Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12](C(OC(C)(C)C)=O)[CH3:13])=[CH:8][C:7]=1[CH3:21].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:22])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH3:13])=[CH:8][C:7]=1[CH3:21]
Reactant: COC(=O)COc1ccc(N(C)C(=O)OC(C)(C)C)cc1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNc1ccc(OCC(=O)OC)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of crude 25.8 g (77 mmol) of the above prepared [4-(tert-butoxycarbonyl-methyl-amino)-2-methyl-phenoxy]-acetic acid methyl ester in 600 ml CH2Cl2 was treated at 0° C. with 198 ml TFA and stirred at RT for 30 min. The reaction was evaporated and treated with chilled aqueous saturated NaHCO3 solution/Et2O (3×). The organic phases were washed with aqueous 10% NaCl, dried over sodium sulfate, and evaporated to give 16.2 g of crude product. Purification by flash chromatography on SiO2 with a gradient of n-heptane: AcOEt (9:1 to 4:1) yielded 12.7 g of (2-methyl-4-methylamino-phenoxy)-acetic acid methyl ester as an orange oil.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[N:11]=[C:10]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[NH:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=[C:30]1[CH2:38][C:39]#[N:40]>>[OH:22][C:19]([CH:16]1[CH2:17][CH2:18][N:13]([CH2:12][C:10]2[CH:9]=[CH:8][C:6]3[N:7]=[C:2]([N:29]4[C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=5[N:31]=[C:30]4[CH2:38][C:39]#[N:40])[N:3]=[C:4]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:5]=3[N:11]=2)[CH2:14][CH2:15]1)([CH3:21])[CH3:20]
Reactant: CC(C)(O)C1CCN(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Reactant: N#CCc1nc2ccccc2[nH]1
Product: CC(C)(O)C1CCN(Cc2ccc3nc(-n4c(CC#N)nc5ccccc54)nc(N4CCOCC4)c3n2)CC1

Procedure:
Following General Procedure D, 2-(1-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)propan-2-ol from Example 8 was reacted with 2-(1H-benzo[d]imidazol-2-yl)acetonitrile to give 158. 1H NMR (400 MHz, DMSO) δ 8.32 (d, J=7.8 Hz, 1H), 8.21 (d, J=8.5 Hz, 1H), 7.91 (d, J=8.6 Hz, 1H), 7.76 (d, J=7.8 Hz, 1H), 7.38 (overlapping m, 2H), 4.88 (s, 2H), 4.54 (s, 4H), 4.04 (s, 1H), 3.86 (s, 4H), 3.73 (s, 2H), 2.92 (d, J=10.5 Hz, 2H), 1.99 (t, J=11.5 Hz, 2H), 1.67 (d, J=11.7 Hz, 2H), 1.26 (overlapping m, 3H), 1.04 (s, 6H). LCMS: 527.3
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13]([C:15]3[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=3)[C:18]([NH:20][NH2:21])=[O:19])=[N:12][CH:11]=2)=[CH:6][CH:5]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[CH3:47][O:48][C:49](=[O:60])[C:50]1[CH:55]=[CH:54][C:53]([CH2:56][C:57](O)=[O:58])=[CH:52][CH:51]=1.C(N(C(C)C)CC)(C)C>CN(C)C=O.O>[CH3:47][O:48][C:49](=[O:60])[C:50]1[CH:55]=[CH:54][C:53]([CH2:56][C:57]([NH:21][NH:20][C:18](=[O:19])[C:17]2[CH:22]=[CH:23][CH:24]=[C:15]([C:13]3[O:14][C:10]([C:7]4[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:9][CH:8]=4)=[CH:11][N:12]=3)[CH:16]=2)=[O:58])=[CH:52][CH:51]=1
Reactant: COc1ccc(-c2cnc(-c3cccc(C(=O)NN)c3)o2)cc1
Reactant: COC(=O)c1ccc(CC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CC(=O)NNC(=O)c2cccc(-c3ncc(-c4ccc(OC)cc4)o3)c2)cc1
Reaction time: 14 h
Yield: 49.4 %

Procedure:
0.7 g (2.0 mmol) of 3-[5-(4-Methoxy-phenyl)-oxazol-2-yl]-benzoic acid hydrazide hydrochloride from Preparation 6, 0.49 g (2.6 mmol) EDAC.HCl, 0.35 g (2.6 mmol) HOBT, and 0.50 g (2.6 mmol) 4-carboxymethyl-benzoic acid methyl ester from Preparation 7 was dissolved in 20 mL of dimethylformamide. 0.33 g (2.6 mmol) Di-isopropylethylamine was then added. Stirring was continued 14 hours at room temperature. Water (60 ml) was added and the product was extracted with 1:1 Et2O/EtOAc (2×). Combined the organic extracts and washed with saturated aqueous NaCl solution (4×), dried (MgSO4). The resulting solid was triturated in EtOAc and filtered. Dried in a vacuum oven overnight at 70° C. to provide 0.48 g (49%) desired product. MS: m/z (APCI, AP+) 486 [M−]+
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:28])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]2[O:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][CH:21]=2)=[O:16])=[CH:10][CH:9]=1)C>O.C(O)C>[C:22]1([C:19]2[O:18][C:17]([C:15]([NH:14][C:11]3[CH:10]=[CH:9][C:8]([CH2:7][C:6]([OH:28])=[O:5])=[CH:13][CH:12]=3)=[O:16])=[CH:21][CH:20]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)Cc1ccc(NC(=O)c2ccc(-c3ccccc3)o2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)Cc1ccc(NC(=O)c2ccc(-c3ccccc3)o2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
A solution of sodium hydroxide (100 mg) in water (5 ml) was added to a stirred solution of {4-[(5-phenyl-furan-2-carbonyl)-amino]-phenyl}-acetic acid ethyl ester (1) (75 mg, 0.214 mmoles) in ethanol (10 ml) and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated and the residue was diluted with water (10 ml) and acidified to pH=2 with 1 M aqueous hydrochloric acid. The precipitate was collected, washed with water and the residue was triturated with cyclohexane to afford (2) (61.5mg) as a white solid. LC/MS System D; Rt=3.01 mins, m/z (ES−)=320 (M−H for C19H15NO4).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[O:9])[CH:7]=1.[CH2:32](OC(OCC)OCC)C.[N-:42]=[N+:43]=[N-:44].[Na+]>C(O)(=O)C.O.[OH-].[Na+]>[N:26]1([C:5]2[CH:4]=[CH:3][C:2]([N:1]3[CH:32]=[N:44][N:43]=[N:42]3)=[CH:7][C:6]=2[C:8]([N:10]2[CH2:11][CH2:12][N:13]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:20][CH:21]=3)[CH2:14][CH2:15]2)=[O:9])[CH2:27][CH2:28][O:29][CH2:30][CH2:31]1
Reactant: CCOC(OCC)OCC
Reactant: Nc1ccc(N2CCOCC2)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=C(c1cc(-n2cnnn2)ccc1N1CCOCC1)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Temperature: 75 °C
Reaction time: 1 h
Yield: 51.7 %

Procedure:
A suspension of (5-Amino-2-morpholin-4-yl-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone (50 mg, 0.115 mmol) in Acetic acid (1 ml) was heated to 75° C. under nitrogen and then triethylorthoformate (36.76 ul, 0.34 mmol) was slowly added. After 1 hour, sodium azide (22.4 mg, 0.34 mmol) was added portionwise and the reaction mixture was stirred at 75° C. for 1 h30. The reaction mixture was cooled to room temperature, diluted with water and basified with 1N NaOH solution. The aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried over Na2SO4, filtered and evaporated to dryness. The residue was chromatographed on silica gel: Eluent: Heptane/Ethylacetate 0% to 60% (10 minutes) to provide the title compound (29 mg, 52%) as yellow solid, MS (m/e): 488.2 (M+H+, 100%)
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:7]([N:8]=[N+:9]=[N-:10])[CH2:6][C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][C@H:3]1[O:16][CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19].C(N(CC)CC)C.[C:29](OC(=O)C)(=[O:31])[CH3:30]>C(Cl)Cl>[C:29]([NH:1][C@@H:2]1[C@@H:7]([N:8]=[N+:9]=[N-:10])[CH2:6][C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][C@H:3]1[O:16][CH:17]([CH2:18][CH3:19])[CH2:20][CH3:21])(=[O:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](N)[C@@H](N=[N+]=[N-])C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@@H](N=[N+]=[N-])C1
Temperature: 20 °C
Reaction time: 3 h
Yield: 53.2 %

Procedure:
Ethyl (3R,4R,5S)-4-Amino-5-azido-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate (14 gm) was added to triethyl amine (10 gm) and methylene chloride (110 ml) and then the contents were cooled to 20° C. To the contents added acetic anhydride (5.6 gm) at 20-25° C. for 1 hour and then stirred for 3 hours at 20-25° C. The reaction mass was quenched into water (140 ml) and then separated the layers. The organic layer was washed with 8% sodium bicarbonate solution (140 ml) and then washed with 30% sodium chloride solution (140 ml). The organic layer was distilled and recrystallized from n-hexane (70 ml) to give 8.5 gm of Ethyl (3R,4R,5S)-4-(Acetylamino)-5-azido-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate.
Reaction SMILES: [C:1]([C:4]1[C:13]2[O:12][CH2:11][C:10](=[O:14])[NH:9][C:8]=2[CH:7]=[C:6]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=1)(=[O:3])[CH3:2].C(O)(=O)C.O.S([O-])(O)=O.[Na+].[Cl:33]C(Cl)C>>[CH2:16]([O:15][C:6]1[CH:5]=[C:4]([C:1](=[O:3])[CH2:2][Cl:33])[C:13]2[O:12][CH2:11][C:10](=[O:14])[NH:9][C:8]=2[CH:7]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(=O)c1cc(OCc2ccccc2)cc2c1OCC(=O)N2
Reactant: CC(Cl)Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C1COc2c(cc(OCc3ccccc3)cc2C(=O)CCl)N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
13.8 g (46.0 mmol) 8-acetyl-6-benzyloxy-4H-benzo[1,4]oxazin-3-one and 35.3 g (101.5 mmol) benzyltrimethylammonium-dichloriodate are stirred in 250 mL dichloroethane, 84 mL glacial acetic acid and 14 mL water for 5 hours at 65° C. After cooling to ambient temperature the mixture is combined with 5% sodium hydrogen sulfite solution and stirred for 30 minutes. The precipitated solid is suction filtered, washed with water and diethyl ether and dried. Yield: 13.2 g (86%); mass spectroscopy [M+H]+=330/32.
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[C:8]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:9]=3[S:10][C:11]=2[C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:33]([C:35]1[N:36]=[CH:37][N:38]([CH3:40])[CH:39]=1)=[CH2:34]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]2[S:10][C:9]3[CH:19]=[C:20]([OH:23])[CH:21]=[CH:22][C:8]=3[C:7]=2[O:6][C:5]2[CH:24]=[CH:25][C:2](/[CH:34]=[CH:33]/[C:35]3[N:36]=[CH:37][N:38]([CH3:40])[CH:39]=3)=[CH:3][CH:4]=2)=[CH:13][CH:14]=1
Reactant: Oc1ccc(-c2sc3cc(O)ccc3c2Oc2ccc(Br)cc2)cc1
Reactant: C=Cc1cn(C)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1cnc(/C=C/c2ccc(Oc3c(-c4ccc(O)cc4)sc4cc(O)ccc34)cc2)c1
Temperature: 150 °C
Yield: 57.9 %

Procedure:
To a microwave vial, 3-(4-bromophenoxy)-2-(4-hydroxyphenyl)benzo[b]thiophen-6-ol (50 mg, 0.121 mmol) was dissolved in DMF (2 ml) and triethyl amine (0.506 ml, 3.63 mmol). To the solution was added the 4-vinyl-1-methyl imidazole (39.2 mg, 0.363 mmol) and Pd(PPh3)2Cl2 (8.49 mg, 0.012 mmol). The system was flushed with nitrogen and heated at 150° C. for 1 h under microwave radiation. The mixture was cooled to room temperature and diluted with DCM and sat. NH4Cl. The organic layer was collected (phase separator) and purified by reverse phase HPLC (acidic condition, 0.1% TFA in 1-100% CH3CN/H2O) to afford (E)-2-(4-hydroxyphenyl)-3-(4-(2-(1-methyl-1H-imidazol-4-yl)vinyl)phenoxy)benzo[b]thiophen-6-ol (31 mg, 0.070 mmol, 58.2% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm=3.82 (s, 3H) 6.57-6.74 (m, 3H) 6.75-6.93 (m, 3H) 6.98-7.14 (m, 3H) 7.32-7.54 (m, 5H) 8.73 (s, 1H). LC/MS (m/z, MH+): 441.3.
Reaction SMILES: C(N(CC)CC)C.[SH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([NH2:18])(=[O:17])=[O:16].Br[CH2:20][CH:21]([F:23])[F:22]>CO>[F:22][CH:21]([F:23])[CH2:20][S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([NH2:18])(=[O:17])=[O:16]
Reactant: FC(F)CBr
Reactant: NS(=O)(=O)c1ccccc1S
Solvent: CO
Solvent: CCN(CC)CC
Product: NS(=O)(=O)c1ccccc1SCC(F)F
Reaction time: 16 h
Yield: 94.8 %

Procedure:
A mixture of 145.2 g of the 2-mercaptophenylsulfonamide triethylamine salt obtained in accordance with Example H6 and 79.7 g of 2-bromo-1,1-difluoroethane in 600 ml of methanol is stirred for 16 hours at a temperature of +55° C. to +60° C. The reaction mixture is then evaporated. Triturating the residue with ice water and filtering the suspension thus obtained gives 120 g (95% of theory) of 2-(2,2-difluoroethylthio)-phenylsulfonamide having a melting point of +111° C. to +112° C.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH:20]([C:21]3[N:25]([CH3:26])[N:24]=[CH:23][N:22]=3)[C:19](=O)[C:18]3[C:17]([C:28]([O:30]CC)=O)=[CH:16][C:15]([F:33])=[CH:14][C:13]=3[NH:12]2)=[CH:7][CH:6]=1)[CH3:3].O.[NH2:35][NH2:36]>CO>[CH3:3][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]2[NH:12][C:13]3[C:18]4[C:19](=[N:35][NH:36][C:28](=[O:30])[C:17]=4[CH:16]=[C:15]([F:33])[CH:14]=3)[C@@H:20]2[C:21]2[N:25]([CH3:26])[N:24]=[CH:23][N:22]=2)=[CH:7][CH:6]=1)[CH3:1].[CH3:3][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[NH:12][C:13]3[C:18]4[C:19](=[N:35][NH:36][C:28](=[O:30])[C:17]=4[CH:16]=[C:15]([F:33])[CH:14]=3)[C@H:20]2[C:21]2[N:25]([CH3:26])[N:24]=[CH:23][N:22]=2)=[CH:7][CH:6]=1)[CH3:1]
Reactant: CCOC(=O)c1cc(F)cc2c1C(=O)C(c1ncnn1C)C(c1ccc(CN(C)C)cc1)N2
Reactant: NN
Solvent: O
Solvent: CO
Product: CN(C)Cc1ccc([C@@H]2Nc3cc(F)cc4c(=O)[nH]nc(c34)[C@@H]2c2ncnn2C)cc1
Product: CN(C)Cc1ccc([C@H]2Nc3cc(F)cc4c(=O)[nH]nc(c34)[C@H]2c2ncnn2C)cc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a solution of ethyl 2-(4-((dimethylamino)methyl)phenyl)-7-fluoro-3-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (560 mg, 1.24 mmol, a mixture of cis and trans isomers) in methanol (2 mL) was added hydrazine monohydrate (0.5 mL) and the mixture was stirred under 25° C. for 10 hr. The mixture was concentrated in vacuum and the residue was purified by prep-TLC then prep-HPLC to obtain the two pairs of diastereomers as white solids (racemate of (8R,9R)-8-(4-((dimethylamino)methyl)phenyl)-5-fluoro-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one and (8S,9S)-8-(4-((dimethylamino)methyl)phenyl)-5-fluoro-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one: 20 mg, yield 4%). LC-MS (ESI) m/z: 420 (M+1)+; 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 2.16 (s, 6H), 2.88 (s, 3H), 3.34 (s, 2H), 4.73-4.74 (d, J2=4.0 Hz, 1H), 5.02-5.03 (d, J2=4.0 Hz, 1H), 6.92-6.95 (dd, J1=10.8 Hz, J2=2.4 Hz, 1H), 7.07-7.09 (dd, J1=10.8 Hz, J2=2.4 Hz, 1H), 7.04-7.06 (d, J=7.6 Hz, 2H), 7.23-7.25 (d, J=7.6 Hz, 2H), 7.56 (s, 1H), 7.69 (s, 1H), 12.45 (s, 1H). Racemate of (8S,9R)-8-(4-((dimethylamino)methyl)phenyl)-5-fluoro-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one and (8R,9S)-8-(4-((dimethylamino)methyl)phenyl)-5-fluoro-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one: 140 mg, yield 27%). LC-MS (ESI) m/z: 420 (M+1)+; 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 2.10 (s, 6H), 3.36 (s, 2H), 3.59 (s, 3H), 4.91-4.99 (m, 2H), 6.91-6.95 (dd, J1=2.4, J2=11.2 Hz, 1H), 7.05-7.08 (dd, J1=2.4, J2=9.2 Hz, 1H), 7.20-7.23 (d, J=8.0 Hz, 2H), 7.35-7.37 (d, J=8.0 Hz, 2H), 7.72 (s, 1H), 7.79 (s, 1H), 12.33 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[CH3:15][C:16]1[O:17][C:18]2[C:24]([NH2:25])=[CH:23][CH:22]=[CH:21][C:19]=2[CH:20]=1>>[CH3:15][C:16]1[O:17][C:18]2[C:24]([NH:25][C:8]3[CH:7]=[CH:6][C:5]4[C:4]([NH2:1])=[CH:13][CH:12]=[CH:11][C:10]=4[N:9]=3)=[CH:23][CH:22]=[CH:21][C:19]=2[CH:20]=1
Reactant: Cc1cc2cccc(N)c2o1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Product: Cc1cc2cccc(Nc3ccc4c(N)cccc4n3)c2o1

Procedure:
The title compound, MS: m/e=290.3 (M+H+), was prepared in accordance with the general method of example 1 from 5-nitro-2-chloroquinoline and (2-methyl-1-benzofuran-7-yl)amine.
Reaction SMILES: [CH2:1]([O:5][CH2:6][C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH3:22])=[CH:17][CH:16]=2)=[CH:9][C:8]=1[C:23]1(OC)[C@H:28]([OH:29])[C@@H:27]([OH:30])[C@H:26]([OH:31])[C@@H:25]([CH2:32][OH:33])[O:24]1)[CH2:2][C:3]#[CH:4].CC#N.[SiH](CC)(CC)CC.B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:1]([O:5][CH2:6][C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([CH2:21][CH3:22])=[CH:19][CH:20]=2)=[CH:9][C:8]=1[C@H:23]1[C@H:28]([OH:29])[C@@H:27]([OH:30])[C@H:26]([OH:31])[C@@H:25]([CH2:32][OH:33])[O:24]1)[CH2:2][C:3]#[CH:4]
Reactant: C#CCCOCc1cc(Cl)c(Cc2ccc(CC)cc2)cc1C1(OC)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Solvent: CC#N
Product: C#CCCOCc1cc(Cl)c(Cc2ccc(CC)cc2)cc1[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reaction time: 4 h
Yield: 31 %

Procedure:
To a cooled solution (−30° C.) of (3R,4S,5S,6R)-2-(2-((but-3-ynyloxy)methyl)-4-chloro-5-(4-ethylbenzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (BW) (12 mg, 0.0238 mmol) in 0.5 mL of 1:1 CH2Cl2:CH3CN was added Et3SiH (16 μL, 0.1 mmol) followed by addition of BF3.OEt2 (10 μL, 0.0789 mmol). After stirring for about 4 h, the reaction was quenched with a saturated solution of NaHCO3. The solution was extracted with ethyl acetate and the extracts were washed with brine, followed by drying over Na2SO4. The solution was concentrated and the resulting residue was purified by preparative HPLC to afford 3.5 mg of title product. 1H-NMR (CD3OD, 400 MHz) δ 7.47 (s, 1H), 7.45 (s, 1H), 7.10 (s, 4H), 4.80 (d, J=12.4 Hz, 1H), 4.61 (d, J=12.4 Hz, 1H), 4.49 (d, J=8.8 Hz, 1H), 4.10 (d, J=15.0 Hz, 1H), 4.05 (d, J=15.0 Hz, 1H), 3.88 (dd, J=12.0, 2.0 Hz, 1H), 3.70-3.64 (m, 3H), 3.50 (t, J=8.4 Hz, 1H), 3.46-3.40 (m, 3H), 2.60 (q, J=7.4 Hz, 2H), 2.53-2.49 (m, 2H), 2.30 (t, J=2.6 Hz, 1H), 1.21 (t, J=7.4 Hz, 3H); LC-MS (m/z): 475 [M+H]+, 519 [M+HCO2]−.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[CH2:17]1[O:28][C:27]2[CH:26]=[CH:25][C:21]([CH2:22][CH2:23][NH2:24])=[CH:20][C:19]=2[O:18]1>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:24][CH2:23][CH2:22][C:21]2[CH:25]=[CH:26][C:27]3[O:28][CH2:17][O:18][C:19]=3[CH:20]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Reactant: NCCc1ccc2c(c1)OCO2
Solvent: CCN(CC)CC
Product: Clc1nc(NCCc2ccc3c(c2)OCO3)c2ncn(C3CCCC3)c2n1

Procedure:
2-Chloro-6-[2-(3,4-methylenedioxyphenyl)ethylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 3,4-methylenedioxyphenethylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=4[Cl:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:30][NH2:31]>>[CH3:30][NH:31][CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[Cl:29])[C:15]=2[O:14]1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4ccc(Cl)cc4Cl)c3O2)cc1
Product: CNCC1Cc2cccc(-c3ccc(Cl)cc3Cl)c2O1

Procedure:
The title compound was prepared (0.137 g, 47%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.125 g, 0.278 mmol) and methylamine (0.086 g, 2.78 mmol). mp 190-192° C.
Reaction SMILES: [CH:1]([C:4]1[NH:5][C:6]2[C:11]([C:12]=1[C:13]([OH:15])=O)=[CH:10][CH:9]=[C:8]([O:16][CH3:17])[CH:7]=2)([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[F:36])[CH2:31][NH2:32].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl.CCOC(C)=O>[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[F:36])[CH2:31][NH:32][C:13]([C:12]1[C:11]2[C:6](=[CH:7][C:8]([O:16][CH3:17])=[CH:9][CH:10]=2)[NH:5][C:4]=1[CH:1]([CH3:2])[CH3:3])=[O:15]
Reactant: COc1ccc2c(C(=O)O)c(C(C)C)[nH]c2c1
Reactant: NCc1ccc(F)c(F)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)C)[nH]c2c1

Procedure:
To a solution of 2-isopropyl-6-methoxy-1H-indole-3-carboxylic acid (Compound 155, 10 mg, 0.046 mmol) in CH2Cl2 (1 ml) was added i-Pr2NEt (17 μl, 0.098 mmol) and 3,4-difluorobenzylamine (11 μl, 0.092 mmol), followed by BOP. After completion, the reaction was diluted with EtOAc, washed with H2O and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→25% EtOAc-hexanes) to yield the title compound.
Reaction SMILES: N12CCN(CC1)[CH2:3][CH2:2]2.[C:9]([O-:12])(=[O:11])[CH3:10].[CH3:13][CH:14]([CH3:20])[CH2:15][C:16](=C)[C:17]#[N:18]>[Pd]>[C:17]([C:16](=[CH:15][CH:14]([CH3:13])[CH3:20])[CH2:10][C:9]([O:12][CH2:2][CH3:3])=[O:11])#[N:18]
Reactant: C1CN2CCN1CC2
Reactant: C=C(C#N)CC(C)C
Reactant: CC(=O)[O-]
Agent: [Pd]
Product: CCOC(=O)CC(C#N)=CC(C)C

Procedure:
In the synthesis of a compound 1a according to Scheme 2, amine catalyzed addition of acrylonitrile (i.e., the Baylis-Hillman reaction) to 2-methylpropanal affords the cyano allylic alcohol. Typical amines used to catalyze the condensation include agents such as 1,4-diazabicyclo[2,2,2]octane (Dabco). The cyano allylic alcohol is subsequently converted to either an alkyl carbonate (e.g., by reaction with an alkyl halo formate such as ethyl chloro formate) or the respective acetate (by reaction with acetic anhydride or acetyl chloride). The resulting 2-(2-methylpropyl)prop-2-enenitrile is then subjected to palladium-catalyzed carbonylation to produce ethyl 3-cyano-5-methylhex-3-enoate 1a (e.g., where R1 is methyl or ethyl).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[F:12][C:13]1[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:14]=1[NH2:15]>>[F:12][C:13]1[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:14]=1[NH:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: Nc1ccc(Br)cc1F
Reactant: O=C(O)Cc1ccccc1Br
Product: O=C(O)Cc1ccccc1Nc1ccc(Br)cc1F

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 2-fluoro-4-bromoaniline to yield 2-[(2-fluoro-4-bromophenyl)amino]phenylacetic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].Cl.[CH2:15]([O:17][C:18](=[O:21])[CH2:19][NH2:20])[CH3:16].C(N(CC)CC)C.O>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:20][CH2:19][C:18]([O:17][CH2:15][CH3:16])=[O:21])=[O:10])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C=Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CNC(=O)Nc1ccc(F)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.1 %

Procedure:
A solution of 4-fluoro-3-nitrophenyl isocyanate (10 g, 0.055 mol) in anhydrous tetrahydrofuran is cooled to 0° C., treated with glycine ethyl ester hydrochloride (7.7 g, 0.055 mol), treated with triethylamine (5.56 g, 0.055 mol) while maintaining the temperature below 10° C., stirred at room temperature for 1 hour and poured into water. The aqueous mixture is extracted with ether. The combined organic extracts are washed sequentially with 1N hydrochloric acid and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a solid which is air-dried to give the title product as a yellow solid (8.8 g, mp 115°-120° C.).