Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]#[N:21])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:18])[C:15]([OH:17])=O)[C:10](=[O:19])[CH:9]=2)[CH:7]=1.[F:22][C:23]([F:37])([F:36])[C:24]1[N:28]=[C:27]([C:29]2[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=2)[NH:26][N:25]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]#[N:21])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:18])[C:15]([NH:33][C:32]3[CH:34]=[CH:35][C:29]([C:27]4[NH:26][N:25]=[C:24]([C:23]([F:37])([F:36])[F:22])[N:28]=4)=[CH:30][CH:31]=3)=[O:17])[C:10](=[O:19])[CH:9]=2)[CH:7]=1
Reactant: CC(C(=O)O)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O
Reactant: Nc1ccc(-c2nc(C(F)(F)F)n[nH]2)cc1
Product: CC(C(=O)Nc1ccc(-c2nc(C(F)(F)F)n[nH]2)cc1)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
95 mg (purity 83%, 0.26 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoic acid (racemate) (Example 2.2B) and 75 mg (0.31 mmol) of 4-[3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl]aniline (Example 1.1C) were reacted according to General Method 1. Yield: 30 mg (purity 92%, 21% of theory)
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2)(=[O:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:27]>ClCCl>[C:1]([C:4]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N+:9]2[O-:27])(=[O:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)c1ccc(OCc2ccccc2)c2ncccc12
Solvent: ClCCl
Product: CC(=O)c1ccc(OCc2ccccc2)c2c1ccc[n+]2[O-]
Temperature: 27.5 °C
Reaction time: 2 h

Procedure:
5-Acetyl-8-benzyloxyquinoline (200 gms/0.72 moles) was dissolved in dichloromethane (4 liters) at room temperature. To this solution was added m-chloroperoxybenzoic acid (355.64 gms/1.44 moles) in 90 minutes under stiffing. The mixture was stirred at 25-30° C. for 2 hours. After completion of reaction, reaction mass was quenched with 8% sodium bicarbonate solution (3.04 liter) slowly in 30 minutes and stirred for 5-10 minutes at same temperature. The organic layer was separated and aqueous layer was extracted with dichloromethane (2.5 liters). The organic layers were combined and washed with brine solution (2.5 liters). The dichloromethane was distilled out under vacuum at 40° C. The residue was stripped with acetone (500 ml) to remove traces of dichloromethane. The residue was stirred with acetone (200 ml) and chilled to 0-5° C. for 2 hours. The resulting 5-Acetyl-8-benzyloxyquinoline-N-oxide was isolated by filtration and washed with diethyl ether (200 ml), dried under vacuum at 60-65° C. for 2-3 hours. Yield-116 gms.
Reaction SMILES: [CH3:1][C:2]([CH3:49])([CH3:48])[CH2:3][O:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:24]CC4C=CC=CC=4)[CH:20]=3)[C:15]=2[O:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][N:42]3[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]3)=[CH:35][CH:34]=2)=[CH:10][CH:9]=1)(=[O:7])=[O:6].C([O-])=O.[NH4+]>[Pd].CO>[CH3:1][C:2]([CH3:49])([CH3:48])[CH2:3][O:4][S:5]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([OH:24])[CH:20]=3)[C:15]=2[O:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][N:42]3[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]3)=[CH:35][CH:34]=2)=[CH:12][CH:13]=1)(=[O:6])=[O:7]
Reactant: CC(C)(C)COS(=O)(=O)c1ccc(-c2ccc3cc(OCc4ccccc4)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)COS(=O)(=O)c1ccc(-c2ccc3cc(O)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)cc1
Yield: 73.8 %

Procedure:
To a round bottom flask add the product from Example 66 (42 mg, 0.062 mmol), ammonium formate (29 mg, 0.464 mmol), 10% Pd/C (6 mg, ˜15% by weight) and MeOH (5 mL). Heat the mixture at reflux for 35 minutes. Cool the reaction to ambient temperature and filter it through a pad of Celite, then rinse the Celite with hot ethyl acetate and hot methanol. Evaporate the filtrate in vacuo and purify the resulting residue by radial chromatography over silica (2-5% MeOH gradient in CH2Cl2) to provide 27 mg of 4-{6-hydroxy-1-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-naphthalen-2-yl}-benzenesulfonic acid 2,2-dimethyl-propyl ester (74%). Dissolve the free base (6.7 mg) in CH2Cl2 (3 mL) and add 0.023 mL (2 equivalents (eq.)) of a 1.0M solution of hydrochloric acid in diethyl ether. Shake this solution for 1-2 minutes at ambient temperature and evaporate it in vacuo to provide 7.1 mg of the title compound. MS (IS+) m/e 590 (M+1−HCl).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.[NH2:12][C:13]1[CH:18]=[N:17][C:16](Br)=[CH:15][N:14]=1.C(=O)([O-])[O-].[Na+].[Na+].C(COC)OC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:16]2[N:17]=[CH:18][C:13]([NH2:12])=[N:14][CH:15]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cnc(Br)cn1
Reactant: COc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cccc(-c2cnc(N)cn2)c1
Temperature: 90 °C
Yield: 63 %

Procedure:
Nitrogen was bubbled through a solution of 3-methoxyphenyl boronic acid (393 mg, 2.59 mmol), 2-amino-5-bromopyrazine (300 mg, 1.72 mmol), sodium carbonate (603 mg, 5.69 mmol), dimethoxyethane (10 mL), and water (3 mL) for 15 min. After this time, the solution was treated with dichlorobis(triphenylphosphine)palladium(II) (121 mg, 0.17 mmol), and the resulting reaction mixture was heated at 90° C. for 2 d. The reaction was then poured into water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 40/60 hexanes/ethyl acetate) afforded 5-(3-methoxy-phenyl)-pyrazin-2-ylamine (218 mg, 63%) as a light yellow solid: mp 113.2–115.5° C.; EI-HRMS m/e calcd for C11H11N3O (M+) 201.0902, found 201.0905.
Reaction SMILES: [C:1]([CH2:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[CH:20](OC)[N:21]([CH3:23])[CH3:22]>C1(C)C=CC=CC=1>[CH3:20][N:21]([CH:23]=[C:9]([C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:8])[C:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:17])[CH3:22]
Reactant: O=C(CC(=O)c1ccccc1)c1ccccc1
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: CN(C)C=C(C(=O)c1ccccc1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
To a solution of dibenzoylmethane (1.072 g, 4.78 mmol) in 6 mL of toluene was added neat N,N-dimethylformamide dimethylacetal (0.7 mL, 630 mg, 5.25 mmol) dropwise via syringe. The resulting solution was stirred at rt for 1 h and then heated at reflux for 16 h. Once at rt, the reaction was concentrated in vacuo. The residue was dissolved in a minimum of CH2Cl2 and added to 13 cm of flash silica gel in a 5 cm dia. column. Elution with 1 L of 1%, 500 mL of 2% and 300 mL of 3% MeOH/CH2Cl2 gave 975 mg of the desired product as a semisolid. Trituration with 50 mL of hexanes gave 772 mg of the title compound as a light yellow solid, mp 123-124° C. (lit mp 120° C., Schenone, P. et al. J. Het. Chem. 1982,19(6), 1355-61).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([S:9][CH3:10])[CH:5]=[CH:4][C:3]=1[C:11](=[O:19])[C:12]([CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[CH2:13]>S(=O)(=O)(O)O>[CH:14]1([CH:12]2[CH2:13][C:4]3[C:3](=[C:2]([Cl:1])[C:7]([Cl:8])=[C:6]([S:9][CH3:10])[CH:5]=3)[C:11]2=[O:19])[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: C=C(C(=O)c1ccc(SC)c(Cl)c1Cl)C1CCCC1
Agent: O=S(=O)(O)O
Product: CSc1cc2c(c(Cl)c1Cl)C(=O)C(C1CCCC1)C2

Procedure:
2-Cyclopentyl-5-methylthio-6,7-dichloro-1-indanone is prepared following substantially the same procedure described in Example 3, Step C, using the following substances: 2',3'-dichloro-4'-methylthio-2-cyclopentylacrylophenone (10 g.) and concentrated sulfuric acid (50 ml.).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:6](=[S:8])[NH2:7])#[N:2].[CH2:17]([O:19][C:20](=[O:26])[CH:21](Cl)[C:22]([CH3:24])=O)[CH3:18]>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:4]=[C:5]([C:6]2[S:8][C:21]([C:20]([O:19][CH2:17][CH3:18])=[O:26])=[C:22]([CH3:24])[N:7]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH:14]([CH3:16])[CH3:15])#[N:2]
Reactant: CC(C)COc1ccc(C(N)=S)cc1C#N
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1sc(-c2ccc(OCC(C)C)c(C#N)c2)nc1C
Temperature: 25 °C
Yield: 54.4 %

Procedure:
Toluene (50 mL) was placed into a round bottom flask and 3-cyano-4-isobutoxybenzothioamide (5.0 g) was added, followed by addition of ethyl-2-chloroacetoacetate (4.25 g). The mixture was heated to reflux and maintained until reaction completion. After the reaction was completed, the mass was cooled to about 25° C. and maintained at that temperature for about 20 minutes. The reaction mass was then filtered and the solid was washed with toluene (10 mL). The wet solid was dried at about 75° C. to a constant weight to yield 4.0 g of the title compound. Purity by HPLC: 99.41%.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[NH:25]1[CH2:30][CH2:29][CH:28]([CH2:31][CH2:32][OH:33])[CH2:27][CH2:26]1>CN(C=O)C.CS(C)=O.CO>[OH:33][CH2:32][CH2:31][CH:28]1[CH2:29][CH2:30][N:25]([C:2]2[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=3)[CH:3]=2)[CH2:26][CH2:27]1
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Reactant: OCCC1CCNCC1
Solvent: CO
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(N3CCC(CCO)CC3)n2n1
Temperature: 25 °C
Yield: 58.4 %

Procedure:
A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 86 mg, 0.25 mmol) and 2-(piperidin-4-yl)ethanol (100 mg, 0.75 mmol) in DMF (1.0 mL) was stirred at 100° C. for 2 h. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC (30-35% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (63.9 mg, 58%). Melting point (234.0-234.1° C.). 1H NMR (DMSO-d6) δ: 10.93 (s, 1H), 8.00 (d, J=8.6 Hz, 2H), 7.61 (d, J=8.6 Hz, 2H), 7.20 (s, 1H), 6.20 (s, 1H), 4.51 (d, J=12.6 Hz, 2H), 3.50 (t, J=6.4 Hz, 2H), 3.07 (t, J=11.5 Hz, 2H), 2.38 (s, 3H), 1.84 (d, J=12.9 Hz, 2H), 1.68-1.81 (m, 1H), 1.46 (s, 6H), 1.41-1.45 (m, 2H), 1.29-1.41 (m, 2H); ESI-MS: m/z 438.3 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:15]=[N:16][CH:17]=[C:18]([CH3:20])[CH:19]=2)[C:3]=1[CH3:21].[O:22]1[CH2:27][CH2:26][N:25]([C:28]2[C:33]([NH2:34])=[CH:32][C:31]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[CH:30][N:29]=2)[CH2:24][CH2:23]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C.[Na+]>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].C1(C)C=CC=CC=1>[O:22]1[CH2:27][CH2:26][N:25]([C:28]2[C:33]([NH:34][C:2]3[C:11]4[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=4[F:12])[N:5]=[C:4]([C:14]4[CH:15]=[N:16][CH:17]=[C:18]([CH3:20])[CH:19]=4)[C:3]=3[CH3:21])=[CH:32][C:31]([N:35]3[CH2:36][CH2:37][O:38][CH2:39][CH2:40]3)=[CH:30][N:29]=2)[CH2:24][CH2:23]1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: Cc1cncc(-c2nc3cc(F)cc(F)c3c(Cl)c2C)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1cncc(-c2nc3cc(F)cc(F)c3c(Nc3cc(N4CCOCC4)cnc3N3CCOCC3)c2C)c1
Temperature: 105 °C
Reaction time: 2 h

Procedure:
A screw-cap vial was charged with 4-chloro-5,7-difluoro-3-methyl-2-(5-methylpyridin-3-yl)quinoline (50 mg, 0.16 mmol), 2,5-dimorpholinopyridin-3-amine (43.4 mg, 0.16 mmol), tris(dibenzylideneacetone)dipalladium (0) (15.0 mg, 0.016 mmol), XPhos (15.6 mg, 0.033 mmol), sodium tert-butoxide (47.3 mg, 0.49 mmol), and toluene (1.5 mL). The mixture was stirred at 105° C. for 2 h, then cond. The resulting residue was partitioned between DCM and water, and the organic layer was dried over magnesium sulfate and cond. The crude material was purified by recrystallization in MeOH, affording N-(2,5-dimorpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(5-methylpyridin-3-yl)quinolin-4-amine. Mass Spectrum (ESI) m/e=533.0 (M+1). 1H NMR (400 MHz, chloroform-d) δ ppm 8.64 (1H, d, J=1.8 Hz), 8.57 (1H, d, J=1.6 Hz), 7.83 (1H, s), 7.78 (1H, br. s.), 7.67 (1H, d, J=2.5 Hz), 7.63 (1H, d, J=9.4 Hz), 6.98-7.09 (1H, m), 6.32-6.42 (1H, m), 3.91 (4H, br. s.), 3.77-3.86 (4H, m), 3.09-3.41 (4H, br. s.), 2.99-3.09 (4H, m), 2.48 (3H, s), 2.17 (3H, s).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][NH2:19])[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3][CH2:2]1.[CH:20]1([C:26](Cl)=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>ClCCl>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][NH:19][C:26]([CH:20]4[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]4)=[O:27])[CH2:15][CH2:16]3)[C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: NCCN1CCN(c2cccc3c2OCCO3)CC1
Reactant: O=C(Cl)C1CCCCC1
Solvent: ClCCl
Product: O=C(NCCN1CCN(c2cccc3c2OCCO3)CC1)C1CCCCC1
Reaction time: 8 h
Yield: 88.1 %

Procedure:
A solution of 2-[4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl-]ethylamine (0.20 g, 0.76 mmol) in dichloromethane (5 mL) was treated with cyclohexanecarbonyl chloride (0.11 g, 0.76 mmol) at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred overnight, during which time it came up to room temperature. The product was precipitated by the addition of hexane to yield the hydrochloride semihydrate salt of the titled compound (0.25 g, 80%) as a white solid; mp=165-166° C.; MS (+) ESI m/z=374 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].C1(CN)CCCCC1.[O:20]=[C:21]1[C:29]2([CH2:33][O:32][C:31]3[CH:34]=[C:35]4[C:39](=[CH:40][C:30]2=3)[CH2:38][CH2:37][O:36]4)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]1[CH2:41][C:42]1[CH:50]=[CH:49][C:45]([C:46](O)=[O:47])=[CH:44][CH:43]=1.O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>>[O:20]=[C:21]1[C:29]2([CH2:33][O:32][C:31]3[CH:34]=[C:35]4[C:39](=[CH:40][C:30]2=3)[CH2:38][CH2:37][O:36]4)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]1[CH2:41][C:42]1[CH:43]=[CH:44][C:45]([C:46]([NH:5][C:4]2[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=2[C:2]([F:10])([F:11])[F:1])=[O:47])=[CH:49][CH:50]=1
Reactant: Nc1ccccc1C(F)(F)F
Reactant: O=C(O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1
Agent: NCC1CCCCC1
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: O=C(Nc1ccccc1C(F)(F)F)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using 2-(trifluoromethyl)aniline to replace cyclohexanemethylamine, and 4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, 4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]-N-[2-(trifluoromethyl)phenyl]benzamide was obtained (53%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ8.39 (d, J=8.2 Hz, 1H), 8.17 (s, 1H), 7.85 (d, J=8.2 Hz, 2H), 7.62 (dd, J=15.9, 7.9 Hz, 2H), 7.48 (d, J=8.2 Hz, 2H), 7.31-7.14 (m, 4H), 7.04 (dd, J=7.6, 7.6, 0.7 Hz, 1H), 6.76 (d, J=7.7 Hz, 1H), 6.47 (s, 1H), 6.43 (s, 1H), 5.02 (ABq, 2H), 4.85 (ABq, 2H), 4.54 (t, J=8.7 Hz, 2H), 3.10-2.90 (m, 2H); 13C NMR (75 MHz, CDCl3) δ178.0, 164.9, 161.9, 161.3, 142.6, 141.7, 140.4, 133.8, 133.1, 132.7, 128.8, 128.0, 127.7, 126.2, 124.6, 124.1 (2C), 123.7, 120.0, 118.8, 109.0, 93.3, 80.6, 72.4, 57.7, 43.8, 29.0; MS (ES+) m/z 557.1 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1.[CH3:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[CH3:19][C:20]1[CH:25]=[C:24]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:12][C:13]3[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=3)[N:3]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Reactant: Cc1cccc(B(O)O)c1
Product: Cc1cccc(-c2nc(Nc3cc(C)[nH]n3)cc3ccccc23)c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 3-methyl-phenylboronic acid to give [1-(3-methyl-phenyl)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 315(MH+).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[NH2:11][CH2:12][CH2:13][OH:14].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH2:5][NH:11][CH2:12][CH2:13][OH:14])[C:3]=1[OH:10]
Reactant: NCCO
Reactant: O=Cc1cccc(Br)c1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCNCc1cccc(Br)c1O
Reaction time: 8 h
Yield: 85.9 %

Procedure:
To a solution of 3-bromo-2-hydroxybenzaldehyde (Preparation 98) (9.6 g, 47.8 mmol) in tetrahydrofuran (250 ml) at 0° C. under nitrogen was added 2-aminoethanol (3.02 ml, 50.1 mmol) then finely powdered sodium triacetoxyborohydride (10.6 g, 50.1 mmol) and the resulting mixture was stirred at 0° C. for 1 h, then stirred overnight and concentrated in vacuo. The residue was triturated under dichloromethane (˜200 mL) and insoluble material was filtered off. The organic phase was concentrated in vacuo and the residue purified using an SCX column to give the title compound as a white solid (10.1 g). MS (ES) C9H1079BrNO2 requires 243 found 244 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.[OH-].[Na+].[CH:21](Cl)(Cl)[Cl:22]>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.O>[Cl:22][C:21]1[CH:7]=[N:8][C:9]2[C:5]([C:6]=1[CH2:12][CH:13]1[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]1)=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2
Reactant: COc1ccc2[nH]cc(CC3CCNCC3)c2c1
Reactant: ClC(Cl)Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: COc1ccc2ncc(Cl)c(CC3CCNCC3)c2c1

Procedure:
The operation is as in Example 1, but starting from 10.2 g of 4-[(5-methoxy-3-indolyl)-methyl]-piperidine and 0.21 g of triethylbenzylammonium chloride in 100 ml of chloroform, and 12.5 g of sodium hydroxide in solution in 25 ml of water. 3.7 g of 3-chloro-6-methoxy-4-[(4-piperidyl)-methyl]-quinoline are finally obtained, the monohydrochloride of which melts above 260° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:10][CH2:11][N:12](C(OC(C)(C)C)=O)[CH2:13][CH:14]=2)=[C:5]([CH:22]([CH3:27])[C:23]([O:25][CH3:26])=[O:24])[CH:4]=1>C(OCC)(=O)C.C(Cl)Cl>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH:10]=2)=[C:5]([CH:22]([CH3:27])[C:23]([O:25][CH3:26])=[O:24])[CH:4]=1
Reactant: COC(=O)C(C)c1cc(Cl)ccc1C1=CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)C(C)c1cc(Cl)ccc1C1=CCNCC1
Reaction time: 1 h
Yield: 112.6 %

Procedure:
A saturated solution of hydrogen chloride in ethyl acetate (6 mL) was added to a solution of tert-butyl 4-[4-chloro-2-(2-methoxy-1-methyl-2-oxoethyl)phenyl]-3,6-dihydropyridine-1(2H)-carboxylate (0.730 g, 1.92 mmol) in methylene chloride (6 mL) at 0° C. After 1 h, the volatiles were evaporated in vacuo, and the crude residue triturated twice with dry diethyl ether to give 2-3 (0.605 g) (m/z (ES) 280 (MH+).
Reaction SMILES: [C:1]([C:3]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2]>C(O)(=O)C.C(O)C.[Pt]=O>[NH2:2][CH2:1][C:3]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccccc2)CC1
Agent: O=[Pt]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(CN)(c2ccccc2)CC1
Yield: 31.7 %

Procedure:
Tert-butyl 4-cyano-4-phenylpiperidine-1-carboxylate (2.6 g, 9.08 mmol) was dissolved in 15% acetic acid/ethanol and hydrogenated at 50 psi over platinum oxide (0.052 g) for a week. HPLC showed only 50% conversion and the reaction was resubmitted to the same conditions and hydrogenated for 4 more days. The reaction was then filtered and the filtrate was evaporated. The residue was diluted with ethyl acetate and 1N hydrochloric acid. The aqueous phase was collected, basified with sodium carbonate and extracted with ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated to give the title material (0.835 g, 32%) as an oil which was used as such for the next reaction. LC/MS (M-(t-Bu)+H)+: 235. HPLC ret. time (Condition B): 1.322 min.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([F:18])[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][C:3]=1[O:4][CH:5]([CH2:11][CH2:12]Br)[C:6]([O:8][CH2:9][CH3:10])=[O:7].CC(C)([O-])C.[K+].Cl>C1COCC1>[Cl:1][C:2]1[CH:17]=[C:16]([F:18])[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][C:3]=1[O:4][C:5]1([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:12][CH2:11]1
Reactant: CCOC(=O)C(CCBr)Oc1cc([N+](=O)[O-])c(F)cc1Cl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(Oc2cc([N+](=O)[O-])c(F)cc2Cl)CC1
Temperature: 25 °C

Procedure:
To a solution containing the obtained ethyl 2-(2-chloro-4-fluoro-5-nitrophenoxy)-4-bromobutanoate (1 equivalent) in THF is added potassium t-butoxide (1 equivalent) at −15° C. and the mixture is stirred. After warming the reaction solution up to room temperature, to the solution is added aqueous diluted hydrochloric acid and extracted with ethyl acetate. After concentrating the organic layer, the residue is subjected to chromatography to give ethyl 1-(2-chloro-4-fluoro-5-nitrophenoxy)cyclopropanecarboxylate.
Reaction SMILES: [CH2:1]([N:3]([CH2:57][CH3:58])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([CH2:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][C:34](O)=[O:35])[CH:16]=[CH:17][CH:18]=2)=[O:12])=[C:6]([C:37]2[CH:42]=[C:41]([C:43](=[O:56])[NH:44][CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[C:48]([C:52]([F:55])([F:54])[F:53])[CH:47]=3)[CH:40]=[CH:39][N:38]=2)[CH:5]=1)[CH3:2].[N:59]1(C(OC(C)(C)C)=O)[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:57]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:12])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][C:34](=[O:35])[N:59]3[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]3)[CH:14]=2)=[C:6]([C:37]2[CH:42]=[C:41]([CH:40]=[CH:39][N:38]=2)[C:43]([NH:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([C:52]([F:53])([F:54])[F:55])[CH:47]=2)=[O:56])[CH:5]=1)[CH3:58]
Reactant: CCN(CC)c1ccc(NC(=O)c2cccc(CCCOCCOCCOCCOCCC(=O)O)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)c1ccc(NC(=O)c2cccc(CCCOCCOCCOCCOCCC(=O)N3CCNCC3)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reaction time: 0.5 h
Yield: 177.4 %

Procedure:
To a mixture of 16-(3-(4-(diethyl amino)-2-(4-(3-(trifluoromethyl)benzylcarbamoyl)pyridin-2-yl)phenylcarbamoyl)phenyl)-4,7,10,13-tetraoxahexadecan-1-oic acid (292 mg, 0.36 mmol), tert-butyl piperazine-1-carboxylate (75 mg, 0.40 mmol) and DIPEA (142 mg, 1.1 mmol) in DMF (3 mL) was added HATU (160 mg, 0.42 mmol). After 30 minutes, the solvent was removed under vacuum and the residue was dissolved in DCM (50 mL). This was washed with water (4×25 mL), dried (Na2SO4) and concentrated. The resulting oil was dissolved in DCM (2 mL) and TFA (2 mL) was added dropwise. After 30 minutes, the solvents were removed under vacuum. The residue was dissolved in 50% ACN/water (30 mL) and freeze dried to give the title compound (560 mg) as a TFA salt.