Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[Br-].O=[C:14]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:15][CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][C:17]1=[N+]1CCCC1>C(O)(=O)C>[C:7]([C:6]1[CH:10]=[C:2]([N:1]2[C:17]3[CH2:18][CH2:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=4[C:16]=3[CH:15]=[C:14]2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:3]=[CH:4][C:5]=1[OH:11])([OH:9])=[O:8]
Reactant: Nc1ccc(O)c(C(=O)O)c1
Reactant: O=C(CC1C(=[N+]2CCCC2)CCc2ccccc21)c1ccccc1
Agent: [Br-]
Solvent: CC(=O)O
Product: O=C(O)c1cc(-n2c(-c3ccccc3)cc3c2CCc2ccccc2-3)ccc1O
Temperature: 60 °C

Procedure:
304 g of 5-aminosalicylic acid are added to 3800 ml of acetic acid while stirring. The stirred suspension is heated to 60° C. and 791 g of tautomeric 1-[3,4-dihydro-1-(2-oxo-2-phenylethyl)-2(1H)-naphthalenylidene]pyrrolidinium bromide in equilibrium with 1-phenacyl-2-(1-pyrrolidino)-3,4-dihydronaphthalene hydrobromide are added. An additional 150 ml of acetic acid are added to the reaction mixture, which is stirred at 70° C. for 3 to 4 hours and then cooled to ambient temperature. A solid appears and is collected by filtration, washed successively with acetic acid and petroleum ether and dried for 16 hours under vacuum to give 3-(3-carboxy-4-hydroxyphenyl)-4,5-dihydro-2-phenylbenz[e]indole.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:10]2[CH2:11][N:12](C(OC(C)(C)C)=O)[CH2:13][C:9]=2[C:8]([NH:21][C:22](=[O:35])[CH:23]([C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)[CH3:24])=[N:7]1)=[O:5])[CH3:2].C(O)(C(F)(F)F)=O.C(Cl)Cl>C(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]1[C:10]2[CH2:11][NH:12][CH2:13][C:9]=2[C:8]([NH:21][C:22](=[O:35])[CH:23]([C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)[CH3:24])=[N:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)n1nc(NC(=O)C(C)c2ccc3ccccc3c2)c2c1CN(C(=O)OC(C)(C)C)C2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)n1nc(NC(=O)C(C)c2ccc3ccccc3c2)c2c1CNC2
Reaction time: 0.5 h
Yield: 101.6 %

Procedure:
2.5 g (5.2 mmol) of 3-(2-naphthalen-2-yl-propionylamino)-4,6-dihydro-pyrrolo[3,4-c]pyrazole-1,5-dicarboxylic acid 5-tert-butyl ester 1-ethyl ester in 15 ml DCM was treated with 16 ml of (1:1) TFA/DCM. The reaction mixture was stirred for 30 min. and evaporated to dryness. The resulting residue was dissolved in DCM and the solution was washed with brine and then treated with NaHCO3 aq. The obtained precipitate was filtered, washed with water and DCM, and then dried under vacuum to give 2.0 g (quantitative yield) of the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)[N:3]=1.[CH:19]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)=[O:20]>[Pd]>[F:16][C:15]([F:18])([F:17])[O:14][C:11]1[CH:12]=[CH:13][C:8]([C:4]2[N:3]=[C:2]([C:24]3[CH:25]=[CH:26][C:21]([CH:19]=[O:20])=[CH:22][CH:23]=3)[CH:7]=[N:6][CH:5]=2)=[CH:9][CH:10]=1
Reactant: FC(F)(F)Oc1ccc(-c2cncc(Cl)n2)cc1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: [Pd]
Product: O=Cc1ccc(-c2cncc(-c3ccc(OC(F)(F)F)cc3)n2)cc1

Procedure:
The compound was prepared by palladium-catalyzed arylation of the product of step 1 with 4-formylphenyl boronic acid: 1H NMR (400 MHz, CDCl3) δ 10.13 (s, 1H), 9.07 (s, 1H), 9.03 (s, 1H), 8.33 (d, J=8.1 Hz, 2H), 8.21 (d, J=8.7 Hz, 2H), 8.07 (d, J=7.6 Hz, 2H), 7.40 (d, J=8.3 Hz, 2H); EIMS m/z 344 (M+).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:9]([O:17]CC)(=O)[CH2:10][C:11]([O:13]CC)=O>>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:11](=[O:13])[CH2:10][C:9]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[F:1])=[O:17]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Nc1ccccc1F
Product: O=C(CC(=O)Nc1ccccc1F)Nc1ccccc1F
Temperature: 170 °C
Reaction time: 8 h

Procedure:
100 mmol 2-fluoroaniline and 50 mmol diethyl malonate were put together and stirred overnight at 170° C. The formed ethanol was distilled off directly (100 mmol≡6.6 mL) on a stream of nitrogen. N1,N3-di(2-fluoro-phenyl)-malonamide was formed as one solid block. The reaction was cooled and EtOAc was added. The product had to be crushed with a mortar, because it resembled very hard brick. The crushed material was stirred in EtOAc and filtered. EtOAc added was added twice and the mixture was stirred and filtered each time. 9.9 g N1,N3-di(2-fluoro-phenyl)-malonamide was obtained (yield 68.2%, purity 99.3%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[NH:12][C:11](=[O:21])[C@:10]([CH2:23][CH:24]3[CH2:28][O:27][C:26]([CH3:30])([CH3:29])[O:25]3)([CH3:22])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[C:31]1([CH3:37])[CH:36]=[CH:35][CH:34]=CC=1.C([Li])CCC.BrC1CCC=C1>CCCCC.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([CH:31]3[CH2:36][CH2:35][CH:34]=[CH:37]3)[C:11](=[O:21])[C@:10]([CH2:23][CH:24]3[CH2:28][O:27][C:26]([CH3:30])([CH3:29])[O:25]3)([CH3:22])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccccc1
Reactant: CC1(C)OCC(C[C@@]2(C)C[C@H](c3cccc(Cl)c3)[C@@H](c3ccc(Cl)cc3)NC2=O)O1
Agent: BrC1C=CCC1
Agent: [Li]CCCC
Solvent: CCCCC
Solvent: C1CCOC1
Product: CC1(C)OCC(C[C@@]2(C)C[C@H](c3cccc(Cl)c3)[C@@H](c3ccc(Cl)cc3)N(C3C=CCC3)C2=O)O1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To (3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-methylpiperidin-2-one (Example 102, Step B) (0.909 g, 2.027 mmol) was added toluene (15 mL) and the mixture was concentrated under reduced pressure. This step was repeated three times. Inhibitor free THF (20 mL) was added and the solution was cooled to −78° C. Butyllithium in pentane (2.0M) (1.014 mL, 2.027 mmol) was added dropwise and the reaction mixture remained colorless. The reaction mixture warmed to 0° C. and the reaction color turned very light yellow. nBuLi in pentane (2.0M) was added dropwise until the reaction mixture remained bright yellow. The reaction mixture was cooled to −78° C. and freshly prepared 3-bromocyclopent-1-ene (0.4 g, 2.72 mmol) in THF (2 mL) was added dropwise. The reaction mixture was wrapped in foil and warmed to 0° C. The reaction mixture was stirred at 0° C. for 1 h and then at rt for 2 days. The reaction was quenched with sat. NH4Cl and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: 0 to 100% EtOAc in hexanes) to give the title compound as a colorless film.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:22][CH3:23])=[CH:19][CH:20]=3)[N:15]=[CH:14][CH:13]=2)=[O:10])[CH:5]=[N:4][CH:3]=1.[CH2:24]1[C@@H:28]2[CH2:29][NH:30][CH2:31][C@@H:27]2[CH2:26][N:25]1[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33]>>[CH3:23][O:22][C:18]1[CH:17]=[C:16]2[C:21]([C:12]([NH:11][C:9](=[O:10])[NH:8][C:6]3[N:7]=[C:2]([N:30]4[CH2:29][C@@H:28]5[CH2:24][N:25]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:26][C@@H:27]5[CH2:31]4)[CH:3]=[N:4][CH:5]=3)=[CH:13][CH:14]=[N:15]2)=[CH:20][CH:19]=1
Reactant: COc1ccc2c(NC(=O)Nc3cncc(Br)n3)ccnc2c1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CNC[C@H]2C1
Product: COc1ccc2c(NC(=O)Nc3cncc(N4C[C@H]5CN(C(=O)OC(C)(C)C)C[C@H]5C4)n3)ccnc2c1
Yield: 65 %

Procedure:
The compound was prepared by the method described for Example 1 using 1-(6-bromopyrazin-2-yl)-3-(7-methoxyquinolin-4-yl)urea and (3aR,6aS)-tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate as starting compounds and was obtained as a white solid (96 mg, 65%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]#[N:5].F[P-](F)(F)(F)(F)F.N1([PH+](N2CCCC2)N2CCCC2)CCCC1.[CH3:29][S:30][C:31]1[CH:36]=[CH:35][C:34]([S:37][CH2:38][CH:39]2[CH2:45][CH:44]3[CH:42]([CH2:43]3)[CH2:41][CH:40]2[C:46](O)=[O:47])=[CH:33][CH:32]=1.C(N(CC)CC)C>CN(C)C=O>[C:4]([CH2:3][NH:2][C:46]([CH:40]1[CH:39]([CH2:38][S:37][C:34]2[CH:35]=[CH:36][C:31]([S:30][CH3:29])=[CH:32][CH:33]=2)[CH2:45][CH:44]2[CH:42]([CH2:43]2)[CH2:41]1)=[O:47])#[N:5]
Reactant: CSc1ccc(SCC2CC3CC3CC2C(=O)O)cc1
Reactant: N#CCN
Agent: C1CCN([PH+](N2CCCC2)N2CCCC2)C1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSc1ccc(SCC2CC3CC3CC2C(=O)NCC#N)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of aminoacetonitrile hydrochloride (153 mg, 1.65 mmol) and benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP) (800 mg, 1.54 mmol) was added 1S/R,3R/S,4R/S,6R/S)-4-({[4-(methylsulfanyl)phenyl]sulfanyl}methyl)bicyclo[4.1.0]-heptane-3-carboxylic acid and dimethylformamide (4 mL). After adding triethylamine (0.52 mL, 3.7 mmol) the reaction mixture was stirred at ambient temperature for 4 h. The reaction mixture was partitioned between water and ethyl acetate. The product was extracted into ethyl acetate and the combined organic phases were washed with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvents were removed and the residue was chromatographed on a silica gel with methanol:dichloromethane (1.5:98.5) as eluent to give crude product which was purified in 1.4 mg portions by preparative RP HPLC (Waters, RCM, C18, μBondapak, 1×24 mm) by gradient elution with acetonitrile:water (containing 25 mM ammonium acetate)/30:70 to 50:50, 6.0 mL/min flowrate, UV detector set at 300 nM to give the title compound as a colorless solid. 1H NMR (500 MHz, acetone-d6): δ=7.83 (1H, br s), 7.28 (2H, d), 7.19 (2H, d), 4.20 (2H, m), 3.12 (1H, dd), 2.62 (1H, dd), 2.46 (3H, s), 2.26 (1H, m), 2.21 (1H, m), 2.10 (1H, m), 1.67 (1H, m), 1.58 (1H, m), 1.52 (1H, m), 0.99 (1H, m), 0.90 (1H, m), 0.57 (1H, m), −0.06 (1H, m). MS [ESI, (M−H)] m/z=345.2 amu.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C:7]2[C:11]([C:12]#[N:13])=[C:10]([C:14]3[CH2:15][CH2:16][O:17][CH2:18][CH:19]=3)[S:9][C:8]=2[C:20]([O:22]CC)=[O:21])=[CH:4][CH:3]=1.O1CCCC1.[OH-].[Na+].CO>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C:7]2[C:11]([C:12]#[N:13])=[C:10]([C:14]3[CH2:15][CH2:16][O:17][CH2:18][CH:19]=3)[S:9][C:8]=2[C:20]([OH:22])=[O:21])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1sc(C2=CCOCC2)c(C#N)c1Cc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1c(C2=CCOCC2)sc(C(=O)O)c1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.6 %

Procedure:
To a round bottom flask containing ethyl 3-(4-chlorobenzyl)-4-cyano-5-(3,6-dihydro-2H-pyran-4-yl)thiophene-2-carboxylate (43.0 mg, 0.111 mmol) were added tetrahydrofuran (1.23 mL, 15.2 mmol), sodium hydroxide (1.0N in water, 0.925 mL, 0.925 mmol), and methanol (0.617 mL, 15.2 mmol). The mixture was stirred at room temperature overnight. Reaction was quenched via addition of 1N HCl in water (2 mL), then diluted with EtOAc and transferred to separatory funnel. The layers were separated, and the aqueous layer was extracted 2× with EtOAc. Combined organics were washed with brine, dried over Na2SO4, and filtered, at adsorbed to Celite (10 mL). Column chromatography (40 g ISCO column, gradient elution 0-8% MeOH/DCM afforded 3-(4-chlorobenzyl)-4-cyano-5-(3,6-dihydro-2H-pyran-4-yl)thiophene-2-carboxylic acid (95) (25 mg, 63%) as a white solid. LC/MS: (FA) ES− 358, 360; 1H NMR (400 MHz, DMSO) δ 14.04 (br s, 1H), 7.33 (d, J=8.5, 2H), 7.26 (d, J=8.5, 2H), 6.64 (s, 1H), 4.43 (s, 2H), 4.24 (d, J=2.9, 2H), 3.79 (dd, J=5.4, 5.4, 2H), 3.32 (br s, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10](Cl)=[O:11])[CH:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20].C(N(CC)CC)C>ClCCl>[OH:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[NH:13][C:10]([C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=1)=[O:11]
Reactant: O=C(Cl)c1cc(Cl)c(Cl)c(Cl)n1
Reactant: Nc1ccccc1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccccc1O)c1cc(Cl)c(Cl)c(Cl)n1
Temperature: 25 °C
Yield: 97.6 %

Procedure:
A solution of 4,5,6-trichloropyridine-2-carbonyl chloride (1.0 g, 4.1 mmol) in dichloromethane (10 mL) was added dropwise to a solution of 2-aminophenol (0.45 g, 4.1 mmol) and triethylamine (0.6 mL) in dichloromethane (30 mL) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for an additional thirty minutes. The solvents were removed and the residue partitioned between 20% tetrahydrofuran/ethyl acetate and 1M hydrochloric acid. The organic layer was separated, washed with saturated sodium bicarbonate, brine, dried (MgSO4) and concentrated to provide N-(2-hydroxyphenyl)-4,5,6-trichloropyridine-2-carboxamide (1.26 g, 4.0 mmol), mp 240° C. (dec).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][NH:6][CH2:7][CH2:8][O:9][CH3:10])[CH3:2].C(N(CC)CC)C.[N:19]#[N:20].[CH:21]1[C:29]2[C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[S:26][C:25]=2[CH:24]=[CH:23][C:22]=1[S:34]([NH:37][C@H:38]([C:46](Cl)=[O:47])[CH2:39][CH2:40][CH2:41][NH:42][C:43](=[NH:45])[NH2:44])(=[O:36])=[O:35]>C(Cl)(Cl)Cl>[N:19]#[N:20].[CH2:1]([O:3][C:4](=[O:11])[CH2:5][N:6]([C:46](=[O:47])[C@H:38]([CH2:39][CH2:40][CH2:41][NH:42][C:43](=[NH:44])[NH2:45])[NH:37][S:34]([C:22]1[CH:23]=[CH:24][C:25]2[S:26][C:27]3[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=3[C:29]=2[CH:21]=1)(=[O:35])=[O:36])[CH2:7][CH2:8][O:9][CH3:10])[CH3:2]
Reactant: N=C(N)NCCC[C@H](NS(=O)(=O)c1ccc2sc3ccccc3c2c1)C(=O)Cl
Reactant: CCOC(=O)CNCCOC
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CN(CCOC)C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc2sc3ccccc3c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2.42 g of N-(2-methoxyethyl) glycine ethyl ester and 4.0 ml of triethylamine in 50 ml of chloroform, which was cooled in an ice-salt bath, was added in portions N2 -(2-dibenzothienylsulfonyl)-L-arginyl chloride obtained above. The reaction mixture was stirred overnight at room temperature. At the end of this period, 50 ml of chloroform was added and the chloroform solution was washed twice with 25 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated in vacuo. The oily residue was washed with ethyl ether to give 5.5 g of powdery N2 -(2-dibenzothienylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine ethyl ester
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]([Cl:10])=[CH:8][CH:9]=1)(=O)[CH3:2].[CH:11]1([C:14]([NH:16][NH2:17])=[O:15])[CH2:13][CH2:12]1>C(O)C>[Cl:10][C:7]1[N:6]=[CH:5][C:4]([C:1](=[N:17][NH:16][C:14]([CH:11]2[CH2:13][CH2:12]2)=[O:15])[CH3:2])=[CH:9][CH:8]=1
Reactant: NNC(=O)C1CC1
Reactant: CC(=O)c1ccc(Cl)nc1
Solvent: CCO
Product: CC(=NNC(=O)C1CC1)c1ccc(Cl)nc1

Procedure:
Following the general method of procdure 53 and making non-critical variations, except the product was purified by recrystallization from absolute ethanol rather than by chromotography, 5.25 gm (0.0337 mole) of 3-acetyl-6-chloropyridine and 3.40 gm (0.034 mole) of cyclopropanecarboxylic acid hydrazide yield 6.52 gm (81%) of the title compound having a melting point of 218.1° C.
Reaction SMILES: Br[C:2]1[C:3]([F:13])=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[CH:7][CH:6]=[CH:5]2.[CH2:14]([Sn](CCCC)(CCCC)C=C)[CH2:15]CC>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.O1CCOCC1>[F:13][C:3]1[C:2]([CH:14]=[CH2:15])=[C:11]([F:12])[CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2
Reactant: Fc1cc2ncccc2c(F)c1Br
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: C=Cc1c(F)cc2ncccc2c1F
Temperature: 150 °C
Reaction time: 0.42 h

Procedure:
6-Bromo-5,7-difluoro-quinoline (v) (1 g, 4.10 mmol), tetrakis(triphenylphosphine)palladium(0) (47 mg, 0.041 mmol) and tributyl(vinyl)tin (1.34 g, 4.10 mmol) were put together with dioxane (3.7 mL) in a microwave reactor and stirred for 25 min at 150° C. under microwave irradiations. The solvent was removed and the residue was purified by MPLC with hexane and EtOAc. The title compound was obtained as a colorless oil (tR 1.1 min (conditions 2), MH+=192).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[C:5]([NH:7][CH2:8]/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:6].[CH2:20](N)[CH:21]=[CH:22][C:23]1C=CC=CC=1.C1C2C(=CC=CC=2)C=CC=1C(O)=O>>[CH2:8]([NH:7][C:5]([C:4]1[CH:17]=[CH:18][C:19]2[C:2](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:3]=1)=[O:6])/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(NC/C=C/c1ccccc1)c1cccc(Cl)c1
Reactant: NCC=Cc1ccccc1
Agent: O=C(O)c1ccc2ccccc2c1
Product: O=C(NC/C=C/c1ccccc1)c1ccc2ccccc2c1

Procedure:
(E)-N-Cinnamyl-2-naphthalenecarboxamide may be obtained in the following manner: working in a manner similar to that described in Example 21 for the preparation of (E)-3-chloro-N-cinnamylbenzamide, starting with cinnamylamine (5.3 g) and 2-naphthoic acid (7.6 g), and after recrystallization in ethyl acetate, (E)-N-cinnamyl-2-naphthalenecarboxamide (4.3 g) is obtained.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:11][C:12](=[O:14])[CH3:13])[CH:8]=2)[NH:3]1.[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([CH:24]=O)[CH:22]=2)[CH:17]=[N:16]1.N1CCCCC1>CO>[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21](/[CH:24]=[C:10]3/[C:2](=[O:1])[NH:3][C:4]4[C:9]/3=[CH:8][C:7]([NH:11][C:12](=[O:14])[CH3:13])=[CH:6][CH:5]=4)[CH:22]=2)[CH:17]=[N:16]1
Reactant: O=Cc1ccc2cn[nH]c2c1
Reactant: CC(=O)Nc1ccc2c(c1)CC(=O)N2
Solvent: CO
Solvent: C1CCNCC1
Product: CC(=O)Nc1ccc2c(c1)/C(=C\c1ccc3cn[nH]c3c1)C(=O)N2
Temperature: 85 °C
Yield: 34.6 %

Procedure:
To a solution of N-(2-oxoindolin-5-yl)acetamide (19 mg, 0.1 mmol) was added 1H-indazole-6-carbaldehyde (16 mg, 0.12 mmol), piperidine (2 uL, 0.011 mmol) and MeOH (2 mL). The reaction was then heated to 85° C. for 30 min. The MeOH was removed in vacuo and the solid triturated with ether to give 11 mg, 34% of the title compound as an orange solid. 1H NMR (400 MHz, CD3OD) δ 8.13 (s, 1H), 8.06 (s, 1H), 7.92-7.88 (m, 2H), 7.84 (s, 1H), 7.49 (d, J=8.6 Hz, 1H), 7.35 (d, 1H), 6.88 (d, J=8.3 Hz, 1H), 2.04 (s, 3H); MS ESI 319.1 [M+H]+, calcd for [C18H17N5O3S+H]+ 319.11.
Reaction SMILES: [OH:1][C:2]1[C:7]2[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:15]([O-])([O-])=O.[K+].[K+].IC>CC(C)=O>[CH3:15][O:1][C:2]1[C:7]2[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Oc1cccc2c1oc1ccccc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cccc2c1oc1ccccc12
Temperature: 40 °C
Yield: 98 %

Procedure:
4-hydroxy-dibenzofuran (5.19 g, 28.2 mmoles) is dissolved in acetone (175 mL) under nitrogen atmosphere. Solid K2CO3 (5.85 g, 42.3 mmoles) and iodomethane (7.9 mL, 126.9 mmoles) are added and the resulting mixture is vigorously stirred to reflux (40° C.) to complete conversion of the starting material (7h). The reaction mixture is evaporated to dryness, the crude is then dissolved in water and extracted with DCM; the combined organic layers are washed again with water and brine, dried over sodium sulphate and evaporated to dryness to give the desired product as a white solid (5.48 g) which is employed in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][C:3]=1[CH2:10][NH:11][C:12](=[O:15])[O:13][CH3:14].CO.C[Si]([N:22]=[N+:23]=[N-:24])(C)C>CN(C)C=O.[Cu]I>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:24][N:23]=[N:22][CH:9]=2)=[CH:4][C:3]=1[CH2:10][NH:11][C:12](=[O:15])[O:13][CH3:14]
Reactant: C#Cc1ccc(Cl)c(CNC(=O)OC)c1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)NCc1cc(-c2cnn[nH]2)ccc1Cl
Temperature: 100 °C

Procedure:
To a solution of methyl N-[(2-chloro-5-ethynylphenyl)methyl]carbamate (i.e. the product of Step D) (0.43 g, 1.92 mmol) in N,N-dimethylformamide (3.9 mL) and methanol (0.4 mL) was added trimethylsilyl azide (0.38 mL, 2.89 mmol) and copper(I) iodide (0.019 g, 0.1 mmol). The reaction mixture was heated in a CEM Discover microwave apparatus at 100° C. for 8 h and then allowed to cool to room temperature. The reaction mixture was partitioned between ethyl acetate and aqueous sodium chloride, the layers were separated and the aqueous layer was extracted with ethyl acetate (2×). The combined organic layers were washed with water (3×), dried over magnesium sulfate, filtered and concentrated under reduced pressure to provide the title compound, a compound of the present invention, as a brown solid (0.30 g).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([C:6]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[C:7]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[NH:8]2)=[CH:4][CH:3]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>C(OCC)(=O)C>[O:26]=[C:24]([NH:1][C:2]1[N:10]=[C:9]2[C:5]([C:6]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[C:7]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[NH:8]2)=[CH:4][CH:3]=1)[CH3:25]
Reactant: Nc1ccc2c(-c3ccncc3)c(-c3ccc(F)cc3)[nH]c2n1
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc2c(-c3ccncc3)c(-c3ccc(F)cc3)[nH]c2n1
Temperature: 23 °C

Procedure:
6-Amino-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (17) (50 mg, 0.164 mmol) and acetic anhydride (0.5 mL) were warmed to 60° C. for 1 h. After cooling to 23° C., the reaction was diluted with ethyl acetate (50 mL), washed with NaOH (1N, 50 mL), and dried (Na2SO4). Concentration in vacuo afforded 6-(1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (57): Mass Spectrum (CI) 347 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[Br:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])=[CH:14][CH:13]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: O=[N+]([O-])c1cnccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: O=[N+]([O-])c1cnccc1-c1ccc(Br)cc1
Temperature: 100 °C
Yield: 76.1 %

Procedure:
4-Chloro-3-nitro-pyridine (6.9 g, 43.5 mmol), 4-bromophenyl boronic acid (8.05 g, 40.1 mmol), potassium carbonate (11.10 g, 80.3 mmol) and tetrakis triphenylphosphine palladium (2.31 g, 2.0 mmol) are taken up in DME (200 ml) and heated under reflux (100° C.) overnight. The mixture is cooled down to room temperature and filtered through Celite® pad, which is washed with EtOAc. The filtrate is concentrated to give a crude brown oil. Purification by flash chromatography (Silica gel-hexane/EtOAc) yields 4-(4-Bromo-phenyl)-3-nitro-pyridine (8.52 g) as a yellow oil (76% yield).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][NH:8][N:7]=1.Cl[CH2:17][C:18]1[CH:36]=[CH:35][C:21]([O:22][CH2:23][C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:27][CH:28]=2)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:29]1([C:26]2[O:27][CH:28]=[C:24]([CH2:23][O:22][C:21]3[CH:20]=[CH:19][C:18]([CH2:17][N:8]4[CH:9]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([C:2]5[S:1][CH:5]=[CH:4][CH:3]=5)=[N:7]4)=[CH:36][CH:35]=3)[N:25]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: ClCc1ccc(OCc2coc(-c3ccccc3)n2)cc1
Reactant: CCOC(=O)c1c[nH]nc1-c1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(Cc2ccc(OCc3coc(-c4ccccc4)n3)cc2)nc1-c1cccs1
Temperature: 80 °C
Reaction time: 8 h
Yield: 92.3 %

Procedure:
A mixture of ethyl 3-(2-thienyl)-1H-pyrazole-4-caboxylate (1.43 g), 4-(4-chloromethylphenoxy)methyl-2-phenyloxazole (1.88 g), potassium carbonate (1.30 g), and N,N-dimethylformamide (30 ml) was stirred at 80° C. for 8 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 1-[4-(2-phenyl-4-oxazolylmethoxy)benzyl]-3-(2-thienyl)-1H-pyrazole-4-carboxylate as colorless crystals (2.81 g, yield: 92%) from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 114˜115° C.