Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:46])=[O:45])=[C:40]([N+:48]([O-:50])=[O:49])[CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:51][C:52]1[CH:57]=[CH:56][C:55]([Br:58])=[CH:54][N:53]=1>C(Cl)Cl>[Br:58][C:55]1[CH:56]=[CH:57][C:52]([NH:51][C:35](=[O:37])[CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:46])=[O:45])=[C:40]([N+:48]([O-:50])=[O:49])[CH:39]=2)[CH2:33][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)=[N:53][CH:54]=1
Reactant: Nc1ccc(Br)cn1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1[N+](=O)[O-]
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ccc(Br)cn2)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 33.4 %

Procedure:
A solution of triphenylphosphine (212 mg, 0.81 mmol) in methylene chloride (3 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (144 mg, 0.81 mmol). The reaction mixture was stirred at 0° C. for 10 min and then treated with 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid (250 mg, 0.73 mmol). The resulting reaction mixture was stirred at 0° C. for 5 min and then allowed to warm to 25° C., where it was stirred for 30 min. The reaction mixture was then treated with 2-amino-5-bromopyridine (279 mg, 1.61 mmol). The resulting reaction mixture was stirred at 25° C. for 15 h. The crude reaction mixture was directly purified by flash chromatography, (Merck Silica gel 60, 230-400 mesh, 3/1 hexanes/ethyl acetate), to afford N-(5-bromo-pyridin-2-yl)-3-cyclopentyl-2-(4-methanesulfonyl-3-nitro-phenyl)-propionamide (121 mg, 33%) as a white foam: mp 80-83° C. (foam to gel); FAB-HRMS m/e calcd for C20H22BrN3O5S (M+H)+ 496.0542, found 496.0543.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[N:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl.[OH-].[Na+]>[CH:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:15][N:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cncc3ccccc23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc2c(C3CCNCC3)cncc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.3 %

Procedure:
A mixture of 0.57 gm (1.8 mMol) 1-tert-butoxycarbonyl-4-(isoquinolin-4-yl)piperidine and 6 mL trifluoroacetic acid in 6 mL dichloromethane was stirred at room temperature for 18 hours. The reaction mixture was diluted with 2N sodium hydroxide and the phases were separated. The aqueous phase was extracted well with dichloromethane. The organic phases were combined, washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography, eluting with dichloromethane containing from 10% to 40% methanol and a trace of ammonium hydroxide. Fractions containing product were combined and concentrated under reduced pressure to provide 0.242 gm (63%) of 4-(isoquinolin-4-yl)piperidine as a tan solid. A portion of this material was converted to the oxalate salt to provide the title compound.
Reaction SMILES: N(OS(=O)(=O)O)=[O:2].[N+:8]([C:11]1[O:15][C:14]([C:16]2[C:20]([C:21](N)=[O:22])=[CH:19][N:18]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:17]=2)=[CH:13][CH:12]=1)([O-:10])=[O:9].O>P(=O)(O)(O)O>[N+:8]([C:11]1[O:15][C:14]([C:16]2[C:20]([C:21]([OH:2])=[O:22])=[CH:19][N:18]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:17]=2)=[CH:13][CH:12]=1)([O-:10])=[O:9]
Reactant: NC(=O)c1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Reactant: O=NOS(=O)(=O)O
Agent: O=P(O)(O)O
Solvent: O
Product: O=C(O)c1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Temperature: 0 °C
Yield: 98 %

Procedure:
Add 36 g of 98% nitrosylsulfuric acid (under cooling with ice) dropwise to a suspension of 50 g 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carboxamide in 830 ml of 89% orthophosphoric acid, whereupon the temperature rises from 0° C to 35° C. Stir the resulting reaction mixture for 18 hours at room temperature and pour the produced solution onto 5 kg of ice and water. Separate the formed precipitate and wash it with water until it is no longer acid to obtain a 98% yield of 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carboxylic acid [m.p. 264° to 265.5° C (with decomposition) from dioxane].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][C:11]1([OH:16])[CH2:15][CH2:14][CH2:13][CH2:12]1.[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]>C(OCC)(=O)C>[Br:8][C:6]1[CH:5]=[CH:4][C:3]([NH:9][CH2:10][C:11]2([OH:16])[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:2]([NH:1][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[CH:7]=1
Reactant: Nc1cc(Br)ccc1NCC1(O)CCCC1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)Nc1cc(Br)ccc1NCC1(O)CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.8 %

Procedure:
To a solution of 1-([(2-amino-4-bromophenyl)amino]methyl)cyclopentanol (Step B, 1.3 g, 4.15 mmol) in ethyl acetate (100 mL) was added pivaloyl chloride (511 mg, 4.15 mmol) at room temperature. After stirring for 2 h at room temperature, the mixture was quenched with saturated sodium hydrogen carbonate aqueous solution. The mixture was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=5:1 as eluent) to afford the title compound (1.3 g, 75%) as a beige amorphous.
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5](N)=[N:4][C:2]1=[O:3].[CH3:9][Si:10]([CH3:17])([CH3:16])[NH:11][Si:12]([CH3:15])([CH3:14])[CH3:13].S([O-])([O-])(=O)=O.[NH4+].[NH4+]>ClCCl>[CH3:9][Si:10]([N:11]([Si:12]([CH3:15])([CH3:14])[CH3:13])[C:8]1[CH:7]=[CH:5][NH:4][C:2](=[O:3])[N:1]=1)([CH3:17])[CH3:16]
Reactant: Nc1cc[nH]c(=O)n1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: ClCCl
Product: C[Si](C)(C)N(c1cc[nH]c(=O)n1)[Si](C)(C)C
Temperature: 27 °C

Procedure:
To 5.78 g of cytosine were added 112 ml of hexamethyldisilazane and 50 mg of ammonium sulfate. The mixture was heated to 115° C.-120° C. for 3 hours with stirring and the excess hexamethyldisilazane was subsequently removed. This solution was then cooled to 27° C. and a solid residue formed which was reconstituted in 35 ml of dichloromethane to form a homogenous bis-trimethylsilylcytosine solution.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[C:8](=[CH:14]/[N:15](C)C)/[C:9]([O:11]CC)=O)[CH:5]=[N:6][CH:7]=1.[NH:18]([C:20]1[N:25]=[CH:24][C:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:22][CH:21]=1)N.C1(C)C=CC(S(O)(=O)=O)=CC=1.[ClH:44]>C(O)C.O1CCOCC1>[ClH:44].[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9](=[O:11])[N:18]([C:20]3[N:25]=[CH:24][C:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:22][CH:21]=3)[NH:15][CH:14]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(NN)nc1
Reactant: CCOC(=O)/C(=C\N(C)C)c1cncc(Br)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)c1ccc(-n2[nH]cc(-c3cncc(Br)c3)c2=O)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
500 mg (1.7 mmol) of the compound from Example 9A and 350 mg (1.7 mmol) of the compound from Example 15A are dissolved in 2 ml of ethanol, and 58 mg (0.3 mmol) of p-toluenesulfonic acid are added. The mixture is heated under reflux for 24 h and then cooled to RT, and 0.5 ml of a 4 N solution of hydrogen chloride in dioxane is added. The mixture is stirred at RT for 30 min. The precipitate is filtered off, washed with ethanol and diethyl ether and dried under high vacuum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[NH2:6].Cl.N([O-])=O.[Na+].[N-:19]=[N+:20]=[N-].[Na+]>O.ClCCl>[CH3:13][O:12][C:8]1[CH:7]=[C:5]([N:6]=[N+:19]=[N-:20])[CH:4]=[C:3]([O:2][CH3:1])[C:9]=1[O:10][CH3:11]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1cc(N)cc(OC)c1OC
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1cc(N=[N+]=[N-])cc(OC)c1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.6 %

Procedure:
3,4,5-Trimethoxyaniline (1.83 g; 10 mmol) is added to a 100 mL flask containing water (20 mL) and HCl (conc. aqueous solution, 5 mL). The solution is chilled to 0° C. and a solution of sodium nitrite (830 mg; 12 mmol) in water (5 mL) is added. The solution is stirred at 0° C. for 30 minutes, and then a solution of sodium azide (1.3 g; 20 mmol) in water (5 mL) is added. After another 30 minutes of stirring, dichloromethane is added (20 mL) and the organic phase was collected and filtered through a plug of silica, dried over magnesium sulfate and the solvent was evaporated to give approximately two grams of 3,4,5-trimethoxyphenyl azide.
Reaction SMILES: C([O:5][C:6](=[O:24])[C@@H:7]1[CH2:11][C@@H:10]([CH2:12][NH:13][C:14](=[NH:16])[SH:15])[CH2:9][N:8]1C(OC(C)(C)C)=O)(C)(C)C.[ClH:25]>O1CCOCC1>[ClH:25].[ClH:25].[NH:13]([CH2:12][C@@H:10]1[CH2:9][NH:8][C@H:7]([C:6]([OH:24])=[O:5])[CH2:11]1)[C:14](=[NH:16])[SH:15]
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@@H](CNC(=N)S)CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: N=C(S)NC[C@@H]1CN[C@H](C(=O)O)C1

Procedure:
(4S)-1-(tert-Butyloxycarbonyl)-4-[(isothioureido)methyl]-L-proline tert-butyl ester (25 mg, 0.070 mmol) was treated with 4N HCl in dioxane (1 mL) for 18 hours at room temperature. The reaction mixture was evaporated under diminished pressure, coevaporated several times with diethyl ether, several times with methanol, and finally ether. The product was dried under high vacuum to afford the title compound; yield 14 mg (73%). Mass spectrum: m/z 203 (M); 400 MHz 1H NMR (CD3OD): δ1.92 (m, 1H); 3.18 (m, 1H); 4.48 (m, 1H).
Reaction SMILES: [OH-].[Li+].[NH2:3][C:4]1[N:5]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([CH:28]3[CH2:30][CH2:29]3)=[CH:20][CH:19]=2)[C:6]([S:9][C:10]([CH3:17])([CH3:16])[C:11]([O:13]CC)=[O:12])=[N:7][N:8]=1.Cl>C1COCC1.CO>[NH2:3][C:4]1[N:5]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([CH:28]3[CH2:30][CH2:29]3)=[CH:20][CH:19]=2)[C:6]([S:9][C:10]([CH3:17])([CH3:16])[C:11]([OH:13])=[O:12])=[N:7][N:8]=1
Reactant: CCOC(=O)C(C)(C)Sc1nnc(N)n1-c1ccc(C2CC2)c2ccccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(Sc1nnc(N)n1-c1ccc(C2CC2)c2ccccc12)C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 74.3 %

Procedure:
Lithium hydroxide solution (1M aqueous, 0.757 mL, 0.757 mmol) was added to a solution of ethyl 2-(5-amino-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)-2-methylpropanoate (100 mg, 0.252 mmol) in THF (2 mL) and methanol (1 mL) and the mixture stirred at room temperature for 20 h. The crude reaction mixture was acidified with HCl (1N, 1 mL) and sonicated to break up the solids, which were then isolated by filtration to give 2-(5-amino-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)-2-methylpropanoic acid as a white solid (69 mg, 74%).
Reaction SMILES: NC1C(F)=C([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH3:17])[C:10]=2[F:18])N=C(C(OC(C)C)=O)C=1.[C:25]([NH:28][C:29]1[C:34]([F:35])=[C:33](Cl)[N:32]=[C:31]([C:37]([O:39][CH3:40])=[O:38])[C:30]=1[Cl:41])(=[O:27])[CH3:26]>>[C:25]([NH:28][C:29]1[C:34]([F:35])=[C:33]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH3:17])[C:10]=2[F:18])[N:32]=[C:31]([C:37]([O:39][CH3:40])=[O:38])[C:30]=1[Cl:41])(=[O:27])[CH3:26]
Reactant: COc1c(Cl)ccc(-c2nc(C(=O)OC(C)C)cc(N)c2F)c1F
Reactant: COC(=O)c1nc(Cl)c(F)c(NC(C)=O)c1Cl
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)c(F)c(NC(C)=O)c1Cl

Procedure:
Methyl 4-(acetylamino)-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoro-picolinate was prepared in analogous fashion to isopropyl 4-(amino)-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoro-picolinate in Example 10 except that methyl 4-acetamido-3,6-dichloro-5-fluoropicolinate was used in place of isopropyl 4-amino-6-bromo-5-fluoropicolinate: mp=175-177° C.; 1H NMR (400 MHz, DMSO-d6) δ 7.52 (dd, J=8.4, 1.6 Hz, 1H), 7.38 (dd, J=8.4, 7 Hz, 1H), 3.95 (d, J=0.8 Hz, 3H), 3.94 (s, 3H), 2.17 (s, 3H); 13C NMR (100.6 MHz, DMSO-d6) δ 168.0, 163.9, 154.4, 153.7, 151.9, 151.0, 144.9 (d, JF-C=4.4 Hz), 143.9 (d, JF-C=13.3 Hz), 139.5 (d, JF-C=16.7 Hz), 133.7 (d, JF-C=14.4 Hz), 129.3 (d, JF-C=3.2 Hz), 126.7, 125.9 (dd, JF-C=14.6, 3.6 Hz), 121.9 (d, JF-C=13.2, 4.3 Hz), 61.7 (d, JF-C=4.4 Hz), 53.1, 22.5; 19F{1H} NMR (376.5 MHz, DMSO-d6) δ −119.0 (d, JF-F=28.6 Hz), −129.0 (d, JF-F=28.6 Hz); IR: 3182, 3008, 2952, 1736, 1674, 1512, 1464, 1422, 1401, 1372, 1263, 1238, 1213, 1173, 1049, 1026, 977, 904, 687; MS Calcd. for C16H12Cl2F2N2O4: 404.0. Found: 404 (M+), 369.
Reaction SMILES: CC1C=CC(S(O)(=O)=O)=CC=1.O.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)(O)[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[CH:17][CH:16]=1.C([O-])(O)=O.[Na+]>C1C=CC=CC=1>[CH3:39][O:38][C:35]1[CH:34]=[CH:33][C:32]([C:21]([C:18]2[CH:17]=[CH:16][C:15]([O:14][CH3:13])=[CH:20][CH:19]=2)=[CH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[CH:37][CH:36]=1
Reactant: COc1ccc(CC(O)(c2ccc(OC)cc2)c2ccc(OC)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: COc1ccc(C=C(c2ccc(OC)cc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C

Procedure:
To the Grignard reagent prepared from 20 g 4-bromoanisole (107 mmol) and 2.43 g Mg turnings (107 mg-atom) in 20 mL Et2O was added 19.25 g dry (P2O5) desoxyanisoin (76 mmol) as a solid in four portions, each followed by a 50 mL wash of Et2O. The mixture was stirred at reflux 17 h, cooled to room temperature, poured onto 200 g ice and 40 mL 1N H2SO4, and filtered into a separatory funnel. 100 mL Et2O was added and the organic layer was washed with 100 mL H2O and saturated NaHCO3 (2×100 mL). The organic layer was dried (MgSO4), filtered, and the Et2O was removed under reduced pressure to give crude 1,1,2-Tris(4-methoxyphenyl)ethanol as an orange oil which crystallized (25 mL EtOH with a trace of NH4OH) as an orange solid, 18.6 g (67% crude yield), mp: 109°-127° C.; NMR δ7.47 to 6.63 (m, 12H, ArH), 3.73 (3 overlapping s, 9H, OCH3), 3.48 (s, 2H, CH2), 2.27 (s, 1H, OH). p-TsOH.H2O (2 g; 10.5 mmol) and 18.5 g of the crude carbinol (50.8 mmol) were dissolved in 50 mL C6H6, heated to reflux 2 h, cooled to room temperature, and poured onto 75 mL 5% NaHCO3. The organic layer was washed with 75 mL 5% NaHCO3. The combined aqueous layers were extracted with 25 mL C6H6. The combined organic layers were washed with 100 mL H2O, dried (Na2SO4), filtered, and the solvent removed to give a dark oil. The oil was purified on 80 g flash SiO2 (gradient elution with petroleum ether-CH2Cl 2) yielding an amber oil which solidified at room temperature to yield 1,1,2-Tris(4-methoxyphenyl)ethene as white cubes (11.3 g, 64%), mp: 100°-101° C. (lit. 100°-101° C.). NMR δ7.29 to 6.55 (m, 13H, ArH and C=CH), 3.78 (s, 3H, geminal ring OCH3), 3.75 (s, 3H, vicinal ring OCH3), 3.69 (s, 3H, central ring OCH3).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([Cl:10])[CH:5]=[C:4]([F:11])[C:3]=1[N:12]1[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]1=[O:24].[N:25]([O-])=O.[Na+].O.O.Cl[Sn]Cl>Cl>[Cl:10][C:6]1[CH:5]=[C:4]([F:11])[C:3]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])=[C:2]([NH:1][NH2:25])[C:7]=1[O:8][CH3:9]
Reactant: O=N[O-]
Reactant: COc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1N
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: COc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1NN
Temperature: -15 °C
Reaction time: 0.33 h

Procedure:
3-(2-Amino-4-chloro-6-fluoro-3-methoxyphenyl)-1-methyl-6-trifluoromethyl-2,4(1H, 3H)-pyrimidinedione (0.9 g, 2.4 mmol) was dissolved in conc. hydrochloric acid (5 ml) and the mixture cooled to −15° C., a solution of NaNO2 (0.2 g in 2 ml of H2O) was added slowly. After stirred for 20 min, a solution of SnCl2.2H2O (1.5 g in 4 ml of conc. hydrochloric acid) was added and the reaction continued at −15° C. for 30 min, then at room temperature for 30 min. The aqueous mixture was extracted with ethyl acetate (5 ml×3) and the organic phase washed with brine and dried over Na2SO4. Column chromatography was used to purify the product (silica gel, hexane/ethyl acetate=6/4). Yield: 0.5 g, 1.3 mmol.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[F:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](O)=O>>[F:17][C:18]1[CH:19]=[C:20]([C:21]2[O:14][C:13]([C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:15][N:16]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Reactant: O=C(O)c1cccc(F)c1
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2cccc(F)c2)o1
Yield: 59 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (2.00 g, 9.21 mmol) was converted using 3-fluorobenzoic acid instead of o-toluic acid to the title compound (SiO2, heptane:ethyl acetate:dichloromethane=70:10:20 to 40:40:20, 1.75 mg, 59%) which was obtained as an off-white solid. MS: m/e 322.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9](Cl)(=[O:11])=[O:10])=[C:4]([Cl:13])[CH:3]=1.[CH3:14][C:15]1[C:20]([NH2:21])=[CH:19][CH:18]=[CH:17][N:16]=1>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9]([NH:21][C:20]2[C:15]([CH3:14])=[N:16][CH:17]=[CH:18][CH:19]=2)(=[O:11])=[O:10])=[C:4]([Cl:13])[CH:3]=1
Reactant: O=S(=O)(Cl)c1c(Cl)cc(Br)cc1Cl
Reactant: Cc1ncccc1N
Solvent: c1ccncc1
Product: Cc1ncccc1NS(=O)(=O)c1c(Cl)cc(Br)cc1Cl
Yield: 64.5 %

Procedure:
Prepared from 4-bromo-2,6-dichlorobenzenesulfonyl chloride (1.00 g, 3.1 mmol) and 2-methyl-3-aminopyridine (0.33 g, 3.1 mmol) in pyridine (6 ml) according to the method of intermediate 1, to give the title compound as a yellow solid (0.80 g, 2.0 mmol, 65%). 5H (CDCl3, 300K) 8.31 (1H, dd J 4.8 Hz 1.4 Hz), 7.65 (1H, d J 1.4 Hz), 7.64 (2H, s), 7.10 (2H, m), 2.52 (3H, s). m/z (ES+, 70V) 396.9 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=[O:5])[CH3:2].[NH2:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][N:20]=[CH:19]2.C(N(CC)CC)C>CO>[CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:15][C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[NH:21][N:20]=[CH:19]3)=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: Nc1ccc2[nH]ncc2c1
Solvent: CCN(CC)CC
Solvent: CO
Product: CCOC(=O)c1cnc(SC)nc1Nc1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
To the solution of 4-chloro-2-methylthio-5-pyrimidine carboxylic acid ethyl ester (5 g) and 5-aminoindazole (3.15 g) in methanol (70 ml) was added triethylamine (3.5 ml), and then the solution was reacted at 30° C. for 3 hr. The reaction mixture was cooled at room temperature, stirred at 20° C. for 1 hr. Then the reaction mixture was filtered and washed with methanol (20 ml). The obtained solid was dried at 40-50° C. in vacuo to obtain the desired compound (6.15 g, 87%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([NH:15][C:16]#[N:17])=[O:14])=[N:4][C:5]([Cl:12])=[C:6]([NH:8][CH:9]([CH3:11])[CH3:10])[N:7]=1.C(N(CC)CC)C.[SH2:25]>N1C=CC=CC=1>[NH2:1][C:2]1[C:3]([C:13]([NH:15][C:16]([NH2:17])=[S:25])=[O:14])=[N:4][C:5]([Cl:12])=[C:6]([NH:8][CH:9]([CH3:11])[CH3:10])[N:7]=1
Reactant: CC(C)Nc1nc(N)c(C(=O)NC#N)nc1Cl
Reactant: S
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC(C)Nc1nc(N)c(C(=O)NC(N)=S)nc1Cl

Procedure:
To a stirred solution of (3-amino-5-isopropylamino-6-chloropyrazinoyl)cyanamide (6.0 g., 0.0235 mole) in pyridine (40 ml) is added triethylamine (4 ml.). The reaction mixture is heated on a steam bath for 11/2 hours while a slow stream of hydrogen sulfide gas is bubbled into the solution. The reaction mixture is cooled and added to ice-water to give 6 g. of (3-amino-5-isopropylamino-6-chloropyrazinoyl)thiourea which melts at 195° C. after recrystallization from ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:9]2[C:17]3[C:12](=[C:13]([CH2:19][S:20][CH3:21])[CH:14]=[C:15]([F:18])[CH:16]=3)[NH:11][CH:10]=2)=[CH:4][CH:3]=1.ClC1C=CC(C(C2C=CC(Cl)=CC=2)C2C3C(=C(CS(C)=[O:48])C=CC=3)NC=2)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[C:9]2[C:17]3[C:12](=[C:13]([CH2:19][S:20]([CH3:21])=[O:48])[CH:14]=[C:15]([F:18])[CH:16]=3)[NH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CSCc1cc(F)cc2c(C(c3ccc(F)cc3)c3ccc(Cl)cc3)c[nH]c12
Reactant: CS(=O)Cc1cccc2c(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)c[nH]c12
Product: CS(=O)Cc1cc(F)cc2c(C(c3ccc(F)cc3)c3ccc(Cl)cc3)c[nH]c12

Procedure:
The title compound was prepared starting from 100 mg (0.24 mmol) of the compound from Example 291 in analogy to the synthesis of the compound from Example 296. 102 mg (98% of theory) of the target compound were obtained as mixture of diastereomers.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[NH2:13][C:14]1[CH:15]=[C:16]([C:20]2[NH:24][N:23]=[N:22][N:21]=2)[CH:17]=[CH:18][CH:19]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2[NH:24][N:23]=[N:22][N:21]=2)[CH:15]=1)(=[O:11])=[O:10]
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1cc(Cl)ccc1Cl
Yield: 45 %

Procedure:
The product was prepared according to General Procedure 6, described in Example 65, with 2,5-dichlorobenzenesulfonyl chloride (13.5 mg, 0.055 mmol) and 5-(3-aminophenyl)tetrazole (8.0 mg, 0.050 mmol). The title compound was obtained in 45% yield (8.3 mg). MS (ESI+) calcd mass for C13H9Cl2N5O2S 368.985401, found 368.985761.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][N:11]=2)[CH2:6][CH2:5]1.Cl[CH2:20][CH:21]1[CH2:23][CH2:22]1.[BrH:24].CCOCC>CN(C)C=O.CCOCC>[BrH:24].[CH:21]1([CH2:20][N:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10]([CH:7]3[CH2:6][CH2:5][N:4]([CH3:3])[CH2:9][CH2:8]3)=[N:11]2)[CH2:23][CH2:22]1
Reactant: CN1CCC(c2n[nH]c3ccccc23)CC1
Reactant: ClCC1CC1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CN1CCC(c2nn(CC3CC3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
To a stirred mixture of 1.19 g of sodium hydride (50% oil dispersion) in 65 ml of dimethylformamide was added, dropwise, 4.0 g of 3-(1-methyl-4-piperidinyl)-1H-indazole in 20 ml of hot dimethylformamide. The mixture was stirred for 1 hr at ambient temperature and then 1.40 g of chloromethylcyclopropane in 10 ml of dimethylformamide was added dropwise. The reaction mixture was stirred for 21/2 days at ambient temperature. The reaction mixture was quenched with water, extracted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate and the solvent was removed in vacuo to yield an oil. The oil was dissolved in ether and saturated hydrogen bromide/ether solution was added dropwise to precipitate a salt. The salt was recrystallized from toluene and ethyl acetate to yield 2.8 g (32%) of product, mp 177°-179° C.