Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[C:9]2[CH:13]1[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]1)=[O:3]>CO.Cl.O1CCOCC1>[F:32][C:29]1[CH:28]=[CH:27][C:26]([C:6]2[CH:7]=[C:8]3[C:12](=[C:4]([C:2]([NH2:1])=[O:3])[CH:5]=2)[NH:11][CH:10]=[C:9]3[CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(F)cc4)cc23)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NC(=O)c1cc(-c2ccc(F)cc2)cc2c(C3CCNCC3)c[nH]c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.8 %

Procedure:
To a solution of 1,1-dimethylethyl 4-[7-(aminocarbonyl)-5-(4-fluorophenyl)-1H-indol-3-yl]-1-piperidinecarboxylate (92.9 g, 0.205 mmol) in methanol (10 mL), HCl in dioxane (4M, 2.01 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and the resulting residue was partitioned between ethyl acetate (50 mL) and 5% of aqueous NaOH (50 mL). The aqueous layer washed with ethyl acetate (2×50 mL) and the combined organic phases were dried and concentrated under reduced pressure to give desired product (55.9 mg, 78%), which was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:12])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][N:8]=[CH:7][CH:6]=2.[CH2:13]([O:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25](Cl)=[CH:26][CH:27]=[N:28]2)=[CH:23][C:22]=1[O:32][CH3:33])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH2:13]([O:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25]([O:1][C:2]3[C:3]([CH3:12])=[N:4][C:5]4[C:10]([CH:11]=3)=[CH:9][N:8]=[CH:7][CH:6]=4)=[CH:26][CH:27]=[N:28]2)=[CH:23][C:22]=1[O:32][CH3:33])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cc1nc2ccncc2cc1O
Reactant: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2c(Oc3cc4cnccc4nc3C)ccnc2cc1OCc1ccccc1
Temperature: 140 °C
Reaction time: 4 h
Yield: 56.5 %

Procedure:
3-Hydroxy-2-methyl-[1,6]naphthyridine (400 mg), 7-benzyloxy-4-chloro-6-methoxyquinoline (2.25 g), and 4-dimethylaminopyridine (915 mg) were suspended in o-dichlorobenzene (8 ml), and the suspension was stirred at 140° C. for 4 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform-methanol to give the title compound (597 mg, yield 56%).
Reaction SMILES: C([Li])(C)(C)C.[OH:6][CH:7]([C:20]1[CH:21]=[C:22]([Si:25]([CH3:28])([CH3:27])[CH3:26])[O:23][CH:24]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[CH:29]1([C:35](Cl)=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>CCCCC.O1CCCC1>[CH:29]1([C:35]([O:6][CH:7]([C:20]2[CH:21]=[C:22]([Si:25]([CH3:28])([CH3:27])[CH3:26])[O:23][CH:24]=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: CCCCCCCCCCCCC(O)c1coc([Si](C)(C)C)c1
Reactant: O=C(Cl)C1CCCCC1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCCCCCCCCCCCC(OC(=O)C1CCCCC1)c1coc([Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
tert-Butyl lithium (a 1.7 M solution in pentane; 0.33 ml, 0.55 mmol) was added dropwise to a solution of 4-(1-hydroxytridecyl)-2-trimethylsilylfuran (170 mg, 0.50 mmol) in tetrahydrofuran (5 ml) at 0 degrees under argon. After 10 minutes, cyclohexanecarboxylic acid chloride (74 microliter, 0.55 mmol) was added. The mixture was stirred at room temperature for 15 hours and quenched with water. Extraction and evaporation of the dried (magnesium sulphate) extracts gave an oil, which was purified by preparative TLC (20×20 cm, 1000u silica plate; developed with 5% ethyl ether/hexane). The title ester was obtained as a pale yellow oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[H-].[K+].[NH2:8][C:9]1[N:14]=[C:13](Br)[C:12]([C:16]#[N:17])=[C:11]([S:18][CH3:19])[N:10]=1>COCCOCCOC>[NH2:8][C:9]1[N:10]=[C:11]([S:18][CH3:19])[C:12]([C:16]#[N:17])=[C:13]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)[N:14]=1
Reactant: c1cn[nH]c1
Reactant: CSc1nc(N)nc(Br)c1C#N
Agent: [H-]
Agent: [K+]
Solvent: COCCOCCOC
Product: CSc1nc(N)nc(-n2cccn2)c1C#N
Temperature: 60 °C
Yield: 27.4 %

Procedure:
To a stirred solution of 500 mg (7.34 mmol) pyrazole in 15 ml diglyme at room temperature under argon was added 0.90 ml (7.34 mmol) potassium hydride (35% dispersion in oil) and the reaction mixture heated at 60° C. for 2 hours. 1.50 g (6.12 mmol) 2-amino-4-bromo-6-methylsulfanyl-pyrimidine-5-carbonitrile was then added and the reaction mixture heated at 60° C. for 16 h, then cooled to room temperature, 2 g of kieselgel added, and the mixture concentrated in vacuo. Flash chromatography (ethyl acetate/hexane 1/3) afforded 390 mg (27%) 2-amino-4-methylsulfanyl-6-pyrazol-1-yl-pyrimidine-5-carbonitrile as a white crystalline solid. EI-MS m/e (%): 232 (M+, 61), 231 ([M—H]+, 100).
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[CH3:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=1[CH3:12].F>>[CH3:5][C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:2]([NH2:3])=[S:1]
Reactant: N#C[S-]
Reactant: Cc1ccccc1C
Agent: F
Agent: [K+]
Product: Cc1ccc(C(N)=S)cc1C
Temperature: 25 °C
Reaction time: 10 h

Procedure:
At a temperature as indicated in Example 1, 59 g of potassium thiocyanate (0.6 mol) and 79.5 g of o-xylene (0.75 mol) are stirred with 0.5 l of 98% hydrofluoric acid. and the mixture is then stirred for 10 hours at room temperature. Subsequently, the batch is poured onto ice, the precipitated product is suction-filtered after having been stirred for one-half hour, and the greater part of the non-reacted o-xylene (15 g) is separated from the still moist filter cake by steam distillation. The distillation residue is subsequently suction-filtered and dried. The yield of dimethylthiobenzamide having a melting point of 120° - 125° C is 99 g and therefore quantitative, relative to the potassium thiocyanate used.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:31]=[CH:30][C:16]([CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]([F:29])=[C:23]([CH:28]=3)[C:24]([O:26][CH3:27])=[O:25])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH:32]1([CH:35]=O)[CH2:34][CH2:33]1>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][N:18]([CH2:35][CH:32]3[CH2:34][CH2:33]3)[C:19]3[CH:20]=[CH:21][C:22]([F:29])=[C:23]([CH:28]=3)[C:24]([O:26][CH3:27])=[O:25])=[CH:30][CH:31]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=CC1CC1
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc(F)c(C(=O)OC)c3)cc2)cc1
Product: CCCCc1ccc(C#Cc2ccc(CN(CC3CC3)c3ccc(F)c(C(=O)OC)c3)cc2)cc1
Yield: 54.6 %

Procedure:
The title compound was prepared following procedure described in example 23, step b) from methyl 5-({4-[(4-butylphenyl)ethynyl]benzyl}amino)-2-fluorobenzoate (326 mg; 0.78 mmol) and cyclopropanecarboxaldehyde (Aldrich, 87.94 μl; 1.18 mmol). Purification of the crude by preparative HPLC using a X-Terra column gave 200 mg (54%) of the title compound as a beige oil. HPLC, Rt: 5.91 min (purity: 99.7%), LC/MS, M+(ESI): 470.4, 1H NMR (CDCl3) δ: 7.66 (m, 1H), 7.39 (d, J=7.9 Hz, 4H), 7.00-7.17 (m, 6H), 4.62 (s, 2H), 3.93 (s, 3H), 3.44 (m, 3H), 2.59 (t, J=7.7 Hz, 2H), 1.57 (m, 2H), 1.31 (m, 2H), 0.90 (t, J=7.2 Hz, 3H), 0.53 (d, J=7.2 Hz, 2H), 0.24 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[NH:3]1.[O:11]1[CH2:35][CH:12]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH:32]3[O:34][CH2:33]3)=[CH:26][CH:25]=2)([CH3:23])[CH3:22])=[CH:17][CH:16]=1>C(O)(C)(C)C>[OH:34][CH:32]([CH2:33][N:3]1[C:4]([CH3:9])([CH3:8])[CH2:5][CH2:6][CH2:7][C:2]1([CH3:10])[CH3:1])[CH2:31][O:30][C:27]1[CH:26]=[CH:25][C:24]([C:21]([C:18]2[CH:19]=[CH:20][C:15]([O:14][CH2:13][CH:12]([OH:11])[CH2:35][N:3]3[C:4]([CH3:9])([CH3:8])[CH2:5][CH2:6][CH2:7][C:2]3([CH3:10])[CH3:1])=[CH:16][CH:17]=2)([CH3:22])[CH3:23])=[CH:29][CH:28]=1
Reactant: CC(C)(c1ccc(OCC2CO2)cc1)c1ccc(OCC2CO2)cc1
Reactant: CC1(C)CCCC(C)(C)N1
Solvent: CC(C)(C)O
Product: CC(C)(c1ccc(OCC(O)CN2C(C)(C)CCCC2(C)C)cc1)c1ccc(OCC(O)CN2C(C)(C)CCCC2(C)C)cc1

Procedure:
To 50 ml of t-butanol were added 14.1 g of 2,2,6,6-tetramethylpiperidine and 10.2 g of 2,2-bis[p-(2,3-epoxypropoxy)phenyl]propane, and the mixture was reacted following the procedure described in Example 21 to give the desired Compound No. 1 in the form of white crystals melting at 110°-112° C.
Reaction SMILES: [ClH:1].Cl.[CH2:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[NH:14][C:15]([C:17]2[N:21]3[CH:22]=[CH:23][C:24]([C:26]([N:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:27])=[CH:25][C:20]3=[N:19][CH:18]=2)=[O:16])[N:7]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[N:36]=2)[N:6]=1)[CH3:4].[C:42](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C=O>ClCCl.CO>[ClH:1].[ClH:1].[CH2:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[NH:14][C:15]([C:17]2[N:21]3[CH:22]=[CH:23][C:24]([C:26]([N:28]4[CH2:29][CH2:30][N:31]([CH3:42])[CH2:32][CH2:33]4)=[O:27])=[CH:25][C:20]3=[N:19][CH:18]=2)=[O:16])[N:7]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[N:36]=2)[N:6]=1)[CH3:4]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(C(=O)N5CCNCC5)ccn34)c12
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(C(=O)N5CCN(C)CC5)ccn34)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(piperazine-1-carbonyl)imidazo[1,2-a]pyridine-3-carboxamide dihydrochloride (Example 12; 5 mg, 0.0084 mmol) in dichloromethane/methanol (1:1; 1 mL) was added an excess of sodium triacetoxyborohydride and formaldehyde solution. The mixture was stirred at ambient temperature for 2 hours. Further excess sodium triacetoxyborohydride and formaldehyde solution were added and the mixture was stirred an additional 0.5 hours. The mixture was concentrated under a stream of nitrogen and the residue was purified using preparative thin layer chromatography on silica, eluting with 15% methanol and 0.5% ammonium hydroxide in dichloromethane to provide the desired product (free base form). This material was dissolved in methanol and filtered. To the filtrate was added hydrogen chloride (1 mL; 2M in ether) and the solvent was evaporated to a residual film under a stream of nitrogen. The material was dried under high vacuum to give N-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(4-methylpiperazine-1-carbonyl)imidazo[1,2-a]pyridine-3-carboxamide dihydrochloride (3.3 mg). MS (APCI), positive scan, m/z=537.3 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[NH:34][C:35]([C:37]1([C:40](=[O:48])[NH:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:39][CH2:38]1)=[O:36])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([N:12](C(OC2C=CC=CC=2)=O)[C:13](=O)[O:14]C2C=CC=CC=2)[CH:7]=1.[CH3:49][N:50]([CH3:56])[CH:51]1[CH2:55][CH2:54][NH:53][CH2:52]1>CN(C)C=O>[CH3:49][N:50]([CH3:56])[C@@H:51]1[CH2:55][CH2:54][N:53]([C:13]([NH:12][C:8]2[CH:7]=[C:6]([O:5][C:4]3[CH:31]=[CH:32][C:33]([NH:34][C:35]([C:37]4([C:40]([NH:41][C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=5)=[O:48])[CH2:39][CH2:38]4)=[O:36])=[C:2]([F:1])[CH:3]=3)[CH:11]=[CH:10][N:9]=2)=[O:14])[CH2:52]1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccccc4)CC3)c(F)c2)ccn1
Reactant: CN(C)C1CCNC1
Solvent: CN(C)C=O
Product: CN(C)[C@@H]1CCN(C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccccc5)CC4)c(F)c3)ccn2)C1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 78.6 %

Procedure:
To a solution of phenyl N-[4-(3-fluoro-4-{[1-(phenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate (50.0 mg) in N,N-dimethylformamide (1.0 ml) was added 3R)-(+)-3-dimethylaminopyrrolidine (44 mg), followed by stirring at room temperature for 3.5 hr. The reaction mixture was partitioned between ethyl acetate and 1N sodium hydroxide. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (Fuji Silysia NH, ethyl acetate:methanol=98:2). Fractions containing the target compound were concentrated. A solid was precipitated by addition of diethyl ether:hexane=1:2 to the residue. The solvent was removed, and the residue was dried under reduced pressure to provide the titled compound as white powder (33.2 mg, 79%).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4][OH:5].N(C(OC(C)C)=O)=NC(OC(C)C)=O.O[C:26]1[CH:27]=[C:28]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:29]=[CH:30][C:31]=1[O:32][CH3:33].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CCOCC>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4][O:5][C:30]1[CH:29]=[C:28]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:27]=[CH:26][C:31]=1[O:32][CH3:33]
Reactant: CCOC(=O)Cc1ccc(OC)c(O)c1
Reactant: Cc1cccc(C)c1CO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)Cc1ccc(OC)c(OCc2c(C)cccc2C)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 2,6-Dimethylbenzyl alcohol (3.23 g, 23.7 mmol) and diisopropyl azodicarboxylate (DIAD, 5.23 g, 25.9 mmol) in THF (20 ml) was added drop wise to a solution of Ethyl 2-(3-Hydroxy-4-methoxyphenyl)acetate (Step A, 5.48 g, 26.12 mmol) and triphenylphosphine (6.79 g, 25.9 mmol) in THF (100 ml) at 0° C. The reaction mixture was stirred at room temperature for 4 hours, diluted with ether and washed with water and brine. The organic layer was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex:ethyl acetate 4:1) to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10](I)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:13][C:14]1[CH:15]=[CH:16][C:17]([Sn](CCCC)(CCCC)CCCC)=[N:18][CH:19]=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.O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:17]2[CH:16]=[CH:15][C:14]([CH3:13])=[CH:19][N:18]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Br)cc(I)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: COC(=O)c1cc(Br)cc(-c2ccc(C)cn2)c1

Procedure:
A microwave vial was charged with methyl 3-bromo-5-iodobenzoate (2.00 g, 5.87 mmol), 5-methyl-2-(tributylstannyl)pyridine (2.24 g, 5.87 mmol), tetrakis(triphenylphosphine)palladium(0) (339 mg, 0.29 mmol) and 1,4-dioxane (30 mL). The reaction mixture was subjected to microwave irradiation at 120° C. for 1 hour. The reaction was filtered through Celite and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography to afford the product as a white solid. 1H NMR (400 Hz, DMSO-d6): 8.64 (t, J=1.51 Hz, 1H), 8.55 (m, 1H), 8.52 (t, J=1.89 Hz, 1H), 8.07 (t, J=1.89 Hz, 1H), 8.03 (d, J=8.31 Hz, 1H), 7.75 (dd, J=8.31 & 2.27 Hz, 1H), 3.91 (s, 1H), 2.36 (s, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[N:14]=[C:13]([C:15]2[N:19](COCC[Si](C)(C)C)[C:18]([C:28]3[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=3[CH3:35])=[C:17]([C:36]([NH2:38])=[O:37])[CH:16]=2)[C:12]([C:39]#[C:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]([N:49]3[CH2:54][CH2:53][N:52]([CH3:55])[CH2:51][CH2:50]3)=[O:48])=[CH:43][CH:42]=2)=[CH:11][N:10]=1>C(Cl)Cl>[NH2:8][C:9]1[N:14]=[C:13]([C:15]2[NH:19][C:18]([C:28]3[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=3[CH3:35])=[C:17]([C:36]([NH2:38])=[O:37])[CH:16]=2)[C:12]([C:39]#[C:40][C:41]2[CH:42]=[CH:43][C:44]([C:47]([N:49]3[CH2:54][CH2:53][N:52]([CH3:55])[CH2:51][CH2:50]3)=[O:48])=[CH:45][CH:46]=2)=[CH:11][N:10]=1
Reactant: Cc1ccc(Cl)cc1-c1c(C(N)=O)cc(-c2nc(N)ncc2C#Cc2ccc(C(=O)N3CCN(C)CC3)cc2)n1COCC[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(Cl)cc1-c1[nH]c(-c2nc(N)ncc2C#Cc2ccc(C(=O)N3CCN(C)CC3)cc2)cc1C(N)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 70.9 %

Procedure:
Trifluoroacetic acid (1.4 mL) was added to a solution of 5-[2-amino-5-({4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}ethynyl)pyrimidin-4-yl]-2-(5-chloro-2-methylphenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxamide (0.110 g, 0.14 mmol) in dry DCM (2.8 mL) and stirred for 4 h at room temperature. After solvent removal, the residue was treated with EtOH (3 mL), 33% NH4OH (0.4 mL) and stirred for 0.5 h. The solvent was evaporated to dryness and the residue was purified by flash-chromatography on silica gel (DCM/MeOH/7N NH3 in MeOH 94/5/1) to afford the title compound as white solid (0.055 g, 71%).
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([CH2:14][CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[CH3:21])=[CH:11][C:10]=2[CH:22]=1)=[O:5].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[Mg]Br>>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([CH2:14][CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[CH3:21])=[CH:11][C:10]=2[CH:22]=1)=[O:5]
Reactant: COc1ccccc1[Mg]Br
Reactant: CON(C)C(=O)c1ccc2oc(CCN3CCC[C@H]3C)cc2c1
Product: COc1ccccc1C(=O)c1ccc2oc(CCN3CCC[C@H]3C)cc2c1

Procedure:
The product from Example 71E and 2-methoxyphenylmagnesium bromide were processed as described in Example 71F to provide the title compound. 1HNMR (300 MHz, CD3OD) δ 1.42 (d, 3H), 1.72 (m, 1H), 2.10 (m, 2H), 2.35 (m, 1H), 3.30 (m, 4H), 3.55 (m, 1H), 3.70 (s 3H), 3.80 (m, 2H), 6.80 (s, 1H), 7.1 (m, 2H), 7.30 (dd, 1H), 7.53 (m, 2H), 7.75 (dd, 1H), 7.95 (d, 1H); MS (ESI) m/z 364 (M+14H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[C:8]([CH3:16])[CH:9]=[N:10]2.[Br:18]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[C:8]([CH2:16][Br:18])[CH:9]=[N:10]2
Reactant: COC(=O)Cc1c(Cl)ccc2ncc(C)cc12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)Cc1c(Cl)ccc2ncc(CBr)cc12
Temperature: 40 °C
Yield: 60.3 %

Procedure:
To a solution of (6-chloro-3-methyl-quinolin-5-yl)-acetic acid methyl ester (1.70 g, 6.81 mmol) in tetrachloromethane (140 mL) was added N-bromosuccinimide (1.28 g, 6.8 mmol). The reaction mixture was heated to 40° C. for 1 h under simultaneous irradiation by a 300 W UV lamp. The reaction mixture was filtered and the filtrate concentrated in vacuo. The crude product was purified by flash column chromatography (silica gel, gradient of cyclohexane/EtOAc 100:0 to 80:20) to afford the title compound as a white powder (1.34 g, 4.1 mmol, 60%). %). 1H NMR (400 MHz, CDCl3, 298 K): δ=8.97 (s, 1H), 8.30 (s, 1H), 8.07 (d, J=9.0 Hz, 1H), 7.76 (d, J=9.0 Hz, 1H), 4.69 (s, 2H), 4.30 (s, 2H), 3.73 (s, 3H). MS (ES+): 328 (M(Cl3H1179Br35ClNO2)+H)+.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4](/[C:17](/[CH2:22][CH3:23])=[C:18](/[F:21])\[CH2:19][OH:20])[C:3]=1[O:24][CH2:25][CH3:26].C[N+]1([O-])CCOCC1.ClCCl>C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:15])[CH3:16])[C:6]=2[CH:5]=[C:4](/[C:17](/[CH2:22][CH3:23])=[C:18](/[F:21])\[CH:19]=[O:20])[C:3]=1[O:24][CH2:25][CH3:26]
Reactant: CCOc1c(/C(CC)=C(/F)CO)cc2c(c1Br)C(C)(C)CC=C2C(C)C
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: ClCCl
Product: CCOc1c(/C(CC)=C(/F)C=O)cc2c(c1Br)C(C)(C)CC=C2C(C)C

Procedure:
As described in General Procedure H-1, (2E)-3-(4-bromo-3-ethoxy-8-isopropyl-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-2-fluoro-pent-2-en-1-ol (Compound A-137, 885 mg, 2.08 mmol), tetrapropylammonium perruthenate (20 mg, 0.057 mmol) and 4-methylmorpholine N-oxide (487 mg, 4.16 mmol) were reacted in acetonitrile and dichloromethane to give the title compound after purification by flash column chromatography (silica gel, 5% ethyl acetate in hexane).
Reaction SMILES: F[C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:13]([C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[C:19]([F:24])[CH:18]=1)[CH2:14][CH2:15][CH3:16].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[CH2:13]([C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:2]2[C:10]([F:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[C:19]([F:24])[CH:18]=1)[CH2:14][CH2:15][CH3:16]
Reactant: O=C(O)c1ccc(F)c(F)c1F
Reactant: CCCCc1ccc(N)c(F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCc1ccc(Nc2c(C(=O)O)ccc(F)c2F)c(F)c1
Yield: 40 %

Procedure:
2,3,4-Trifluorobenzoic acid and 4-butyl-2-fluoroaniline were reacted in the presence of LiHMDS solution in THF by the general procedure of Example 1, Step B, affording crude 2-(4-butyl-2-fluoroanilino)-3,4-difluorobenzoic acid after workup. The crude material was further purified by flash chromatography on silica (10% EtOAc/Hexane as eluant) to give the desired compound (40%). 1H NMR [400 MHz, CH30D] δ 7.86 (ddd, J=8.4, 5.8, 2.1 Hz, 1 H), 6.96–6.86 (m, 3 H), 6.78 (ddd, J=9.4, 9.4, 7.1 Hz, 1 H), 2.58 (t, J=7.7 Hz, 2 H), 1.63–1.55 (m, 2 H), 1.36 (sextet, J=7.4, 2H), 0.94 (t, J=7.5, 3 H). LCMS (ACPI+) 329 (100%).
Reaction SMILES: [CH:1]([C:4]1[CH:39]=[CH:38][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH:14]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([C:28]([O:30]CC4C=CC=CC=4)=[O:29])([CH3:27])[CH3:26])[CH:19]=3)[CH2:13]2)=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].CO>O>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH:14]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([C:28]([OH:30])=[O:29])([CH3:27])[CH3:26])[CH:19]=3)[CH2:13]2)=[O:11])=[CH:38][CH:39]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(COC(=O)N2CCCC(c3cccc(OC(C)(C)C(=O)OCc4ccccc4)c3)C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)c1ccc(COC(=O)N2CCCC(c3cccc(OC(C)(C)C(=O)O)c3)C2)cc1
Temperature: 25 °C
Yield: 94 %

Procedure:
A mixture of 3-[3-(1-Benzyloxycarbonyl-1-methyl-ethoxy)-phenyl]-piperidine-1-carboxylic acid 4-isopropyl-benzyl ester (1.07 g, 2.02 mmol), potassium carbonate (0.56 g, 4.04 mmol), methanol (15 mL) and water (3 mL) was heated at reflux for 3 h, cooled to room temperature and concentrated under reduced pressure. The resulting residue was taken up in water (150 mL), acidified with 1N aqueous hydrochloric acid and extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resultant oil was eluted through a 20 g plug of silica with 300 mL methylene chloride then 300 mL ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to yield 835 mg (94%) of 3-[3-(1-carboxy-1-methyl-ethoxy)-phenyl]-piperidine-1-carboxylic acid 4-isopropyl-benzyl ester as a clear glassy solid.