Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6]1.[C:18]1([N:24]=[C:25]=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[CH2:11]([N:8]1[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:25]([NH:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:26])[CH2:10][CH2:9]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCCCN1CCN(Cc2ccccc2)CC1
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: O=C(NCCCN1CCN(Cc2ccccc2)CC1)Nc1ccccc1
Yield: 60.9 %

Procedure:
A solution of 1-(3-aminopropyl)-4-benzylpiperazine (3.0 g; 12.9 mmole) and phenyl isocyanate (1.54 g; 12.9 mmole) in methylene chloride (20 ml) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from aqueous acetone to provide the title compound as colorless crystals (2.77 g; 61% yield), m.p. 45°-47° C.
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([OH:10])=[N:3][CH:2]=1.C(OC(=O)[NH:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[C:23]([CH:28]=[O:29])[C:22]=1[F:30])C1C=CC=CC=1>>[NH2:20][C:21]1[C:22]([F:30])=[C:23]([C:28]([C:9]2[C:5]3[C:4]([OH:10])=[N:3][CH:2]=[N:1][C:6]=3[NH:7][CH:8]=2)=[O:29])[C:24]([F:27])=[CH:25][CH:26]=1
Reactant: O=Cc1c(F)ccc(NC(=O)OCc2ccccc2)c1F
Reactant: Oc1ncnc2[nH]ccc12
Product: Nc1ccc(F)c(C(=O)c2c[nH]c3ncnc(O)c23)c1F

Procedure:
(3-Amino-2,6-difluoro-phenyl)-(4-hydroxy-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone 39 is synthesized in two steps from 7H-pyrrolo[2,3-d]pyrimidin-4-ol 37 and (2,4-difluoro-3-formyl-phenyl)-carbamic acid benzyl ester 33 as shown in Scheme 1g.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[C:29]3[C:24](=[C:25]([Cl:31])[CH:26]=[C:27]([Cl:30])[CH:28]=3)[CH2:23][N:22]([CH3:32])[CH2:21]2)=[CH:16][CH:15]=1)(=[O:13])=[O:12].[CH3:33][C:34]([CH3:55])([C:45]([O:47]N1C(=O)CCC1=O)=O)[C:35]([O:37]N1C(=O)CCC1=O)=O>>[Cl:30][C:27]1[CH:28]=[C:29]2[C:24](=[C:25]([Cl:31])[CH:26]=1)[CH2:23][N:22]([CH3:32])[CH2:21][CH:20]2[C:17]1[CH:16]=[CH:15][C:14]([S:11]([NH:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:45](=[O:47])[C:34]([CH3:33])([CH3:55])[C:35]([NH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][NH:10][S:11]([C:14]2[CH:15]=[CH:16][C:17]([CH:20]3[C:29]4[C:24](=[C:25]([Cl:31])[CH:26]=[C:27]([Cl:30])[CH:28]=4)[CH2:23][N:22]([CH3:32])[CH2:21]3)=[CH:18][CH:19]=2)(=[O:13])=[O:12])=[O:37])(=[O:13])=[O:12])=[CH:19][CH:18]=1
Reactant: CC(C)(C(=O)ON1C(=O)CCC1=O)C(=O)ON1C(=O)CCC1=O
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(S(=O)(=O)NCCOCCOCCN)cc2)C1
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(S(=O)(=O)NCCOCCOCCNC(=O)C(C)(C)C(=O)NCCOCCOCCNS(=O)(=O)c3ccc(C4CN(C)Cc5c(Cl)cc(Cl)cc54)cc3)cc2)C1

Procedure:
Compound 183 was prepared from intermediate 175.1 and bis(2,5-dioxopyrrolidin-1-yl) 2,2-dimethylmalonate (prepared using the methods outlined in example 168) following the procedure outlined in example 175. The crude product was purified by Prep-HPLC with acetonitrile:water (0.05% CF3COOH)(10%-100%). This resulted in 29.5 mg (5%) of a TFA salt of N1,N3-bis(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethyl)-2,2-dimethylmalonamide as a white solid. 1H-NMR (300 MHz, CD3OD, ppm): δ 7.94-7.92 (m, 4H), 7.57 (m, 2H), 7.51-7.49 (m, 4H), 6.87 (m, 2H), 4.83-4.74 (m, 4H), 4.55-4.50 (m, 2H), 3.92-3.87 (m, 2H), 3.67-3.48 (m, 8H), 3.40-3.38 (m, 4H), 3.18 (s, 6H), 3.14-3.00 (m, 4H), 1.41 (s, 6H). MS (m/z): 551 [1/2M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11](=[O:14])[CH2:12]Br.[CH2:18]([NH:21][CH2:22][CH:23]=[CH2:24])[CH:19]=[CH2:20]>C(#N)C>[Br:7][C:8]1[CH:9]=[C:10]([C:11](=[O:14])[CH2:12][N:21]([CH2:22][CH:23]=[CH2:24])[CH2:18][CH:19]=[CH2:20])[CH:15]=[CH:16][CH:17]=1
Reactant: C=CCNCC=C
Reactant: O=C(CBr)c1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCN(CC=C)CC(=O)c1cccc(Br)c1
Temperature: 0 °C
Yield: 97.6 %

Procedure:
Potassium carbonate (38.8 g, 281 mmol) is added to 3-bromophenacyl bromide (60 g 216 mmol) in acetonitrile (430 mL), and the mixture is cooled under nitrogen to 0° C. Diallylamine (34.6 mL, 280.63 mmol) is added drop wise over 1 hour and the reaction is allowed to warm to 22° C. overnight. The crude reaction mixture is concentrated and the residue is partitioned in water (300 mL) and MTBE (300 mL). The aqueous layer is discarded and the organic layer is washed with water (100 mL, 2×) and with brine (100 mL). The organic layer is dried over sodium sulfate, filtered, and the solvent evaporated to constant weight to give the title compound (62 g, 98%). ES/MS (m/e): 294 (M+1).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[O:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12]1[CH:21]=C(C(O)=O)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1>C(Cl)Cl>[O:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12]1[CH:21]=[C:1]([C:2]([Cl:4])=[O:3])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(-c2ccco2)nc2ccccc12
Solvent: ClCCl
Product: O=C(Cl)c1cc(-c2ccco2)nc2ccccc12
Temperature: -10 °C
Reaction time: 8 h
Yield: 100.6 %

Procedure:
5.2 ml (60.4 mmol) of oxalyl chloride were dissolved in 70 ml of CH2Cl2. The solution was cooled at −10° C. and 8.5 g (35.5 mmol) of 2-(2-furyl)quinoline-4-carboxylic acid were added portionwise. The reaction mixture was left overnight at room temperature and then evaporated to dryness to yield 9.2 g of the title compound, used without further purification.
Reaction SMILES: ClS([N:5]=[C:6]=[O:7])(=O)=O.[C:8]([O:11][CH:12]=[C:13]([CH3:16])[CH:14]=[CH2:15])(=[O:10])[CH3:9]>C(OCC)C>[CH3:16][CH:13]([CH:14]1[NH:5][C:6](=[O:7])[CH2:15]1)[CH2:12][O:11][C:8](=[O:10])[CH3:9]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: C=CC(C)=COC(C)=O
Solvent: CCOCC
Product: CC(=O)OCC(C)C1CC(=O)N1

Procedure:
In words relative to the above diagram for the preparation of 3 (where R2 =H), the 4-(1-substituted-2-acetoxyvinyl)azetidinone-2-one (3') is prepared by reacting, for example (R1 =CH3): chlorosulphonyl isocyanate and acyloxybutadiene (1') such as 1-acetoxy-2-methylbutadiene in a solvent such as anhydrous diethyl ether at a temperature of from about -30° C. to 0° C. under a nitrogen atmosphere. The reaction intermediate 2' is converted to 3' by hydrolysis. The reduction of 3' to provide 4-(1-methyl-2-acetoxyethyl)-2-azetidinone (4') is conducted by any convenient means such as hydrogenation in the presence of a catalyst such as platinum, palladium or oxides thereof under a hydrogen pressure of from 1 to 20 atmospheres in a solvent such as ethanol, ethylacetate, or the like at a temperature of from 0° to 25° C. for from 5 minutes to 1 hour. The 4-(2-hydroxy-1-methyl-ethyl)-2-azetidinone species 5' is obtained from 4' by hydrolysis. The 8-oxo-2,2,5-trimethyl-3-oxo-1-azabicyclo[4.2.0]octane species 6' is obtained on treatmentn of 5' with 2,2-dimethoxypropane in the presence of a catalyst such as boron trifluoride etherate in a solvent such as methylene chloride at a temperature of from 0° to 40° C. for from 1 to 40 minutes. Alkylation of 6' provides 7'. Typically, 6' is treated with a strong base such as lithium diisopropylamide, sodium hydride, phenyl lithium or butyl lithium and the like in a solvent such as tetrahydrofuran (THF), ether, dimethoxyethane, and the like at a temperature of from -80° to 0° C., whereupon the alkylating agent of choice, R6S is added (R6 is as described above and X is chloro or bromo; alternatively, the alkylating agent may be R6 tosylate, R 6 -mesylate or an aldehyde or ketone such as acetaldehyde and the like) to provide mono-alkylated species 7'. When the desired dialkylated species 8' may be obtained from 7' by repeating the alkylating procedure, 6'→7'.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9](=[N:22][OH:23])[CH2:10][N:11]2[C:15](=[O:16])[C:14]3=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]3[C:12]2=[O:21])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:31][CH2:32][CH3:33].O>CN(C)C=O>[Cl:1][C:2]1[C:3]([C:9](=[N:22][O:23][CH2:31][CH2:32][CH3:33])[CH2:10][N:11]2[C:12](=[O:21])[C:13]3=[CH:20][CH:19]=[CH:18][CH:17]=[C:14]3[C:15]2=[O:16])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1CC(=NO)c1ncc(Cl)cc1Cl
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCON=C(CN1C(=O)c2ccccc2C1=O)c1ncc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.2 %

Procedure:
To 265 mg of N-[2-(3,5-dichloropyridin-2-yl)-2-(hydroxyimino)ethyl]phthalimide in 2 ml of N,N-dimethylformamide, 310 mg of potassium carbonate and 387 mg of 1-iodopropane were added, and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, the reaction mixture was mixed with 30 ml of water and extracted with ethyl acetate (50 ml×1), the resulting organic layer was washed with water (50 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 15:85 to 25:75) as the eluent to obtain 235 mg of the desired product as a yellow resinous substance.
Reaction SMILES: [CH2:1]([C:5]1=[CH:6][N:7]([C:21]([CH3:24])([CH3:23])[CH3:22])[S:8]/[C:9]/1=[N:10]\[C:11](=[O:20])[C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[OH:19])[CH2:2][CH2:3][CH3:4].[H-].[Na+].Br[CH2:28][C:29]#[N:30]>C1COCC1.CN(C=O)C>[CH2:1]([C:5]1=[CH:6][N:7]([C:21]([CH3:23])([CH3:22])[CH3:24])[S:8]/[C:9]/1=[N:10]\[C:11](=[O:20])[C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[O:19][CH2:28][C:29]#[N:30])[CH2:2][CH2:3][CH3:4]
Reactant: N#CCBr
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)c1cc(Cl)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)c1cc(Cl)ccc1OCC#N
Temperature: 80 °C
Reaction time: 8 h
Yield: 4.5 %

Procedure:
To a solution of Example 135 (300 mg, 0.82 mmol) in THF/DMF (1:1, 4 mL) were added sodium hydride (39.2 mg, 0.98 mmol) and 2-bromoacetonitrile (65 μl, 0.98 mmol). The reaction was stirred at 40° C. for 4 hrs and at 80° C. for overnight. The reaction mixture was cooled to room temperature, quenched with saturated NaHCO3 (10 mL) and extracted with ethyl acetate (3×20 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-50% ethyl acetate in dichloromethane) to afford 15 mg of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.93 (t, J=7.3 Hz, 3 H), 1.20-1.48 (m, 2 H), 1.53-1.77 (m, 2 H), 1.63 (s, 9 H), 2.62-2.82 (m, 2 H), 5.22 (s, 2 H), 7.29 (d, J=9.1 Hz, 1H), 7.58 (dd, J=8.7, 2.8 Hz, 1 H), 7.86 (d, J=2.8 Hz, 1 H), 8.67 (s, 1 H); MS (ESI+) m/z 406 (M+H)+; Anal. Calculated C20H24ClN3O2S: C, 59.17; H, 5.96; N, 10.35. Found: C, 59.18; H, 5.78; N, 10.37.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C([Sn](CCCC)(CCCC)[C:36]1[S:37][CH:38]=[CH:39][CH:40]=1)CCC>>[CH2:1]([O:3][C:4]([C:6]1([S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:36]3[S:37][CH:38]=[CH:39][CH:40]=3)=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(Cc2ccc(Br)cc2)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Product: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(Cc2ccc(-c3cccs3)cc2)CC1

Procedure:
4-(4-Methoxy-benzenesulfonyl)-1-(4-thiophen-2-yl-benzyl)-piperidine-4-carboxylic acid ethyl ester was prepared starting from 1-(4-Bromo-benzyl)-4-(4-methoxy-benzensulfonyl)- piperidine-4-carboxylic acid ethyl ester (3 g, 6.05 mmol) and 2-(tributylstannyl)-thiophene (6.8 g, 18.14 mmol) in the presence of tetrakis palladium (0) in boiling tolune. Yield 1.58 g (52%); brown solid; mp 130° C.; MS: 500 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:29])[CH:10]=[CH:11][C:12]([CH3:28])=[CH:13][CH:14]([CH3:27])[CH:15]([O:25]C)[C:16]1[CH:21]=[CH:20][C:19]([N:22]([CH3:24])[CH3:23])=[CH:18][CH:17]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1C=CC=CC=1.C(OCC)(=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:29])[CH:10]=[CH:11][C:12]([CH3:28])=[CH:13][CH:14]([C:15](=[O:25])[C:16]1[CH:17]=[CH:18][C:19]([N:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)[CH3:27]
Reactant: COC(c1ccc(N(C)C)cc1)C(C)C=C(C)C=CC(=O)Nc1ccccc1N
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CC(C=CC(=O)Nc1ccccc1N)=CC(C)C(=O)c1ccc(N(C)C)cc1
Reaction time: 0.25 h
Yield: 7.4 %

Procedure:
To a stirred solution of compound 34 (85 mg, 0.216 mmol) in wet benzene (2 mL, benzene: H2O=9:1) at room temperature was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ, 98 mg, 0.432 mmol). After being stirred vigorously for 15 min., the mixture was diluted with ethyl acetate (30 mL), washed with water (2×5 mL), dried (anhydr.MgSO4), and concentrated. Purification by flash silica gel chromatography (50% ethyl acetate in hexanes, and then ethyl acetate only) afforded the title compound 35 (6 mg, 7% yield): 1H NMR (300 MHz, CDCl3) δ 7.83 (d, J=9.0, 2H), 7.87 (br. s, 1H), 7.29 (d, J=15.6 Hz, 1H), 7.27 (d, 7.8 Hz, 1H), 7.00 (m, 1H), 6.72 (m, 2H), 6.62 (d, J=9.0 Hz, 2H), 5.97 (d, J=15.6 Hz, 1H), 5.97 (d, J=9.3 Hz, 1H), 4.34 (dq, J=9.3, 6.9 Hz, 1H), 3.03 (s, 3H), 1.87 (br. s, 3H), 1.29 (d, J=6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 12.6, 17.6, 39.9, 40.8, 110.7, 118.0, 119.0, 119.3, 123.8, 124.4, 125.1, 126.9, 130.6, 132.5, 140.8, 146.2, 153.4, 164.8, 198.6.
Reaction SMILES: [NH2:1][N:2]1[C:13](=[O:14])[C:12]2[C:15]3[N:4]([CH:5]([CH3:18])[CH2:6][O:7][C:8]=3[C:9](F)=[C:10]([F:16])[CH:11]=2)[C:3]1=[O:19].[C:20]([O:24][C:25](=[O:34])[NH:26][C@@H:27]([C@H:29]1[CH2:33][CH2:32][NH:31][CH2:30]1)[CH3:28])([CH3:23])([CH3:22])[CH3:21].C(N(CC)CC)C>C(#N)C>[C:20]([O:24][C:25](=[O:34])[NH:26][C@H:27]([C@@H:29]1[CH2:33][CH2:32][N:31]([C:9]2[C:8]3=[C:15]4[C:12]([C:13](=[O:14])[N:2]([NH2:1])[C:3](=[O:19])[N:4]4[CH:5]([CH3:18])[CH2:6][O:7]3)=[CH:11][C:10]=2[F:16])[CH2:30]1)[CH3:28])([CH3:21])([CH3:22])[CH3:23]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)[C@H]1CCNC1
Reactant: CC1COc2c(F)c(F)cc3c(=O)n(N)c(=O)n1c23
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC1COc2c(N3CC[C@@H]([C@H](C)NC(=O)OC(C)(C)C)C3)c(F)cc3c(=O)n(N)c(=O)n1c23
Yield: 73.7 %

Procedure:
A solution of 0.11 g (0.41 mmol) of 5-amino-8,9-difluoro-3-methyl-2,3-dihydro-1-oxa-3a,5-diazaphenalene-4,6-dione (Example 24h), 0.26 g (1.3 mmol) of ((R)-(S)-1-pyrrolidin-3-ylethyl)carbamic acid tert-butyl ester (J. Het. Chem., 1992; 29:1481), 0.25 g (2.5 mmol) of triethylamine and 10 mL of acetonitrile is heated at reflux for 18 hours. The solvent is removed in vacuo and the residue is partitioned between ethyl acetate/water. The organic layer is washed with water, dried (MgSO4) and concentrated in vacuo. The residue is chromatographed over flash grade silica gel (230–400 mesh) eluting with dichloromethane/ethanol (95:5) to give 0.14 g of the title compound. 1H NMR (400 MHz, CDCl3): 7.43 (d, 1H), 5.24 (bs, 2H), 4.82 (m, 1H), 4.56 (m, 1H), 4.33 (d, 1H), 3.99 (m, 1H), 3.86 (m, 1H), 3.73 (m, 1H), 3.59 (m, 2H), 2.18 (m, 1H), 3.01 (m, 1H), 1.67 (m, 1H), 1.44 (s, 9H), 1.40 (m, 3H), 1.25 (m, 1H), 1.20 (d, 3H).
Reaction SMILES: Cl[C:2]1[NH:16][C:5]2=[N:6][CH:7]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:9]=[C:4]2[N:3]=1.[NH:17]1[CH2:22][CH2:21][C:20]2([C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24](=[O:31])[O:23]2)[CH2:19][CH2:18]1>CC(N(C)C)=O>[C:10]1([C:8]2[N:9]=[C:4]3[N:3]=[C:2]([N:17]4[CH2:22][CH2:21][C:20]5([C:30]6[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=6)[C:24](=[O:31])[O:23]5)[CH2:19][CH2:18]4)[NH:16][C:5]3=[N:6][CH:7]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Clc1nc2nc(-c3ccccc3)cnc2[nH]1
Reactant: O=C1OC2(CCNCC2)c2ccccc21
Solvent: CC(=O)N(C)C
Product: O=C1OC2(CCN(c3nc4nc(-c5ccccc5)cnc4[nH]3)CC2)c2ccccc21

Procedure:
Stir 2-chloro-5-phenyl-1H-imidazo[4,5-b]pyrazine (231 mg, 1 mmol) and spiro[isobenzofuran-1,4′-piperidin]-3-one (406 mg, 2 mmol) in dimethylacetamide (5 mL) at 120° C. for 14 hours. Cool the mixture and partition between EtOAc and half-saturated NaHCO3, wash several times with water, dry and concentrate in vacuo. Purify by chromatography (1:1 hexanes/EtOAc) to obtain 1′-(5-Phenyl-1H-imidazo[4,5-b]pyrazin-2-yl)-spiro[isobenzofuran-1,4′-piperidin]-3-one as a tan solid.
Reaction SMILES: [C:1]([CH:4]([NH:13][C:14]1[C:23]([C:24]([OH:26])=[O:25])=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([Cl:27])[CH:20]=2)[N:15]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)([OH:3])=[O:2].[H-].[Na+].Cl[C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:32]=1.Cl>CN(C=O)C.O>[C:1]([CH:4]([NH:13][C:14]1[C:23]([C:24]([OH:26])=[O:25])=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([Cl:27])[CH:20]=2)[N:15]=1)[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][C:31]2[CH:40]=[CH:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]=2)=[CH:10][CH:11]=1)([OH:3])=[O:2]
Reactant: Clc1ccc2ccccc2n1
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1NC(Cc1ccc(O)cc1)C(=O)O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1NC(Cc1ccc(Oc2ccc3ccccc3n2)cc1)C(=O)O
Temperature: 110 °C
Reaction time: 40 h

Procedure:
A mixture of 2-[1-carboxy-2-(4-hydroxy-phenyl)-ethylamino]-6-chloro-quinoline-3-carboxylic acid (114 mg, 0.294 mmol) (prepared according to the procedure described in Example 34), sodium hydride (60% oil dispersion; 65 mg, 1.44 mmol) and 2-chloroquinoline (118 mg, 0.72 mmol) in dry DMF (1 mL) is stirred for 40 h at 110° C. in closed reaction vial. After cooling, the reaction mixture is poured in water and acidified by aqueous HCl. Precipitate is filtered, washed with water, then with hexane. The residue is treated with methanol and filtered. Filtrate is concentrated under reduced pressure, water is added and the precipitate is recrystallized from a mixture of acetone-water, 4:1, to provide the title compound in low yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[NH2:9][C:10]1[C:15]([C:16]#[N:17])=[CH:14][N:13]=[C:12](Cl)[N:11]=1>>[NH2:9][C:10]1[C:15]([C:16]#[N:17])=[CH:14][N:13]=[C:12]([NH:5][C:4]2[CH:6]=[CH:7][CH:8]=[C:2]([Cl:1])[CH:3]=2)[N:11]=1
Reactant: Nc1cccc(Cl)c1
Reactant: N#Cc1cnc(Cl)nc1N
Product: N#Cc1cnc(Nc2cccc(Cl)c2)nc1N
Yield: 87.5 %

Procedure:
3-Chloroaniline (277 mg, 2.2 mmol) was treated with 4-amino-2-chloro-5-cyanopyrimidine (0.3 g, 2.0 mmol) by the procedure described in Example 1 to give the title compound (430 mg, 90%). NMR: 7.00 (d, 1H), 7.28 (dd, 1H), 7.55 (s, 2H), 7.70 (d, 1H), 7.89 (s, 1H), 8.38 (s, 1H), 9.81 (s, 1H); m/z 246 (MH)+.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]1.[H-].[Na+].[C:13](Cl)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>O1CCCC1>[C:14]1([C:13]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:1]2[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 55.5 %

Procedure:
Ethyl 1 H-pyrazole-4-carboxylate (1.50 g, 10.7 mmol) was added in portions to a stirred suspension of sodium hydride (353 mg, 80% oil dispersion, 11.8 mmol) in anhydrous tetrahydrofuran (100 ml) under nitrogen at room temperature. After 20 minutes, the mixture was cooled to 0° C. and trityl chloride (3.28 g, 11.8 mmol) was added. The mixture was stirred at 0° C. for 4 h and allowed to warm to room temperature overnight. The mixture was then heated at 50° C. for 3 h, cooled, and further portions of sodium hydride (321 mg, 10.7 mmol) and trityl chloride (1.0 g, 3.59 mmol) were added. The mixture was heated at 50° C. for 2 h, cooled, treated with water (50 ml) and concentrated under reduced pressure. The product was extracted into ethyl acetate (200 ml), the solution was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient elution with hexane/ethyl acetate) to give ethyl 1 -(triphenylmethyl)-pyrazole-4-carboxylate (2.273 g, 56%), as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([CH:11]1[CH2:13][CH2:12]1)=O.[CH3:14][C:15]1[N:16]=[CH:17][NH:18][C:19]=1[CH3:20]>C(OCC)(=O)C>[CH3:14][C:15]1[N:16]=[C:17]2[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])=[CH:11][CH2:13][CH2:12][N:18]2[C:19]=1[CH3:20]
Reactant: Cc1nc[nH]c1C
Reactant: O=C(c1ccc(Cl)cc1Cl)C1CC1
Solvent: CCOC(C)=O
Product: Cc1nc2n(c1C)CCC=C2c1ccc(Cl)cc1Cl
Temperature: 205 °C

Procedure:
Cyclopropyl 2,4-dichlorophenyl ketone (1) (54 g, 0.25 mol) and 4,5-dimethylimidazole (2) (90 g, 1 mol) are combined and heated at 200 to 210° C. under nitrogen for 20 hours. The reaction is cooled and diluted with ethyl acetate (700 ml). The ethyl acetate solution is washed with saturated aq potassium carbonate (300 ml) and water (4×200 ml) and dried over sodium sulfate. The drying agent is removed by filtration and the solvent is removed in vacuo to provide 3.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[S:68][C:67]([C:69]#[N:70])=[CH:66][CH:65]=1>>[C:69]([C:67]1[S:68][C:64]([NH:63][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:36])([CH3:35])[CH3:37])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[CH:65][CH:66]=1)#[N:70]
Reactant: N#Cc1ccc(N)s1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C#N)s2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Yield: 40.4 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.3 g, 0.52 mmol), was reacted with diisopropylethylamine (0.34 g, 2.6 mmol), diphenylphosphinic chloride (0.37 g, 1.6 mmol), then reacted with 5-amino-thiophene-2-carbonitrile prepared in Example 186 (0.11 g, 0.85 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (5-cyano-thiophen-2-yl)-amide as a white solid (Yield 0.12 g, 37%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C([O:18][C:19](OCC)(N(C)C)[CH2:20][CH3:21])C>C(OCC)(=O)C>[N+:13]([C:3]1[C:2]([CH2:1][C:19](=[O:18])[CH2:20][CH3:21])=[CH:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6])([O-:15])=[O:14]
Reactant: CCOC(=O)c1cccc(C)c1[N+](=O)[O-]
Reactant: CCOC(CC)(OCC)N(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cccc(CC(=O)CC)c1[N+](=O)[O-]
Temperature: 145 °C
Yield: 29.6 %

Procedure:
A stirred mixture of ethyl 3-methyl-2-nitrobenzoate (0.96 g) and N,N-dimethylpropionamide diethyl acetal (2.3 g) was heated at 145° C. for 36 hours. The reaction mixture was dissolved in ethyl acetate. The solution was washed with dilute hydrochloric acid and then water, dried and concentrated to dryness. The residue was purified by column chromatography on silica gel to give a pale brown syrup (0.36 g, 33%).