Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[C:20]1([CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:27][NH2:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:28][CH2:27][CH:26]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: NCC(c1ccccc1)c1ccccc1
Product: CC(C)(C)N1C(=O)C(NCC(c2ccccc2)c2ccccc2)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 2-tert-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 2,2-diphenylethanamine in a similar manner as described for Example 1. 1H NMR (500 MHz CDCl3): δ 7.59-7.54 (m, 2H), 7.48-7.43 (m, 3H), 7.27 (t, 4H), 7.22 (t, 2H), 6.97 (d, 4H), 5.25 (t, 1H), 3.96 (t, 1H), 3.50 (dd, 2H), 1.70 (s, 9H); 13C NMR (125 MHz CDCl3): δ159.6, 140.8, 135.0, 131.7, 129.9, 129.0, 128.0, 127.3, 125.3, 108.1, 61.7, 50.7, 48.3, 27.8; Mass Spectrum: M+H+ 461.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH2:9][C@H:10]([N:17]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:11][O:12]2)(=O)=O.CCCC[Sn]([C:47]1[CH:52]=[CH:51][CH:50]=[N:49][CH:48]=1)(CCCC)CCCC.O>O1CCOCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH2:18]([N:17]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@H:10]1[CH2:9][C:8]2[C:13](=[CH:14][CH:15]=[CH:16][C:7]=2[C:47]2[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=2)[O:12][CH2:11]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Reactant: O=S(=O)(Oc1cccc2c1C[C@H](N(Cc1ccccc1)Cc1ccccc1)CO2)C(F)(F)F
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: c1ccc(CN(Cc2ccccc2)[C@@H]2COc3cccc(-c4cccnc4)c3C2)cc1
Reaction time: 1 h
Yield: 36.9 %

Procedure:
Palladium-tetrakis(triphenylphosphine) (48 mg, 0.042 mmol) and (3S)-3-(dibenzylamino) -3,4-dihydro-2H-chromen-5-yl trifluoromethanesulfonate (200 mg, 0.42 mmol) in dioxane (4 mL) were added to 3-(tri-N-butylstannyl)pyridine (232 mg, 0.63 mmol) under an atmosphere of argon and the resulting reaction mixture was irradiated in a microwave at 120-140° C. for 1.5 h. More palladium-tetrakis(triphenylphosphine) (48 mg, 0.042 mmol) was added and the irradiation was continued at 140° C. for 1 h. Water (20 mL) was added and the mixture was extracted with ethyl acetate. The organic phases was dried over sodium sulfate, the solvent was evaporated in vacuo and the residue purified by column chromatography, using a gradient of ethyl acetate in heptanes as the eluent, gave 63 mg (74%) of the title compound: MS (ES) m/z 407[M+H+].
Reaction SMILES: [NH2:1][C:2](=[S:14])[CH2:3][N:4]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[N:5]1.Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=1)=O>>[Cl:26][C:21]1[CH:20]=[C:19]([C:17]2[N:1]=[C:2]([CH2:3][N:4]3[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[N:5]3)[S:14][CH:16]=2)[CH:24]=[CH:23][C:22]=1[Cl:25]
Reactant: CCOC(=O)c1cnn(CC(N)=S)c1
Reactant: O=C(CBr)c1ccc(Cl)c(Cl)c1
Product: CCOC(=O)c1cnn(Cc2nc(-c3ccc(Cl)c(Cl)c3)cs2)c1
Yield: 75.9 %

Procedure:
By a reaction in the same manner as in Example 1c and using the compound (213 mg, 1.00 mmol) obtained in Example 1b and 2-bromo-1-(3,4-dichlorophenyl)ethanone (268 mg, 1.00 mmol) to give the title compound (290 mg, 76%) as colorless crystals.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.O.Cl.[Fe]>[CH2:1]([NH:8][C:9]1[C:10]([NH2:15])=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccccc1NCc1ccccc1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1ccccc1NCc1ccccc1
Yield: 57.1 %

Procedure:
To a solution of benzyl-(2-nitro-phenyl)-amine (1068) (2.5 g, 10.43 mmol) in ethanol (150 mL) and water (10 mL) was added iron (8.7 g, 155.7 mmol) followed by 30 drops of concentrated HCl, and the resulting mixture was heated overnight at reflux. The reaction mixture was quenched with water, diluted with DCM and the layers were separated. The organic layer was washed with saturated sodium bicarbonate solution, brine, dried over sodium sulfate and concentrated to give a brown oily residue. Further purification by column chromatography (SiO2, 20% ethyl acetate/hexanes) afforded N-benzyl-benzene-1,2-diamine (1069) as a dark yellow oil (1.18 g, 57%). 1H NMR (400 MHz, CDCl3) 7.41-7.24 (m, 5H), 6.82-6.67 (m, 4H), 4.32 (s, 2H), 3.56 (b, 3H, NH).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][N:8]([C:13](=[O:24])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=1)[CH2:7][CH2:6]2.[H][H]>C(O)C.[C].[Pd]>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][C:13]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[C:4]=3[O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:9]2)=[O:24])=[CH:16][CH:17]=1
Reactant: [H][H]
Reactant: CCCCCOc1c(OC)ccc2c1CCN(C(=O)Cc1ccc([N+](=O)[O-])cc1)C2
Agent: [Pd]
Solvent: CCO
Product: CCCCCOc1c(OC)ccc2c1CCN(C(=O)Cc1ccc(N)cc1)C2
Yield: 89 %

Procedure:
The crude product of 1-(6-methoxy-5-pentyloxy-3,4-dihydro-1H-isoquinolin-2-yl)-2 -(4-nitrophenyl)ethanone obtained in Example 7-50 was dissolved in ethanol (4 ml), and 10% palladium-carbon catalyst (38 mg) was added to this solution. The reaction mixture was stirred in a stream of hydrogen for 3 hours, and then filtered. The solvent was concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (hexane/ethyl acetate=1/2) to give 2-(4-aminophenyl)-1-(6-methoxy-5-pentyloxy-3,4-dihydro-1H-isoquinolin-2-yl)ethanone (159 mg, 89% in 2 steps) as a colorless oil.
Reaction SMILES: O.[NH2:2][NH2:3].[Br:4][C:5]1[CH:6]=[CH:7][C:8](Cl)=[N:9][CH:10]=1>C(O)C.O>[Br:4][C:5]1[CH:6]=[CH:7][C:8]([NH:2][NH2:3])=[N:9][CH:10]=1
Reactant: Clc1ccc(Br)cn1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNc1ccc(Br)cn1

Procedure:
9.3 ml (9.5 g, 190.2 mmol) hydrazine hydrate are added to a solution of 1.8 g (9.5 mmol) 5-bromo-2-chloropyridine in 25 ml ethanol at RT, while stirring, and the mixture is then stirred at 90° C. for 46 h. After concentration of the reaction mixture in vacuo, the residue is stirred in water and the solid is filtered off, washed with water and diethyl ether and dried in vacuo.
Reaction SMILES: [C:1]1([CH2:7][C:8](=[O:10])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.N1CCCC[CH2:14]1.CC(O)=O>CO>[C:1]1([C:7](=[CH2:14])[C:8](=[O:10])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1CCNCC1
Reactant: CC(=O)Cc1ccccc1
Agent: C=O
Solvent: CO
Solvent: CC(=O)O
Product: C=C(C(C)=O)c1ccccc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
1-Phenyl-propan-2-one (40.8 g) was dissolved in 200 ml of MeOH. Formaline (37%) (79 mL), piperidine (4 ml) and HOAc (4 ml) where added and de reaction was stirred for 3 h at 60° C. The reaction mixture was evaporated to dryness under reduced pressure. The residue was taken up in diethyl ether, and extracted with water. The organic layer was washed with 1M HCl, dried over MgSO4 and evaporated under reduced pressure to yield 36.3 g of a yellow liquid. 1H NMR (400 MHz, CDCl3) δ 2.41 (s, 3H), 5.87 (s, 1H), 6.18 (s, 1H), 7.24-7.40 (m, 5H).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[N:7]([CH2:8][C@H:9]2[CH2:14][NH:13][CH2:12][CH2:11][NH:10]2)[CH2:6][CH2:5][NH:4][C:3]1=[O:15].C(N(CC)CC)C.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[CH3:1][C:2]1([CH3:16])[N:7]([CH2:8][C@H:9]2[CH2:14][N:13]([S:29]([C:25]3[S:24][CH:28]=[CH:27][CH:26]=3)(=[O:31])=[O:30])[CH2:12][CH2:11][NH:10]2)[CH2:6][CH2:5][NH:4][C:3]1=[O:15]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CC1(C)C(=O)NCCN1C[C@H]1CNCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C(=O)NCCN1C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.7 %

Procedure:
A 20-mL vial was charged with 3,3-dimethyl-4-((2R)-2-piperazinylmethyl)-2-piperazinone (0.104 g, 0.461 mmol), triethylamine (0.200 mL, 1.44 mmol), and CH2Cl2 (3 mL). To this mixture thiophene-2-sulfonyl chloride (0.0951 g, 0.521 mmol, Sigma-Aldrich, St. Louis, Mo.) in CH2Cl2 (1 mL) was added drop wise at room temperature. The clear solution was stirred at room temperature for 30 min and then the mixture was concentrated and dissolved in CH2Cl2 (20 mL). The organic phase was washed with water (2×20 mL) and saturated aqueous NaCl (20 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to afford 3,3-dimethyl-4-(((2S)-4-(2-thiophenylsulfonyl)-2-piperazinyl)methyl)-2-piperazinone (0.166 g) as an off-white foam.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([S:13]([N:16]2[C:20]3=[N:21][CH:22]=[C:23]([OH:25])[CH:24]=[C:19]3[CH:18]=[C:17]2[C:26]([C:33]2[CH:38]=[CH:37][C:36]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH:35][CH:34]=2)=[CH:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl[CH2:44][C:45]([N:47]([CH3:49])[CH3:48])=[O:46]>CN(C)C=O.C(OCC)(=O)C>[C:7]1([S:13]([N:16]2[C:20]3=[N:21][CH:22]=[C:23]([O:25][CH2:44][C:45]([N:47]([CH3:49])[CH3:48])=[O:46])[CH:24]=[C:19]3[CH:18]=[C:17]2[C:26]([C:33]2[CH:34]=[CH:35][C:36]([S:39]([CH3:42])(=[O:40])=[O:41])=[CH:37][CH:38]=2)=[CH:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)(=[O:14])=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CS(=O)(=O)c1ccc(C(=CC2CCCC2)c2cc3cc(O)cnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: CN(C)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)C(=O)COc1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(S(C)(=O)=O)cc1)n2S(=O)(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
Potassium carbonate (246 mg, 1.78 mmol) was added to a solution of 1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-ol (310 mg, 0.59 mmol) in N,N-dimethylformamide (2 mL) at room temperature and stirred for 30 min. 2-Chloro-N,N-dimethyl-acetamide (0.061 mL, 0.59 mmol) was then added to the above mixture and stirred at room temperature for 13 h. The mixture was diluted with ethyl acetate (150 mL), washed with brine, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-{1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-yloxy}-N,N-dimethyl-acetamide (340 mg, quant.) as a light yellow solid which was used in the next step without further purification: LC/MS m/e calcd for C31H33N3O6S2 [M+H]+ 608.75, observed 608.1.
Reaction SMILES: [F:1][CH:2]([F:37])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:6]=1[C:15]1[C:16]2[N:17]([N:21]=[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([CH:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)=[CH:27][CH:26]=3)[N:23]=2)[CH:18]=[CH:19][CH:20]=1.Cl[CH2:39][C:40]([N:42]([CH3:44])[CH3:43])=[O:41]>>[F:37][CH:2]([F:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:12])([F:13])[F:14])=[CH:7][C:6]=1[C:15]1[C:16]2[N:17]([N:21]=[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([CH:31]4[CH2:32][CH2:33][N:34]([CH2:39][C:40]([N:42]([CH3:44])[CH3:43])=[O:41])[CH2:35][CH2:36]4)=[CH:27][CH:26]=3)[N:23]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: FC(F)COc1ccc(C(F)(F)F)cc1-c1cccn2nc(Nc3ccc(C4CCNCC4)cc3)nc12
Reactant: CN(C)C(=O)CCl
Product: CN(C)C(=O)CN1CCC(c2ccc(Nc3nc4c(-c5cc(C(F)(F)F)ccc5OCC(F)F)cccn4n3)cc2)CC1

Procedure:
2-[4-(4-{8-[2-(2,2-Difluoro-ethoxy)-5-trifluoromethyl-phenyl]-[1,2,4]-triazolo[1,5-a]pyridin-2-ylamino}-phenyl)-piperidin-1-yl]-N,N-dimethyl-acetamide was prepared from {8-[2-(2,2-difluoro-ethoxy)-5-trifluoromethyl-phenyl]-[1,2,4]-triazolo[1,5-a]pyridin-2-yl}-(4-piperidin-4-yl-phenyl)-amine (0.067 g, 0.130 mmol) and 2-chloro-N,N-dimethyl-acetamide (0.020 mL, 0.190 mmol) in a manner analogous to Example 313 to give product (0.020 g, 26%). MP=98-101° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.54 (s, 1H), 8.80 (d, 1H), 8.08 (s, 1H), 7.82 (d, 1H), 7.68 (d, 1H), 7.58 (m, 2H), 7.45 (d, 1H), 7.10 (m, 3H), 6.30 (br m, 1H), 4.49 (m, 2H), 3.15 (s, 2H), 3.05 (s, 3H), 2.95 (m, 2H), 2.82 (s, 3H), 2.38 (m, 1H), 2.12 (m, 2H), 1.55-1.72 (br m, 4H): MS=603 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][C:15]=2Cl)=O)=[CH:4][CH:3]=1.O.[NH2:18][NH2:19]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:10]3[CH:11]=[N:12][CH:13]=[CH:14][C:15]=3[NH:19][N:18]=2)=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Cl)cc1)c1cnccc1Cl
Reactant: NN
Solvent: CO
Solvent: O
Product: Clc1ccc(-c2n[nH]c3ccncc23)cc1
Reaction time: 3 h
Yield: 33 %

Procedure:
(4-Chlorophenyl)-(4-chloropyridin-3-yl)-methanone (3.88 g, 15.4 mmol) was dissolved in MeOH (20 mL) at room temperature and hydrazine hydrate (20 mL) was added. The reaction mixture was stirred for 3 h. The precipitate was filtered and purified by recrystallisation from PhMe/MeOH (˜4:1, ˜150 mL) to give 3-(4-chlorophenyl)-1H-pyrazolo[4,3-c]pyridine (1.16 g, 33.0%) as a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[CH2:20]([NH2:23])[CH:21]=[CH2:22]>CO>[CH2:20]([NH:23][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1)[CH:21]=[CH2:22]
Reactant: Clc1cnc(-c2ccccc2)c(-c2ccccc2)n1
Reactant: C=CCN
Solvent: CO
Product: C=CCNc1cnc(-c2ccccc2)c(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 54 h
Yield: 30.6 %

Procedure:
To a solution of 1.00 g of 2-chloro-5,6-diphenylpyrazine in 10 ml of methanol, 2.14 g of allylamine was added and the mixture was reacted in a sealed tube at 80° C. for 41 hours, followed by stirring at room temperature for 54 hours. After the solvent was evaporated under reduced pressure, the reaction solution was combined with water, extracted with chloroform, dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 330 mg of the desired compound as a pale yellow crystal having a melting point of 97 to 100° C.
Reaction SMILES: Cl.[CH2:2]([NH:6][CH2:7][C@@H:8]([C@H:10]([C@@H:12]([C@@H:14]([CH2:16]O)[OH:15])[OH:13])[OH:11])[OH:9])[CH2:3][CH2:4][CH3:5].[OH-:18].[Na+]>O>[CH2:2]([NH:6][CH:7]([C@:8]1([O:15][C@@H:14]([CH3:16])[C@@H:12]([OH:13])[C@@H:10]1[OH:11])[OH:9])[OH:18])[CH2:3][CH2:4][CH3:5]
Reactant: [OH-]
Reactant: CCCCNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCCCNC(O)[C@@]1(O)O[C@@H](C)[C@@H](O)[C@@H]1O
Temperature: 15 °C
Reaction time: 27 h
Yield: 80 %

Procedure:
A reaction solution is is prepared by adding 170 ml of a bulk solution of N-n-butylglucamine hydrochloride with a concentration of 450 gm/L (by HPLC) to 210 ml of water in a 1-L bioreactor. The solution is adjusted to pH 5 by adding dilute sodium hydroxide and cooled to about 15° C. A total of 20 gm (wet weight) of washed G. oxydans cell paste is added and the reaction mixture is agitated (1000 rpm) and aerated (1 vvm) while controlling the temperature at 15° C. and pH at 5. After 27 hours, the HPLC assay indicates that over 97% of the substrate has been converted for a 80% yield of N-n-butylamino-6-deoxy-α-L-sorbofuranose.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N:7]2[CH2:12][CH2:11][CH:10]([NH:13]C(=O)OC(C)(C)C)[CH2:9][CH2:8]2)=[C:5]([NH2:21])[CH:4]=[N:3]1.C(OC([NH:29][C:30]1[S:34][C:33]([C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])=[N:32][C:31]=1[C:43](O)=[O:44])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[NH2:29][C:30]1[S:34][C:33]([C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])=[N:32][C:31]=1[C:43]([NH:21][C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[N:7]1[CH2:8][CH2:9][CH:10]([NH2:13])[CH2:11][CH2:12]1)=[O:44]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: Cn1ncc(N)c1N1CCC(NC(=O)OC(C)(C)C)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1N1CCC(N)CC1
Yield: 21 %

Procedure:
Following the procedures as described in Example 113, tert-butyl 1-(1-methyl-4-amino-1H-pyrazol-5-yl)piperidin-4-ylcarbamate, 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid, and HATU were reacted to give 108 as a white solid (27 mg, 21%) over two steps. 1H NMR (400 MHz, DMSO) δ 8.70 (s, 1H), 7.60-7.37 (m, 4H), 7.27 (t, J=8.7, 2H), 3.62 (s, 3H), 3.12-2.92 (m, 4H), 2.66 (dd, J=11.9, 8.2, 1H), 1.77 (d, J=9.5, 2H), 1.36 (td, J=15.3, 4.7, 2H). ESIMS m/z=434.1 (M+1).
Reaction SMILES: [CH3:1][NH:2][C:3](=[N:6][N+:7]([O-:9])=[O:8])SC.[NH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[N:16][CH:17]=1>C(O)C>[Cl:18][C:15]1[N:16]=[CH:17][C:12]([CH2:11][NH:10][C:3]([NH:2][CH3:1])=[N:6][N+:7]([O-:9])=[O:8])=[CH:13][CH:14]=1
Reactant: CNC(=N[N+](=O)[O-])SC
Reactant: NCc1ccc(Cl)nc1
Solvent: CCO
Product: CNC(=N[N+](=O)[O-])NCc1ccc(Cl)nc1
Yield: 34 %

Procedure:
A mixture of 0.45 g of 1,2-dimethyl -3-nitroisothiourea, 0.43 g of 5-(aminomethyl)-2-chloropyridine and 25 ml of ethanol was refluxed for 6 hours and concentrated. The residue was purified by a column chromatography [developing solvent: chloroform-ethanol (5:1)] to afford 0.25 g of 1-(6-chloro-3-pyridylmethyl)-3-methyl2-nitroguanidine (Compound No. 5).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11](=[O:19])[NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=2)[CH2:3]1.[CH3:20][S:21](Cl)(=[O:23])=[O:22].C(N(CC)CC)C>C(Cl)Cl>[CH3:20][S:21]([O:1][CH:2]1[CH2:3][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11](=[O:19])[NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=2)[CH2:5]1)(=[O:23])=[O:22]
Reactant: O=C(Nc1ccccc1)c1csc(N2CC(O)C2)n1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CN(c2nc(C(=O)Nc3ccccc3)cs2)C1
Temperature: 0 °C
Yield: 89.7 %

Procedure:
To a solution of 3-hydroxy-1-(4-phenylcarbamoyl-1,3-thiazol-2-yl)azetidine (1.18 g, 4.29 mmol) (obtained as described in Reference Example 32(2)) in methylene chloride (60 ml) were added methanesulfonyl chloride (0.50 ml, 6.44 mmol) and triethylamine (0.90 ml, 6.44 mmol) in an ice bath, and then the mixture was stirred in the ice bath for 2 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using methylene chloride:ethyl acetate (9:1) as the eluant to afford 3-methanesulfonyloxy-1-(4-phenylcarbamoyl-1,3-thiazol-2-yl)azetidine (1.36 g, yield 89%) as a pale yellow solid.
Reaction SMILES: [H-].[Na+].CS(C)=O.[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16].Cl[C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][CH:20]=1>O>[CH3:30][O:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][C:25]=1[O:31][CH3:32])[N:22]=[CH:21][CH:20]=[C:19]2[O:14][C:11]1[CH:12]=[CH:13][C:8]([NH2:7])=[C:9]([N+:15]([O-:17])=[O:16])[CH:10]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc2nccc(Oc3ccc(N)c([N+](=O)[O-])c3)c2cc1OC
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 23.2 %

Procedure:
Sodium hydride (60 wt %, 0.54 g) was added to dimethyl sulfoxide (15 ml), and the mixture was stirred at 70° C. for 30 min and was then cooled to room temperature. 4-Amino-3-nitrophenol (2.07 g) was added to the cooled mixture, and the mixture was stirred at room temperature for 10 min. Next, 4-chloro-6,7-dimethoxyquinoline (1.50 g) was added thereto, and the mixture was stirred at 100° C. for 4 hr. Water was added to the reaction solution, followed by extraction with chloroform. The chloroform layer was then washed with a saturated aqueous sodium hydrogencarbonate solution and was dried over anhydrous sodium 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 (1/1) to give 0.53 g (yield 23%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:9][CH:10]2[CH2:12][CH2:11]2)[N:3]=1.C(N(CC)CC)C.[C:20](OC(=O)C)(=[O:22])[CH3:21]>O1CCCC1>[CH:10]1([NH:9][C:4]2[N:3]=[C:2]([NH:1][C:20](=[O:22])[CH3:21])[N:7]=[C:6]([NH2:8])[N:5]=2)[CH2:12][CH2:11]1
Reactant: Nc1nc(N)nc(NC2CC2)n1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(N)nc(NC2CC2)n1

Procedure:
To a suspension of 49.8 g of 2,4-diamino-6-cyclopropylamino-1,3,5-triazine and 45.5 g of triethylamine in 1200 ml of tetrahydrofuran are slowly added dropwise, at about 60° C. (in about 6 hours), 31.7 g of acetic acid anhydride dissolved in 100 ml of tetrahydrofuran. The reaction mixture is subsequently refluxed for 18 hours, filtered hot and then concentrated by evaporation until crystallisation commences. After the addition of about 300 ml of diethyl ether, the product if filtered off as white crystalline powder. It has a melting point of 190°-195° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH:12]=[O:13].[H-].[Na+].CI.[C:18](=O)(O)[O-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:18])[CH:7]=[C:6]2[CH:12]=[O:13]
Reactant: COc1ccc2[nH]cc(C=O)c2c1
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc2c(c1)c(C=O)cn2C
Yield: 99 %

Procedure:
5-Methoxyindole-3-carboxaldehyde (300 mg, 1.71 mmol) was added in portions over 5 min to a suspension of sodium hydride (82 mg, 2.05 mmol, 60% dispersion in mineral oil) in DMF (8 mL) stirring under argon. The mixture was stirred for 30 min, methyl iodide (0.13 mL, 2.05 mmol) was added and the mixture was stirred for 1 h. Sodium bicarbonate (10%, 40 mL) was added and the mixture was extracted with EtOAc (4×). The combined organic layers were washed with sodium bicarbonate (10%, 2×) and saturated NaCl, dried (MgSO4), filtered and evaporated. Column chromatography of the crude product (50:50 EtOAc:hexanes) afforded 43 (320 mg, 99%) as a light yellow solid; Rf=0.35 (50:50 EtOAc:hexanes); mp=130–1320C; lit mp=132–133° C.53; 1H NMR (CDCl3): δ 9.95 (s, 1H), 7.79 (d, 1H, J=2.4 Hz), 7.62 (s, 1H), 7.25 (d, J=8.8 Hz), 6.96 (dd, 1H, J=2.4 and 8.9 Hz), 3.90 (s, 3H), 3.85 (s, 3H).
Reaction SMILES: C(O)(=O)C.OO.[NH2:7][C:8]1[N:12]=[C:11]([SH:13])[NH:10][N:9]=1.[OH-].[Na+]>O>[NH2:7][C:8]1[N:12]=[C:11]([S:13][S:13][C:11]2[NH:10][N:9]=[C:8]([NH2:7])[N:12]=2)[NH:10][N:9]=1
Reactant: Nc1n[nH]c(S)n1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Nc1n[nH]c(SSc2nc(N)n[nH]2)n1
Reaction time: 1.25 h

Procedure:
Glacial acetic acid (2.60 g) was added to 4.89 g of a 15% aqueous hydrogen peroxide solution. The resulting solution was added over 20 minutes to a solution prepared from 5.01 g 3-amino-1,2,4-triazole-5-thiol, 65.2 g of water and 4.33 g 40% NaOH. The reaction mixture was kept between 18 C-22 C by use of an ice bath during the addition. After stirring for 75 min, the product was filtered, washed with water and then dried under vacuum at 70 C.