Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=4)[N:20]=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[CH2:31]([N:33]=[C:34]=[S:35])[CH3:32].O.[Cl-].[Na+]>CN(C)C=O>[CH3:28][O:27][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][C:23]=1[O:29][CH3:30])[N:20]=[CH:19][N:18]=[C:17]2[N:14]1[CH2:13][CH2:12][N:11]([C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:34]([NH:33][CH2:31][CH3:32])=[S:35])=[CH:3][CH:4]=2)=[O:10])[CH2:16][CH2:15]1
Reactant: CCN=C=S
Reactant: COc1cc2ncnc(N3CCN(C(=O)Nc4ccc(N)cc4)CC3)c2cc1OC
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCNC(=S)Nc1ccc(NC(=O)N2CCN(c3ncnc4cc(OC)c(OC)cc34)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
To a solution of 514.0 mg (1.26 mmol) of N-(4-aminophenyl)-4-(6,7-dimethoxy-4-quinazolinyl)-1-piperazinecarboxamide obtained in Example 221 in 10 ml of dimethylformamide was added 0.13 ml (1.51 mmol) of ethyl isothiocyanate, followed by overnight stirring at room temperature. To the resulting mixture was added 0.13 ml (1.51 mmol) of ethyl isothiocyanate, followed by overnight stirring. The reaction mixture was poured into water, and sodium chloride was added thereto. The precipitated crystals were collected by filtration, washed with water, and dried, followed by purification by silica gel chromatography to give the desired compound as colorless crystals.
Reaction SMILES: [Na].[C:2]1([NH:8][NH2:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][CH:11]([CH3:16])[CH:12]=[CH:13][C:14]#[N:15]>C(O)C>[NH2:15][C:14]1[CH2:13][CH:12]([CH:11]([CH3:16])[CH3:10])[N:8]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:9]=1
Reactant: NNc1ccccc1
Reactant: CC(C)C=CC#N
Agent: [Na]
Solvent: CCO
Product: CC(C)C1CC(N)=NN1c1ccccc1

Procedure:
A 0.31 g. amount of sodium metal is dissolved in 150 ml. of absolute ethanol, then 6.3 g. of phenylhydrazine is added followed by 5.5 g. of 4-methyl-2-pentenonitrile. The reaction mixture is refluxed for 16 hours. The solvent is removed in vacuo, water is added to the residue and the mixture is extracted with dichloromethane. The extract is dried over anhydrous magnesium sulfate and evaporated to give a gum. The gum is chromatographed on a column containing 400 g. of a synthetic magnesium silicate absorbent. The column is eluted first with protions of 21/2% acetone-hexane and 5% acetone-hexane to remove exteraneous colored material, then with portions of 25% and 10% acetone-hexane to remove the product. The product cuts are evaporated to give 2.7 g. of a dark gum which solidifies on standing. This material is recrystallized twice from ether-hexane to give 1.7 g. of the product of the Example as tan crystals, m.p. 115°-117° C.
Reaction SMILES: [I-:1].[Na+].[CH3:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11](=[O:26])[CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22]Cl)=[C:16]([O:24][CH3:25])[CH:15]=2)[CH2:6][CH2:5]1>CC(CC)=O>[CH3:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11](=[O:26])[CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][I:1])=[C:16]([O:24][CH3:25])[CH:15]=2)[CH2:6][CH2:5]1
Reactant: [I-]
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCCl
Agent: [Na+]
Solvent: CCC(C)=O
Product: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCI
Reaction time: 19 h

Procedure:
19.5 g of sodium iodide was added to a solution of 4.57 g of N-(trans-4-methylcyclohexyl)-4-(2-chloroethoxy)-3-methoxycinnamamide (Example 138) in 300 ml of methylethylketone. The solution was stirred for 19 hours, while it was refluxed. After reaction, the reaction solution was washed three times with 200 ml of an aqueous sodium thiosulfate solution and once with an aqueous sodium chloride solution, and was dried over magnesium sulfate. Then, the solvent was removed in vacuo. The product obtained was recrystallized from methylene chloride/ether, yielding 4.86 g of N-(trans-4-methylcyclohexyl)-4-(2-iodoethoxy)-3-methoxycinnamamide (a compound of the present invention) as white crystal, which had the following physiochemical properties:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[N:3]=1.FC(F)(F)C(O)=O.C(N(CC)CC)C.[CH3:40][N:41]([CH3:51])[C:42]1[CH:47]=[CH:46][C:45]([N:48]=[C:49]=[O:50])=[CH:44][CH:43]=1>>[CH3:40][N:41]([CH3:51])[C:42]1[CH:47]=[CH:46][C:45]([NH:48][C:49]([N:23]2[CH2:22][CH2:21][CH:20]([NH:19][C:4]3[N:3]=[C:2]([NH2:1])[C:7]([C:8](=[O:9])[C:10]4[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=4[O:17][CH3:18])=[CH:6][N:5]=3)[CH2:25][CH2:24]2)=[O:50])=[CH:44][CH:43]=1
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Reactant: CN(C)c1ccc(N=C=O)cc1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(C(=O)Nc3ccc(N(C)C)cc3)CC2)nc1N
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred suspension of the compound of Example 59 in the form of its trifluoroacetic acid salt (45 mg), triethylamine (150 μL, 1.08 mmol) was added followed by 4-dimethylamino-phenyl-isocyanate (Aldrich, 33 mg, 0.20 mmol), and the solution was stirred at room temperature for 1.5 hours. The solution was then concentrated and the residue was purified by reverse phase HPLC to give a solid, (34 mg). MS(ES) (M+H)+=508.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].O.[C:11](Cl)(Cl)=[S:12]>C(Cl)Cl>[Cl:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[N:4]=[C:11]=[S:12]
Reactant: Nc1ccc(I)cc1Cl
Reactant: S=C(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: S=C=Nc1ccc(I)cc1Cl
Reaction time: 8 h
Yield: 86.8 %

Procedure:
To a stirred solution of 2-chloro-4-iodoaniline (1.0 g, 3.9 mmol) in DCM (50 mL) was added water (20 mL) followed by thiophosgene (476 mg, 4.1 mmol). The reaction mixture was stirred overnight before the layers were separated and the organic layer dried (Na2SO4) and evaporated in vacuo to give the desired product as a brown solid (1.0 g, 86%). δH (CDCl3) 7.79 (1H, d, J=1.9 Hz), 7.58 (1H, dd, J 1.9, 8.4 Hz), 6.97 (1H, d, J=8.4 Hz).
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)C.[OH-].[Li+:26].C(#N)C>O1CCCC1>[Li+:26].[C:20]([C:17]1[CH:16]=[CH:15][C:14]([N:11]2[CH2:10][CH2:9][N:8]([CH2:7][CH2:6][CH2:5][C:4]([O-:24])=[O:3])[CH2:13][CH2:12]2)=[CH:19][CH:18]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CCOC(=O)CCCN1CCN(c2ccc(C(C)(C)C)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(N2CCN(CCCC(=O)[O-])CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 189.9 %

Procedure:
To 4-[4-(4-tert-butyl-phenyl)-piperazin-1-yl]-butyric acid ethyl ester (1.41 g; 4.24 mmol, prepared in accordance with Example 166) is added a solution of lithium hydroxide (59 mg; 2.46 mmol in 3 mL of water) diluted with tetrahydrofuran (3 mL) and the resulting mixture is stirred at room temperature for one hour. Acetonitrile (50 mL) is added and the precipitate formed is then filtered and dried under high vacuum to afford the desired product (1.45 g) which is used in the next step without further purification.
Reaction SMILES: [CH:1]12[CH2:6][CH:5]1[CH2:4][N:3]([C:7]1[S:8][CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=3[F:19])[N:11]=1)[CH2:2]2.Br[C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1.C([O-])(=O)C.[K+]>CC(N(C)C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:5]12[CH2:6][CH:1]1[CH2:2][N:3]([C:7]1[S:8][C:9]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=3[F:19])[N:11]=1)[CH2:4]2
Reactant: Fc1ccc(-c2csc(N3CC4CC4C3)n2)c(F)c1
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: NS(=O)(=O)c1ccc(-c2sc(N3CC4CC4C3)nc2-c2ccc(F)cc2F)cc1
Temperature: 150 °C
Yield: 24.8 %

Procedure:
To a solution of 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-(2,4-difluorophenyl)thiazole (Step 2 of compound 66, 0.23 g, 0.82 mmol) in dimethyl acetamide (5 ml) were added 4-bromobenzenesulfonamide (0.21 g, 0.90 mmol) and potassium acetate (0.16 g, 1.65 mmol) at 25° C. in a tube, the nitrogen gas was bubbled through reaction mixture for 15 minutes. To the reaction mixture was added palladium (II) acetate (0.019 gm, 0.08 mmol) under nitrogen and the reaction mixture was heated at 150° C. for 15 hr with stirring. The progress of reaction was monitored by TLC. The reaction mixture was cooled to 25° C. and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (50 ml). The reaction mixture was washed with water (2×10 ml), dried over sodium sulphate and concentrated under reduced pressure to obtain a crude product; which was purified by flash column chromatography using 40% ethyl acetate in hexanes as an eluent to obtain the title compound (0.088 g, 24.5%). MS: m/z 434 (M+1).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[C:6](=[O:16])[NH:5]2.[CH3:17][C:18]1[NH:19][CH:20]=[CH:21][N:22]=1>CN(C=O)C>[CH3:17][C:18]1[NH:19][CH:20]=[C:21]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[C:6](=[O:16])[NH:5]3)[N:22]=1
Reactant: Cc1ncc[nH]1
Reactant: O=c1[nH]c2cc(F)c([N+](=O)[O-])cc2[nH]c1=O
Solvent: CN(C)C=O
Product: Cc1nc(-c2cc3[nH]c(=O)c(=O)[nH]c3cc2[N+](=O)[O-])c[nH]1
Temperature: 130 °C
Yield: 42.3 %

Procedure:
In DMF, 1 g of 6-fluoro-7-nitroquinoxaline-2,3-(1H,4H)-dione and 1.8 g of 2-methylimidazole were stirred with heating at 130° C. for 8 hours. The reaction mixture was then concentrated and diluted with water, whereupon crystals separated out. The crystals were recrystallized from DMF-water to provide 540 mg of 6-(2-methylimidazolyl)-7-nitroquinoxaline-2,3-(1H,4H)-dione.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[S:6][C:7]([CH:10]=O)=[CH:8][N:9]=1.N1C=CC=CC=1.Cl.[NH2:25][OH:26]>O>[Cl:1][C:2]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[S:6][C:7]([CH:10]=[N:25][OH:26])=[CH:8][N:9]=1
Reactant: COc1ccc(Oc2ncc(C=O)s2)c(Cl)c1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(Oc2ncc(C=NO)s2)c(Cl)c1
Temperature: 80 °C
Yield: 95.8 %

Procedure:
To a solution of Example 30B (13.05 g, 48.4 mmol) in pyridine (38.8 g, 484 mmol) was added hydroxylamine hydrochloride (33.7 g, 484 mmol). The mixture was heated at 80° C. for 0.5 hours, cooled to ambient temperature, treated with water (1000 mL) and filtered. The collected solids were dried in a vacuum oven to provide 13.2 g of the title compound (96%) as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.82 (s, 3H) 7.03 (dd, J=9.01, 3.13 Hz, 1H) 7.25 (d, J=2.94 Hz, 1H) 7.52 (d, J=8.82 Hz, 1H) 7.68 (s, 1H) 7.81 (s, 1H) 12.02 (s, 1H); MS (ESI) m/z 284.9 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]12[CH2:17][C:16]([CH3:19])([CH3:18])[C:15](=[O:20])[C:14]([CH3:21])=[C:13]1[C:12]1[C:7](=[CH:8][C:9]([O:22]COC)=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4].Cl.C([O-])(O)=O.[Na+]>CO.CCOC(C)=O>[CH2:1]([C:5]12[CH2:17][C:16]([CH3:19])([CH3:18])[C:15](=[O:20])[C:14]([CH3:21])=[C:13]1[C:12]1[C:7](=[CH:8][C:9]([OH:22])=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC12Cc3cc(OCOC)ccc3C1=C(C)C(=O)C(C)(C)C2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCC12Cc3cc(O)ccc3C1=C(C)C(=O)C(C)(C)C2
Temperature: 67.5 °C

Procedure:
A solution of 9a-butyl-7-methoxymethoxy-2,2,4-trimethyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (28 mg, 0.08 mmol) in methanol (2 mL) was placed under a nitrogen atmosphere and treated with 2N aqueous HCl (0.12 mL, 0.24 mmol). The resulting yellow solution was stirred and heated in an oil bath at 55-80° C. for 45 minutes. After cooling to room temperature, the mixture was diluted with EtOAc (60 mL) and shaken with 5% aqueous NaHCO3. The aqueous portion was separated and extracted with EtOAc (40 mL). The combined organics were washed with water and brine, dried over MgSO4, filtered, and concentrated under vacuum to an oil. The crude product was purified by PLC on a 0.1×20×20 cm silica gel GF plate, developing twice with 4:1 hexanes-EtOAc. The band at Rf 0.34-0.43 was eluted with EtOAc and the eluant evaporated under vacuum to a residue which was lyophilized from benzene to afford 9a-butyl-7-hydroxy-2,2,4-trimethyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one as an amorphous solid.
Reaction SMILES: CON=[C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[C:14]([C:22]4[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=4)=[N:15][N:16]4[CH:21]=[CH:20][CH:19]=[N:18][C:17]=34)=[CH:10][CH:11]=2)[CH2:6][CH2:5]1.Cl.[O:29]1CCOCC1>C(OCC)(=O)C>[N:25]1[CH:26]=[CH:27][C:22]([C:14]2[C:13]([C:9]3[CH:8]=[C:7]4[C:12](=[CH:11][CH:10]=3)[C:4](=[O:29])[CH2:5][CH2:6]4)=[C:17]3[N:18]=[CH:19][CH:20]=[CH:21][N:16]3[N:15]=2)=[CH:23][CH:24]=1
Reactant: CON=C1CCc2cc(-c3c(-c4ccncc4)nn4cccnc34)ccc21
Reactant: C1COCCO1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C1CCc2cc(-c3c(-c4ccncc4)nn4cccnc34)ccc21
Temperature: 100 °C

Procedure:
To 5-(2-(pyridin-4-yl)pyrazolo[1.5-a]pyrimidin-3-yl)-2,3-dihydroinden-1-one O-methyl oxime (0.090 g; Example 7, Step 5) in 1.3 mL dioxane was added 1.3 mL 4M hydrochloric acid and the mixture was heated to 100° C. for 5 hours. The cooled reaction mixture was diluted with ethyl acetate, washed with 10% aqueous potassium carbonate, dried over sodium sulfate, filtered, and evaporated to yield 75 mg product as a yellow-brown-solid. This material was carried on without further purification.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[C:5]([OH:10])=[N:6][CH:7]=[CH:8][CH:9]=1.S([O-])([O-])=O.[Na+].[Na+]>CN(C)C=O.O>[Br:1][C:8]1[CH:9]=[C:4]([Cl:3])[C:5]([OH:10])=[N:6][CH:7]=1
Reactant: Oc1ncccc1Cl
Reactant: BrBr
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Oc1ncc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
10.5 ml (203.0 mmol) of bromine are added dropwise at 0° C. to 23.9 g (184.5 mmol) of 3-chloro-2-hydroxypyridine in 240 ml of dimethylformamide, and the mixture is stirred at room temperature for 2 hours. 200 ml of water are subsequently added, and 30 g of sodium sulfite in 100 ml of water are added dropwise. After 15 minutes, the mixture is extracted three times with 200 ml of dichloromethane in each case, the combined organic phases are dried over sodium sulfate and filtered, and the filtrate is evaporated to dryness, giving 36.58 g of 5-bromo-3-chloro-2-hydroxypyridine. ##STR13## m.p.: 168° C. (decomp.)
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([SH:10])[NH:9][C:5]=2[CH:4]=1.[OH-].[Na+].Br[CH2:18][C:19]1[C:24]([O:25][CH3:26])=[C:23]([O:27][CH3:28])[CH:22]=[CH:21][N:20]=1>CO>[CH3:26][O:25][C:24]1[C:19]([CH2:18][S:10][C:8]2[NH:9][C:5]3[CH:4]=[C:3]([C:2]([F:13])([F:1])[F:14])[CH:12]=[CH:11][C:6]=3[N:7]=2)=[N:20][CH:21]=[CH:22][C:23]=1[O:27][CH3:28]
Reactant: FC(F)(F)c1ccc2nc(S)[nH]c2c1
Reactant: COc1ccnc(CBr)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccnc(CSc2nc3ccc(C(F)(F)F)cc3[nH]2)c1OC
Reaction time: 1 h
Yield: 16.6 %

Procedure:
To a solution of 5-trifluoromethyl-2-mercaptobenzimidazole (1.10 g), 1N-sodium hydroxide (7.2 ml), and methanol (5 ml) was added a solution of 2-bromomethyl-3,4-dimethoxypyridine (1.3 g) in methanol (35 ml) at room temperature over 10 minutes. The mixture was stirred for one hour, concentrated, and extracted with chloroform. The organic layer was washed with 1N-sodium hydroxide and then with water, dried, and evaporated. The residue was purified by column chromatography on silica gel (chloroform-ethyl acetate-acetone (1:1:0.1)) and recrestallized from chloroform-isopropyl ether, to give 2-[(3,4-dimethoxypyrid-2-yl)methylthio]-5-trifluoromethylbenzimidazole (310 mg) as white crystals.
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]4[N:23]([C:35]5[CH:36]=[C:37]([N:41]6[S:45](=[O:47])(=[O:46])[NH:44][C:43](=[O:48])[CH2:42]6)[CH:38]=[CH:39][CH:40]=5)[CH:24]=[C:25]([C:27]5[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=5[Cl:34])[N:26]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:49](=O)[CH3:50]>>[CH:1]1([CH2:7][N:8]([CH2:49][CH3:50])[C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:16]=[CH:17][C:18]([CH2:21][C:22]4[N:23]([C:35]5[CH:36]=[C:37]([N:41]6[S:45](=[O:47])(=[O:46])[NH:44][C:43](=[O:48])[CH2:42]6)[CH:38]=[CH:39][CH:40]=5)[CH:24]=[C:25]([C:27]5[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=5[Cl:34])[N:26]=4)=[CH:19][CH:20]=3)=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(NCC5CCCCC5)cc4)cc3)c2)S(=O)(=O)N1
Reactant: CC=O
Product: CCN(CC1CCCCC1)c1ccc(-c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3-c3cccc(N4CC(=O)NS4(=O)=O)c3)cc2)cc1

Procedure:
5-{3-[2-[4′-(Cyclohexylmethyl-amino)-biphenyl-4-ylmethyl]-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-[1,2,5]thiadiazolidin-3-one-1,1-dioxide (7 mg, 0.01 mmol) was reacted with acetaldehyde (2 mg, 0.04 mmol) following general procedure X to give 5-{3-[2-[4′-(cyclohexylmethyl-ethyl-amino)-biphenyl-4-ylmethyl]-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]#[N:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1>CN(C=O)C.C1(C)C=CC=CC=1>[C:1]1([S:7]([C:10](=[CH:18][C:17]2[CH:20]=[CH:21][C:14]([OH:13])=[CH:15][CH:16]=2)[C:11]#[N:12])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CCS(=O)(=O)c1ccccc1
Reactant: O=Cc1ccc(O)cc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: N#CC(=Cc1ccc(O)cc1)S(=O)(=O)c1ccccc1
Yield: 66 %

Procedure:
Phenylsulphonyl acetonitrile (2.0 g, 11.04 mmol) was mixed with 4-hydroxybenzaldehyde (1.35 g, 11.04 mmol) in DMF (10 mL) and toluene (20 mL). The mixture was refluxed for 3 hours and subsequently evaporated to dryness in vacuo. The residue was treated with diethyl ether and toluene. The solid formed was filtered to afford 2.08 g (66%) of 2-benzenesulfonyl-3-(4-hydroxyphenyl)acrylonitrile.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>S(=O)(=O)(O)O.[OH-].[Na+]>[C:1]1([C:7]2[C:15]([C:16](=[O:18])[CH3:17])=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2cc3ccccn3n2)cc1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)c1c(-c2ccccc2)nn2ccccc12
Yield: 47.7 %

Procedure:
2-Phenylpyrazolo[1,5-a]pyridine (2.00 g) was added to a stirred solution of acetic anhydride (4.20 g) and two drops of sulfuric acid at room temperature. After being stirred under reflux for 14 hours, the reaction mixture was poured onto 80 ml of 4N NaOH aqueous solution and extracted with chloroform (30 ml×2). The extracts were combined and washed with water (30 ml), saturated sodium chloride aqueous solution (30 ml), then dried over magnesium sulfate and evaporated in vacuo. The residual crystals were recrystallized from diisopropyl ether to give 2-phenyl-3-acetylpyrazolo[1,5-a]pyridine (1.16 g).
Reaction SMILES: [CH3:1][Si:2]([CH3:52])([CH3:51])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:43][O:44][CH2:45][CH2:46][Si:47]([CH3:50])([CH3:49])[CH3:48])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:34][CH2:33][N:32]([C:35]3[O:39][C:38]([C@H:40]([OH:42])[CH3:41])=[N:37][N:36]=3)[CH2:31][CH2:30]2)[CH:9]=1.C1C(=O)N([Br:60])C(=O)C1>C(#N)C>[CH3:48][Si:47]([CH3:50])([CH3:49])[CH2:46][CH2:45][O:44][CH2:43][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:51])([CH3:1])[CH3:52])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:30][CH2:31][N:32]([C:35]3[O:39][C:38]([C@H:40]([OH:42])[CH3:41])=[N:37][N:36]=3)[CH2:33][CH2:34]2)[C:9]=1[Br:60]
Reactant: C[C@@H](O)c1nnc(N2CCC(c3cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n4ncc(-c5ccc(-c6ccccc6)nc5)c4n3)CC2)o1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: C[C@@H](O)c1nnc(N2CCC(c3nc4c(-c5ccc(-c6ccccc6)nc5)cnn4c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c3Br)CC2)o1
Reaction time: 0.17 h
Yield: 27.4 %

Procedure:
To a solution of (R)-1-(5-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)ethanol (32 mg, 0.04 mmol) in acetonitrile (1 mL) was added NBS (7 mg, 0.04 mmol) and the resulting solution was stirred for 10 minutes and concentrated. The residue was purified on silica gel. Elution with EtOAc provided a relatively pure product (9 mg).
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C@@H:13]3[CH2:15][C@H:14]3[C:16]3[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=3)[C:19]#[N:20])=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.C(N)(=[O:26])C>C1COCC1.O.[Pd](Cl)Cl>[CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C@@H:13]3[CH2:15][C@H:14]3[C:16]3[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=3)[C:19]([NH2:20])=[O:26])=[O:12])[CH2:7][CH2:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: N#Cc1cccc([C@@H]2C[C@H]2C(=O)N2CCN(C3CCC3)CC2)c1
Reactant: CC(N)=O
Agent: Cl[Pd]Cl
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)c1cccc([C@@H]2C[C@H]2C(=O)N2CCN(C3CCC3)CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.3 %

Procedure:
33C (180 mg, 0.58 mmol) was dissolved in THF (3 mL) and added to acetamide (687 mg, 11.64 mmol) and palladium(II) chloride (61.9 mg, 0.35 mmol) in H2O (1 mL). This suspension was left stirring at RT for 1 h then the temperature was increased to 50° C. and reaction stirred for 2 h. The reaction mixture was filtered on a Varian C18 reverse phase cartridge and the cartridge was washed with MeOH. The crude material was purified on preparative HPLC MS using the long high pH 25 to 45% gradient method (ACN in H2O ammonium carbonate buffer, 25 min.) on XBridge Prep C18 OBD, 30×150 mm, 5 mm, Waters reverse phase column. Evaporation of the desired pure fractions provided 105 mg 33D (55.1% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.28-1.39 (m, 1H) 1.63-1.79 (m, 3H) 1.80-1.96 (m, 2H) 1.97-2.13 (m, 3H) 2.32 (q, J=4.82 Hz, 4H) 2.56 (ddd, J=9.28, 5.76, 4.10 Hz, 1H) 2.65-2.83 (m, 1H) 3.54-3.77 (m, 4H) 5.58 (br. s., 1H) 6.07 (br. s., 1H) 7.30-7.43 (m, 2H) 7.52-7.61 (m, 2H), ES (M+H)+=328.3.
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH2:22][CH2:21][N:13]3[C:14]4[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=4[CH:20]=[C:12]3[C:11]2=[O:23])[C:3]=1[CH:4]=[O:5].[CH3:24][N:25]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[C:27]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([N:47]3[CH2:52][CH2:51][N:50]([CH:53]4[CH2:56][O:55][CH2:54]4)[CH2:49][CH2:48]3)=[CH:43][N:42]=2)[C:26]1=[O:57]>[Pd].O1CCCC1>[CH3:24][N:25]1[C:26](=[O:57])[C:27]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([N:47]3[CH2:52][CH2:51][N:50]([CH:53]4[CH2:54][O:55][CH2:56]4)[CH2:49][CH2:48]3)=[CH:43][N:42]=2)=[CH:28][C:29]([C:2]2[N:9]=[CH:8][CH:7]=[C:6]([N:10]3[CH2:22][CH2:21][N:13]4[C:14]5[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=5[CH:20]=[C:12]4[C:11]3=[O:23])[C:3]=2[CH:4]=[O:5])=[CH:30]1
Reactant: O=Cc1c(N2CCn3c(cc4c3CCCC4)C2=O)ccnc1Cl
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Agent: [Pd]
Solvent: C1CCOC1
Product: Cn1cc(-c2nccc(N3CCn4c(cc5c4CCCC5)C3=O)c2C=O)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Temperature: 25 °C
Yield: 63 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 104b (658 mg, 1.0 mmol), 1-methyl-3-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl)pyridin-2(1H)-one 101l (622 mg, 2.0 mmol), Pd (dppf) Cl2 (65 mg, 0.08 mmol), K3PO4.3H2O (361 mg, 1.6 mmol), and tetrahydrofuran (40 mL). After three cycles of vacuum/argon flush, the mixture was heated at reflux for 4 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (40:1) to afford 104c as a yellow solid (400 mg, 63%). MS: [M+H]+ 635.