Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:9][N:10]=2)[N:7]=1.[OH:22][CH2:23][C:24]1[N:25]([CH3:29])[N:26]=[CH:27][N:28]=1.[H-].[Na+]>CN(C=O)C.O>[CH3:29][N:25]1[C:24]([CH2:23][O:22][C:2]2[C:3]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:4][C:5]3[N:6]([C:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:9][N:10]=3)[N:7]=2)=[N:28][CH:27]=[N:26]1
Reactant: Cn1ncnc1CO
Reactant: Clc1nn2c(-c3ccccc3)nnc2cc1N1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ncnc1COc1nn2c(-c3ccccc3)nnc2cc1N1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
To a solution of 6-chloro-3-phenyl-7-(pyrrolidin-1-yl)-1,2,4-triazolo[4,3-b]pyridazine (100 mg, 0.33 mmol) and 3-hydroxymethyl-2-methyl-1,2,4-triazole in dry DMF (5 ml) was added sodium hydride (60% dispersion in oil, 20 mg, 0.36 mmol). The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (50 ml) and extracted with dichloromethane (3×25 ml). The combined extracts were washed with brine, dried over magnesium sulphate, filtered and evaporated. The solid was triturated with methanol, and collected by filtration to afford the title pyridazine (68 mg, 55%). 1H NMR (360 MHz, CDCl3) δ1.93-1.97 (4 H, m), 3.41-3.45 (4 H, m), 4.00 (3 H, s), 5.58 (2 H, s), 6.66 (1 H, s), 7.43-7.53 (3 H, m), 7.94 (1 H, s), 8.28 (2 H, d, J=8.3 Hz). MS (ES+) 377 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=O)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1.[O:24]=[C:25]1[N:29]([C@H:30]2[C@H:35]([OH:36])[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31]2)[C:28](=[O:44])[CH2:27][S:26]1>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:27]4/[C:28](=[O:44])[N:29]([C@H:30]5[C@H:35]([OH:36])[CH2:34][CH2:33][NH:32][CH2:31]5)[C:25](=[O:24])[S:26]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:20]([F:21])([F:23])[F:22])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)[C@H](N2C(=O)CSC2=O)C1
Reactant: O=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1[C@@H]1CNCC[C@H]1O

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[trans-4-hydroxypiperidin-3-yl]-1,3-thiazolidine-2,4-dione was prepared from [4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-carbaldehyde (from Example 1) and 1,1-dimethylethyl trans-3-(2,4-dioxo-1,3-thiazolidin-3-yl)-4-hydroxypiperidine-1-carboxylate (from Example 270) following General Procedure F.
Reaction SMILES: Cl[C:2]1[C:3]2[C@H:10]([CH3:11])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[OH:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(C)C.O.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:11][C@H:10]1[C:3]2[C:2]([C:16]3[CH:17]=[CH:18][C:13]([OH:12])=[CH:14][CH:15]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH2:8][CH2:9]1
Reactant: C[C@@H]1CCc2ncnc(Cl)c21
Reactant: OB(O)c1ccc(O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: C[C@@H]1CCc2ncnc(-c3ccc(O)cc3)c21
Temperature: 100 °C
Reaction time: 16 h
Yield: 87.1 %

Procedure:
(R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (137 mg, 0.812 mmol) and 4-hydroxybenzeneboronic acid (123 mg, 0.894 mmol) was dissolved in isopropyl alcohol (1.6 mL). Sodium carbonate in water (0.97 mL, 1.0M) was added slowly, followed by bis(triphenylphosphine)palladium chloride (26.5 mg, 0.0378 mmol). The mixture was stirred at 100° C. (bath) for 16 hours. The contents were diluted with water (5 mL) and EtOAc (10 mL). The aqueous layer was separated and extracted with EtOAc (2×5 mL). The combined EtOAc solutions were washed with brine (5 mL) and dried (Na2SO4). The crude was purified by flash chromatography to give (R)-4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenol (160 mg, 87%) as viscous oil which solidified upon standing.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[S:11])[CH:5]2[CH3:12].[Cl:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Cl:13][C:5]1([CH3:12])[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=2)[NH:7][C:6]1=[S:11]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC1C(=S)Nc2ccc(Cl)cc21
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(Cl)C(=S)Nc2ccc(Cl)cc21

Procedure:
A solution of 5-chloro-3-methylthiooxindole (1.35 g, 6.3 mmol) and N-chlorosuccinimide (950 mg, 7 mmol) in carbon tetrachloride (100 ml) was refluxed for 1 hour, cooled, and the precipitate was removed by filtration. The filtrate was concentrated to dryness, yielding crude 3,5-dichloro-3-methylthiooxindole. The residue was dissolved in 25 ml of tetrahydrofuran and added rapidly to a vigorously stirred slurry of red mercuric oxide (1.37 g, 6.3 mmol) and boron trifluoride etherate (900 mg, 6.3 mmol) in 100 ml of 20 percent aqueous tetrahydrofuran. After stirring for 3 hours, the solution was filtered through a pad of Celite and the filtrate was extracted with chloroform. The chloroform extracts were dried over anhydrous magnesium sulfate, filtered and the filtrates were concentrated to give a red solid which was chromatographed on silica gel with chloroform as the eluent. There was obtained 5-chloroisatin (850 mg, 75%), mp 248°-251° (recrystallized from ethanol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:16]2[CH2:20][C@H:19]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])[O:18][C:17]2=[O:26])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][S:11](=[O:15])(=[O:14])[NH:10][CH2:9]1.[C:27](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([N:16]2[CH2:20][C@H:19]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])[O:18][C:17]2=[O:26])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][S:11](=[O:14])(=[O:15])[N:10]([CH3:27])[CH2:9]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3CCS(=O)(=O)NC3)c(F)c2)C(=O)O1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CC(=O)NC[C@H]1CN(c2ccc(C3CCS(=O)(=O)N(C)C3)c(F)c2)C(=O)O1
Yield: 75.1 %

Procedure:
N-[[(5S)-3-[3-fluoro-4-(tetrahydro-1,1-dioxido-2H-1,2-thiazin-4-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (200 mg, 0.52 mmol), powdered potassium carbonate (85 mg, 0.62 mmol) and methyl iodide (88 mg, 0.62 mmol) were stirred under nitrogen in dry DMF (1 mL) for 24 hours. After evaporation of the solvent, the residue is partitioned between chloroform (65 mL) and water (15 mL). The chloroform is dried (MgSO4), filtered and evaporated. The residue is chromatographed over silica gel, eluting with 2-6% methanol-chloroform. The product is obtained as a white foam (156 mg, 75%). HRMS (FAB) calc'd for M+H=400.1342; Found: 400.1343.
Reaction SMILES: [C:1]1([S:7](Cl)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([C@:13]1(O)[C:18](=[CH2:19])[CH2:17][C@H:16]2[C@H:20]3[C:30](=[CH:31][CH2:32][C@:14]12[CH3:15])[C@:28]1([CH3:29])[C:23](=[CH:24][C:25](=[O:33])[CH:26]=[CH:27]1)[CH2:22][CH2:21]3)(=[O:12])[CH3:11].P([O-])([O-])([O-])=O>C(Cl)Cl.C(N(CC)CC)C>[C:1]1([S:7]([CH2:19][C:18]2[CH2:17][C@@H:16]3[C@:14]([CH3:15])([CH2:32][CH:31]=[C:30]4[C@H:20]3[CH2:21][CH2:22][C:23]3[C@:28]4([CH3:29])[CH:27]=[CH:26][C:25](=[O:33])[CH:24]=3)[C:13]=2[C:10](=[O:12])[CH3:11])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)c1ccccc1
Reactant: C=C1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)[C@]1(O)C(C)=O
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)C1=C(CS(=O)c2ccccc2)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]12C

Procedure:
Phenylsulfinyl chloride in methylene chloride (2.5N, 2.4 ml) was added to a mixture of 17α-acetyl-17β-hydroxy-16-methyleneandrost-1,4,9(11)-trien-3-one (VB, Example 17, 1 g) in methylene chloride (10 ml) and triethylamine (0.82 ml) previously cooled to -30° over a period of 2 hrs. The reaction is plunged into phosphate buffer (pH 7, 10 ml); the phases are separated; the aqueous phase is extracted with methylene chloride; the organic phases are combined and dried over sodium sulfate and concentrated under reduced presure to an isomeric mixture of the title compound. The isomers are separated by chromatography on silica gel (50 g), eluting with acetone/hexane: 5/95 to give the title compound, NMR (CDCl3) 0.89, 1.42, 2.10, 4.03, 5.5, 6.0, 6.27, 7.20 δ.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:15]=[CH:14][CH:13]=[C:7]2[C:8]([O:10][C:11](=[O:12])[C:6]=12)=O)(=[O:3])[CH3:2].FC(F)(F)C(O)=O.[NH2:23][CH:24]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:25]1=[O:26].CC([O-])=O.[Na+]>C(O)(=O)C>[O:10]=[C:8]1[C:7]2[C:6](=[C:5]([O:4][C:1](=[O:3])[CH3:2])[CH:15]=[CH:14][CH:13]=2)[C:11](=[O:12])[N:23]1[CH:24]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:25]1=[O:26]
Reactant: CC(=O)Oc1cccc2c1C(=O)OC2=O
Reactant: NC1CCC(=O)NC1=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: CC(=O)Oc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Yield: 57 %

Procedure:
1,3-Dioxo-2-(2,6-dioxopiperidin-3-yl)-4-acetoxyisoindoline was prepared and isolated as follows. A mixture of 3-acetoxyphthalic anhydride (40 mg), aminoglutarimide trifluoroacetate (47 mg), and NaOAc (32 mg) in acetic acid (2 mL) was refluxed for 5 h. The solvent was evaporated, water (10 mL) was added, and the resulting solution was stirred for several minutes. The solid was filtered out and recrystallized from ethyl acetate to give 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-acetoxyisoindoline as pale yellow crystals (35 mg, 66%): 1H NMR (DMSO) δ 11.16 (s, 1H), 11.07 (s, 1H), 7.64 (t, J=7.2 Hz, 1H), 7.22-7.31 (m, 2H), 5.05 (dd, J=5.4 Hz, J=12.5 Hz, 1H), 2.87-2.92 (m, 2H), 2.48 (s, 3H), 2.08-2.00 (m, 2H).
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[CH:10]=[O:11].[CH3:12][Mg]Cl>C1COCC1>[NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[CH:10]([OH:11])[CH3:12]
Reactant: C[Mg]Cl
Reactant: O=Cc1cc2ccncc2[nH]1
Solvent: C1CCOC1
Product: CC(O)c1cc2ccncc2[nH]1
Reaction time: 0.75 h
Yield: 75.5 %

Procedure:
To a solution of 1H-pyrrolo[2,3-c]pyridine-2-carboxaldehyde (0.80 g, 5.47 mmol) in THF (27.4 mL) was slowly added methylmagnesium chloride (22% by weight in THF, 5.0 mL, 15.3 mmol) at 0° C. under a nitrogen atmosphere. The ice/water bath was removed, and the reaction mixture was stirred for 45 min. The reaction mixture was quenched with methanol and concentrated to dryness. The solid residue was treated with water (50 mL) and sonicated. The solids were filtered and collected, but they were shown to be undesired material. The water filtrate was concentrated to dryness, treated with 6 N HCl (2.55 mL) and concentrated to dryness again. The resulting orange solid was diluted with EtOAc and treated with saturated NaHCO3. The aqueous layer was extracted with EtOAc (3×). The combined organic extracts were washed with saturated NaCl and dried over Na2SO4. The organic extract was filtered and concentrated to provide 1-(1H-pyrrolo[2,3-c]pyridin-2-yl)ethanol (0.67 g, 75%) as a tan solid: 1H NMR (300 MHz, CD3OD) δ1.59 (3H, d, J=6.6 Hz), 5.05 (1H, q, J=6.6 Hz), 6.41 (1H, s), 7.49-7.51 (1H, m), 8.00 (1H, d, J=5.6 Hz), 8.60 (1H, s); ESI MS m/z 163 [C9H10N2O+H]+; HPLC (Method A) 89.0% (AUC), tR=9.34 min.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]2[N:3]=1.Cl.Cl.[F:18][C:19]1[CH:20]=[C:21]([C@H:27]2[CH2:31][CH2:30][CH2:29][NH:28]2)[C:22]([O:25][CH3:26])=[N:23][CH:24]=1.C(N(C(C)C)CC)(C)C.C(O)CCC>CCOC(C)=O>[F:18][C:19]1[CH:20]=[C:21]([C@H:27]2[CH2:31][CH2:30][CH2:29][N:28]2[C:2]2[CH:7]=[CH:6][N:5]3[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]3[N:3]=2)[C:22]([O:25][CH3:26])=[N:23][CH:24]=1
Reactant: COc1ncc(F)cc1[C@H]1CCCN1
Reactant: CCOC(=O)c1cnn2ccc(Cl)nc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)cnc3OC)nc12
Yield: 56.3 %

Procedure:
Ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (Preparation B, 0.75 g, 3.32 mmol), (R)-5-fluoro-2-methoxy-3-(pyrrolidin-2-yl)pyridine dihydrochloride (0.984 g, 3.66 mmol), diisopropylethylamine (2.32 mL, 13.3 mmol) and n-butanol (1.11 mL) were heated at 90° C. for 48 hours. The reaction mixture was diluted with EtOAc and the mixture was washed with water, brine and saturated NaHCO3. The organic layer was dried with MgSO4, filtered and concentrated afford a dark orange oil. The oil was purified by silica chromatography, eluting with a 50-80% EtOAc/Hexane gradient, to afford (R)-ethyl 5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (0.72 g, 56.2%) as a yellow foam. MS (apci) m/z=386.0 (M+H).
Reaction SMILES: [CH3:1][S:2][CH:3]([C:5]1[CH:6]=[N:7][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:10]=1)[CH3:4].[N:15]#[C:16][NH2:17].[O-]Cl.[Na+].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].C(O)(=O)C>C(#N)C>[F:12][C:11]([F:14])([F:13])[C:8]1[N:7]=[CH:6][C:5]([CH:3]([S:2]([CH3:1])=[N:17][C:16]#[N:15])[CH3:4])=[CH:10][CH:9]=1
Reactant: CSC(C)c1ccc(C(F)(F)F)nc1
Reactant: N#CN
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Agent: [O-]Cl
Solvent: CC(=O)O
Solvent: CC#N
Product: CC(c1ccc(C(F)(F)F)nc1)S(C)=NC#N
Temperature: -5 °C
Reaction time: 0.75 h

Procedure:
A solution of 22.1 g (0.1 mol) of 3-[1-(methylthio)ethyl]-6-(trifluoromethyl)pyridine and 5.04 g (0.12 mol) of cyanamide in 150 mL of acetonitrile was cooled to −5° C. To this solution was added 150 g (0.115 mol, Clorox™ 5.7% wt) of aqueous NaOCl dropwise over 15 min. The reaction mixture was allowed to stir at −5° C. for 45 min, and then allowed to warm to 5° C. To the mixture was added 5 mL of 25% aq sodium metabisulfite and the two phase mixture was allowed to settle. To the organic phase was added 5.7 mL (0.1 mol) of glacial acetic acid, and the solution concentrated in vacuo to an oil. This oil was dissolved in 70 mL of CH2Cl2 and washed with 50 mL of water. The aqueous layer was re-extracted with 30 mL of CH2Cl2. The organics were combined and dried over MgSO4. After filtration, the dichloromethane solution was analyzed by LC and contained 42:52 (area) ratio of isomers A and B above.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[K+].Br[CH2:11][CH2:12][CH2:13][C:14]#[N:15].[CH3:16]N(C=O)C>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][CH2:16][CH2:11][CH2:12][CH2:13][C:14]#[N:15]
Reactant: Nc1ccccn1
Reactant: N#CCCCBr
Reactant: CN(C)C=O
Agent: [H-]
Agent: [K+]
Product: N#CCCCCNc1ccccn1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 2-aminopyridine (8.7 g, Aldrich) in DMF (75 mL) was added potassium hydride (12.6 g, 30 wt. % dispersion in mineral oil, Aldrich). After 1 hr, 4-bromobutyronitrile (15 g, Aldrich) was added. The mixture was heated to 60° C. for 16 hr. The mixture was quenched with water and the volatiles were removed in vacuo. The residue was extracted with ethyl acetate. The extract was filtered through a bed of silica gel and distilled in vacuo. The fraction boiling at 150° C. to 170° C. was collected to provide the title product as a white solid. 1H (CDCl3) δ 1.78 (4H, m); 2.41 (2H, t); 3.36 (2H, q); 4.53 (2H, broad t); 6.38 (1H, dt); 6.57 (1H, ddd); 7.42 (1H, ddd); 8.08 (1H, ddd). Step 2 (Alternate Procedure to Step 3, EXAMPLE A)
Reaction SMILES: [I:1][C:2]1[CH:32]=[CH:31][C:5]([C:6]([NH:8][NH:9][C:10](=O)[C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH:23]4[CH2:28][CH2:27][CH:26]([CH3:29])[CH2:25][CH2:24]4)[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)=O)=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:34].[OH-].[Na+]>N1C=CC=CC=1.O>[I:1][C:2]1[CH:32]=[CH:31][C:5]([C:6]2[S:34][C:10]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([CH:23]5[CH2:28][CH2:27][CH:26]([CH3:29])[CH2:25][CH2:24]5)[CH2:19][CH2:18]4)=[CH:13][CH:12]=3)=[N:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CC1CCC(N2CCN(c3ccc(C(=O)NNC(=O)c4ccc(I)cc4)cc3)CC2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: CC1CCC(N2CCN(c3ccc(-c4nnc(-c5ccc(I)cc5)s4)cc3)CC2)CC1
Temperature: 120 °C
Reaction time: 2.5 h
Yield: 119.7 %

Procedure:
A suspension of N′-(4-iodobenzoyl)-4-[4-(4-methylcyclohexyl)-1-piperazinyl]benzohydrazide (22.95 g) in pyridine (459 ml) was treated with phosphorus pentasulfide (11.2 g) and stirred at 120° C. for 2.5 hours. The reaction mixture was added a solution of sodium hydroxide (510 g) in water (9200 ml). The resulting precipitate was collected, washed with acetone. The powder was recrystallized from THF (800 ml) and dried to give 1-[4-[5-(4-iodophenyl)-1,3,4-thiadiazol-2-yl]phenyl]-4-(4-methylcyclohexyl)piperazine (16.42 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:27][C@H:28]3[CH2:32][CH2:31][CH2:30][N:29]3[C:33](=[O:37])[CH2:34][C:35]#[N:36])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=4[F:25])=[CH:13][C:12]=3[F:26])[C:3]=12.[CH2:38]([O:40][C:41]([CH3:45])([CH3:44])[CH:42]=O)[CH3:39].N1CCCCC1>CCO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:27][C@H:28]3[CH2:32][CH2:31][CH2:30][N:29]3[C:33]([C:34](=[CH:42][C:41]([O:40][CH2:38][CH3:39])([CH3:45])[CH3:44])[C:35]#[N:36])=[O:37])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=4[F:25])=[CH:13][C:12]=3[F:26])[C:3]=12
Reactant: N#CCC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3cccc(F)c3F)cc2F)c2c(N)ncnc21
Reactant: CCOC(C)(C)C=O
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(C)(C)C=C(C#N)C(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3cccc(F)c3F)cc2F)c2c(N)ncnc21
Reaction time: 0.33 h
Yield: 12.4 %

Procedure:
A solution of 3-((R)-2-((4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)-3-oxopropanenitrile (202.8 mg, 0.40 mmol, 1.0 equiv), 2-ethoxy-2-methylpropanal (232 mg, 2.00 mmol, 5.0 equiv), piperidine (68 mg, 0.80 mmol, 2.0 equiv) in EtOH (20 mL) was stirred at room temperature overnight. The volatile phase was removed off under reduced pressure. The residue was purified on Prep-HPLC. Conditions: (1#-Pre-HPLC-001 (SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water in 0.05% TFA and CH3CN (40% CH3CN up to 100% in 20 min); Detector, 254 nm. This resulted in 30 mg (10.43%) of the title compound as a white solid. MS (ESI, pos. ion) m/z: 606 (M-TFA+1)
Reaction SMILES: [NH2:1][C:2]1[C:7]([SH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1)(=[O:11])=[O:10].[N:22]#[C:23]Br>C1COCC1>[NH2:22][C:23]1[S:8][C:7]2[C:2](=[C:3]([S:9]([NH:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=3)(=[O:10])=[O:11])[CH:4]=[CH:5][CH:6]=2)[N:1]=1
Reactant: Nc1c(S)cccc1S(=O)(=O)Nc1ccc(C(=O)O)cc1
Reactant: N#CBr
Solvent: C1CCOC1
Product: Nc1nc2c(S(=O)(=O)Nc3ccc(C(=O)O)cc3)cccc2s1
Temperature: 80 °C
Reaction time: 8 h
Yield: 100.9 %

Procedure:
To a solution of 4-(2-amino-3-mercaptophenylsulfonamido)benzoic acid (671 mg, 2.07 mmol) in THF (15 mL) was added cyanic bromide (439.1 mg, 4.14 mmol) at r.t. The reaction mixture was stirred at 80° C. for 8 h. The resulting mixture was then cooled, and partitioned between water and EtOAc. The organic phase was washed with brine, dried over anhy. Na2SO4 and concentrated in vacuo to afford the title compound (730 mg). LC-MS: m/z 348.7 (M+H)+
Reaction SMILES: [CH:1]1([CH2:8][CH2:9][NH:10][C:11](=[O:42])[C@H:12]([CH3:41])[C@H:13]([C@@H:16]2[CH2:20][CH2:19][CH2:18][N:17]2[C:21](=[O:40])[CH2:22][C@@H:23]([O:38][CH3:39])[C@@H:24]([N:29]([CH3:37])[C:30](=[O:36])[C@H:31]([CH:33]([CH3:35])[CH3:34])[NH2:32])[C@@H:25]([CH3:28])[CH2:26][CH3:27])[O:14][CH3:15])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=[CH:2]1.[C:43]([O:47][C:48]([N:50]1[CH2:57][CH2:56][CH2:55][C@@:51]1([CH3:58])[C:52](O)=[O:53])=[O:49])([CH3:46])([CH3:45])[CH3:44].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>ClCCl>[C:43]([O:47][C:48]([N:50]1[CH2:57][CH2:56][CH2:55][C@@:51]1([CH3:58])[C:52]([NH:32][C@H:31]([C:30]([N:29]([C@@H:24]([C@@H:25]([CH3:28])[CH2:26][CH3:27])[C@H:23]([O:38][CH3:39])[CH2:22][C:21]([N:17]1[CH2:18][CH2:19][CH2:20][C@H:16]1[C@H:13]([O:14][CH3:15])[C@@H:12]([CH3:41])[C:11]([NH:10][CH2:9][CH2:8][CH:1]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=[CH:2]1)=[O:42])=[O:40])[CH3:37])=[O:36])[CH:33]([CH3:34])[CH3:35])=[O:53])=[O:49])([CH3:46])([CH3:44])[CH3:45]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)NCCC1C=CC=CC=C1)OC)N(C)C(=O)[C@@H](N)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCC[C@@]1(C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)NCCC1C=CC=CC=C1)OC)N(C)C(=O)[C@@H](NC(=O)[C@]1(C)CCCN1C(=O)OC(C)(C)C)C(C)C

Procedure:
According to the general procedure D, from #176 (100 mg, 0.170 mmol, 1 eq.), (S)-1-(tert-butoxycarbonyl)-2-methyl-L-proline (50.7 mg, 0.221 mmol, 1.3 eq.), dichloromethane (4.3 mL), HATU (84.9 mg, 0.221 mmol, 1.3 eq.) and N,N-diisopropylethylamine (0.123 mL, 0.697 mmol, 4.1 eq.), was synthesized the crude desired material, which was purified by silica gel chromatography (Gradient: 0 to 100% ethyl acetate in heptane) to afford #181 (142 mg, assume quantitative yield). LC-MS (Protocol Q1): m/z 800.6 [M+H+], retention time=1.11 minutes.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1.[Mg].II.BrC1SC2C=CC=CC=2C=1.CON(C)[C:27](=[O:29])[CH3:28]>O1CCCC1>[S:6]1[CH:7]=[CH:8][C:4]2[CH:3]=[C:2]([C:27](=[O:29])[CH3:28])[CH:10]=[CH:9][C:5]1=2
Reactant: CON(C)C(C)=O
Reactant: Brc1ccc2sccc2c1
Agent: Brc1cc2ccccc2s1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(=O)c1ccc2sccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Approximately 1 ml of a solution of 5-bromobenzo[b]thiophene (6.6 g; prepared in a manner similar to that described in Example 21) in tetrahydrofuran (35 ml) was added under nitrogen to a mixture of magnesium turnings (0.8 g), tetrahydrofuran (7 ml) and a few small crystals of iodine, heat was applied to initiate the reaction, then the remainder of the bromobenzo[b]thiophene solution was added at reflux temperature over 20 minutes. When the addition was complete, the mixture was heated under reflux for 45 minutes, then a solution of N-methoxy-N-methylacetamide (3.8 g) in tetrahydrofuran (35 ml) was added. The mixture was heated under reflux for 30 minutes, cooled to ambient temperature, then quenched by the addition of 2M hydrochloric acid (90 ml) and stirred at ambient temperature for 30 minutes. The majority of the tetrahydrofuran was removed in vacuo, then water (150 ml) was added to the residue and the product was extracted into ethyl acetate (150 ml). The extract was washed with saturated aqueous sodium chloride solution (100 ml), dried (MgSO4) and the solvent removed in vacuo. The residue was purified by flash chromatography over silica using a 95:5 mixture of petroleum ether (b.p. 60-80° C.) and ethyl acetate as eluant. Appropriate fractions were combined and the solvents removed in vacuo to give 1-(benzo[b]thiophen-5-yl]ethan-1-one (2.35 g) as a white solid which was used without further purification.
Reaction SMILES: S([O-])([O-])=O.[C:5](=[O:8])([O-])[O-].[K+].[K+].[C:11]([NH:14][C:15]1[CH:20]=[CH:19][C:18](O)=[CH:17][CH:16]=1)(=[O:13])[CH3:12]>CN(C)C=O>[C:11]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([O:8][CH3:5])=[CH:17][CH:16]=1)(=[O:13])[CH3:12]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: O=S([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(NC(C)=O)cc1
Temperature: 100 °C
Yield: 138.4 %

Procedure:
To a three-necked 100 ml flask equipped for reflux and fitted with a mechanical stirrer was added 10 ml (0.12 mol) of diemthyl sulfite, 2.0 g (0.014 mol) of potassium carbonate, 10 ml dimethylformamide and 5.0 g (0.033 mol) of p-acetamidophenol. The mixture was heated to 100° C. for six hours then quenched while hot with 200 ml of water. The solution was made basic with dilute caustic and the organic materials were extracted into methylene chloride. The extracts were concentrated in vacuo to give 3.2 g of p-acetamidoanisole.