Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[S:2]1(=[O:23])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[N:17]=[C:16]([C:18]([O:20]C)=O)[C:15]([OH:22])=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2.[Cl-].[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][NH3+:33])=[C:28]([S:34]([CH3:37])(=[O:36])=[O:35])[CH:27]=1>C(O)C>[O:23]=[S:2]1(=[O:1])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[N:17]=[C:16]([C:18]([NH:33][CH2:32][C:29]2[CH:30]=[CH:31][C:26]([F:25])=[CH:27][C:28]=2[S:34]([CH3:37])(=[O:36])=[O:35])=[O:20])[C:15]([OH:22])=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2
Reactant: CS(=O)(=O)c1cc(F)ccc1C[NH3+]
Reactant: COC(=O)c1nc(N2CCCCS2(=O)=O)c2cccnc2c1O
Agent: [Cl-]
Solvent: CCO
Product: CS(=O)(=O)c1cc(F)ccc1CNC(=O)c1nc(N2CCCCS2(=O)=O)c2cccnc2c1O
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a slurry of methyl 5-(1,1-dioxido-1,2-thiazinan-2-yl)-8-hydroxy-1,6-naphthyridine-7-carboxylate (2.11 g, 6.26 mmol) in ethanol (30 mL) in a pressure flask was added 1-[4-fluoro-2-(methylsulfonyl)phenyl]methanaminium chloride followed by N,N,N-diisopropylethylamine (2.17 mL, 12.52 mmol). The pressure flask was purged with nitrogen and closed. The reaction was heated to 80 degrees C. for 16 hours. The reaction containing residual solids was cooled and determined to be incomplete by LCMS analysis. Added degassed DMF (10 mL) to solubilize the remaining solids, resealed the pressure tube and reheated to 80 degrees C. overnight. The reaction was cooled, transferred to a round bottom flask and reduced to a small volume in vacuo. The residue was partitioned between methylene chloride and saturated aqueous sodium bicarbonate. The organic layer was washed with water, dried over Na2SO4, filtered and reduced to a small volume in vacuo. The residue was crystallized via the addition of 5 mL of methanol. The crystals were filtered and dried in vacuo to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH:4]([CH2:5][C:6](Cl)([Cl:8])[Cl:7])[CH:3]1[C:10]([O:12][CH3:13])=[O:11].N12CCCCC1C=NCCC2.Cl>CN(C)C=O>[Cl:7][C:6]([Cl:8])=[CH:5][CH:4]1[CH:3]([C:10]([O:12][CH3:13])=[O:11])[C:2]1([CH3:1])[CH3:14]
Reactant: COC(=O)C1C(CC(Cl)(Cl)Cl)C1(C)C
Agent: C1=NCCCN2CCCCC12
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)C1C(C=C(Cl)Cl)C1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
A mixture of 13.0 g (0.050 mol) of methyl 2,2-dimethyl-3-(2,2,2-trichloroethyl)cyclopropane-1-carboxylate (compound Z, C/T=77/23), 9.12 g (0.060 mol) of 1,5-diazabicyclo[5.4.0]undec-5-ene and 50 ml of dimethylformamide was stirred at 100° for 1 hour, then allowed to cool to room temperature and poured into 1 N hydrochloric acid. The mixture was extracted with ether and the ether extracts were combined, washed with brine, dried over magnesium sulfate and concentrated to give 10.15 g (91% yield) of methyl 3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropane-1-carboxylate, 94% purity, C/T=76/24.
Reaction SMILES: [CH2:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:4][CH2:3]1.FS([C:24]([F:30])([F:29])C(OC)=O)(=O)=O>[F-].[Na+].C1(C)C=CC=CC=1>[F:29][C:24]1([F:30])[C:2]2([C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:4][CH2:3]2)[CH2:1]1
Reactant: C=C1CCN(NC(=O)OC(C)(C)C)c2ccccc21
Reactant: COC(=O)C(F)(F)S(=O)(=O)F
Agent: [F-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NN1CCC2(CC2(F)F)c2ccccc21
Yield: 70.2 %

Procedure:
0.275 g of tert-butyl 4-methylene-3,4-dihydro-2H-quinoline-1-carbamate, 0.0028 g of sodium fluoride and 1.5 ml of toluene are placed in a 10 ml round-bottomed flask equipped with a magnetic stirrer and placed under an inert atmosphere. The reaction mixture is heated at reflux for 1 h. 0.449 g of methyl fluorosulfonyldifluoroacetate is subsequently added and the reaction mixture is heated at reflux for 2 h, filtered through celite and then concentrated under reduced pressure. The residue is chromatographed twice on silica gel eluted with dichloromethane. 0.23 g of tert-butyl 2,2-difluoro-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-quinoline]-1′-carbamate is obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]1[CH:7]=[C:8]([NH2:14])[C:9]([NH2:13])=[CH:10][C:11]=1[F:12].[N+:16]([C:19]1[C:20]([CH:30]=O)=[N:21][N:22]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[CH:23]=1)([O-:18])=[O:17]>CO>[F:12][C:11]1[C:6]([NH:5][CH2:4][CH2:3][N:2]([CH3:15])[CH3:1])=[CH:7][C:8]2[NH:14][C:30]([C:20]3[C:19]([N+:16]([O-:18])=[O:17])=[CH:23][N:22]([CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][O:25]4)[N:21]=3)=[N:13][C:9]=2[CH:10]=1
Reactant: O=Cc1nn(C2CCCCO2)cc1[N+](=O)[O-]
Reactant: CN(C)CCNc1cc(N)c(N)cc1F
Solvent: CO
Product: CN(C)CCNc1cc2[nH]c(-c3nn(C4CCCCO4)cc3[N+](=O)[O-])nc2cc1F
Yield: 17.8 %

Procedure:
A solution of 1 g of N4-(2-dimethylaminoethyl)-5-fluorobenzene-1,2,4-triamine in 30 mL of methanol with 1.06 g of 4-nitro-1-(tetrahydropyran-2-yl)-1H-pyrazole-3-carbaldehyde is stirred at ambient temperature for 72 hours. After evaporation of the solvent under vacuum in a rotary evaporator, the reaction crude is purified by flash chromatography on an Intelliflash apparatus on an Analogix RS-90 cartridge with an eluent of 100% dichloromethane to 85/15 dichloromethane/methanol. 350 mg of N1-{6-fluoro-2-[4-nitro-1-(tetrahydropyran-2-yl)-1H-pyrazol-3-yl]-3H-benzimidazol-5-yl}-N2,N2-dimethylethane-1,2-diamine are isolated in the form of an orange foam. ES mass spectrum: 418(+)=(M+H)(+); 334(+)=(M+H)(+)-THP+H, 209.6=(M+2H)(2+)
Reaction SMILES: [Cl:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[CH2:11]O.[Br:13]P(Br)Br>C(Cl)(Cl)Cl>[Br:13][CH2:11][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]2[C:2]=1[Cl:1]
Reactant: OCc1nc2ccccn2c1Cl
Reactant: BrP(Br)Br
Solvent: ClC(Cl)Cl
Product: Clc1c(CBr)nc2ccccn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of {3-chloroimidazo[1,2-a]pyridin-2-yl}methanol (0.799 g, 4.39 mmol) in anhydrous chloroform (25 mL) at 0° C. was added tribromophosphane (1.20 g, 0.41 mL, 4.43 mmol), and the reaction mixture was allowed to stir at room temperature overnight. The solvent was evaporated to provide the crude 2-(bromomethyl)-3-chloroimidazo[1,2-a]pyridine, which was used for the next step without any further purification; M+1 246.2.
Reaction SMILES: C[O:2][C:3](=[O:33])[C@@H:4]([NH:9][C:10]([C:12]1[O:16][N:15]=[C:14]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:25])=[CH:19][CH:18]=2)[CH:13]=1)=[O:11])[CH2:5][CH:6]([CH3:8])[CH3:7].[K+].[Br-]>>[CH:27]1([NH:26][C:24](=[O:25])[NH:23][C:20]2[CH:21]=[CH:22][C:17]([C:14]3[CH:13]=[C:12]([C:10]([NH:9][C@@H:4]([CH2:5][CH:6]([CH3:7])[CH3:8])[C:3]([OH:33])=[O:2])=[O:11])[O:16][N:15]=3)=[CH:18][CH:19]=2)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)c1cc(-c2ccc(NC(=O)NC3CCCCC3)cc2)no1
Agent: [Br-]
Agent: [K+]
Product: CC(C)C[C@H](NC(=O)c1cc(-c2ccc(NC(=O)NC3CCCCC3)cc2)no1)C(=O)O
Yield: 70.7 %

Procedure:
The title compound was prepared from (S)-2-({3-[4-(3-cyclohexyl-ureido)-phenyl]-isoxazole-5-carbonyl}-amino)-4-methyl-pentanoic acid methyl ester as set forth in Example 8 and was obtained in 70.7% yield. Mass (ES+): 443 (M++1); IR (KBr): 3326, 3305, 2935, 1748, 1635 (br), 1544, 1529; 1H NMR (DMSO-d6) δ: 0.87, 0.91 (2×d, 6H), 1.09-1.81 (5×m, 13H), 3.45 (br, 1H), 4.38 (m, 1H), 6.16 (d, 1H), 7.50 (d, 2H), 7.56 (s, 1H), 7.75 (d, 2H), 8.58 (s, 1H), 9.14 (d, 1H), 12.76 (br, 1H).
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@:45]2([CH3:46])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:44]2[CH2:43][CH2:42][C@@:41]2([CH3:47])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]([CH2:39][CH3:40])([O:31][Si](CC)(CC)CC)[CH2:29][CH3:30])([CH3:23])[CH3:22])[CH2:12][C@@H:11]([O:48][Si](C(C)(C)C)(C)C)[CH2:10]1)(C(C)(C)C)(C)C.O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[OH:8][C@@H:9]1[C@@:45]2([CH3:46])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:44]2[CH2:43][CH2:42][C@@:41]2([CH3:47])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]([CH2:39][CH3:40])([OH:31])[CH2:29][CH3:30])([CH3:22])[CH3:23])[CH2:12][C@@H:11]([OH:48])[CH2:10]1
Reactant: CCC(CC)(CCCOC(C)(C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C)O[Si](CC)(CC)CC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(O)(CC)CCCOC(C)(C)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 99.6 %

Procedure:
1α,3β-Bis(tert-butyldimethylsilyloxy)-20-{4-ethyl-4-(triethylsilyloxy)hexyloxy}-20-methylpregna-5,7,16-triene (140 mg, 0.172 mmol) and a 1M tetra-n-butylammonium fluoride tetrahydrofuran solution (3 ml) were subjected to reaction using a procedure similar to that of Example 5(2) (3 hours), worked up and purified by column chromatography (ethyl acetate) to give the titled compound (81 mg, 100%) as a colorless foam.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[N:19]=[C:18]([C:20]([N:22]([CH2:28][CH2:29][CH3:30])[C:23]([N:25]([CH3:27])[CH3:26])=[O:24])=[O:21])[CH:17]=[CH:16][CH:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:27][N:25]([CH3:26])[C:23]([N:22]([C:20]([C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([C:12]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:13]=2)[N:19]=1)=[O:21])[CH2:28][CH2:29][CH3:30])=[O:24]
Reactant: CCCN(C(=O)c1cccc(C#N)n1)C(=O)N(C)C
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCN(C(=O)c1cccc(-c2nc(=O)c3ccccc3s2)n1)C(=O)N(C)C
Yield: 73 %

Procedure:
A mixture of methyl thiosalicylate (1.6 g, 9.6 mmol), N-[(6-cyano-2-pyridyl)carbonyl]-N′,N′-dimethyl-N-propylurea (1.2 g, 4.7 mmol), triethylamine (2.0 ml, 14 mmol) and toluene (4 ml) was refluxed for 9 hrs as described in Example 1. After cooling, the precipitated crystals were collected by filtration and recrystallized from hexane-tetrahydrofuran to give the titled compound (1.36 g, 72%) as crystals.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[N:9][S:10][C:6]=2[C:5]([N+:11]([O-:13])=[O:12])=[CH:4][CH:3]=1.[OH-].[Na+].O.S(=O)(=O)(O)[OH:18]>C(O)C>[N+:11]([C:5]1[C:6]2[S:10][N:9]=[CH:8][C:7]=2[C:2]([OH:18])=[CH:3][CH:4]=1)([O-:13])=[O:12]
Reactant: O=S(=O)(O)O
Reactant: O=[N+]([O-])c1ccc(Cl)c2cnsc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1ccc(O)c2cnsc12
Yield: 86 %

Procedure:
43 g of 4-chloro-7-nitro-1,2-benzisothiazole and 16 g of sodium hydroxide powder in 400 ml of ethanol are stirred for 1 hour at 70° C. When the mixture has cooled, 500 ml of water are added, the batch is neutralized with dilute sulfuric acid whilst cooling with ice, and the product which has precipitated is filtered off. The filter cake is then washed with a little ice-cold methanol, and dried. 34 g (86% of theory) of 7-nitro-4-hydroxy-1,2-benzisothiazole are obtained, melting at 284° C. (with decomposition) after one recrystallization from n-butanol.
Reaction SMILES: B(C1CCCCC1)C1CCCCC1.[CH3:14][C:15]([CH3:19])([CH3:18])[C:16]#[CH:17].[Zn](CC)CC.[CH:25](=[O:28])[CH2:26][CH3:27]>>[CH3:14][C:15]([CH3:19])([CH3:18])[CH:16]=[CH:17][C@@H:25]([OH:28])[CH2:26][CH3:27]
Reactant: CCC=O
Reactant: C#CC(C)(C)C
Agent: B(C1CCCCC1)C1CCCCC1
Agent: CC[Zn]CC
Product: CC[C@H](O)C=CC(C)(C)C
Yield: 68 %

Procedure:
The product was prepared by General procedure S using 196 mg (1.1 mmol) Cy2BH, 137 μL (1.1 mmol) 3,3-dimethyl-1-butyne, 1.1 mL (2.1 mmol, 2.0 M in hexanes) Et2Zn, 9.6 mg (0.04 mmol) (−)-MIB, and 72 μL (1.0 mmol) propanal. The crude product was purified by column chromatography (5% ethyl acetate in hexanes) to afford the title compound as a colorless oil in 68% yield (96 mg, 0.68 mmol). [α]D20=−60.3 (c=0.63, CHCl3, 77% ee); 1H NMR (CDCl3, 500 MHz): δ 0.86 (t, 3H, J=7.4 Hz), 0.98 (s, 9H), 1.26 (br s, 1H), 1.44-1.59 (m, 2H), 3.93 (dt, 1H, J=6.6, 6.6 Hz), 5.31 (dd, 1H, J=15.7, 7.1 Hz), and 5.62 (d, 1H, J=15.7 Hz) ppm; 13C{1H} NMR (CDCl3, 125 MHz): δ 9.7, 22.6, 29.5, 30.2, 74.7, 127.4, and 143.2 ppm; IR (neat): 3360, 3025, 2960, 2866, 1660, 1478, 1463, 1414, 1384, 1363, 1331, and 1262 cm−1; HRMS-CI m/z 141.1274 [(M−H)+; calcd for C9H17O: 141.1279].
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:3]=1[C:4]([NH:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([CH:13]=O)[CH2:9][CH2:8]1)=[O:5].[F:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH2:27].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:3]=1[C:4]([NH:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:27][C:26]2[CH:28]=[CH:29][CH:30]=[C:24]([F:23])[CH:25]=2)[CH2:9][CH2:8]1)=[O:5]
Reactant: Nc1cccc(F)c1
Reactant: O=C[C@H]1CC[C@H](NC(=O)c2cc(C(F)(F)F)ccc2Cl)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(N[C@H]1CC[C@H](CNc2cccc(F)c2)CC1)c1cc(C(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 50 mL round-bottomed flask containing trans-2-chloro-N-(4-formyl-cyclohexyl)-5-trifluoromethyl-benzamide (Ex. 1 step 3) (1.0 g, 3.0 mmol) and 3-fluoroaniline (0.29 mL, 3.0 mmol) in dry DCM (25 mL) is added sodium triacetoxyborohydride (953 mg, 4.49 mmol) in three portions over 1-2 minutes. The suspension is stirred at RT for 1 hour. 1N sodium hydroxide (25 mL) is added and the mixture is stirred at RT for 20 min. The mixture is then diluted with DCM (50 mL) and the DCM layer separated and washed with 1M HCl (25 mL) and brine (15 mL), dried (MgSO4), filtered and evaporated to give a colourless solid. The crude product is redissolved in DCM, absorbed directly onto silica gel and columned on silica gel using a 50 g pre-packed column and eluted with 30% EtOAc/isohexane. Product is isolated as a colourless oil which is triturated with diether ether-isohexane to afford the title compound as colourless crystals. [MH+429.24].
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:5]=[C:6]([C:13]([CH3:20])([CH3:19])[C:14]([O:16]CC)=[O:15])[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11]>CO>[Cl:3][C:4]1[CH:5]=[C:6]([C:13]([CH3:20])([CH3:19])[C:14]([OH:16])=[O:15])[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11]
Reactant: CCOC(=O)C(C)(C)c1ccc([N+](=O)[O-])c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C(=O)O)c1ccc([N+](=O)[O-])c(Cl)c1
Temperature: 80 °C
Yield: 95 %

Procedure:
A 2N solution of potassium hydroxide (18 ml) is added at a temperature of approximately 20° C. to a solution of ethyl 2-(3-chloro-4-nitrophenyl)-2-methylpropanoate (1 g) in methanol (20 ml). The mixture is then heated at 80° C. for 1.5 hours then cooled down to ambient temperature. The methanol is evaporated by concentration of the mixture under reduced pressure. The remaining aqueous phase is washed with dichloromethane then cooled down to 0° C. and acidified with acetic acid. After the addition of dichloromethane, decantation and extractions, the combined organic phases are washed with salt water, dried over Na2SO4 and concentrated under reduced pressure in order to produce the expected compound in the form of an oil which crystallizes (852 mg, 95% yield).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[O:6][CH:7]=[CH:8][CH:9]=1)=O.[Cl:10][C:11]1[N:16]=[N:15][C:14]([NH2:17])=[CH:13][CH:12]=1.C(Cl)(Cl)Cl.C(O)(C)C>O1CCOCC1.O>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH:2]=[C:3]([C:5]3[O:6][CH:7]=[CH:8][CH:9]=3)[N:17]=2)[N:16]=1
Reactant: Nc1ccc(Cl)nn1
Reactant: O=C(CBr)c1ccco1
Solvent: O
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: Clc1ccc2nc(-c3ccco3)cn2n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2-bromo-1-(2-furyl)ethanone (220 mg, 1.16 mmol) and 6-chloropyridazin-3-amine (150 mg, 1.16 mmol) in dioxane (4 ml) was stirred at room temperature for 1.5 hours, and at 65° C. for 16 hours. The reaction mixture was then cooled to ambient temperature, diluted with 3:1 (chloroform:isopropanol) and water. The layers were separated and the organic layer was concentrated under reduced pressure. Silica gel chromatography (0-15% methanol in dichloromethane) afforded the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[C:6]([C:9]2[N:14]=[C:13]([N:15]3[CH2:20][CH2:19][O:18][C@@H:17]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[CH2:16]3)[N:12]([CH3:28])[C:11](=[O:29])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:30][O-:31].[Na+]>O1CCCC1>[Cl:8][C:7]1[C:2]([O:31][CH3:30])=[N:3][CH:4]=[CH:5][C:6]=1[C:9]1[N:14]=[C:13]([N:15]2[CH2:20][CH2:19][O:18][C@@H:17]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH2:16]2)[N:12]([CH3:28])[C:11](=[O:29])[CH:10]=1
Reactant: C[O-]
Reactant: Cn1c(N2CCO[C@@H](c3ccc(F)cc3)C2)nc(-c2ccnc(Cl)c2Cl)cc1=O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1nccc(-c2cc(=O)n(C)c(N3CCO[C@@H](c4ccc(F)cc4)C3)n2)c1Cl
Temperature: 60 °C
Yield: 50.4 %

Procedure:
A suspension of 6-(2,3-dichloropyridin-4-yl)-2-((2S)-2-(4-fluorophenyl)morpholin-4-yl)-3-methyl-3H-pyrimidin-4-one (0.50 g, 1.15 mmol), and sodium methoxide (1.1 g, 20.4 mmol) in tetrahydrofuran (10 ml) was heated at 60° C. for 5 hours. The resulting suspension was partitioned between chloroform and brine and the aqueous layer was extracted with chloroform. The combined organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting 5-10% methanol in chloroform to furnish 6-(3-chloro-2-methoxypyridin-4-yl)-2-((2S)-2-(4-fluorophenyl) morpholin-4-yl)-3-methyl-3H-pyrimidin-4-one (0.27 g, 0.58 mmol, 50%) as white crystals.
Reaction SMILES: C([O-])(=O)C.[Pd+2:5].C([O-])(=O)C.[F:10][C:11]([F:16])([F:15])[C:12]([OH:14])=[O:13]>>[F:10][C:11]([F:16])([F:15])[C:12]([O-:14])=[O:13].[Pd+2:5].[F:10][C:11]([F:16])([F:15])[C:12]([O-:14])=[O:13]
Reactant: O=C(O)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: O=C([O-])C(F)(F)F

Procedure:
Into 40 ml of distilled trifluoroacetic acid was dissolved 1.0 g of palladium acetate. The solvent was distilled off and an additional 20 ml of trifluoroacetic acid was added and distilled off. The residual solid was dried in facuo at 40° C. to afford 1.3 g of brown product, i.e. palladium (II) trifluoroacetate, mp 210° C. (dec).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[NH:11][C:10](=[O:15])[CH:9]=2)=[CH:4][CH:3]=1.C1C(=O)N([Br:23])C(=O)C1>CN(C=O)C>[Br:23][C:13]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[CH:9][C:10](=[O:15])[NH:11][C:12]=1[CH3:14]
Reactant: Cc1cc(-c2ccc(Cl)cc2)cc(=O)[nH]1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Cc1[nH]c(=O)cc(-c2ccc(Cl)cc2)c1Br
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 16.7 %

Procedure:
To a solution of 4-(4-chlorophenyl)-6-methylpyridin-2(1H)-one (1.1 g, 5.0 mmol) in DMF (20 mL) was added NBS (1.07 g, 6.0 mmol) in small portions over 15 min. The reaction mixture was stirred at room temperature for 20 min. Analysis by HPLC/MS indicated the starting 4-(4-chlorophenyl)-6-methylpyridin-2(1H)-one was consumed, and about 17% (based on the UV absorption) of the desired product had formed. The reaction mixture was partitioned between water (50 mL) and EtOAc (50 mL). The resulting suspension was filtered, and the collected solid was washed with water, the dried in a vacuum oven at 50° C. for 16 h to afford 250 mg (17%) of the title compound as an off-white solid. HPLC/MS: retention time=3.35 min, [M+H]+=298.2.
Reaction SMILES: N(C(OC(C)(C)C)=O)CC(O)=O.[CH3:13][C@@H:14]([C@@H:29]1[C@@:33]2([CH3:49])[CH2:34][CH2:35][CH2:36]/[C:37](=[CH:38]\[CH:39]=[C:40]3/[CH2:41][C@@H:42]([OH:48])[CH2:43][C@H:44]([OH:47])[C:45]/3=[CH2:46])/[C@@H:32]2[CH2:31][CH2:30]1)[CH2:15][C@H:16]([OH:28])[CH2:17][C:18]([OH:27])([C:23]([F:26])([F:25])[F:24])[C:19]([F:22])([F:21])[F:20].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[CH3:13][C@@H:14]([C@@H:29]1[C@@:33]2([CH3:49])[CH2:34][CH2:35][CH2:36]/[C:37](=[CH:38]\[CH:39]=[C:40]3/[CH2:41][C@@H:42]([OH:48])[CH2:43][C@H:44]([OH:47])[C:45]/3=[CH2:46])/[C@@H:32]2[CH2:31][CH2:30]1)[CH2:15][C:16]([CH2:17][C:18]([OH:27])([C:23]([F:24])([F:25])[F:26])[C:19]([F:22])([F:21])[F:20])=[O:28]
Reactant: C=C1/C(=C/C=C2\CCC[C@]3(C)[C@@H]([C@H](C)C[C@H](O)CC(O)(C(F)(F)F)C(F)(F)F)CC[C@@H]23)C[C@@H](O)C[C@@H]1O
Agent: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: C=C1/C(=C/C=C2\CCC[C@]3(C)[C@@H]([C@H](C)CC(=O)CC(O)(C(F)(F)F)C(F)(F)F)CC[C@@H]23)C[C@@H](O)C[C@@H]1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 26 %

Procedure:
N-Boc-Gly (300 mg, 1.43 mmol) was dissolved in DCM 30 mL, next added DIPA (1 mL, 5 mmol), after several minutes added ST-232 (180 mg, 1.43 mmol), after 10 min added TBTU (550 mg, 1.71 mmol). The reaction mixture was stirred at r.t. for 1.5 h, next diluted DCM and washed with 1N HCl, 5% NaHCO3, brine and dried over MgSO4. The solvent was evaporated, and the product was purified by flash column chromatography (silica gel, DCM:MeOH 60:1 50:1 20:1), to give 200 mg (49%) of ST-233 as colorless oil.
Reaction SMILES: F[C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([C:9]3[C:10]([NH2:26])=[N:11][CH:12]=[C:13]([C:15]4[CH:16]=[N:17][N:18]([CH:20]5[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH:19]=4)[CH:14]=3)[S:8][C:4]=2[CH:3]=1.ClC1SC2C=C([C:39]([F:42])([F:41])[F:40])C=CC=2N=1>>[NH:23]1[CH2:22][CH2:21][CH:20]([N:18]2[CH:19]=[C:15]([C:13]3[CH:14]=[C:9]([C:7]4[S:8][C:4]5[CH:3]=[C:2]([C:39]([F:42])([F:41])[F:40])[CH:28]=[CH:27][C:5]=5[N:6]=4)[C:10]([NH2:26])=[N:11][CH:12]=3)[CH:16]=[N:17]2)[CH2:25][CH2:24]1
Reactant: FC(F)(F)c1ccc2nc(Cl)sc2c1
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2ccc(F)cc2s1
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2ccc(C(F)(F)F)cc2s1

Procedure:
Same procedure as 3-(6-fluorobenzothiazol-2-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine except using 2-chloro-6-trifluoromethyl-1,3-benzothiazole in place of 2-chloro-6-fluorobenzothiazole to afford the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=2.11-2.30 (m, 4H), 3.11 (q, J=10.8 Hz, 2H), 3.41 (d, J=12.4 Hz, 2H), 4.47-4.58 (m, 1H), 7.92 (d, J=8.4 Hz, 1H), 8.08 (s, 1H), 8.32 (d, J=8.4 Hz, 1H), 8.43 (br. s., 2H), 8.58 (br. s., 1H), 8.76 (br. s., 1H). MS (ES+): m/z=445.08 [MH+]. HPLC: tR=2.25 min (ZQ2, polar—5 min).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]1=[O:14].[CH2:15]=[CH:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>CC(C)=O>[OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH:4]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:3]1=[O:14].[CH2:15]=[CH:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([O-:25])(=[O:1])=[O:24])=[CH:19][CH:18]=1
Reactant: C=Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C1CC(c2ccccc2)C(=O)N1O
Solvent: CC(C)=O
Product: C=Cc1ccc(S(=O)(=O)[O-])cc1
Yield: 115.6 %

Procedure:
50 ml of acetone was added to 3.8 g of N-hydroxy-2-phenylsuccinimide and 4.1 g of p-styrenesulfonyl chloride and then the same procedure as that of Preparation Example 1 was repeated to obtain 4.3 g of N-hydroxy-2-phenylsuccinimide-p-styrenesulfonate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6](Cl)=[O:7].[Cl:14][C:15]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:16]=1[NH2:17].O>N1C=CC=CC=1>[Cl:14][C:15]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:16]=1[NH:17][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: Nc1cc([N+](=O)[O-])ccc1Cl
Reactant: COc1ccc(C(=O)Cl)cc1OC
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(C(=O)Nc2cc([N+](=O)[O-])ccc2Cl)cc1OC
Temperature: 100 °C
Yield: 35.8 %

Procedure:
3,4-Dimethoxybenzoyl chloride (2 g) was added to a stirred suspension of 2-chloro-5-nitroaniline (1.72 g) in pyridine (10 ml) at 20° C. The reaction mixture was heated to 100° C. for 1 hour. After cooling to ambient temperature, the reaction mixture was poured into water (100 ml). The resulting precipitate was collected, washed with water and dried. The solid was triturated under methylene chloride (20 ml) to give N-(2-chloro-5-nitrophenyl)-3,4-dimethoxybenzamide (1.2 g), m.p. 231-232° C.; NMR Spectrum: (DMSOd6) 3.82 (s, 6H), 7.08 (d, 1H), 7.62 (m, 1H), 7.82 (d, 1H), 8.08 (m, 1H), 8.54 (d, 1H), 10.07 (m, 1H);