Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)=[O:27].C(=O)(O)[O-].[K+].[I-].[K+]>C1(C)C=CC=CC=1.O>[ClH:21].[F:34][C:31]1[CH:30]=[CH:29][C:28]([C:26](=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][N:12]2[CH2:13][CH2:14][CH:9]([C:7]([OH:8])([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:10][CH2:11]2)=[CH:33][CH:32]=1
Reactant: OC(c1ccccc1)(c1ccccc1)C1CCNCC1
Reactant: O=C(CCCCCl)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cl
Product: O=C(CCCCN1CCC(C(O)(c2ccccc2)c2ccccc2)CC1)c1ccc(F)cc1
Reaction time: 70 h

Procedure:
A mixture of 19.3 g (0.07 mole) of α,α -diphenyl-4-piperidinemethanol, 17.1 g (0.08 mole) of 5-chloro-4'-fluorovalerophenone, 20.0 g (0.2 mole) of potassium bicarbonate, and 0.1 g of potassium iodide in 250 ml of toluene and 35 ml of water is stirred on a steam bath for 70 hours. The organic layer is separated and combined with two 50 ml toluene extracts of the aqueous layer. The combined organic material is washed with water and saturated sodium chloride solution, dried over magnesium sulfate and filtered. The filtrate is diluted with about 200 ml of ether then made acidic with ethereal HCl. The resulting precipitate is recrystallized from methanol-butanone to give 4'-fluoro-5-[4-(α-hydroxy-α-phenylbenzyl)piperidino]valerophenone hydrochloride, M.P. 177°-179°C.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[N:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:5](=[O:18])[CH:4]=1.[OH-].[Na+].CCOC(C)=O.Cl>C1COCC1.O>[OH:2][C:3]1[CH:8]=[N:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:5](=[O:18])[CH:4]=1
Reactant: COc1ccc(Cn2ncc(OC)cc2=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2ncc(O)cc2=O)cc1
Temperature: 80 °C
Yield: 87 %

Procedure:
To a stirring solution of 5-methoxy-2-(4-methoxybenzyl)pyridazin-3(2H)-one (117 mg, 0.47 mmol) in THF (3 mL) at room temperature under argon was added 1M NaOH (2.0 mL, 2.0 mmol). The resulting reaction mixture was heated at 80° C. under argon for a day and monitored by LCMS until the reaction was completed. EtOAc (20 mL), 1 M HCl (2 mL), and water (10 mL) were added to the reaction mixture. Layers were separated. Organic layer were washed with water (15 mL), and brine (15 mL). Organic phase was dried (MgSO4), filtered and concentrated. The crude product was dissolved in a small amount of DCM (˜2 ml) and loaded onto a 40 g ISCO silica gel column which was eluted with a 20 min gradient from 20% to 100% EtOAc/Hexanes. 95 mg (77%) of 5-hydroxy-2-(4-methoxybenzyl)pyridazin-3(2H)-one was obtained as a gum. MS (ESI) 233 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:12][CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1[CH:20]=O.[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][S:30]([C:33]2[CH:34]=[C:35]3[C:39](=[CH:40][CH:41]=2)[NH:38][C:37](=[O:42])[CH2:36]3)(=[O:32])=[O:31])=[CH:25][CH:24]=1.N1CCCCC1>C(O)C>[F:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:29][S:30]([C:33]2[CH:34]=[C:35]3[C:39](=[CH:40][CH:41]=2)[NH:38][C:37](=[O:42])[C:36]3=[CH:20][C:3]2[NH:4][C:5]3[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][N:14]4[CH2:15][CH2:16][CH2:17][CH2:18]4)[C:7](=[O:19])[C:6]=3[C:2]=2[CH3:1])(=[O:32])=[O:31])=[CH:27][CH:28]=1.[F:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:29][S:30]([C:33]2[CH:34]=[C:35]3[C:39](=[CH:40][CH:41]=2)[NH:38][C:37](=[O:42])/[C:36]/3=[CH:20]\[C:3]2[NH:4][C:5]3[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][N:14]4[CH2:15][CH2:16][CH2:17][CH2:18]4)[C:7](=[O:19])[C:6]=3[C:2]=2[CH3:1])(=[O:32])=[O:31])=[CH:27][CH:28]=1
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3ccc(F)cc3)ccc2N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCC1)CCC2
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4ccc(F)cc4)cc32)[nH]c2c1C(=O)N(CCN1CCCC1)CCC2
Product: Cc1c(C=C2C(=O)Nc3ccc(S(=O)(=O)Cc4ccc(F)cc4)cc32)[nH]c2c1C(=O)N(CCN1CCCC1)CCC2
Temperature: 25 °C
Yield: 164.3 %

Procedure:
3-Methyl-4-oxo-5-(2-pyrrol 8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 28c (60.2 mg, 0.21 mmol) and 5-(4-fluoro-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one 65a (57.6 mg, 0.19 mmol) were dissolved in 2 ml of ethanol, and added with 50 μl of piperidine to the solution at room temperature. Upon completion of the addition, the reaction mixture was heated to reflux for 3 hours. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was naturally cooled down to room temperature, and filtered. The filter cake was washed with anhydrous ethanol (3 ml×2) and dried to obtain the title compound (Z)-2-[5-(4-fluoro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-3-methyl-5-(2-pyrrolidin-1-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 65 (90 mg, yield 81.8%) as an orange solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)[CH3:2].[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])[CH3:12]>>[CH2:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CC(=O)c1ccccc1
Reactant: CCc1ccc(C=O)cc1
Product: CCc1ccc(C=CC(=O)c2ccccc2)cc1

Procedure:
By a procedure similar to that of example 1.59.1, starting from 4-ethylbenzaldehyde and acetophenone, 3-(4-ethylphenyl)-1-phenylprop-2-en-1-one was obtained as yellow oil.
Reaction SMILES: [N:1]#[N:2].C([O:10][C:11]([C:13]1[CH:52]=[CH:51][C:16]([C:17]([NH:19][C@H:20]([C:25]([NH:27][C@@H:28]([CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C@H:29]([OH:43])[CH2:30][C@@:31]2([C:40]([NH2:42])=[O:41])[CH2:35][CH2:34][CH2:33][N:32]2[C:36]([CH3:39])([CH3:38])[CH3:37])=[O:26])[CH2:21][C:22](=[O:24])[NH2:23])=[O:18])=[CH:15][CH:14]=1)=[O:12])C1C=CC=CC=1>C(O)(C)C.[Pd]>[N:1]#[N:2].[C:11]([C:13]1[CH:52]=[CH:51][C:16]([C:17]([NH:19][C@H:20]([C:25]([NH:27][C@@H:28]([CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C@H:29]([OH:43])[CH2:30][C@@:31]2([C:40]([NH2:42])=[O:41])[CH2:35][CH2:34][CH2:33][N:32]2[C:36]([CH3:39])([CH3:38])[CH3:37])=[O:26])[CH2:21][C:22](=[O:24])[NH2:23])=[O:18])=[CH:15][CH:14]=1)([OH:12])=[O:10]
Reactant: CC(C)(C)N1CCC[C@@]1(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)c1ccc(C(=O)OCc2ccccc2)cc1)C(N)=O
Agent: [Pd]
Agent: N#N
Solvent: CC(C)O
Product: CC(C)(C)N1CCC[C@@]1(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)c1ccc(C(=O)O)cc1)C(N)=O
Yield: 80.6 %

Procedure:
274 mg of N2 -[3(S)-[[N-[4-(benzyloxycarbonyl)-benzoyl]-L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N1 -tert.butyl-L-prolinamide in 100 ml of isopropanol were hydrogenated over 10% palladium-on-carbon at 20° C. and under atmospheric pressure for 16 hours. The catalyst was removed by filtration and the filtrate was evaporated to give 193 mg of N2 -[3(S)-[[N-(4-carboxybenzoyl)-L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N1 -tert.butyl-L-prolinamide as a white solid from methanol/ethylacetate: MS: m/e 596 [M+H]+.
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:12]2[NH:11][C:10](=[O:15])[C:9]3[NH:16][CH:17]=[C:18]([C:19]([OH:21])=[O:20])[C:8]=3[C:7]=2[CH:6]=1)(=[O:4])=[O:3].Cl.[CH3:23][NH:24][CH3:25]>>[CH3:23][N:24]([CH3:25])[S:2]([C:5]1[CH:14]=[CH:13][C:12]2[NH:11][C:10](=[O:15])[C:9]3[NH:16][CH:17]=[C:18]([C:19]([OH:21])=[O:20])[C:8]=3[C:7]=2[CH:6]=1)(=[O:4])=[O:3]
Reactant: O=C(O)c1c[nH]c2c(=O)[nH]c3ccc(S(=O)(=O)Cl)cc3c12
Reactant: CNC
Agent: Cl
Product: CN(C)S(=O)(=O)c1ccc2[nH]c(=O)c3[nH]cc(C(=O)O)c3c2c1

Procedure:
8-Dimethylsulfamoyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid is prepared according to synthesis 178, from 326 mg (1 mmol) of 8-chlorosulfonyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid and 85 mg (1.05 mmol) of dimethylamine hydrochloride to give, after purification by precipitation and trituration in water, 210 mg (62%) of 8-dimethylsulfamoyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid in the form of a gray solid.
Reaction SMILES: CC([O:5][C:6](=[O:37])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:36])[C:16]#[C:17][C:18]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=2/[C:20](=[CH:28]/[C:29]2[NH:30][CH:31]=[CH:32][C:33]=2[O:34][CH3:35])/[C:21](=[O:27])[NH:22]3)=[CH:11][CH:10]=1)(C)C.O[Li].O>C1COCC1.O>[CH3:35][O:34][C:33]1[CH:32]=[CH:31][NH:30][C:29]=1/[CH:28]=[C:20]1\[C:21](=[O:27])[NH:22][C:23]2[C:19]\1=[C:18]([C:17]#[C:16][CH:15]([C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:7][C:6]([OH:37])=[O:5])=[CH:14][CH:13]=1)[OH:36])[CH:26]=[CH:25][CH:24]=2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CC(O)c3ccc(OCC(=O)OC(C)(C)C)cc3)c21
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CC(O)c3ccc(OCC(=O)O)cc3)c21

Procedure:
Using Method F above, rac-(Z)-[4-[3-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-4-yl]-1-hydroxy-2-propynyl]phenoxy]acetic acid 1,1-dimethylethyl ester (from Example 58 above) (30 mg, 0.061 mmol) was hydrolyzed with LiOH.H2O (58 mg, 1.22 mmol) in THF (0.5 mL) and H2O (0.5 mL) for 12 h, yielding rac-(Z)-[4-[3-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-4-yl]-1-hydroxy-2-propynyl]phenoxy]acetic acid. (Yield 24 mg, 89%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:9]([CH3:10])[CH2:8][CH2:7][CH2:6][CH:5]1[CH3:11].[C:12]([N:16]=[C:17]=[S:18])(=[O:15])[CH2:13][CH3:14]>>[C:12]([NH:16][C:17]([NH:1][CH2:2][CH2:3][N:4]1[CH:9]([CH3:10])[CH2:8][CH2:7][CH2:6][CH:5]1[CH3:11])=[S:18])(=[O:15])[CH2:13][CH3:14]
Reactant: CC1CCCC(C)N1CCN
Reactant: CCC(=O)N=C=S
Product: CCC(=O)NC(=S)NCCN1C(C)CCCC1C

Procedure:
By the general method described in Example 1, 1-(2-aminoethyl)-2,6-dimethylpiperidine is reacted with propionyl isothiocyanate to give the title compound which may be hydrolysed with 10% sodium hydroxide to give N-2[(2,6-dimethylpiperidino)-ethyl]thiourea.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](OB(O)O)=[CH:11][C:10]=1[C:19]#[N:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][N:31]=1)[C:25]([O:27][CH3:28])=[O:26].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:22]2[CH:23]=[C:24]([CH:29]=[CH:30][N:31]=2)[C:25]([O:27][CH3:28])=[O:26])=[CH:11][C:10]=1[C:19]#[N:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cc(OB(O)O)ccc1OCc1ccccc1
Reactant: COC(=O)c1ccnc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccnc(-c2ccc(OCc3ccccc3)c(C#N)c2)c1
Temperature: 10 °C

Procedure:
[4-(Benzyloxy)-3-cyanophenyl]boric acid and methyl 2-chloroisonicotinate were dissolved in a mixture liquid of toluene and an aqueous 2 M sodium carbonate solution, and in the presence of tetrakis(triphenylphosphine)palladium, the mixture was stirred under heating in an argon atmosphere at 10° C. to obtain methyl 2-[4-(benzyloxy)-3-cyanophenyl]isonicotinate. F: 345.
Reaction SMILES: [OH-:1].[K+].[C:3]([N:7]=[N:8][C:9](Cl)([CH3:19])[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:13])([CH3:6])([CH3:5])[CH3:4].[CH3:21]O>>[C:3]([N:7]=[N:8][C:9]([O:1][CH3:21])([CH3:19])[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:13])([CH3:6])([CH3:5])[CH3:4]
Reactant: [OH-]
Reactant: CO
Reactant: CCCCOC(=O)CCC(C)(Cl)N=NC(C)(C)C
Agent: [K+]
Product: CCCCOC(=O)CCC(C)(N=NC(C)(C)C)OC
Reaction time: 0.5 h
Yield: 71 %

Procedure:
To a stirred solution of 19.7 grams (0.3 moles) of 85% KOH in 150 ml. of methanol cooled in an ice bath was added 80 grams (0.29 moles) of n-butyl 4-t-butylazo-4-chlorovalerate (prepared as in Example XX) dropwise over 1/2 hour. The reaction mixture was stirred an additional 1/2 hour after the addition was complete, poured into 300 ml. of water and extracted with pentane. The pentane solution was washed with water, saturated NaHCO3 solution, water, dried over anhydrous Na2SO4, filtered and the pentane evaporated to leave 55.5 grams (71% yield) of the desired ester.
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1>C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.O.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.ClC1C=CC(B(O)O)=CC=1>[Cl:1][C:2]1[C:3]([C:14]2[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=2)=[CH:4][C:5]([F:8])=[N:6][CH:7]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Fc1cc(I)c(Cl)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Fc1cc(-c2ccc(Cl)cc2)c(Cl)cn1
Temperature: 140 °C
Yield: 107.4 %

Procedure:
A suspension of 5-chloro-2-fluoro-4-iodopyridine (2.57 g, 10 mmol), 4-chlorophenylboronic acid (1.72 g, 11 mmol) and Pd(Ph3P)4 (462 mg, 0.4 mmol) in a mixture of 2.0 M aqueous sodium carbonate (6 mL) and toluene (10 mL) was heated at 140 ° C. in a microwave oven for 30 min. Analysis by HPLC/MS indicated that the reaction was not complete. Additonal 4-chlorophenylboronic acid (0.156 g, 1 mmol) was added, followed by Pd(Ph3P)4 (116 mg, 0.1 mmol). The reaction mixture was again heated at 140° C. in a microwave oven for 30 min. After cooling to room temperature, the reaction mixture was diluted with water and extracted with EtOAc (50 mL×3). The combined EtOAc extracts were washed with saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified using a silica gel cartridge (120 g) eluted with a gradient of EtOAc (0-50%) in hexanes to afford 2.6 g of the product (˜60% pure) as an off-white solid. This was crystallized in EtOAc-hexanes to obtain the pure title compound (0.9 g) as a white solid. HPLC/MS: retention time=3.80 min, [M+H]+=242.0.
Reaction SMILES: [OH:1][CH:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]1([C:6]([O:8]C(C)(C)C)=[O:7])[CH2:5][CH2:4]1.[OH-].[Na+]>C1COCC1.CO.Cl>[OH:1][CH:2]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:3]1([C:6]([OH:8])=[O:7])[CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)C1(C(O)c2ccccc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1(C(O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 80.8 %

Procedure:
To a solution of tert-butyl 1-(hydroxy(phenyl)methyl)cyclopropanecarboxylate (0.56 g, 2.255 mmol) in THF (4 mL) and MeOH (1 mL) was added 10 N sodium hydroxide (3 mL, 30.0 mmol). The reaction mixture was stirred at rt for 12 h. The reaction was diluted with 1 N HCl, extracted with 2×EtOAc, and the combined organic phase was washed with sat. NaCl, dried (anhydrous Na2SO4), filtered and concentrated to yield 1-(hydroxy(phenyl)methyl)cyclopropanecarboxylic acid (0.35 g, 81% yield) as Cap N-11. 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.48-7.26 (m, 5H), 4.94 (s, 1H), 1.46 (ddd, J=9.8, 7.0, 4.3 Hz, 1H), 1.38-1.30 (m, 1H), 1.08 (ddd, J=9.5, 7.1, 4.3 Hz, 1H), 0.93-0.84 (m, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([N+:34]([O-])=O)=[C:13]([NH:15][C:16]3[S:17][C:18]([C:31]([NH2:33])=[O:32])=[C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=4)[N:20]=3)[CH:14]=2)[CH2:4][CH2:3]1.[H][H].[CH:39]([OH:41])=[O:40]>[Pd]>[F:28][C:27]([F:30])([F:29])[C:39]([OH:41])=[O:40].[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]3[N:34]=[CH:39][N:15]([C:16]4[S:17][C:18]([C:31]([NH2:33])=[O:32])=[C:19]([C:21]5[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=5)[N:20]=4)[C:13]=3[CH:14]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(Cc2ccc([N+](=O)[O-])c(Nc3nc(-c4cccc(C(F)(F)F)c4)c(C(N)=O)s3)c2)CC1
Reactant: O=CO
Reactant: [H][H]
Agent: [Pd]
Product: CN1CCN(Cc2ccc3ncn(-c4nc(-c5cccc(C(F)(F)F)c5)c(C(N)=O)s4)c3c2)CC1
Product: O=C(O)C(F)(F)F

Procedure:
A mixture of 0.1244 g (0.239 mmole) of 2-[5-(4-methyl-piperazin-1-ylmethyl)-2-nitro-phenylamino]-4-(3-trifluoromethylphenyl)-thiazole-5-carboxylic acid amide (VI.48c), 0.1186 g of 10% palladium on carbon catalyst and 10.4 mL of 96% formic acid was stirred under one atmosphere of hydrogen for 16 hours. The mixture was filtered through diatomaceous earth and the filter pad was washed with tetrahydrofuran. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase silica gel chromatography, eluting with acetonitrile-water-trifluoroacetic acid (gradient 10:90:0.1-60:40:0.1) to give 0.0693 g of 2-[6-(4-methyl-piperazin-1-ylmethyl)-benzoimidazol-1-yl]-4-(3-trifluoromethyl-phenyl)thiazole-5-carboxylic acid amide trifluoroacetic acid salt (I.48a). This salt was partitioned between 10 mL of saturated sodium carbonate solution and 150 mL of ethyl acetate. The organic layer was washed with 15 mL of water, then 15 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 0.0693 g of 2-[6-(4-methyl-piperazin-1-ylmethyl)-benzoimidazol-1-yl]-4-(3-trifluoromethyl-phenyl)thiazole-5-carboxylic acid amide (I.48) as a white solid. MH+/Z=501.
Reaction SMILES: [CH3:1][NH2:2].[Cl:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][C:8]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][N:15]=3)=[CH:9][CH:10]=2)[N:5]=1.[ClH:22]>CO.C(OCC)(=O)C.O1CCOCC1>[ClH:3].[ClH:22].[CH3:21][O:20][C:18]1[CH:17]=[CH:16][N:15]=[C:14]([C:8]2[CH:7]=[C:6]3[C:11]([CH:12]=[CH:13][C:4]([NH:2][CH3:1])=[N:5]3)=[CH:10][CH:9]=2)[CH:19]=1
Reactant: COc1ccnc(-c2ccc3ccc(Cl)nc3c2)c1
Reactant: CN
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CO
Product: CNc1ccc2ccc(-c3cc(OC)ccn3)cc2n1

Procedure:
To a solution of methylamine in methanol (40% w/w, 5 ml) was added 2-chloro-7-(4-methoxypyridin-2-yl)quinoline (140 mg). The mixture was heated in a steel autoclave at 120° C. for 16 hours. After cooling, the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 25 g, 5% methanol in dichloromethane). The compound obtained was dissolved in ethyl acetate, and a solution of hydrogen chloride in 1,4-dioxane (4N, 1 ml) was added. The precipitate was collected by filtration and dried to give 7-(4-methoxypyridin-2-yl)-2-methylaminoquinoline dihydrochloride (106 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[OH:11].C([O-])([O-])=O.[K+].[K+].[Cl:18][CH2:19][CH2:20][CH2:21]Br>CC(C)=O>[Cl:18][CH2:19][CH2:20][CH2:21][O:11][C:4]1[CH:5]=[C:6]([O:9][CH3:10])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: ClCCCBr
Reactant: COc1ccc(OC)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(OC)c(OCCCCl)c1
Yield: 86.2 %

Procedure:
A mixture of 2,5-dimethoxyphenol (29 g, 0.19 mol), K2CO3 (35 g), 3-chlorobromopropane (38.5 g, 0.25 mol) and acetone (250 ml) was stirred and refluxed for 6 hours, and then stirred at ambient temperature for 16 hours. The reaction was filtered, and the filtrate was concentrated to an orange liquid. The liquid was taken up into ET2O, and the organic layer washed with 1N NaOH, H2O, dried (MgSO4) and was concentrated to yield 37.8 g of an orange solid. An 11.7 g sample of this solid was flash chromatographed on silica gel (180 g) with 5% EtOAc/CH2Cl2 as eluent. Concentration of similar fractions gave 7.2 g of white, waxy solid, which was recrystallized from petroleum ether to afford a white solid, m.p. 48°-50° C.
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12]C(C#N)=[CH:8][C:7]=2[C:14]([F:17])([F:16])[F:15])[CH:5]=[CH:4][N:3]=[CH:2]1.Cl.[C:19]([OH:22])(=[O:21])[CH3:20]>>[N:1]1([C:6]2[CH:13]=[CH:12][C:20]([C:19]([OH:22])=[O:21])=[CH:8][C:7]=2[C:14]([F:15])([F:16])[F:17])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: N#Cc1ccc(-n2ccnc2)c(C(F)(F)F)c1
Reactant: CC(=O)O
Agent: Cl
Product: O=C(O)c1ccc(-n2ccnc2)c(C(F)(F)F)c1
Temperature: 95 °C
Reaction time: 16 h

Procedure:
A mixture of 4-(1H-imidazol-1-yl)-3-(trifluoromethyl)-benzonitrile (1.99 g, 8.4 mmol), 12 mL of acetic acid and 6 mL of 12M hydrochloric acid (37%) is shaken for 16 hours at 95° C. After cooling down the reaction mixture is evaporated under reduced pressure. The resulting residue is dissolved in water and the pH is adjusted to ˜5-6 by dropwise addition of 1M sodium hydroxide solution. The precipitate is filtered off, washed with water and dried in vacuo to afford the title compound as a solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[N:12]2[CH:13]=[CH:14][N:15]=[C:11]2[CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>>[CH3:23][S:24]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[N:12]2[CH:13]=[CH:14][N:15]=[C:11]2[CH:10]=[CH:9][CH:8]=1)(=[O:26])=[O:25]
Reactant: OCCCCOc1cccc2nccn12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCCOc1cccc2nccn12

Procedure:
Using 1.65 g (8.0 mmol) of 5-(4-hydroxybutyloxy)-imidazo[1,2-a]pyridine, 1.23 ml (8.8 mmol) of triethylamine and 0.68 ml (8.8 mmol) of methanesulfonyl chloride, the same procedure as in Reference Example 8 was followed, to yield 5-(4-methanesulfonyloxybutyloxy)imidazo[1,2-a]pyridine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:21]([C:22]([OH:24])=O)[CH2:20][C:19]2[CH:18]=[C:17]3[C:12]([O:13][C@@H:14]([C:26]4[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]5[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([Cl:41])[CH:35]=5)=[CH:28][CH:27]=4)[CH2:15][N:16]3[CH3:25])=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:75][O:76][C:77](=[O:95])[C@@H:78]([NH2:94])[CH2:79][C:80]1[CH:85]=[CH:84][C:83]([C:86]2[CH:91]=[CH:90][C:89]([C:92]#[N:93])=[CH:88][CH:87]=2)=[CH:82][CH:81]=1>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH:21]([C:22](=[O:24])[NH:94][C@H:78]([C:77]([O:76][CH3:75])=[O:95])[CH2:79][C:80]2[CH:81]=[CH:82][C:83]([C:86]3[CH:91]=[CH:90][C:89]([C:92]#[N:93])=[CH:88][CH:87]=3)=[CH:84][CH:85]=2)[CH2:20][C:19]2[CH:18]=[C:17]3[C:12]([O:13][C@@H:14]([C:26]4[CH:27]=[CH:28][C:29]([O:32][CH2:33][C:34]5[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([Cl:41])[CH:35]=5)=[CH:30][CH:31]=4)[CH2:15][N:16]3[CH3:25])=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccc(C#N)cc2)cc1
Reactant: CN1C[C@H](c2ccc(OCc3ccc(Cl)c(Cl)c3)cc2)Oc2cc3c(cc21)CC(C(=O)O)N(C(=O)OC(C)(C)C)C3
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CN3C

Procedure:
To a stirring solution of (S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylic acid 6-tert-butyl ester, HBTU (95 mg) and DIEA in DMF (5 mL) was added (S)-2-amino-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (79 mg). After 4 hours a sufficient amount of water was added and the mixture was extracted with ethyl acetate. The organic was washed with 1 N HCl, saturated NaHCO3 and brine, and dried over sodium sulfate. The solvent was removed under reduced pressure to provide the crude amide. The residue was purified by column chromatography on silica gel (hexanes/ethyl acetate from 80:20 to 60:40) to afford the product (180 mg).