Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:23][CH:22]=[C:21]([C:24]([OH:26])=O)[CH:20]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.Cl.[CH3:59][O:60][CH:61]1[CH2:64][N:63]([CH2:65][C:66]2[CH:71]=[CH:70][C:69]([CH2:72][NH:73][CH3:74])=[CH:68][CH:67]=2)[CH2:62]1>C(Cl)Cl>[CH:1]1([N:4]([CH2:18][C:19]2[O:23][CH:22]=[C:21]([C:24]([N:73]([CH2:72][C:69]3[CH:68]=[CH:67][C:66]([CH2:65][N:63]4[CH2:64][CH:61]([O:60][CH3:59])[CH2:62]4)=[CH:71][CH:70]=3)[CH3:74])=[O:26])[CH:20]=2)[S:5]([C:8]2[C:9]([CH3:17])=[CH:10][C:11]([O:15][CH3:16])=[CH:12][C:13]=2[CH3:14])(=[O:7])=[O:6])[CH2:3][CH2:2]1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2cc(C(=O)O)co2)C2CC2)c(C)c1
Reactant: CNCc1ccc(CN2CC(OC)C2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(Cc2cc(C(=O)N(C)Cc3ccc(CN4CC(OC)C4)cc3)co2)C2CC2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BH using 5-({cyclopropyl[(4-methoxy-2,6-dimethylphenyl)sulfonyl]amino}methyl)furan-3-carboxylic acid (45 mg, 0.12 mmol), EDCI (32 mg, 0.168 mmol), HOBt (24 mg, 0.18 mmol), DIPEA (0.04 mL, 0.24 mmol), 1-{4-[(3-methoxyazetidin-1-yl)methyl]phenyl}-N-methylmethanamine dihydrochloride (37 mg, 0.14 mmol) and DCM (10 mL).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([O:8][C:9]([C:11]1[C:20](=O)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][C:12]=1[CH:22]1[CH2:24][CH2:23]1)=[O:10])[CH3:7].C(=O)(O)[O-].[Na+]>C(#N)C>[CH2:6]([O:8][C:9]([C:11]1[C:12]([CH:22]2[CH2:24][CH2:23]2)=[N:13][C:14]2[C:19]([C:20]=1[Cl:3])=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:10])[CH3:7]
Reactant: CCOC(=O)c1c(C2CC2)[nH]c2ccccc2c1=O
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1c(C2CC2)nc2ccccc2c1Cl
Temperature: 75 °C
Yield: 10.2 %

Procedure:
Phosphorus oxychloride (0.77 ml, 0.082 mols) was added in one portion to a suspension of 2-cyclopropyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester (1.0 g, 0.041 mols) in acetonitrile and the mixture was heated at 75° C. for 90 minutes (becomes a clear solution above 65° C.). The resulting light brown solution was poured into saturated sodium bicarbonate (100 ml); the suspension was extracted with ethyl acetate and the combined organic extracts were dried and concentrated in vacuo to leave 4-Chloro-2-cyclopropyl-quinoline-3-carboxylic acid ethyl ester (1.15 g, 106%) as an off-white solid. Rf (AcOEt)=0.73.
Reaction SMILES: [F:1][C:2]1[C:20](F)=[CH:19][C:5]2=[N:6][C:7]3[N:8]([CH3:18])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1.[NH2:22][CH:23]1[CH2:26][NH:25][CH2:24]1.O>CS(C)=O>[NH2:22][CH:23]1[CH2:26][N:25]([C:20]2[C:2]([F:1])=[CH:3][C:4]3[C:5]([CH:19]=2)=[N:6][C:7]2[N:8]([CH3:18])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=2[CH:13]=3)[CH2:24]1
Reactant: NC1CNC1
Reactant: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(F)cc3nc21
Solvent: CS(C)=O
Solvent: O
Product: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CC(N)C4)cc3nc21
Temperature: 95 °C
Reaction time: 6 h
Yield: 51.2 %

Procedure:
A suspension of 1.16 g of 7,8-difluoro-1-methyl-4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid and 1.38 g of 3-aminoazetidine in 15 cm3 of dimethyl sulphoxide is heated with stirring to a temperature in the region of 95° C. for 6 hours. After cooling to approximately 20° C., 100 cm3 of water are added to the reaction mixture. The insoluble matter is drained, washed with 3 times 20 cm3 of water, taken up with 100 cm3 of water and treated with 4 cm3 of N methanesulphonic acid. After removal of some slight insoluble matter by filtration through diatomaceous silica and addition of 4 cm3 of N aqueous sodium hydroxide, the suspension obtained is concentrated under reduced pressure (20 kPa) at a temperature in the region of 60°C. to a volume of approximately 80 cm3. The insoluble matter is drained, washed with 100 cm3 of water and 100 cm3 of ethanol and recrystallized in 150 cm3 of dimethylformamide. 0.7 g of 8-(3-amino-1-azetidinyl)-7-fluoro-1-methyl-4-oxo1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid is obtained in the form of a yellow solid, which decomposes at 358° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.C([Li])CCC.[Cl:17][C:18]1[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]2[C:19]=1[C:20](=[O:29])[C:21](=[O:28])[NH:22]2.Cl>C1COCC1.CCCCCC>[Cl:17][C:18]1[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]2[C:19]=1[C:20]([OH:29])([C:2]1[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=1)[C:21](=[O:28])[NH:22]2
Reactant: O=C1Nc2cc(Cl)cc(Cl)c2C1=O
Reactant: Brc1ccc2ccccc2c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1Nc2cc(Cl)cc(Cl)c2C1(O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26.6 %

Procedure:
To a solution of 2-bromonaphthalene (2.952 g) in anhydrous THF (25 mL) was added portion wise a solution of n-butyl lithium in n-hexane (1.55 N, 10.12 mL) at −78° C. The reaction solution was stirred for 30 minutes. To the mixture was then added portion wise a solution of 4,6-dichloroisatin (1.54 g) in anhydrous THF (25 ml) for 50 minutes. The reaction mixture was stirred for 2 hours. Then the mixture was allowed to warm to room temperature. To the mixture was added 1N HCl and extracted by ethyl acetate. The organic phase was separated, washed with 1N HCl and brine and dried over MgSO4 and concentrated . Purification was carried out by silica gel chromatography (hexane:ethyl acetate, 2:1 to 1:1 gradient) to give the title compound (0.652 g, yield: 27%).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=O)[CH2:3][CH2:2]1.Cl.[NH2:13][OH:14].CC([O-])=O.[Na+]>CCO.O>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[N:13][OH:14])[CH2:3][CH2:2]1
Reactant: O=C1CCOc2ccccc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: ON=C1CCOc2ccccc21
Temperature: 25 °C

Procedure:
To a mixture of 4-chromanone (10.00 g, 67.50 mmol) and hydroxylamine hydrochloride (7.04 g, 101 mmol) in EtOH (100 mL) was added a solution of NaOAc (16.61 g, 202.5 mmol) in H2O (30 mL). The reaction was heated to reflux for 2 h. The mixture was cooled to RT and concentrated in vacuo. The residue was diluted with H2O and acidified with 1 N HCl. The aqueous was extracted with EtOAc until tlc analysis showed no evidence of title compound in the aqueous layer. The combined organics were dried with MgSO4 and concentrated in vacuo to furnish the crude title compound which was used without further purification. MS (APCI pos) 164 (M+H).
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[C:9](=[O:14])[NH:8][C@@H:7]3[CH2:15][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][C@H:6]3[C:5]=2[CH:4]=1)[CH3:2].P([O-])([O-])([O-])=O.[K+].[K+].[K+].I[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CNCCNC>C1(C)C=CC=CC=1.[Cu]I>[CH2:1]([C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[C:9](=[O:14])[N:8]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C@@H:7]3[CH2:15][N:16]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:17][C@H:6]3[C:5]=2[CH:4]=1)[CH3:2]
Reactant: Ic1ccccc1
Reactant: CCc1cc(C)c2c(c1)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1NC2=O
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: CCc1cc(C)c2c(c1)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1N(c1ccccc1)C2=O
Temperature: 110 °C
Reaction time: 48 h
Yield: 41 %

Procedure:
To a solution of (±)-trans-tert-butyl 8-ethyl-6-methyl-5-oxo-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]isoquinoline-2(9bH)-carboxylate from Example 74, Part A (50 mg, 0.15 mmol) in 2 mL of degassed toluene was added copper (I) iodide (2.1 mg, 0.011 mmol), potassium phosphate (70 mg, 0.33 mmol), iodobenzene (0.020 mL, 0.18 mmol) and N,N′-dimethylethylenediamine (0.0025 mL, 0.022 mmol). The mixture was stirred at 110° C. for 2 days. The reaction was cooled and quenched with 1N HCl and diluted with ethyl acetate. The organics were washed sequentially with sat'd aq. NaHCO3, and brine, dried (MgSO4), and concentrated. The residue was purified by flash chromatography (elution with 6:1 hexane/EtOAc) to afford 25 mg (41%) of the title compound as an oil. LRMS (ESI): 407.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:11]2[S:12][C:13]([CH2:16]Cl)=[CH:14][CH:15]=2)[CH2:10][CH:9]=[CH:8][CH2:7]1)=[O:5])[CH3:2].[CH2:18]([O:20][C:21]([C:23]1[NH:24][C:25]([CH2:29][CH2:30][CH2:31][CH3:32])=[N:26][C:27]=1[Cl:28])=[O:22])[CH3:19]>>[CH2:18]([O:20][C:21]([C:23]1[N:24]([CH2:16][C:13]2[S:12][C:11]([C:6]3([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][CH:8]=[CH:9][CH2:10]3)=[CH:15][CH:14]=2)[C:25]([CH2:29][CH2:30][CH2:31][CH3:32])=[N:26][C:27]=1[Cl:28])=[O:22])[CH3:19]
Reactant: CCCCc1nc(Cl)c(C(=O)OCC)[nH]1
Reactant: CCOC(=O)C1(c2ccc(CCl)s2)CC=CC1
Product: CCCCc1nc(Cl)c(C(=O)OCC)n1Cc1ccc(C2(C(=O)OCC)CC=CC2)s1

Procedure:
Alkylation was carried out on 1-(5-chloromethylthiophen-2-yl)cyclopent-3-ene carboxylic acid ethyl ester (5) as described in Example 1, Step 5, using 2-butyl-5-chloro-3H-imidazole-4-carboxylic acid ethyl ester (69) to yield the title compound (71).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:28]=[CH:27][C:13]([CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[CH:12][CH:11]=1)=O)(C)(C)C.[ClH:29]>C(O)C>[ClH:29].[ClH:29].[NH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:17][CH2:16]2)=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(CN2CCC(c3ccccc3)CC2)cc1
Agent: Cl
Solvent: CCO
Product: NCc1ccc(CN2CCC(c3ccccc3)CC2)cc1
Reaction time: 2 h

Procedure:
To 5.77 g (15.16 mM) of 1-[4-[N-(tert-butoxycarbonyl)aminomethyl]benzyl]-4-phenylpiperidine was added 10 ml (120 mM) of 12N-hydrochloric acid at room temperature and the mixture was stirred at the prevailing temperature for 2 hours. To this reaction mixture was added ethanol and the mixture was concentrated under reduced pressure. To the residue were added ethanol and diethyl ether and the resulting crystals were harvested by filtration. This crystal crop was rinsed with ethanol and diethyl ether to provide the title compound as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([CH2:11]Br)=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].Br.[Cl:14][C:15]1[C:25]([Cl:26])=[CH:24][CH:23]=[C:22]([F:27])[C:16]=1[CH2:17][S:18]C(=N)N.C(=O)([O-])[O-].[K+].[K+].Cl>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[C:10]([CH2:11][S:18][CH2:17][C:16]2[C:22]([F:27])=[CH:23][CH:24]=[C:25]([Cl:26])[C:15]=2[Cl:14])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1nccnc1CBr
Reactant: N=C(N)SCc1c(F)ccc(Cl)c1Cl
Agent: Br
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: COC(=O)c1nccnc1CSCc1c(F)ccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 3-bromomethyl-pyrazine-2-carboxylic acid methyl ester (2.5 g) and 2-(2,3-dichloro-6-fluoro-benzyl)-isothiourea hydrobromide (2.75 g) in acetonitrile (20 ml) was added potassium carbonate (3.8 g). The reaction mixture was stirred at ambient temperature for 5 hours, then stored at ambient temperature for 16 hours. The reaction mixture was poured into aqueous hydrochloric acid (2M) and extracted with ethyl acetate. The phases were separated and the organic layer was washed with saturated aqueous sodium hydrogen carbonate (saturated) and brine. The organic layer was concentrated and the residue purified by chromatography on silica gel (eluent: 0-10% v/v ethyl acetate in hexane) to give Compound No. A1 of Table A (0.26 g). 1H-NMR (400 MHz, CDCl3): 8.63 (d, 1H), 8.59 (d, 1H), 7.30-7.34 (m, 1H), 6.91-6.95 (m, 1H), 4.37 (m, 2H), 4.00 (s, 3H), 3.99 (m, 2H) ppm.
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8](=[O:20])[N:9]([CH3:19])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3C(O)=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.C>C(Cl)Cl.C(OCC)(=O)C.C(O)C>[Br:1][C:2]1[C:7]2[C:8](=[O:20])[N:9]([CH3:19])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][CH:15]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1Cc2c(C(=O)O)ncn2-c2cccc(Br)c2C1=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN1Cc2cncn2-c2cccc(Br)c2C1=O

Procedure:
19.1 g (56.8 mmol) of 7-bromo-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid are decarboxylated at 290°-300°. The melt was taken up in methylene chloride, the solution was diluted with ethyl acetate and ethanol and decolorized with animal charcoal. After evaporation and recrystallization from ethyl acetate and ethanol there was obtained 7-bromo-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 196°-197°.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br-].Br[C:20]1[CH:21]=[C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2/[CH:32]=[CH:33]/[C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:23]=[CH:24][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:24]2[CH:23]=[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3/[CH:32]=[CH:33]/[C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:21]=[CH:20][CH:25]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)/C=C/c1ccccc1-c1cccc(Br)c1
Reactant: OB(O)c1ccccc1OCc1ccccc1
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: [Br-]
Solvent: COCCOC
Product: CCOC(=O)/C=C/c1ccccc1-c1cccc(-c2ccccc2OCc2ccccc2)c1
Temperature: 80 °C
Yield: 94.6 %

Procedure:
As described in Example 1 (step 1), a mixture of 2-(phenylmethoxy) benzeneboronic acid (545 mg, 2.39 mmol), ethyl (E)-3-[2-(3-bromophenyl)phenyl]prop-2-enoate bromide (390 mg, 1.18 mmol) of Example 1 (step 2), 2M Na2CO3 (3.5 mL) and (Ph3P)4Pd (66 mg, 0.06 mmol) in DME (7 mL) was heated to 80° C. for 2 h. Purification by flash chromatography (Tol) provided the desired material as a yellow solid (485 mg, 95%). 1H NMR (acetone-d6) δ 2.04 (3H, t), 4.12 (2H, q), 5.16 (2H, s), 6.51 (1H, d), 7.07 (1H, td), 7.20 (1H, dd), 7.2-7.4 (8H, m), 7.4-7.5 (4H, m), 7.6-7.7 (2H, m), 7.79 (1H, d) and 7.89 (1H, dd).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.C(N(C(C)C)C(C)C)C.[Cl:28][CH2:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][N:38]=1)[C:33](Cl)=[O:34]>O1CCCC1>[Cl:28][CH2:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][N:38]=1)[C:33]([NH:12][C:10]1[S:11][C:7]2[C:6]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=2[N:9]=1)=[O:34]
Reactant: COc1ccc(N2CCOCC2)c2sc(N)nc12
Reactant: O=C(Cl)c1ccnc(CCl)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(CCl)c3)nc12
Temperature: 0 °C
Yield: 79.6 %

Procedure:
To a solution of 4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine (2.3 g, 8.7 mmol) in tetrahydrofurane (80 ml) is added N-ethyldiisopropylamine (6.0 ml, 35 mmol) and the solution cooled to 0° C. 2-chloromethyl-isonicotinoyl chloride (2.4 g, 10.5 mmol), dissolved in tetrahydrofurane (50 ml), is added over 15 minutes and the mixture heated to 70° C. for 1 h. After evaporation of the volatile components, the residue was disolved in ethyl acetate and water, filtered and the residue combined with the dryed and evaporated organic phase. Recrystallization from dichloromethane/ethyl acetate afforded the title compound as light brown solid (2.9 g, 81% yield). MS: m/e=420(M+H+).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:19])[CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)=O)[CH3:4].[C:20]12[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=1)[NH:25]C(=O)O[C:21]2=[O:22]>CC(N(C)C)=O>[CH2:3]([O:5][C:6]([C:7]1[C:21](=[O:22])[C:20]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][C:8]=1[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)=[O:19])[CH3:4]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CCOC(=O)CC(=O)c1ccc([N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1c(-c2ccc([N+](=O)[O-])cc2)[nH]c2ccccc2c1=O
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 23.8 %

Procedure:
Sodium hydride (0.92 g, 0.023 mol; 60% suspension in mineral oil) was added portionwise to a stirred solution of 3-(4-nitrophenyl)-3-oxopropionic acid ethyl ester (5.46 g, 0.023 mol) in dimethylacetamide (20 mL) at room temperature. A solution of isatoic anhydride (3.4 g, 0.02 mol) in dimethylacetamide (20 mL) was added to this solution. The reddish mixture was stirred at 120° C. for 30 min and then the solvent was concentrated in vacuo. The crude solid was partitioned between water and ethyl acetate and the organic phase then separated. The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to leave a residue which was washed once with cold tert-butylmethyl ether to yield 2-(4-nitrophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (1.61 g, 28%) as a white solid, LCMS m/z 339.33 [M+H]+ @ RT 1.16 min, 100% purity.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[C:14](C(C)(C)C)[C:13]([OH:20])=[C:12](C(C)(C)C)[CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C1(C)C=CC=CC=1.[N+](C)([O-])=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:20])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)c1cc(-c2ccc([N+](=O)[O-])cc2)cc(C(C)(C)C)c1O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: C[N+](=O)[O-]
Product: O=[N+]([O-])c1ccc(-c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.2 %

Procedure:
To a solution of 5.0 g (15 mmol) of 4-(4'nitrophenyl)- 2,6-di-tert-butylphenol in 50 mL of toluene was added a solution of 9.2 g (69 mmol) of aluminum chloride in 10 mL of nitromethane. This mixture was stirred at ambient temperature for 4 hours and poured into 100 mL of 1N HCl mixed with ice. The resulting aqueous mixture was extracted with two 100-mL portions of ethyl acetate. Combination, drying (MgSO4), and concentration of the organic layers resulted in crystallization of 2.3 g (69% yield) of yellow 4-(4'-nitrophenyl)phenol, which may also be named as 4'-nitro-(1,1'-biphenyl)-4-ol: 1H NMR (DMSO-d6) 6.93 (d, 2H, J=9 Hz), 7.64 (d, 2H, J=9 Hz), 7.82 (d, 2H, J=9 Hz), 8.25 (d, 2H, J=9 Hz), 9.98 (broad s, 1H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[OH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16](O)=[O:17])=[CH:10][CH:9]=1.Cl>C1COCC1.O>[OH:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][CH2:16][OH:17])=[CH:12][CH:13]=1
Reactant: O=C(O)CCc1ccc(O)cc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: OCCCc1ccc(O)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 69.9 %

Procedure:
To a suspension of LiAlH4 (8.37 g, 220.6 mmol, 1.5 equiv) in THF (300 ml) was added dropwise a solution of 3-(4-hydroxyphenyl)propionic acid (25.0 g, 150 mmol, 1 equiv) in THF (50 ml) at rt and mixture stirred at 60° C. for 2 h. The reaction mixture was acidified with 1 N HCl, diluted with water, and extracted with EtOAc. The combined extracts were washed with water, saturated aqueous NaHCO3, brine and dried over MgSO4 and concentrated under vacuum to give a 3-(4-hydroxyphenyl)-1-propanol as a white solid (15.95 g, 69.9%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[NH:21][CH:22]=[CH:23][C:16]=23)=[C:9]2[CH2:14][CH2:13][CH2:12][N:10]2[N:11]=1.[H-].[K+].I[CH3:27].Cl>CN(C)C=O.C(OCC)C.CCCCCC>[CH3:27][N:21]1[C:17]2=[N:18][CH:19]=[CH:20][C:15]([C:8]3[C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[N:11][N:10]4[CH2:12][CH2:13][CH2:14][C:9]=34)=[C:16]2[CH:23]=[CH:22]1
Reactant: c1ccc(-c2nn3c(c2-c2ccnc4[nH]ccc24)CCC3)nc1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOCC
Product: Cn1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc21
Yield: 79.3 %

Procedure:
Dissolve 4-[2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-pyrrolo[2,3-b]pyridine (Example 1; 0.150 g, 0.50 mmol) in N,N-dimethylformamide (10 ml). Add n-hexane (2 mL) and cool to 0° C. Add potassium hydride (35% suspension in mineral oil, 0.12 g, 1.0 mmol) and stir under nitrogen at 0° C. for 5 min. Add iodomethane (0.18 g, 1.3 mmol) and stir at 0° C. for 15 min. Dilute the reaction mixture by adding 1.0M aqueous hydrochloric acid (10 mL) and with excess diethyl ether. Extract the mixture with 0.2M aqueous hydrochloric acid. Combine the acidic aqueous extracts, add 5M aqueous sodium hydroxide until basic, and extract with dichloromethane. Concentrate the organic extracts under reduced pressure and purify via chromatography (silica gel, 95% ethyl acetate/5% methanol containing 0.1M ammonia) to obtain 0.125 g (79%) of the title compound as a cream colored solid. TOF MS (ES) exact mass calculated for C19H18N5 (p+H): m/z=316.1562, Found: 316.1536.
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]2[NH:6][C:7](=[O:16])[O:8][CH:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:4]=2[CH:3]=1.[CH3:19][C:20]1[C:24](B(O)O)=[C:23]([CH3:28])[O:22][N:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC>[CH3:19][C:20]1[C:24]([C:2]2[CH:18]=[CH:17][C:5]3[NH:6][C:7](=[O:16])[O:8][CH:9]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:4]=3[CH:3]=2)=[C:23]([CH3:28])[O:22][N:21]=1
Reactant: O=C1Nc2ccc(Br)cc2C(c2ccccc2)O1
Reactant: Cc1noc(C)c1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1noc(C)c1-c1ccc2c(c1)C(c1ccccc1)OC(=O)N2

Procedure:
6-Bromo-4-phenyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one (150 mg, 0.493 mmol), 3,5-dimethyl-4-isoxazolylboronic acid (208.5 mg, 1.480 mmol), 1,1′-bis(diphenylphosphino)ferocene-palladium(II)dichloride dichloromethane complex (80.5 mg, 0.099 mmol) are added to a microwave vessel. A saturated acqueous solution of sodium carbonate (1 mL) and dimethoxyethane (2 mL) are added. The vessel is purged with argon for 10 min. The reaction mixture is heated in a microwave reactor for 90 minutes. The mixture is filtered and the filter cake is washed with dichloromethane. The volatiles are removed on in vacuo and the residue purified by reversed phase HPLC.
Reaction SMILES: [CH3:1][N:2]([CH2:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[C:15]([CH:20]=[C:21]3[S:25][C:24](=[O:26])[NH:23][C:22]3=[O:27])[CH:16]=[N:17]2)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>O1CCOCC1.[Pt]=O>[CH3:1][N:2]([CH2:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[C:15]([CH2:20][CH:21]3[S:25][C:24](=[O:26])[NH:23][C:22]3=[O:27])[CH:16]=[N:17]2)=[CH:12][CH:11]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CN(Cc1ccc2cc(C=C3SC(=O)NC3=O)cnc2c1)c1ccccc1
Agent: O=[Pt]
Solvent: C1COCCO1
Product: CN(Cc1ccc2cc(CC3SC(=O)NC3=O)cnc2c1)c1ccccc1

Procedure:
The above 5-[[7-(methylphenylamino)methyl-3-quinolyl]methylene]thiazolidine-2,4-dione (164 mg, 0.47 mmol.) was dissolved in 1,4-dioxane (5 mL), and hydrogenated at room temperature for 27 hours after addition of platinum oxide (170 mg). The reaction mixture was filtered over Celite® to remove the catalyst. The residue was washed with methanol. The methanol washings and the filtrate were combined. Then, the solvent was distilled off under reduced pressure. The residue was purified by thin layer chromatography (hexane/ethyl acetate=1/1), to give the desired compound as a yellow amorphous product (39.1 mg, yield: 22%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[CH:4]=[N:3]1.[CH3:10][O:11][CH2:12][CH2:13][NH:14][CH3:15]>>[CH3:10][O:11][CH2:12][CH2:13][N:14]([CH3:15])[C:7]([C:5]1[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=1)=[O:9]
Reactant: CNCCOC
Reactant: Cn1cc(C(=O)O)cn1
Product: COCCN(C)C(=O)c1cnn(C)c1

Procedure:
This compound was prepared in the same manner as described in example 97, step a starting from 1-methyl-1H-pyrazole-4-carboxylic acid (500 mg, 3.96 mmol) and 2-methoxy-N-methylethanamine (389 mg, 4.36 mmol). Yield: 580 mg (74%); colorless liquid; MS: m/z=198.1 [M+H]+.