Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C2C3C=CC=CC=3NC(=O)C([NH:20][C:21]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=3)=[O:22])N=2)CCCCCC1.BrCC(N1CC2CCC(CC2)C1)=O.[H-].[Na+].C(O)(=O)C>CN(C)C=O>[CH3:30][C:26]1[CH:25]=[C:24]([NH:23][C:21](=[O:22])[NH2:20])[CH:29]=[CH:28][CH:27]=1
Reactant: Cc1cccc(NC(=O)NC2N=C(C3CCCCCC3)c3ccccc3NC2=O)c1
Agent: O=C(CBr)N1CC2CCC(CC2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Cc1cccc(NC(N)=O)c1
Reaction time: 0.5 h
Yield: 237.7 %

Procedure:
To a solution of N-[(3RS)-5-cycloheptyl-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea (0.102 g) and N-bromomethylcarbonyl-3-azabicyclo[3.2.2]nonane (0.079 g) in dry N,N-dimethylformamide (10 ml) was added sodium hydride (0.011 g of a 63.8% dispersion in mineral oil) at 5°-10° C. The mixture was stirred at the same temperature for 30 minutes and then at ambient temperature overnight. The resultant mixture was treated with 0.1 g of acetic acid at room temperature for 30 minutes and then concentrated in vacuo. The residue was disolved with ethyl acetate (100 ml) and washed with saturated sodium hydrogen carbonate aqueous solution (20 ml) and a brine (20 ml). The organic layer was dried over magnesium sulfate. Filtration and evaporation gave a crude product. The crude product was purified by column chromatography on silica gel with chloroform and a mixture of chloroform and ethyl acetate (5:1) as eluents to afford N-[(3RS)-1-[(3-azabicyclol3.2.2]non-3-yl)carbonylmethyl]-5-cycloheptyl-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea (0.090 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH:11]1[CH2:14][CH2:13][CH2:12]1.[H-].[Na+].Br[CH:18]([CH3:20])[CH3:19]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:18]([CH3:20])[CH3:19])[N:6]=[C:5]2[CH:11]1[CH2:14][CH2:13][CH2:12]1
Reactant: CC(C)Br
Reactant: Brc1ccc2[nH]nc(C3CCC3)c2c1
Agent: [H-]
Agent: [Na+]
Product: CC(C)n1nc(C2CCC2)c2cc(Br)ccc21
Yield: 69.7 %

Procedure:
The title compound was prepared by the method outlined for Preparative Example 59 using 5-bromo-3-cyclobutyl-1H-indazole intermediate (1.05 g, 4.16 mmol), NaH (211 mg, 5.26 mmol), and 2-bromopropane (667 mg, 5.42 mmol) to afford titled compound as a light yellow oil (850 mg, 70%). 1H NMR (CDCl3) 7.86 (s, 1H), 7.37 (d, J=8.8, 1H), 7.27 (d, J=8.8, 1H), 4.75 (m, 1H), 3.88 (pent, J=8.4, 1H), 2.55-2.43 (m, 4H), 2.15-2.05 (m, 1H), 2.01 (m, 1H), 1.57 (d, J=6.8, 6H). LC/MS (Method B) 4.72 min, [M+1]+ 293/295.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH:3]=1.[NH:19]1[CH2:27][CH2:26][CH:22]([C:23]([NH2:25])=[O:24])[CH2:21][CH2:20]1.C1(O)C=CC=CC=1>O>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:4]2[CH:3]=[C:2]([N:19]3[CH2:27][CH2:26][CH:22]([C:23]([NH2:25])=[O:24])[CH2:21][CH2:20]3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)=[CH:13][CH:14]=1
Reactant: NC(=O)C1CCNCC1
Reactant: Fc1ccc(-c2cc(Cl)c3ccccc3n2)cc1
Solvent: O
Solvent: Oc1ccccc1
Product: NC(=O)C1CCN(c2cc(-c3ccc(F)cc3)nc3ccccc23)CC1

Procedure:
A mixture of 1.44 g of 4-chloro-2-(4-fluorophenyl)quinoline 1.3 g (10 mmol) of isonipecotamide, and 3 g of phenol was stirred and heated in an oil bath at 165°-170° for 4.5 hr. It was then cooled and diluted with water. It wa made alkaline with 3N sodium hydroxide, and crystallization was induced by the addition of ether and scratching. The solid was collected and washed with ether to give 1.6 g of crude product. Recrystallization from ethanol/water gave white needles (0.42g). mp 218°-220° dec.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.C([O:37][C@@H:38]([CH3:42])[C:39](Cl)=[O:40])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:29][CH2:30][N:31]([C:39](=[O:40])[C@@H:38]([OH:37])[CH3:42])[CH2:32][CH2:33]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: Cc1cc(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: Cc1cc(-c2ncnc3c(C(=O)NC4CCN(C(=O)[C@H](C)O)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methylphenyl]-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f40) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:22])=[CH:13]/[CH:14]([CH2:16]/[C:17](/[CH3:21])=[CH:18]\[CH2:19][OH:20])C.[BH4-].[Na+].CC1CCCC(C)(C)C=1/C=C/C(/C)=C\C=C\C(\C)=C\C=O>>[CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:8])([CH3:9])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:22])=[CH:13]\[CH:14]=[CH:16]\[C:17](\[CH3:21])=[CH:18]\[CH2:19][OH:20]
Reactant: CC1=C(/C=C/C(C)=C/C(C)C/C(C)=C\CO)C(C)(C)CCC1
Agent: CC1=C(/C=C/C(C)=C\C=C\C(C)=C\C=O)C(C)(C)CCC1
Agent: [BH4-]
Agent: [Na+]
Product: CC1=C(/C=C/C(C)=C\C=C\C(C)=C\CO)C(C)(C)CCC1

Procedure:
All-trans-retinol was obtained as a gift from Dr. Christian Eckhoff of Hoffmann-LaRoche, Inc. (Nutley, N.J.), and 13-cis-retinol was purchased from Sigma. 9-cis-Retinol was synthesized by NaBH4 reduction of authentic 9-cis-retinaldehyde (Sigma) and subsequently purified by normal phase HPLC essentially as we have described for 11-cis-retinol synthesis and purification (25). All-trans-, 13-cis-, and 9-cis-retinaldehydes were purchased from Sigma.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[N:7]([CH3:30])[CH2:8][C:9]#[C:10][C:11]1[S:12][CH:13]=[C:14]([C:16](=[O:29])[N:17]([CH3:28])[C@H:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21][CH2:20][CH2:19]2)[N:15]=1)([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6](=[O:31])[N:7]([CH3:30])[CH2:8][CH2:9][CH2:10][C:11]1[S:12][CH:13]=[C:14]([C:16](=[O:29])[N:17]([CH3:28])[C@H:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21][CH2:20][CH2:19]2)[N:15]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CN(CC#Cc1nc(C(=O)N(C)[C@@H]2CCCc3ccccc32)cs1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CN(CCCc1nc(C(=O)N(C)[C@@H]2CCCc3ccccc32)cs1)C(=O)OC(C)(C)C
Yield: 75 %

Procedure:
A solution of methyl-{3-[4-((R)-methyl-1,2,3,4-tetrahydro-naphthalen-1-yl-carbamoyl)-thiazol-2-yl]-prop-2-ynyl}-carbamic acid tert-butyl ester (0.176 g, 0.4 mmol) in methanol (3 mL) was pumping through Pd/C cartridge using H-Cube apparatus (50° C., 80 bar, 1 mL/min.). The solvent was then evaporated under reduce pressure to give methyl-{3-[4-((R)-methyl-1,2,3,4-tetrahydro-naphthalen-1-yl-carbamoyl)-thiazol-2-yl]-propyl}-carbamic acid tert-butyl ester (0.133 g, 75%), which can be used in the next step without further purification. 1H-NMR (400 MHz, CDCl3): δ=7.54 (s, 1H (conformers)), 7.03-6.87 (m, 4H), 5.54-5.46 (m, 1H (conformers)), 3.12-2.98 (m, 2H), 2.83-2.71 (m, 2H (conformers)), 2.63 (s, 3H (conformers)), 2.61-2.51 (m, 5H), 2.04-1.56 (m, 6H), 1.20 (s, 9H (conformers)). MS: m/z=444 (M+1).
Reaction SMILES: F[C:2]1[C:25]([F:26])=[C:24]([F:27])[C:23]([F:28])=[C:22](F)[C:3]=1[C:4]([C:6](=[CH:12][NH:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[F-:30].[Na+]>CN(C)C=O>[F:30][C:22]1[C:23]([F:28])=[C:24]([F:27])[C:25]([F:26])=[C:2]2[C:3]=1[C:4](=[O:5])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:12][N:13]2[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21]
Reactant: CCOC(=O)C(=CNc1ccc(F)cc1F)C(=O)c1c(F)c(F)c(F)c(F)c1F
Reactant: [F-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2c(F)c(F)c(F)c(F)c2c1=O
Temperature: 0 °C
Yield: 94.6 %

Procedure:
A mixture of 135.4 g of ethyl 2-(2,3,4,5,6-pentafluorobenzoyl)-3-(2,4-difluorophenylamino)acrylate, 20.6 g of sodium fluoride and 300 ml of anhydrous dimethylformamide is heated at 140°-150° C. for 3 hours. The suspension is poured hot onto 2 kg of ice and the precipitate is filtered off with suction, washed with water and dried. 122 g of the title compound of melting point 160°-162° C. are obtained.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]([CH3:20])=[C:11]([CH:17]=[CH:18][CH:19]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:21](=O)[CH3:22].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.O>[CH2:1]([N:8]([CH2:21][CH3:22])[C:9]1[C:10]([CH3:20])=[C:11]([CH:17]=[CH:18][CH:19]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cccc(NCc2ccccc2)c1C
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: O
Product: CCOC(=O)c1cccc(N(CC)Cc2ccccc2)c1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85.1 %

Procedure:
To a stirred solution of ethyl 3-(benzylamino)-2-methylbenzoate (396 mg, 1.47 mmol) in DCE (10 ml) was added acetaldehyde (164 μl, 2.94 mmol) followed by acetic acid (0.17 ml, 2.94 mmol) The reaction was stirred at room temperature for 10 min and then sodium triacetoxyborohydride (0.62 g, 2.94 mmol) was added and the reaction stirred for 16 h. Distilled water (30 ml) was added and solid NaHCO3 was then added until the aqueous phase was pH7, the phases were separated, the aqueous phase was washed with DCM (2×50 ml), the combined organics were then washed with brine (50 ml), dried using Na2SO4, filtered and evaporated. The resultant residue was then purified using a 25 g silica Isolute column eluting using a gradient of 0% to 5% EtOAc in heptane to afford the title compound as a colourless oil (372 mg, 81%). LC-MS 94%, m/z=298.1, 1H NMR (500 MHz, Chloroform-d) δ 7.48 (dd, J=7.5, 1.3 Hz, 1H), 7.29-7.08 (m, 8H), 4.32 (q, J=7.1 Hz, 2H), 4.05 (s, 2H), 2.92 (q, J=7.1 Hz, 2H), 2.56 (s, 3H), 1.35 (t, J=7.1 Hz, 3H), 0.92 (t, J=7.1 Hz, 3H).
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]2[C:23]([CH3:25])([CH3:24])[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:26])[CH:20]=3)[NH:15]2)[CH:9]=1)([CH3:6])[CH3:5].Cl>O1CCCC1.[OH-].[Li+].O>[Cl:26][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]([C:10]1[CH:9]=[C:8]([NH:7][C:4]([CH3:6])([CH3:5])[C:3]([OH:27])=[O:2])[CH:13]=[CH:12][CH:11]=1)[C:23]([CH3:25])([CH3:24])[CH2:22]2
Reactant: COC(=O)C(C)(C)Nc1cccc(C2Nc3ccc(Cl)cc3CC2(C)C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(Nc1cccc(C2Nc3ccc(Cl)cc3CC2(C)C)c1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 11.6 %

Procedure:
A mixture of 2-[3-(6-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-2-methyl-propionic acid methyl ester (450 mg, 1.16 mmol) in tetrahydrofuran (30 mL), 2M lithium hydroxide in water (15 mL) was stirred at 25° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-[3-(6-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-2-methyl-propionic acid (50 mg, 11%) as a white solid: LC/MS m/e calcd for C21H25ClN2O2 (M+H)+: 373.90, observed: 373.1.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([C:8](Cl)=[O:9])[S:4][N:3]=1.[NH2:11][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.N1C=CC=CC=1>O1CCCC1>[N:12]1([NH:11][C:8]([C:5]2[S:4][N:3]=[C:2]([Cl:1])[C:6]=2[Cl:7])=[O:9])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: O=C(Cl)c1snc(Cl)c1Cl
Reactant: NN1CCOCC1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(NN1CCOCC1)c1snc(Cl)c1Cl
Temperature: 2.5 °C
Yield: 63.4 %

Procedure:
At 0 to 5° C. and with ice-cooling and stirring, 2.43 g (0.01 mol) of 3,4-dichloro-isothiazole-5-carbonyl chloride are added dropwise over a period of 5 minutes to a mixture of 1.21 g (0.011 mol) of 4-amino-morpholine and 22 ml of absolute pyridine. After the addition, the reaction mixture is admixed with 1.5 ml of absolute tetrahydrofuran, allowed to warm to room temperature and then stirred at room temperature for one hour. The reaction mixture is subsequently concentrated under reduced pressure. The residue that remains is admixed with 60 ml of water and 60 ml of ethyl acetate. The organic phase is separated off and the aqueous phase is extracted twice more with ethyl acetate. The combined organic phases are successively washed with 20 ml of saturated aqueous sodium bicarbonate solution and 50 ml of water, then dried over sodium sulphate and concentrated under reduced pressure. The residue is triturated in a mixture of 30 ml methylene chloride and 70 ml of petroleum ether. The resulting solid is filtered off with suction and dried. In this manner, 1.79 g (63% of theory) of N-morpholinyl-3,4-dichloro-isothiazole-5-carboxamide are obtained in the form of a solid of melting point 198 to 199° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:5]2=[N:6][S:7][N:8]=[C:4]2[C:3]=1[Cl:14].[Cl:15][C:16]1[C:17]([N:22]2[C:26]([C:27](O)=O)=[CH:25][C:24]([C:30]([F:33])([F:32])[F:31])=[N:23]2)=[N:18][CH:19]=[CH:20][CH:21]=1.N1C=CC=CC=1.CS(Cl)(=O)=O>C(#N)C>[Cl:14][C:3]1[C:4]2[C:5](=[N:6][S:7][N:8]=2)[CH:9]=[C:10]2[C:2]=1[N:1]=[C:27]([C:26]1[N:22]([C:17]3[C:16]([Cl:15])=[CH:21][CH:20]=[CH:19][N:18]=3)[N:23]=[C:24]([C:30]([F:33])([F:31])[F:32])[CH:25]=1)[O:12][C:11]2=[O:13]
Reactant: Nc1c(C(=O)O)cc2nsnc2c1Cl
Reactant: O=C(O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: O=c1oc(-c2cc(C(F)(F)F)nn2-c2ncccc2Cl)nc2c(Cl)c3nsnc3cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.4 %

Procedure:
To a suspension of 300 mg (1.31 mmol) of 6-amino-7-chloro-benzo[1,2,5]thiadiazole-5-carboxylic acid in 12 ml of acetonitrile, is added 381 mg (1.31 mmol) of 2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid followed by 0.47 ml (5.88 mmol) of pyridine. The mixture is stirred at ambient temperature during 30 min. Then the suspension is cooled at a temperature of 0° C. and 0.36 ml (4.57 mmol) of methanesulfonyl chloride is added dropwise. The mixture is stirred at a temperature of 0° C. during 30 min and 2 hours at ambient temperature. Then the solvent is evaporated and the residue is precipitated in a minimum of cold H2O. After filtration and washing of the solid with a minimum of cold H2O, 585 mg (1.21 mmol, 92%) of a dark violet solid is obtained. LC/MS: 485/487 (M+1)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][N:4]=1>C(Cl)(Cl)Cl>[CH:2]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][N:4]=1)=[O:1]
Reactant: OCc1ccc(CO)nc1
Solvent: ClC(Cl)Cl
Product: O=Cc1ccc(CO)cn1
Reaction time: 0.5 h

Procedure:
2,5-Di(hydroxymethyl)pyridine (10 g.) in 300 ml. of hot chloroform is treated with 100 g. of mangenese dioxide. After 1/2 hour of stirring, the mixture is filtered and the filtrate is evaporated to dryness to give 2-formyl-5-hydroxymethylpyridine.
Reaction SMILES: [CH3:1][N:2]([C:11]1[CH:12]=[C:13]([C:20]2([CH3:25])OCC[O:21]2)[CH:14]=[CH:15][C:16]=1[N+:17]([O-])=O)[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[F:10].Cl>CC(C)=O>[NH2:17][C:16]1[CH:15]=[CH:14][C:13]([C:20](=[O:21])[CH3:25])=[CH:12][C:11]=1[N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[F:10]
Reactant: CN(c1ccc(F)cc1F)c1cc(C2(C)OCCO2)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: CC(C)=O
Product: CC(=O)c1ccc(N)c(N(C)c2ccc(F)cc2F)c1
Yield: 21.1 %

Procedure:
A solution of 2-{3-[N-methyl-N-(2,4-difluorophenyl)amino]-4-nitrophenyl}-2-methyl-1,3-dioxolane (6.6 g) and 3N-hydrochloric acid (60 ml) in acetone (120 ml) was stirred at room temperature overnight and evaporated. The residue was dissolved in ethyl acetate, washed with water and an aqueous solution of sodium bicarbonate, and concentrated to dryness. A mixture of the residual oil (5.3 g), iron powder (5 g) and ammonium chloride (0.5 g) in ethanol (120 ml) and water (60 ml) was stirred and refluxed for 1 hour. The mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography on silica gel eluting with a mixture of toluene and ethyl acetate (20:1) to give crystals of 4'-amino-3'-[N-methyl-N-(2,4-difluorophenyl)amino]acetophenone (1.1 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:18]=[CH:19]/[CH:20]=[CH:21]/[C:22]([NH:24][CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][CH:30]([C:33]3[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[NH:35][CH:34]=3)[CH2:29][CH2:28]2)=[O:23])[CH:6]=[C:7]([O:16][CH3:17])[C:8]=1[O:9]COCCOC.CS(O)(=O)=O.[OH-].[Na+].C(=O)(O)[O-].[Na+]>CO.O>[OH:9][C:8]1[C:3]([O:2][CH3:1])=[CH:4][C:5](/[CH:18]=[CH:19]/[CH:20]=[CH:21]/[C:22]([NH:24][CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][CH:30]([C:33]3[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[NH:35][CH:34]=3)[CH2:29][CH2:28]2)=[O:23])=[CH:6][C:7]=1[O:16][CH3:17]
Reactant: COCCOCOc1c(OC)cc(/C=C/C=C/C(=O)NCCN2CCC(c3c[nH]c4ccccc34)CC2)cc1OC
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(/C=C/C=C/C(=O)NCCN2CCC(c3c[nH]c4ccccc34)CC2)cc(OC)c1O
Reaction time: 2 h
Yield: 79.3 %

Procedure:
To a stirred solution of 1-[2-[5-[3, 5-dimethoxy-4-{(2-methoxyethoxy)methoxy}phenyl]-(2E, 4E)-2, 4-pentadienoylamino]ethyl]-4-(3-indolyl)piperidine (10.0 g) in methanol (100 ml) was added slowly methanesulfonic acid (2.3 ml) at ambient temperature. After stirring for 2 hours, the reaction mixture was adjusted to pH 7.2 with aqueous 2N sodium hydroxide solution, and poured into a solution of 4.5 g of sodium bicarbonate in 500 ml of water. After stirring for 30 minutes, the resulting precipitate was collected by filtration and washed with 100 ml of water. The residue was subjected to column chromatography on silica gel and eulted with a mixture of chloroform and methanol. The fractions containing the object compound were combined and concentrated under reduced pressure. The residue was recrystallized from ethanol to give 1-[2-{5-(4-hydroxy-3, 5-dimethoxyphenyl)-(2E, 4E)-2, 4-pentadienoylamino}ethyl]-4-(3-indolyl)-piperidine (6.69 g).
Reaction SMILES: [O:1]=[C:2]1[CH:6]([CH2:7][CH2:8][CH:9]2[O:14][CH2:13][CH2:12][O:11][CH2:10]2)[CH2:5][CH2:4][NH:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>C1COCC1>[O:1]=[C:2]1[CH:6]([CH2:7][CH2:8][CH:9]2[O:14][CH2:13][CH2:12][O:11][CH2:10]2)[CH2:5][CH2:4][N:3]1[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)CBr
Reactant: O=C1NCCC1CCC1COCCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CN1CCC(CCC2COCCO2)C1=O
Reaction time: 0.33 h

Procedure:
To a rapidly stirred solution of 2-3 (0.86 g, 4.3 mmol) and THF (25 mL) at -78° C. was added NaN(TMS)2 (5.2 mL, 5.2 mmol, 1.0 M in THF). After 20 min, ethyl bromoacetate (0.58 mL, 5.2 mmol) was added followed by removal of the cooling bath. After 1 h, the reaction mixture was diluted with EtOAc and then washed with H2O, sat. NaHCO3 and brine, dried (MgSO4), and concentrated to give 2-4 as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([Cl:10])[C:3]=1[CH2:11]O.P(Br)(Br)[Br:14]>C(Cl)Cl>[Br:14][CH2:11][C:3]1[C:2]([Cl:1])=[C:7]([O:8][CH3:9])[CH:6]=[CH:5][C:4]=1[Cl:10]
Reactant: BrP(Br)Br
Reactant: COc1ccc(Cl)c(CO)c1Cl
Solvent: ClCCl
Product: COc1ccc(Cl)c(CBr)c1Cl
Reaction time: 0.17 h
Yield: 112.7 %

Procedure:
Dissolve (2,6-dichloro-3-methoxy-phenyl)-methanol (9.43 g, 45.5 mmol) in methylene chloride (180 ml) cool to 0° and add phosphorus tribromide (1.0M, 23 ml, 23 mmol) dropwise. Stir for 10 minutes at 0°, dilute with methylene chloride, quench with saturated aqueous sodium bicarbonate, separate layers, wash organic with water, brine dry over sodium sulfate, filter and concentrate to yield 7 g (57%) of the title compound: NMR (CDCl3) δ 7.28 (d, 1H), 6.85 (d, 1H), 4.77 (s, 2H), 3.90 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]3)[C:4]=2[N:5]=[CH:6][N:7]=1.C1C(=O)N([I:31])C(=O)C1.O>CN(C=O)C>[Cl:1][C:2]1[C:3]2[C:10]([I:31])=[CH:9][N:8]([C@@H:11]3[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](n2ccc3c(Cl)ncnc32)C1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](n2cc(I)c3c(Cl)ncnc32)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 85.6 %

Procedure:
A mixture of (R)-tert-butyl 3-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylate (1.7 g, 5.05 mmol) and NIS (1.25 g, 5.55 mmol) in DMF (20 mL) was stirred for 12 h at room temperature. Water was added to the mixture, which was extracted with EA, the combined organic layers were dried and purified by column to give (R)-tert-butyl 3-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylate (2.0 g, 86% in yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][C:9]([C:13]([OH:15])=O)=[C:8]2[NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([NH:25][CH:26]2[CH2:31][CH2:30][N:29]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:28][CH2:27]2)=[O:24])=[CH:19][CH:18]=1.CC(C1C=CC(C[N:50]2CCC(N)CC2)=CC=1)(C)C.ClC1C=C2C(C(NC3C=CC(C(NC4CCN(CC5C=CC=CC=5)CC4)=O)=CC=3)=C(C(O)=O)C=N2)=CC=1.C(OC(C1C(=O)C2C(=C(OC)C=CC=2)NC=1)=O)C.C(C1C=CC(CBr)=CC=1)(C)(C)C.O1C2(CCNCC2)OCC1>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][C:9]([C:13]([NH2:50])=[O:15])=[C:8]2[NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([NH:25][CH:26]2[CH2:31][CH2:30][N:29]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:28][CH2:27]2)=[O:24])=[CH:19][CH:18]=1
Reactant: COc1cccc2c(Nc3ccc(C(=O)NC4CCN(Cc5ccccc5)CC4)cc3)c(C(=O)O)cnc12
Reactant: CC(C)(C)c1ccc(CN2CCC(N)CC2)cc1
Agent: C1CC2(CCN1)OCCO2
Agent: CC(C)(C)c1ccc(CBr)cc1
Agent: CCOC(=O)c1c[nH]c2c(OC)cccc2c1=O
Solvent: O
Product: COc1cccc2c(Nc3ccc(C(=O)NC4CCN(Cc5ccccc5)CC4)cc3)c(C(N)=O)cnc12

Procedure:
N-[1-[4-(1,1-Dimethylethyl)pheny]]methyl]-4-piperidiny]]-8-methoxy-4-[[4-[[[1-(phenylmethyl)-4-piperidinyl]amino]carbonyl]phenyl]amino]-3-quinoline-carbox-amide was prepared as a hygroscopic solid (0.2 hydrate) by coupling 8-methoxy-4-[[4-[[[1-(phenylmethyl)-4-piperidinyl]amino]carbonyl]phenyl]amino]-3-quinoline-carboxylic acid and 1-[[4-(1,1-dimethylethyl)phenyl]methyl]-4piperidinamine as described for Example 17, Step 5. 8-Methoxy-4-[[4-[[[1-(phenylmethyl)-4-piperi-dinyl]amino]carbonyl]phenyl]amino]-3-quinolinecarboxylic acid can be prepared as described for 7-chloro-4-[[4-[[[1-(phenylmethyl)-4-piperidinyl]amino]carbonyl]phenyl]amino]-3-quinolinecarboxylic acid in Example 17, Steps 1-4, by starting with 1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid ethyl ester in Step 1. 1,4-Dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid ethyl ester can be prepared as described by C. C. Price et al in J. Am. Chem. Soc., 68, 1204 (1946). 1-[[4-(1,1-Dimethylethyl)phenyl]methyl]-4-piperidinamine can be prepared from 4-(tert-butyl)benzyl bromide and 1,4-dioxa-8-azaspiro[4.5]-decane as described in U.S. Pat. Nos. 3,875,165 and 4,816,464: mp 154°-162 ° C.; 1H NMR (Me2SO-d6, 400 MHz) δ9.47 (s, 1 H), 8.76 (s, 1 H), 8.39 (d, J=7.5 Hz, 1 H), 7.99 (d, J=7.6 Hz, 1 H), 7.68 (d, J=8.7 Hz, 2 H), 7.57 (d, jr=8.3 Hz, 1 H), 7.41 (m, 1 H), 7.10-7.36 (m, 10 H), 6.87 (d, J=8.7 Hz, 2 H), 3.95 (s, 3 H), 3.7 (m, 1 H), 3.2-3.6 (m, 5 H), 2.6-2.9 (m, 4 H), 1.8-2.1 (m, 4 H), 1.3-1.8 (m, 3 H), 1.24 (s, 9 H); Karl Fisher, 0.47% H2O.