 and the solvent is removed in vacuo. A yellow solid is obtained which is purified by being titurated twice with 20 ml of diethyl ether and subsequently being filtered off. The product is dried in vacuo and 1.9 g are obtained of a white solid, mp 218-221° C. Rf (CH2Cl2/MeOH 20:1)=0.57 MS (ES):508 (M+1)