Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:16])[O:4][C:5]1[C:13]2[O:12][C:11]([CH3:15])([CH3:14])[CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.[CH2:17]([O:19][C:20]([N:22]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[S:23]Cl)=[O:21])[CH3:18].N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH2:17]([O:19][C:20]([N:22]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[S:23][N:2]([CH3:1])[C:3](=[O:16])[O:4][C:5]1[C:13]2[O:12][C:11]([CH3:14])([CH3:15])[CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:21])[CH3:18]
Reactant: CCOC(=O)CN(SCl)C(=O)OCC
Reactant: CNC(=O)Oc1cccc2c1OC(C)(C)C2
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CN(SN(C)C(=O)Oc1cccc2c1OC(C)(C)C2)C(=O)OCC
Reaction time: 24 h

Procedure:
2.2 g (0.01 mole) of 2,3-dihydro-2,2-dimethylbenzofuran-7-yl N-methyl-carbamate, 2.4 g (0.01 mole) of N-ethoxycarbonyl-N-ethoxycarbonylmethylaminosulfenyl chloride obtained in Example 17, and 3.2 g (0.04 mole) of pyridine were dissolved in 30 ml of chloroform, and the resulting solution was stirred for 24 hours at 20° to 30° C. After completion of the reaction, the reaction solution was washed successively with water, diluted hydrochloric acid and water. The chloroform layer was dried and concentrated under reduced pressure to obtain an oily product which was almost entirely composed of the desired product although containing small amounts of the starting materials and impurities.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[OH-].[Na+].[CH:14]1[C:19](=[O:20])[C:18]([OH:21])=[CH:17][O:16][C:15]=1[CH2:22]Cl>>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([O:7][CH2:22][C:15]1[O:16][CH:17]=[C:18]([OH:21])[C:19](=[O:20])[CH:14]=1)=[O:6]
Reactant: O=C(O)c1ccc(O)c(O)c1
Reactant: O=c1cc(CCl)occ1O
Agent: [Na+]
Agent: [OH-]
Product: O=C(OCc1cc(=O)c(O)co1)c1ccc(O)c(O)c1
Yield: 43.3 %

Procedure:
By following the procedure of Example 1 by employing 4.22 g(27.4 mmole) of 3,4-dihydroxybenzoic acid, 1.1 g (27.5 mmole) of sodium hydroxide and 4 g(24.9 mmole) of chlorokojic acid, there was obtained 3.0 g(43.3%) of 2-(3,4-dihydroxybenzoyl)oxymethyl-5-hydroxy-4H-pyran-4-one as as a solid.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][C:6]1[CH:20]=[CH:19][C:9]([O:10][CH:11]([C:13]2[S:17][C:16]([NH2:18])=[N:15][N:14]=2)[CH3:12])=[CH:8][CH:7]=1>C(OC(=O)C)C>[CH3:5][C:6]1[CH:7]=[CH:8][C:9]([O:10][CH:11]([C:13]2[S:17][C:16]([N:18]=[C:1]=[O:2])=[N:15][N:14]=2)[CH3:12])=[CH:19][CH:20]=1
Reactant: Cc1ccc(OC(C)c2nnc(N)s2)cc1
Reactant: O=C(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1ccc(OC(C)c2nnc(N=C=O)s2)cc1
Reaction time: 8 h

Procedure:
A 500 milliliter, 3-neck flask equipped with a magnetic stirrer, thermometer, dry ice condenser/drying tube and inlet from a phosgene (COCl2) tank via a calibrated rotometer was charged with 50 milliliters of ethylacetate which was saturated with phosgene at 20° C. (approximately 0.5 mole of phosgene) and cooled in an ice bath. An additional 50 milliliters of ethylacetate was added and then 4.8 grams of 5-[1-(4-methylphenoxy)ethyl]-2-amino-1,3,4-thiadiazole (prepared above) was added, the solution was stirred overnight and then filtered to remove a small amount of insoluble sediment. The clear solution was topped on a roto-vac at 70° C. to form 4.0 grams of a viscous orange oil of 5-[1-(4-methylphenoxy)ethyl]-1,3,4-thiadiazol-2-yl isocyanate dimer.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>CCOCC>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][CH2:13][CH2:12][O:10][C:7]1[CH:8]=[CH:9][C:2]([Br:1])=[C:3]([CH:4]=[O:5])[CH:6]=1)[CH3:19]
Reactant: O=Cc1cc(O)ccc1Br
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: CCOC(=O)CCCOc1ccc(Br)c(C=O)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 80.2 %

Procedure:
A mixture of 3.5 g (17.4 mmol) of 2-bromo-5-hydroxybenzaldehyde, 3.7 g (19 mmol) of ethyl 4-bromobutyrate, 5.5 g (40 mmol) of anhydrous, granular potassium carbonate, and 40 mL of dry dimethyl sulfoxide was stirred at room temperature for 5 hr and then kept at room temperature overnight. The resulting slurry was poured into ice-water and worked-up with ether in the usual manner giving an oily product which was flash-chromatographed on silica gel. Elution with 2:1 hexane-ether afforded 4.4 g (80.3%) of 4-(4-bromo-3-formylphenoxy)butanoic acid ethyl ester as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([NH2:11])[CH:7]=[C:8]([Cl:10])[CH:9]=1)=[O:4].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1>CO>[CH3:1][O:2][C:3]([C:5]1[N:6]([N:11]=[CH:17][C:16]2[CH:19]=[CH:20][C:13]([F:12])=[CH:14][CH:15]=2)[CH:7]=[C:8]([Cl:10])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(Cl)cn1N
Reactant: O=Cc1ccc(F)cc1
Solvent: CO
Product: COC(=O)c1cc(Cl)cn1N=Cc1ccc(F)cc1

Procedure:
Prepared according to the imine formation condition used in Example 18 step b) from 1-amino-4-chloro-1H-pyrrole-2-carboxylic acid methyl ester and 4-fluoro benzaldehyde in refluxing methanol for 12 h. ESI (m/z): 281 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[Br:13]Br>ClC(Cl)Cl>[Br:13][CH:7]1[C:2](=[O:1])[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6]1
Reactant: CCOC(=O)N1CCC(=O)CC1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCC(=O)C(Br)C1

Procedure:
To a stirred mixture of 17.1 parts of ethyl 4-oxo-1-piperidinecarboxylate and 225 parts of trichloromethane was added dropwise a solution of 16 parts of bromine in 75 parts of trichloromethane at -5°-0° C. The trichloromethane-phase was washed with ice-water, dried, filtered and evaporated, yielding 25 parts of ethyl 3-bromo-4-oxo-1-piperidinecarboxylate as an oily residue (intermediate 62).
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=1.C([Mg]Cl)(C)C.[Li+].[Cl-].CON(C)[C:18]([C:20]1[CH:21]=[CH:22][C:23]2[O:27][C:26]([CH3:28])=[N:25][C:24]=2[CH:29]=1)=[O:19]>C1COCC1>[CH3:7][N:6]1[C:2]([C:18]([C:20]2[CH:21]=[CH:22][C:23]3[O:27][C:26]([CH3:28])=[N:25][C:24]=3[CH:29]=2)=[O:19])=[CH:3][N:4]=[CH:5]1
Reactant: CON(C)C(=O)c1ccc2oc(C)nc2c1
Reactant: Cn1cncc1Br
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc2cc(C(=O)c3cncn3C)ccc2o1
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
To a flask containing 5-bromo-1-methyl-1H-imidazole (700 mg, 4.35 mmol) was added THF (14 mL) and the solution was cooled to 0° C. To this clear homogeneous solution was added isopropylmagnesium chloride-LiCl complex (1.3 M in THF, 3.4 mL, 4.38 mmol) which resulted in a white suspension. The reaction was stirred at 0° C. for 25 min, then a THF solution (5 mL) of (N-methoxy-N,2-dimethylbenzo[d]oxazole-5-carboxamide (700 mg, 3.20 mmol, Intermediate 43, step a) was introduced and the mixture was allowed to warm to room temperature. The reaction was heated to 40° C. for 20 hours and then quenched with a saturated NH4Cl solution. The aqueous portion was extracted with EtOAc (4×50 mL). The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated. The crude material was triturated with DCM-Et2O (1:10) to afford the title compound as an amber solid. The mother liquors were concentrated and again triturated with Et2O to provide a second crop of the material. Finally, the mother liquors were concentrated and chromatographed on silica gel (10-50% acetone-DCM increasing gradient to 5% MeOH-DCM) to provide the title compound as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[P:10]([O:17]CC)([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13]>>[CH2:12]([O:11][P:10]([O:14][CH2:15][CH3:16])[O:17][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=1)[CH3:13]
Reactant: CCOP(OCC)OCC
Reactant: BrCc1ccc(Br)cc1
Product: CCOP(OCC)OCc1ccc(Br)cc1
Temperature: 140 °C

Procedure:
A reaction vessel was loaded with 4-bromobenzyl bromide and 1 equivalent of triethyl phosphite. The content of the chamber was heated to 140° C. for 6 hours with stirring. Excess triethyl phosphite was removed from the mixture by vacuum distillation to yield phosphorous acid-4-bromobenzyl diethylester. One equivalent of cyclohexanone and 1.2 equivalent of sodium hydride in a mixed solvent of toluene-dimethylsulfoxide were reacted with the phosphorous acid-4-bromobenzyl diethyl ester whith heating moderately.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.O[C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=1>C(Cl)Cl.CN(C=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][C:24]3[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=3)=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: Cc1ccc(-c2ccc(C(=O)O)cc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc(C(=O)Oc3ccc(C=O)cc3)cc2)cc1
Reaction time: 18 h
Yield: 40.4 %

Procedure:
Prepared using General Procedure 2: To a stirred solution of 4′-methyl-[1,1′-biphenyl]-4-carboxylic acid (0.5 g, 2.35 mmol) in DCM (10 mL) was added DMF (3 drops) then oxalyl chloride (0.262 mL, 3.1 mmol) and left for 2 h. The reaction mixture was added to a solution of 4-hydroxybenzaldehyde (0.31 g, 2.6 mmol) and TEA (0.4 mL, 2.82 mmol) in DCM (10 mL) and stirred for 18 h. The reaction mixture was diluted with DCM (100 mL) and washed with NaHCO3 (100 mL). The organic layer was pre-absorbed onto silica gel and then purified by chromatography (EA/isohexanes) to afford 300 mg (40%) 4-formylphenyl 4′-methyl-[1,1′-biphenyl]-4-carboxylate INT-27 as a white solid. LCMS-ESI (m/z) calculated for C21H16O3: 316; no m/z observed, tR=4.25 min (Method 1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[C:17]3[C:12](=[CH:13][N:14]=[C:15]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[CH:16]=3)[N:11](COCC[Si](C)(C)C)[N:10]=2)=[N:6][C:7]=1F.[NH:32]1[CH2:37][CH2:36][CH:35]([OH:38])[CH2:34][CH2:33]1>>[Br:1][C:2]1[C:7]([N:32]2[CH2:37][CH2:36][CH:35]([OH:38])[CH2:34][CH2:33]2)=[N:6][C:5]([C:9]2[C:17]3[C:12](=[CH:13][N:14]=[C:15]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[CH:16]=3)[NH:11][N:10]=2)=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccc(Br)c(F)n2)c2cc(-c3cccnc3)ncc21
Reactant: OC1CCNCC1
Product: OC1CCN(c2nc(-c3n[nH]c4cnc(-c5cccnc5)cc34)ccc2Br)CC1
Yield: 26.8 %

Procedure:
Following the procedures as described in Example 241 and starting with 3-(5-bromo-6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine and piperidin-4-ol, 292 was obtained as an off-white solid (9.50 mg, 26.8%) over two steps. 1H NMR (400 MHz, DMSO) δ 9.26-9.20 (m, 2H), 8.99 (s, 1H), 8.61 (d, J=3.7 Hz, 1H), 8.41 (d, J=7.9 Hz, 1H), 8.06 (d, J=8.1 Hz, 1H), 7.70 (d, J=8.1 Hz, 1H), 7.55 (dd, J=8.0, 4.8 Hz, 1H), 4.75 (d, J=3.7 Hz, 1H), 3.91-3.71 (m, 3H), 3.18 (d, J=10.1 Hz, 2H), 1.96 (d, J=11.1 Hz, 2H), 1.65 (dd, J=18.8, 9.2 Hz, 2H); ESI MS m/z=451.2 (M+1)
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:35]([O:37][CH3:38])=[O:36])=[CH:12][C:13]=3[N:14]3[CH:20]=[C:19]([C:21]([O:23]CC4C=CC=CC=4)=[O:22])[CH2:18][C:17]4[CH:31]=[CH:32][CH:33]=[CH:34][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd].C1COCC1.CO>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:35]([O:37][CH3:38])=[O:36])=[CH:12][C:13]=3[N:14]3[CH2:20][CH:19]([C:21]([OH:23])=[O:22])[CH2:18][C:17]4[CH:31]=[CH:32][CH:33]=[CH:34][C:16]=4[C:15]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C=C(C(=O)OCc1ccccc1)Cc1ccccc1-3
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)O)Cc1ccccc1-3
Temperature: 22 °C
Reaction time: 18 h
Yield: 92.1 %

Procedure:
Method A: The intermediate ester (14, R=H, 53 mg, 0.13 mmol) in a 1:1 mixture of THF/MeOH (2 mL) was treated with a catalytic amount of Pd (10% on C) under hydrogen (balloon pressure). The mixture was stirred at 22° C. for 18 hr. The catalyst was removed by filtration through a fine pad of celite and the solution was concentrated in vacuo to afford the title compound as a pale tan solid (50 mg, 92%). ESI-MS m/z 418 (MH+).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:16](O)[CH:17]2[CH2:22][CH2:21][O:20][N:19]([CH:23]([CH3:25])[CH3:24])[C:18]2=[O:26])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([CH:8]=[C:9]([C:12]([CH3:14])([CH3:13])[CH3:15])[C:10]=1[OH:11])[CH:16]=[C:17]1[CH2:22][CH2:21][O:20][N:19]([CH:23]([CH3:24])[CH3:25])[C:18]1=[O:26])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)N1OCCC(C(O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC(C)N1OCCC(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O

Procedure:
The dihydro-4-[(3,5-di-tert-butyl-4-hydroxyphenyl)hydroxymethyl]-2-isopropyl-2H-1,2-oxazin-3(4H)-one of Step B was refluxed in 40 ml of benzene with a catalytic amount of p-toluenesulfonic acid monohydrate for 6 hours and concentrated in vacuo. The concentrate was triturated in ether and filtered to yield 0.9 g (2.5 mmol) of dihydro-4-(3,5-di tert-butyl-4-hydroxybenzylidene)-2-isopropyl-2H-1,2-oxazin-3(4H)-one, mp 181°-183° C.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:7][CH:8]=2)[CH:3]=1.[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.BrBr>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:7][CH:8]=2)[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2ccc(-c3ccccc3)cc2c1
Agent: BrBr
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc2ccc(-c3ccccc3)cc2c1

Procedure:
2-Methyl-7-phenylnaphthalene (5.4 g, 25 mmole) and N-bromosuccinimide (4.4 g, 25 mmole) were suspended in CCl4 (60 ml). Benzoylperoxide (0.25 g) and Br2 (20 mkl) were added, the mixture was refluxed for 3 h, filtered, evaporated and dried giving practically pure product. The yield 7.4 g (˜100%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]#[N:19])=[CH:13][CH:12]=1.[O:20]1[C:25]2[CH:26]=[CH:27][C:28]([CH:30]=O)=[CH:29][C:24]=2[O:23][CH2:22][CH2:21]1>>[O:20]1[C:25]2[CH:26]=[CH:27][C:28](/[CH:30]=[C:17](/[C:14]3[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1])=[CH:16][CH:15]=3)\[C:18]#[N:19])=[CH:29][C:24]=2[O:23][CH2:22][CH2:21]1
Reactant: O=Cc1ccc2c(c1)OCCO2
Reactant: N#CCc1ccc(OCCCCCCCCO)cc1
Product: N#C/C(=C\c1ccc2c(c1)OCCO2)c1ccc(OCCCCCCCCO)cc1
Yield: 41 %

Procedure:
(2Z)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-{4-[(8-hydroxyoctyl)oxy]phenyl}prop-2-enenitrile is prepared starting from {4-[(8-hydroxyoctyl)oxy]phenyl}acetonitrile and commercial 1,4-Benzodioxan-6-carboxaldehyde according the same procedure following for example 1 in 41% yield.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]3[CH:16]=[CH:17][C:18]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([N:28]5[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]5)=[O:27])=[CH:22][CH:21]=4)=[CH:19][C:14]3=[N:13][CH:12]=2)=[CH:7][CH:6]=1.[F:35][C:36]([F:47])([F:46])[C:37]1[CH:38]=[C:39]([N:43]=[C:44]=[O:45])[CH:40]=[CH:41][CH:42]=1.C(N(CC)CC)C>CS(C)=O>[CH3:34][N:31]1[CH2:32][CH2:33][N:28]([C:26]([C:23]2[CH:22]=[CH:21][C:20]([C:18]3[CH:17]=[CH:16][N:15]4[C:11]([C:8]5[CH:7]=[CH:6][C:5]([CH2:4][NH:3][C:44]([NH:43][C:39]6[CH:40]=[CH:41][CH:42]=[C:37]([C:36]([F:35])([F:46])[F:47])[CH:38]=6)=[O:45])=[CH:10][CH:9]=5)=[CH:12][N:13]=[C:14]4[CH:19]=3)=[CH:25][CH:24]=2)=[O:27])[CH2:29][CH2:30]1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: CN1CCN(C(=O)c2ccc(-c3ccn4c(-c5ccc(CN)cc5)cnc4c3)cc2)CC1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CN1CCN(C(=O)c2ccc(-c3ccn4c(-c5ccc(CNC(=O)Nc6cccc(C(F)(F)F)c6)cc5)cnc4c3)cc2)CC1
Yield: 52.5 %

Procedure:
Combine {4-[3-(4-aminomethyl-phenyl)-imidazo[1,2-a]pyridin-7-yl]-phenyl}-(4-methyl-piperazin-1-yl)-methanone, bis hydrochloride (0.30 g, 0.56 mmol), 3-trifluoromethylphenyl isocyanate (0.1 mL, 0.73 mmol) and triethylamine (0.4 mL, 2.9 mmol) in DMSO (10 mL). Filter the solution through 10 g SCX column eluting with methanol→2 N ammonia in methanol. Concentrate fractions containing product to give a residue. Purify by chromatography (5% methanol in dichloromethane→10% methanol in dichloromethane→10% 2 N ammonia methanol in dichloromethane) to afford product (0.18 g, 52%). MS(ES), m/z 613 (M+1).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:17][CH2:16][CH2:15]2)[C:11]([C:18]([F:21])([F:20])[F:19])=[CH:10][C:9]=1[NH:22][C:23](=[O:39])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[O:37][N:36]=[C:35]([CH3:38])[CH:34]=2)[CH:28]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:14]1([C:12]2[C:11]([C:18]([F:21])([F:19])[F:20])=[CH:10][C:9]3[NH:22][C:23](=[O:39])[CH2:24][C:25]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]5[O:37][N:36]=[C:35]([CH3:38])[CH:34]=5)[CH:28]=4)=[N:7][C:8]=3[CH:13]=2)[CH2:17][CH2:16][CH2:15]1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N4CCC4)cc3NC(=O)OC(C)(C)C)c2)on1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C3=Nc4cc(N5CCC5)c(C(F)(F)F)cc4NC(=O)C3)c2)on1

Procedure:
The title compound was prepared from (5-azetidin-1-yl-2-{3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example M53) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (94 mg).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.B(O)(O)[C:19]1[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=1>>[F:17][C:4]1[CH:3]=[C:2]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Product: Cc1ccc(-c2cc(F)cc3c(C)c4n(c23)CCNC4=O)cc1

Procedure:
The title compound, off-white solid (66 mg, 86%), MS (ISP) m/z=309.5 [(M+H)+], mp 226° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available p-tolylboronic acid (44.2 mg, 0.325 mmol).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][C:12]2[C:16]3[C:17](=[O:31])[N:18]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:19]4[N:20]=[CH:21][CH:22]=[CH:23][C:24]=4[C:15]=3[NH:14][N:13]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>CN(C=O)C.CO.[C].[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][C:12]2[C:16]3[C:17](=[O:31])[N:18]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:19]4[N:20]=[CH:21][CH:22]=[CH:23][C:24]=4[C:15]=3[NH:14][N:13]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=c1c2c(CCc3cccc([N+](=O)[O-])c3)n[nH]c2c2cccnc2n1-c1ccccc1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CO
Product: Nc1cccc(CCc2n[nH]c3c2c(=O)n(-c2ccccc2)c2ncccc32)c1
Reaction time: 8 h
Yield: 95.3 %

Procedure:
To a solution of 3-[2-(3-nitrophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (216 mg, 0.52 mmol, prepared in Example 15) in DMF (5 ml) and methanol (5 ml) was added activated carbon-palladium (22 mg), and the mixture was stirred overnight under hydrogen atmosphere, and filtered. After methanol was distilled off, the resultant solution was admixed with water, and filtered to give precipitates which were dried to afford 3-[2-(3-aminophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4 (5H)-one (189 mg, 94%).
Reaction SMILES: O.[NH2:2][NH2:3].[CH:4](=[C:11]([CH2:14][CH3:15])[CH:12]=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O>CCOCC>[CH2:14]([CH:11]1[CH:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[NH:3][N:2]=[CH:12]1)[CH3:15]
Reactant: NN
Reactant: CCC(C=O)=Cc1ccccc1
Solvent: CCOCC
Solvent: O
Product: CCC1C=NNC1c1ccccc1
Temperature: -10 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
62 ml (10 equiv.) hydrazine hydrate was added to 150 mL diethylether. The emulsion was cooled with an ice/NaCl bath to −10° C. A solution of 20.4 g 2-benzylidene-butyraldehyde in 100 mL ether was added dropwise at −10° C. and stirred at −10° C. for 3 hours. The mixture was stirred overnight (with ice bath) and allowed to slowly reach room temperature. H2O was added, the organic layer was separated and the aqueous layer was extracted 2 times with diethylether. The combined organic layers were dried over Na2SO4, filtrated and concentrated in vacuo. Vacuum destillation yielded 6.1 g of a clear fluid (102-106° C., 0.6 mbar) containing 94% of the desired product (mixture of diastereomeric pairs). Characteristic signals of the first diastereomeric pair: 1H NMR (400 MHz, CDCl3) δ 0.83 (t, J=6.5 Hz, 3H), 3.03-3.13 (m, 1H), 4.74-4.81 (m, 1H), 6.83 (br s, 1H). Characteristic signals of the second diastereomeric pair: 1H NMR (400 MHz, CDCl3) δ 1.00 (t, J=7.5 Hz, 3H), 2.84-2.93 (m, 1H), 4.28-4.34 (m, 1H), 6.76 (br s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2.[CH:13]([C:15]1[CH:23]=[C:22]2[C:18]([C:19](/[CH:24]=[CH:25]/[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N:20][NH:21]2)=[CH:17][CH:16]=1)=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])/[C:6]/2=[CH:13]/[C:15]1[CH:23]=[C:22]2[C:18]([C:19](/[CH:24]=[CH:25]/[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N:20][NH:21]2)=[CH:17][CH:16]=1
Reactant: COc1ccc2c(c1)CC(=O)N2
Reactant: CCOC(=O)/C=C/c1n[nH]c2cc(C=O)ccc12
Product: CCOC(=O)/C=C/c1n[nH]c2cc(/C=C3/C(=O)Nc4ccc(OC)cc43)ccc12
Yield: 77 %

Procedure:
The title compound (60 mg, 77%) was synthesized as an orange red solid according to the method described for Example A67 (oil temp 75° C., reflux 2 h) using 5-methoxyoxindole (26.8 mg, 0.2 mmol) and (E)-ethyl 3-(6-formyl-1H-indazol-3-yl)acrylate (48.8 mg, 0.2 mmol). 1H NMR (400 MHz, DMSO-d6) δ 13.80 (brs, 1H, NH), 10.44 (s, 1H, NH), 8.26 (d, J=8.4 Hz, 1H), 7.96 (s, 1H), 7.92 (d, J=16.4 Hz, 1H), 7.77 (s, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.14 (d, 1H), 6.90-6.80 (m, 3H), 4.23 (q, J=7.2 Hz, 2H), 3.58 (s, 3H), 2.29 (t, J=7.2 Hz, 3H); MS ESI 390.3 [M+H]+, calcd for [C22H19N3O4+H]+ 390.1.
Reaction SMILES: C(OC([N:8]1[C:31](=[O:32])[C:11]2[CH:12]=[N:13][C:14]3[C:15]([NH:20][C:21](=[O:30])[C:22]4[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:29])=[CH:16][CH:17]=[CH:18][C:19]=3[C:10]=2[N:9]1[CH3:33])=O)(C)(C)C.Cl>CO.C(OCC)(=O)C>[ClH:28].[Cl:28][C:27]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:29])[C:22]=1[C:21]([NH:20][C:15]1[C:14]2[N:13]=[CH:12][C:11]3[C:31](=[O:32])[NH:8][N:9]([CH3:33])[C:10]=3[C:19]=2[CH:18]=[CH:17][CH:16]=1)=[O:30]
Reactant: Cn1c2c(cnc3c(NC(=O)c4c(Cl)cccc4Cl)cccc32)c(=O)n1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: Cn1[nH]c(=O)c2cnc3c(NC(=O)c4c(Cl)cccc4Cl)cccc3c21
Reaction time: 1 h
Yield: 137.3 %

Procedure:
To a solution of 2-tert-butoxycarbonyl-6-(2,6-dichlorobenzoylamino)-2,3-dihydro-1-methyl-1H-pyrazolo[4,3-c]quinolin-3-one (30 mg) in methanol (1 ml) was added 4M solution of hydrogen chloride in ethyl acetate (1 ml) at ambient temperature, and the mixture was stirred for 1 hour at the same temperature. The mixture was concentrated in vacuo, and the residue was crystallized from ethanol-ethyl acetate to give 6-(2,6-dichlorobenzoylamino)-2,3-dihydro-1-methyl-1H-pyrazolo[4,3-c]quinolin-3-one hydrochloride (17.9 mg).
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[CH2:21][NH:22][CH2:23][CH3:24])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)C.[CH2:26]([N:33]=[C:34]=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([NH:33][C:34](=[O:35])[N:22]([CH2:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[C:8]1[C:9]([O:12][CH3:13])=[CH:10][CH:11]=[C:6]([CH2:5][C:4]([OH:3])=[O:25])[CH:7]=1)[CH2:23][CH3:24])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C=NCc1ccccc1
Reactant: CCNCc1cc(F)ccc1-c1cc(CC(=O)OCC)ccc1OC
Product: CCN(Cc1cc(F)ccc1-c1cc(CC(=O)O)ccc1OC)C(=O)NCc1ccccc1

Procedure:
[2′-(3-Benzyl-1-ethyl-ureidomethyl)-4′-fluoro-6-methoxy-biphenyl-3-yl]-acetic acid (Compound 1-187) was prepared by following the procedures of Example 24 and using (2′-ethylaminomethyl-4′-fluoro-6-methoxy-biphenyl-3-yl)-acetic acid ethyl ester and benzyl isocyanate.