Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:21]=[CH:20][C:14]([C:15](=[NH:19])OCC)=[CH:13][CH:12]=2)=[O:10])=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[C:11]2[CH:12]=[CH:13][C:14]([C:15](=[NH:19])[N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:20][CH:21]=2)=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1
Reactant: CCOC(=N)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1
Reactant: C1CCNCC1
Product: N=C(c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1)N1CCCCC1

Procedure:
Ethyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzimidate (17.5 ml of a 0.0155 M solution, 0.27 mmol) was treated with piperidine (1.0 ml, 10.0 mmol) for 3 days. The ethanol was evaporated, and the residue purified by reverse phase HPLC to afford 26 mg of N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(imino(piperidin-1-yl)methyl)benzamide. MS (Q1) 419 (M)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[Cl:11][C:12](Cl)([O:14]C(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1>C(Cl)Cl>[Cl:11][C:12]([O:10][C:3]1[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1])=[O:14]
Reactant: Cc1cc(C)c(O)c(C)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(C)c(OC(=O)Cl)c(C)c1
Temperature: 0 °C

Procedure:
2,4,6-trimethylphenol (272 mg, 2.00 mmol, 1.0 equiv) was dissolved in CH2Cl2 (3.33 mL, 0.3 M) under nitrogen (N2) and cooled to 0° C. Triphosgene (208 mg, 0.700 mmol, 0.35 equiv) was dissolved in CH2Cl2 (3.33 mL) and added dropwise, followed by pyridine (0.162 mL, 2.00 mmol, 1.0 equiv). The mixture was allowed to warm to 25° C. over 18 h, at which point the reaction was quenched with 10 mL 1 normal (N) hydrochloric acid (HCl; aq) and extracted with EtOAc. The organic layer was washed with 1 N HCl (aq), dried over Na2SO4, and concentrated to give mesityl chloroformate as an oil (88% purity by 1H NMR spectroscopy). The chloroformate so prepared was used directly in the next step without further purification.
Reaction SMILES: O=[C:2]([CH3:17])[CH2:3][CH2:4][P:5]([CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])(=[O:9])[O:6][CH2:7][CH3:8].C([O-])(=O)C.[NH4+].C([BH3-])#[N:24].[Na+].Cl>CO>[NH2:24][CH:2]([CH3:17])[CH2:3][CH2:4][P:5]([CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])(=[O:9])[O:6][CH2:7][CH3:8]
Reactant: [BH3-]C#N
Reactant: CCOC(OCC)P(=O)(CCC(C)=O)OCC
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CO
Product: CCOC(OCC)P(=O)(CCC(C)N)OCC
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 8.0 g of ethyl 3-oxobutyl(diethoxymethyl)phosphinate in 100 ml of methanol is added 22.8 g of ammonium acetate and 1.3 g of sodium cyanoborohydride. The mixture is stirred under an atmosphere of nitrogen at room temperature for a period of 2.5 h, and then left to stand overnight. The mixture is then acidified to pH 2 with the requisite amount of dilute hydrochloric acid and the methanol is evaporated under reduced pressure. The crude product is dissolved in 25 ml of water, washed twice with 20 ml of diethyl ether and the aqueous phase is then made alkaline to pH 12 with potassium hydroxide. The solution is then saturated with sodium chloride and extracted with 3×25 ml of dichloromethane. The organic phase is dried over magnesium sulphate, filtered and evaporated under reduced pressure and the crude product distilled to give ethyl 3-aminobutyl(diethoxymethyl)phosphinate, b.p. 150° C./0.01 mbar, 31P=+46.1 ppm (CDCl3).
Reaction SMILES: Br[C:2]1[C:3]([CH3:23])=[C:4]([C:7]2[N:11]3[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]3=[N:9][C:8]=2[CH3:22])[S:5][CH:6]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.CN(C1C=CC=CC=1C1C=CC=CC=1)C.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:17]([CH:16]([C:15]1[C:10]2[N:11]([C:7]([C:4]3[S:5][CH:6]=[C:2]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[C:3]=3[CH3:23])=[C:8]([CH3:22])[N:9]=2)[N:12]=[C:13]([CH3:21])[CH:14]=1)[CH2:19][CH3:20])[CH3:18]
Reactant: CCC(CC)c1cc(C)nn2c(-c3scc(Br)c3C)c(C)nc12
Reactant: C1COCCN1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: CCOC(C)=O
Product: CCC(CC)c1cc(C)nn2c(-c3scc(N4CCOCC4)c3C)c(C)nc12
Temperature: 65 °C
Yield: 15.8 %

Procedure:
To a flask containing 3-(4-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.30 g, 0.76 mmol), morpholine (0.10 mL, 1.15 mmol), Pd2(dba)3 (0.035 g, 0.038 mmol), and 2-dicyclohexylphosphino-biphenyl-2′-(N,N-dimethyl-amino)biphenyl (0.018 g, 0.046 mmol) is added 1 M LiHMDS (1.9 mL, 1.91 mmol). The solution is heated at 65° C. overnight, diluted with EtOAc (30 mL), washed with water (20 mL), brine (20 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO (15%-30% EtOAc gradient), dissolved in Et2O (20 mL) and extracted with 1 M HCl (2×30 mL). The aqueous layer is washed with Et2O (20 mL), made basic with 5 M NaOH (15 mL), extracted with EtOAc (2×20 mL), the combined organic layers washed with brine (40 mL), dried over MgSO4, filtered and concentrated to furnish the title compound (0.047 g, 0.12 mmol, 16%). 1H NMR (CDCl3) δ 0.87 (t, J=7.5 Hz, 6H), 1.73-1.91 (m, 4H), 2.01 (s, 3H), 2.45 (s, 3H), 2.49 (s, 3H), 2.99-3.05 (m, 4H), 3.28-3.37 (m, 1H), 3.84-3.88 (m, 4H), 6.65 (s, 1H), 6.71 (s, 1H). LC/MS (m/z): calcd. for C22H30N4OS (M+H)+: 399.2; found: 399.2.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[C@H:15]([OH:16])[CH2:14][CH2:13][CH2:12][O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:19](Br)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].O>CN(C)C=O>[CH2:1]([O:8][CH2:9][C@H:10]1[C@H:15]([O:16][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19])[CH2:14][CH2:13][CH2:12][O:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@@H]1CCCO[C@H]1COCc1ccccc1
Reactant: CCCCCCCCCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCO[C@@H]1CCCO[C@H]1COCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2.22 g of dl-trans-2-benzyloxymethyltetrahydropyran-3-ol (prepared as described in Preparation 2) in 10 ml of dimethylformamide was added dropwise, with ice-cooling, to 10 ml of dimethylformamide containing 0.480 g of a 55% w/w suspension of sodium hydride in mineral oil. The reaction mixture was stirred at room temperature for 60 minutes, after which 5.49 g of hexadecyl bromide were added, and the resulting mixture was stirred for a further 4 hours. Finally, the mixture was stirred at 60° C. for 60 minutes and then cooled. It was then poured into 100 ml of water, and extracted twice with ethyl acetate. The combined extracts were washed with water, dried over anhydrous magnesium sulfate and condensed by evaporation under reduced pressure. The resulting oily residue was subjected to column chromatography through 100 g of silica gel. Those fractions eluted with mixtures of diethyl ether and hexane ranging from 1:20 to 1:10 by volume gave 3.82 g of the title compound as a solid having a low melting point, i.e. 28.5°-29.5° C. (after recrystallization from cold methanol).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][O:6][CH:7]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[CH:29]=1)[C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]1)C.[BH4-].[Na+]>CCO>[F:27][C:23]1[C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[CH:29]=2)=[C:21]([CH:7]([O:6][CH2:5][CH2:4][OH:3])[C@@H:8]2[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:9]2)[CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)COC(c1cccc(F)c1-c1cccc(C)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cccc(-c2c(F)cccc2C(OCCO)[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
To a solution of (3R)-tert-butyl 3-((2-ethoxy-2-oxoethoxy)(6-fluoro-3′-methylbiphenyl-2-yl)methyl)piperidine-1-carboxylate (1.1 g, 2.3 mmol) in EtOH (20 mL) was added NaBH4 (0.7 g, 18.1 mmol) in portions. After addition, the mixture was stirred at rt overnight. TIc showed the start material had disappeared. The solvent was removed in vacuo to leave a residue, which was partitioned between water and EtOAc. The organic layer was washed with H2O and brine, dried over Na2SO4, filtered and evaporated to give (3R)-tert-butyl 3-((6-fluoro-3′-methylbiphenyl-2-yl)(2-hydroxyethoxy)methyl)piperidine-1-carboxylate (1 g, 99%) which was used in the next step without purification.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.[F:14][C:15]1[N:20]=[CH:19][C:18]([C:21](=O)[CH3:22])=[CH:17][CH:16]=1.[BH4-].[Na+].[NH4+]>C1COCC1.C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C.C(OCC)(=O)C.O.C(O)C>[F:14][C:15]1[N:20]=[CH:19][C:18]([CH:21]([N:1]2[CH2:5][CH2:4][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]2)[CH3:22])=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: CC(=O)c1ccc(F)nc1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: [BH4-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(c1ccc(F)nc1)N1CC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 44 %

Procedure:
To a solution of (S)-tert-butyl pyrrolidin-3-ylcarbamate (0.94 g, 5.04 mmol), 1-(6-fluoropyridin-3-yl)ethanone (0.35 g, 2.52 mmol) in THF (10 mL) was added tetraisopropoxytitanium (1.48 mL, 5.04 mmol) and the reaction mixture was stirred at ambient temperature for 18 hours. Ethanol (2 mL) and NaBH4 (0.38 g, 10.1 mmol) were added and the mixture was stirred at ambient temperature for 2 hours. Water (10 mL), concentrated ammonium (2 mL) and ethyl acetate (20 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue obtained was purified by flash chromatography on silica gel (1:1 hexane/ethyl acetate) to give tert-butyl (3S)-1-(1-(6-fluoropyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (0.343 g, 44.0%) as solid.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[OH:11])[CH:2]=[CH2:3].[OH-:12].[Na+].OO.Cl>>[OH:12][CH2:3][CH2:2][CH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[OH:11]
Reactant: C=CCc1cccc(C)c1O
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [Na+]
Product: Cc1cccc(CCCO)c1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a borane-tetrahydrofuran complex solution (100 mL, 1M solution) was added dropwise 2-allyl-6-methylphenol (21 g) under ice-cooling. After stirring at room temperature for 3 hours, a 2N aqueous sodium hydroxide solution (55 mL) and a 30% aqueous hydrogen peroxide solution (12 mL) were added to the reaction mixture under ice-cooling. After stirring overnight at room temperature, the reaction mixture was acidified with a 2N hydrochloric acid and extracted with diethyl ether. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by silica gel column chromatography and dried to give the title compound (15 g).
Reaction SMILES: NC1C=CC(C#N)=NC=1N.ClC1C=C(C=CC=1Cl)[O:15]C1C=CC(C=O)=CC=1.CN(C)C(=O)C.[Cl:34][C:35]1[CH:36]=[C:37]([CH:56]=[CH:57][C:58]=1[Cl:59])[O:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[NH:46][C:47]3[C:48]([N:55]=2)=[N:49][C:50]([C:53]#[N:54])=[CH:51][CH:52]=3)=[CH:41][CH:40]=1>O.[OH-].[Na+]>[Cl:34][C:35]1[CH:36]=[C:37]([CH:56]=[CH:57][C:58]=1[Cl:59])[O:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[NH:46][C:47]3[C:48]([N:55]=2)=[N:49][C:50]([C:53]([NH2:54])=[O:15])=[CH:51][CH:52]=3)=[CH:41][CH:40]=1
Reactant: O=Cc1ccc(Oc2ccc(Cl)c(Cl)c2)cc1
Reactant: N#Cc1ccc2[nH]c(-c3ccc(Oc4ccc(Cl)c(Cl)c4)cc3)nc2n1
Agent: N#Cc1ccc(N)c(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)N(C)C
Product: NC(=O)c1ccc2[nH]c(-c3ccc(Oc4ccc(Cl)c(Cl)c4)cc3)nc2n1
Temperature: 120 °C
Reaction time: 24 h
Yield: 94.6 %

Procedure:
2-[4-(3,4-Dichloro-phenoxy)-phenyl]-1H-imidazo[4,5-b]pyridine-5-carboxylic acid amide. A flask containing 6-amino-5-nitro-pyridine-2-carbonitrile (67 mg, 0.40 mmol), 10% palladium on carbon (catalytic) and ethanol (2.0 mL) was put under an atmosphere of H2 using a balloon. The mixture was stirred at room temperature for 3 h, and filtered through a pad of celite. The filtrate was concentrated to provide crude 5,6-diamino-pyridine-2-carbonitrile. A portion of this 5,6-diamino-pyridine-2-carbonitrile (89 mg, 0.66 mmol) was treated with 4-(3,4-dichloro-phenoxy)-benzaldehyde (177 mg, 0.66 mmol), Na2S2O5 (188 mg, 0.99 mmol) and N,N-dimethylacetamide (3.0 mL). The mixture was stirred at 120° C. for 24 h. The reaction mixture was then diluted with water (8 mL), and the resulting precipitate was collected by filtration. The crude filtrate, 2-[4-(3,4-dichloro-phenoxy)-phenyl]-1H-imidazo[4,5-b]pyridine-5-carbonitrile (35 mg, 0.09 mmol), was treated with boron trifluoride/acetic acid complex (461 μL) and water (10 μL), and held at 115° C. for 30 min. The reaction mixture was cooled to room temperature and diluted with 4 N NaOH (10 mL). The resulting precipitate was collected by filtration, washed with water, and dried to provide 34 mg (94%) of the title compound.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([OH:15])=[O:14])[CH:9]=[CH:10][CH:11]=1.[CH3:16]O>>[Cl:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:9]=[CH:10][CH:11]=1
Reactant: CO
Reactant: O=C(O)Cc1cccc(Cl)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1cccc(Cl)c1
Temperature: 80 °C

Procedure:
Thionyl chloride (11 g, 100 mmol) was added dropwise to a mixture of 3-chlorophenylacetic acid (1.7 g, 10 mmol) in methanol (20 mL) at 0° C. The resulting mixture was refluxed at 80° C. for 12 hours. The volatiles were removed under vacuum and the residue was diluted with water and extracted with ethyl acetate. The combined organic solution was washed with water, dried over sodium sulfate and the concentrated to give 1.5 g of methyl 2-(3-chlorophenyl)acetate as a yellow oil, which was used without further purification.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].[H-].[Na+].[CH3:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][OH:37]>O1CCOCC1>[CH3:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6]
Reactant: COCCOCCO
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Cl)c3)nc12
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COCCOCCOc1cc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)ccn1

Procedure:
From 2-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with sodium hydride and diethylene glycol monomethyl ether in dioxane. ES-MS m/e (%): 511 (M+Na+, 13), 489 (M+H+, 100).
Reaction SMILES: [C:1]1([NH:7][N:8]=[C:9]([CH:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:26])[CH3:25])[CH2:20][CH2:19]2)[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2F)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[H][H].O>CN(C)C=O>[C:24]([N:21]1[CH2:22][CH2:23][CH:18]([C:9]2[C:10]3[C:15](=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=2)[CH2:19][CH2:20]1)(=[O:26])[CH3:25]
Reactant: [H][H]
Reactant: CC(=O)N1CCC(C(=NNc2ccccc2)c2ccc(F)cc2F)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N1CCC(c2nn(-c3ccccc3)c3cc(F)ccc23)CC1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 84.7 %

Procedure:
To a stirred solution of 3.0 g of 1-acetyl-4-(2,4-difluorobenzoyl)piperidine phenylhydrazone in 30 ml of dimethylformamide, under nitrogen, was added 0.44 g of a 50% oil dispersion of sodium hydride. The reaction mixture was heated, and at about 40° C. a vigorous evolution of hydrogen occurred. The temperature was then raised to 80° C. and held there for 1.5 hrs. The reaction mixture was poured into water and the aqueous suspension was extracted with ethyl acetate. The ethyl acetate extracts were washed with water, dried over anhydrous magnesium sulfate and concentrated to yield an oil. The oil was combined with the oil from another experiment and a total of 13.5 g of material was chromatographed on a Water's Prep LC 500. Two silica gel columns were utilized and dichloromethane-methanol (3%) was used as the eluent. The appropriate fractions were evaporated. The residue was recrystallized twice from isopropyl alcohol-water (one charcoal treatment) to yield 2.4 g (18%) of product, mp 126°-128° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[Cl:7].[CH3:8][N:9]1[C:13]([C:14](Cl)=[O:15])=[C:12]([CH3:17])[CH:11]=[C:10]1[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].Cl[Sn](Cl)(Cl)Cl.Cl>C(Cl)Cl>[CH3:8][N:9]1[C:13]([C:14]([C:6]2[N:2]([CH3:1])[C:3]([Cl:7])=[CH:4][CH:5]=2)=[O:15])=[C:12]([CH3:17])[CH:11]=[C:10]1[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: Cn1cccc1Cl
Reactant: CCOC(=O)Cc1cc(C)c(C(=O)Cl)n1C
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)Cc1cc(C)c(C(=O)c2ccc(Cl)n2C)n1C
Temperature: 0 °C
Reaction time: 3 h
Yield: 58.9 %

Procedure:
1-Methyl-2-chloropyrrole (5.83 g, 0.05 mole) and ethyl 1,4-dimethyl-5-chlorocarbonylpyrrole-2-acetate (11.5 g, 0.05 mole) are dissolved in 25 ml methylene chloride and stirred under nitrogen atmosphere at 0° C. Thirteen grams (0.05 mole) of SnCl4 in 10 ml methylene chloride is added slowly to the vigorously stirred solution. The resulting orange-brown mixture is stirred at 0° C. for 30 minutes then at room temp. for 3 hours. At the end of this period, 20 ml of 6 N HCl is added and stirred for 30 minutes. The mixture is extracted three times with 100 ml portions of methylene chloride and the crude product is purified by column chromatography and recrystallized from ether/petroleum ether to afford 9.5 g (63% yield) of ethyl 1,4-dimethyl-5-(1-methyl-5'-chloropyrrol-2-oyl)pyrrole-2-acetate.
Reaction SMILES: C([N:8]1[CH2:13][C:12]2[C:14]3[C:23]([OH:24])=[CH:22][C:21]([CH:25]([CH:27]([CH3:33])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH3:26])=[CH:20][C:15]=3[O:16][C:17]([CH3:19])([CH3:18])[C:11]=2[CH2:10][CH2:9]1)C1C=CC=CC=1>[Pd].C1(C)C(C)=CC=CC=1>[CH3:19][C:17]1([CH3:18])[C:11]2=[CH:10][CH:9]=[N:8][CH:13]=[C:12]2[C:14]2[C:23]([OH:24])=[CH:22][C:21]([CH:25]([CH:27]([CH3:33])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH3:26])=[CH:20][C:15]=2[O:16]1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: Cc1ccccc1C
Product: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)c1ccncc1-2

Procedure:
A mixture of 2.23 g. of 2-benzyl-5,5-dimethyl-10-hydroxy-8-(3-methyl-2-octyl)-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-d]pyridine, 0.8 g. (10%) palladium on carbon, and 100 ml. of xylene was stirred and refluxed for 24 hours. After removal of the catalyst, the filtrate was evaporated in vacuo and the residue was recrystallized from acetonitrile; m.p. 154°-156°.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:4]=1[NH:10][NH2:11].C(O[CH:15]=[C:16]([C:19]#[N:20])[C:17]#[N:18])C>>[NH2:20][C:19]1[N:10]([C:4]2[C:5]([F:9])=[CH:6][CH:7]=[CH:8][C:3]=2[Cl:2])[N:11]=[CH:15][C:16]=1[C:17]#[N:18]
Reactant: CCOC=C(C#N)C#N
Reactant: NNc1c(F)cccc1Cl
Agent: Cl
Product: N#Cc1cnn(-c2c(F)cccc2Cl)c1N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(2-Chloro-6-fluorophenyl)hydrazine hydrochloride (CAS no. 529512-79-6) (5 g, 25.38 mmol) was partitioned between EtOAc (100 mL) and NaOH (2M, aq) (40 mL). The organic layer separated and washed with water (50 mL), brine (50 mL), dried (MgSO4), filtered and concentrated. The resultant oil was suspended in MeOH (50 mL) under nitrogen at -5° C. 2-(Ethoxymethylene)malononitrile (3.10 g, 25.38 mmol) added portionwise over 5 mins and the mixture stirred at ˜0° C. for 30 mins. The reaction mixture was allowed to warm to room temperature and then heated at reflux under nitrogen for 2 hours. The reaction mixture was allowed to cool and evaporated to dryness to afford the product (3.52 g) which was used without further purification.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH2:26][CH3:27])=[N:4][C:3]=1[CH:28]1[CH2:30][CH2:29]1.[CH3:31][CH:32]1[CH2:36][C:35]2[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][C:34]=2[O:33]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:24]([C:5]1[N:6]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:14][CH:15]=2)[C:7](=[O:8])[C:2]([C:38]2[CH:39]=[CH:40][C:34]3[O:33][CH:32]([CH3:31])[CH2:36][C:35]=3[CH:37]=2)=[C:3]([CH:28]2[CH2:29][CH2:30]2)[N:4]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CC1Cc2cc(B(O)O)ccc2O1
Reactant: CCCCc1nc(C2CC2)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCCCc1nc(C2CC2)c(-c2ccc3c(c2)CC(C)O3)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 84.3 %

Procedure:
To a solution of 4′-[(5-bromo-2-butyl-4-cyclopropyl-6-oxopyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.5 g) and 2-methyl-2,3-dihydro-1-benzofuran-5-ylboronic acid (0.29 g) in 1,4-dioxane (10 mL) were added 2 M aqueous cesium carbonate solution (2 mL) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.05 g), and the mixture was stirred at 90° C. for 12 hr under an argon atmosphere. The reaction mixture was diluted with ethyl acetate, and the insoluble material was filtered off through celite. The filtrate was washed successively with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.47 g, 84%) as a pale-yellow solid.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][C:10]3[C:15]([C:16]=2[C:17]2[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[C:24]([F:27])([F:26])[F:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[CH:32][CH:31]=1>>[C:1]1([C:7]2[CH:8]=[N:9][C:10]3[C:15]([C:16]=2[C:17]2[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=2)[O:23][CH2:29][C:30]2[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[CH:32][CH:31]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[C:24]([F:27])([F:25])[F:26])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccc(CBr)cc1
Reactant: Oc1cccc(-c2c(-c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: O=C(O)c1ccc(COc2cccc(-c3c(-c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
The title compound was prepared from [3-(3-Phenyl-8-trifluoromethyl-quinolin-4-yl)-phenol and 4-Bromomethyl-benzoic acid following the procedure of Example 1: mp 108-112° C.; MS m/z 500; HRMS: calcd for C30H20F3NO3+H+, 500.14680; found (ESI, [M+H]+), 500.1461.