Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([C:35]4[CH2:36][CH2:37][N:38](C(OC(C)(C)C)=O)[CH2:39][CH:40]=4)=[C:28]4[C:32]=3[C:31](=[O:33])[N:30]([CH3:34])[CH2:29]4)[C:20]([C:48]([F:51])([F:50])[F:49])=[CH:19][N:18]=2)=[CH:12][CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:7]([O:6][P:4]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([C:35]4[CH2:36][CH2:37][NH:38][CH2:39][CH:40]=4)=[C:28]4[C:32]=3[C:31](=[O:33])[N:30]([CH3:34])[CH2:29]4)[C:20]([C:48]([F:50])([F:51])[F:49])=[CH:19][N:18]=2)=[CH:14][CH:15]=1)(=[O:5])[O:3][CH2:1][CH3:2])[CH3:8]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(C4=CCN(C(=O)OC(C)(C)C)CC4)c4c3C(=O)N(C)C4)n2)cc1)OCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(C4=CCNCC4)c4c3C(=O)N(C)C4)n2)cc1)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To tert-butyl 4-(7-{[2-({4-[(diethoxyphosphoryl)methyl]phenyl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino}-2-methyl-1-oxo-2,3-dihydro-1H-isoindol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (Compound 246A, 180 mg, 0.25 mmol) was added methylene chloride (1 mL) and trifluoroacetic acid (1 mL). The mixture was stirred at room temperature for 1 hour, after which, the reaction mixture was concentrated and purified by MDP. 1H NMR (400 MHz, methanol-d4) δ=1.27 (t, J=6.9 Hz, 6H), 2.77-2.85 (m, 2H), 3.19 (s, 3H), 3.29 (d, J=21.5 Hz, 2H), 3.50 (t, J=6.1 Hz, 2H), 3.88-3.94 (m, 2H), 4.01-4.17 (m, 4H), 4.59 (s, 2H), 6.02 (dt, J=3.3, 1.7 Hz, 1H), 7.35 (dd, J=8.5, 2.4 Hz, 2H), 7.50 (d, J=8.8 Hz, 1H), 7.57 (d, J=8.1 Hz, 2H), 8.35-8.43 (m, 1H), 8.72 (br. s., 1H). MS (ES+): m/z 631.23 (100) [MH+]; HPLC: tR=0.68 min (UPLC, purity).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[O:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26]Cl)[CH:21]=1>>[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][N:7]2[C:8]([O:9][C:10]3[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=3)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]2=[O:18])[CH:21]=1
Reactant: CCc1c(Oc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: ClCc1cccnc1
Product: CCc1c(Oc2cc(C)cc(C)c2)n(Cc2cccnc2)c(=O)[nH]c1=O
Yield: 28.7 %

Procedure:
5-ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 3-picolyl chloride were reacted by the same way with the example 1 to obtain the titled compound (101 mg, yield: 28.7%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7].C(N(CC)CC)C.O>ClCCl>[CH:6]([N:8]1[CH2:13][CH2:12][N:11]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:10][CH2:9]1)=[O:7]
Reactant: CS(=O)(=O)Cl
Reactant: O=CN1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)N1CCN(C=O)CC1

Procedure:
3.5 mL of methane sulfonylchloride in 50 mL of dichloromethane was added slowly to a solution of 4.9 g of 1-formylpiperazine and 6.1 mL of triethylamine in 100 mL of dichloromethane at 0° C. After stirring for 1 hour water was added and the organic layer was separated. The aqueous layer was extracted several times with dichloromethane. The combined organic layers were dried (MgSO4) and concentrated to yield 5.8 g of 1-formyl-4-(methylsulfonyl)piperazine. The crude product was dissolved in 15 ml of ethanol and 15 mL of aqueous 2N NaOH and stirred for 1.5 hours at 80° C. After cooling to room temperature water was added and extracted several times with dichloromethane. The combine organic layers were dried (MgSO4) and concentrated to give 2.9 g of the title compound 14b. 1H-NMR 200 MHz (DMSOd6) δ: 2.70-2.77 (4H, m), 2.83 (3H, s), 2.95-3.02 (4H, m).
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-:4])[CH3:3].[Na+].[Cl:7][CH2:8][C:9]([CH3:14])([CH3:13])[C:10](Cl)=[O:11]>C1(C)C=CC=CC=1>[Cl:7][CH2:8][C:9]([CH3:14])([CH3:13])[C:10]([O:4][C:2]([CH3:5])([CH3:3])[CH3:1])=[O:11]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(CCl)C(=O)Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)C(C)(C)CCl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A slurry of sodium tert-butoxide (195.3 g, 2.03 mol) in 800 mL of dry toluene was cooled to 0° C. in an ice bath. To the stirred slurry was added 3-chloropivaloyl chloride (XIII) (300.0 g 1.94 mol) dropwise at a rate sufficient to maintain the reaction temperature below 10° C. After the addition was complete, the reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched with water, the mixture extracted with ether, and the ether layer washed with water and saturated NaHCO3. After drying over MgSO4, the solution was filtered and concentrated to give the product as an amber oil. 1H NMR (CDCl3) δ 1.24 (s,6H), 1.46 (s,9H), 3.57 (s,2H); 13C NMR (CDCl3) δ 22.96, 27.70, 44.80, 53.32, 80.87, 174.5.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=2)[CH:6]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[CH:6]=1
Reactant: O=[N+]([O-])c1ccc(-n2cc(Cl)cn2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(-n2cc(Cl)cn2)cc1

Procedure:
Iron powder (0.75 g, 13.5 mmol) is added to a mixture of 4-chloro-1-(4-nitrophenyl)pyrazole (0.61 g, 2.7 mmol) and ammonium chloride (1.46 g, 27.0 mmol) in 45 ml ethanol and 16 ml water at 65°-70° over a period of 45 min. The reaction mixture is filtered and the solid is washed with ethyl acetate. Solvent is removed from the filtrate and the residue is taken into ethyl acetate, washed with water and with brine and dried to give 4-(4-chloro-1-pyrazolyl)aniline.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([OH:11])=[O:10])=[N:7][CH:8]=1.[CH3:12]O>>[CH3:12][O:10][C:9]([C:6]1[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][N:7]=1)=[O:11]
Reactant: O=C(O)c1ccc(O)cn1
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc(O)cn1
Reaction time: 48 h
Yield: 70 %

Procedure:
Gaseous hydrogen chloride was passed through a solution of 5 g of dry 5-hydroxy-2-pyridinecarboxylic acid in 100 ml methanol for 5 hours at 70° C. The mixture was kept for 2 days at room temperature and the solvent removed in vacuo. The residue was taken up in a minimum amount of water and neutralized with ammonium hydroxide. The precipitate was removed by filtration and the ester was separated in 70% yield from the acid by recrystallizing from isopropyl alcohol; m.p. 188°-190°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:39])[CH:5]=[C:6]([Cl:38])[C:7]=1[CH2:8][C@H:9]([O:20][C:21](=[O:37])[C:22]1[CH:27]=[CH:26][C:25]([NH:28]C(OC(C)(C)C)=O)=[CH:24][C:23]=1[F:36])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1.Cl.O1CCOCC1>>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:39])[CH:5]=[C:6]([Cl:38])[C:7]=1[CH2:8][C@H:9]([O:20][C:21](=[O:37])[C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][C:23]=1[F:36])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1
Reactant: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2ccc(NC(=O)OC(C)(C)C)cc2F)cc1OC
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2ccc(N)cc2F)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.7 %

Procedure:
[(1S)-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl]-4-(tert-butoxycarbonylamino)-2-fluorobenzoate (0.690 g, 1.19 mmol) was stirred in a 4N HCl in 1,4-dioxane solution (14.8 mL, 5.94 mmol). The reaction was stirred at room temperature for 3 hours. The solvent was removed in vacuo. The residue was purified by silica gel chromatography eluting sequentially with iso-hexane and 10% methanol in ethyl acetate to afford the title compound as a beige solid (0.451 g, 79%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[N:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].C(=O)(O)[O-].[Na+]>CO.O1CCCC1.[Cl-].[Na+].O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NN=C1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Cl-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NNC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 60 °C
Yield: 99.3 %

Procedure:
A solution of 4-(tert-butoxycarbonyl-hydrazono)-piperidine-1-carboxylic acid tert-butyl ester (from Step 1; 12.0 g, 38.3 mmol) in methanol (60 mL) and tetrahydrofuran (120 mL) was cooled to 0° C. Sodium borohydride (9.0 g, 238 mmol) was added slowly in three portions in 15-30 min intervals. The reaction mixture was heated to 60° C. for 2 h and then cooled to room temperature. A solution of 20% brine (90.0 mL) and 10% sodium bicarbonate (200 mL) were slowly added to the stirred reaction mixture. The organic layer was separated and the aqueous layer was extracted with methyl tert-butyl ether (2×50 mL). The combined organic layers were washed with brine (3×50 mL) and concentrated. To the residue was added acetonitrile (15 mL). The mixture was concentrated again to remove trace amounts of water, to give 4-(tert-butoxycarbonyl-hydrazino)-piperidine-1-carboxylic acid tert-butyl ester (12.0 g, 99%) as a white solid. 1H NMR (CDCl3) δ 1.27 (m, 2H), 1.44 (s, 18H), 1.76 (m, 2H), 2.84 (t, 2H, J=11.7 Hz), 3.00 (m, 1H), 3.95 (m, 3H), 6.03 (br, 1H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[CH3:21][O:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:7]([NH:6][C:4]([CH2:3][NH:2][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)=[O:5])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Agent: Cl
Product: COc1ccc(C(=O)NCC(=O)NC(c2ccccc2)c2ccc(Cl)cc2)cc1

Procedure:
Prepared in analogy to example 1.13 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and 4-methoxybenzoyl chloride.
Reaction SMILES: [C:1]([O:4][CH2:5][O:6][C:7]1[C:8]([C:15]([NH:17][C@H:18]2[CH2:26][O:25][C:24](=[O:27])[C@H:23]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C@@H:22]([O:35][CH2:36][C:37]([CH3:39])=[CH2:38])[C@H:21]([CH3:40])[O:20][C:19]2=[O:41])=[O:16])=[N:9][CH:10]=[CH:11][C:12]=1[O:13][CH3:14])(=[O:3])[CH3:2].[H][H]>[Pd].C(OCC)(=O)C>[C:1]([O:4][CH2:5][O:6][C:7]1[C:8]([C:15]([NH:17][C@H:18]2[CH2:26][O:25][C:24](=[O:27])[C@H:23]([CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C@@H:22]([O:35][CH2:36][CH:37]([CH3:38])[CH3:39])[C@H:21]([CH3:40])[O:20][C:19]2=[O:41])=[O:16])=[N:9][CH:10]=[CH:11][C:12]=1[O:13][CH3:14])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: C=C(C)CO[C@H]1[C@H](C)OC(=O)[C@@H](NC(=O)c2nccc(OC)c2OCOC(C)=O)COC(=O)[C@@H]1Cc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccnc(C(=O)N[C@H]2COC(=O)[C@H](Cc3ccccc3)[C@@H](OCC(C)C)[C@H](C)OC2=O)c1OCOC(C)=O
Yield: 95 %

Procedure:
Compound 12 was prepared in 95% yield using Compound 6 (6.0 g, 10.5 mmol) with 10% palladium on charcoal (1.2 g) and hydrogen (40 psi) in ethyl acetate (150 mL) for 1.5 hour. Recrystallization from a mixture of hot methylcyclohexane and toluene (4:1) gave 5.7 g of white needles: m.p.134-136° C. Spectral data were consistent with the assigned structure.
Reaction SMILES: [CH3:1][C:2]1[CH:3]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]2([CH2:9][CH2:10][CH:11]=1)[CH2:8][CH2:7][CH2:6][CH2:5]2.CC1CCCC2(CCCC2)C=1C(OC)=O.CC1C(C(OC)=O)C2(CCC=1)CCCC2.CC12OC1CCC1(CCCC1)C2C(OCC)=O.OC1CCC2(CCCC2)C(C(OCC)=O)=C1C.C([SiH](CC)CC)C.B(F)(F)F.CCOCC>ClCCl>[CH3:1][C:2]1[CH2:11][CH2:10][CH2:9][C:4]2([CH2:8][CH2:7][CH2:6][CH2:5]2)[C:3]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C1C(C)=CCCC12CCCC2
Agent: CCOC(=O)C1=C(C)C(O)CCC12CCCC2
Agent: CCOC(=O)C1C2(CCCC2)CCC2OC21C
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)C1=C(C)CCCC12CCCC2

Procedure:
Prepared from ethyl 7-methylspiro[4.5]dec-7-ene-6-carboxylate (prepared as described in Example 14), as described for the preparation of methyl 7-methylspiro[4.5]dec-6-ene-6-carboxylate from methyl 7-methylspiro[4.5]dec-7-ene-6-carboxylate (Example 26), via crude ethyl 1-methyl-7-oxaspiro[bicyclo[4.1.0]heptane-3,1′-cyclopentane]-2-carboxylate (MCPBA, CH2Cl2), transformed into crude ethyl 8-hydroxy-7-methylspiro[4.5]dec-6-ene-6-carboxylate (NaOEt, reflux, 4 h) that was reduced using triethylsilane and BF3.OEt2 in dichloromethane (64% overall yield after FC (400 g SiO2, hexane/MTBE 40:1)).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][C:23]([OH:29])=[CH:24][CH:25]=3)[CH2:20]2)[CH2:16][CH2:17][CH3:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:37][C:38]([F:44])([F:43])[S:39](Cl)(=[O:41])=[O:40].O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][N:15]([CH2:16][CH2:17][CH3:18])[CH:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][C:23]([O:29][S:39]([C:38]([F:44])([F:43])[F:37])(=[O:41])=[O:40])=[CH:24][CH:25]=3)[CH2:20]2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: CCCN(CC1CCN(C(=O)OC(C)(C)C)CC1)C1CCc2ccc(O)cc2C1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCCN(CC1CCN(C(=O)OC(C)(C)C)CC1)C1CCc2ccc(OS(=O)(=O)C(F)(F)F)cc2C1
Temperature: 0 °C
Yield: 54.9 %

Procedure:
To an ice cold solution of 4-{[(7-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester (300 mg, 0.75 mmol) in methylene chloride (30 mL) under a nitrogen atmosphere was added triethylamine (0.16 ml, 1.125 mmol) followed by trifluoromethanesulfonyl chloride (0.08 ml, 0.78 mmol). The reaction was stirred in the ice bath for 30 min. and then added to water (60 ml). The organic layer was separated, dried over MgSO4, filtered, and concentrated. Chromatography with 40% acetone in hexanes affords 4-{[propyl-(7-trifluoromethanesulfonyloxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-amino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester (220 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([N:22]3[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]3)=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[ClH:35]>C1COCC1.C(OCC)C>[ClH:35].[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)c3ccccc23)cc1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)Nc2ccc(N3CCNCC3)c3ccccc23)cc1

Procedure:
1-tert-Butyl 4-(4-{[(4-methylphenyl)sulfonyl]amino}-1-naphthyl)-1-piperazinecarboxylate (intermediate 10) (0.4 g, 0.8 mmol) was dissolved in THF (20 mL) and treated with a 1N solution of HCl in diethyl ether (30 mL) for twelve hours. The product was collected as a pale pink solid. Yield 0.2 g (60%). mp 181° C. (dec); 1H NMR (DMSO-d6) δ 2.80 (s, 3H), 3.1 (br, 4H), 3.3 (br, 4H), 7.00 (q, J=8.06 Hz, 2H), 7.27 (ab, J=8.30 Hz, 2 H), 7.4-7.5 (m, 2H), 7.53 (ab, J=8.30 Hz, 2H), 7.99 (d, J=8.06 Hz, 1H), 8.07 (d, J=7.57 Hz, 1H), 9.2 (br, 2H); MS (ESI+) for C21 H23 N3 O2 S Found m/z 381.1499. M+ Calc. 381.1611.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:9](=[O:10])[O:8][C:7]2([C:13]1[N:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[N:14]=1)[OH:12].[C:23](OC(=O)C)(=[O:25])[CH3:24].Cl>N1C=CC=CC=1>[C:23]([O:12][C:7]1([C:13]2[N:14]=[C:15]([O:21][CH3:22])[CH:16]=[C:17]([O:19][CH3:20])[N:18]=2)[C:6]2[C:11](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=2)[C:9](=[O:10])[O:8]1)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(OC)nc(C2(O)OC(=O)c3c(Cl)cccc32)n1
Agent: Cl
Solvent: c1ccncc1
Product: COc1cc(OC)nc(C2(OC(C)=O)OC(=O)c3c(Cl)cccc32)n1

Procedure:
1.1 g of 7-chloro-3-(4,6-dimethoxy-2-pyrimidinyl)-3-hydroxy-phthalide is dissolved in 20 ml of pyridine and 0.3 ml of acetic anhydride added with stirring. After stirring for 20 min the mixture is poured into 2N HCl and extracted with two portions of ethyl acetate. The combined ethyl acetate extracts are washed once with 2N HCl, once with H2O and once with brine and dried over magnesium sulfate. Filtration and evaporation produced the title compound as a white solid, m.p. 213°-215°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21](O)=[O:22])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[S:24]([C:28]1[CH:29]=[C:30]([NH2:34])[CH:31]=[CH:32][CH:33]=1)(=[O:27])(=[O:26])[NH2:25]>>[S:24]([C:28]1[CH:29]=[C:30]([NH:34][C:21]([C:20]2[CH:19]=[N:18][N:11]3[C:12]([C:14]([F:17])([F:16])[F:15])=[CH:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[N:9][C:10]=23)=[O:22])[CH:31]=[CH:32][CH:33]=1)(=[O:26])(=[O:27])[NH2:25]
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)cc3)nc12
Product: NS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(Cl)cc4)nc23)c1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.4) and 3-sulfamoyl-phenylamine [commercially available] according to general procedure II. Yellow solid. MS (ISP) 494.0 [(M−H)−]; mp 260° C.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:11][OH:12])[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][OH:10])[CH:4]=1.[C:13]([Si:17](Cl)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:16])([CH3:15])[CH3:14].O>C1COCC1>[Si:17]([O:10][CH2:9][C:5]1[CH:4]=[C:3]([CH2:11][OH:12])[CH:8]=[CH:7][CH:6]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCc1cccc(CO)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](OCc1cccc(CO)c1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 52.8 %

Procedure:
Under a nitrogen atmosphere, to a suspension of 60% sodium hydride (1.40 g) in THF (70 mL) was slowly added 1,3-phenylenedimethanol (4.84 g) at 0° C., and the mixture was stirred at 0° C. for 1 hr. tert-Butylchlorodiphenylsilane (9.63 g) was added, and the mixture was stirred at room temperature for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (6.97 g) as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].Cl.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18]Cl)[CH:13]=1>CN(C)C=O>[N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:18][C:14]2[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=2)[N:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc[nH]n1
Reactant: ClCc1cccnc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccn(Cc2cccnc2)n1
Reaction time: 1.5 h
Yield: 55.8 %

Procedure:
3-Nitro-1H-pyrazole (prepared as in Example 15, 113 mg, 1.00 mmol) was dissolved in N,N-dimethylformamide (5 mL) and cooled in an ice bath. A 60% suspension of sodium hydride in mineral oil (88 mg, 2.2 mmol) was added in portions and the cooling bath was removed. After stirring 1.5 h, a mixture of 3-picolyl chloride hydrochloride (164 mg, 1.00 mmol) in N,N-dimethylformamide (1 mL) was added. The reaction mixture was stirred 65 h, then evaporated in vacuo. The residue was treated with saturated aqueous sodium bicarbonate solution (1 mL) and extracted with chloroform (2×3 mL). The combined organic phases were dried over sodium sulfate and evaporated in vacuo. The residue was stirred in ethyl acetate (50 mL) and filtered. The filtrate was evaporated in vacuo and the remaining material was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; (50% ethyl acetate/hexanes to 100% ethyl acetate) to afford 3-(3-nitro-pyrazol-1-ylmethyl)-pyridine (114 mg, 56%) as a clear, faintly yellow oil which began to solidify over time: LC-MS (ESI) m/e calcd for C9H8N4O2 [M+] 204.06, found 205 [M+H+].
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=2[O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:11](Cl)=[O:12])[C:5]2[CH:24]=[CH:25][NH:26][C:4]=2[C:3]1=[O:27].[CH2:28]([NH2:30])[CH3:29]>O1CCCC1>[CH2:28]([NH:30][C:11](=[O:12])[C:10]1[CH:14]=[CH:15][C:16]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:8]([C:6]2[C:5]3[CH:24]=[CH:25][NH:26][C:4]=3[C:3](=[O:27])[N:2]([CH3:1])[CH:7]=2)[CH:9]=1)[CH3:29]
Reactant: CCN
Reactant: Cn1cc(-c2cc(C(=O)Cl)ccc2Oc2ccccc2)c2cc[nH]c2c1=O
Solvent: C1CCOC1
Product: CCNC(=O)c1ccc(Oc2ccccc2)c(-c2cn(C)c(=O)c3[nH]ccc23)c1
Yield: 61 %

Procedure:
A solution of Example 13a (0.040 g, 0.11 mmol) in tetrahydrofuran (1 mL) was treated with ethylamine (0.21 mL of a 2 M solution in tetrahydrofuran, 0.42 mmol) for 2 h. The reaction mixture was concentrated and the residue purified by preparative HPLC (C18, 10-90% acetonitrile in 0.1% TFA in water) to afford the title compound (0.025 g, 61%). 1H NMR (500 MHz, DMSO-d6) δ 1.12 (t, J=7.32 Hz, 3H), 3.25-3.32 (m, 2H), 3.54 (s, 3H), 6.23-6.24 (m, 1H), 6.95-6.99 (m, 3H), 7.11 (t, J=7.48 Hz, 1H), 7.27 (t, J=2.75 Hz, 1H), 7.31-7.37 (m, 3H), 7.84 (dd, J=8.54, 2.44 Hz, 1H), 7.98 (d, J=2.44 Hz, 1H), 8.46 (t, J=5.49 Hz, 1H), 11.99 (s, 1H). MS (ESI+) m/z 388.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12]C)=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[N:6]=[CH:5]2.B(Br)(Br)Br.[OH-].[NH4+]>C(Cl)Cl.ClCCCl.CO.[Cl-].[NH4+]>[Br:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:11])[N:6]=[CH:5][C:4]=2[C:3]=1[OH:12]
Reactant: COc1c(Br)ccc2c1cnn2C
Agent: BrB(Br)Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: ClCCl
Solvent: ClCCCl
Product: Cn1ncc2c(O)c(Br)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.1 %

Procedure:
A solution of 5-bromo-4-methoxy-1-methyl-1H-indazole (86.1 mg, 0.357 mmol) in methylene chloride (1.74 mL) was treated with boron tribromide (0.0405 mL, 0.428 mmol) at 0° C. The reaction mixture was warmed to RT and stirred at RT for 16 h, after which time the reaction mixture was cooled to 0° C., treated with additional boron tribromide (0.0405 mL, 0.428 mmol), warmed to RT and stirred at RT for 1.5 h. The reaction mixture was cooled to 0° C., treated with more boron tribromide (0.0405 mL, 0.428 mmol), and stirred for 2 h. The reaction mixture was then cooled to 0° C. and quenched carefully with saturated sodium bicarbonate (30 mL) and extracted with dichloromethane (2×30 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to yield a crude mixture. This mixture was re-subjected to the initial reaction conditions. The crude mixture was suspended in 1,2-dichloroethane (1.74 mL), cooled to 0° C., treated with boron tribromide (0.0810 mL, 0.857 mmol), warmed to RT and stirred at RT for 2 h. The reaction mixture was cooled to 0° C. and quenched carefully with saturated solution of sodium bicarbonate (30 mL) and extracted with dichloromethane (2×30 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give the crude product. This material was diluted with methanol (2.0 mL), treated with ammonium hydroxide (0.278 mL, 7.14 mmol), and stirred for 15 min. The resultant suspension was diluted with saturated ammonium chloride (30 mL) and extracted with dichloromethane (2×30 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to give the desired product (73 mg, 90%) as a yellow solid. LCMS calculated for C8H8BrN2O (M+H)+: m/z=227.0, 229.0. found: 226.9, 228.9.