Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH2:15])=[CH:12][CH:11]=1>>[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH:15][CH:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[CH:12][CH:11]=1
Reactant: NCc1ccc(F)cc1
Reactant: CN1CCC(=O)CC1
Product: CN1CCC(NCc2ccc(F)cc2)CC1

Procedure:
Starting materials: 1-Methyl-4-piperidone (1.13 g, 10.0 mmol, 1.0 eq.), 4-fluorobenzylamine (1.25 g, 1.0 eq.).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([N:13]1[C:17]2[CH:18]=[C:19]([F:23])[C:20]([F:22])=[CH:21][C:16]=2[N:15]=[C:14]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[CH:6]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+].C(OCC)(=O)C>O1CCCC1>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([C:14]2[N:13]([CH:5]([CH:6]3[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]3)[CH2:4][OH:3])[C:17]3[CH:18]=[C:19]([F:23])[C:20]([F:22])=[CH:21][C:16]=3[N:15]=2)=[CH:25][CH:26]=1
Reactant: CCOC(=O)C(C1CCCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCC(C1CCCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1.4 g (3.13 mmol) [2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-cycloheptyl-acetic acid ethyl ester in 20 ml dry tetrahydrofuran was added 0.125 g (3.29 mmol) lithium aluminum hydride at 0° C. The reaction mixture was stirred for 2 hours at room temperature and then poured on 100 ml 10% aqueous sodium-potassium-tartrate solution and 100 ml ethyl acetate. The aqueous layers were extracted again with 100 ml ethyl acetate. The organic layers were washed with 100 ml brine, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (2:1). Colorless solid (74%). MS (TurboSpray): 405.3 [M+H].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]1[CH:31]=[C:30]([F:32])[C:29]([F:33])=[CH:28][C:26]=1[NH2:27]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([NH:27][C:26]4[CH:28]=[C:29]([F:33])[C:30]([F:32])=[CH:31][C:25]=4[F:24])=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Reactant: Nc1cc(F)c(F)cc1F
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Nc4cc(F)c(F)cc4F)ncnc32)CC1

Procedure:
4-[4-(2,4,5-Trifluoro-phenylamino)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester was prepared according to General Procedure C by the reaction of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19) with 2,4,5-trifluoroaniline (available from Oakwood Products, Inc., West Columbia, S.C., USA). 1H NMR (400 MHz, DMSO-d6) δ 1.43 (s, 9H), 1.91-1.99 (m, 4H), 2.95-3.05 (m, 2H), 4.00-4.10 (m, 2H), 4.88-4.93 (m, 1H), 7.71-7.74 (m, 1H), 7.96-7.99 (m, 1H), 8.24 (br s, 1H), 8.36 (s, 1H), 10.17 (s, 1H). Mass spectrum MH+=449.
Reaction SMILES: [CH2:1]([C@H:8]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C@H:9]([OH:14])[CH2:10][CH2:11][CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:42]=[N+:43]=[N-:44].CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH2:1]([C@H:8]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C@H:9]([OH:14])[CH2:10][CH2:11][CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:42]([C@@H:9]([CH2:10][CH2:11][CH2:12][CH3:13])[C@@H:8]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[N+:43]=[N-:44]
Reactant: [N-]=[N+]=N
Agent: CCCC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCC[C@H](N=[N+]=[N-])[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl (1S,2R)-1-benzyl-2-hydroxyhexylcarbamate (1.24 g, 4.03 mmol), triphenylphosphine (1.06 g, 4.03 mmol) in 40 mL THF was added hydrozoic acid HN3 (4 mL, 8.07 mmol, 2M in benzene) followed by dropwise addition of diethylazodicarboxylate (0.7 mL, 4.44 mmol) in 10 mL THF. The reaction mixture was stirred at room temperature for 8 h, combined with a previous 250 mg tert-butyl (1S,2R)-1-benzyl-2-hydroxyhexylcarbamate probe reaction, concentrated in vacuo, and purified by flash chromatography (120 g silica, 0−>50% EtOAc/hexanes) to afford tert-butyl (1S,2R)-1-benzyl-2-hydroxyhexylcarbamate and tert-butyl (1S,2S)-2-azido-1-benzylhexylcarbamate as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.36-7.16 (m, 5H), 4.63 (d, J=10.1 Hz, 1H), 4.00-3.88 (m, 1H), 3.40-3.28 (m, 1H), 2.91 (A of ABX, dd, J=13.6, 6.8 Hz, 1H), 2.76 (B of ABX, dd, J=13.6, 9.1 Hz, 1H), 1.70-1.48 (m, 2H), 1.42-1.20 (m, 4H), 1.39 (s, 9H), 0.52 (t, J=7.1 Hz, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH2:5].F[C:7]1[CH:12]=[CH:11][C:10]([N:13]=[N+:14]=[N-:15])=[CH:9][C:8]=1[N+:16]([O-:18])=[O:17].O.Cl>C(O)C>[N:13]([C:10]1[CH:11]=[CH:12][C:7]([NH:1][CH2:2][CH2:3][CH2:4][NH2:5])=[C:8]([N+:16]([O-:18])=[O:17])[CH:9]=1)=[N+:14]=[N-:15]
Reactant: NCCCN
Reactant: [N-]=[N+]=Nc1ccc(F)c([N+](=O)[O-])c1
Agent: Cl
Solvent: O
Solvent: CCO
Product: [N-]=[N+]=Nc1ccc(NCCCN)c([N+](=O)[O-])c1

Procedure:
2.5 ml (30 mM) 1,3-diaminopropane was dissolved in 25 ml ethanol. To this solution, was added a solution of 1.82 g (10 mM) 4-fluoro-3-nitrophenyl azide in 25 ml ethanol. The addition was performed dropwise with stirring. The mixture was stirred at room temperature for 16 hours. After this time, 150 ml of water were added and the pH adjusted to between 1 and 2 with concentrated HCl. This solution was filtered to remove the disubstituted amine, cooled on ice and the product was precipitated by the slow addition of concentrated aqueous ammonia with stirring. The product was collected by filtration of the cold mixture, washed with ice-cold water and dried in vacuo.
Reaction SMILES: C1(C)C=CC=CC=1.S(=O)(=O)(O)O.[Cl:13][C:14]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:16]([C:17]([OH:19])=[O:18])[C:15]=1[OH:24].[C:25](OC(=O)C)(=[O:27])[CH3:26]>O>[C:25]([O:24][C:15]1[C:14]([Cl:13])=[CH:22][C:21]([Cl:23])=[CH:20][C:16]=1[C:17]([OH:19])=[O:18])(=[O:27])[CH3:26]
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1O
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)Oc1c(Cl)cc(Cl)cc1C(=O)O
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
A 1 L, round-bottom, three neck flask equipped with: a mechanical stirrer, a thermometer and a 125 mL dropping funnel with pressure equilibration was placed in a water bath maintained at 65° C. The following reagents were subsequently charged to the flask with an efficient stirring: 250 mL of dry toluene, 2.5 mL of concentrated sulfuric acid and 207 g of well ground, solid 3,5-dichlorosalicylic acid, which forms a mobile suspension. When the temperature of this constantly stirred mixture reached 60° C. (with the water bath temperature maintained at 65° C.) a drop-wise addition of 108 g (100 mL) of acetic anhydride was initiated and completed within 30 min. During the acetic anhydride addition the temperature of the reaction mixture was not allowed to exceed 75° C. After completing the addition, the mixture was stirred and heated to 70° C. for another 4 h. After this time, the agitation was stopped and the mixture cooled over night to room temperature. The white crystals that separated from the mixture were filtered off, washed with 2×10 mL of ice-cold toluene and vacuum dried at 50° C. to yield 206 g (82.7% yield) of 2-acetoxy-3,5-dichlorobenzoic acid. An additional 30.6 g (12.3%% yield) of the product was recovered by: concentrating the filtrate to ½ of the original volume, cooling the solution in an ice-water bath, filtering off the crystalline product and vacuum drying it at 50° C.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.C(N1CCOCC1)C.C(OC([NH:29][CH:30]([CH2:34][NH:35][S:36]([C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][C:40]=1[Cl:46])(=[O:38])=[O:37])[C:31]([OH:33])=O)=O)C1C=CC=CC=1.[NH2:47][CH:48]([CH2:63][C:64]1[CH:69]=[CH:68][C:67]([Cl:70])=[CH:66][CH:65]=1)[C:49]([N:51]([CH2:55][CH:56]([O:60][CH2:61][CH3:62])[O:57][CH2:58][CH3:59])[CH:52]([CH3:54])[CH3:53])=[O:50]>CN(C=O)C.C(Cl)CCl>[Cl:70][C:67]1[CH:66]=[CH:65][C:64]([CH2:63][CH:48]([NH:47][C:31](=[O:33])[CH:30]([NH:29][S:36]([CH3:39])(=[O:38])=[O:37])[CH2:34][NH:35][S:36]([C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][C:40]=2[Cl:46])(=[O:37])=[O:38])[C:49](=[O:50])[N:51]([CH2:55][CH:56]([O:60][CH2:61][CH3:62])[O:57][CH2:58][CH3:59])[CH:52]([CH3:54])[CH3:53])=[CH:69][CH:68]=1
Reactant: CCOC(CN(C(=O)C(N)Cc1ccc(Cl)cc1)C(C)C)OCC
Reactant: O=C(NC(CNS(=O)(=O)c1ccc(Cl)cc1Cl)C(=O)O)OCc1ccccc1
Agent: CCN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCOC(CN(C(=O)C(Cc1ccc(Cl)cc1)NC(=O)C(CNS(=O)(=O)c1ccc(Cl)cc1Cl)NS(C)(=O)=O)C(C)C)OCC
Reaction time: 12 h

Procedure:
52 mg of EDC, 45 mg of HOBt and 100 μl of N-ethylmorpholine are added to a solution of 124 mg of 2-benzyloxycarbonylamino-3-(2,4-dichlorobenzenesulfonylamino)propionic acid in 1 ml of DMF. A solution of 100 mg of 2-amino-3-(4-chlorophenyl)-N-(2,2-diethoxyethyl)-N-isopropylpropionamide in 1 ml of DMF is added dropwise thereto, and the solution is left to stir for 12 h. The reaction solution is filtered, mixed with ethyl acetate and then extracted with 5% aqueous sodium bicarbonate solution and aqueous sodium chloride solution. Drying of the organic phase over sodium sulfate is followed by concentration under reduced pressure, and the residue is separated by HPLC (Knauer Eurospher-100-10-C18, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid)=80/20→10/90). The desired product is obtained with MW=784.186 (calculated); measured value (M−CO2+H)+: 741.10.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH2:11])=[CH:5][CH:4]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25](O)=[O:26])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(OCC)(=O)C>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([NH:11][CH2:10][CH2:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[O:26])=[CH:21][CH:20]=2)=[CH:17][CH:18]=1
Reactant: COc1ccc(CCN)cc1
Reactant: O=C(O)c1ccc(-c2ccc(Cl)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(CCNC(=O)c2ccc(-c3ccc(Cl)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.1 %

Procedure:
To a solution of 2-(4-methoxyphenyl)ethaneamine (500 mg, 3.31 mmol), 4′-chloro[1,1′-biphenyl]-4-carboxylic acid (846 mg, 3.64 mmol) and 1-hydroxybenzotriazole (760 mg, 4.96 mmol) in dimethylformamide (10 ml) was added ethyldimethylaminopropylcarbodiimide hydrochloride (951 mg, 4.96 mmol) at 0° C., and the mixture was was stirred at room temperature for 16 hrs. Ethyl acetate was added to the reaction mixture, and the mixture was washed with 1N aqueous sodium hydroxide solution and brine, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure to give the title compound (1.03 g).
Reaction SMILES: OC(C(F)(F)F)=O.[CH3:8][N:9]1[CH:13]([C:14]([OH:16])=O)[CH2:12][N:11]([C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[C:10]1=[O:24].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N1CCOCC1)C.Cl.[Cl:57][C:58]1[C:63]([F:64])=[C:62]([F:65])[CH:61]=[CH:60][C:59]=1[CH2:66][NH2:67]>ClCCl>[Cl:57][C:58]1[C:63]([F:64])=[C:62]([F:65])[CH:61]=[CH:60][C:59]=1[CH2:66][NH:67][C:14]([CH:13]1[CH2:12][N:11]([C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[C:10](=[O:24])[N:9]1[CH3:8])=[O:16]
Reactant: NCc1ccc(F)c(F)c1Cl
Reactant: Cc1cccnc1N1CC(C(=O)O)N(C)C1=O
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1cccnc1N1CC(C(=O)NCc2ccc(F)c(F)c2Cl)N(C)C1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 45.9 %

Procedure:
A mixture of 3-methyl-1-(3-methyl-2-pyridinyl)-2-oxo-4-imidazolidinecarboxylic acid TFA salt (279 mg, 0.8 mmol), 1-hydroxybenzotriazole hydrate (147 mg, 0.96 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (184 mg, 0.96 mmol) and N-ethyl morpholine (0.613 ml, 4.8 mmol) in dichloromethane (20 ml) was stirred at room temperature for 10 minutes. [(2-Chloro-3,4-difluorophenyl)methyl]amine hydrochloride (171 mg, 0.8 mmol) was added and the reaction stirred at room temperature for 18 hours. The mixture was diluted with dichloromethane and was washed with 3N citric acid solution. The organic phase was separated, washed with brine, dried and evaporated. The residue was purified by mass-directed automated HPLC to give N-[(2-chloro-3,4-difluorophenyl)methyl]-3-methyl-1-(3-methyl-2-pyridinyl)-2-oxo-4-imidazolidinecarboxamide (145 mg, 46%). LC/MS [M+H]+=395, retention time=2.36 minutes.
Reaction SMILES: [I:1]Cl.[CH3:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][C:5]=1[C:11]([F:14])([F:13])[F:12].C(=O)(O)[O-].[Na+]>ClCCl.CO.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>[I:1][C:9]1[CH:10]=[C:4]([CH3:3])[C:5]([C:11]([F:12])([F:13])[F:14])=[CH:6][C:7]=1[NH2:8]
Reactant: ClI
Reactant: Cc1ccc(N)cc1C(F)(F)F
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(I)c(N)cc1C(F)(F)F
Reaction time: 3 h
Yield: 103.1 %

Procedure:
Add a solution of iodine monochloride (27.8 g, 171 mmol) in dichloromethane (180 mL) to a solution of 4-methyl-3-trifluoromethylaniline (25.0 g, 143 mmol) and sodium bicarbonate (14.4 g, 171 mmol) in methanol (180 mL) and dichloromethane (730 mL) at room temperature under nitrogen. Stir the mixture for 3 h and dilute the cooled mixture with aqueous sodium metabisulfite (500 mL). Collect the organic phase, and extract the aqueous phase with methylene chloride (200 mL). Wash the combined organic extracts with brine (250 mL), dry over anhydrous sodium sulfate and filter. Remove the solvent under reduced pressure to provide a brown oil, which crystallizes upon standing to afford the title compound as brown needles (44.4 g, >99%), which is used in the next step without purification. APCI MS m/z 302 (M+H)+.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:34])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]4[CH:17]=[C:18]([C:26]#[C:27][CH2:28][CH2:29][C:30]([NH:32][CH3:33])=[O:31])[N:19]=[C:20]([NH:21][CH2:22][CH:23]([CH3:25])[CH3:24])[C:15]4=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[N-]=[N+]=[N-].[Na+]>CN1C(=O)CCC1.[Cu]I>[CH:1]1([NH:4][C:5](=[O:34])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]4[CH:17]=[C:18](/[CH:26]=[C:27]5/[N:32]([CH3:33])[C:30](=[O:31])[CH2:29][CH2:28]/5)[N:19]=[C:20]([NH:21][CH2:22][CH:23]([CH3:24])[CH3:25])[C:15]4=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1
Reactant: CNC(=O)CCC#Cc1cn2c(-c3ccc(C(=O)NC4CC4)cc3)cnc2c(NCC(C)C)n1
Agent: [Cu]I
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CC(C)CNc1nc(/C=C2\CCC(=O)N2C)cn2c(-c3ccc(C(=O)NC4CC4)cc3)cnc12
Temperature: 160 °C
Yield: 18.8 %

Procedure:
To a solution of 23 mg (0.05 mmol) N-cyclopropyl-4-{6-[5-(methylamino)-5-oxopent-1-yn-1-yl]-8-[(2-methylpropyl)amino]imidazo[1,2-a]pyrazin-3-yl}benzamide in 1.00 mL NMP were added 6.5 mg (0.1 mmol) sodium azide and 0.5 mg (0.003 mmol) copper(I)iodide and the mixture was heated at 160° C. for 30 min in a microwave tube. The mixture was filtered and purified by HPLC to yield 4.3 mg (19%) of the title compound. UPLC-MS: RT=1.08 min; m/z (ES+) 459.6 [MH+]; required MW=458.6. 1H-NMR (300 MHz, CDCl3): δ=7.91 (2H, d), 7.59 (4H, m), 7.39 (1H, s), 6.31 (1H, tr), 6.28 (1H, s), 3.45 (1H, m), 3.40 (2H, t), 2.95 (1H, m), 2.82 (3H, s), 2.56 (1H, m), 2.33 (1H, s), 2.05 (1H, m), 1.95 (1H, m), 1.05 (6H, d), 0.92 (2H, m), 0.66 (2H, m) ppm.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:21])([CH3:20])[C:16]([O:18][CH3:19])=[O:17])C(=O)C2=CC=CC=C12.O.NN.Cl.C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[NH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:21])([CH3:20])[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)C(C)(C)CCCCCCCCCN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: NN
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CO
Product: COC(=O)C(C)(C)CCCCCCCCCN
Reaction time: 0.33 h
Yield: 67.8 %

Procedure:
A solution of 15.4 g of methyl 11-phthalimido-2,2-dimethylundecanoate and 2.33 cm3 of 98% hydrazine hydrate in 500 cm3 of methanol is stirred for 12 hours at a temperature in the region of 20° C. 32 cm3 of 5N methanolic hydrochloric acid are added. The solvent is evaporated under reduced pressure (2.7 kPa) at a temperature in the region of 40° C. The residue is taken up in 150 cm3 of distilled water. After stirring for 20 minutes, the solid is separated by filtration and washed with a total of 90 cm3 of distilled water. The aqueous phase is brought to a pH in the region of 9-10 by means of a 10% sodium carbonate solution, extracted with a total of 500 cm3 of diisopropyl ether, dried over magnesium sulphate and then concentrated under reduced pressure (2.7 kPa) at a3 temperature in the region of 40° C. The residue is taken up in a mixture of 15 cm3 of methanol and 50 cm3 of diethyl ether. 10 cm3 of 5N methanolic hydrochloric acid are added and the mixture is evaporated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40° C. The yellow oil obtained is taken up in 100 cm3 of distilled water. 2 cm3 of 4N hydrochloric acid are added and the mixture is then brought to a pH in the region of 9-10 by means of a 10% sodium carbonate solution. Extraction is carried out with a total of 450 cm3 of ethyl acetate. The organic phase is dried over magnesium sulphate and then concentrated to dryness under reduced pressure (13.5 Pa) at a temperature in the region of 40° C. 6.8 g of methyl 11-amino-2,2-dimethylundecanoate are thus obtained in the form of a viscous yellow oil [Rf =0.54; silica thin layer chromatography; eluent: chloroform/methanol/28% aqueous ammonia 24/6/1 (by volume)].
Reaction SMILES: C([O:3][C:4](=[O:29])[C:5]([CH3:28])=[CH:6][C:7]1[O:8][C:9]([C:12](=[O:27])[CH2:13][CH:14]([CH3:26])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:25])[CH2:19][CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:10][CH:11]=1)C.[OH-].[Na+].Cl>C(O)C.O>[CH3:28][C:5](=[CH:6][C:7]1[O:8][C:9]([C:12](=[O:27])[CH2:13][CH:14]([CH3:26])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:25])[CH2:19][CH2:20][CH2:21][CH:22]([CH3:23])[CH3:24])=[CH:10][CH:11]=1)[C:4]([OH:29])=[O:3]
Reactant: CCOC(=O)C(C)=Cc1ccc(C(=O)CC(C)CCCC(C)CCCC(C)C)o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=Cc1ccc(C(=O)CC(C)CCCC(C)CCCC(C)C)o1)C(=O)O

Procedure:
A mixture of ethyl-2-methyl-3-[5-(1-oxo-3,7,11-trimethyldodecyl)-2-furanyl]-2-propenoate (20.2 g-0.05 mole) in 200 ml ethanol is heated to reflux, 100 ml of 1 N aqueous NaOH is added and the mixture is refluxed for 2 hours, cooled, diluted with water, acidified with 200 ml 1 N aqueous hydrochloric acid and extracted with ether. The ether layer is evaporated to dryness to give 2-methyl-3-[5-(1-oxo-3,7,11-trimethyldodecyl)-2-furanyl]-2-propenoic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[C:8](=[O:24])[NH:9][C:10]3[C:15]([C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:14][C:13]([Cl:23])=[CH:12][CH:11]=3)[O:4][N:3]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>N1C=CC=CC=1>[Cl:23][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:24])[C:7]([C:5]1[O:4][N:3]=[C:2]([NH:1][S:26]([CH3:25])(=[O:28])=[O:27])[CH:6]=1)=[C:16]2[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc(-c2c(-c3ccccc3)c3cc(Cl)ccc3[nH]c2=O)on1
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc(-c2c(-c3ccccc3)c3cc(Cl)ccc3[nH]c2=O)on1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A flask charged with 3-(3-amino-isoxazol-5-yl)-6-chloro-4-phenyl-1H-quinolin-2-one (Example 59)(17 mg, 0.050 mmol), methanesulfonyl chloride (7.5 mg, 0.066 mmol), and pyridine (0.2 mL) was stirred at 25° C. for 3 hrs. The reaction was concentrated and the title compound was purified by RP-HPLC, eluting with 40-70% CH3CN in 0.1% TFA/H2O over 10 mins to give 10 mg (50%). 1H NMR (400 MHz, CD3OD) δ 7.52 (dd, 1H), 7.46 (m, 3H), 7.36 (d, 1H), 7.22 (m, 2H), 7.12 (d, 1H), 6.54 (s, 1H), 3.00 (s, 3H). Mass spectrum (ESI, m/z) calcd. for C19H14ClN3O4S 415.0, found 416.0 (M+H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[C:7]([CH:16]=1)[C:8]([N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:9].B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([NH:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[C:7]([CH:16]=1)[C:8]([N:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1)=[O:9]
Reactant: COc1ccc(Nc2ccncc2)c(C(=O)N2CCCCC2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(c1cc(O)ccc1Nc1ccncc1)N1CCCCC1
Reaction time: 8 h
Yield: 55.8 %

Procedure:
1-[5-Methoxy-2-(4-pyridinylamino)benzoyl]piperidine (Example 30b) (9.2 g) was dissolved in 100 ml of methylene dichloride. To this solution was added dropwise 80 ml of boron tribromide solution (0.8M in methylene dichloride). The mixture was kept at room temperature overnight and the solvent removed at reduced pressure. The residue was made basic with aqueous potassium carbonate and the solid product collected by filtration. The product was dissolved in methanol and acetonitrile added to produce 4.9 g of 1-[5-hydroxy-2-(4-pyridinylamino)benzoyl]piperidine. A further recrystallization from methanol gave a sample with m.p. 242°-243° C.(decompn.).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=2)[C:6](=[C:18](OCC)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]1=[O:28])(=O)C.[CH3:29][N:30]([CH3:40])[CH2:31][CH2:32][C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=1>>[CH3:40][N:30]([CH3:29])[CH2:31][CH2:32][C:33]1[CH:34]=[CH:35][C:36]([NH:37]/[C:18](=[C:6]2\[C:5](=[O:28])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=3)/[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:38][CH:39]=1
Reactant: CN(C)CCc1ccc(N)cc1
Reactant: CCOC(=O)c1ccc2c(c1)N(C(C)=O)C(=O)C2=C(OCC)c1ccccc1
Product: CCOC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CCN(C)C)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-ethoxycarbonyl-2-indolinone and 4-(2-dimethylamino-ethyl)-aniline Rf value: 0.2 (silica gel, methylene chloride/ethanol=5:1) C28H29N3O3
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC(C)=O.C(OCC)(=O)C>[CH2:16]([N:4]1[C:3](=[O:8])[C:2]([CH3:9])([CH3:1])[NH:6][C:5]1=[O:7])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC1(C)NC(=O)NC1=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC1(C)NC(=O)N(Cc2ccccc2)C1=O
Temperature: 25 °C
Yield: 91.3 %

Procedure:
To the stirred solution of 5,5-dimethylhydantoin (7 g, 54.7 mmole) in dry acetone (150 mL) under nitrogen were added potassium carbonate (10.6 g, 76.8 mmole) and benzylbromide (11.2 g, 65.9 mmole) at room temperature. The reaction mixture was refluxed for 20 hr. The reaction mixture was cooled to room temperature and the solid was filtered off by suction filtration. The titrate was concentrated on a rotary evaporator to give a residue. The residue was diluted with ethyl acetate and washed with water and brine, dried over sodium sulfate and evaporated to give 10.9 g (yield=91.3 %) of 3-benzyl-5,5-dimethylhydantoin as a white solid, mp=101°-104° C. This intermediate was subjected to the next step without further purification.