Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[C:28]([C:29]2[N:33](C3CCCCO3)[N:32]=[CH:31][CH:30]=2)=[CH:27][C:12]([C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([Cl:26])([F:25])[F:24])=[CH:18][CH:17]=2)=[O:14])=[CH:11][N:10]=1>C(Cl)Cl>[Cl:8][C:9]1[C:28]([C:29]2[NH:33][N:32]=[CH:31][CH:30]=2)=[CH:27][C:12]([C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([Cl:26])([F:25])[F:24])=[CH:18][CH:17]=2)=[O:14])=[CH:11][N:10]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2ccnn2C2CCCCO2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2ccn[nH]2)c1
Temperature: 25 °C

Procedure:
TFA (7.3 mL) was added to a solution of 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide (Stage 48.2, 1.285 g, 2.366 mmol) in DCM (20 mL) and the RM was stirred at RT. The solvent was evaporated off under reduced pressure and the residue was dissolved in EtOAc (150 mL), washed with aq. sat. NaHCO3 solution (2×50 mL) and water (2×50 mL) dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a residue was crystallized from iPr2O/EtOAc to give the title product as a white solid. HPLC (Condition 7) tR=6.797 min, UPLC-MS (Condition 3) tR=1.05-min, m/z=398.9/401.0 [M+H]+.
Reaction SMILES: [C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl.[CH3:17][N:18]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](Cl)=[O:26])[CH3:19]>C1(C)C=CC=CC=1>[CH3:17][N:18]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:1]1=[O:8])=[O:26])[CH3:19]
Reactant: CN(C)CCCCCC(=O)Cl
Reactant: O=C1CCCCCN1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CN(C)CCCCCC(=O)C1CCCCNC1=O
Temperature: 101 °C
Yield: 83.9 %

Procedure:
To a 1000 mL three-necked round-bottomed flask equipped with a reflux condenser, internal thermometer, argon inlet, and mechanical stirrer, are added ε-caprolactam (48.04 g, 0.42 mol), toluene (340 mL), and triethylamine (189.00 g, 1.87 mol). The mixture is heated to reflux (ca. 101° C.) for 15 min. While at that temperature, acid chloride 3 (100.00 g, 0.47 mol) is added as a solid over 30 min. The reaction is maintained at reflux for an additional 1.75 h before the heat is removed. At room temperature, the mixture is filtered and the salts washed with toluene. The dark filtrate is washed with saturated sodium bicarbonate solution (3×250 mL), water (100 mL), and dried over MgSO4. The mixture is filtered and concentrated by rotary evaporation at about 50° C. (water aspirator) and then by Kugelrohr distillation at 60° C. for 1 h to give 89.64 g (83%) of 4 as an oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[C:9]#[N:10])[NH2:5].[F-].[Cs+].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN1C(=O)CCC1.CCOC(C)=O.Cl[Pd](Cl)(P(C1CCCCC1)(C1CCCCC1)C1CCCCC1)P(C1CCCCC1)(C1CCCCC1)C1CCCCC1>[C:9]([C:8]1[CH:7]=[CH:6][C:4]([NH2:5])=[CH:3][C:2]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)#[N:10]
Reactant: N#Cc1ccc(N)cc1Cl
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([PH](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[PH](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: N#Cc1ccc(N)cc1-c1ccccc1
Temperature: 100 °C
Yield: 95.5 %

Procedure:
Commercially available 3-chloro-4-cyanoaniline (305 mg, 2.0 mmol) was dissolved in NMP (8 mL), and CsF (608 mg, 4.0 mmol), phenyl boronic acid (268 mg, 2.2 mmol) and dichlorobis(tricyclohexylphosphino)palladium (73mg, 0.1 mmol) were added. The reaction was then heated to 100° C. for 16 h. After cooling to rt, the reaction mixture was taken up in EtOAc, washed with water (2×), dried (Na2SO4), concentrated under reduced pressue, and purified by silica gel flash chromatography eluting with EtOAc/hexanes (1:1) to give compound 47A (371 mg, 96%) as a yellow solid. LC/MS m/z 195 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[NH:8][C:9](=[O:25])[N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:15][CH:14]=3)[C:11](=[O:12])[C:6]=2[CH:5]=[CH:4][N:3]=1.I[CH2:27][CH3:28].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:1][C:2]1[C:7]2[N:8]=[C:9]([O:25][CH2:27][CH3:28])[N:10]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]([F:23])([F:22])[F:24])=[CH:17][CH:18]=3)[C:11](=[O:12])[C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: O=c1[nH]c2c(Cl)nccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1nc2c(Cl)nccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
To a mixture of 8-chloro-3-[4-(2,2,2-trifluoroethoxy)phenyl]pyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (437 mg), iodoethane (0.19 ml) and N,N-dimethylformamide (10 ml) was added potassium carbonate (326 mg) at room temperature, and the mixture was stirred at 80° C. for 15 hr, and allowed to be cooled to room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (116 mg).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:27])[N:19]([CH2:23][C:24](O)=[O:25])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:30]([F:33])([F:32])[F:31])[CH:3]=1.[CH3:34][S:35]([NH2:38])(=[O:37])=[O:36]>>[F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:27])[N:19]([CH2:23][C:24]([NH:38][S:35]([CH3:34])(=[O:37])=[O:36])=[O:25])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:30]([F:32])([F:33])[F:31])[CH:3]=1
Reactant: CS(N)(=O)=O
Reactant: O=C(O)CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(F)cc3C(F)(F)F)c2)C1=O
Product: CS(=O)(=O)NC(=O)CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(F)cc3C(F)(F)F)c2)C1=O

Procedure:
2-[(5Z)-5-({1-[4-Fluoro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]-N-(methylsulfonyl)-acetamide was prepared from [(5Z)-5-({1-[4-fluoro-2-(trifluoromethyl)-benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]acetic acid (Example 122) following General Procedure L using methanesulfonic acid amide in place of the sulfamide.
Reaction SMILES: C[O:2][C:3]1[C:12]2[O:11][CH2:10][CH2:9][C:8](=[O:13])[C:7]=2[CH:6]=[CH:5][CH:4]=1.[Cl-].[Al+3].[Cl-].[Cl-].O>C1(C)C(C)=CC=CC=1>[OH:2][C:3]1[C:12]2[O:11][CH2:10][CH2:9][C:8](=[O:13])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1OCCC2=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1C
Solvent: O
Product: O=C1CCOc2c(O)cccc21
Temperature: 100 °C
Reaction time: 2 h
Yield: 56.6 %

Procedure:
2,3-Dihydro-8-methoxy-4H-1-benzopyran-4-one (7.59 g, 42.4 mmol) was dissolved in xylene (80 mL) followed by addition of anhydrous aluminum chloride (11.4 g, 85.5 mmol), and the mixture was stirred at 100° C. for 2 hours. After cooling, the reaction mixture was poured into iced water and extracted with ethyl acetate. The organic layer was washed with 1N-hydrochloric acid and saturated aqueous sodium chloride solution, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure and the residue was crystallized from methanol-ethyl acetate-diethyl ether to provide 3.94 g of the title compound. Yield 56%.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:17][CH3:18])=[C:4]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:5]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:7]=1.C[O:20][C:21](=O)[C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([N:29]2[CH:33]=[C:32]([C:34]3[CH:35]=[N:36][N:37]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:38]=3[CH2:39][CH3:40])[N:31]=[CH:30]2)[CH:23]=1>>[C:8]([C:6]1[CH:5]=[C:4]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:3]([O:17][CH3:18])=[C:2]([NH:1][C:21](=[O:20])[C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([N:29]3[CH:33]=[C:32]([C:34]4[CH:35]=[N:36][N:37]([C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)[C:38]=4[CH2:39][CH3:40])[N:31]=[CH:30]3)[CH:23]=2)[CH:7]=1)([CH3:10])([CH3:11])[CH3:9]
Reactant: COc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: CCc1c(-c2cn(-c3cc(C(=O)OC)ccc3C)cn2)cnn1-c1ccccc1
Product: CCc1c(-c2cn(-c3cc(C(=O)Nc4cc(C(C)(C)C)cc(NS(C)(=O)=O)c4OC)ccc3C)cn2)cnn1-c1ccccc1

Procedure:
Example 158 was prepared from N-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methanesulfonamide and 3-[4-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-4-methyl-benzoic acid methyl ester (Example 151) in the same manner as Example 151. ESI MS m/z 627 [C34H38N6O4S+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:7]=2[C:6]([C:16]2([C:27]#[N:28])[CH2:25][CH2:24][C:23]3[N:22]=[CH:21][NH:20][C:19](=[O:26])[C:18]=3[CH2:17]2)=[CH:5][CH:4]=1.[C:29](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:7]=2[C:6]([C:16]2([C:27]#[N:28])[CH2:25][CH2:24][C:23]3[N:22]=[CH:21][N:20]([CH3:29])[C:19](=[O:26])[C:18]=3[CH2:17]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2(C#N)CCc3nc[nH]c(=O)c3C2)c2c1oc1ccccc12
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc(C2(C#N)CCc3ncn(C)c(=O)c3C2)c2c1oc1ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.9 %

Procedure:
To a well stirred slurry of compound obtained in example 13 (75 mg, 0.2 mmol) and cesium carbonate (73 mg, 0.22 mmol) in dry DMF (5 ml) was added iodomethane (36.92 mg, 0.26 mol) and the mixture was allowed to stir for 1 hr at room temperature under nitrogen atmosphere. The reaction mixture was quenched with ice water (50 ml), and then extracted with ethyl acetate (50 ml). The organic layer was washed with water followed by brine and dried over sodium sulfate. The organic layer was concentrated under vacuum and the crude product was purified by column chromatography to get 40 mg of the pure product (Yields-52%) MP-235.4-240.8° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)[CH:5]=[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:3]=1.[OH-:37].[K+].O>C(O)C>[NH2:1][C:2]1[C:7]([C:8](=[O:37])[NH2:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)[CH:5]=[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:3]=1
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3ccccc3OCc3ccccc3)nc(N)c2C#N)C1
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3ccccc3OCc3ccccc3)nc(N)c2C(N)=O)C1
Temperature: 70 °C
Reaction time: 60 h
Yield: 73 %

Procedure:
To a stirred suspension of tert-butyl 3-{2-amino-6-[2-(benzyloxy)phenyl]-3-cyano-4-pyridinyl}-1-piperidinecarboxylate (0.300 g, 0.619 mmol), which was obtained in the step (1) of Example 1-1, in ethanol (10 mL) was added a solution of potassium hydroxide (0.695 g, 12.381 mmol) in ethanol (20 mL). The reaction mixture was stirred at 70° C. for 60 hrs. After cooled to room temperature, the reaction mixture was poured into water and the resulting solid was filtrated and dried under reduced pressure to give tert-butyl 3-{2-amino-6-[2-(benzyloxy)phenyl]-3-carbamoyl-4-pyridinyl}-1-piperidinecarboxylat as a white amorphous. (0.226 g, yield; 73%).
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([S:7][CH3:8])[N:3]=1.[CH3:9][CH:10]1[CH2:15][CH:14]([CH3:16])[CH2:13][NH:12][CH2:11]1>CN(C)C=O.COC(C)(C)C>[CH3:8][S:7][C:4]1[N:3]=[C:2]([N:12]2[CH2:13][CH:14]([CH3:16])[CH2:15][CH:10]([CH3:9])[CH2:11]2)[S:6][N:5]=1
Reactant: CC1CNCC(C)C1
Reactant: CSc1nsc(Cl)n1
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: CSc1nsc(N2CC(C)CC(C)C2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 79.6 %

Procedure:
In 9 ml of N,N-dimethylformamide was dissolved 740 mg of 5-chloro-3-methylthio-1,2,4-thiadiazole, and 1.25 g of 3,5-dimethylpiperidine (a mixture of 8:2 geometrical isomers) was added dropwise under ice-cooling. The mixture was stirred at room temperature for 20 minutes. The reaction mixture was diluted with tert-butyl methyl ether, and extracted with tert-butyl methyl ether after the addition of 10% hydrochloric acid. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 860 mg of 3-methylthio-5-(3,5-dimethylpiperidino)-1,2,4-thiadiazole.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=O)=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:22]1([NH2:29])[C:23]([NH2:28])=[CH:24][CH:25]=[CH:26][CH:27]=1>ClCCl>[NH2:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[NH:29][C:7]([C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1)=[O:9]
Reactant: O=C(O)c1ccncc1
Reactant: Nc1ccccc1N
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: Nc1ccccc1NC(=O)c1ccncc1
Reaction time: 1.42 h
Yield: 34 %

Procedure:
A stirred suspension of 4-pyridinecarboxylic acid (2.15 g, 17.5 mmol) in dichloromethane (40 ml) was treated with 1,1'-carbonyldiimidazole (3.115 g, 19.2 mmol) and the resulting solution was stirred for 85 minutes and added to 1,2-benzenediamine (3.777 g, 34.9 mmol) in dichloromethane (125 ml). After 3 hours, the precipitate formed was filtered and purified by chromatography (SiO2 ; ethyl acetate) to give the title compound as pale yellow crystals (1.267 g), m.p. 225°-235°.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][CH2:4][CH:5]=[O:6].[Br:9]Br>O1CCOCC1>[Br:9][CH:4]([CH2:3][C:2]([F:8])([F:7])[F:1])[CH:5]=[O:6]
Reactant: O=CCCC(F)(F)F
Reactant: BrBr
Solvent: C1COCCO1
Product: O=CC(Br)CC(F)(F)F
Temperature: 0 °C
Reaction time: 2 h
Yield: 76.2 %

Procedure:
To a mixture of 4,4,4-trifluorobutyraldehyde (5 g, 39.68 mmol) in 1,4-dioxane (5 ml) cooled to 0° C., bromine (2.24 ml, 43.65 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 2 h. The resulting reaction mixture was filtered through a pad of diatomaceous earth and the filtrate was washed with NaHCO3 (aqueous sat. solution). The organic layer was separated, dried (MgSO4) and evaporated in vacuo to yield compound D4 (6.2 g, 76%) that was used in the next reaction step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:56][CH:57]1[CH2:62][CH2:61][O:60][CH2:59][CH2:58]1>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:56][CH:57]4[CH2:62][CH2:61][O:60][CH2:59][CH2:58]4)=[O:21])=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: NC1CCOCC1
Reactant: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)NC2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.2 %

Procedure:
To a solution of 6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (60 mg, 0.2 mmol) in DMF (300 μL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (71 mg, 0.22 mmol), N,N-diisopropyl ethyl amine (171 μL, 1.0 mmol) and 4-aminotetrahydropyran (17.3 μL, 0.22 mmol). The resulting reaction mixture was stirred for 1 h at room temperature. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (38 mg, 85%) which was obtained as a white solid. MS: m/e=412.5 [M+H]+.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:20]3=[N:21][S:22](=[O:26])(=[O:25])[CH2:23][CH2:24][N:19]3[CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C1COCC1.CO.[Pt](=O)=O>[Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[C:20]3=[N:21][S:22](=[O:25])(=[O:26])[CH2:23][CH2:24][N:19]3[CH2:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C2=CC=CN3CCS(=O)(=O)N=C23)cc1
Agent: O=[Pt]=O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C2CCCN3CCS(=O)(=O)N=C23)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.6 %

Procedure:
Platinum(IV) oxide (2.0 g) was added to a solution of 9-(4-((tert-butyl(dimethyl)silyl)oxy)phenyl)-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (20.0 g) in THF (dry) (500 mL) and MeOH (300 mL) and the mixture was stirred at room temperature under H2 for 4 hr. The mixture was passed through NH silica gel cartridge with Celite (eluted with THF). The filtrate was concentrated in vacuo. The residual solid was recrystallized from THF (100 mL)-IPE (300 mL) to give the title compound (17.3 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[I:19]Cl.C(Cl)Cl>C(O)(=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:6][C:7]=1[I:19]
Reactant: ClI
Reactant: COc1ccc2nc(-c3ccc(N)cc3)sc2c1
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc2nc(-c3ccc(N)c(I)c3)sc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76 %

Procedure:
To a solution of 2-(4′-aminophenyl)-6-methoxy benzothiazole (22 mg, 0.09 mmol) in glacial acetic acid (2.0 mL) was injected 1 M iodochloride solution in CH2Cl2 (0.10 mL, 0.10 mmol, 1.2 eq.) under N2 atmosphere. The reaction mixture was stirred at room temperature for 16 hr. The glacial acetic acid was removed under reduced pressure and the residue was dissolved in CH2Cl2. After neutralizing the solution with NaHCO3, the aqueous layer was separated and extracted with CH2Cl2. The organic layers were combined and dried over MgSO4. Following the evaporation of the solvent, the residue was purified by preparative TLC(Hexanes:ethyl acetate=6:1) to give 2-(4′-amino-3′-iodophenyl)-6-methoxy benzothiazole (25 mg, 76%) as brown solid. 1HNMR (300 MHz, CDCl3) δ (ppm): 8.35 (d, J=2.0 Hz, 1H), 7.87 (dd, J1=2.0 Hz, J2=9.0 Hz, 1H), 7.31 (d, J=2.2 Hz, 1H), 7.04 (dd, J1=2.2 Hz, J2=9.0 Hz, 1H), 6.76 (d, J=9.0 Hz, 1H), 3.87 (s, 3H).
Reaction SMILES: O.[C:2]1([CH3:12])[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[C:14](Cl)(=[O:16])[CH3:15]>>[C:2]1([CH3:12])[CH:3]=[CH:4][C:5]([S:8]([O:11][C:14](=[O:16])[CH3:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: O
Product: CC(=O)OS(=O)(=O)c1ccc(C)cc1
Temperature: 60 °C
Reaction time: 0.42 h

Procedure:
Acetyl chloride (100 ml.; density=1.104 g./ml.) was charged into a suitable reaction flask containing 30 g. (0.158 mole) p-toluenesulfonic acid monohydrate. Vigorous evolution of HCl gas occurred immediately. An efficient HCl trap was attached to the reaction system. The reaction mixture was then heated to mild reflux (~55° C.) and was held to this temperature for 25 minutes. Heating was stopped and the reaction mixture allowed to drop to room temperature over 10-20 minutes with stirring. Vacuum (~20-50 mm) was applied cautiously to remove acetyl chloride without carryover. At the same time the mixture was heated gradually to 60° C. Distillation of acetyl chloride was complete in ~30 minutes with collection in an ice cold flask for reuse. The oil obtained was then subjected to vacuum (~5-10 mm) to remove the last traces of acetyl chloride and acetic acid at 37° C. A snow white solid then crystallized in about 30 minutes as the title product.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4](Cl)[N:3]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>C(O)C>[Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1
Reactant: C1COCCN1
Reactant: N#Cc1c(-c2ccccc2)cc(Cl)nc1Cl
Solvent: CCO
Product: N#Cc1c(-c2ccccc2)cc(N2CCOCC2)nc1Cl
Yield: 86.1 %

Procedure:
A suspension of 24.9 gm (0.1 mol) of 2,6-dichloro-4-phenyl-3-cyano-pyridine in 400 ml of ethanol was slowly admixed with 17.4 gm (0.2 mol) of morpholine, and the resulting mixture was refluxed for about two hours. Even while refluxing, but primarily upon subsequent cooling (optionally on an ice water bath) of the reaction mixture, a colorless crystalline precipitate formed which was collected by suction filtration, very thoroughly washed with water and dried. 25.8 gm (86% of theory) of 2-chloro-6-morpholino-4-phenyl-3-cyanopyridine, m.p. 198°-200° C., were obtained.
Reaction SMILES: [CH:1]1([C@H:7]([NH:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][C:26](OCC)=[O:27])=[N:22][CH:23]=2)[C:8]([O:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:32][OH:33].[OH-].[K+]>C(O)C.O>[CH:1]1([C@H:7]([NH:16][CH2:17][C:18]2[CH:23]=[N:22][C:21]([CH2:24][CH2:25][C:26]([NH:32][OH:33])=[O:27])=[CH:20][CH:19]=2)[C:8]([O:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CCc1ccc(CN[C@H](C(=O)OC2CCCC2)C2CCCCC2)cn1
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(CCc1ccc(CN[C@H](C(=O)OC2CCCC2)C2CCCCC2)cn1)NO
Reaction time: 0.33 h
Yield: 16.9 %

Procedure:
Ethyl 3-[5-({[(1S)-1-cyclohexyl-2-(cyclopentyloxy)-2-oxoethyl]amino}methyl)pyridin-2-yl]propanoate (0.9 g, 2.16 mmol) and hydroxylamine hydrochloride (0.6 g, 8.64 mmol) were dissolved in ethanol (10 mL) then cooled to <5° C. Potassium hydroxide (0.97 g, 17.28 mmol) was dissolved in water (2.07 mL) and then charged to the reaction which was stirred at <5° C. for 20 min. The reaction was quenched to pH ˜7 and extracted with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4) and concentrated under reduced pressure. The residue was dissolved in hot EtOH (2 mL) and water (3 mL) added. On cooling some of the resulting solid (235 mg) was collected by filtration and dried to give cyclopentyl (2S)-cyclohexyl[({6-[3-(hydroxyamino)-3-oxopropyl]pyridin-3-yl}methyl)amino]ethanoate (147 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7](I)=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:29][CH2:28][C:23]2([O:27][CH2:26][CH2:25][O:24]2)[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].C(N(CC)CC)C.[CH3:38][C:39]([CH3:43])([CH3:42])[C:40]#[CH:41]>[Cu](I)I.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:41]#[C:40][C:39]([CH3:43])([CH3:42])[CH3:38])=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:29][CH2:28][C:23]2([O:27][CH2:26][CH2:25][O:24]2)[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4]
Reactant: C#CC(C)(C)C
Reactant: COC(=O)c1sc(I)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCC2(CC1)OCCO2
Agent: I[Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCC2(CC1)OCCO2
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To a 25 mL RBF under nitrogen, 3-[(1,4-dioxa-spiro[4.5]dec-8-yl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-5-iodo-thiophene-2-carboxylic acid methyl ester (1 eq.), copper iodide (0.025 eq.) and tris(dibenzylideneacetone)dipalladium (0) (0.01 eq.) are taken. DMF, triethylamine (2.5 eq.) and 3,3-dimethyl-but-1-yne (2 eq.) are added and the reaction mixture is stirred at 40° C. for 2 h under a N2 atmosphere. The reaction mixture is filtered on celite and washed with ethyl acetate. The solution is diluted with water and extracted 2 times with ethyl acetate. The organic phases are combined and washed 3 times with water. The organic layer is separated, dried (Na2SO4), evaporated to about 2 mL and then 8 mL of heptane is added. It is evaporated to 2-4 mL and cooled in an ice bath. The formed white solid is filtered, washed with heptane and dried in oven to obtain 5-(3,3-dimethyl-but-1-ynyl)-3-[(1,4-dioxa-spiro[4.5]dec-8-yl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester.