Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30](O)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(O[N:47]1N=N[C:49]2[CH:50]=[CH:51]C=C[C:48]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N)CCC>C(Cl)Cl>[CH2:48]([NH:47][C:30](=[O:31])[C:29]1[CH:33]=[CH:34][C:35]([CH3:36])=[C:27]([C:10]2[C:11]3[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]4[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=4[F:26])[C:12]=3[N:13]=[C:8]([NH:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:37][CH3:38])[CH2:1][CH3:2])[N:9]=2)[CH:28]=1)[CH2:49][CH2:50][CH3:51]
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCCCN
Product: CCCCNC(=O)c1ccc(C)c(-c2nc(NCCCN(CC)CC)nc3c2ccc(=O)n3-c2c(F)cccc2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (40 mg, 0.074 mmol) in methylene chloride (2 mL) were added HBTU (30 mg, 0.079 mmol) and butylamine (0.038 mL, 0.37 mmol). The mixture was stirred at rt overnight. Solvent was removed by rotovap. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (29 mg, 66%). LC-MS m/z 577 (M+H)+.
Reaction SMILES: P([O-])([O-])(O)=O.[Na+].[Na+].O.[C:9]([OH:21])(=[O:20])[CH2:10][C:11](CC(O)=O)([C:13]([OH:15])=[O:14])O.CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@@H]2O[C@@H](C)[C@H](O)[C@@](OC)(C)C2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@@](O)(C)C[C@@H](C)C[N:28](C)[C@H](C)[C@@H](O)[C@@]1(O)C>O>[NH2:28][C@H:11]([C:13]([OH:15])=[O:14])[CH2:10][C:9]([OH:21])=[O:20]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)CN(C)[C@H](C)[C@@H](O)[C@]1(C)O
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: O
Product: N[C@@H](CC(=O)O)C(=O)O

Procedure:
To water (80 mL) agitated at 15° C. to 25° C., disodium hydrogenphosphate 12 hydrate (3.3 g) and citric acid monohydrate (0.44 g) were added. After these buffers were completely dissolved, azithromycin (1.0 g) was added and dissolved with agitation. After confirming that the solution became clear, sterile purified water was added to prepare 100 mL of the azithromycin-containing aqueous pharmaceutical composition (Comparative Example 2).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9]C(=O)C)=[C:5]([C:13]#[C:14][CH2:15][CH2:16][OH:17])[CH:4]=1)=[O:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:17][CH2:16][CH2:15][C:14]1[NH:9][C:6]2[C:5]([CH:13]=1)=[CH:4][C:3]([CH:1]=[O:2])=[CH:8][CH:7]=2
Reactant: CC(=O)Nc1ccc(C=O)cc1C#CCCO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=Cc1ccc2[nH]c(CCO)cc2c1
Temperature: 25 °C

Procedure:
To a solution of N-[4-formyl-2-(4-hydroxy-but-1-ynyl)-phenyl]-acetamide (0.85 g, approximately 2.80 mmol) in THF (20 mL) was added a THF solution of TBAF (6.0 mL, 6.0 mmol) and the reaction mixture was stirred at reflux for 36 hours under nitrogen and cooled to room temperature. Solvent was evaporated and the residue was taken in ethyl acetate (200 mL). The organic phase was washed with water (2×100 mL), brine (100 mL) and dried over anhydrous Na2SO4. Solvent was evaporated; crude compound was purified by simpliflash system (50% ethyl acetate in hexanes as eluent) to give 2-(2-hydroxy-ethyl)-1H-indole-5-carbaldehyde as yellow solid. Yield: 0.31 g (58% for two steps).
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([N:22]2[CH2:27][CH2:26][C:25]([F:29])([F:28])[CH2:24][CH2:23]2)[CH2:20][NH2:21])=[CH:15][CH:14]=1>>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]([N:22]2[CH2:23][CH2:24][C:25]([F:29])([F:28])[CH2:26][CH2:27]2)[CH2:20][NH:21][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:2]=2[CH3:1])=[CH:17][CH:18]=1
Reactant: Cc1cccc(C(=O)O)c1C
Reactant: NCC(c1ccc(Cl)cc1)N1CCC(F)(F)CC1
Product: Cc1cccc(C(=O)NCC(c2ccc(Cl)cc2)N2CCC(F)(F)CC2)c1C

Procedure:
From 2,3-dimethylbenzoic acid and 2-(4-chloro-phenyl)-2-(4,4-difluoro-piperidin-1-yl)-ethylamine.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[N:5]=[C:6]([S:16][CH3:17])[N:7]=[N:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(OCC)(=O)C>O1CCCC1>[CH3:3][CH:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][NH:7][C:6]([S:16][CH3:17])=[N:5]1
Reactant: CSc1nnc(-c2ccccc2)c(C)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CSC1=NC(C)C(c2ccccc2)=NN1
Yield: 34.3 %

Procedure:
Sodium borohydride (3.4 g) was added portionwise to a stirred solution of 5-methyl-3-methylthio-6-phenyl-1,2,4-triazine (10 g) in tetrahydrofuran (25 ml). To the reaction mixture was added ethyl acetate, and the mixture was washed successively with 1N-hydrochloric acid, water and brine, dried over sodium sulfate, and concentrated to dryness. The residual solid was recrystallized from a mixture of ethanol and water to give 5-methyl-3-methylthio-6-phenyl-2,5-dihydro-1,2,4-triazine (3.46 g), m.p. 159°~160° C.
Reaction SMILES: [C:1]([C:3]1[C:8]2[CH2:9][C:10](=O)[C:11]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:12]=3[S:13][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2].O.[NH2:21][NH2:22]>C(O)C>[C:1]([C:3]1[C:8]2[CH2:9][C:10](=[N:21][NH2:22])[C:11]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:12]=3[S:13][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2]
Reactant: NN
Reactant: N#Cc1cccc2c1CC(=O)c1cc(F)ccc1S2
Solvent: CCO
Solvent: O
Product: N#Cc1cccc2c1CC(=NN)c1cc(F)ccc1S2
Yield: 95 %

Procedure:
The mixture of 0.3g of 9-cyano-2-fluoro-10,11-dihydrodibenzo[b,f]thiepin-11-one, 0.3g of 100% hydrazine hydrate and 10ml of ethanol was heated under reflux on water-bath for 5 hours. The reaction mixture was concentrated to 5ml to separate crystals on cooling, which was collected by filtration. Recrystallization from ethanol afforded 0.3g of 9-cyano-2-fluoro-10,11-dihydrodibenzo[b,f]thiepin-11-one hydrazone as pale yellow needles having a melting point of 220°-222° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23](=[S:25])[NH2:24])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[Cl:26][CH:27](Cl)[C:28](=O)[CH3:29]>>[Cl:26][CH2:27][C:28]1[N:24]=[C:23]([CH:11]2[CH2:10][CH:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=3)[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12]2)[S:25][CH:29]=1
Reactant: CC(=O)C(Cl)Cl
Reactant: CCc1ccc(C2CC(C(N)=S)CN(C(=O)N3CCOCC3)C2)cc1
Product: CCc1ccc(C2CC(c3nc(CCl)cs3)CN(C(=O)N3CCOCC3)C2)cc1

Procedure:
860 mg (2.38 mmol) of 5-(4-ethylphenyl)-1-(morpholin-4-ylcarbonyl)piperidine-3-carbothioamide (Example 140A) and 362 mg (2.85 mmol) of dichloroacetone were reacted according to the General Method 3. Yield: 498 mg (43% of theory).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH:5]([CH3:19])[CH2:4][NH:3]1)=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[C:10]=3[Cl:18].[OH-:20].[K+]>>[C:2]([C:7]1[NH:8][C:9]2[C:14]([C:6]=1[CH:5]([CH3:19])[CH2:4][NH2:3])=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[C:10]=2[Cl:18])([OH:20])=[O:1]
Reactant: COc1cc2c3c([nH]c2c(Cl)c1Cl)C(=O)NCC3C
Reactant: [OH-]
Agent: [K+]
Product: COc1cc2c(C(C)CN)c(C(=O)O)[nH]c2c(Cl)c1Cl

Procedure:
Following the procedure of Example 2, 1.85 g (6.18 mmoles) of 1-oxo-4-methyl-6-methoxy-7,8-dichloro-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole were hydrolyzed with aqueous alcoholic KOH. The yield of crude amino acid, 2-carboxy-3-(1-amino-2-propyl)-5-methoxy-6,7-dichloroindole, thus formed was quantitative. The amino acid was decarboxylated without further purification, using the procedure of Example 2, with 3M hydrochloric acid for 48 hours to yield 3-(1-amino-2-propyl)-5-methoxy-6,7-dichloroindole.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:5][CH:4]=1)#[N:2].CO.C1COCC1>[C].[Pd].C(O)(=O)C>[NH2:2][CH2:1][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(C#N)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)CCc1ccc(CN)cc1
Reaction time: 3 h
Yield: 77.3 %

Procedure:
To 223 mg of tert-butyl (2E)-3-(4-cyanophenyl)acrylate were added 12 mL of methanol, 5 ml of THF, 1 ml of an acetic acid solution, and 90 mg of 10% palladium-carbon in this order, followed by stirring for 3 hours under hydrogen at 3 atm. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. To the residue were added a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate to carry out a layer separation operation. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to obtain 177 mg of tert-butyl 3-[4-(aminomethyl)phenyl]propanoate.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:42][CH:43]([CH3:45])[CH3:44])[CH2:14][C@@H:15]([OH:41])[C@@H:16]([NH:29][C:30](=[O:40])[O:31][C@@H:32]3[C@H:39]4[C@H:35]([O:36][CH2:37][CH2:38]4)[O:34][CH2:33]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][OH:28])=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.Cl[C:47]([O:49][C:50]1[CH:55]=[CH:54][C:53]([N+:56]([O-:58])=[O:57])=[CH:52][CH:51]=1)=[O:48]>>[C:47](=[O:48])([O:49][C:50]1[CH:51]=[CH:52][C:53]([N+:56]([O-:58])=[O:57])=[CH:54][CH:55]=1)[O:28][CH2:27][CH2:26][CH2:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][C@H:16]([NH:29][C:30]([O:31][C@@H:32]2[C@H:39]3[C@H:35]([O:36][CH2:37][CH2:38]3)[O:34][CH2:33]2)=[O:40])[C@H:15]([OH:41])[CH2:14][N:13]([S:10]([C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][O:3][C:4]=3[CH:9]=2)(=[O:12])=[O:11])[CH2:42][CH:43]([CH3:45])[CH3:44])=[CH:19][CH:20]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCCO)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCCOC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2

Procedure:
(3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-2-hydroxy-1-[4-(3-hydroxypropoxy)benzyl]propylcarbamate was treated with 4-nitrophenyl chloroformate as described previously to provide the title compound as a solid foam. 1H NMR (DMSO-d6): δ 0.86 (3H, d), 0.92 (3H, d), 1.2 (1H, dd), 1.38 (1H, quintuplet), 1.9-2.0 (1H, m), 2.05-2.15 (2H, m), 2.2 (1H, t), 2.6-2.8 (3H, m), 2.9 (1H, d), 2.96 (1H, dd), 3.2-3.3 (2H, m), 3.4-3.5 (1H, m), 3.5-3.6 (2H, m), 3.7 (1H, t), 3.8 (1H, dd), 4.0 (2H, t), 4.37 (2H, t), 4.8 (1H, dt), 5.0 (1H, d), 5.45 (1H, d), 6.18 (2H, s), 6.78 (2H, d), 7.0-7.1 (3H, m), 7.20-7.25 (2H, m), 7.3 (1H, dd), 7.56 (2H, d), 8.25 (2H, d); MS: 816 (MH+)
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=2)=[CH:5][N:4]=1.Br[C:19]1[CH:20]=[CH:21][C:22]2[C:23]3[CH2:32][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:30][CH2:29][C:24]=3[N:25]([CH3:28])[C:26]=2[CH:27]=1>>[CH3:28][N:25]1[C:26]2[CH:27]=[C:19]([N:12]3[CH:13]=[CH:14][C:9]([C:6]4[CH:5]=[N:4][C:3]([C:2]([F:1])([F:16])[F:17])=[N:8][CH:7]=4)=[CH:10][C:11]3=[O:15])[CH:20]=[CH:21][C:22]=2[C:23]2[CH2:32][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:30][CH2:29][C:24]1=2
Reactant: O=c1cc(-c2cnc(C(F)(F)F)nc2)cc[nH]1
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CC2
Product: Cn1c2c(c3ccc(-n4ccc(-c5cnc(C(F)(F)F)nc5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Yield: 24.4 %

Procedure:
4-(2-(Trifluoromethyl)pyrimidin-5-yl)pyridin-2(1H)-one (100 mg, 0.42 mmol) and tert-butyl 7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (116 mg, 0.32 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (41 mg, 24%) as a yellow oil: ESI MS m/z 526 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[N:17]=[C:16]([NH2:18])[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][CH:13]=2)[N:5]2[N:22]=[CH:23][N:24]=[C:4]2[CH:3]=1.[N:25]1([C:30]2[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=2)[CH2:29][CH2:28][CH2:27][CH2:26]1>>[N+:19]([C:15]1[C:16]([NH2:18])=[N:17][C:12]([NH:11][CH2:10][CH2:9][NH:8][C:6]2[N:5]3[N:22]=[CH:23][N:24]=[C:4]3[CH:3]=[C:2]([C:32]3[CH:33]=[CH:34][CH:35]=[C:30]([N:25]4[CH2:26][CH2:27][CH2:28][CH2:29]4)[CH:31]=3)[N:7]=2)=[CH:13][CH:14]=1)([O-:21])=[O:20]
Reactant: OB(O)c1cccc(N2CCCC2)c1
Reactant: Nc1nc(NCCNc2nc(Cl)cc3ncnn23)ccc1[N+](=O)[O-]
Product: Nc1nc(NCCNc2nc(-c3cccc(N4CCCC4)c3)cc3ncnn23)ccc1[N+](=O)[O-]

Procedure:
In analogy to the procedure described for Example 94, 17.5 mg (28% of theory) of the product are obtained as a solid starting from 50 mg (0.133 mmol) of N6-{2-[(7-chloro[1,2,4]triazolo-[1,5-c]pyrimidin-5-yl)amino]ethyl}-3-nitropyridine-2,6-diamine (Example 55A) by coupling with 25.3 mg (0.13 mmol) of (3-pyrrolidin-1-ylphenyl)boronic acid and subsequent purification by preparative HPLC.
Reaction SMILES: [CH3:1][C:2]([N:7]1[CH:11]=[C:10]([NH:12][C:13]2[N:18]=[C:17]([NH:19][CH3:20])[C:16]([C:21]([F:24])([F:23])[F:22])=[CH:15][N:14]=2)[C:9]([CH3:25])=[N:8]1)([CH3:6])[C:3]([NH2:5])=O>O=P(Cl)(Cl)Cl>[CH3:6][C:2]([N:7]1[CH:11]=[C:10]([NH:12][C:13]2[N:18]=[C:17]([NH:19][CH3:20])[C:16]([C:21]([F:22])([F:24])[F:23])=[CH:15][N:14]=2)[C:9]([CH3:25])=[N:8]1)([CH3:1])[C:3]#[N:5]
Reactant: CNc1nc(Nc2cn(C(C)(C)C(N)=O)nc2C)ncc1C(F)(F)F
Solvent: O=P(Cl)(Cl)Cl
Product: CNc1nc(Nc2cn(C(C)(C)C#N)nc2C)ncc1C(F)(F)F
Yield: 42.1 %

Procedure:
A stirred solution of 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanamide (250 mg, 0.7 mmol) in POCl3 (5 mL) was stirred at 90° C. for 1 hour. POCl3 was removed by evaporation, the mixture was added into ice/H2O (10 ml) and the pH of the solution was adjusted to 8 with sat.Na2CO3, the aqueous phase was extracted with ethyl acetate (5 mL×3). The combined organic phase was washed with sat. sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dry to give a residue which was purified by recrystallization to give 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile (100 mg, 42%) as a white solid. 1H-NMR (300 MHz, DMSO-d6) δ ppm 9.18 (s, 1H), 8.29 (s, 1H), 8.14 (s, 1H), 7.10 (s, 1H), 2.91 (d, 3H), 2.22 (s, 3H), 1.94 (s, 2H). LCMS (m/z) ES+340 (m+1). Purity, 99.3% (HPLC at 214 nm); Ki=0.0005.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[NH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:22][C:23]1[S:24][CH:25]=[C:26]([CH3:28])[N:27]=1>CN(C=O)C>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:22][C:23]2[S:24][CH:25]=[C:26]([CH3:28])[N:27]=2)[N:3]=1
Reactant: O=[N+]([O-])c1cccc2[nH]nc(I)c12
Reactant: Cc1csc(CCl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1csc(Cn2nc(I)c3c([N+](=O)[O-])cccc32)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60 %

Procedure:
To a solution of 3-iodo-4-nitro-1H-indazole (0.500 g, 1.73 mmol) in DMF (8 mL) was added potassium carbonate (0.478 g, 3.46 mmol) at ambient temperature. After 15 minutes, 2-(chloromethyl)-4-methylthiazole hydrochloride was added. The mixture was allowed to stir at ambient temperature for 18 hours, concentrated under reduced pressure and diluted with DCM and brine. The organic phase was dried (phase separator silicone treated filter paper), and purified by silica gel chromatography (10-50% ether in DCM) to provide 2-((3-iodo-4-nitro-1H-indazol-1-yl)methyl)-4-methylthiazole (0.414 g, 60% yield) as a yellow solid.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([CH3:11])[C:5]=1[CH3:12].[CH2:13]([O:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25](Cl)=[CH:26][CH:27]=[N:28]2)=[CH:23][C:22]=1[O:32][CH3:33])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])O.[Na+]>CS(C)=O>[CH2:13]([O:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25]([O:10][C:7]3[CH:8]=[CH:9][C:4]([NH2:3])=[C:5]([CH3:12])[C:6]=3[CH3:11])=[CH:26][CH:27]=[N:28]2)=[CH:23][C:22]=1[O:32][CH3:33])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cc1c(N)ccc(O)c1C
Reactant: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cc2c(Oc3ccc(N)c(C)c3C)ccnc2cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.7 %

Procedure:
Sodium hydride (60 wt %, 0.32 g) was added to dimethyl sulfoxide (6 ml), and the mixture was stirred at room temperature for 30 min. 4-Amino-2,3-dimethylphenol (1.10 g) was then added thereto, and the mixture was stirred at room temperature for 10 min. Next, 7-(benzyloxy)-4-chloro-6-methoxyquinoline (1.20 g) was added thereto, and the mixture was stirred at 110° C. for 6 hr. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, followed by extraction with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by chromatography on silica gel by development with chloroform/acetone (6/1) to give 0.78 g (yield 49%) of the title compound.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][C@H:9]([N:12]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:10][OH:11])=[O:4].[CH:38](=O)[CH2:39][CH3:40]>>[NH2:26][C:23]1[CH:22]=[CH:21][C:20]([S:17]([N:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[C@H:9]([CH2:10][OH:11])[CH2:8][CH2:7][CH2:6][NH:5][C:3](=[O:4])[C@@H:2]([NH:1][CH2:38][CH2:39][CH3:40])[CH2:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][CH:29]=2)(=[O:19])=[O:18])=[CH:25][CH:24]=1
Reactant: CCC=O
Reactant: CC(C)CN([C@H](CO)CCCNC(=O)[C@@H](N)Cc1cccc2ccccc12)S(=O)(=O)c1ccc(N)cc1
Product: CCCN[C@@H](Cc1cccc2ccccc12)C(=O)NCCC[C@@H](CO)N(CC(C)C)S(=O)(=O)c1ccc(N)cc1

Procedure:
The title compound was prepared from (2S,4S)-2-amino-N-{4-[(4-amino-benzenesulfonyl)-isobutyl-amino]-5-hydroxy-pentyl}-3-naphthalen-1-yl-propionamide (product of example 8) as described in general procedure F using propionaldehyde. The final product was obtained in 54% yield.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[CH2:11][S:10][C:9]2=[S:14])=[CH:4][CH:3]=1.[C:15]([NH:18][C@@H:19]1[C@@H:35]([OH:36])[C@H:34]([OH:37])[C@@H:33]([CH2:38][OH:39])[O:32][C@H:20]1[O:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]=O)=[CH:24][C:23]=1[O:30][CH3:31])(=[O:17])[CH3:16].C([O-])(=O)C.[NH4+]>C(O)C>[C:15]([NH:18][C@@H:19]1[C@@H:35]([OH:36])[C@H:34]([OH:37])[C@@H:33]([CH2:38][OH:39])[O:32][C@H:20]1[O:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]=[C:11]2[S:10][C:9](=[S:14])[N:8]([C:5]3[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=3)[C:12]2=[O:13])=[CH:24][C:23]=1[O:30][CH3:31])(=[O:17])[CH3:16]
Reactant: COc1cc(C=O)ccc1O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1NC(C)=O
Reactant: O=C1CSC(=S)N1c1ccc(O)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Product: COc1cc(C=C2SC(=S)N(c3ccc(O)cc3)C2=O)ccc1O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1NC(C)=O
Yield: 82.9 %

Procedure:
3-(4-Hydroxyphenyl)-2-thioxothiazolidin-4-one (0.23 g, 1.0 mmol) was added to a stirred suspension of 4-formyl-2-methoxyphenyl 2-acetamido-2-deoxy-β-D-glucopyranoside (1b)(0.32 g, 0.9 mmol) in absolute ethanol (10 ml) containing ammonium acetate (0.08 g, 1.0 mmol) and the pale yellow heterogeneous reaction mixture boiled gently. After 5 h the mixture was cooled in ice and the yellow product was filtered off and washed well with methanol and acetone to give 5b (0.42 g, 74%), m.p. 234°-236° C., [α]D +2.5° (c 0.81, DMOS) Found: C, 53.62; H, 4.65; N, 4.73, C25H26N2O9S2 calc: C, 53.38; H, 4.63; N, 4.98).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]=[CH:13][N:14]([CH3:16])[CH:15]=3)[S:10][C:3]=12.[F:17][C:18]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:19]=1[NH2:20].C1CCC(P(C2C(C3C=CC=CC=3)=CC=CC=2)C2CCCCC2)CC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:17][C:18]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:19]=1[NH:20][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]=[CH:13][N:14]([CH3:16])[CH:15]=3)[S:10][C:3]=12
Reactant: Cn1cnc(-c2cc3nccc(Cl)c3s2)c1
Reactant: Nc1ccc([N+](=O)[O-])cc1F
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: Cn1cnc(-c2cc3nccc(Nc4ccc([N+](=O)[O-])cc4F)c3s2)c1
Temperature: 110 °C
Yield: 50.1 %

Procedure:
A stirred suspension of 10 (500 mg, 2.00 mmol), 337 (406 mg, 2.60 mmol), Pd2 (dba)3 (73 mg, 0.08 mmol), (2-biphenyl)dicyclohexylphosphine (56 mg, 0.16 mmol), and K3PO4 (638 mg, 3.00 mmol) in toluene (20 ml) was degased for 15 min with nitrogen at room temperature, and then heated in a sealed flask at 110° C. for 22 hrs (J. P. Wolfe, H. Tomori, J. P. Sadighi, J. Yin, S. L. Buchwald J. Org. Chem. 2000, 65, 1158-1174). After cooling to room temperature the reaction mixture was filtered, rinsed with toluene, concentrated and adsorbed on silica gel. The crude product was purified by flash column chromatography (eluents MeOH/CH2Cl2: 2/98 to 10/90) and precipitated in AcOEt/hexanes to afford title compound 338 (370 mg, 50% yield) as a yellow-orange solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.57 (bs, 1H), 8.45 (d, J=5.1 Hz, 1H), 8.22 (dd, J=11.3, 2.5 Hz, 1H), 8.06 (dd, J=8.9, 2.3 Hz, 1H), 7.83 (d, J=1.2 Hz, 1H), 7.70 (d, J=1.2 Hz, 1H), 7.63 (s, 1H), 7.24 (t, J=8.7 Hz, 1H), 6.94 (bd, J=4.7 Hz, 1H), 3.71 (s, 3H). MS (m/z): 370.0 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:3]([OH:16])=[N:4][C:5]2[C:6]([N:15]=1)=[C:7]1[C:12](=[CH:13][CH:14]=2)[N:11]=[CH:10][CH:9]=[N:8]1.[N+:17]([O-])([O-:19])=[O:18].[K+].[OH-].[Na+]>S(=O)(=O)(O)O>[OH:1][C:2]1[C:3]([OH:16])=[N:4][C:5]2[C:6]([N:15]=1)=[C:7]1[C:12](=[C:13]([N+:17]([O-:19])=[O:18])[CH:14]=2)[N:11]=[CH:10][CH:9]=[N:8]1
Reactant: Oc1nc2ccc3nccnc3c2nc1O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [Na+]
Product: O=[N+]([O-])c1cc2nc(O)c(O)nc2c2nccnc12
Temperature: 0 °C
Reaction time: 24 h
Yield: 46.9 %

Procedure:
To a solution of 0,38 g (1,4 mmol) 2,3-dihydroxy-pyrazino(2,3-f)quinoxaline in 25 ml concentrated sulfuric acid was added at 0° C. 0,28 g (2,8 mmol) potassium nitrate. Stirring was continued at 0° C. for 30 min. and at 25° C. for 24 h. The reaction mixture was poured into 100 ml ice-water. The solution was added 10N sodium hydroxide to pH 7, and then extracted with ethyl acetate (5×100 ml). The combined and dried ethyl acetate phases were evaporated to give 0,17 g (47%) 2,3-dihydroxy-6-nitropyrazino(2,3-f)quinoxaline, m.p.>300° C. NMR (DMSO-d6): 9.10 (2H,s), 8.23 (1H,s).