Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:16][N:17]([CH3:21])[C:18](Cl)=[O:19]>C(#N)C>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][C:18]([N:17]([CH3:21])[CH3:16])=[O:19])[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1cc(O)cc(C)n1
Reactant: CN(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(OC(=O)N(C)C)cc(C)n1
Temperature: 80 °C

Procedure:
30,8 g (0,25 mole) of 2,6-dimethyl-4-hydroxypyridine were suspended in 500 ml of acetonitrile, 69 g (0,5 mole) of potassium carbonate were added and the mixture was heated to reflux temperature for 2 hours. Subsequently 47 g (0,44 mole) of dimethylcarbamic acid chloride were added at an interior temperature of approximately 60°-70° C. and the mixture was maintained for two hours at about 80° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.C([Li])CCC.[F:16][C:17]([F:31])([F:30])[C:18]([C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]([CH3:29])[CH:21]=1)=[O:19]>CCOCC>[F:31][C:17]([F:16])([F:30])[C:18]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2)([C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]([CH3:29])[CH:21]=1)[OH:19]
Reactant: Cn1cc(C(=O)C(F)(F)F)c2ccccc21
Reactant: Brc1ccc2[nH]ncc2c1
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cn1cc(C(O)(c2ccc3[nH]ncc3c2)C(F)(F)F)c2ccccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 26.6 %

Procedure:
To a chilled (−78° C.) solution of 1.5 g (7.61 mmol) of 5-bromoindazole in 15 mL ether was added 9.2 mL (23.0 mmol) of a 2.5 M solution of n-butyllithium in hexanes. After 5 minutes, the cold bath was removed and the mixture stirred 6 hours at room temperature. The mixture was cooled to −78° C. and 3.5 g (15.4 mmol) of 2,2,2-trifluoro-1-(1-methyl-1H-indol-3-yl)ethanone in 4 mL of a 1:1 mixture of ether-THF was added. The mixture was stirred overnight while warming to room temperature and was then quenched with aqueous ammonium chloride and extracted with ether. The organic layer was washed with water, brine, and dried over magnesium sulfate. Removal of the volatiles in vacuo provided a residue which was purified by CombiFlash chromatography using 0-90% EtOAc-hexanes (product eluted at 35% EtOAc) to afford 700 mg (26%) of 2,2,2-trifluoro-1-(1H-indazol-5-yl)-1-(1-methyl-1H-indol-3-yl)ethanol as a pale yellow foam.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=2)[CH:9]=1)=[O:4].C1C=C(Cl)C=C(C(OO)=[O:33])C=1.CCOC(C)=O>C(Cl)Cl.CCCCCC>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([S:16]([CH3:17])=[O:33])=[CH:14][CH:15]=2)[CH:9]=1)=[O:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1cc(-c2ccc(SC)cc2)c(-c2ccc(F)cc2)s1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: COC(=O)c1cc(-c2ccc(S(C)=O)cc2)c(-c2ccc(F)cc2)s1
Yield: 85.5 %

Procedure:
To a solution of 5-(4-fluorophenyl)-4-(4-(methylthio)phenyl)-thiophene-2-carboxylic acid methyl ester (5.60 g) in CH2Cl2 (84.0 mL) at 0° C. was added portionwise m-CPBA 50 to 60% (5.39 g). After TLC showed completion (50% EtOAc in hexane), the reaction mixture was extracted with saturated NaHCO3, dried over Na2SO4, filtered and evaporated to dryness to provide the title compound as a white foam (5.00 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[OH:63][CH2:64][C@@H:65]1[CH2:69][CH2:68][CH2:67][NH:66]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:66]1[CH2:67][CH2:68][CH2:69][C@H:65]1[CH2:64][OH:63])=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: OC[C@@H]1CCCN1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2cc(C(=O)N3CCC[C@H]3CO)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and (2S)-2-hydroxymethyl-pyrrolidine in DMSO at ambient temperature.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:21](=[O:23])[NH2:22])([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:24](OCC)(OCC)OCC.C(O)(=O)C>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]2([N:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:24]=[N:22][C:21]2=[O:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC(Nc2ccccc2)(C(N)=O)C1
Reactant: CCOC(OCC)OCC
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCCC2(C1)C(=O)N=CN2c1ccccc1

Procedure:
To a solution of 3-carbamoyl-3-phenylamino-piperidine-1-carboxylic acid tert-butyl ester (300 mg, 0.94 mmol) in toluene (10 ml) was added triethyl orthoformate (0.47 ml, 2.8 mmol) and acetic acid (0.5 ml, 8.7 mmol). The mixture was heated at reflux overnight. The reaction mixture was cooled and washed with a saturated solution of sodium bicarbonate (25 ml). The organics were separated and the aqueous extracted with EtOAc (10 ml). The organics portions were combined, dried (MgSO4) and concentrated in vacuo to afford an oil. Purification of the crude product by chromatography on silica eluting with 0-50% EtOAc in iso-hexane afforded the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]=[N:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)=[CH:7][C:6]=1[C:21]#[N:22].C(N(CC)CC)C.[C:30](Cl)(=[O:34])[C:31]([CH3:33])=[CH2:32]>O1CCOCC1>[C:30]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]=[N:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)=[CH:7][C:6]=1[C:21]#[N:22])(=[O:34])[C:31]([CH3:33])=[CH2:32]
Reactant: C=C(C)C(=O)Cl
Reactant: N#Cc1ccc(N=Nc2ccc(OCCO)c(C#N)c2)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: C=C(C)C(=O)OCCOc1ccc(N=Nc2ccc(C#N)cc2)cc1C#N
Temperature: 65 °C
Reaction time: 2 h

Procedure:
5.8 g (4-(2-hydroxyethyloxy)-3,4′-dicyanoazobenzene are dissolved in 15 ml dioxane at 65° C.; 2.4 g triethylamine are added. A solution of 3.1 g methacrylic acid chloride in 3 ml dioxane is added and the reaction mixture is stirred at 65° C. for 2 h and then introduced into 350 ml ice-water. The precipitate is filtered off with suction and dried. Purification is carried out by chromatography on silica gel in toluene/THF (½). The yield of 4-(2-methacryloyloxyethyloxy)-3,4′-dicyanoazobenzene is 5.9 g. M.p.=110° C.; max=352 nm (DMF).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:14]1([C:17](Cl)=[O:18])[CH2:16][CH2:15]1.C(N(C(C)C)CC)(C)C.CCOC(C)=O>ClCCCl>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:17]([CH:14]2[CH2:16][CH2:15]2)=[O:18])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=C(Cl)C1CC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: O=C(C1CC1)N1CCN(Cc2ccccc2)CC1
Temperature: 50 °C
Reaction time: 15 h
Yield: 99.2 %

Procedure:
To a mixture of 1-benzyl-piperazine (1.20 g, 6.81 mmol) in anhydrous DCE (23 mL) was added cyclopropane carboxylic acid chloride (854 mg, 8.17 mmol, 1.2 eq) followed by diisopropylethylamine (1.3 mL, 7.49 mmol, 1.1 eq), and the reaction mixture was stirred at 50° C. under N2 for 15 h. The mixture was cooled to rt and poured into EtOAc. The organic phase was washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by MPLC (Biotage®, gradient elution 75% EtOAc/hexane) to give the product (1.65 g, 99%) as a brown oil. 1H-NMR (300 MHz, DMSO-d6) 7.34 to 7.23 (m, 5H), 3.64 (broad s, 2H), 3.48 (s, 2H), 3.44 (broad s, 2H), 2.37 (broad s, 2H), 2.28 (broad s, 2H), 1.95 to 1.91 (m, 1H), 0.70 to 0.65 (m, 4H); ES-MS m/z 245.2 [M+H]+, RT (min) 1.12.
Reaction SMILES: NC1C=CC(C)=C(N[C:9]2[CH:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[C:18]([Cl:23])[CH:17]=3)[N:12]=[CH:11][N:10]=2)C=1.ClC1C=C(C2(N)C=C(Cl)N=CN2)C=CC=1F.[CH3:41][C:42]1[CH:48]=[CH:47][C:46]([N+:49]([O-:51])=[O:50])=[CH:45][C:43]=1[NH2:44].Cl>C(O)CCC.CCOC(C)=O>[Cl:23][C:18]1[CH:17]=[C:16]([NH:15][C:13]2[CH:14]=[C:9]([NH:44][C:43]3[CH:45]=[C:46]([N+:49]([O-:51])=[O:50])[CH:47]=[CH:48][C:42]=3[CH3:41])[N:10]=[CH:11][N:12]=2)[CH:21]=[CH:20][C:19]=1[F:22]
Reactant: Cc1ccc([N+](=O)[O-])cc1N
Reactant: Cc1ccc(N)cc1Nc1cc(Nc2ccc(F)c(Cl)c2)ncn1
Agent: Cl
Agent: NC1(c2ccc(F)c(Cl)c2)C=C(Cl)N=CN1
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: Cc1ccc([N+](=O)[O-])cc1Nc1cc(Nc2ccc(F)c(Cl)c2)ncn1
Temperature: 120 °C

Procedure:
Synthesis of N-(5-Amino-2-methylphenyl)-N′-(3-chloro-4-fluorophenyl)-pyrimidine-4,6-diamine (Int-F) A mixture of 4-(3-chloro-4-fluorophenyl)-6-chloropyrimidin-4-ylamine (IR-4) (1.2 g, 4.6 mmol), 2-methyl-5-nitroaniline (0.85 g, 5.5 mmol) and 1 mL of concentrated HCl in 10 mL of n-butanol was heated at 120° C. for 16 h. With stirring, 5 mL of EtOAc was added to the reaction mixture. The light yellow colored product that precipitated was filtered and dried under vacuum to give N-(3-chloro-4-fluorophenyl)-N′-(2-methyl-5-nitrophenyl)pyrimidine-4,6-diamine. MS (APCI) (m/z): 374/376 (M+1). A mixture of N-(3-chloro-4-fluorophenyl)-N′-(2-methyl-5-nitrophenyl)pyrimidine-4,6-diamine (0.55 g, 1.5 mmol) and iron powder (35 mesh, 0.5 g, 5 eq) in 5 mL of HOAc and 2 mL of MeOH was heated at reflux for 2 h. The solvent was removed in vacuo and the dark colored residue was mixed with 150 mL of CH2Cl2 and 15 mL of sat. K2CO3 solution and was stirred at room temperature for 30 min. The organic layer was dried (MgSO4), was concentrated, and was then purified by flash chromatography (silica gel, MeOH/NH4OH/CH2Cl2) to afford 0.115 g of N-(5-amino-2-methylphenyl)-N′-(3-chloro-4-fluorophenyl)pyrimidine-4,6-diamine as a light colored solid. (Int-F) MS (m/z): 344/346 (M+1).
Reaction SMILES: [CH3:1][NH:2][C:3](=[S:6])[NH:4][NH2:5].[CH3:7][C:8]([CH3:10])=O.[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1>N1C=CC=CC=1>[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([N:5]2[C:8]([CH3:10])([CH3:7])[S:6][C:3]([NH:2][CH3:1])=[N:4]2)=[O:17])=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CC(C)=O
Reactant: CNC(=S)NN
Solvent: c1ccncc1
Product: CNC1=NN(C(=O)c2ccc(F)cc2)C(C)(C)S1

Procedure:
A 42 g. portion of 4-methylthiosemicarbazide was reacted with 400 ml. of acetone, and then with 32 ml. of pyridine and 63.6 g. of 4-fluorobenzoyl chloride, and the mixture was worked-up as described in Example 1. The product was recrystallized from 80 ml. of nitromethane to obtain 43 g. of the desired product, 138°-144°.
Reaction SMILES: [CH3:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].ClCCl.C(N(CC)CC)C.[S:23](Cl)([CH3:26])(=[O:25])=[O:24]>O>[CH3:26][S:23]([O:5][CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[C:2]=1[CH3:1])(=[O:25])=[O:24]
Reactant: Cc1c(CO)cccc1[N+](=O)[O-]
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1c(COS(C)(=O)=O)cccc1[N+](=O)[O-]
Temperature: 5 °C
Reaction time: 2 h

Procedure:
200 g 2-Methyl-3-nitro benzylalcohol is added to dichloromethane (2000 ml) and triethylamine (250 ml). Mesyl chloride is added drop wise while maintaining temperature between 0-10° C. and stirred until the completion of reaction. It is further stirred 2 hours at room temperature. Water is added to the reaction mixture and stirred for 10 minutes. Organic layer was separated and washed with brine. Dichloromethane was evaporated to yield the oily brown 2-Methyl-3-nitrobenzyl methanesulfonate (207-210 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)[N:5]2[N:12]=[CH:13][C:14]([CH:15]=[O:16])=[C:4]2[N:3]=1.[C:17]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+].C(N(C(C)C)CC)(C)C>CN(C)C=O.O>[CH:9]1([NH:8][C:6]2[N:5]3[N:12]=[CH:13][C:14]([CH:15]=[O:16])=[C:4]3[N:3]=[C:2]([N:27]3[CH2:26][CH2:25][N:24]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:29][CH2:28]3)[CH:7]=2)[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1cnn2c(NC3CC3)cc(Cl)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2cc(NC3CC3)n3ncc(C=O)c3n2)CC1
Temperature: 80 °C
Yield: 80.3 %

Procedure:
To 5-chloro-7-(cyclopropylamino) pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (500 mg, 2.11 mmol) in dimethylformamide was added 1-Boc-piperazine (1.17 g, 6.33 mmol), potassium carbonate (583 mg, 4.21 mmol) and diisopropyl ethylamine (0.41 mL, 2.5 mmol). The mixture was heated to 80° C. for overnight. Cooled the reaction mixture, added water and filtered the white precipitate to yield tert-butyl 4-(7-(cyclopropylamino)-3-formylpyrazolo[1,5-a]pyrimidin-5-yl)piperazine-1-carboxylate (655 mg, 80% yield). LCMS (M+1=387)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C:5]([OH:7])=O.O[NH:18][C:19](=[NH:28])[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=1.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:7][N:28]=[C:19]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=3)[N:18]=2)[CH:8]=[CH:9][C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: N=C(NO)c1ccc(CO)cc1
Reactant: O=C(O)c1ccc(C2CCCCC2)c(Cl)c1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: OCc1ccc(-c2noc(-c3ccc(C4CCCCC4)c(Cl)c3)n2)cc1
Temperature: 132.5 °C
Reaction time: 2 h

Procedure:
N,N-Dicyclohexylcarbodiimide (0.615 g, 0.003 mol) is added to a solution of 3-chloro-4-cyclohexyl benzoic acid (0.475 g, 0.002 mol), N-hydroxy-4-hydroxymethylbenzamidine (0.45 g, 0.003 mol) and N-hydroxybenzotriazole monohydrate (0.457 g, 0.003 mol) in N,N-dimethylformamide (10 mL). The reaction mixture is stirred at 130-135° C. for 2 hrs. It is then cooled to 0-5° C., filtered and washed with dichloromethane (2×20 mL). The filtrate is evaporated under reduced pressure and the residue is treated with demineralized water (20 mL). It is extracted with ethyl acetate (3×15 mL) and the combined extract is dried over sodium sulfate. Removal of solvent under reduced pressure gives a crude residue which is purified by column chromatography (silica gel 230-400, ethyl acetate:toluene, 15:85) to give {4-[5-(3-chloro-4-cyclohexylphenyl)-[1,2,4]-oxadiazol-3-yl]phenyl}methanol.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[C:5]2[NH:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[OH:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=O>>[OH:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][N:17]1[CH2:18][CH2:19][CH:14]([NH:13][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([CH3:1])[CH:3]=3)[O:8][C:7](=[O:12])[CH:6]=2)[CH2:15][CH2:16]1
Reactant: O=Cc1cccc(O)c1
Reactant: Cc1ccc2oc(=O)cc(NC3CCNCC3)c2c1
Product: Cc1ccc2oc(=O)cc(NC3CCN(Cc4cccc(O)c4)CC3)c2c1

Procedure:
According to Procedure A above, 6-methyl-4-(piperidin-4-ylamino)-chromen-2-one and 3-hydroxybenzaldehyde were processed to give the title compound. MS (DCI/NH3) m/z 465 [M+H]+; 1H NMR (500 MHz, DMSO) δ ppm 9.41-9.63 (m, 1H), 7.94 (m, 1H), 7.40 (m, 1H), 7.29 (m, 2H), 7.20 (m, 1H), 6.90 (m, 3H), 5.36 (m, 1H), 4.22 (m, 2H), 3.74 (m, 1H), 3.48 (m, 2H), 3.09 (m, 2H), 2.37 (m, 3H), 2.18 (m, 2H), 1.80 (m, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([C@H:14]2[CH2:19][CH2:18][CH2:17][NH:16][C@H:15]2[CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:13])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:32][C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35](Cl)=[O:36]>C(Cl)Cl.C(OCC)(=O)C>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([C@H:14]2[CH2:19][CH2:18][CH2:17][N:16]([C:35](=[O:36])[C:34]3[CH:38]=[CH:39][CH:40]=[CH:41][C:33]=3[CH3:32])[C@H:15]2[CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24]2)=[O:13])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: CC(C)(C)c1cccc(NC(=O)[C@H]2CCCN[C@H]2C2CCCC2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1ccccc1C(=O)N1CCC[C@H](C(=O)Nc2cccc(C(C)(C)C)c2)[C@@H]1C1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
To a solution of the cis-2-cyclopentylpiperidine-3-carboxylic acid (3-tert-butylphenyl)amide prepared above (123 mg, 0.34 mmol) in dry CH2Cl2 (1 mL) containing Et3N (142 μL, 1.02 mmol) was added 2-methylbenzoyl chloride (53 mg, 0.34 mmol) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was then diluted with ethyl acetate (20 mL), washed with 1 N aqueous HCl, water, and brine. The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC (20-95% gradient of CH3CN—H2O) and dried (Lyophilizer) to give the title compound in 65% yield (109 mg). 1H NMR (400 MHz, CDCl3): δ 1.22-1.48 (m, 11H), 1.56-1.80 (m, 5H), 1.84-2.06 (m, 4H), 2.10-2.23 (m, 1H), 2.30 (s, 1.6H), 2.39 (s, 1.4H), 2.41-2.50 (m, 1H), 2.71-2.76 (m, 1H), 3.02-3.09 (m, 1H), 3.25-3.39 (m, 1H), 5.11 (bs, 1H), 7.05-7.30 (m, 6H), 7.47-7.55 (m, 2H), 8.32 (bs, 1H). LC-MS Rt (retention time): 3.16 min; MS: (ES) m/z 447 (M+H)+. LC-MS method: Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C., 1 mL/min flow rate, a 2.5 min gradient of 20% to 100% B with a 1.0 min wash at 100% B; A=0.1% formic acid/5% acetonitrile/94.9 water, B=0.1% formic acid/5% water/94.9 acetonitrile.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([C:14]2[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16]([OH:18])=[O:17])=O)=[C:4]1[CH3:23])[CH3:2].[CH3:24][N:25]([CH3:35])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]([CH3:34])[CH3:33])[CH:27]=1.C(OC(=O)C)(=O)C>C(O)C>[CH3:33][N:32]([CH3:34])[C:28]1[CH:27]=[C:26]([N:25]([CH3:35])[CH3:24])[CH:31]=[CH:30][C:29]=1[C:12]1([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:3]([CH2:1][CH3:2])[C:4]=2[CH3:23])[C:14]2[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:16](=[O:18])[O:17]1
Reactant: CN(C)c1cccc(N(C)C)c1
Reactant: CCn1c(C)c(C(=O)c2ccccc2C(=O)O)c2ccccc21
Solvent: CC(=O)OC(C)=O
Solvent: CCO
Product: CCn1c(C)c(C2(c3ccc(N(C)C)cc3N(C)C)OC(=O)c3ccccc32)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.1 %

Procedure:
In a procedure similar to that described above in part B of this example, 12.28 g (0.04 mole) of 2-[(1-ethyl-2-methyl-3-indolyl)carbonyl]benzoic acid, prepared as described in part A above, 8.57 g (0.05 mole) of N,N,N',N'-tetramethyl-m-phenylenediamine and 6.0 ml of acetic anhydride were interacted with stirring at room temperature overnight. The reaction mixture was then diluted with 13.0 ml of ethanol and the precipitate which separated was filtered and washed with 6.0 ml of ethanol. The filter cake was then reslurried in 30 ml of methanol, filtered and washed successively with methanol and diethylether. The material was dried in vacuo to obtain 15.8 g of 3-[2,4-bis(dimethylamino)phenyl]-3-(1-ethyl-2-methyl-3-indolyl)phthalide (Formula III: Ro =R1 =R2 =R3 =Y1 =H; R=R5 =CH3 ; R4 =N(CH3)2 ; R6 =CH2CH3), a white crystalline solid which melted at 218°-222° C. The infrared spectrum was consistent with the structure. A benzene solution of the above product developed an intense grape-red color when streaked on a phenolic resin coated paper.
Reaction SMILES: O[N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C(N(CC)CC)C.Cl[CH2:21][C:22]1[N:23]=[C:24]([NH:27][C:28]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[S:25][CH:26]=1.C(OCC)(=[O:49])C>C(#N)C.ClCCl>[C:28]([NH:27][C:24]1[S:25][CH:26]=[C:22]([CH2:21][O:49][C:8]2[CH:9]=[CH:10][CH:11]=[C:4]3[C:3]([NH:2][C:6](=[O:7])[C:5]=23)=[O:12])[N:23]=1)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: ClCc1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC#N
Product: O=C1NC(=O)c2c(OCc3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cccc21
Temperature: 80 °C
Reaction time: 7 h

Procedure:
In 150 ml of acetonitrile was suspended 11.48 g of N-hydroxyphthalimide. To the suspension was added 7.11 g of triethylamine and dissoled therein. To the solution was added a solution of 27.5 g of 4-chloromethyl-2-tritylaminothiazole dissolved in 200 ml of dichloromethane and the mixture was stirred on an oil bath of 80° C. for 7 hours. The reaction mixture thus obtained was concentrated and the residue formed was dissolved in ethyl acetate. The solution was washed with water, dried by anhydrous magnesium sulfate, and concentrated. The residue was applied to column chromatography and the product was eluted with chloroform to provide 14.5 g of (2-tritylamino-4-thiazolyl)methoxyphthalimide.
Reaction SMILES: C([C@H]1COC(=O)N1[C:14](=[O:49])[CH2:15][C@@H:16]([C:22]1[CH:48]=[CH:47][C:25]([O:26][CH2:27][C:28]2[CH:29]=[C:30]([NH:34][C:35](=[O:46])[C:36]3[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=3)[CH:31]=[CH:32][CH:33]=2)=[CH:24][CH:23]=1)[C:17]1[CH:21]=[CH:20][O:19][N:18]=1)C1C=CC=CC=1.[OH:50]O.[Li+].[OH-].Cl>C1COCC1.O>[F:44][C:42]([F:43])([F:45])[C:39]1[CH:40]=[CH:41][C:36]([C:35]([NH:34][C:30]2[CH:29]=[C:28]([CH:33]=[CH:32][CH:31]=2)[CH2:27][O:26][C:25]2[CH:24]=[CH:23][C:22]([C@@H:16]([C:17]3[CH:21]=[CH:20][O:19][N:18]=3)[CH2:15][C:14]([OH:49])=[O:50])=[CH:48][CH:47]=2)=[O:46])=[CH:37][CH:38]=1
Reactant: O=C(Nc1cccc(COc2ccc([C@H](CC(=O)N3C(=O)OC[C@@H]3Cc3ccccc3)c3ccon3)cc2)c1)c1ccc(C(F)(F)F)cc1
Reactant: OO
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C[C@@H](c1ccc(OCc2cccc(NC(=O)c3ccc(C(F)(F)F)cc3)c2)cc1)c1ccon1
Reaction time: 2 h
Yield: 46.1 %

Procedure:
To a solution of oxazolidinone 27.4 (71.8 mg, 0.107 mmol) dissolved in THF (10 mL), was added a 30% hydrogen peroxide solution (0.121 mL, 1.07 mmol) followed by a 2M LiOH solution (0.268 mL, 0.535 mmol). The resulting slurry was stirred for two hours. The reaction mixture was diluted with water and acidified with hydrochloric acid to a pH ˜3. The mixture was then extracted with EtOAc (1×50 mL), and the organic layer was washed with acidic sodium sulfite solution (2×30 mL), brine (1×30 mL), and dried over magnesium sulfate. The filtrate was concentrated under reduced pressure, and the residue was purified by reverse phase HPLC to give 27 (25.2 mg). MS ESI (pos.) m/e 511.1 (M+H). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.21 (1H, br. s.), 10.51 (1H, s), 8.75 (1H, d, J=1.6 Hz), 8.15 (2H, d, J=8.2 Hz), 7.91 (2H, d, J=8.2 Hz), 7.87 (1H, s), 7.74 (1H, d, J=8.2 Hz), 7.38 (1H, t, J=7.8 Hz), 7.23 (2H, d, J=8.6 Hz), 7.19 (1H, d, J=7.8 Hz), 6.96 (2H, d, J=9.0 Hz), 6.50 (1H, d, J=1.6 Hz), 5.08 (2H, s), 4.48 (1H, t, J=7.8 Hz), 3.07 (1H, dd, J=16.4, 8.2 Hz), 2.88 (1H, dd, J=16.2, 7.2 Hz).