Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][C:16]([C:23]45[CH2:32][CH:27]6[CH2:28][CH:29]([CH2:31][CH:25]([CH2:26]6)[CH2:24]4)[CH2:30]5)=[C:17]([OH:22])[CH:18]=3)[CH:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].I[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>>[OH:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][C:16]([C:23]45[CH2:24][CH:25]6[CH2:26][CH:27]([CH2:28][CH:29]([CH2:31]6)[CH2:30]4)[CH2:32]5)=[C:17]([O:22][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:18]=3)[CH:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: CCCCCCI
Reactant: COC(=O)c1ccc(-c2ccc3cc(O)c(C45CC6CC(CC(C6)C4)C5)cc3c2)cc1O
Product: CCCCCCOc1cc2ccc(-c3ccc(C(=O)OC)c(O)c3)cc2cc1C12CC3CC(CC(C3)C1)C2
Yield: 54.6 %

Procedure:
Following the procedure of Example 1(a), but reacting 430 mg (1 mmol) of methyl 2-hydroxy-4-[7-(1-adamantyl)-6-hydroxy-2-naphthyl]benzoate with 180 μl (1.2 mmol) of 6-iodohexane, 280 mg (55%) of methyl 2-hydroxy-4-[7-(1-adamantyl)-6-hexyloxy-2-naphthyl]benzoate were obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[N:10]([C:13]([CH3:22])=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:15]=2)[C:11]=1[OH:12])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[F:29][C:30]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:31]=1[CH2:32]Cl.[I-].[K+]>CN(C=O)C.O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]2[C:13]([CH3:22])=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:15]=[C:9]2[N:8]([CH2:32][C:31]2[C:30]([F:29])=[CH:37][CH:36]=[CH:35][C:34]=2[F:38])[CH:7]=1)=[O:5])[CH3:2]
Reactant: Fc1cccc(F)c1CCl
Reactant: CCOC(=O)c1cnc2nc(-c3ccccc3)c(C)n2c1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cn(Cc2c(F)cccc2F)c2nc(-c3ccccc3)c(C)n2c1=O
Temperature: 20 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
To a solution of the compound obtained in Example 1 (157 mg, 0.53 mmol) in DMF (15 ml), potassium carbonate (80 mg, 0.58 mmol), 2,6-difluorobenzyl chloride (103 mg, 0.64 mmol) and potassium iodide (44 mg, 0.26 mmol) are added, followed by stirring at about 15 to 25° C. for 1 hour and stirring under heating at 80° C. for 1 hour. The brownish white crystalline substance obtained by concentration under reduced pressure of the reaction mixture is dispensed to ethyl acetate (30 ml) and water (30 ml). The water layer is extracted with ethyl acetate (10 ml), and the organic layers are combined and dried over sodium sulfate, after which the solvent is distilled off under reduced pressure to yield a crude brownish white crystalline product (204 mg), which is then purified by flush column chromatography to yield a white crystal (146 mg, 65%).
Reaction SMILES: [OH-].[Na+].Cl.[F:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[N:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([OH:16])=O)=[CH:7][CH:6]=1.CN(C=O)C.C(N=C=NCCCN(C)C)C.[NH2:37][C:38]1[S:39][C:40]2[CH:46]=[C:45]([N+:47]([O-:49])=[O:48])[CH:44]=[CH:43][C:41]=2[N:42]=1>C(O)C>[N+:47]([C:45]1[CH:44]=[CH:43][C:41]2[N:42]=[C:38]([NH:37][C:14](=[O:16])[C:13]3[CH:17]=[CH:18][CH:19]=[N:20][C:12]=3[NH:11][C:8]3[CH:7]=[CH:6][C:5]([F:4])=[CH:10][CH:9]=3)[S:39][C:40]=2[CH:46]=1)([O-:49])=[O:48]
Reactant: O=C(O)c1cccnc1Nc1ccc(F)cc1
Reactant: Nc1nc2ccc([N+](=O)[O-])cc2s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: O=C(Nc1nc2ccc([N+](=O)[O-])cc2s1)c1cccnc1Nc1ccc(F)cc1
Temperature: 27 °C
Reaction time: 9 h

Procedure:
Compound 13 (185 mg, 1 mmol) and 4-fluoro aniline (16, 147 mg, 1 mmol) was taken in ethylene glycol and refluxed at 150° C. for 5 h. Then the reaction mixture was cooled and extracted in ethyl acetate (4×25 mL) from the aqueous layer and concentrated in vacuo. The compound was further purified by column chromatography using 60-120 silica gel (ethyl acetate/hexane, 1:9) to obtain Ethyl 2-(4-fluoroanilino) nicotinate (23) as pure product. Ethyl 2-(4-fluoroanilino) nicotinate (23, 260 mg, 1 mmol) were refluxed with 2N NaOH in ethanol for 2 h. The reaction mixture was cooled and left acidified with 2N HCl white solids obtained, filtered and washed with water to give pure compound of 2-(4-fluoroanilino)nicotic acid (30). To a stirred solution of 2-(4-fluorophenylamino) nicotinic acid (30, 232 mg 1 mmol) in dry DMF (10 mL) hydroxy benzotriazole HOBt (1.2 mmol) were added at 0° C. After 10 min 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCI) (1.2 mmol) was added and finally 2-amino 6-nitro benzothiazole 37 (137 mg, 0.7 mmol) were added, then the resulting mixture was stirred at room temperature (27° C.) for 8-10 h and then the reaction mixture was quenched with NaHCO3 and extracted in ethyl acetate (4×25 mL) from the ice cold aqueous layer and dried over anhydrous Na2SO4. The resulting product (6) was purified by column chromatography employing EtOAc/Hexane as an eluent.
Reaction SMILES: COC1C=CC(C[N:8]2[CH:12]=[C:11]([C:13]3[N:14]=[C:15]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)[S:16][C:17]=3[N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:10]=[N:9]2)=CC=1>C(O)(C(F)(F)F)=O>[N:18]1([C:17]2[S:16][C:15]([NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)=[N:14][C:13]=2[C:11]2[CH:10]=[N:9][NH:8][CH:12]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: COc1ccc(Cn2cc(-c3nc(Nc4ccccn4)sc3N3CCCCC3)cn2)cc1
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(Nc2nc(-c3cn[nH]c3)c(N3CCCCC3)s2)nc1
Yield: 103.4 %

Procedure:
According to Scheme 5 Step 3: A solution N-(4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-5-(piperidin-1-yl)thiazol-2-yl)pyridin-2-amine (0.58 mmol, 260 mg) in TFA (4 mL) was microwaved for 8 minutes at 140° C. After evaporation of the solvent, the crude residue was neutralized with a solution of NaOH (1 M). The aqueous phase was extracted with DCM. The organic phase was dried over MgSO4, was filtered and was concentrated to yield 5-(piperidin-1-yl)-4-(1H-pyrazol-4-yl)-N-(pyridin-2-yl)thiazol-2-amine (0.60 mmol, 195 mg, 99%) as a pale yellow solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[O:8][CH3:9])(=O)[CH3:2].BrC1C=[CH:25][C:17]([C:18]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.[Cu]I>[CH2:23]([N:20]([CH2:21][CH3:22])[C:18](=[O:19])[C:17]1[CH:16]=[CH:15][C:1]([NH:4][C:5]2[CH:12]=[CH:11][CH:10]=[C:7]([O:8][CH3:9])[CH:6]=2)=[CH:2][CH:25]=1)[CH3:24]
Reactant: CCN(CC)C(=O)c1ccc(Br)cc1
Reactant: COc1cccc(NC(C)=O)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccc(Nc2cccc(OC)c2)cc1
Temperature: 250 °C
Yield: 437.1 %

Procedure:
3.7 g (2.3 mmol) of N-acetyl-m-anisidine, 10.6 g (41.4 mmol) of 4-bromo-N,N-diethylbenzamide and 0.42 g of CuI were heated to 1000° C.; 3 g (22.3 mmol) of K2CO3 were added and the resulting mixture was heated to 250° C. for 2 hours. The residue was dissolved in CH2Cl2 and washed with H2O, the organic layer was dried over Na2SO4 and the solvent was removed in vacuo. The resulting residue was dissolved in 20 ml of absolute EtOH and refluxed for 2 h. The solvent was removed in vacuo, the residue was taken up in H2O and the aqueous layer extracted with AcOEt. The organic layer was dried over Na2SO4 and the solvent removed in vacuo. The resulting residue was purified by flash chromatography (AcOEt/Hexane 6:4), yielding 3 g of the title compound.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:45]=[CH:44][C:16]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([CH2:34][CH2:35][CH2:36][C:37]([F:43])([F:42])[C:38]([F:41])([F:40])[F:39])([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:15][CH:14]=3)=[O:12])=[C:9]([C:46]3[CH:51]=[CH:50][C:49]([O:52]C)=[CH:48][CH:47]=3)[S:8][C:7]=2[CH:54]=1.[Cl-].[Al+3].[Cl-].[Cl-].C(S)C.O1CCCC1>ClCCl.O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:45]=[CH:44][C:16]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([CH2:34][CH2:35][CH2:36][C:37]([F:43])([F:42])[C:38]([F:39])([F:40])[F:41])([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:15][CH:14]=3)=[O:12])=[C:9]([C:46]3[CH:51]=[CH:50][C:49]([OH:52])=[CH:48][CH:47]=3)[S:8][C:7]=2[CH:54]=1
Reactant: CCOC(=O)C(CCCCCOc1ccc(C(=O)c2c(-c3ccc(OC)cc3)sc3cc(OC)ccc23)cc1)(CCCC(F)(F)C(F)(F)F)C(=O)OCC
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCS
Product: CCOC(=O)C(CCCCCOc1ccc(C(=O)c2c(-c3ccc(O)cc3)sc3cc(O)ccc23)cc1)(CCCC(F)(F)C(F)(F)F)C(=O)OCC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78.7 %

Procedure:
Diethyl 2-[5-[4-[(6-methoxy-2-(4-methoxyphenyl)benzo-[b]thiophen-3-yl)carbonyl]phenoxy]pentyl]-2-(4,4,5,5,5-pentafluoropentyl)malonate (1.58 g, 2.03 mmol) was dissolved in dichloromethane (40 ml), and aluminum chloride (1.62 g, 12.2 mmol) and ethanethiol (0.25 ml, 10.15 mmol) were added to the resulting solution followed by stirring for 1.5 hours at room temperature. After the reaction mixture was cooled to 0° C., tetrahydrofuran (30 ml) was slowly added to the reaction mixture, which was then diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane 1/2) to give diethyl 2-[5-[4-[(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)carbonyl]phenoxy]-pentyl]-2-(4,4,5,5,5-pentafluoropentyl)malonate (1.2 g, Yield 79%) as a brown foam.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH:10]=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CC=C(c2c[nH]c3ncccc23)CC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)N1CCC(c2c[nH]c3ncccc23)CC1
Yield: 62.4 %

Procedure:
7.8 g (0.029 mol) of 4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid ethyl ester were dissolved in 250 ml of ethanol and 7.8 g of palladium over carbon at 10% were added. The crude mixture was hydrogenated at 30 psi for 24 hours. After filtering the catalyst and removal of the solvent at reduced pressure, 4.95 g (62% of yield) of 4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidine-1-carboxylic acid ethyl ester were obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:34]=[CH:33][N:32]=[C:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:34]=[CH:33][N:32]=[C:31]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[CH:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: Brc1ccnc(-c2ccccc2)c1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4ccnc(-c5ccccc5)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 68, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 4-bromo-2-phenyl-pyridine.
Reaction SMILES: [C:1]1([S:7][CH:8]2[CH2:12][CH2:11][C:10](=O)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:15][OH:16]>N1C=CC=CC=1>[C:1]1([S:7][CH:8]2[CH2:12][CH2:11][C:10](=[N:15][OH:16])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCC(Sc2ccccc2)C1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: ON=C1CCC(Sc2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.1 %

Procedure:
To a solution of 3-phenylthiocyclopentanone (Syn. Commun., 1987, 17, 1607) (6.00 g, 30 mmol) in dry pyridine (50 ml) was added hydroxylamine hydrochloride (3.20 g, 45 mmol) and the reaction mixture was stirred for 3 h at room temperature. After the solvent was evaporated off, the residue was partitioned between water (50 ml) and ethyl acetate (100 ml), the aqueous layer separated and extracted with ethyl acetate (100 ml). The combined organic layer was washed with 1N aqueous hydrochloric acid (100 ml), saturated aqueous sodium hydrogen carbonate solution (100 ml) and brine (100 ml), dried (MgSO4) and concentrated under reduced pressure to afford 6.10 g (98%) of the title compound as a pale yellow oil: 1 H NMR δ7.42-7.38 (m, 2H), 7.33-7.22 (m, 3H), 3.71 (m, 1H), 3.00-3.24 (m, 4H), 2.16 (m, 1H), 1.86 (m, 1H).
Reaction SMILES: [NH2:1][C:2](=[N:12][N:13]=[CH:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([O:24]CC3C=CC=CC=3)[CH:22]=2)[NH:17][CH:16]=1)[N:3]([CH3:11])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>CCO.[Pd]>[NH2:1][C:2](=[N:12][N:13]=[CH:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([OH:24])[CH:22]=2)[NH:17][CH:16]=1)[N:3]([CH3:11])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCN(C)C(N)=NN=Cc1c[nH]c2ccc(OCc3ccccc3)cc12
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCN(C)C(N)=NN=Cc1c[nH]c2ccc(O)cc12
Reaction time: 8 h

Procedure:
To a solution of 0.48 g 5-benzyloxy-indole-3-carboxaldehyde amino(N-methyl-N-heptylamino)methylene hydrazone (1.1 mmol) in EtOH there is added 0.25 g 10% Pd/C. The suspension is hydrogenated overnight at 45° C. Afterwards the suspension is filtered over silica gel, the solvent is evaporated and the residue is chromatographed over silica gel (eluant:toluene/EtOH/NH3 85:15:1) to yield the title compound. The pure material is crystallized from CH2Cl2 /Hexane 2: 8.
Reaction SMILES: [Cl:1][C:2]1[C:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:10]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:36])[C:5]([CH:34]=O)=[CH:6][N:7]2[CH2:32][CH3:33].[NH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(Cl)Cl>ClCCCl>[Cl:1][C:2]1[C:11]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)=[C:10]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:36])[C:5]([CH2:34][N:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1)=[CH:6][N:7]2[CH2:32][CH3:33]
Reactant: CCn1cc(C=O)c(=O)c2c(Cl)c(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: CCn1cc(CN2CCCC2)c(=O)c2c(Cl)c(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.8 %

Procedure:
To a solution of 5-chloro-1-ethyl-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydro quinoline-3-carbaldehyde (21.3 g, 34.4 mmol) in 1,2-Dichloroethane (DCE) (200 mL) was added pyrrolidine (3.13 mL, 37.8 mmol) and sodium triacetoxyborohydride (10.93 g, 51.6 mmol). The mixture was stirred at r.t. for 3 h. Then reaction mixture was concentrated, partitioned between DCM and brine, and extracted with DCM twice. The combined organic extracts were dried over sodium sulfate and the solvent was removed in vacuo. The crude product was then purified through normal phase chromatography (CombiFlash Rf), eluting with [DCM/MeOH/NH4OH (v:v:v=80:20:2)]:DCM (0% to 60%) to afford 5-chloro-1-ethyl-6,7-bis((4-methoxybenzyl)oxy)-3-(pyrrolidin-1-ylmethyl)quinolin-4(1H)-one (17 g, 30.2 mmol, 88% yield) as a light yellow solid. LCMS: (M+H)+: 563.2.
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])=[CH:13][CH:12]=1)C1C=CC=CC=1.Br.C(OCC)C>C(O)(=O)C>[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][N:23]([CH3:24])[CH3:25])=[CH:13][CH:12]=1
Reactant: CN(C)CCCCC(=O)Nc1ccc(NC(=O)OCc2ccccc2)cc1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: CN(C)CCCCC(=O)Nc1ccc(N)cc1
Yield: 82.9 %

Procedure:
Compound 3 (1.94 g, 0.005 mol) was stirred in 48% w/v hydrobromic acid in acetic acid (11 mL) for 1 h. Diethylether was added till a cream precipitate appeared and the ethereal solution decanted. The resulting white sticky solid was suspended in dichloromethane (100 mL) and 1 M aqueous sodium hydroxide (20 mL). The aqueous layer was extracted with dichloromethane (1×50 mL) and the combined organic layers were washed with saturated brine (1×50 mL), dried (MgSO4) and concentrated in vacuo to give 4 as a pale yellow oil (975 mg, 82%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8])(=O)[CH3:2].[N:13]1[NH:14][C:15](=[O:19])[CH:16]=CC=1>>[O:19]=[C:15]1[NH:14][N:13]=[C:1]([C:4]2[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=2)[C:7]([OH:9])=[O:8])[CH:2]=[CH:16]1
Reactant: CC(=O)c1cccc(C(=O)O)c1
Reactant: O=c1cccn[nH]1
Product: O=C(O)c1cccc(-c2ccc(=O)[nH]n2)c1

Procedure:
15 g of 3-acetylbenzoic acid is converted into the pyridazinone in accordance with GWP 1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]([Cl:13])=[CH:10][C:11]=1Cl)=[O:5])[CH3:2].[F:14][C:15]1[CH:16]=[C:17]([CH:20]=[C:21]([F:23])[CH:22]=1)[CH2:18][NH2:19]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]([Cl:13])=[CH:10][C:11]=1[NH:19][CH2:18][C:17]1[CH:16]=[C:15]([F:14])[CH:22]=[C:21]([F:23])[CH:20]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Reactant: NCc1cc(F)cc(F)c1
Product: CCOC(=O)c1cnc(Cl)cc1NCc1cc(F)cc(F)c1

Procedure:
From 4,6-dichloropyridine-3-carboxylic acid ethylester synthesized according to the method described in US2006/0217417 and 3,5-difluorobenzylamine in a manner similar to Example 1, 6-chloro-4-[(3,5-difluorobenzyl)amino]pyridine-3-carboxylic acid ethyl ester was obtained as a light brown crystalline powder (yield 82%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([CH2:9][C:10]([C:12]1[CH:17]=CC(F)=C[CH:13]=1)=[O:11])[C:6](=[O:8])[CH3:7])[CH3:2].Cl[CH2:21]C(=O)C(C)(C)C>>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([C:6](=[O:8])[CH3:7])[CH2:9][C:10](=[O:11])[C:12]([CH3:13])([CH3:17])[CH3:21])[CH3:2]
Reactant: CC(C)(C)C(=O)CCl
Reactant: CCOC(=O)C(CC(=O)c1ccc(F)cc1)C(C)=O
Product: CCOC(=O)C(CC(=O)C(C)(C)C)C(C)=O

Procedure:
Prepared in analogy to that of 2-[2-(4-fluoro-phenyl)-2-oxo-ethyl]-3-oxo-butyric acid ethyl ester from 1-chloro-3,3-dimethyl-butan-2-one. The title compound, 1H NMR (200 MHz, CDCl3): δ (ppm)=4.19 (q, 2H, J=7.2 Hz), 4.02 (m, 1H), 3.23 (dd, 1H, J=8.2 Hz, 18.4 Hz), 3.00 (dd, J=6.0 Hz, J=18.4 Hz), 2.37 (s, 3H), 1.8 (t, 3H, J=7.2 Hz), 1.17 (s, 9H).
Reaction SMILES: O.O.O.O.O.[OH-].[CH3:7][N+:8]([CH3:11])([CH3:10])[CH3:9].[F:12][C:13]([F:36])([C:17]([F:35])([F:34])[C:18]([F:33])([F:32])[C:19]([F:31])([F:30])[C:20]([F:29])([F:28])[C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])[C:14]([OH:16])=[O:15]>O>[F:12][C:13]([F:36])([C:17]([F:34])([F:35])[C:18]([F:32])([F:33])[C:19]([F:30])([F:31])[C:20]([F:28])([F:29])[C:21]([F:26])([F:27])[C:22]([F:25])([F:24])[F:23])[C:14]([O-:16])=[O:15].[CH3:7][N+:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: O=C(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: C[N+](C)(C)C
Agent: [OH-]
Solvent: O
Product: O=C([O-])C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
One equivalent of tetramethyl ammonium hydroxide pentahydrate (18 g) was reacted with 0.1 equivalent of perfluorooctanoic acid (41 g) in water, to form tetra methylammonium perfluorooctanoate at a concentration of 5 percent by weight of the solution.
Reaction SMILES: [CH3:1][C:2]1([CH3:36])[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12](=[O:28])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][C:14]=3[NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[CH:8][CH:9]=2)[N:4]([CH2:29][CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH2:3]1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:41](C)=O.[Na+]>ClCCCl>[CH3:1][C:2]1([CH3:36])[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12](=[O:28])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][C:14]=3[NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[CH:8][CH:9]=2)[N:4]([CH2:29][CH:30]2[CH2:31][CH2:32][N:33]([CH3:41])[CH2:34][CH2:35]2)[CH2:3]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC1(C)CN(CC2CCNCC2)c2cc(NC(=O)c3cccnc3NCc3ccc(F)cc3)ccc21
Agent: C=O
Agent: [Na+]
Solvent: ClCCCl
Product: CN1CCC(CN2CC(C)(C)c3ccc(NC(=O)c4cccnc4NCc4ccc(F)cc4)cc32)CC1
Reaction time: 4 h

Procedure:
To N-(3,3-dimethyl-1-piperidin-4-ylmethyl-2,3-dihydro-1H-indol-6-yl)-2-(4-fluoro-benzylamino)-nicotinamide (0.92 g) dissolved in DCE (20 mL) at RT was added formaldehyde (37% aqueous, 0.42 mL) followed by NaBH(OAc)3 (1.59 g). After 4 h, the mixture was quenched with 1 N HCl (20 mL) and H2O (20 mL). It was basified with sat NaHCO3, extracted with CH2Cl2 (3×50 mL) and the combined extracts were washed with brine, dried (K2CO3) and concentrated onto SiO2 (previously treated with 10% MeOH (2 M NH3 in MeOH/CH2Cl2 and then concentrated in vacuo). The residue was purified by flash chromatography (Isco, 35 g column, 1-7% MeOH (2M NH3 in MeOH/CH2Cl2). The bulk of the crude yellow material was further purified by reverse phase Prep HPLC. The isolated fractions were partially concentrated and basified with 1 N NaOH and dried under vacuum to afford a slightly yellow powder. M+H=502.3. Calc'd for C30H36FN5O: 501.29.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)#N.[H-].C([Al+]CC(C)C)C(C)C.C[OH:28].O>C1(C)C=CC=CC=1.CCCCCC>[C:11]1([CH2:10][CH2:9][N:6]2[CH2:7][CH2:8][CH:3]([CH:1]=[O:28])[CH2:4][CH2:5]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N#CC1CCN(CCc2ccccc2)CC1
Reactant: CO
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCCCCC
Product: O=CC1CCN(CCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-cyano-1-(2-phenylethyl)piperidine (6.5 g, 30.3 mmol) in dry toluene (100 ml) cooled in an ice bath was added dropwise 43 ml (43 mmol) of 1M diisobutylaluminum hydride in hexane. After the addition was complete, the mixture was warmed to room temperature and stirred overnight (16 h). Methanol was added to decompose any unreacted reagent and H2O was added with vigorous stirring. The gelatinous aluminum salts were removed by filtration through Celite and the filtrate extracted with toluene (2×100 ml). The extracts were combined, washed with saturated aqueous NaCl, dried (MgSO4) filtered and evaporated to give a clear oil. This oil was flash chromatographed on silica gel using acetone as eluent to give product as a clear oil, which was used without further purification.
Reaction SMILES: [BH4-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14](=[O:21])[CH2:13]2)=[CH:4]1.N1C2C(=CC=CC=2)C=C1[C@@H]1C2C(=CC=CC=2)[C@H](O)C1>CO.C1COCC1>[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C@@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C@H:14]([OH:21])[CH2:13]2)=[CH:4]1
Reactant: O=C1CC(c2c[nH]c3ccccc23)c2ccccc21
Agent: O[C@@H]1C[C@H](c2cc3ccccc3[nH]2)c2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: O[C@@H]1C[C@H](c2c[nH]c3ccccc23)c2ccccc21
Temperature: 25 °C

Procedure:
NaBH4 (6.2 g, 163 mmol, 2 equiv.) was added to 3-(1H-indol-3-yl)-indan-1-one (20 g, 80.9 mmol ) in 200 mL methanol and 100 mL THF at 0° C. The reaction mixture was allowed to warm to room temperature over night. Aqueous work up gave racemic cis-3-indolyl-indan-1-ol (quantitative).