Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([S:13]([NH:16][CH2:17][CH2:18][O:19][CH3:20])(=[O:15])=[O:14])[CH:10]=[CH:11][CH:12]=2)[N:5]=[C:4]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:31]1([O:37][C:38](Cl)=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(OCC)(=O)C>C1COCC1>[C:31]1([O:37][C:38](=[O:39])[NH:1][C:2]2[N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([S:13](=[O:14])(=[O:15])[NH:16][CH2:17][CH2:18][O:19][CH3:20])[CH:8]=3)[N:5]=[C:4]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:3]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COCCNS(=O)(=O)c1cccc(-n2nc(C(C)(C)C)cc2N)c1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCCNS(=O)(=O)c1cccc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 70.3 %

Procedure:
To a mixture of 3-(5-amino-3-tert-butyl-pyrazol-1-yl)-N-(2-methoxyethyl)benzene sulfonamide (940 mg, 2.67 mmol) and solid sodium carbonate (493 mg, 5.87 mmol, 2.2 eq) in anhydrous THF was slowly added phenylchloroformate (0.40 mL, 3.20 mmol, 1.2 eq), and the reaction mixture was stirred at room temperature under nitrogen for 6 h. The reaction mixture was poured into ethyl acetate, and then the organic phase was separated and washed with water and brine, dried over Na2SO4, filtered, and concentrated at reduced pressure. Purification by MPLC (35% EtOAc/hexane) afforded the title compound (887 mg, 70%) as a white solid. 1H-NMR (CD3OD) δ 10.17 (broad s, 1H), 7.94 (t, J=1.5 Hz, 1H), 7.89 (t, J=6.0 Hz, 1H), 7.81 to 7.69 (m, 3H), 7.34 to 7.29 (m, 2H), 7.19 (t, J=7.2 Hz, 1H), 7.09 (broad s, 2H), 6.38 (s, 1H), 3.25 (t, J=6.0 Hz, 2H), 3.09 (s, 3H), 2.90 (broad s, 2H), 1.26 (s, 9H).
Reaction SMILES: C([O:4][C:5]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][C:8]([OH:15])=[C:7]([CH2:16][CH:17]=[CH2:18])[C:6]=1[C:19]([CH3:22])([CH3:21])[CH3:20])(=O)C.B(F)(F)F.O.[OH-].[Na+]>ClCCl>[C:19]([C:6]1[C:7]2[CH2:16][CH:17]([CH3:18])[O:15][C:8]=2[CH:9]=[C:10]([C:11]([CH3:14])([CH3:12])[CH3:13])[C:5]=1[OH:4])([CH3:20])([CH3:21])[CH3:22]
Reactant: C=CCc1c(O)cc(C(C)(C)C)c(OC(C)=O)c1C(C)(C)C
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC1Cc2c(cc(C(C)(C)C)c(O)c2C(C)(C)C)O1
Temperature: 25 °C
Reaction time: 24 h
Yield: 52 %

Procedure:
4-Acetoxy-3,5-di-tert-butyl-2-(2-propenyl)phenol (1.0 g, 3.3 mmol) was dissolved in dichloromethane (10 ml) and BF3 etherate (0.7 ml) was added dropwise to the solution under a nitrogen atmosphere. The mixture was stirred for 24 h at room temperature and, thereafter, water was added and the mixture was extracted with ethyl acetate. The extracted layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous magnesium sulfate and concentrated. The concentrate was dissolved in tetrahydrofuran (5 ml) and the solution was added dropwise to a suspension of lithium aluminum hydride (76 mg) in tetrahydrofuran (5 ml) that had been prepared under a nitrogen atmosphere. After refluxing for 3 h, the reaction mixture was cooled to room temperature and water was added dropwise. Following the addition of 1N aqueous sodium hydroxide, the mixture was subjected to extraction with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel chromatography (10% ethyl acetate in n-hexane) to afford 4,6-di-tert-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran [450 mg (yield, 52%)].
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH2:12]([O:14][C:15](=[O:18])[CH2:16][SH:17])[CH3:13].F[C:20]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:21]=1[CH:22]=O>C1COCC1.[NH4+].[Cl-].CCOC(C)=O>[F:29][C:28]([F:30])([F:31])[C:26]1[CH:27]=[CH:20][C:21]2[CH:22]=[C:16]([C:15]([O:14][CH2:12][CH3:13])=[O:18])[S:17][C:24]=2[CH:25]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1F
Reactant: CCOC(=O)CS
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2ccc(C(F)(F)F)cc2s1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene, 5 equiv) in THF (1 M) at 0° C. was added a solution of ethyl-2-mercaptoacetate (1.15 equiv) and the reaction stirred at 0° C. for 20 min. A solution of 2-fluoro4-(trifluoromethyl)benzaldehyde (1 equiv) in THF (2 M) was added and the reaction was stirred for an additional 2 h at 0° C. The reaction was diluted with half-saturated NH4Cl and EtOAc. The organic layer was washed with brine and dried over magnesium sulfate. The volatiles were removed under reduced pressure to obtain the title compound as a viscous oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[C:28]4[O:27][CH2:26][CH2:25][NH:24][CH2:23][C:22]=4[CH:21]=[CH:20][CH:19]=3)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:38][CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42]>CN(C)C=O.O>[Cl:2][C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[C:28]4[O:27][CH2:26][CH2:25][N:24]([CH2:38][CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:23][C:22]=4[CH:21]=[CH:20][CH:19]=3)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3OCCNC4)no2)cc1Cl
Reactant: CCOC(=O)CCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCN1CCOc2c(cccc2-c2noc(-c3ccc(OC(C)C)c(Cl)c3)n2)C1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of 9-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine hydrochloride (Example 31) (20 g, 47.4 mmol), potassium carbonate (16.4 g, 118 mmol) and potassium iodide (7.86 g, 47.4 mmol) in N,N-dimethylformamide (DMF) (250 ml) was treated with ethyl 4-bromobutanoate (7.46 ml, 52.1 mmol) and the resulting mixture stirred at 80° C. under nitrogen for 180 minutes. The mixture was allowed to cool and poured into water (1000 ml). The resulting precipitate was extracted into ethyl acetate (3×250 ml) and the extracts combined, washed with water (2×250 ml), then brine (150 ml), dried (sodium sulphate) and evaporated to give a colourless viscous oil. The crude material was purified by chromatography on silica, eluting with a 20-100% gradient of ethyl acetate in isohexane to give the title compound as a colourless, viscous oil which crystallised on standing (18.3 g).
Reaction SMILES: [OH:1][NH:2][C:3]([NH2:5])=[O:4].CO[CH:8](OC)[CH2:9][C:10](=O)[CH3:11].[ClH:15]>>[ClH:15].[CH3:11][C:10]1[N:5]=[C:3]([OH:4])[N+:2]([O-:1])=[CH:8][CH:9]=1
Reactant: COC(CC(C)=O)OC
Reactant: NC(=O)NO
Agent: Cl
Product: Cc1cc[n+]([O-])c(O)n1
Temperature: 2 °C

Procedure:
0.10 mol (7.61 g) hydroxy urea were dissolved in 150 ml of 1 M HCl and 0.11 mol (16.15 g, techn. 90%) of 4,4,-dimethoxy-2-butanone was added dropwise under ice cooling whereby the internal temperature was maintained at 1-3° C. The solution was thawed in an ice bath to room temperature and stirred over night, then filtered and evaporated to dryness. The residue was suspended with 100 ml of acetone, the mixture was cooled to −18° C., the solid filtered off and washed with a little ice-cold acetone. After drying, 10.7 g or crude product were obtained. The crude product was recrystallized with 1750 ml ethanol from the boiling heat, cooled in an ice/ethanol bath, filtered off, washed with a little ethanol and dried (fraction 1). The mother liquor was concentrated on a rotary evaporator until again product started to precipitate, cool stored and a second fraction isolated. After drying, 6.15 g (1. fraction) and 1.86 g (2. fraction) product was obtained. Both fractions were combined and recrystallized from the boiling heat with 230 ml 90% ethanol (10 (D/0 water) similarly. After drying, 3.75 g (3. fraction) and 2.36 g (4. fraction) of the title compound were obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@@H:10]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:9]2)=[N:6][C:5](Br)=[CH:4][N:3]=1.[CH3:29][C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([Sn](C)(C)C)[CH:37]=2)[NH:32][N:31]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[NH2:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@@H:10]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:9]2)=[N:6][C:5]([C:36]2[CH:37]=[C:38]3[C:33](=[CH:34][CH:35]=2)[NH:32][N:31]=[C:30]3[CH3:29])=[CH:4][N:3]=1
Reactant: Cc1n[nH]c2ccc([Sn](C)(C)C)cc12
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(Br)cnc2N)C[C@@H]1Cc1ccccc1
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1n[nH]c2ccc(-c3cnc(N)c(N4CCN(C(=O)OC(C)(C)C)[C@@H](Cc5ccccc5)C4)n3)cc12
Temperature: 120 °C
Yield: 70.9 %

Procedure:
To a solution of -amino-5-bromo-3-[(S)-4-Boc-3-benzylpiperazinyl]pyrazine 108 (100 mg, 0.223 mmol) and 3-methyl-5-trimethylstannanyl-1H-indazole 105 (66 mg, 0.223 mmol.) in DMF (3.5 mL) was added tris(dibenzylideneacetone)bipalladium (10 mg, 0.011 mmol), tri-o-tolylphosphine (7 mg, 0.023 mmol) and triethylamine (23 mg, 0.23 mmol). The reaction mixture was heated in a microwave reactor at 120° C. for 10 minutes. Ethyl acetate (100 mL) was added. The organic layer was washed with water and brine. The organic layer was dried over sodium sulfate and filtered through Celite. The organic solvent was evaporated under reduced pressure. The crude product was purified by RP-HPLC to yield the desired 2-amino-3-[(S)-4-Boc-3-benzylpiperazinyl]-5-(3-methyl-1H-indazol-5-yl)pyrazine 109 (79 mg, 0.158 mmol).
Reaction SMILES: [Cl:1][CH:2]([C:7]([CH3:9])=O)[C:3]([O:5][CH3:6])=[O:4].[S:10]([NH:20][NH2:21])([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)(=[O:12])=[O:11]>C1COCC1.CCOCC>[Cl:1][CH:2]([C:7](=[N:21][NH:20][S:10]([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)(=[O:11])=[O:12])[CH3:9])[C:3]([O:5][CH3:6])=[O:4]
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Reactant: COC(=O)C(Cl)C(C)=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)C(Cl)C(C)=NNS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 25 ml of methyl 2-chloroacetoacetate in 25 ml of THF was added dropwise over 30 minutes to a solution of 37.5 g of tosyl hydrazine in 150 ml of THF. The mixture was allowed to stand overnight, then heated at reflux for 2 hours, cooled to room temperature and stripped of solvent. The residue was then dissolved in 200 ml of ether. Crystallization occurred at room temperature. The collected solids were dried to give methyl 2-chloro-3-(tosylhydrazono)butanoate (7B), as a light yellow solid, m.p.: 97°-101° C.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:11][C@@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][C@@H:13]2[OH:21])=[N:5][C:6]([CH2:9]C)=[CH:7][N:8]=1)[CH3:2].Cl[C:23]1C(C2CC2)=NC=C(C)N=1>>[CH:1]1([C:3]2[C:4]([NH:11][C@@H:12]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH2:14][C@@H:13]3[OH:21])=[N:5][C:6]([CH3:9])=[CH:7][N:8]=2)[CH2:2][CH2:23]1
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Reactant: Cc1cnc(C2CC2)c(Cl)n1
Product: Cc1cnc(C2CC2)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 3-chloro-2-cyclopropyl-5-methylpyrazine and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 0.92-1.01, 1.25, 1.76, 2.36, 3.08, 3.24, 4.80, 5.38, 5.59, 7.22-7.49, 7.64; MS (ESI+) for C17H19N3O m/z 282 (M+H)+.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]([CH3:23])[C:12](=[O:22])[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[C:14]=1[F:21])(C(C)(C)C)(C)C.OC1C=C(C=C(O[C@@H](C)CO[Si](C(C)C)(C(C)C)C(C)C)C=1)C(NC1C=CN(C)N=1)=O.C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[Cl:20][C:15]1[C:14]([F:21])=[C:13]([CH:18]=[CH:17][C:16]=1[F:19])[C:12]([N:11]([CH2:10][CH2:9][OH:8])[CH3:23])=[O:22]
Reactant: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1ccc(F)c(Cl)c1F
Agent: CC(C)[Si](OC[C@H](C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1)(C(C)C)C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CN(CCO)C(=O)c1ccc(F)c(Cl)c1F
Temperature: 160 °C
Yield: 728.3 %

Procedure:
N-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-3-chloro-2,4-difluoro-N-methylbenzamide (100 mg, 0.275 mmol) was added to 3-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)-5-{(1S)-1-methyl-2-[(triisopropylsilyl)oxy]ethoxy}benzamide (123 mg, 0.275 mmol) and potassium carbonate (76 mg, 0.551 mmol) in dry dimethylacetamide. The mixture was heated in a Smith Creator microwave at 160° C. for 2 hours. Water (25 mL) was added to the reaction mixture and extracted with ethyl acetate (3×30 mL). The combined organic extracts were dried (MgSO4), filtered and evaporated. Purification by column chromatography on silica, eluting with 50-100% ethyl acetate in hexanes, gave the title compound as a pale yellow oil (500 mg). 1H NMR δ (CDCl3): 1.29 (d, 3H), 2.09 (t, 1H), 3.23 (s, 3H), 3.59 (t, 2H), 3.71-3.76 (m, 2H), 3.79 (s, 3H), 4.54 (t, 2H), 4.50-4.57 (m, 1H), 6.74 (t, 1H), 6.77 (d, 1H), 6.80 (d, 1H), 7.04 (t, 1H), 7.23 (t, 1H), 7.28 (d, 1H), 7.70 (d, 1H), 8.52 (s, 1H)
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]3[CH2:13][CH:12]3[N:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)=[CH:10][C:5]=2[CH2:4][O:3]1.Cl.O1CCOCC1>C(Cl)Cl>[N:14]1([CH:12]2[CH2:13][CH:11]2[C:9]2[CH:8]=[CH:7][C:6]3[C:2](=[O:1])[O:3][CH2:4][C:5]=3[CH:10]=2)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCN(C2CC2c2ccc3c(c2)COC3=O)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C1OCc2cc(C3CC3N3CCNCC3)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyl 4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)cyclopropyl]piperazine-1-carboxylate (30 mg, 0.08 mmol) in 5 mL of DCM was added 3 mL of 4N HCl/dioxane, and then the mixture was stirred at room temperature for 2 hours. The solvents was removed off under vacuum to afford 5-[2-(piperazin-1-yl)cyclopropyl]-2-benzofuran-1(3H)-one.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]2[O:17][CH2:16][CH2:15][N:14]([C@@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])[CH2:13]2)=[CH:8][CH:7]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:33][NH:34][CH3:35]>O1CCCC1.C(#N)C>[CH3:33][N:34]([CH3:35])[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]2[O:17][CH2:16][CH2:15][N:14]([C@@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])[CH2:13]2)=[CH:8][CH:7]=1)=[O:4]
Reactant: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(NC(=O)CCl)cc2)C1
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC#N
Product: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(NC(=O)CN(C)C)cc2)C1
Yield: 125.2 %

Procedure:
A solution of 2-chloro-N-((2S)-4-(((1R)-1-phenylethyl)morpholin-2-yl)phenyl)acetamide (0.9 g, 2.5 mmol), potassium carbonate (1.72 g, 12.5 mmol), and dimethylamine hydrochloride (1.00 g, 12.5 mmol) in tetrahydrofuran (40 ml) and acetonitrile (80 ml) was stirred at 95° C. for 10 hours. After filtration, the solvent was removed in vacuo and the residue was partitioned between water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure give N2,N2-dimethyl-N1-(4-((2S)-4-((1R)-1-phenylethyl)morpholin-2-yl)phenyl)glycinamide (1.15 g, quant.) as an yellow oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][O:12][C:13]3[C:22]4[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=4)[N:16]=[CH:15][CH:14]=3)=[N:9][N:10]=2)[N:7]=1.[CH3:25][C:26]([OH:30])([C:28]#[CH:29])[CH3:27].C(N(CC)CC)C.C(#N)C>[Cu]I>[CH3:24][O:23][C:19]1[CH:18]=[C:17]2[C:22]([C:13]([O:12][CH2:11][C:8]3[N:6]4[N:7]=[C:2]([C:29]#[C:28][C:26]([CH3:27])([OH:30])[CH3:25])[CH:3]=[CH:4][C:5]4=[N:10][N:9]=3)=[CH:14][CH:15]=[N:16]2)=[CH:21][CH:20]=1
Reactant: COc1ccc2c(OCc3nnc4ccc(Cl)nn34)ccnc2c1
Reactant: C#CC(C)(C)O
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc2c(OCc3nnc4ccc(C#CC(C)(C)O)nn34)ccnc2c1
Temperature: 90 °C
Yield: 51.3 %

Procedure:
A 25×200 mm test tube was charged with 4-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)-7-methoxyquinoline (0.150 g, 0.439 mmol), 2-methylbut-3-yn-2-ol (0.213 ml, 2.19 mmol), copper (I) iodide (0.0209 g, 0.110 mmol), triethylamine (1.83 ml, 13.2 mmol), and acetonitrile (5.00 ml, 96.2 mmol), flushed with argon, sealed, and placed in a 90° C. oil bath for 30 minutes. PdCl2(dppf)-CH2Cl2Adduct (0.0358 g, 0.0439 mmol) was added in one portion, the tube flushed with argon, sealed, then heated in a 90° C. oil bath for 4 hours. The reaction mixture was filtered thru a pad of silica gel (eluting with EtOAc/DCM/MeOH), then concentrated to yield a dark brown oil. This was purified by MPLC, using a 40 g RediSep column, eluting with 1-7% MeOH/DCM over 40 minutes. The appropriate fractions were collected to give 4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-2-methylbut-3-yn-2-ol (0.0877 g, 51.3% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:16])=[C:9]([C:11]([O:13]CC)=[O:12])[N:10]=2)[N:7]=1.[OH-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:16])=[C:9]([C:11]([OH:13])=[O:12])[N:10]=2)[N:7]=1
Reactant: CCOC(=O)c1nc2ccc(Cl)nn2c1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)nc2ccc(Cl)nn12
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.1 %

Procedure:
3.9 g of ethyl 6-chloro-3-methylimidazo[1,2-b]pyridazine-2-carboxylate was suspended in 40 ml of tetrahydrofuran; 30 ml of a 1 N aqueous solution of sodium hydroxide was added, followed by stirring at room temperature for 3 hours. The mixture was concentrated under reduced pressure; the residue was ajusted to pH 4 by the addition of 50 ml of water and 1 N hydrochloric acid; the crystal precipitated was collected by filtration and dried to yield 2.55 g of 6-chloro-3-methylimidazo[1,2-b]pyridazine-2-carboxylic acid. 1.27 g of this carboxylic acid was dissolved in 20 ml of N,N-dimethylformamide; 1.07 g of N,N′-carbonyldiimidazole was added, followed by stirring at room temperature for 30 minutes. To this mixture, 0.922 g of glycine ethyl ester hydrochloride and 0.915 ml of triethylamine were added, followed by further stirring for 3 hours. 60 ml of ice water was added to the reaction mixture; the crystal precipitated was collected by filtration, washed with water and dried to yield 1.18 g of the title compound.
Reaction SMILES: [CH3:1]NCCNC.C[Al](C)C.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[N:22]([C:23]2[CH:24]=[N:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([S:35]([CH3:38])(=[O:37])=[O:36])[CH:30]=3)=[CH:27][CH:28]=2)[N:21]=[C:20]([C:39](OC)=[O:40])[CH:19]=1>C1(C)C=CC=CC=1>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[N:22]([C:23]2[CH:24]=[N:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([S:35]([CH3:38])(=[O:37])=[O:36])[CH:30]=3)=[CH:27][CH:28]=2)[N:21]=[C:20]([C:39](=[O:40])[CH3:1])[CH:19]=1
Reactant: COC(=O)c1cc(-c2ccccc2Cl)n(-c2ccc(-c3cccc(S(C)(=O)=O)c3)nc2)n1
Reactant: CNCCNC
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC(=O)c1cc(-c2ccccc2Cl)n(-c2ccc(-c3cccc(S(C)(=O)=O)c3)nc2)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 22.1 %

Procedure:
To a stirred solution of N,N′-dimethylethylenediamine (56 μL, 0.52 mmol) in toluene (3 mL, anhyd) at 0° C. was added dropwise a 2.0M solution of trimethylaluminum in hexanes (0.75 mL, 1.5 mmol). After addition was complete the flask was removed from the ice-water bath and allowed to warm to ambient temperature. After 50 min the reaction mixture was charged slowly with a solution of methyl 5-(2-chlorophenyl)-1-{6-[3-(methylsulfonyl)phenyl]pyridin-3-yl}-1H-pyrazole-3-carboxylate (0.22 g, 0.47 mmol) in toluene (3 mL, anhyd) and then heated at reflux. After 90 min the reaction mixture was allowed to cool to ambient temperature and quenched by addition of 1N HCl. The resulting mixture was extracted with EtOAc (2×50 mL). The combined extracts were washed with brine, dried (Na2SO4), concentrated and purified by chromatography (silica, EtOAc/Hex, 30:70 to 60:40) to yield the title compound (47 mg, 22%) as a white solid. 1H-NMR (DCM-d2): δ 8.65 (m, 1H), 8.57 (m, 1H), 8.30 (m, 1H), 7.99 (m, 1H), 7.79-7.87 (m, 2H), 7.71 (m, 1H), 7.36-7.47 (m, 4H), 7.02 (s, 1H), 3.09 (s, 3H), 2.68 (s, 3H); MS(ES): 452 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7](=[O:14])[N:6]([CH3:15])[C:5]2[CH:16]=[CH:17][C:18](OS(C(F)(F)F)(=O)=O)=[N:19][C:4]1=2)[CH3:2].[CH3:28][N:29]1[CH:33]=[C:32](I)[CH:31]=[N:30]1>>[CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7](=[O:14])[N:6]([CH3:15])[C:5]2[CH:16]=[CH:17][C:18]([C:32]3[CH:31]=[N:30][N:29]([CH3:28])[CH:33]=3)=[N:19][C:4]1=2)[CH3:2]
Reactant: CCN1c2ncccc2C(=O)N(C)c2ccc(OS(=O)(=O)C(F)(F)F)nc21
Reactant: Cn1cc(I)cn1
Product: CCN1c2ncccc2C(=O)N(C)c2ccc(-c3cnn(C)c3)nc21

Procedure:
The title compound (mp 65°-67° C.) was prepared from 5,11-dihydro-11-ethyl-5-methyl-2-trifluoromethanesulfonyloxy-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one and N-methyl-4-iodopyrazole in a manner analogous to that described in Example 1.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[C@H:10]([C@H:23]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH3:24])[CH2:11][N:12]1C(=O)C2=CC=CC=C2C1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>C(O)C>[CH2:1]([O:8][C:9](=[O:33])[C@H:10]([C@H:23]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH3:24])[CH2:11][NH2:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](CN1C(=O)c2ccccc2C1=O)C(=O)OCc1ccccc1
Agent: NN
Solvent: CCO
Solvent: O
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](CN)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 79.4 %

Procedure:
A mixture of (2S)-3-phthalimido-2-((1R)-1-tert-butyldimethylsilyloxyethyl)propionic acid benzyl ester (1.12 g), hydrazine monohydrate (612 mg) and ethanol (20 ml) was stirred at 25° C. for 17 hr. The reactant crystals were filtered off and the filtrate was evaporated. The residue was suspended in hexane and filtered. The filtrate was evaporated, and the residue was purified by silica-gel column chromatography (chloroform:methanol=40:1) to afford 642.2 mg of (2S)-3-amino-2-((1R)-1-tert-butyldimethylsilyloxyethyl)propionic acid benzyl ester in colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[C:15]([N+]([O-])=O)[CH:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl.[CH3:26][O:27][NH2:28]>>[N+:19]([C:16]1[CH:17]=[CH:18][C:13]([O:12][C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:10])([F:11])[F:9])=[CH:5][N:4]=2)=[CH:14][C:15]=1[CH2:26][O:27][NH2:28])([O-:21])=[O:20]
Reactant: CON
Reactant: O=[N+]([O-])c1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1[N+](=O)[O-]
Agent: Cl
Product: NOCc1cc(Oc2ncc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
Following the procedure of Example 29, 4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)-1,2-dinitrobenzene and methoxyamine hydrochloride are reacted together to give N-[2-nitro-5-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenyl]methoxyamine (XV; R'=H). ##STR29##