Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[CH:16]=[C:15]([C:17]3[CH:18]=[N:19][C:20]([O:23]C)=[CH:21][CH:22]=3)[CH:14]=[C:13]([NH:25][C:26]3[CH:31]=[N:30][CH:29]=[CH:28][N:27]=3)[N:12]=2)[CH3:9])=[CH:4][CH:3]=1.[I-].[Na+].C[Si](Cl)(C)C.C(=O)(O)[O-].[Na+]>C(#N)C.C(OCC)(=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[CH:16]=[C:15]([C:17]3[CH:18]=[N:19][C:20]([OH:23])=[CH:21][CH:22]=3)[CH:14]=[C:13]([NH:25][C:26]3[CH:31]=[N:30][CH:29]=[CH:28][N:27]=3)[N:12]=2)[CH3:9])=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2cc(Nc3cnccn3)nc(N[C@@H](C)c3ccc(F)cc3)c2)cn1
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: C[C@H](Nc1cc(-c2ccc(O)nc2)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Temperature: 70 °C
Reaction time: 3.5 h
Yield: 74.7 %

Procedure:
108 mg of (S)—N2′-[1-(4-fluorophenyl)ethyl]-6-methoxy-N6′-(pyrazin-2-yl)-3,4′-bipyridine-2′,6′-diamine was dissolved in 3 ml of acetonitrile, 116 mg of sodium iodide and 99 μl of trimethylsilyl chloride were added, and the mixture was stirred at 70° C. for 3.5 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate and water, and the pH of the mixture was adjusted to 9 by using saturated sodium bicarbonate aqueous solution. The organic layer was washed with brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 78 mg of (S)-2′-[1-(4-fluorophenyl)ethylamino]-6′-(pyrazin-2-ylamino)-3,4′-bipyridin-6-ol as pale yellow powder. The obtained compound was dissolved in methanol, and an equivalent of 1N hydrochloric acid was added thereto, and then the solvent was removed to obtain the objective compound as pale yellow powder.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][C@H:26]([C:52]([O:54]C)=[O:53])[CH2:27][C:28]1[N:32]=[CH:31][N:30]([C:33]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:29]=1.Cl.[NH:57]1[C:61](=[O:62])[CH2:60][CH2:59][C@H:58]1[C:63](O)=[O:64].CCN(C(C)C)C(C)C>CN(C=O)C>[NH:57]1[C:61](=[O:62])[CH2:60][CH2:59][C@H:58]1[C:63]([NH:25][C@H:26]([C:52]([OH:54])=[O:53])[CH2:27][C:28]1[N:32]=[CH:31][N:30]([C:33]([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:29]=1)=[O:64]
Reactant: O=C1CC[C@@H](C(=O)O)N1
Reactant: COC(=O)[C@@H](N)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CC[C@@H](C(=O)N[C@@H](Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)C(=O)O)N1
Yield: 99.3 %

Procedure:
According to the general procedure for HBTU promoted coupling, 4.7 g (10.5 mmol) H-His(Trt)-OMe.HCl, 4.54 g (10.8 mmol) HBTU, 2.69 g (10.5 mmol) Pyr-OH and 8.3 ml (26.3 mmol) DIPEA were reacted in a CYTOS® Lab System in anhydrous DMF at total flow of 26.7 ml/min and a residence time of 1.2 min to yield 5.3 g of crude Pyr-His(Trt)-OH which was used in the next step without purification. Yield based on HPLC: 81%.
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[C:7]2[NH:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1.[CH3:22][O:23][C:24]1[CH:46]=[CH:45][C:27]([CH2:28][N:29]2[CH:37]=[N:36][C:35]3[C:30]2=[N:31][CH:32]=[N:33][C:34]=3[C:38]2[C:39](F)=[N:40][CH:41]=[CH:42][CH:43]=2)=[CH:26][CH:25]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl.C([O-])(O)=O.[Na+]>C1COCC1>[CH3:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:28][N:29]2[CH:37]=[N:36][C:35]3[C:30]2=[N:31][CH:32]=[N:33][C:34]=3[C:38]2[C:39]([NH:1][C:2]3[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]4[C:3]=3[CH:4]=[CH:5][N:6]=[C:7]4[NH:13][C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)=[N:40][CH:41]=[CH:42][CH:43]=2)=[CH:45][CH:46]=1
Reactant: Cc1ccc2c(Nc3ccc(C#N)cc3)nccc2c1N
Reactant: COc1ccc(Cn2cnc3c(-c4cccnc4F)ncnc32)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: COc1ccc(Cn2cnc3c(-c4cccnc4Nc4c(C)ccc5c(Nc6ccc(C#N)cc6)nccc45)ncnc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-(5-amino-6-methylisoquinolin-1-ylamino)benzonitrile (0.250 g, 0.91 mmol) and 9-(4-methoxybenzyl)-6-(2-fluoropyridin-3-yl)-9H-purine (0.34 g, 1.0 mmol) in anhydrous THF (20 mL) was treated dropwise with lithium bis(trimethylsilyl)amide (1.0 M solution in THF; 2.7 mlL, 2.7 mmol) to give a dark suspension. The suspension was sonicated for 2 min and then stirred at RT for 30 min. The reaction mixture was sonicated again for 2 min. The mixture was treated with 1N aq HCl (5 mL) and stirred at RT for 10 min. The reaction mixture was added to satd NaHCO3 (70 mL) and extracted with 3:1 CHCl3:IPA (3×50 mL). The combined organic layers were washed with satd NaCl, dried over Na2SO4, filtered, and concentrated in vacuo to give 840 mg crude product. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (80 g), eluting with a gradient of 10% to 50% EtOAc in CH2Cl2, to give 4-(5-(3-(9-(4-methoxybenzyl)-9H-purin-6-yl)pyridin-2-ylamino)-6-methylisoquinolin-1-ylamino)benzonitrile. MS (ESI, pos. ion) m/z: 590.2 [M+H]+
Reaction SMILES: [C:1]([O-:4])([O-])=[O:2].[K+].[K+].Br[C:8]1([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[NH:10][C:9]1=[O:18]>O1CCOCC1>[Cl:17][C:13]1[CH:12]=[C:11]2[C:16]([C:8]([NH:10][CH:9]([CH2:8][CH:16]([CH3:11])[CH3:15])[C:1]([OH:4])=[O:2])([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[C:9](=[O:18])[NH:10]2)=[CH:15][CH:14]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1Nc2cc(Cl)ccc2C1(Br)Cc1cccc(Cl)c1
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)CC(NC1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To the aqueous solution K2CO3 (1.6 μL, 1N) was added (2S)-amino-4-methyl-pentanoic (106 mg, 0.81 mmol), then followed by the addition of rac-3-bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (200 mg, 0.54 mmol) in dioxane (5 mL). After the mixture was stirred at room temperature for 4 h, the reaction mixture was concentrated in vacuo. Water (10 mL) was added and the crude was acidified with HCl to PH=4. The mixture was extracted with ethyl acetate (3×10 mL). The combined organic layer was concentrated in vacuo. The residue was purified by chromatography (DCM: MeOH=80:1) to give 184 mg of rac-(2S)-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-4-methyl-pentanoic acid as a white solid. MS: 421 (M+H)+. H1-NMR (400 MHz, CDCl3) δ 10.04 (s, 1H), 7.12 (m, 5H), 6.93 (t, 1H), 6.76 (m, 2H), 3.32 (m, 1H), 3.16 (dd, 2H), 1.89 (m, 1H), 1.50 (m, 2H), 0.90 (dd, 6H).
Reaction SMILES: Cl.Cl.[C:3]1([CH:9]([NH2:19])[C:10]2[NH:18][C:13]3=[CH:14][N:15]=[CH:16][CH:17]=[C:12]3[CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.[C:29](O)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[N:32][CH:31]=1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:3]1([CH:9]([C:10]2[NH:18][C:13]3=[CH:14][N:15]=[CH:16][CH:17]=[C:12]3[CH:11]=2)[NH:19][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[N:32][CH:31]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NC(c1ccccc1)c1cc2ccncc2[nH]1
Reactant: O=C(O)c1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC(c1ccccc1)c1cc2ccncc2[nH]1)c1cccnc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 32.2 %

Procedure:
To a solution of 1-phenyl-1-(1H-pyrrolo[2,3-c]pyridin-2-yl)methylamine dihydrochloride (Example 40) (51 mg, 0.17 mmol), N,N-diisopropylethylamine (DIPEA) (0.15 mL, 0.85 mmol) and nicotinic acid (22 mg, 0.18=mmol) in methylene chloride (2.0 mL) was added 1-ethyl-3-dimethylaminopropylcarbodiimide hydrochloride (EDC-HCl) (30 mg, 0.20 mmol) followed by a catalytic amount of 4-dimethylaminopyridine (DMAP). The reaction mixture was stirred at room temperature overnight (20 h) under a N2 atmosphere. TLC analysis showed the starting amine, therefore the reaction mixture was heated to reflux. After refluxing overnight, the reaction mixture was concentrated to dryness. The residue was dissolved in EtOAc and water. The organic layer was washed with water, 1 M citric acid, saturated NaHCO3, and saturated NaCl. TLC analysis showed that the majority of desired product was extracted into the 1 M citric acid washing. The citric acid extracts were made basic with 15% NaOH solution and extracted with methylene chloride. The organic extracts were dried over Na2SO4, filtered and concentrated to dryness. Trituration with Et2O/CH2Cl2 (1:1) provided N-[phenyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methyl]nicotinamide (18 mg, 32%) as a light yellow solid after drying: mp 178-188° C.; 1H NMR (300 MHz, CD3OD) δ6.30 (1H, s), 6.67 (1H, s), 7.35-7.55 (7H, m), 8.03 (1H, d, J=5.5 Hz), 8.30-8.38 (1H, m), 8.61 (1H, s), 8.69-8.71 (1H, m), 9.05-9.07 (1H, m); ESI MS m/z 329 [C20H16N4O+H]+; HPLC (Method A) >99% (AUC) tR=13.3 min.
Reaction SMILES: C([O:8][C:9](=[O:29])[CH:10]([NH:25][C:26](=[O:28])[CH3:27])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:14][CH:13]=1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[C:26]([NH:25][CH:10]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:16][CH:17]=1)[C:9]([OH:29])=[O:8])(=[O:28])[CH3:27]
Reactant: [H][H]
Reactant: CC(=O)NC(Cc1ccc(C(=O)OC(C)(C)C)cc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(=O)NC(Cc1ccc(C(=O)OC(C)(C)C)cc1)C(=O)O
Yield: 92.5 %

Procedure:
A suspension of rac.-2-acetamido-3-[4-[(1,1-dimethyl-ethoxy)carbonyl]phenyl]propanoic acid benzyl ester (3.3 g, 8 mmol) and 10% Pd/C (320 mg) in ethanol (100 mL) was blanketed with hydrogen (1 atm) at room temperature. Upon the consumption of 1 equivalent of hydrogen, the mixture was filtered through celite. The celite pad was washed with ethanol (50 mL) and the filtrates were combined and concentrated. The resultant solid was purified by recrystallization from ethyl acetate/hexane to give rac.-2-acetamido-3-[4-[(1,1-dimethylethoxy)carbonyl]phenyl]propanoic acid, (2.3 g, 7.4 mmol) in 89% yield, mp. 187°-188° C.
Reaction SMILES: [Cl:1][C:2]1[C:12]([Cl:13])=[C:11]([Cl:14])[C:10]([Cl:15])=[C:4]2[C:5]([O:7][C:8](=O)[C:3]=12)=[O:6].[OH-].[NH4+:17]>>[Cl:1][C:2]1[C:12]([Cl:13])=[C:11]([Cl:14])[C:10]([Cl:15])=[C:4]2[C:5]([NH:17][C:8](=[O:7])[C:3]=12)=[O:6]
Reactant: O=C1OC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Reactant: [NH4+]
Agent: [OH-]
Product: O=C1NC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21

Procedure:
3,4,5,6-Tetrachlorophthalic anhydride (0.30 mole) is charged into a glass reaction vessel. Concentrated ammonium hydroxide (280 ml) is incrementally added at room temperature with stirring. After the addition is completed the reaction slurry is heated with stirring for a period sufficient to evaporate most of the water present in the reaction mixture. The remaining solid is then dried in a forced air oven and is recrystallized. The recrystallized product is washed with acetone, filtered and dried to yield the desired product 3,4,5,6-tetrachlorophthalimide.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][NH:16][CH2:15][C@H:14]2[O:19][CH2:20][CH3:21])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9].Br[C:23]1[S:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[S:24]1[C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=[C:23]1[N:16]1[CH2:17][CH2:18][C@H:13]([NH:12][C:10]([C:5]2[NH:6][C:7]([CH2:8][CH3:9])=[C:3]([Cl:2])[N:4]=2)=[O:11])[C@H:14]([O:19][CH2:20][CH3:21])[CH2:15]1
Reactant: Brc1nc2ccccc2s1
Reactant: CCO[C@@H]1CNCC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCO[C@@H]1CN(c2nc3ccccc3s2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 64.7 %

Procedure:
cis(±)-4-Chloro-N-(3-ethoxypiperidin-4-yl)-5-ethyl-1H-imidazole-2-carboxamide hydrochloride obtained in Example (131a) (100 mg, 0.297 mmol), 2-bromobenzothiazole (95 mg, 0.44 mmol) and sodium carbonate (157 mg, 1.48 mmol) were suspended in DMF (3 mL). The suspension was subjected to the same operation as in Example (131b) to obtain 83.4 mg of the title compound as a colorless oily substance (65%).
Reaction SMILES: [C:1]1([C@@H:7]([C@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[OH:10])[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20](S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C1(=O)CCC=C1>C1CCCCC1>[C:11]1([C@H:9]2[C@H:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][C:17]3([CH2:22][CH2:21][CH:20]=[CH:27]3)[O:10]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O[C@@H](c1ccccc1)[C@@H](O)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C1C=CCC1
Agent: c1cc[nH+]cc1
Solvent: C1CCCCC1
Product: C1=CC2(CC1)O[C@@H](c1ccccc1)[C@H](c1ccccc1)O2
Yield: 676.8 %

Procedure:
A solution of (S,S)-hydrobenzoin (10.0 g, 46.7 mmol), pyridinium p-toluene sulfonate (1.4 g, 5.6 mmol), 2-cyclopentene-1-one (20 mL, 238.7 mmol) and cyclohexane (200 mL) was heated under reflux for 4 h with a Dean-Stark trap to remove water formed during the reaction. The mixture was then cooled in an ice bath for 20 min, and the insolubles were filtered off through filter aid. The resulting solution was washed with a 10% aqueous potassium bicarbonate solution (2×25 mL) and water (2×25 mL), and then dried over anhydrous sodium sulfate. The dried solution was passed through a pad of silica gel 60 (26 g of 230–400 mesh). The pad was further eluted with additional hexanes (475 mL). The resulting solution was concentrated in vacuo to afford 2(S),3(S)-diphenyl-1,4-dioxa-spiro[4.4]non-6-ene (10.55 g, 81%) as a white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=2)[S:8][C:7]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:5])C.[OH-].[Na+].Cl>O.CCO>[NH2:17][C:13]1[N:12]=[C:11]([C:9]2[S:8][C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:6]([C:4]([OH:5])=[O:3])[CH:10]=2)[CH:16]=[CH:15][N:14]=1
Reactant: CCOC(=O)c1cc(-c2ccnc(N)n2)sc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1nccc(-c2cc(C(=O)O)c(-c3ccccc3)s2)n1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of ester 58 (220 mg, 0.68 mmol) in 1:1 H2O/EtOH (9 mL), 4M aq NaOH (10 eq) was added and the mixture stirred at 100° C. for 1 h. After cooling to rt, the solution was acidified with 2M HCl yielding 5-(2-amino-pyrimidin-4-yl)-2-phenyl-thiophene-3-carboxylic acid as a solid which was filtered, washed with water and dried under reduced pressure (185 mg, 90%).
Reaction SMILES: [C:1]1([S:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])C=C[CH:4]=[CH:3][CH:2]=1.C(S)CCC.CC[O-].[Na+].BrCC(OCC)=O>C(O)C>[CH2:1]([S:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)CSc1ccccc1
Agent: CCOC(=O)CBr
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCCCS
Product: CCCCSCC(=O)OCC

Procedure:
The procedure is as in Example 2 for the preparation of ethyl (phenylthio)acetate, starting with n-butylmercaptan (10.7 cc), a 2M ethanolic solution of sodium ethylate (50 cc) and ethyl bromoacetate (16.7 g) in ethanol (100 cc). Ethyl (n-butylthio)acetate (15.4 g) is thereby obtained, and is used in the crude state in the subsequent syntheses.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[CH2:11][S:10]/[C:9]/1=[N:14]\[CH:15]([CH3:17])[CH3:16].[O:18]1[C:23]2[CH:24]=[CH:25][C:26]([CH:28]=O)=[CH:27][C:22]=2[O:21][CH2:20][CH2:19]1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[O:18]1[C:23]2[CH:24]=[CH:25][C:26](/[CH:28]=[C:11]3/[C:12](=[O:13])[N:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[CH3:1])/[C:9](=[N:14]/[CH:15]([CH3:17])[CH3:16])/[S:10]/3)=[CH:27][C:22]=2[O:21][CH2:20][CH2:19]1
Reactant: O=Cc1ccc2c(c1)OCCO2
Reactant: Cc1ccccc1N1C(=O)CS/C1=N\C(C)C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1ccccc1N1C(=O)/C(=C/c2ccc3c(c2)OCCO3)S/C1=N\C(C)C
Temperature: 25 °C

Procedure:
A solution of 3-(2-methylphenyl)-2-[(Z)-isopropylimino]-thiazolidin-4-one (50 mg, 0.200 mmol), 2,3-dihydro-benzo[1,4]dioxine-6-carbaldehyde (49 mg, 0.300 mmol) and sodium acetate (33 mg, 0.400 mmol) in acetic acid (1 mL) is stirred at 110° C. for 5 h. The reaction mixture is cooled to rt and subjected to prep. HPLC purification. The product containing fractions are evaporated and dried to give 5-(2,3-dihydro-benzo[1,4]dioxin-6-ylmeth-(Z)-ylidene)-2-[(Z)-isopropylimino]-3-o-tolyl-thiazolidin-4-one.
Reaction SMILES: [BH4-].[Na+].[CH:3]([C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:6]=1[C:7]#[N:8])=[O:4]>CO.C1COCC1>[OH:4][CH2:3][C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:6]=1[C:7]#[N:8]
Reactant: N#Cc1c(C=O)cccc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1c(CO)cccc1[N+](=O)[O-]

Procedure:
Sodium borohydride (92.0 mg, 2.43 mmol) was added to a solution of 2-formyl-6-nitrobenzonitrile (Example 207e) (0.86 g, 4.88 mmol) in MeOH (38 mL) and THF (38 mL) at −8° C., and was stirred at that temperature for no more than 30 min. The reaction was quenched with HCl (6 M, 4.88 mL), followed by addition of water (50 mL), and brine (50 mL). The mixture was extracted with EtOAc, the combined extract was dried over MgSO4, filtered and concentrated. The crude product was purified by chromatography on silica using the solvent gradient CH2Cl2→CH2Cl2/MeOH (8:2) to give the title compound in amount of 0.32 g, (37%), which was used immediately in the next step. 1H NMR (400 MHz, DMSO-d6) δ 4.77 (d, J=5.6 Hz, 2H), 5.87 (t, J=5.6 Hz, 1H), 7.97 (t, J=8.0 Hz, 1H), 8.07 (dd, J=0.4, 8.0 Hz, 1H), 8.28 (dd, J=0.8, 8.0 Hz, 1H).
Reaction SMILES: Br[C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([C:6](=[O:13])[C:7](=[O:12])[NH:8]2)=[CH:4][CH:3]=1.[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])(O)=O.[Na+]>COCCOC.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>[CH3:11][C:10]1[C:2]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:3][CH:4]=[C:5]2[C:9]=1[NH:8][C:7](=[O:12])[C:6]2=[O:13]
Reactant: OB(O)c1ccccc1
Reactant: Cc1c(Br)ccc2c1NC(=O)C2=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1c(-c2ccccc2)ccc2c1NC(=O)C2=O
Yield: 55.5 %

Procedure:
6-Bromo-7-methyl-1H-indole-2,3-dione (100 mg, 0.38 mmol) and phenylboronic acid (53 mg, 1.1 eq) were dissolved in 10 mL DME. Pd(PPh3)4 (22 mg, 0.05 eq) were added followed by NaHCO3 (65 mg, 2.0 eq) dissolved in 10 mL water. The mixture was refluxed for 2.5 hr and the organic solvent was removed by evaporation. The mixture was extracted with ethyl acetate and the combined organic layers were dried over Na2SO4 and purified by SiO2 chromatography to give the title compound (50 mg, 51%).
Reaction SMILES: Cl.[NH2:2][CH:3]([CH:5]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)[CH3:4].[OH:21][CH2:22][C:23]([CH3:28])([CH3:27])[C:24](O)=[O:25].ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CCOC(C)=O>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([CH:5]([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[CH:3]([NH:2][C:22](=[O:21])[C:23]([CH3:28])([CH3:27])[CH2:24][OH:25])[CH3:4])=[CH:19][CH:18]=1
Reactant: CC(N)C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: CC(C)(CO)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)C(C)(C)CO)C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-amino-3,4-bis(4-chlorophenyl)butane hydrochloride salt (Reference Example 1, Diastereomer a) (3.7 g, 11 mmol), 3-hydroxy-2,2-dimethylpropionic acid (2.0 g, 17 mmol) in CH2Cl2 (100 mL) was added 1-hydroxybenzotriazole (2.3 g, 17 mmol), diisopropylethylamine (7.7 mL, 44 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (3.2 g, 17 mmol). After stirring at room temperature overnight. The reaction mixture was diluted with EtOAc (200 mL), washed with water and saturated aqueous sodium bicarbonate, and concentrated to dryness, and the residue was purified by flash column chromatography on silica gel eluted with 50% EtOAc in hexane to give the title compound. 1H NMR (500 MHz, CD3OD): δ7.24 (d, 2H), 7.12 (d, 2H), 7.10 (d, 2H), 6.92 (d, 2H), 4.25 (m, 1H), 3.68 (ABq, 2H), 3.18 (dd, 1H), 2.93 (ddd, 1H), 2.76 (dd, 1H), 1.20 (s, 3H), 1.19 (s, 3H), 0.96 (d, 3H). LC-MS: m/e 394 (M+H)+ (3.5 min).
Reaction SMILES: [CH3:1][C:2]1[NH:6][NH:5][C:4](=[O:7])[CH:3]=1.[C:8]12(O)[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2>>[C:8]12([C:3]3[C:4](=[O:7])[NH:5][NH:6][C:2]=3[CH3:1])[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2
Reactant: OC12CC3CC(CC(C3)C1)C2
Reactant: Cc1cc(=O)[nH][nH]1
Product: Cc1[nH][nH]c(=O)c1C12CC3CC(CC(C3)C1)C2
Temperature: 0 °C
Reaction time: 24 h
Yield: 107.7 %

Procedure:
A suspension of 5-methyl-1,2-dihydro-pyrazol-3-one (4.0 g) and adamantan-1-ol (5.6 g) in a round bottom flask was cooled to 0° C. with an ice/water bath. To the cooled suspension was added borontrifluoride ethyl etherate (9.2 mL) over 10 minutes. The reaction mixture was then allowed to warm up to ambient temperature and stirred for 24 hours. The suspension was then re-cooled to 0° C. and quenched with 50% KOH solution. The mixture was then acidified with 2 N aqueous HCl solution and diluted with EtOAc. The resultant white precipitate was then collected by filtration and the solid was washed with ether. The white solid was dried in a dessicator to give the desired 4-adamantan-1-yl-5-methyl-1,2-dihydro-pyrazol-3-one (9.2 g) as a white solid. MS (ESI+): 233.3 [M+H]+).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:14]([O-:16])=[O:15])=[C:6]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:23][N:24](C)[CH:25]=O.Cl.CNC>O>[CH3:23][N:24]([CH3:25])[C:2]1[CH:3]=[CH:4][C:5]([N+:14]([O-:16])=[O:15])=[C:6]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])[CH:7]=1
Reactant: CN(C)C=O
Reactant: CN(C)S(=O)(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Product: CN(C)c1ccc([N+](=O)[O-])c(S(=O)(=O)N(C)C)c1
Temperature: 50 °C

Procedure:
To a suspension of 5-Chloro-N,N-dimethyl-2-nitro-benzenesulfonamide (1.8 g, 0.0068 mol) and Potassium carbonate (3.3 g, 0.024 mol) in N,N-Dimethylformamide (20 mL, 0.2 mol) was added Dimethylamine hydrochloride (0.83 g, 0.010 mol). The suspension was heated at 50° C. The mixture was cooled to room temperature and poured into water. The precipitate was filtered and rinsed with water then hexane. The recovered material was purified by silica gel chromatography using 0%→20% Methanol:Dichloromethane solvent gradient. 5-Dimethylamino-N,N-dimethyl-2-nitro-benzenesulfonamide isolated as a yellow solid (0.55 g, 30%).