Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:8][Si:9]([C:12]#[C:13][Si](C)(C)C)([CH3:11])[CH3:10].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[CH3:8][Si:9]([C:12]#[C:13][C:1]([CH2:2][CH2:3][CH2:4][CH3:5])=[O:6])([CH3:11])[CH3:10]
Reactant: C[Si](C)(C)C#C[Si](C)(C)C
Reactant: CCCCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCC(=O)C#C[Si](C)(C)C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 14.4 g. of valeryl chloride and 20.4 g. of bis-trimethylsilylacetylene in 300 ml. of dry methylene chloride, cooled in an ice bath, is added powdered anhydrous aluminum chloride, portionwise, over a period of 20 minutes. The mixture is stirred for 5 minutes, then the cooling bath is removed and the mixture is stirred at room temperature for 4 l hours. The mixture is poured into 500 ml. of ice-water. The organic layer is separated, washed with water and brine, dried over anhydrous sodium sulfate and filtered through diatomaceous earth. The mother liquor is evaporated to dryness giving a brownish residue. This residue is Kugelrohr-distilled to give 16.56 g. of colorless liquid at 45° C./0.3 mm which is essentially identical with the authentic product.
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH:13]1([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH2:16][CH2:15][CH2:14]1>CC(N(C)C)=O>[CH:13]1([N:17]2[CH2:22][CH2:21][N:20]([C:2]3[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=3)[CH2:19][CH2:18]2)[CH2:16][CH2:15][CH2:14]1
Reactant: C1CC(N2CCNCC2)C1
Reactant: CCOC(=O)c1ccc(F)cc1
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1ccc(N2CCN(C3CCC3)CC2)cc1
Temperature: 150 °C
Reaction time: 1 h
Yield: 11.3 %

Procedure:
Ethyl 4-fluorobenzoate (0.225 mL, 1.53 mmol) and 1-cyclobutylpiperazine (0.430 g, 3.07 mmol) were taken up in DMA (3 mL) and sealed into a microwave tube. The reaction was heated to 150° C. for 90 mins in the microwave reactor and cooled to room temperature. The reaction was not complete, so it was reheated at 150° C. for a further 1 h. The reaction mixture was evaporated to dryness and the crude product purified by silica column chromatography, eluting with a gradient of 0-2.5% MeOH in DCM. Pure fractions were evaporated to dryness to afford ethyl 4-(4-cyclobutylpiperazin-1-yl)benzoate (0.050 g, 11.31%) as a yellow solid.
Reaction SMILES: [S:1]1[C:5]([CH2:6]O)=[CH:4][C:3]2[CH:8]=[C:9]3[C:14](=[CH:15][C:2]1=2)[CH:13]=[CH:12][CH:11]=[CH:10]3.C(OCC)C.P(Br)(Br)[Br:22]>CO>[Br:22][CH2:6][C:5]1[S:1][C:2]2[CH:15]=[C:14]3[C:9](=[CH:8][C:3]=2[CH:4]=1)[CH:10]=[CH:11][CH:12]=[CH:13]3
Reactant: OCc1cc2cc3ccccc3cc2s1
Reactant: BrP(Br)Br
Solvent: CO
Solvent: CCOCC
Product: BrCc1cc2cc3ccccc3cc2s1
Temperature: 0 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
Naptho[2,3-b]thiophene-2-methanol (12, 2.71 g, 12.6 mmol., 1.00 equiv.) and diethyl ether (76 mL) were added to a 280 mL Schlenk flask and the mixture was cooled to 0° C. Phosphorus tribromide was added (0.89 mL, 9.5 mmol., 0.75 equiv.) and the mixture was left to warm slowly to room temperature while stirring for 16 hours. The mixture was diluted with methanol (300 mL) and the solids were collected by filtration and washed with methanol (50 mL), giving a beige solid (2.98 g, 85% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.27 (s, 1H), 8.23 (s, 1H), 7.97-7.86 (m, 2H), 7.52-7.43 (m, 2H), 7.41 (s, 1H), 4.81 (s, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18](=[O:27])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[C:10]=1N)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29]=O.[C:31]([BH3-])#[N:32].[Na+].[NH4+].[Cl-]>C1COCC1.CC#N>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18](=[O:27])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[C:10]=1[N:32]([CH3:31])[CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=O
Reactant: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)c(N)c4CC[C@H]3[C@@H]1CCC2=O
Reactant: [BH3-]C#N
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Product: CN(C)c1c(OCc2ccccc2)ccc2c1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 3 h
Yield: 54 %

Procedure:
To a suspension of 3-benzyloxy-4-aminoestra-1,3,5(10)-trien-17-one (85, 0.188 g, 0.5 mmol) in THF (1.0 mL) and CH3CN (5.0 mL) were added 37% aqueous formaldehyde (1.0 mL) and sodium cyanoborohydride (0.251 g, 4.0 mmol); the mixture was then stirred for 3 h at room temperature. Additional sodium cyanoborohydride (0.251 g, 4.0 mmol) was then added, and the mixture stirred for 24 h. Saturated aqueous NH4Cl at 0° C. was added, and the mixture extracted with EtOAc. The combined organic layers were washed with H2O, saturated aqueous NaCl, and then dried (Na2SO4). The desiccant was filtered and the solvent was evaporated at reduced pressure. The residue was purified by column chromatography (silica gel) using n-hexane:EtOAc (3:1→1:1, v/v) to afford 0.109 g of 86 (54% yield).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=1)=[O:11])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[NH2:1][CH2:4][C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]([C:12]1[CH:13]=[CH:14][C:15]([Br:18])=[CH:16][CH:17]=1)=[O:11]
Reactant: [N-]=[N+]=NC[C@@H]1CCCN1C(=O)c1ccc(Br)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NC[C@@H]1CCCN1C(=O)c1ccc(Br)cc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 99.2 %

Procedure:
The title compound (194 mg, 0.63 mmol) produced in step (vi) of Reference Example 8 was dissolved in 10 ml of tetrahydrofuran and 1 ml of water, 852 mg (3.1 mmol) of triphenylphosphine was added to the solution, and the mixture was stirred at 60° C. for 5 hr. The reaction solution was concentrated under the reduced pressure, and the residue was purified by column chromatography on silica gel (chloroform:methanol=40:1 to 5:1) to give 177 mg (yield 100%) of the title compound.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].C(=O)(O)[O-].[Na+].[F:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[N+:23]([O-:25])=[O:24])[C:17](Cl)=[O:18]>O1CCCC1>[CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH:5][C:17](=[O:18])[C:16]1[CH:20]=[CH:21][C:22]([N+:23]([O-:25])=[O:24])=[C:14]([F:13])[CH:15]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])c(F)c1
Reactant: COC(CN)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(CNC(=O)c1ccc([N+](=O)[O-])c(F)c1)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
To a cooled solution of amino acetaldehyde dimethyl acetal (0.91 mL, 8.30 mmol) in dry tetrahydrofuran (15 mL) was added sodium bicarbonate (769 mg, 9.16 mmol) and then a solution of 3-fluoro-4-nitro-benzoyl chloride (1.7 g, 8.30 mmol) in dry tetrahydrofuran (15 mL) was added dropwise at 0° C. over a period of 30 min. The reaction mixture was stirred overnight at ambient temperature, the solvent was removed in vacuo, and the residue was diluted with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated to yield N-(2,2-dimethoxyethyl)-3-fluoro-4-nitro-benzamide (2.0 g, 90%) as a brown liquid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([CH:11]=1)[C:7]([NH:9][CH3:10])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:22])=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([CH:11]=1)[C:7](=[S:22])[NH:9][CH3:10]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CNC(=O)c1cc(Br)ccc1F
Solvent: Cc1ccccc1
Product: CNC(=S)c1cc(Br)ccc1F
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 99.6 %

Procedure:
A mixture of 5-bromo-2-fluoro-N-methylbenzamide (500 mg, 2 mmol) and Lawesson's reagent (872 mg, 2.16 mmol) in toluene (10 mL) was heated to 100° C. and stirred for 3.5 hours. The reaction was cooled to room temperature, diluted with toluene, and filtered. The filtrate was concentrated and purified by flash column chromatography (0-20% ethyl acetate/heptanes) to give the title compound (494 mg, 92%) as a yellow oil that solidified upon standing. +ESI (M+H+1) 250.1; 1H NMR (400 MHz, CDCl3, δ): 8.20 (dd, J=6.93, 2.63 Hz, 1H), 8.06 (br. s., 1H), 7.47 (ddd, J=8.73, 4.44, 2.63 Hz, 1H), 6.95 (dd, J=11.12, 8.78 Hz, 1H), 3.32 (dd, J=4.88, 0.78 Hz, 3H).
Reaction SMILES: C([O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[O:8][C:9]([CH3:14])=[C:10]([CH2:12][OH:13])[CH:11]=1)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:35]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:40]=[CH:39][C:38](O)=[CH:37][CH:36]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[C:35]1([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:40]=[CH:39][C:38]([O:13][CH2:12][C:10]2[CH:11]=[C:7]([CH2:6][CH2:5][C:4]([OH:3])=[O:15])[O:8][C:9]=2[CH3:14])=[CH:37][CH:36]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)CCc1cc(CO)c(C)o1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1oc(CCC(=O)O)cc1COc1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 3.9 %

Procedure:
To a stirred, cooled 0° C. solution, in tetrahydrofuran (2.5 mL), a solution of 3-(4-hydroxymethyl-5-methyl-furan-2-yl)-propionic acid ethyl ester (36) (400 mg) in tetrahydrofuran (2.5 mL) was cooled to 0° C. and treated successively with triphenylphosphine (542 mg), biphenyl-4-ol (353 mg) and diisopropylazodicarboxylate (0.41 mL). After stirring for 10 mins at 0° C. the reaction mixture was allowed to warm to room temperature and then stirred for a further 16 hours. The reaction mixture was concentrated in-vacuo then re-dissolved in dichloromethane (15 mL) and treated with triethylamine (1.50 mL) and a scavenger resin PS-TsCl (2.5 g) and the mixture was shaken for 6 hours at room temperature. The reaction mixture was purified by flash chromatography, eluting with a mixture of diethyl ether in petroleum ether (40-60° C.) (7:93 by volume). The purified product (320 mg) was dissolved in methanol/tetrahydrofuran (2:1 by volume) (18 mL), treated with 1.0 M aqueous lithium hydroxide solution (9 mL) and allowed to stir at room temperature for 6 hours. The pH of the reaction mixture was adjusted to between pH4 and pH5 by the addition of 1.0 M hydrochloric acid (˜5.0 mL), then treated with saturated ammonium chloride (100 mL) and extracted with ethyl acetate (2×100 mL). The combined organic extracts were further washed with brine (35 mL), then dried (sodium sulphate) and concentrated in vacuo. A sample of the crude product (50 mg) was purified by HPLC to give compound 37 as white solid (25 mg). LC/MS System C: Rt=5.33 mins, m/z (ES−)=335 (M− for C21H20O4).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:15]=2[F:21])=[O:12])[N:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:29]1[C:38]2[C:33](=[CH:34][C:35]([O:41][CH3:42])=[C:36]([O:39][CH3:40])[CH:37]=2)[N:32]=[CH:31][N:30]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([O:20][C:29]3[C:38]4[C:33](=[CH:34][C:35]([O:41][CH3:42])=[C:36]([O:39][CH3:40])[CH:37]=4)[N:32]=[CH:31][N:30]=3)[CH:17]=[CH:16][C:15]=2[F:21])=[O:12])[N:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cc(O)ccc2F)n(-c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Oc3ccc(F)c(NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccccc4)c3)c2cc1OC
Temperature: 35 °C
Reaction time: 15 h
Yield: 5.8 %

Procedure:
To a stirred solution of 1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-5-hydroxyphenyl)urea (217 mg, 0.59 mmol) and 4-chloro-6,7-dimethoxyquinazoline (132 mg, 0.59 mmol) in DMF (4 mL) at rt, was added potassium carbonate (163 mg, 1.18 mmol). The reaction mixture was stirred at 35° C. for 15 h. The mixture was poured into water, and the resulting brown solid was filtrated, washed with water, and dried to afford the crude product. Purification via reverse-phase preparative HPLC afforded 1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(5-(6,7-dimethoxyquinazolin-4-yloxy)-2-fluorophenyl)urea (19 mg, 6%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ 9.02 (brs, 1H), 8.89 (brs, 1H), 8.57 (s, 1H), 8.16 (m, 1H), 7.53-7.59 (m, 5H), 7.37-7.46 (m, 3H), 7.15 (m, 1H), 6.43 (s, 1H), 4.00 (s, 3H), 3.98 (s, 3H), 1.29 (s, 9H); LC-MS (ESI) m/z 557 (M+H)+.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[CH3:11][C@H:12]1[NH:17][CH2:16][C@@H:15]([CH2:18][OH:19])[O:14][CH2:13]1.[NH2:20][C:21]1[N:26]=[C:25](Cl)[CH:24]=[C:23]([Cl:28])[N:22]=1>CC#N>[NH2:20][C:21]1[N:26]=[C:25]([N:17]2[C@H:12]([CH3:11])[CH2:13][O:14][C@H:15]([CH2:18][OH:19])[CH2:16]2)[CH:24]=[C:23]([Cl:28])[N:22]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: C[C@@H]1CO[C@H](CO)CN1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@@H]1CO[C@H](CO)CN1c1cc(Cl)nc(N)n1
Temperature: 160 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
In a 2-5 mL microwave vessel Hunig's base (0.59 mL, 3.35 mmol) was added to [(2S,5R)-5-methyl-2-morpholinyl]methanol hydrochloride (208 mg, 1.12 mmol) in CH3CN (3 mL), and then 2-amino-4,6-dichloropyrimidine (174 mg, 1.06 mmol) was added. The mixture was heated with stirring in a microwave reactor at 160° C. for 1 hour. HPLC indicated complete conversion. The mixture was filtered through a 0.45 um filter disc, evaporated, and the product was purified further by chomatography (Analogix SF25-40 g silica column) eluting with 2-5% CH3OH—CHCl3 to afford the title compound (258 mg) as a white foam. LC-MS (ES) m/z=260 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[N:7][CH:6]=[C:5]([S:9][CH3:10])[N:4]=1)#[N:2].[C:11](OC)(=[O:19])[C:12]1[C:13](=[CH:15][CH:16]=[CH:17][CH:18]=1)[SH:14].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:10][S:9][C:5]1[N:4]=[C:3]([C:1]2[S:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[C:11](=[O:19])[N:2]=2)[CH:8]=[N:7][CH:6]=1
Reactant: COC(=O)c1ccccc1S
Reactant: CSc1cncc(C#N)n1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CSc1cncc(-c2nc(=O)c3ccccc3s2)n1
Yield: 23 %

Procedure:
2-Cyano-6-methylthiopyrazine (0.80 g, 5.29 mmol) and methyl thiosalicylate (1.34 g, 7.94 mmol) were dissolved in toluene (100 ml), and triethylamine (1.48 ml, 10.6 mmol) was added thereto. The mixture was refluxed for 18 hrs. The solvent was evaporated, and the residue was recrystallized from ethanol to give the tilted compound (0.35 g, 23%) as pale yellow crystals.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]#[N:8].[C:9]([OH:13])(=[O:12])[CH:10]=O.CC(C)([O-])C.[K+:19]>CO>[K+:19].[C:7]([C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[CH:10][C:9]([O-:13])=[O:12])#[N:8]
Reactant: O=CC(=O)O
Reactant: N#CCc1cccs1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Product: N#CC(=CC(=O)[O-])c1cccs1
Temperature: 25 °C
Reaction time: 6 h
Yield: 70.3 %

Procedure:
To a stirring solution of thiophene-2-acetonitrile 20 (Aldrich, Milwaukee, Wis.) (80.6 g, 0.655 mol) in MeOH (1.3 L) was added glyoxylic acid (63.3 g, 0.688 mol). To the reaction solution was added portion-wise over 10 minutes potassium tert-butoxide (77.2 g, 0.688 mol). A nitrogen atmosphere was applied, and the solution was brought to reflux. After 6 h, the reaction was warmed to room temperature, filtered, and washed with copious amounts of MeOH. After drying under reduced pressure, 100 g of 21 as a white crystalline solid was obtained.
Reaction SMILES: [C:1]([OH:11])(=S)[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)O.[C:12]([C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1)#[N:13].C(O)(=[S:27])C(C)O.C(C1C=CC=CN=1)#N>>[C:18]([C:17]1[CH:21]=[CH:22][C:14]([C:12]2[S:27][C:2]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)=[C:1]([OH:11])[N:13]=2)=[CH:15][CH:16]=1)([OH:20])=[O:19]
Reactant: CC(O)C(O)=S
Reactant: N#Cc1ccc(C(=O)O)cc1
Reactant: OC(=S)C(O)c1ccccc1
Solvent: N#Cc1ccccn1
Product: O=C(O)c1ccc(-c2nc(O)c(-c3ccccc3)s2)cc1

Procedure:
The title compound was prepared according to the method of Scheme I in a manner analogous to Example 1 except thiomandelic acid and 4-cyanobenzoic acid were used instead of thiolactic acid and 2-cyanopyridine respectively.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:17]C[CH2:15][C@H:14]4[CH3:18])[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:21][O:22][C:23]1[C:28](B(O)O)=[CH:27][CH:26]=[CH:25][N:24]=1.N1C=C(B(O)O)C=NC=1>>[CH:14]([N:13]([C@H:11]1[CH2:10][C@H:9]([C:7]2[S:8][C:4]3[CH:3]=[C:2]([C:28]4[C:23]([O:22][CH3:21])=[N:24][CH:25]=[CH:26][CH:27]=4)[CH:20]=[CH:19][C:5]=3[N:6]=2)[CH2:12]1)[CH3:17])([CH3:18])[CH3:15]
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Reactant: COc1ncccc1B(O)O
Agent: OB(O)c1cncnc1
Product: COc1ncccc1-c1ccc2nc([C@H]3C[C@H](N(C)C(C)C)C3)sc2c1

Procedure:
The title compound was prepared according to the procedure described in Example 1F, substituting the product of Example 52A for the product of Example 1E and substituting 2-methoxypyridine-3-boronic acid for pyrimidine-5-boronic acid. 1H NMR (500 MHz, CDCl3) δ ppm 8.19 (dd, J=4.99, 1.87 Hz, 1H) 7.97-8.05 (m, 2H) 7.66 (dd, J=7.18, 1.87 Hz, 1H) 7.63 (dd, J=8.42, 1.87 Hz, 1H) 7.00 (dd, J=7.49, 4.99 Hz, 1H) 3.99 (s, 3H) 3.78-3.85 (m, 1H) 3.53-3.63 (m, 1H) 2.92-3.09 (m, 1H) 2.63-2.73 (m, 2H) 2.52-2.61 (m, 3H) 2.14 (d, J=5.93 Hz, 3H) 0.96-1.08 (m, 6H). MS: (M+H)+=368.
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].C[Al](C)C.[C:10]([O:14][C:15](=[O:36])[NH:16][C:17]([CH3:35])([CH3:34])[CH2:18][C:19]1[C:27]2[C:22](=[C:23]([C:28]([O:30][CH2:31]OC)=[O:29])[CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1)([CH3:13])([CH3:12])[CH3:11]>ClCCl>[C:10]([O:14][C:15](=[O:36])[NH:16][C:17]([CH3:35])([CH3:34])[CH2:18][C:19]1[C:27]2[C:22](=[C:23]([C:28]([O:30][CH2:31][NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[O:29])[CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1)([CH3:12])([CH3:13])[CH3:11]
Reactant: COCOC(=O)c1cccc2c(CC(C)(C)NC(=O)OC(C)(C)C)c[nH]c12
Reactant: CS(N)(=O)=O
Agent: C[Al](C)C
Solvent: ClCCl
Product: CC(C)(Cc1c[nH]c2c(C(=O)OCNS(C)(=O)=O)cccc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 117.8 %

Procedure:
A solution of methanesulfonamide (106 mg, 1.12 mmol) and trimethyl aluminum (2.0 M in hexanes, 0.56 ml, 1.12 mmol) in dry dichloromethane (5.0 ml) is stirred at room temperature under a nitrogen atmosphere for 20 minutes. A solution of [2-(7-(methoxycarbomethoxy)-1H-indol-3-yl)-1,1-dimethyl-ethyl]-carbamic acid tert-butyl ester (160 mg, 0.425 mmol) in dry dichloromethane (1.5 ml) is added and the mixture is heated under reflux for 15 hours. The mixture is cooled to room temperature and quenched with 1 N HCl solution (3.4 ml) and partitioned between ethyl acetate and water. The organic extracts are dried over anhydrous Na2SO4, filtered and the solvent evaporated to give 220 mg of [2-(7-(methanesulfonamidylcarbomethoxy)-1H-indol-3-yl)-1,1-dimethyl-ethyl]-carbamic acid tert-butyl ester (90%).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[N:4]1.Br[C:9]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:12][CH2:11][CH2:10]1.CN(P(N(C)C)(N(C)C)=O)C>CN(C)C=O.O1CCCC1>[N:3]1([C:9]2([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:12][CH2:11][CH2:10]2)[CH:7]=[CH:6][CH:5]=[N:4]1
Reactant: c1cn[nH]c1
Reactant: CCOC(=O)C1(Br)CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)C1(n2cccn2)CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.2 %

Procedure:
Into a 50 mL round bottom flask was added sodium hydride (60% dispersion in mineral oil, 452 mg, 11 mmol) and anhydrous tetrahydrofuran (18 mL). To the mixture was added pyrazole (511.6 mg, 7.515 mmol) and anhydrous tetrahydrofuran (1 mL). The mixture was stirred at room temperature for 2 h and then cooled to 0° C. Ethyl 1-bromocyclobutanecarboxylate (1.3 mL, 7.5 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 45 minutes and at room temperature over three days. HMPA (1.35 mL, 7.5 mmol) was added and the mixture was stirred at room temperature for 2 h. The reaction mixture was warmed to 70° C. for 2 h followed by the addition of N,N-dimethylformamide (4 mL). The reaction mixture was stirred at 70° C. for another 2 h before more N,N-dimethylformamide (2 mL) was added and then stirred at 70° C. for 18 h. The solvent was removed under reduced pressure. To the residue was added water and extracted with a mixture of heptanes and ethyl acetate (3×). The combined organics were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Flash chromatography (0-40% ethyl acetate in heptanes) provided impure ethyl 1-(1H-pyrazol-1-yl)cyclobutanecarboxylate (688 mg), which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:13](=[O:14])[C:12]([NH:15][CH3:16])=[C:11]([CH:17]=O)[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[C:21]([O:29][CH2:30][CH3:31])(=[O:28])[CH2:22][C:23]([O:25]CC)=O.N1CCCCC1>CCO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:13](=[O:14])[C:12]3[N:15]([CH3:16])[C:23](=[O:25])[C:22]([C:21]([O:29][CH2:30][CH3:31])=[O:28])=[CH:17][C:11]=3[CH:10]=[N:9]2)=[CH:19][CH:20]=1
Reactant: CNc1c(C=O)cnn(Cc2ccc(OC)cc2)c1=O
Reactant: CCOC(=O)CC(=O)OCC
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)c1cc2cnn(Cc3ccc(OC)cc3)c(=O)c2n(C)c1=O
Reaction time: 18 h

Procedure:
A mixture of 1-(4-methoxybenzyl)-5-(methylamino)-6-oxo-1,6-dihydropyridazine-4-carbaldehyde (4) (3.78 g, 13.8 mmol), diethyl malonate (4.20 mL, 27.7 mmol), piperidine (1.44 mL, 14.5 mmol), and EtOH (100 mL) was stirred at reflux in an oil bath for 5 h. The reaction mixture was allowed to stand at RT for 18 h to afford a suspension. The solid was collected by suction filtration, washed with EtOH (10 mL), and dried in vacuo to afford ethyl 7-(4-methoxybenzyl)-1-methyl-2,8-dioxo-1,2,7,8-tetrahydropyrido[2,3-d]pyridazine-3-carboxylate as a tan solid. MS (ESI, pos. ion) m/z: 370 (M+1).
Reaction SMILES: [C:1]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[O:3])[CH3:2].CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>C1C=CC=CC=1>[CH3:12][N:13]([CH:15]=[C:4]([C:1](=[O:3])[CH3:2])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:14]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)CC(C)=O
Solvent: c1ccccc1
Product: CCOC(=O)C(=CN(C)C)C(C)=O
Yield: 101.6 %

Procedure:
To a solution of ethyl acetylacetate (6 g, 46 mmol) in benzene (100 mL) was slowly added a solution of dimethylformamide dimethylacetal (8.2 g, 69 mmol) in benzene (100 mL) at 25° C. After the addition was complete, the reddish mixture was heated at reflux for 1 h and then evaporated to dryness to give ethyl 2-dimethylaminomethylene-3-oxobutanoate (8.66 g) as a reddish oil. This product (3.25 g, 17 mmol) was allowed to react with 4-chlorophenylhydrazine hydrochloride (3.14 g, 17 mmol) in EtOH (50 mL) at reflux for 8 h. The mixture was evaporated to dryness and the product was isolated by flash chromatography to give ethyl 1-(4-chlorophenyl)-5-methyl-1H-pyrazole-4-carboxylate as a white solid (2.07 g, 46%): mp 55°-56° C.; 1H NMR (80 MHz, CDCl3) δ (TMS) 8.02 (s, 1H, pyrazole), 7.50 (d, J=9, 2H, arom), 7.34 (d, J=9, 2H, arom), 4.33 (q, J=7, 2H, OCH2), 2.56 (s, 3H, Me-pyrazole), 1.37 (t, J=7, 3H, OCH2CH3). Analysis calculated for C13H13ClN2O2 : C 58.99; H 4.95; N 10.58. Found: C 59.03; H 5.06; N 10.58.