Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:10][C:11]1[CH:12]=[C:13]([C:23]2[N:28]=[C:27]([C:29]3[CH:30]=[C:31]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH:32]=[C:33]([Cl:35])[CH:34]=3)[N:26]=[C:25]([C:42]3[CH:47]=[C:46](Br)[CH:45]=[C:44](Br)[CH:43]=3)[N:24]=2)[CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.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>[Cl:10][C:11]1[CH:12]=[C:13]([C:23]2[N:28]=[C:27]([C:29]3[CH:30]=[C:31]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH:32]=[C:33]([Cl:35])[CH:34]=3)[N:26]=[C:25]([C:42]3[CH:47]=[C:46]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH:45]=[C:44]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH:43]=3)[N:24]=2)[CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:16]=1
Reactant: Clc1cc(-c2ccccc2)cc(-c2nc(-c3cc(Br)cc(Br)c3)nc(-c3cc(Cl)cc(-c4ccccc4)c3)n2)c1
Reactant: OB(O)c1ccccc1
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: [Cs+]
Solvent: C1CCOC1
Product: Clc1cc(-c2ccccc2)cc(-c2nc(-c3cc(Cl)cc(-c4ccccc4)c3)nc(-c3cc(-c4ccccc4)cc(-c4ccccc4)c3)n2)c1
Yield: 84 %

Procedure:
In a stream of argon, phenylboronic acid (904 mg), 4,6-bis(5-chlorobiphenyl-3-yl)-2-(3,5-dibromophenyl)-1,3,5-triazine (1.70 g), cesium carbonate (2.41 g) and tetrakis(triphenylphosphine)palladium (114 mg) were suspended in tetrahydrofuran (80 mL), and the mixture was refluxed for 18 hours. The reaction mixture was left to stand at room temperature, and then low-boiling ingredients were distilled away under a reduced pressure. Methanol was added to the reaction mixture, and the solid precipitate was recovered by filtration, and purified by silica gel chromatography using a chloroform/hexane (1:2 to 1:0) mixed liquid as a developing solvent to give 1.42 g of the target 2,4-bis(5-chlorobiphenyl-3-yl)-6-[(1,1′:3′,1″)-terphenyl-5′-yl]-1,3,5-triazine as a yellowish white powder (yield: 84%).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:19]=[CH:18][C:11]([O:12][CH:13]([CH3:17])[C:14](Cl)=[O:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[CH3:24][O:25][CH2:26][CH2:27][NH2:28].C(N(CC)CC)C>C(Cl)Cl>[CH3:24][O:25][CH2:26][CH2:27][NH:28][C:14](=[O:15])[CH:13]([O:12][C:11]1[CH:18]=[CH:19][C:8]([O:7][C:6]2[CH:20]=[CH:21][C:3]([C:2]([F:23])([F:22])[F:1])=[CH:4][CH:5]=2)=[CH:9][CH:10]=1)[CH3:17]
Reactant: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)Cl
Reactant: COCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCNC(=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reaction time: 2 h
Yield: 77.7 %

Procedure:
While cooling with ice, 17.2 g (0.05 mole) of α-[4-(p-trifluoromethylphenoxy)-phenoxy]-propionyl chloride are added dropwise to a mixture of 4.1 g (0.055 mole) of 2-methoxyethylamine, 7.5 ml (0.055 mole) of triethylamine and 50 ml of methylene chloride, and the temperature is allowed to rise to 20° C. The reaction mixture is stirred for 2 hours, then concentrated. The residue is filtered in ether over a small column of silica gel. Concentration of the filtrate affords 14.9 g (77.6%) of α-[4-(p-trifluoromethylphenoxy)-phenoxy]-propionic acid (2-methoxy)-ethylamide with a melting point of 73°-75° C.
Reaction SMILES: [NH2:1][C@@H:2]1[C@H:6]([NH:7][C:8]2[N:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[C:23]([Cl:24])=[C:22]([O:25][CH3:26])[CH:21]=[C:20]([O:27][CH3:28])[C:19]=4[Cl:29])[CH:14]=3)[N:9]=2)[CH2:5][C@@H:4]([C:30]([N:32]([CH3:34])[CH3:33])=[O:31])[CH2:3]1.CCN(C(C)C)C(C)C.[C:44](Cl)(=[O:47])[CH:45]=[CH2:46]>C(Cl)Cl>[C:44]([NH:1][C@@H:2]1[C@H:6]([NH:7][C:8]2[N:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[C:23]([Cl:24])=[C:22]([O:25][CH3:26])[CH:21]=[C:20]([O:27][CH3:28])[C:19]=4[Cl:29])[CH:14]=3)[N:9]=2)[CH2:5][C@@H:4]([C:30]([N:32]([CH3:34])[CH3:33])=[O:31])[CH2:3]1)(=[O:47])[CH:45]=[CH2:46]
Reactant: COc1cc(OC)c(Cl)c(-c2ccc3nc(N[C@@H]4C[C@@H](C(=O)N(C)C)C[C@@H]4N)ncc3c2)c1Cl
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)N[C@H]1C[C@H](C(=O)N(C)C)C[C@H]1Nc1ncc2cc(-c3c(Cl)c(OC)cc(OC)c3Cl)ccc2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77.8 %

Procedure:
(1S,3S,4R)-3-amino-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)-N,N-dimethylcyclopentanecarboxamide (0.050 g, 0.099 mmol) was taken up in CH2Cl2 (25 ml) and cooled to 0° C., followed by addition of DIEA (0.017 ml, 0.099 mmol) then acryloyl chloride (8.86 μl, 0.109 mmol) slowly. The reaction mixture was stirred at 0° C. for 30 minutes. After the reaction was complete, the reaction mixture was loaded directly onto silica and purified via flash chromatography (0-10% CH2Cl2/MeOH; 12 g column) to afford (1R,3S,4R)-3-acrylamido-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)-N,N-dimethylcyclopentanecarboxamide (0.043 g, 0.077 mmol, 78% yield). MS (ES+) C27H29Cl2N5O4 requires: 558, found: 559 [M+H]+.
Reaction SMILES: [N:1]1([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][C:29]=2[C:35]([F:38])([F:37])[F:36])[CH2:23][CH2:22]1>C(Cl)Cl.CO>[N:1]1([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][C:17]([NH:34][C:31]3[CH:32]=[CH:33][C:28]([CH2:27][N:24]4[CH2:23][CH2:22][N:21]([CH3:20])[CH2:26][CH2:25]4)=[C:29]([C:35]([F:38])([F:37])[F:36])[CH:30]=3)=[O:19])=[CH:14][CH:15]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CN1CCN(Cc2ccc(N)cc2C(F)(F)F)CC1
Reactant: O=C(O)Cc1ccc(-n2cnc3ccccc32)cc1
Solvent: CO
Solvent: ClCCl
Product: CN1CCN(Cc2ccc(NC(=O)Cc3ccc(-n4cnc5ccccc54)cc3)cc2C(F)(F)F)CC1

Procedure:
The title compound is prepared as described in Example 1 but using (4-benzoimidazol-1-yl-phenyl)-acetic acid and 4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylamine (see WO 03/099771). Title compound: ES-MS: 508.0 [M+H]+; single peak at tR=2.84 min (System 1); Rf=0.10 (CH2Cl2/MeOH+1% NH3aq, 9:1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]2[C:7]([I:15])=[N:6]1.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(N(CC)CC)C>CN(C)C=O>[I:15][C:7]1[C:8]2[C:9](=[N:10][CH:11]=[N:12][C:13]=2[NH2:14])[N:5]([CH2:4][CH2:3][CH2:2][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:6]=1
Reactant: C1COCCN1
Reactant: Nc1ncnc2c1c(I)nn2CCCBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(I)nn2CCCN1CCOCC1
Temperature: 70 °C
Reaction time: 66.25 h
Yield: 48 %

Procedure:
A suspension of 1-(3-bromopropyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.500 g, 1.31 mmol) in dimethylformamide (10 mL) was treated with morpholine (0.137 g, 1.572 mmol) and triethylamine (0.133 g, 1.31 mmol). The reaction mixture was stirred at 70° C. for 66.25 h. Solvent was removed under reduced pressure. Dichloromethane (15 mL) and 1 N hydrochloric acid (20 mL) were added. The layers were partitioned and the aqueous layer was washed with dichloromethane (100 mL). The aqueous layer was neutralized to pH 14 and then extracted with dichloromethane (250 mL). The organic layer was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a step-wise gradient of 10% methanol in dichloromethane to 50% methanol in dichloromethane over 58 minutes on a 35 g ISCO column. The column afforded 0.244 g (48%) of pure 3-iodo-1-(3-morpholinopropyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine. 1H NMR (DMSO-d6, 400 MHz) δ 8.194 (s, 1H), 4.327-4.293 (t, 2H), 3.485-3.364 (m, 4H), 2.253-2.238 (m, 6H), 1.963-1.895(m, 2H); LCMS (Thermoquest AQA single-quad MS, Genesis C18 column, 3 μm particle size, 33×4.6 mm; 70% 50 mM ammonium acetate in water to 95% acetonitrile over 6 min, 0.8 to 0.5 mL/min) R, 0.71 min (100%), MH+ 389.0.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]1[CH2:11][CH2:10][CH:9]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH2:8][C:7]2=1.[N+:23]([C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28]Br)([O-:25])=[O:24].O>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH2:28][C:27]1[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=1[N+:23]([O-:25])=[O:24])[C:12]1[CH2:11][CH2:10][CH:9]([NH:17][C:18](=[O:22])[CH:19]([CH3:20])[CH3:21])[CH2:8][C:7]2=1
Reactant: O=[N+]([O-])c1ccccc1CBr
Reactant: CC(C)C(=O)NC1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)C(=O)NC1CCc2c(c3cc(Cl)ccc3n2Cc2ccccc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79 %

Procedure:
Suspend sodium hydride (60%, 120 mg, 3 mmol) in anhydrous DMF (2.5 mL) under nitrogen and cool in an ice bath. Slowly add N-(6-chloro-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-isobutyramide (prepare essentially as described in Preparation 4)(727 mg, 2.5 mmol) dissolved in DMF (8 mL). After 10 min remove ice bath and allow the reaction to warm to ambient temperature over 1 h. Add DMF (25 mL) and cool in a dry ice/acetone bath. Add dropwise a solution of 2-nitrobenzylbromide (648 mg, 3 mmol) in DMF (2.5 mL). Stir for 18 h, allowing to warm to ambient temperature. Pour into water and extract with ethyl acetate/diethyl ether (100 mL/50 mL). Separate and wash the aqueous portion with ethyl acetate (50 mL). Combine organics and wash with 1N hydrochloric acid (2×100 mL), brine (2×100 mL), dry (MgSO4), and concentrate in vacuo to obtain a yellow solid. Purify by flash chromatography eluting with dichloromethane and then a gradient up to 10% ethyl acetate/dichlorometbane to obtain 833 mg (79%) of a yellow solid.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17](Cl)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[C:23]([NH:30][CH2:31][CH2:32][NH2:33])([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>CN(C=O)C>[Cl:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17]([NH:33][CH2:32][CH2:31][NH:30][C:23](=[O:24])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCNc1c([N+](=O)[O-])c(Cl)nc2ccccc12
Temperature: 25 °C
Yield: 94.9 %

Procedure:
Triethylamine (30.98 g, 306.1 mmol) was added to a solution of 2,4-dichloro-3-nitroquinoline (50.0 g, 204 mmol) in DMF (200 mL). A solution of N-Boc-ethylenediamine (32.7 g, 204 mmol) in DMF (100 mL) was then added in small portions. The reaction was stirred at room temperature, and then most of the DMF was removed under reduced pressure. Water (600 mL) was added to the residue, and the mixture was stirred for three hours. A solid formed and was isolated by filtration, washed with water, and dried under house vacuum to provide 71 g of tert-butyl 2-[(2-chloro-3-nitroquinolin-4-yl)amino]ethylcarbamate as a yellow solid. A portion of the material (15 g) was dissolved in dichloromethane (200 mL), and the resulting solution was washed with brine (2×100 mL) and deionized water (2×100 mL), dried over magnesium sulfate, filtered, concentrated under reduced pressure, and further dried on a vacuum pump for three days to provide 13.99 g of product.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[CH2:14]([N:21]1[C:25]2[CH:26]=[CH:27][C:28]3[CH2:29][CH2:30][C:31](=O)[C:32]=3[C:24]=2[N:23]=[C:22]1[CH3:34])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCCC1.O>[CH2:14]([N:21]1[C:25]2[CH:26]=[CH:27][C:28]3[CH2:29][CH2:30][C:31](=[CH:5][C:3]#[N:4])[C:32]=3[C:24]=2[N:23]=[C:22]1[CH3:34])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1nc2c3c(ccc2n1Cc1ccccc1)CCC3=O
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc2c3c(ccc2n1Cc1ccccc1)CCC3=CC#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
To a suspension of 60% sodium hydride (32 mg, 0.80 mmol) in tetrahydrofuran (5 mL) was added diethyl cyanomethylphosphonate (142 μL, 0.88 mmol), and the mixture was stirred at room temperature for 30 min. A solution of 3-benzyl-2-methyl-6,7-dihydroindeno[4,5-d]imidazol-8(3H)-one (73.4 mg, 0.27 mmol) in tetrahydrofuran (2 mL) was added thereto, and the mixture was stirred at room temperature for 30 min. The reaction solution was diluted with water, extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=30/70→80/20) to give the title compound (53.3 mg, yield 67%).
Reaction SMILES: [K].[O:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:5][NH:4][C:3]1=[S:12].[CH:13](I)([CH3:15])[CH3:14]>>[CH:13]([S:12][C:3]1[O:2][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:5][N:4]=1)([CH3:15])[CH3:14]
Reactant: CCOC(=O)c1n[nH]c(=S)o1
Reactant: CC(C)I
Agent: [K]
Product: CCOC(=O)c1nnc(SC(C)C)o1

Procedure:
The title compound was prepared from ethyl 1,3,4-oxadiazole-2-thione-5-carboxylate potassium salt dimethylsulfoxide solvate (11 g., 0.03 mole) and isopropyl iodide (5.6 g., 0.03 mole) analogously to the procedure described in Experiment A. The yield was 4.1 g. (63%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH:10]([CH3:12])[CH3:11])=[CH:4][N:3]=1.[CH3:13][N:14](C=O)C>[C-]#N.[C-]#N.[Zn+2].C(Cl)Cl.O>[CH:10]([O:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:13]#[N:14])=[N:3][CH:4]=1)([CH3:12])[CH3:11]
Reactant: CC(C)OCc1ccc(Cl)nc1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Solvent: ClCCl
Solvent: O
Product: CC(C)OCc1ccc(C#N)nc1
Temperature: 180 °C

Procedure:
In a microwave reaction tube was placed 2-chloro-5-isopropoxymethyl-pyridine (0.12 g, 0.66 mmol), Zn(CN)2 (0.077 g, 0.66 mmol), tetrakis(triphenylphosphino)dipalladium (76 mg, 0.066 mmol), DMF (2 mL). The reaction mixture was heated at 180° C. for 5 minutes. The resulted mixture was worked up by CH2Cl2/H2O. The CH2Cl2 layer was dried and concentrated to give the crude product. The crude was purified by column chromatography by using 30% EtOAc/Hexane. 1H NMR (CDCl3, 400 MHz) δ 1.26 (d, 6H), 3.73 (m, 1H), 4.59 (s, 2H), 7.68 (d, 1H), 7.85 (m, 1H), 8.67 (s, 1H). Exact mass calculated for C10H12N2O 176.09, found 177.2 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:12]([NH:15][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])(=[O:14])=[O:13])[CH:8]=2)[O:3]1.CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.[Br:43][C:44]1[CH:45]=[C:46]([CH:49]=[C:50]([CH2:52]Br)[CH:51]=1)[C:47]#[N:48]>CC#N>[Br:43][C:44]1[CH:51]=[C:50]([CH:49]=[C:46]([C:47]#[N:48])[CH:45]=1)[CH2:52][N:15]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[S:12]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[O:3][C:2]([CH3:24])([CH3:1])[CH2:11][CH2:10]2)(=[O:14])=[O:13]
Reactant: N#Cc1cc(Br)cc(CBr)c1
Reactant: CC(C)(C)OC(=O)CNS(=O)(=O)c1ccc2c(c1)CCC(C)(C)O2
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CC#N
Product: CC(C)(C)OC(=O)CN(Cc1cc(Br)cc(C#N)c1)S(=O)(=O)c1ccc2c(c1)CCC(C)(C)O2
Temperature: 90 °C
Yield: 79.7 %

Procedure:
To the solution of tert-butyl 2-(2,2-dimethylchroman-6-sulfonamido)acetate (500 mg, 1.407 mmol) in MeCN (15 mL) was added resin-supported BEMP (786 mg, 1.547 mmol) and 3-bromo-5-(bromomethyl)benzonitrile (503 mg, 1.829 mmol). The mixture was heated in a microwave synthesizer at 90° C. for 3 hours. The reaction mixture was filtered, rinsed alternatively with dichloromethane and methanol. The filtrate was concentrated to give a reddish orange residue, which was purified by silica chromatography to obtain a white powder (616 mg, 80% yield). 1H NMR (500 MHz, CDCl3) δ 7.69 (d, J=8.6 Hz, 2H), 7.57-7.52 (m, 2H), 7.49 (s, 1H), 6.85 (d, J=9.3 Hz, 1H), 4.49 (s, 2H), 3.82 (s, 2H), 2.81 (t, J=6.7 Hz, 2H), 1.84 (t, J=6.7 Hz, 2H), 1.36 (s, 9H), 1.36 (s, 6H). LRMS [ESI, MH+] m/z calcd for C25H30BrN2O5S 549.11, found 549.1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C([O-])([O-])=O.[K+].[K+]>O.CCOC(C)=O>[CH3:8][C:6]1[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]2=[C:2]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[N:7]=1
Reactant: C1CNCCN1
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nc(N2CCNCC2)c2nc(-c3ccccc3)cc-2[nH]1
Temperature: 25 °C
Yield: 29.1 %

Procedure:
This compound was prepared according to the method described in Example 26 by employing 4-chloro-2-methyl-6-phenylpyrrolo[3,2-d]pyrimidine (Example 1(e)) (0.10 g, 0.41 mmol), piperazine (Aldrich Chemical Company) (0.382 g, 4.43 mmol) and K2CO3 (0.34 g, 2.50 mmol) in H2O (2.5 mL) to give crude pink solids. These solids were taken up in hot EtOAc, cooled to room temperature, and the impurities were removed by filtration. The filtrate was concentrated to give 0.035 g (29%) of the title compound as an off-white solid. Mp: 236° C. 1H NMR (DMSO-d6; 500 MHz): δ 2.42 (s, 3), 2.85 (t, 4, J=5.2), 3.62 (t, 4, J=5.2), 6.77 (s, 1), 7.36 (m, 1), 7.45 (t, 2, J=7.8), 7.95 (d, 2, J=7.6), 10.96 (s, 1); MS m/z: 294 (M+1). Anal. Calcd for C17H19N5O.0.5 H2O: C 67.53, H 6.67, N 23.16. Found: C 67.35, H 6.59, N 23.01.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH:10]([C:12]2[CH:13]=[C:14]([C:29]([OH:31])=O)[CH:15]=[C:16]3[C:21]=2[O:20][C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:18][C:17]3=[O:28])[CH3:11])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:32][NH:33][CH2:34][CH2:35][OH:36]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH:10]([C:12]2[CH:13]=[C:14]([C:29]([N:33]([CH2:34][CH2:35][OH:36])[CH3:32])=[O:31])[CH:15]=[C:16]3[C:21]=2[O:20][C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:18][C:17]3=[O:28])[CH3:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(Nc1ccc(F)c(Cl)c1)c1cc(C(=O)O)cc2c(=O)cc(N3CCOCC3)oc12
Reactant: CNCCO
Product: CC(Nc1ccc(F)c(Cl)c1)c1cc(C(=O)N(C)CCO)cc2c(=O)cc(N3CCOCC3)oc12
Yield: 70 %

Procedure:
8-(1-(3-chloro-4-fluorophenylamino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (78 mg, 0.17 mmol) was reacted with 2-(methylamino)ethanol (0.017 mL, 0.21 mmol) using a procedure similar to the one described in Example 2.00 to give 8-(1-(3-chloro-4-fluorophenylamino)ethyl)-N-(2-hydroxyethyl)-N-methyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (60.0 mg, 68.2%) as a white solid. Mass Spectrum: M+H+ 504. NMR Spectrum: (DMSOd6) at 323° K: 1.51 (d, 3H), 2.82 (bs, 1.5H), 2.90 (bs, 1.5H), 3.42 (bs, 4H), 3.49-3.63 (m, 4H), 3.69-3.79 (m, 4H), 4.60 (bs, 1H), 4.92-5.01 (m, 1H), 5.56 (s, 1H), 6.37 (dd, 1H), 6.42 (ddd, 1H), 6.61 (dd, 1H), 7.02 (dd, 1H), 7.57 (d, 1H), 7.80 (d, 1H).
Reaction SMILES: [CH2:1]1[C:6]2=[C:7]3[C:12](=[CH:13][CH:14]=[C:5]2[O:4][CH2:3][CH:2]1[OH:15])[N:11]=[CH:10][CH:9]=[CH:8]3.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>N1C=CC=CC=1>[CH3:26][C:16]1[CH:21]=[CH:20][C:19]([S:22]([O:15][CH:2]2[CH2:3][O:4][C:5]3[C:6](=[C:7]4[C:12](=[CH:13][CH:14]=3)[N:11]=[CH:10][CH:9]=[CH:8]4)[CH2:1]2)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC1COc2ccc3ncccc3c2C1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC2COc3ccc4ncccc4c3C2)cc1
Yield: 94.2 %

Procedure:
A solution of 2,3-dihydro-1H-pyrano[3,2-f]quinolin-2-ol (intermediate 10) (0.47 g, 2.3 mmol) and p-toluene sulfonyl chloride (0.89 g, 4.6 mmol) in anhydrous pyridine (20 mL) was stirred at room temperature for 2.5 days. It was then poured into ice-H2O and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Chromatography ((15:4:1) EtOAc-Hexane-MeOH) afforded 0.77 g (93%) of 2,3-dihydro-1H-pyrano[3,2-f]quinolin-2-yl 4-methylbenzenesulfonate as an off-white solid: mp 167.5–169.5° C. MS ESI m/z 356 [M+H]+. Elemental Analysis for C19H17NO4S: Calculated: C, 64.21; H, 4.82; N, 3.94. Found: C, 63.98; H, 4.79; N, 3.84.
Reaction SMILES: [CH2:1]([S:3][CH:4]1[N:7]([CH:8](O)[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[O:10])[C:6](=[O:23])[CH:5]1[CH2:24][CH2:25][O:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=1)=[O:28])[CH3:2].N1C(C)=CC=CC=1C.S(Cl)([Cl:50])=O>O1CCCC1>[CH2:1]([S:3][CH:4]1[N:7]([CH:8]([Cl:50])[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[O:10])[C:6](=[O:23])[CH:5]1[CH2:24][CH2:25][O:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=1)=[O:28])[CH3:2]
Reactant: CCSC1C(CCOC(=O)OCc2ccc([N+](=O)[O-])cc2)C(=O)N1C(O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: Cc1cccc(C)n1
Product: CCSC1C(CCOC(=O)OCc2ccc([N+](=O)[O-])cc2)C(=O)N1C(Cl)C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of 11.3 g p-nitrobenzyl 2(4-ethylthio-3-p-nitrobenzyloxycarbonyloxyethyl-2-oxo-1-azetidinyl)-2-hyroxyacetate and 3.02 ml 2,6-lutidine in 175 ml anhydrous tetrahydrofuran was cooled to 0° C. under a nitrogen atmosphere. Thionyl chloride (1.75 ml) was added dropwise and the resulting mixture was stirred at 0° C. for 20 min. The mixture was filtered through Supercel and the filtrate was concentrated in vacuo. The concentrate was dissolved in methylene chloride and the resulting solution was washed successively with 200 ml 1N aqueous hydrochloric acid, 200 ml saturated aqueous sodium bicarbonate solution and 200 ml saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo to an oil (11.6 g) of the title compound. The NMR spectrum of the title compound in deuterochloroform showed peaks at 1.04-1.6 (c, 6H); 2.6 (m, 2H); 3.4 (m, 1H); 4.8-5.4 (c, 6H); 5.85, 5.9, 5.98, 6.1 (s, 1H); 7.5 (m, 4H); 8.2 (m, 4H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][C:8](=O)[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].[Cl:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([NH:22][C:21]2[CH:23]=[CH:24][CH:25]=[C:19]([Cl:18])[CH:20]=2)[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: COC(=O)C1CC(=O)CN1C(=O)OC(C)(C)C
Reactant: Nc1cccc(Cl)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](Nc2cccc(Cl)c2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.4 %

Procedure:
4-Oxo-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (364.5 mg, 1.5 mmol) and 3-chloroaniline (191 mg, 1.5 mmol) were dissolved in DCM (10 ml). To this solution was added sodium triacetoxyborohydride (413 mg, 1.95 mmol) and acetic acid (0.085 ml, 1.5 mmol), and the reaction stirred at room temperature overnight. The reaction mixture was washed with 2N NaOH (5 ml), saturated brine (5 ml), dried over MgSO4 and evaporated. The residue was purified by flash chromatography on silica eluting with DCM to give the title compound as a colourless oil (215 mg, 40%).