Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.NC1C=CC(Cl)=CC=1[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][N:19]=1)=[O:16].N1C=CC=CC=1>ClCCl.CN(C)C=O>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([NH:17][CH:15]=[O:16])=[N:19][CH:20]=1
Reactant: Nc1ccc(Cl)cc1C(=O)Nc1ccc(Cl)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=CNc1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-{2-{[tert-butyl)amino]sulfonyl}phenyl}benzoic acid (167 mg, 0.5 mmol) in dichloromethane (5 ml) was added oxalyl chloride (0.09 ml, 1 mmol) and a few drops of dimethylformamide. The mixture was stirred at r.t. for 2 hrs. After the evaporation of the solvent, the residue was dissolved in dichloromethane (5 ml). The compound of (2-amino-5-chlorophenyl)-N-(5-chloro(2-pyridyl))carboxamide (0.17 g, 0.6 mmol) and pyridine (0.122 ml, 1.5 mmol) were added to the solution. The mixture was stirred at r.t. overnight. The solvent was evaporated to give (2-{[4-(2-{[tert-butyl)amino]sulfonyl}phenyl)phenyl]-carbonylamino}-5-chlorophenyl)-N-(5-chloro(2-pyridyl))carboxamide. MS found for C29H26Cl2N4O4S M+=597, (M+2)+=599. Step 2: The mixture of the compound of (2-{[4-(2-{[(tert-butyl)amino]sulfonyl}phenyl)phenyl]carbonylamino}-5-chlorophenyl)-N-(5-chloro(2-pyridyl))carboxamide example 12 (0.5 mmol) in trifluoroacetic acid (5 ml) was stirred at r.t. for 5 hrs. After the evaporation of solvent, the crude residue was purified by RP-HPLC to give N-(5-chloro(2-pyridyl))(5-chloro-2-{[4-(2-sulfamoylphenyl)-phenyl]carbonylamino}phenyl)-carboxamide as a white powder (68 mg, 25%). MS found for C25H18Cl2N4O4S
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([C@@H:9]2[CH2:11][C@H:10]2[C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=3[N:13]=2)[CH:3]=1.O.[NH2:23][NH2:24].C(=O)([O-])[O-].[K+].[K+]>CC1OCCC1>[NH:23]([C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([C@@H:9]2[CH2:11][C@H:10]2[C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=3[N:13]=2)[CH:3]=1)[NH2:24]
Reactant: Cc1nc(Cl)cc([C@@H]2C[C@H]2c2nc3ccccc3n2C)n1
Reactant: NN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC1CCCO1
Product: Cc1nc(NN)cc([C@@H]2C[C@H]2c2nc3ccccc3n2C)n1
Temperature: 25 °C

Procedure:
A slurry of 6-4 (4 g, 13.39 mmol), hydrazine hydrate (1.261 ml, 40.2 mmol) and potassium carbonate (5.55 g, 40.2 mmol) in 2-MeTHF (100 ml) was heated at 80° C. for 16 h. After cooling to room temperature, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was separated, dried over sodium sulfate, filtered and concentrated to afford Intermediate 6 as a tan solid. MS: m/z=295.4 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:15]1[NH:19][C:18]2[CH:20]=[CH:21][C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:23][C:17]=2[N:16]=1)[CH:10]([CH3:14])[C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.C([O-])(O)=O.[Na+].[NH3:48]>C1COCC1.CN(C=O)C.O1CCOCC1.N1C=CC=CC=1>[NH2:48][C:11](=[O:13])[CH:10]([CH3:14])[C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])[C:15]1[NH:19][C:18]2[CH:20]=[CH:21][C:22]([C:24]([CH3:25])([CH3:27])[CH3:26])=[CH:23][C:17]=2[N:16]=1
Reactant: CC(C(=O)O)[C@H](NC(=O)OC(C)(C)C)c1nc2cc(C(C)(C)C)ccc2[nH]1
Reactant: N
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CC(C(N)=O)[C@H](NC(=O)OC(C)(C)C)c1nc2cc(C(C)(C)C)ccc2[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of (3S)-3-[(tert-butoxycarbonyl)amino]-3-(5-tert-butyl-1H-benzimidazol-2-yl)-2-methylpropanoic acid (Preparation 30, 7.25 g, 19.33 mmol), Boc2O (5.9 g, 27.0 mmol), pyridine (1 mL) and NaHCO3 (2 g, 25 mmol) in THF/DMF (200 mL/100 mL) was stirred at room temperature for 18 hours. 0.5M Ammonia in dioxane (150 mL) was added and the reaction continued stirring at room temperature for a further 18 hours. The reaction was concentrated to dryness and diluted with saturated aqueous NaHCO3 solution. The solution was extracted with 2-MethylTHF and concentrated in vacuo. The residue was purified using reverse phase column chromatography eluting with 5-70% acetonitrile in 0.1% formic acid in water to afford the title compound as a mixture of diastereomers (3 g, 43%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOC[CH2:24]1>>[ClH:21].[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[N:14]([CH3:24])[CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: C1COCCO1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2Cl)CC1
Agent: Cl
Product: CN(c1ccccc1Cl)C1CCNCC1
Yield: 99 %

Procedure:
To a solution of 4-(2-chloro-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.166 g, 0.00053 mole), in DMF (10 mL) was added, NaH (60% w/w dispersion in oil) (0.0512 g, 0.0021 mole) and the resulting mixture was stirred at ambient temperature for 10 minutes under an atmosphere of nitrogen. Methyl iodide (0.303 g, 0.0021 mole) was then added, and the stirring was continued for 30 minutes at ambient temperature. The reaction mixture was heated to 45° C. for 30 minutes. The reaction mixture was then quenched with aqueous 10% NH4Cl solution and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous NaHCO3 solution followed by brine solution. The organic layer was collected, dried over sodium sulfate and concentrated under reduced pressure to afford 0.08 g (46%) of 4-[(2-chloro-phenyl)-methyl-amino]-piperidine-1-carboxylic acid tert-butyl ester. 1H NMR (CDCl3): δ 7.6-7.54 (m, 1H), 7.28-7.2 (m, 1H), 7.14-7.08 (m, 1H), 6.96-6.88 (m, 1H), 4.2-4.0 (m, 2H), 3.3-3.2 (m, 1H), 2.8-2.7 (m, 2H), 2.7 (s, 3H), 1.7-1.6 (m, 2H), 1.6 (m, 1H), 1.45 (s, 9H). A solution of 4-(2-chloro-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.078 g, 0.00024 mole) in dioxane.HCl (1 mL) was stirred for 30 minutes. The reaction mixture was then concentrated under reduced pressure to afford 0.072 g (99%) of (2-chloro-phenyl)-methyl-piperidin-4-yl-amine hydrochloride which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[CH:8][CH:7]=1)[C:2]([CH3:5])([CH3:4])[CH3:3].[N+:16]([O-])([OH:18])=[O:17].O>C(OC(=O)C)(=O)C>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[C:10]([N+:16]([O-:18])=[O:17])[CH:11]=1)[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc(CC(C)(C)C)cc1
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(CC(C)(C)C)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 96.7 %

Procedure:
To a suspension of N-(4-neopentylphenyl)acetamide (Preparation 98, 2.54 g, 12.4 mmol) in acetic anhydride (20 mL) cooled in an ice bath was added a solution of nitric acid (0.78 mL, 18 mmol) in acetic anhydride (5 mL) dropwise. The solution was allowed to warm to room temperature for 18 hours. The yellow solution was added to water and extracted with dichloromethane (3×). The organic layers were dried over anhydrous magnesium sulphate, filtered, and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with a 0-50% ethyl acetate/hexanes gradient to provide the title compound (3.0 g, 97%) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=1.[S:9](=[O:13])(=[O:12])([OH:11])[OH:10].C(O)(=O)[CH:15]([CH2:17][C:18](O)=O)[OH:16]>[Cl-].[Na+].O>[S:9](=[O:11])(=[O:10])([OH:13])[OH:12].[NH2:1][C:2]1[CH:7]=[CH:6][C:5]2[C:4](=[N:8][C:15]([OH:16])=[CH:17][CH:18]=2)[N:3]=1
Reactant: Nc1cccc(N)n1
Reactant: O=C(O)CC(O)C(=O)O
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: Nc1ccc2ccc(O)nc2n1
Temperature: 20 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
2,6-Diaminopyridine (167 g, 1.53 mol) was added in portions to sulfuric acid (1.14 kg, 11.7 mol) at 40° C. The temperature of the solution was maintained at 40–50° C. during the addition with a water bath. When all of the 2,6-diaminopyridine was dissolved, the solution was cooled to 20° C. Malic acid (206 g, 1.53 mol) was added to the solution and the reaction mixture was gradually heated to 110° C. over 90 minutes. The mixture was stirred at 110–120° C. for one hour, cooled to room temperature, and poured slowly into a cold brine solution (167 g NaCl, 1.6 kg ice water). The quenched mixture was stirred at room temperature for one hour and filtered. The material was washed with hexanes (335 mL) and dried at 60° C. under vacuum to yield 2-amino-7-hydroxy-1,8-naphthyridine sulfuric acid salt as a yellow solid: 354 g, 89% yield; MS (DCl) M+1 at 162, 100%; 1H NMR (200 MHz, DMSO-d6) δ 4.32 (br. s, 5H, —OH, —NH2, H2SO4), 6.41 (d, J=9.0 Hz, 1H, C6), 6.56 (d J=9.0 Hz, 1H, C5), 7.85 (d J=6.6 Hz, 1H, C3), 7.91 (d J=6.6 Hz, 1H, C4).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[C:5]([NH:7][CH:8]([C:10]1[N:15]=[N:14][C:13]([NH:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)=[N:12][CH:11]=1)[CH3:9])=[O:6].NC(C1N=NC(NC2C=C(OC)C(OC)=C(OC)C=2)=NC=1)C.[C:54]([NH:57]C1C=C(C=CC=1)C(O)=O)(=[O:56])[CH3:55].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[C:54]([NH:57][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[C:5]([NH:7][CH:8]([C:10]1[N:15]=[N:14][C:13]([NH:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)=[N:12][CH:11]=1)[CH3:9])=[O:6])(=[O:56])[CH3:55]
Reactant: CC(=O)Nc1cccc(C(=O)O)c1
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3cccc(Br)c3)nn2)cc(OC)c1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: COc1cc(Nc2ncc(C(C)N)nn2)cc(OC)c1OC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(Nc2ncc(C(C)NC(=O)c3cccc(NC(C)=O)c3)nn2)cc(OC)c1OC
Yield: 75 %

Procedure:
In a similar manner as described for Intermediate 18, 6-(1-aminoethyl)-N-(3,4,5-trimethoxyphenyl)-1,2,4-triazin-3-amine (Intermediate 9) (113 mg, 0.33 mmol), 3-(acetylamino)benzoic acid (110 mg, 0.61 mmol), diisopropylethylamine (0.40 mL, 2.3 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (252 mg, 0.66 mmol) in dimethylformamide (2 mL) gave 3-(acetylamino)-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)benzamide (116 mg, 75%) as a yellow solid. MS m/z 466 (M+1).
Reaction SMILES: S1C2C=CC=CC=2N=C1N(COCC[Si](C)(C)C)C(C1C=CC=C2C=1CN(C1SC([CH2:32][N:33]3[CH2:38][CH2:37][N:36]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH2:35][CH2:34]3)=C(C(OC)=O)N=1)CC2)=O.S1C2C=CC=CC=2N=C1NC(C1C=CC=C2C=1CN(C1SC(CCCCI)=C(C(OCC)=O)N=1)CC2)=[O:64].C1C=CC(N2CCNCC2)=CC=1.N1(C2C=CC(O)=CC=2)CCNCC1>>[CH3:32][N:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:44]=[CH:43][C:42]([OH:64])=[CH:41][CH:40]=2)[CH2:35][CH2:34]1
Reactant: CCOC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)sc1CCCCI
Reactant: COC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1CN1CCN(c2ccccc2)CC1
Agent: Oc1ccc(N2CCNCC2)cc1
Agent: c1ccc(N2CCNCC2)cc1
Product: CN1CCN(c2ccc(O)cc2)CC1

Procedure:
Compound 82A was prepared in a similar manner to the synthesis of compound 62A by substituting compound 42C and phenylpiperazine with paraformahyde and 4-(piperazin-1-yl)phenol, respectively: 1H NMR (DMSO-d6): δ 6.74-6.78 (m, 2H), 6.61-6.65 (m, 2H), 2.93-2.95 (m, 4H), 2.41-2.44 (m, 4H), 2.22 (s, 3H). ESI (+)/MS: 193 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][C:10]2[NH:9][C:8]3[CH2:13][CH2:14][N:15]([CH3:17])[CH2:16][C:7]=3[C:6]=2[CH:5]=1)([CH3:3])[CH3:2].N1CCC[C@H]1C(O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[CH:35]=[C:36]([C:38]1[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=1)[CH3:37]>CN(C=O)C.[Cu]I>[CH:1]([C:4]1[CH:12]=[CH:11][C:10]2[N:9](/[CH:35]=[C:36](/[C:38]3[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=3)\[CH3:37])[C:8]3[CH2:13][CH2:14][N:15]([CH3:17])[CH2:16][C:7]=3[C:6]=2[CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: CC(=CBr)c1ccncc1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(C(C)C)ccc31)CN(C)CC2)c1ccncc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
8-Isopropyl-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (150 mg, 0.65 mmol) was dissolved in DMF. Copper (I) iodide (14 mg, 0.074 mmol), L-proline (17 mg, 0.015 mmol) and potassium phosphate (340 mg, 1.48 mmol) were added and the reaction mixture was stirred for 10 min. at RT. 4-(1-Bromoprop-1-en-2-yl)pyridine (220 mg, 0.9 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated overnight at 85° C. (prolonged heating in some cases was required). DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh). The product was further purified by HPLC. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.80 (d, 2H), 8.20 (d, 2H), 7.70 (s, 1H), 7.40 (s, 1H), 7.20 (m, 2H), 4.40 (m, 1H), 3.90 (m, 1H), 3.70 (m, 1H), 3.22 (m, 3H), 3.15 (s, 3H), 3.0 (m, 1H), 2.10 (s, 3H), 1.30 (d, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]([O:14][CH3:15])=[CH:12][C:6]([CH2:7][O:8][CH2:9][CH:10]=[CH2:11])=[C:5]([N+:16]([O-:18])=[O:17])[CH:4]=1.[CH3:19][O:20][SiH:21]([O:24][CH3:25])[O:22][CH3:23]>[H+].[H+].O.O.O.O.O.O.Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[CH3:19][O:20][Si:21]([O:24][CH3:25])([O:22][CH3:23])[CH2:11][CH2:10][CH2:9][O:8][CH2:7][C:6]1[CH:12]=[C:13]([O:14][CH3:15])[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[N+:16]([O-:18])=[O:17]
Reactant: C=CCOCc1cc(OC)c(OC)cc1[N+](=O)[O-]
Reactant: CO[SiH](OC)OC
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: O
Product: COc1cc(COCCC[Si](OC)(OC)OC)c([N+](=O)[O-])cc1OC
Temperature: 37 °C
Reaction time: 0.5 h
Yield: 42.9 %

Procedure:
A 30-ml eggplant type flask was purged with nitrogen, and charged with 1.5 g (5.9 mmol) of allyl 4,5-dimethoxy-2-nitrobenzyl ether, 0.865 g (7.1 mmol) of trimethoxysilane, and an infinitesimal amount of hydrogen hexachloroplatinate(IV) hexahydrate (H2PtCl6·6H2O), followed by stirring at 37° C. for 30 minutes. Thereafter, the bath temperature was raised to 100° C., and the reaction was completed in 2 hours. The reaction mixture was purified by silica gel column chromatography using a medium-pressure column. Using a mixture of hexane, ethyl acetate and tetramethoxysilane (in a volume ratio of 100:20:1) as the eluent, 0.95 g (2.53 mmol) of the desired product was obtained in a 43% yield. Its Rf value (for the aforesaid eluent) was 0.19.
Reaction SMILES: [OH:1][NH:2][CH:3]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[C:4]([NH2:6])=[O:5].[C:17](Cl)(=[O:21])[C:18]([CH3:20])=O.N1C=CC=CC=1>CN(C)C(=O)N(C)C>[OH:1][N:2]1[CH:3]([CH2:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[C:4](=[O:5])[N:6]=[C:18]([CH3:20])[C:17]1=[O:21]
Reactant: NC(=O)C(Cc1c[nH]c2ccccc12)NO
Reactant: CC(=O)C(=O)Cl
Solvent: CN(C)C(=O)N(C)C
Solvent: c1ccncc1
Product: CC1=NC(=O)C(Cc2c[nH]c3ccccc23)N(O)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.7 %

Procedure:
In 5 ml of tetramethylurea was dissolved 0.22 g of 2-hydroxylamino-3-(indol-3-yl)propionic acid amide. The solution was cooled to -5° to 0° C. Thereto was added 0.1 g of pyruvic acid chloride. Then, there was added 1 ml of a tetramethylurea solution containing 90 mg of pyridine. The mixture was stirred for 1.5 hours with ice cooling and for 1 hour at room temperature. The mixture was poured into ice water. The resulting mixture was subjected to extraction with CHCL3. The extract was washed with water, dried over magnesium sulfate, and subjected to TLC (methanol/CH2Cl2 =1/10). The fraction separated was heated for 10-20 minutes at 80° C. under vacuum. The residue was mixed with methanol for crystallization. The resulting crystals were recrystallized from methanol to obtain 40 mg of colorless needle-like cyrstals. Yield: 15%. MS (m/e):M30 271. Melting point: 166°-168° C.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[CH2:10]([C:12]1[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[NH:14][N:13]=1)[CH3:11]>>[CH2:10]([C:12]1[C:16]([N+:6]([O-:9])=[O:7])=[C:15]([C:17]([OH:19])=[O:18])[NH:14][N:13]=1)[CH3:11]
Reactant: O=[N+]([O-])O
Reactant: CCc1cc(C(=O)O)[nH]n1
Agent: O=S(=O)(O)O
Product: CCc1n[nH]c(C(=O)O)c1[N+](=O)[O-]
Temperature: 50 °C

Procedure:
Fuming sulphuric acid (17.8 ml) was added dropwise to stirred, ice-cooled fuming nitric acid (16.0 ml), the resulting solution heated to 50° C., 3-ethyl-1H-pyrazole-5-carboxylic acid added portionwise over 30 minutes whilst maintaining the reaction temperature below 60° C. The resulting solution was heated for 18 hours at 60° C., allowed to cool, then poured onto ice. The title compound was obtained as a brown solid (64%). δ (DMSOd6): 1.18 (3H,t), 2.84 (2H,m), 13.72 (1H,s).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:26]=[CH:25][C:15]([C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])=[O:17])=[C:14]([Cl:27])[CH:13]=1>C([O-])(O)=O.[Na+].CCOC(C)=O>[Cl:27][C:14]1[CH:13]=[C:12]([NH:11][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:26]=[CH:25][C:15]=1[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24])=[O:17]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Cc1ccccc1C(=O)c1ccc(N)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1ccccc1C(=O)c1ccc(Nc2ncccc2[N+](=O)[O-])cc1Cl
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
2-Chloro-3-nitro-pyridine (0.32 g, 2.0 mmol) and 4-amino-2-chloro-2′-methylbenzophenone (compound 2) (0.49 g, 2.0 mmol) was mixed thoroughly. The reaction mixture was warmed at 100° C. for 0.5 h and then at 160° C. for 0.5 h. The reaction mixture was cooled to room temperature, and dissolved in saturated aqueous NaHCO3 (10 mL) and EtOAc (30 mL). The phases were separated, and the organic phase was washed with saturated aqueous NaHCO3 (10 mL), dried (MgSO4), filtered and concentrated in vacuo.
Reaction SMILES: CO[CH:3]=[C:4]1[C:9](=[O:10])[O:8][C:7]([CH3:12])([CH3:11])[O:6][C:5]1=[O:13].[NH2:14][C:15]1[CH2:20][CH:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:18][C:17](=[O:27])[CH:16]=1>C(#N)C>[CH3:12][C:7]1([CH3:11])[O:6][C:5](=[O:13])[C:4](=[CH:3][NH:14][C:15]2[CH2:20][CH:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:18][C:17](=[O:27])[CH:16]=2)[C:9](=[O:10])[O:8]1
Reactant: COC=C1C(=O)OC(C)(C)OC1=O
Reactant: NC1=CC(=O)CC(c2ccccc2)C1
Solvent: CC#N
Product: CC1(C)OC(=O)C(=CNC2=CC(=O)CC(c3ccccc3)C2)C(=O)O1
Temperature: 25 °C
Reaction time: 24 h
Yield: 36.4 %

Procedure:
To a solution of 5-methoxymethylene-2,2-dimethyl-[1,3]dioxane-4,6-dione (1.8 g) in acetonitrile (15 ml) was added 1-amino-5-phenylcyclohexen-3-one (2.0 g), and the mixture was stirred at room temperature for 24 hours. The resulting crystals were filtered and washed with acetonitrile to give crystals of 2,2-dimethyl-5-[(3-oxo-5-phenyl-1-cyclohexenylamino)methylene]-[1,3]dioxane-4,6-dione (1.2 g).
Reaction SMILES: C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.[Si:12]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]>C(Cl)Cl>[Si:12]([O:19][CH2:20][CH2:21][CH2:22][CH:23]=[O:24])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)OCCCCO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCCC=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 119.8 %

Procedure:
To a suspension of PCC (161.5 g, 0.75 mol) in DCM (1000 mL) was added 4-(tert-butyl dimethylsilyl oxy)butan-1-ol (102.0 g, 0.5 mol) in 500 mL of DCM, the mixture was stirred for about 1 hr at 0° C., then was warmed to RT and stirred for 2 hours. Then the mixture was filtered and the filtrate was concentrated in vacuo to give the desired compound of 4-(tert-butyldimethylsilyloxy)butanal (5) (121.2 g, yield 60%) as yellow oil which was purified by column chromatography on silica gel (eluent: PE:EA=50:1). 1H NMR (300 MHz, CDCl3): δ 0.04 (S, 6H), 0.0854 (S, 9H), 1.747 (m, 2H), 3.595 (d, J=12 Hz, 1H), 9.677 (d, J=3.3 Hz, 1H); LC-MC found 203 (M+H)+.
Reaction SMILES: O[CH2:2][N:3]1[C:7]([CH3:8])=[C:6]([N+:9]([O-:11])=[O:10])[C:5]([Cl:12])=[N:4]1.S(Cl)([Cl:15])=O>>[Cl:12][C:5]1[C:6]([N+:9]([O-:11])=[O:10])=[C:7]([CH3:8])[N:3]([CH2:2][Cl:15])[N:4]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1c([N+](=O)[O-])c(Cl)nn1CO
Product: Cc1c([N+](=O)[O-])c(Cl)nn1CCl

Procedure:
A mixture of 13.58 g (0.0708 mole) 1-hydroxymethyl-3-chloro-5-methyl-4-nitropyrazole and 30 ml of thionyl chloride was heated under reflux overnight and concentrated in vacuo. Benzene was added and the solution was concentrated again. This was replicated two more times. This left 15.8 g of an amber liquid. This was distilled at 155°-170° (air bath temperature)/1.25 mm to obtain a colorless liquid which crystallized upon standing. Recrystallization from benzene-Skelly B solvent gave 9.52 g of white crystals.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH:14][C@@H:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C@@H:16]1[NH2:21])=[O:13])=[CH:6]2.C(N(CC)CC)C.[S:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[S:34](Cl)(=[O:36])=[O:35].O>CN(C)C=O>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH:14][C@@H:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C@@H:16]1[NH:21][S:34]([C:30]1[S:29][CH:33]=[CH:32][CH:31]=1)(=[O:36])=[O:35])=[O:13])=[CH:6]2
Reactant: N[C@H]1CCCC[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Reactant: O=S(=O)(Cl)c1cccs1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(N[C@@H]1CCCC[C@@H]1NS(=O)(=O)c1cccs1)c1cc2cc(Cl)ccc2[nH]1
Reaction time: 1.25 h
Yield: 74.4 %

Procedure:
(±)-cis-N-[(5-Chloroindol-2-yl)carbonyl]-1,2-cyclohexanediamine hydrochloride (200 mg) was dissolved in N,N-dimethylformamide (1 ml), and triethylamine (0.28 ml) and 2-thiophenesulfonyl chloride (111 mg) were added to stir the mixture for 75 minutes. Water was added to the reaction mixture, and deposit was collected by filtration and recrystallized from methanol to obtain the title compound (198 mg) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.[CH2:15]([NH2:18])[CH2:16][CH3:17].C(N(C(C)C)CC)(C)C.O>CN1CCCC1=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:18][CH2:15][CH2:16][CH3:17])=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: CCCN
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: O
Product: CCCNc1c(C(N)=O)cnn2cc(Br)cc12
Temperature: 105 °C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
A mixture of 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (Preparation 5, 137 mg, 0.5 mmol), n-propylamine (123 mL, 1.500 mmol) and diisopropylethylamine (0.349 mL, 2.000 mmol) in N-methylpyrrolidinone (1.5 mL) was heated to 105° C. for 0.75 hr. After cooling to rt, water (15 ml) was added and the resulting suspension was stirred at rt for 1 hr. The suspension was filtered and the filter cake was dried. The filter cake was rinsed with hexane and dried to afford the title compound (120 mg, 0.382 mmol, 76% yield) as a tan solid. HPLC (condition M): retention time=2.56 min.; LCMS (ES+) m/z: 297.00/299.00; 1H NMR (400 MHz, MeOD) δ ppm 1.09 (t, J=7.4 Hz, 3 H), 1.72-1.83 (m, 2 H), 3.70 (t, J=6.9 Hz, 2 H), 7.01 (d, J=1.8 Hz, 1 H), 7.60 (d, J=1.8 Hz, 1 H), 8.09 (s, 1 H).
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[C:16]([C:22]([F:25])([F:24])[F:23])[CH:15]=1>>[N:1]1([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:14]3[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[C:16]([C:22]([F:23])([F:25])[F:24])[CH:15]=3)[CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCN(CC2CCNCC2)C1
Reactant: O=Cc1ccc(F)cc1C(F)(F)F
Product: O=Cc1ccc(N2CCC(CN3CCCC3)CC2)cc1C(F)(F)F

Procedure:
Prepared from the product of Example 4 and 4-fluoro-2-trifluoromethyl-benzaldehyde.