Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4](Cl)=[O:5].[CH3:12][C:13]1[CH:14]=[C:15]([O:19][CH3:20])[CH:16]=[CH:17][CH:18]=1.C1(C)C=CC=CC=1>[Fe](Cl)(Cl)Cl.O>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([C:18]1[CH:17]=[CH:16][C:15]([O:19][CH3:20])=[CH:14][C:13]=1[CH3:12])=[O:5]
Reactant: COc1cccc(C)c1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Agent: Cl[Fe](Cl)Cl
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)c2c(Cl)cccc2Cl)c(C)c1
Temperature: 100 °C
Reaction time: 0.75 h

Procedure:
A mixture of 2,6-dichlorobenzoylchloride (5.24 g; 25 mmol), 3-methylanisole(2.44 g; 20 mmol) and iron(III)chloride (20 mg) is heated to 100° C.for 45 minutes with stirring. After cooling, toluene is added, the mixture is shaken with water, the organic phase is dried and the solvent is evaporated. The reaction product is purified chromatograpically (flash column with 70 g of silicagel; elution with petrolether/toluene changing from 75:25 to 40:60 (v/v)). After evaporation the residue from the main fraction is treated with petrolether to give white crystals (1.33 g; 22.5%y); mp. 89° C.
Reaction SMILES: Cl.[CH:2]1[C:15]2[C:6](=[N:7][CH:8]=[C:9]3[C:14]=2[CH2:13][CH2:12][CH2:11][CH2:10]3)[CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.O.[H][H].[Pt]=O>[CH2:2]1[C:15]2[C:6](=[N:7][CH:8]=[C:9]3[C:14]=2[CH2:13][CH2:12][CH2:11][CH2:10]3)[CH2:5][CH2:4][CH2:3]1
Reactant: c1ccc2c3c(cnc2c1)CCCC3
Reactant: [H][H]
Agent: O=[Pt]
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: c1nc2c(c3c1CCCC3)CCCC2
Yield: 100.6 %

Procedure:
7,8,9,10-Tetrahydrophenanthridine hydrochloride (29 g, 0.13 mole) was dissolved in a mixture of glacial acetic acid (200 ml.) and water (10 ml.) and hydrogenated at 50 psi of hydrogen and room temperature over platinum oxide (750 mg.) until the theoretical uptake of hydrogen (0.26 mole) was observed. The solution was filtered and the solvents removed under reduced pressure. The residue was dissolved in water (100 ml.), and pH adjusted to 9 with Na2CO3 and the solution extracted with diethyl ether (3 × 100 ml.). Drying (MgSO4) and evaporation of the combined organic layers gave a colourless oil, distillation of which gave the title compound (24.5 g, 99%) Bpt 110°-2° C./0.05 mm
Reaction SMILES: [C:1]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:14][C:15]([C:17]3([C:20]4[CH:30]=[CH:29][C:23]5[O:24][C:25]([F:28])([F:27])[O:26][C:22]=5[CH:21]=4)[CH2:19][CH2:18]3)=[O:16])[CH:11]=2)[N:6]1[CH2:31][CH2:32]C#N)([CH3:4])([CH3:3])[CH3:2].[Cl:35]CC=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl>[C:1]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:14][C:15]([C:17]3([C:20]4[CH:30]=[CH:29][C:23]5[O:24][C:25]([F:28])([F:27])[O:26][C:22]=5[CH:21]=4)[CH2:19][CH2:18]3)=[O:16])[CH:11]=2)[N:6]1[CH2:31][CH2:32][Cl:35])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=CCCl
Reactant: CC(C)(C)C1Cc2cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2N1CCC#N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)C1Cc2cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2N1CCCl
Reaction time: 0.33 h
Yield: 62.9 %

Procedure:
To a solution of N-(2-tert-butyl-1-(2-cyanoethyl)indolin-5-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (71 mg, 0.17 mmol) in anhydrous dichloromethane (1 mL) was added chloroacetaldehyde (53 μL, 0.41 mmol) at room temperature under N2. After 20 min of stirring, NaBH(OAc)3 (90 mg, 0.42 mmol) was added in two portions. The reaction mixture was stirred overnight at room temperature. The product was purified by column chromatography on silica gel (2-15% ethyl acetate/hexanes) providing N-(2-tert-butyl-1-(2-chloroethyl)indolin-5-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (51 mg, 63%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][C@@H:11]([F:14])[C@H:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]1.[NH2:23][C:24]1[C:25]([C:31](O)=[O:32])=[N:26][C:27]([Br:30])=[CH:28][CH:29]=1>>[NH2:23][C:24]1[C:25]([C:31]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[N:8]2[CH2:13][CH2:12][C@@H:11]([F:14])[C@H:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])[CH2:9]2)=[O:32])=[N:26][C:27]([Br:30])=[CH:28][CH:29]=1
Reactant: Nc1ccc(Br)nc1C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(c2ccncc2N)CC[C@H]1F
Product: CC(C)(C)OC(=O)N[C@@H]1CN(c2ccncc2NC(=O)c2nc(Br)ccc2N)CC[C@H]1F

Procedure:
Following Method 11 of Example 305, trans-(+/−)-tert-butyl 1-(3-aminopyridin-4-yl)-4-fluoropiperidin-3-ylcarbamate and 3-amino-6-bromopicolinic acid were reacted yielding after purification (+/−)-tert-butyl 1-(3-(3-amino-6-bromopicolinamido)pyridin-4-yl)-4-fluoropiperidin-3-ylcarbamate, (20%). LCMS (m/z): 510.9 (MH+).
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[C:27](O)(=[O:31])[CH:28]([CH3:30])[CH3:29]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: CC(C)C(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Product: CC(C)C(=O)N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1

Procedure:
The title compound, off-white solid (70 mg, 70%), MS (ISP) m/z=397.3 [(M+H)+], mp 173° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and isobutyric acid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([C:19]([OH:21])=[O:20])[CH2:15][CH2:14]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:24]I>CN(C)C=O>[CH2:1]([O:8][C:9]([N:11]([CH2:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([C:19]([OH:21])=[O:20])[CH2:15][CH2:14]1)[CH3:24])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC[C@H]1CC[C@H](C(=O)O)CC1)OCc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C[C@H]1CC[C@H](C(=O)O)CC1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solutionoof 20.3 g (0.07 mol) of trans-4-(N-benzyloxycarbonyl-aminomethyl)cyclohexanecarboxylic acid in 380 ml of dimethylformamide is treated at 15°-20° under argon with 0.21 mol of sodium hydride (9.35 g of a 55% dispersion in mineral oil) and thereupon stirred at room temperature for a further 30 minutes. A solution of 17.5 ml (0.28 mol) of methyl iodide in 20 ml of dimethylformamide is added thereto at 25°-30° within 20 minutes and the mixture is stirred at 70° for a further 1 hour. After concentration under reduced pressure the residue is partitioned between water and methylene chloride. The organic phase is evaporated and the residual oil is dissolved in a mixture of 350 ml of ethanol and 350 ml of 1N sodium hydroxide solution. The mixture is heated to reflux for 1 hour, cooled and poured into 700 ml of ice-water The solution is extracted with ethyl acetate and then acidified with 6N hydrochloric acid. The liberated acid is extracted with methylene chloride and the extract is dried over sodium sulphate and evaporated. The residual oil is chromatographed on 270 g of silica gel with a mixture of methylene chloride/ethyl acetate (4:1) as the elution agent. There are obtained 13.6 g (64%) of trans-4-(N-benzyloxycarbonyl-N-methyl-aminomethyl)cyclohexanecarboxylic acid as a thick oil.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.C(O)(C(F)(F)F)=O.[CH2:20]([C@H:27]([O:38][C:39]1[CH:55]=[CH:54][C:42]([C:43]([NH:45][NH:46]C(OC(C)(C)C)=O)=[O:44])=[CH:41][CH:40]=1)[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:46][NH:45][C:43]([C:42]1[CH:54]=[CH:55][C:39]([O:38][C@@H:27]([CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])=[CH:40][CH:41]=1)=[O:44]
Reactant: CC(C)(C)OC(=O)NNC(=O)c1ccc(O[C@@H](Cc2ccccc2)C(=O)OCc2ccccc2)cc1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: O=C1Nc2ccc(I)cc2C1=NNC(=O)c1ccc(O[C@@H](Cc2ccccc2)C(=O)OCc2ccccc2)cc1
Temperature: 100 °C
Yield: 76 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid in the presence of 5% TFA was added tert-butyl 2-{4-[(1S)-1-benzyl-2-(benzyloxy)-2-oxoethoxy]benzoyl}hydrazinecarboxylate. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. for 15 hrs gave 164 mg of the title compound (76%) as a yellow solid in 98.8% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:8]=[C:9]3[C:14](=[C:15]([CH3:17])[CH:16]=2)[NH:13][C:12](=[O:18])[CH:11]=[CH:10]3)[CH:4]=[CH:5][N:6]=1.[Cl:19]N1C(=O)CCC1=O>ClCCl>[Cl:19][C:4]1[N:3]([C:7]2[CH:8]=[C:9]3[C:14](=[C:15]([CH3:17])[CH:16]=2)[NH:13][C:12](=[O:18])[CH:11]=[CH:10]3)[C:2]([CH3:1])=[N:6][CH:5]=1
Reactant: Cc1cc(-n2ccnc2C)cc2ccc(=O)[nH]c12
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: Cc1cc(-n2c(Cl)cnc2C)cc2ccc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 6-(2-methylimidazol-1-yl)-8-methyl-2-(1H)-quinolone (0.24 g) and N-chlorosuccinimide (0.14 g) in dichloromethane (10 cm3) was stirred at room temperature for 2 hours. The mixture was then chromatographed directly on silica (Merck "MK 60.9385" [Trade Mark]) eluting with methanol:dichloromethane, 1:20 by volume. Combination and evaporation of the appropriate fractions afforded the title compound, m.p. 258°-61°, (0.18 g).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.CS(C)=O.[O:16]1[CH:18]2[CH2:19][CH:20]=[CH:21][CH:17]12>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH:20]3[CH2:21][CH:17]([OH:16])[CH:18]=[CH:19]3)[N:3]=[C:2]([I:1])[C:10]=12
Reactant: Nc1ncnc2[nH]nc(I)c12
Reactant: C1=CC2OC2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: Nc1ncnc2c1c(I)nn2C1C=CC(O)C1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 61.4 %

Procedure:
A mixture of tetrakis(triphenylphosphine)palladium(0) (0.04 g, 0.03 mmol), 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.30 g, 1.14 mmol) and dimethyl sulfoxide (3 mL) was stirred at ambient temperature in the dark for 2 minutes and cooled to 0° C. A solution of 2,4a-dihydro-1aH-cyclopenta[b]oxirene (0.14 g, 1.72 mmol) in tetrahydrofuran (3 mL) was added into the mixture at 0° C. and stirred at 0° C. for 3 hours. The mixture was stirred at ambient temperature overnight and purified by preparative HPLC to yield 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-cyclopenten-1-ol (0.24 g, 0.70 mmol) as a white solid: RP-HPLC (Hitachi HPLC, Hypersil C18, 5 μm, 100A, 250×4.6 mm; 25%-100% acetonitrile—0.05M ammonium acetate over 10 min, 1 mL/min) Rt 4.23 min. MS: MH+ 344.
Reaction SMILES: CO[C:3]([C:5]1[S:6][CH:7]=[C:8]([CH3:11])[C:9]=1[NH2:10])=[O:4].[O-:12][C:13]#[N:14].[K+]>C(O)(=O)C.O>[CH3:11][C:8]1[C:9]2[NH:10][C:13](=[O:12])[NH:14][C:3](=[O:4])[C:5]=2[S:6][CH:7]=1
Reactant: N#C[O-]
Reactant: COC(=O)c1scc(C)c1N
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1csc2c(=O)[nH]c(=O)[nH]c12
Temperature: 25 °C
Reaction time: 15 h
Yield: 71.4 %

Procedure:
To a stirred solution of methyl-3-amino-4-methylthiophene-2-carboxylate (530 mg, 3.1 mmol) in acetic acid (15.5 mL) and water (1.6 mL) was added a solution of potassium cyanate (754 mg, 9.3 mmol) dissolved in water (2.5 mL) dropwise via syringe. The reaction was stirred at room temperature for 15 h, upon completion of the reaction; the reaction mixture was concentrated to 75% and filtered off white solid. To the solid was added 6% aqueous sodium hydroxide (16 mL) and refluxed for 2 h. After cooling to room temperature, the solution was acidified using 12N HCl to pH=6. The resultant precipitate was filtered, washed with water and dried in vacuum oven overnight to give 403 mg (71%) of the title compound as a white solid which was used without any further purification:
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][CH:9]=[C:8]([C:11]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[N:22]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[N:21]=[CH:20]4)([OH:16])[C:12]([F:15])([F:14])[F:13])[C:4]=2[N:5]=[CH:6][N:7]=1.FC(F)(F)C(O)=[O:36]>O.O1CCOCC1.C([O-])(O)=O.[Na+]>[F:13][C:12]([F:15])([F:14])[C:11]([C:8]1[C:4]2[N:5]=[CH:6][NH:7][C:2](=[O:36])[C:3]=2[NH:10][CH:9]=1)([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([C:26]1[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=1)[N:21]=[CH:20]2)[OH:16]
Reactant: OC(c1ccc2c(cnn2-c2ccc(F)cc2)c1)(c1c[nH]c2c(Cl)ncnc12)C(F)(F)F
Reactant: O=C(O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=c1[nH]cnc2c(C(O)(c3ccc4c(cnn4-c4ccc(F)cc4)c3)C(F)(F)F)c[nH]c12
Temperature: 70 °C
Reaction time: 18 h
Yield: 44 %

Procedure:
A mixture of 1-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]ethanol (43 mg, 0.09 mmol) and 1 mL of trifluoroacetic acid in 1 mL of water and 2 mL of dioxane was warmed at 70° C. After 18 hours, the reaction was diluted with saturated NaHCO3 and extracted with EtOAc. The combined organic layers were dried, filtered, and concentrated in vacuo. The residue was dissolved in 1 mL of DMF and purified by reverse phase HPLC (5-95% CH3CN/water+0.1% TFA). The desired fractions were combined and the CH3CN was removed in vacuo. The aqueous layer was made basic with saturated sodium bicarbonate and extracted with EtOAc. The combined organics were dried, filtered, and concentrated in vacuo to provide 18 mg (44%) of the title compound as a white solid. MS m/z 444.27 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:48]([CH3:49])=[CH:47][C:39]([O:40][CH:41]2[CH2:45][CH2:44][CH:43]([OH:46])[CH2:42]2)=[CH:38][C:37]=1[CH3:50]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:36]2[C:37]([CH3:50])=[CH:38][C:39]([O:40][CH:41]3[CH2:45][CH2:44][CH:43]([OH:46])[CH2:42]3)=[CH:47][C:48]=2[CH3:49])=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: Cc1cc(OC2CCC(O)C2)cc(C)c1Br
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OC6CCC(O)C6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate and 3-(4-bromo-3,5-dimethylphenoxy)cyclopentanol following a procedure analogous to that described in Step 5 of Intermediate 1. Mass spectrum (ESI+): m/z=547 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([F:11])[CH:5]=2)[CH2:3][CH2:2]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.F[C:23]1[C:31]2[S:30][N:29]=[CH:28][C:27]=2[CH:26]=[CH:25][C:24]=1[C:32]([OH:34])=[O:33]>C1COCC1>[CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([NH:10][C:23]3[C:31]4[S:30][N:29]=[CH:28][C:27]=4[CH:26]=[CH:25][C:24]=3[C:32]([OH:34])=[O:33])=[C:6]([F:11])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: Nc1ccc(C2CC2)cc1F
Reactant: O=C(O)c1ccc2cnsc2c1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1ccc2cnsc2c1Nc1ccc(C2CC2)cc1F
Reaction time: 0.17 h
Yield: 32.1 %

Procedure:
To a solution of 4-cyclopropyl-2-fluoro-phenylamine (445 mg, 2.94 mmol) in anhydrous THF (10 mL) at −78° C. was added a 1.0 M solution of LHMDS in hexanes (4.4 mL, 4.4 mmol) under a nitrogen atmosphere. The reaction mixture was stirred for 10 minutes and a suspension of 7-fluoro-benzo[d]isothiazole-6-carboxylic acid (290 mg, 1.47 mmol) in anhydrous THF (10 mL) was added dropwise. The resultant mixture was stirred at −78° C. for 30 minutes, then allowed to reach room temperature and stirred for 18 hours before being quenched by addition of a 1M aqueous and extracted with ethyl acetate. The organic layer was separated and washed with water followed by brine, dried (Na2SO4), filtered and evaporated in vacuo. The resultant residue was triturated with diethyl ether to give the title compound as a brown solid (155 mg, 32%). LCMS (method B): RT=3.79 min, [M+H]+=329.
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[N:16](COCC[Si](C)(C)C)[N:15]=[CH:14][C:13]=2[C:25]#[N:26])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C(OCC)C>[OH:1][C:2]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]2[C:13]([C:25]#[N:26])=[CH:14][NH:15][N:16]=2)=[CH:9][CH:10]=1)([CH3:4])[CH3:3]
Reactant: CC(C)(O)c1ccc(Nc2c(C#N)cnn2COCC[Si](C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOCC
Solvent: O
Product: CC(C)(O)c1ccc(Nc2n[nH]cc2C#N)cc1
Temperature: 110 °C
Reaction time: 28 h
Yield: 46.8 %

Procedure:
5-(4-(2-Hydroxypropan-2-yl)phenylamino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carbonitrile (480 mg, 1.13 mmol) was taken up in a solution of tetrabutylammonium fluoride (1M, 16.8 ml) and the flask was sealed. The mixture was placed in an oil bath heated to 110° C. and stirred for 28 hours. The mixture was cooled to ambient. Water (60 ml) and diethyl ether (60 ml) were added and the material was shaken in a reparatory funnel and the organic phase was collected. The aqueous phase was back extracted with diethyl ether (2×50 ml). The organic phase was combined, dried from magnesium sulfate, filtered and stripped. The crude remainder was purified through Analogix flash column chromatography using ethyl acetate in hexanes (30% to 90% gradient, 40 g silica gel) to provide 3-(4-(2-hydroxypropan-2-yl)phenylamino)-1H-pyrazol-4-carbonitrile as an off-white powder (128 mg, 47% yield). LC/MS calc'd for C13H14N4O (m/e) 242.28, obs'd 241 (M−H, ES−).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[OH-].[K+].CN(C)C=O.[Cl:19][C:20]1[N:25]=[CH:24][C:23]([CH2:26]Cl)=[CH:22][CH:21]=1>CCO>[Cl:19][C:20]1[N:25]=[CH:24][C:23]([CH2:26][N:5]2[C:1](=[O:11])[C:2]3=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]3[C:4]2=[O:6])=[CH:22][CH:21]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ClCc1ccc(Cl)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(Cl)nc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
In 20 ml of EtOH, 9.4 g (6.4×10−2 mole) of phthalimide and 4.2 g of KOH were stirred for 30 minutes, followed by addition of 100 ml of DMF (dimethylformamide) and 5.2 g (2.5×10−2 mole) of 6-chloro-3-pyridylmethyl chloride. The mixture was stirred at 60° C. for 1 hour. The EtOH and DMF were distilled off under reduced pressure and the residue was chromatographed on a silica gel column and eluted with CH2Cl2. The above procedure gave 6.7 g of the title compound as colorless needles.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:11]I)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].[C:13]([O-:16])(=[S:15])[CH3:14].[K+]>O>[CH3:1][O:2][C:3]([C:5]1([CH2:11][S:15][C:13](=[O:16])[CH3:14])[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(CI)CCOCC1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: O
Product: COC(=O)C1(CSC(C)=O)CCOCC1
Reaction time: 18 h
Yield: 97 %

Procedure:
4-Iodomethyltetrahydropyran-4-carboxylic acid methyl ester (3.05 g) was dissolved in NN-dimethylformamide (20 ml) at room temperature and potassium thioacetate (1.47 g) added. The mixture was stirred for 18 hours then diluted with water (50 ml) and extracted with diethyl ether (4×25 ml). The combined organics were washed with saturated sodium bicarbonate solution (3×20 ml) and brine (20 ml), then dried (MgSO4), filtered and evaporated under reduced pressure to give the title compound as a yellow solid (2.42 g, 97%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][NH2:9])=[N:6][CH:5]=[CH:4][N:3]=1.[N:10]([O-])=O.[Na+]>C(O)(=O)C.O>[Cl:1][C:2]1[C:7]2[N:6]([N:10]=[N:9][N:8]=2)[CH:5]=[CH:4][N:3]=1
Reactant: NNc1nccnc1Cl
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Clc1nccn2nnnc12
Temperature: 10 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
2-Chloro-3-hydrazinylpyrazine (440 g, 3.0 mol) was suspended in acetic acid (500 mL) and cooled to 10° C. A solution of sodium nitrite (220 g, 3.2 mol) in water (200 mL) at 10° C. was added. The resulting mixture was stirred at 10° C. for 1 h, during which time a crystalline solid precipitated. The precipitate was collected by filtration, washed with ethanol (200 mL) and dried to afford the desired product as a red solid (350 g, 73% yield).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8](Cl)=[O:9])[CH2:4][CH2:3]1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([O:22][CH3:23])[C:19]=1[O:20][CH3:21])[NH2:16]>C(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8](=[O:9])[NH:16][C:15]2[CH:17]=[C:18]([O:22][CH3:23])[C:19]([O:20][CH3:21])=[C:13]([O:12][CH3:11])[CH:14]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(C(=O)Cl)CC1
Reactant: COc1cc(N)cc(OC)c1OC
Solvent: ClCCl
Product: COc1cc(NC(=O)N2CCN(C)CC2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 10 g (0.061 mole) 1-methyl-4-chloroformyl-piperazine in 100 ml dry methylene chloride is added to a solution of 11.2 g (0.061 mole) 3,4,5-trimethoxy-aniline in a 100 ml methylenechloride. After stirring at ambient temperature for 24 hours, the solvent is evaporated off in vacuo; the residue is dissolved in the minimum of ethanol and then the crude hydrochloride precipated by the addition of diethyl ether, and dried.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([SH:21])=[CH:17][CH:16]=1)([O-:14])=[O:13].C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.[Cu]>[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([S:21][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[CH:4][CH:3]=2)=[CH:17][CH:16]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1ccc(S)cc1
Reactant: Brc1cccc2ccccc12
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(Sc2cccc3ccccc23)cc1
Yield: 35.5 %

Procedure:
1-Bromonaphthalene (0.15 mole, 31.0 g),4-nitrothiophenol 0.11 mole, 17.0 g), potassium carbonate (0.15 moles, 20.7 g), copper bronze (0.3 moles, 18.9 g) and cuprous chloride (0.06 moles, 6.0 g) were refluxed in 500 ml pyridine for 3 days. The reaction was filtered while hot, and then concentrated. Ethyl acetate was added and the solution washed with water and 5N HCl, dried over sodium sulfate and concentrated. The product was purified twice by HPLC over silica gel eluted with 20% ethyl acetate/hexane followed by 5 ethyl acetate/hexane to yield 1-(4-nitrophenylthio)naphthalene 11.0 g, 26%. Mass Spec (FD) 282. Calculated for C16H11NO2S: C, 68.31 H, 3.94, N, 4.98. Found: C, 68.52; H, 4.00; N, 4.77.