Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[OH2:12].[OH2:13].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:7]=[C:6]([C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1)[C:8]([OH:13])=[O:12]
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Reactant: O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(O)c1cc(Cl)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 110.3 %

Procedure:
2-chloro-4-methyl-5-nitropyridine (1.0 g, 5.8 mmol) was cooled using an ice water bath. Sodium dichromate dihydrate (3.45 g, 11.6 mmol) dissolved in sulphuric acid (50 mL) was added dropwise, ensuring reaction temperature does not exceed 15° C. After complete addition, reaction allowed to warm to room temperature and stirred overnight. Quenched with ice, extracted into ethylacetate and concentrated under reduced pressure to afford 2-chloro-5-nitroisonicotinic acid (1.3 g, 6.4 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]2[NH:6][C:7]([C@@H:9]([NH:14][C:15](=[O:30])[C:16]3[CH:21]=[CH:20][C:19]([C:22]([N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[O:23])=[C:18]([CH3:29])[CH:17]=3)[CH2:10][CH2:11][S:12][CH3:13])=[N:8][C:4]=2[CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:38].ClCCl.C(O)C.ClCl>ClCCl>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]2[NH:6][C:7]([C@@H:9]([NH:14][C:15](=[O:30])[C:16]3[CH:21]=[CH:20][C:19]([C:22]([N:24]4[CH2:25][CH2:26][CH2:27][CH2:28]4)=[O:23])=[C:18]([CH3:29])[CH:17]=3)[CH2:10][CH2:11][S:12]([CH3:13])=[O:38])=[N:8][C:4]=2[CH:3]=1
Reactant: CSCC[C@H](NC(=O)c1ccc(C(=O)N2CCCC2)c(C)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: ClCl
Solvent: CCO
Solvent: ClCCl
Product: Cc1cc(C(=O)N[C@@H](CCS(C)=O)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Yield: 57 %

Procedure:
Prepared analogously to Example 85 from N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulfanylpropyl]-3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzamide and 3-chloroperoxybenzoic acid in dichloromethane/glacial acetic acid. Yield: 57%; Rf value: 0.15 (silica gel; dichloromethane/ethanol=9:1); C24H27ClN4O3S (487.02); mass spectrum: (M+H)+=487/489 (chlorine isotope).
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8]([N:11]([CH3:27])[C:12]2[CH:13]=[CH:14][C:15]([CH3:26])=[C:16]3[C:20]=2[NH:19][C:18]([C:21]([O:23]CC)=[O:22])=[CH:17]3)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[OH-].[Na+].CO.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[Cl:1][C:2]1[C:7]([S:8]([N:11]([CH3:27])[C:12]2[CH:13]=[CH:14][C:15]([CH3:26])=[C:16]3[C:20]=2[NH:19][C:18]([C:21]([OH:23])=[O:22])=[CH:17]3)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cc2c(C)ccc(N(C)S(=O)(=O)c3cccnc3Cl)c2[nH]1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(N(C)S(=O)(=O)c2cccnc2Cl)c2[nH]c(C(=O)O)cc12
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A mixture of ethyl 7-[[(2-chloropyridin-3-yl)sulfonyl](methyl)amino]-4-methyl-1H-indole-2-carboxylate (0.86 g), 1N aqueous sodium hydroxide solution (4.2 mL), methanol (6 mL) and tetrahydrofuran (6 mL) was stirred at 50° C. for 1 hr. 10% Aqueous citric acid solution was added to the reaction mixture, and the mixture was concentrated. The resulting crystals were collected by filtration, washed with water, dried, and concentrated to give 7-[[(2-chloropyridin-3-yl)sulfonyl](methyl)amino]-4-methyl-1H-indole-2-carboxylic acid as crude crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[CH2:7][N:8](S(C1C=CC(OCC2C=CC=CC=2)=CC=1)(=O)=O)[CH2:9][CH2:10][CH2:11][C:12](=[O:14])[CH3:13])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].Cl>O1CCCC1.O>[C:1]([O:5][C:6]([CH:7]1[C:12]([OH:14])([CH3:13])[CH2:11][CH2:10][CH2:9][NH:8]1)=[O:32])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)CCCN(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(OCc2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)C1NCCCC1(C)O
Reaction time: 24 h

Procedure:
To a solution [(4-benzyloxy-benzenesulfonyl)-(4-oxo-pentyl)-amino]-acetic acid tert-butyl ester (compound of formula XVII, 25 g, 56 mmol) in 200 ml of tetrahydrofuran was added potassium tert-butoxide (24 ml of a 1M solution in tetrahydrofuran, 24 mmol). After stirring for about 24 hours at a temperature of about 20° C. to about 25° C., the mixture was diluted with water, acidified with 1M hydrochloric acid and extracted 3 times into ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The stereoisomers were separated by preparative HPLC on a Chiralpak AD column® eluting with 2-propanol-hexane, affording approximately 4 g of each stereoisomer of 1-[4-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-piperidine-2-carboxylic acid tert-butyl ester (compound of formula XVIII) as a colorless oil.
Reaction SMILES: O[CH2:2][C@@H:3]([NH2:8])[C@@H:4]([CH3:7])[CH2:5][CH3:6].[CH3:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[N:19]=[C:20]=[S:21]>>[CH3:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[N:19]=[C:20]1[NH:8][C@@H:3]([C@H:4]([CH2:5][CH3:6])[CH3:7])[CH2:2][S:21]1
Reactant: CC[C@H](C)[C@H](N)CO
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Product: CC[C@H](C)[C@H]1CSC(=Nc2ccc([N+](=O)[O-])cc2C)N1

Procedure:
(1S,2S)-1-(Hydroxymethyl)-2-methylbutylamine was converted to (1S,2S)-1-(chloromethyl)-2-methylbutanammonium chloride as described in Method B7a. 2-Methyl-4-nitrophenyl isothiocyanate was reacted with (1S,2S)-1-(chloromethyl)-2-methylbutanammonium chloride according to Method C1a to give (4S)-2-(2-methyl-4-nitrophenylimino)-4-((2S)-2-butyl)-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (4S)-2-(2-methyl-4-nitrophenylimino)-4-((2S)-2-butyl)-3-isobutyl-1,3-thiazolidine HCl salt.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[C:19]3[CH:20]=[CH:21][NH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[NH:22]1[C:23]2[CH:24]=[CH:25][CH:26]=[C:18]([C:16]([NH:15][C:6]3([C:4]([OH:5])=[O:3])[CH2:7][C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH2:14]3)=[O:17])[C:19]=2[CH:20]=[CH:21]1
Reactant: CCOC(=O)C1(NC(=O)c2cccc3[nH]ccc23)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(NC1(C(=O)O)Cc2ccccc2C1)c1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.7 %

Procedure:
The mixture of 2-[(1H-indole-4-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester (55) (200 mg, 0.57 mmol) and KOH (600 mg, 10.7 mmol) is dissolved in EtOH (8 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until no more white precipitate formed. The precipitate is filtered to give a pure product (56) as white solid (162 mg, 89%).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].Cl.[NH2:33][C:34]([CH3:38])([CH3:37])[C:35]#[N:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[C:35]([C:34]([NH:33][C:3](=[O:4])[CH:2]([OH:1])[C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:30])([F:31])[F:29])[O:14][N:13]=2)=[CH:10][CH:11]=1)([CH3:38])[CH3:37])#[N:36]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: CC(C)(N)C#N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C#N)NC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 10 %

Procedure:
2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-Va, 30 mg, 0.070 mmol), 2-amino-2-methylpropanenitrile-HCl (12.58 mg, 0.104 mmol) [Ingate, S. T. et al., Tetrahedron, 53:17795-17814 (1997)], HATU (34.4 mg, 0.090 mmol), and 4-methylmorpholine (28.1 mg, 0.278 mmol) were dissolved in DMF (1 mL). After stirring 1 h, the mixture was purified via preparative LCMS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 40-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to provide single enantiomer N-(2-cyanopropan-2-yl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (3.7 mg, 0.007 mmol, 10.7% yield): LCMS=498.0 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.13-8.19 (2 H, m), 7.49-7.70 (7 H, m), 5.13 (1 H, s), 1.71 (3 H, s), 1.67 (3 H, s); HPLC peak RT=2.9 min (Method E).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[S:8][C:9]=1[CH2:10]O)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.CS([Cl:33])(=O)=O>ClCCl>[CH2:1]([C:5]1[N:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[S:8][C:9]=1[CH2:10][Cl:33])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1CO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.0 g [4-Butyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-yl]-methanol were dissolved in 50 ml dichloromethane, 0.88 ml triethylamine and 0.39 ml methanesulfonyl chloride were added. The reaction mixture was stirred at room temperature for a period of three hours then 100 ml of dichloromethane were added and the reaction mixture washed with 50 ml of saturated NaHCO3 solution , water and brine. The organic layer was dried over MgSO4 and the solvent removed under reduced pressure. This provided 1.0 g 4-Butyl-5-chloromethyl-2-(4-trifluoromethyl-phenyl)-thiazole as yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([C:18]#[N:19])[CH:15]=[C:14](I)[CH:13]=2)[O:9][N:8]=1.C(N(CC)CC)C.[CH2:28]([OH:31])[C:29]#[CH:30]>CN(C)C=O.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>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([C:18]#[N:19])[CH:15]=[C:14]([C:30]#[C:29][CH2:28][OH:31])[CH:13]=2)[O:9][N:8]=1
Reactant: C#CCO
Reactant: N#Cc1cc(I)cc(-c2nc(-c3ccccn3)no2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#Cc1cc(C#CCO)cc(-c2nc(-c3ccccn3)no2)c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 17.7 %

Procedure:
A mixture of the 3-(2-pyridyl)-5-(5-cyano-3-iodophenyl)-1,2,4-oxadiazole (140 mg, 0.374 mmol), Pd(PPh3)4 (10 mg, 0.009), and Cul (30 mg, 0.158 mmol) in N,N-dimethylformamide (3 mL) was treated with triethylamine (1 mL, 726 mg, 7 mmol). The reaction mixture was cooled to 0° C. and treated with propargyl alcohol (56 mg, 1 mmol). The mixture was stirred at ambient temperature 5 hours and then filtered through a short plug of silica gel, washing with ethyl acetate. The organic solution was concentrated in vacuo. Silica gel chromatography afforded 20 mg (18%) of 3-(2-pyridyl)-5-(5-cyano-3-[3-hydroxypropyn-1-yl]phenyl)-1,2,4-oxadiazole: 1H-NMR (MeOH-d4), δ ppm: 8.80 (d, 1H), 8.60 (s, 1H), 8.58 (s, 1H), 8.30 (d, 1H), 8.10 (m, 2H), 7.60 (m, 1H), 4.5 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:8][C:9]1[C:14]([C:15]#[N:16])=[C:13]([F:17])[C:12]([C:18]#[N:19])=[C:11]([F:20])[C:10]=1F.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(#N)C>[NH:1]([C:11]1([F:20])[CH:10]=[C:9]([F:8])[C:14]([C:15]#[N:16])=[C:13]([F:17])[CH:12]1[C:18]#[N:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1c(F)c(F)c(F)c(C#N)c1F
Reactant: Nc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#CC1=C(F)C(C#N)C(F)(Nc2ccccc2)C=C1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
A solution of 0.85 g of aniline in 20 ml of acetonitrile was dropwise added, while stirring, to a solution of 2.0 g of tetrafluoroisophthalonitrile and 2.0 g of triethylamine in 30 ml of acetonitrile. After dropwise adding, the mixture was stirred at room temperature for 1 hour and an aqueous sodium bicarbonate solution was then added. The mixture was extracted with chloroform and the chloroform extract was washed 5 times with an aqueous sodium chloride solution. After drying with magnesium sulfate, the chloroform was distilled off. The resultant crude crystal was purified by silica gel chromatography (solvent:hexane). Thus, 2.3 g (87% yield) of the desired compound No. 6 was obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C@@H:12]([CH3:15])[CH2:13][OH:14])(=[O:10])=[O:9].[NH2:16][C:17]1[C:18]([C:39]#[N:40])=[N:19][C:20]([C:23]2[CH:28]=[CH:27][C:26](B3OC(C)(C)C(C)(C)O3)=[CH:25][C:24]=2[F:38])=[CH:21][N:22]=1>>[NH2:16][C:17]1[N:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([C:2]3[C:3]([S:8]([NH:11][C@H:12]([CH3:15])[CH2:13][OH:14])(=[O:10])=[O:9])=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:25][C:24]=2[F:38])=[N:19][C:18]=1[C:39]#[N:40]
Reactant: C[C@@H](CO)NS(=O)(=O)c1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)c(C#N)n3)c(F)c2)OC1(C)C
Product: C[C@H](CO)NS(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)c(C#N)n2)c(F)c1

Procedure:
The title compound was prepared in manner similar to that described in Example 88 using (S)-2-bromo-N-(1-hydroxypropan-2-yl)benzenesulfonamide and 3-amino-6-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazine-2-carbonitrile. MS (ESI): mass calcd. for C20H18FN5O3S, 427.11; m/z found, 428.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.73 (d, J=2.1, 1H), 8.16 (dd, J=7.9, 1.4, 1H), 7.93 (m, 1H), 7.69 (m, 1H), 7.60 (m, 1H), 7.45-7.28 (m, 3H), 3.47-3.36 (m, 1H), 3.34-3.18 (m, 2H), 1.03 (d, J=6.6, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[CH:5]=[O:6].[CH3:14][N:15](C=O)C>CCOCC.[C-]#N.[Zn+2].[C-]#N.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>[CH:5]([C:4]1[CH:3]=[C:2]([CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=1)[C:14]#[N:15])=[O:6]
Reactant: CN(C)C=O
Reactant: O=Cc1cc(Br)cc(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOCC
Product: N#Cc1cc(C=O)cc(C(F)(F)F)c1
Temperature: 90 °C

Procedure:
To 3-bromo-5-(trifluoromethyl)benzaldehyde (1.0 gm, 3.95 mmol) in DMF (10 ml), zinc cyanide (278 mg, 2.37 mmol) was added followed by Pd(PPh3)4 (365 mg, 0.32 mmol) was added and heated at 90° C. for 5 h. Then the reaction mixture was cooled, diluted with ether and quenched with aqueous ammonium hydroxide solution. Then the reaction mixture was partitioned between water and ether. Organic layer was dried, evaporated and column purified (10% ethylacetate/90% hexanes) to yield 400 mg of 3-formyl-5-(trifluoromethyl)benzonitrile.
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:22]([NH:24][N:25]1[C:29](=[O:30])[CH2:28][N:27]([CH3:31])[C:26]1=[S:32])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:22]([NH:24][N:25]1[C:29](=[O:30])[CH2:28][N:27]([CH3:31])[C:26]1=[S:32])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:10]
Reactant: CC(C)C[C@@H](C(=O)NN1C(=O)CN(C)C1=S)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: CC(C)C[C@@H](C(=O)NN1C(=O)CN(C)C1=S)[C@H](C/C=C/c1ccccc1)C(=O)NO
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 27.4 %

Procedure:
A solution of 0.209 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-4-methyl-N-(3-methyl-5-oxo-2-thioxo-1-imidazolidinyl)valeramide in 5 ml of methanol was treated with 0.020 g of p-toluenesulphonic acid monohydrate. The mixture was stirred for 2.5 hours at room temperature and then evaporated. The residue was dissolved in ethyl acetate and washed with 5% aqueous sodium hydrogen carbonate. The organic layer was dried over anhydrous magnesium sulphate and evaporated. The residue was triturated with diethyl ether/hexane (2:1) to give 0.048 g of (E)-2(R)-[1(S)-(Hydroxycarbamoyl)-4-phenyl-3-butenyl]-4-methyl-N-(3-methyl-5-oxo-2-thioxo-1-imidazolidinyl)valeramide in the form of a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:21]=[CH:20][N:19]=[CH:18][C:7]=3[CH2:8][NH:9][CH:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.N1C=CC=CC=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:21]=[CH:20][N:19]=[CH:18][C:7]=3[CH2:8][N:9]([S:30]([C:27]3[CH:28]=[CH:29][C:24]([CH3:34])=[CH:25][CH:26]=3)(=[O:32])=[O:31])[CH:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1
Reactant: Clc1ccc2c(c1)C(c1ccccc1Cl)NCc1cncnc1-2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2Cc3cncnc3-c3ccc(Cl)cc3C2c2ccccc2Cl)cc1

Procedure:
A solution of 14.5 g (42 mmole) of 9-chloro-7-(2-chlorophenyl)-6,7-dihydro-5H-pyrimido[5,4-d][2]benzazepine, 14.5 g (76 mmols) of p-toluene-sulfonyl chloride, 30 ml of pyridine and 0.3 g of 4-dimethylaminopyridine in 300 ml of methylene chloride was stirred at room temperature for 24 hr. The mixture was washed with an excess of dilute ice cold hydrochloric acid and dilute aqueous sodium hydroxide. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to dryness. The residue crystallized from a mixture of methylene chloride and ether to give the product as a white solid, mp 200°-201° C. Recrystallization from a mixture of ether and methylene chloride gave the pure product as colorless prisms, mp 200°-201° C.
Reaction SMILES: C([O:4][C:5]1[C:6]([CH3:20])=[C:7]([CH:17]=[CH:18][CH:19]=1)[C:8]([O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])=[O:9])C=C.CN1C[CH2:25][CH2:24][C:23]1=O>>[CH2:25]([C:19]1[CH:18]=[CH:17][C:7]([C:8]([O:10][CH2:11][CH2:12][Si:13]([CH3:14])([CH3:15])[CH3:16])=[O:9])=[C:6]([CH3:20])[C:5]=1[OH:4])[CH:24]=[CH2:23]
Reactant: C=CCOc1cccc(C(=O)OCC[Si](C)(C)C)c1C
Reactant: CN1CCCC1=O
Product: C=CCc1ccc(C(=O)OCC[Si](C)(C)C)c(C)c1O
Temperature: 220 °C

Procedure:
2-(Trimethylsilyl)ethyl 3-(allyloxy)-2-methylbenzoate (500 mg, 1.70 mmol) was dissolved in 1-methylpyrrolidine-2-one (1 ml) in a microwave vial, closed with a cap and subjected to microwave irradiation (CEM discover) with stirring at 220° C., maximum pressure 300 psi, run time 5 min, hold time 15 min. LCMS showed 3 peaks including a major peak with the expected product mass. After cooling, the crude mixture was directly loaded on a silica gel column (12 g) and purified using an ISCO system (hexane:EtOAc solvent mixture, product eluted ˜5% EtOAc in hexane) to give SKC-01-056. The above experiment was repeated several times in 1-2 g scale Total wt of the product isolated was 3.6 g.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][N:13]3[C:17](=[O:18])[CH2:16][S:15][C:14]3=[O:19])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:20](=O)[CH2:21][CH2:22][CH3:23].N1CCCCC1>C(O)C>[CH:20](=[C:16]1[S:15][C:14](=[O:19])[N:13]([CH2:12][CH2:11][S:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:17]1=[O:18])[CH2:21][CH2:22][CH3:23]
Reactant: CCCC=O
Reactant: O=C1CSC(=O)N1CCSc1cccc2nccn12
Solvent: CCO
Solvent: C1CCNCC1
Product: CCCC=C1SC(=O)N(CCSc2cccc3nccn23)C1=O

Procedure:
To a solution of 1.49 g (3.9 mmol) of 3-[2-(imidazo-[1,2-a]pyridin-5-ylthio)ethyl]thiazolidine-2,4-dione and 0.36 ml (4.0 mmol) of n-butyraldehyde in 30 ml of ethanol, 0.04 ml (0.4 mmol) of piperidine was added, followed by refluxing for 2 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, hexane/ethyl acetate=2/1→1/4), followed by recrystallization (solvent, chloroform-diethyl ether-n-hexane) to yield 0.872 g (56.1%, white crystal) of the desired product.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:4]=2[CH:3]=1.[I-:16].[Na+].I>C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[I:16][C:2]1[N:7]=[N:6][C:5]2[O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:4]=2[CH:3]=1
Reactant: [I-]
Reactant: Clc1cc2c(nn1)Oc1ccccc1O2
Agent: I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Ic1cc2c(nn1)Oc1ccccc1O2
Temperature: 140 °C
Reaction time: 1 h
Yield: 27.6 %

Procedure:
Under an argon atmosphere, 3-chloro[1,4]benzodioxino[2,3-c]pyridazine (5.0 g), sodium iodide (6.79 g) and hydrogen iodide (55%) (57.98 g) were added and the mixture was stirred at 140° C. for 1 hr. The reaction mixture was diluted with ethyl acetate and aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted. The organic layer was dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure to give 3-iodo[1,4]benzodioxino[2,3-c]pyridazine (1.95 g).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B1OC(C)(C)C(C)(C)O1.Br[C:19]1[CH:24]=[CH:23][N:22]=[C:21]2[NH:25][CH:26]=[CH:27][C:20]=12.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:19]1[CH:24]=[CH:23][N:22]=[C:21]2[NH:25][CH:26]=[CH:27][C:20]=12
Reactant: CNc1ccccc1B1OC(C)(C)C(C)(C)O1
Reactant: Brc1ccnc2[nH]ccc12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CNc1ccccc1-c1ccnc2[nH]ccc12
Temperature: 80 °C

Procedure:
A 1000 mL round bottom flask containing N-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (18.88 g, 81 mmol) was charged with 4-bromo-1H-pyrrolo[2,3-b]pyridine (11.40 g, 57.9 mmol), potassium phosphate (36.8 g, 174 mmol) and phenylallylchloro[1,3-bis(diisopropylphenyl)-2-imidazol-2-ylidene]palladium (II) (1.873 g, 2.89 mmol) under argon. To this was added a mixture of dioxane (400 mL) and water (100 mL) that had been degassed with argon for 30 minutes. The mixture was purged with nitrogen again, and heated at 80° C. overnight under nitrogen. The reaction mixture was cooled to ambient temperature and partitioned between ethyl acetate (750 mL) and 50% brine (1000 mL). The organic layers were dried over sodium sulfate, filtered and concentrated. The crude residue was dissolved in a minimum of methylene chloride, diluted with an equal volume of heptane and was purified on a Teledyne CombiFlash RF chromatography system on a silica gel Gold Rf cartridge (330 g) eluted with a 5-30% 3:1 ethyl acetate/ethanol in heptane to give the title compound. MS (ESI+) m/z 224 (M+1).