Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:20]3[C:29]([Cl:30])=[C:28]4[C:23]([C:24](=[O:38])[C:25]([C:35]([OH:37])=[O:36])=[CH:26][N:27]4[C@@H:31]4[CH2:33][C@@H:32]4[F:34])=[CH:22][C:21]=3[F:39])[CH:17]=2)[CH2:12]1)=O)C1C=CC=CC=1.C(O)C.[OH-].[Na+].O>C(O)(=O)C.[C].[Pd]>[Cl:30][C:29]1[C:20]([C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[CH2:12][NH:11][CH2:19]3)=[C:21]([F:39])[CH:22]=[C:23]2[C:28]=1[N:27]([C@@H:31]1[CH2:33][C@@H:32]1[F:34])[CH:26]=[C:25]([C:35]([OH:37])=[O:36])[C:24]2=[O:38]
Reactant: O=C(O)c1cn([C@@H]2C[C@@H]2F)c2c(Cl)c(-c3ccc4c(c3)CN(C(=O)OCc3ccccc3)C4)c(F)cc2c1=O
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: O=C(O)c1cn([C@@H]2C[C@@H]2F)c2c(Cl)c(-c3ccc4c(c3)CNC4)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In 25 ml of acetic acid and 50 mg of 5% palladium carbon was suspended 150 mg of 7-[2-(benzyloxycarbonyl)-isoindolin-5-yl]-8-chloro-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, and the suspension was stirred at room temperature for two hours under a hydrogen stream. The reaction mixture was filtered and thereafter 2 ml of 6N hydrochloric acid was added to the filtrate obtained, after which the mixture was concentrated under reduced pressure. To the residue obtained were added ethanol, and the crystals formed were collected by filtration. To the crystals obtained were added 0.7 ml of ethanol, 0.7 ml of 1N aqueous sodium hydroxide solution and 0.7 ml of water to dissolve the crystals, and thereafter, dilute acetic acid was added to the solution to adjust the pH to 7. The crystals precipitated were collected by filtration, to obtain 45 mg of colorless, crystalline 8-chloro-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-7-(isoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N+:11]([O-])=[CH:10][CH:9]=[CH:8]2)=[O:4].P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:8]1[C:7]2[C:12](=[CH:13][CH:14]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=2)[N:11]=[CH:10][CH:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc2c(ccc[n+]2[O-])c1
Product: COC(=O)c1ccc2nccc(Cl)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.8 %

Procedure:
To 6-(methoxycarbonyl)quinoline-N-oxide from the above step was added phosphoryl trichloride (5 mL, 54.6 mmol). The resulting mixture was then stirred at rt under N2 for 2 h. The reaction was then slowly quenched by addition to an ice cold solution of saturated aqueous NaHCO3 (50 mL) in an ice bath with rapid stirring. The aqueous solution was extracted with EtOAc (3×50 mL). The organic layers were combined, washed with saturated aqueous NaHCO3 (25 mL), H2O (25 mL), dried (MgSO4), and concentrated. Purification by ISCO (40 g SiO2, 0-50% EtOAc/hexanes) gave as the major product, methyl 4-chloroquinoline-6-carboxylate (330 mg, 1.489 mmol, 25.8% yield over 3 steps) (m/z=221.9) as a white solid. Also isolated was the more polar, methyl 2-chloroquinoline-6-carboxylate with same mass (m/z=221.9).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[N:16][C:17]=3[NH2:19])[NH:12][N:11]=2)[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].I[CH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>CN(C=O)C>[CH:27]1([N:12]2[C:13]3=[N:14][CH:15]=[N:16][C:17]([NH2:19])=[C:18]3[C:10]([C:4]3[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=[C:2]([F:1])[CH:3]=3)=[N:11]2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: COc1cc(F)cc(-c2n[nH]c3ncnc(N)c23)c1
Reactant: IC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(F)cc(-c2nn(C3CCCC3)c3ncnc(N)c23)c1
Temperature: 25 °C

Procedure:
3-(3-fluoro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (BA75, 100 mg, 0.386 mmol) was dissolved in DMF (10 ml). K2CO3 (250 mg, 1.54 mmol) was added and reaction was stirred at room temperature under an argon atmosphere. Iodocyclopentane (0.134 ml, 1.16 mmol) was added with a syringe and reaction was stirred for 2 hours. Solid K2CO3 was removed by filtration. Solvent was partially removed in vacuo. Sodium citrate (50 ml) was added and reaction was extracted with EtOAc. Organic phases concentrated in vacuo and purified using by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA79.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:15]=[CH:14][C:8]2[O:9][CH2:10][C:11](=[O:13])[NH:12][C:7]=2[CH:6]=1)=[O:4].CCO.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>CCOCC>[O:22]1[CH2:23][CH2:24][N:19]([CH2:2][C:3]([C:5]2[CH:15]=[CH:14][C:8]3[O:9][CH2:10][C:11](=[O:13])[NH:12][C:7]=3[CH:6]=2)=[O:4])[CH2:20][CH2:21]1
Reactant: O=C1COc2ccc(C(=O)CCl)cc2N1
Reactant: C1COCCN1
Solvent: CCO
Solvent: CCOCC
Product: O=C1COc2ccc(C(=O)CN3CCOCC3)cc2N1
Temperature: 80 °C

Procedure:
To a 20 mL scintillation vial with a magnetic stirrer was added commercially available 6-(2-chloroacetyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (113 mg, 0.5 mmol) and EtOH (2.5 mL) followed by morpholine (96 mg, 1.1 mmol). The reaction was heated at 80° C. for 1 h then cooled to room temperature. The solution was diluted with Et2O (10 mL) and the resulting solid was isolated by filtration, washed with Et2O and dried in vacuo to give a white solid: 1H NMR (DMSO-d6, 400 MHz): δ=10.91 (s, 1H), 9.31 (br. s., 1H), 7.65 (dd, J=8.3, 2.0 Hz, 1H), 7.55 (d, J=2.0 Hz, 1H), 7.03 (d, J=8.3 Hz, 1H), 4.68 (s, 2H), 3.67-3.87 (m, 6H), 3.58 (t, J=4.3 Hz, 2H), 3.07 ppm (d, J=5.1 Hz, 2H). ESI-MS: m/z 277.1 (M+H)+.
Reaction SMILES: ClCCl.[CH3:4][NH:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=3[CH3:32])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:10]([C:33]23OCC(C)(C[O:38]2)C[O:34]3)[CH:9]1[CH3:42])=[O:7].FC(F)(F)C(O)=O>O>[F:31][C:29]1[CH:28]=[CH:27][C:26]([CH3:32])=[C:25]([CH:30]=1)[CH2:24][O:23][C:20]1[CH:19]=[CH:18][C:17]([S:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6](=[O:7])[NH:5][CH3:4])[CH:9]([CH3:42])[CH:10]2[C:33]([OH:38])=[O:34])(=[O:16])=[O:15])=[CH:22][CH:21]=1
Reactant: CNC(=O)N1CCN(S(=O)(=O)c2ccc(OCc3cc(F)ccc3C)cc2)C(C23OCC(C)(CO2)CO3)C1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CNC(=O)N1CCN(S(=O)(=O)c2ccc(OCc3cc(F)ccc3C)cc2)C(C(=O)O)C1C
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 102.7 %

Procedure:
To a dichloromethane (7 ml) solution of 4-[4-(5-fluoro-2-methyl-benzyloxy)-benzenesulfonyl]-2-methyl-3-(4-methyl-2,6,7-trioxa-bicyclo[2.2.2]oct-1-yl)-piperazine-1-carboxylic acid methylamide (compound of formula XLIV, 376 mg, 0.67 mmol) at about 23° C. was added water (0.14 ml) and trifluoroacetic acid (0.14 ml). The reaction mixture was stirred for about 0.5 hour then was concentrated in vacuo. The residue was diluted with methanol (20 ml) and water (6 ml) and cesium carbonate (45 ml of a 10% solution in water) was added to the mixture. The reaction mixture was heated to about 40° C. for about 24 hours then was cooled to about 23° C., acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine and dried with sodium sulfate and concentrated in vacuo, to give 330 mg of a compound of formula XLVI.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])([C:13](OC)=[O:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([NH:17][C:18](=[O:19])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])([CH2:13][OH:14])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1(NC(=O)OC(C)(C)C)CCN(Cc2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(CO)CCN(Cc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 56.3 %

Procedure:
To a solution of methyl 1-benzyl-3-(tert-butoxycarbonylamino)pyrrolidine-3-carboxylate (21.7 g, 64.9 mmol) in THF (320 mL) was added dropwise a solution of LiAlH4 in THF (1.0 M, 55.2 mL, 55.2 mmol) at −78° C. under nitrogen. The reaction mixture was warmed to 0° C. for 5 minutes and then quenched by dropwise addition of water (2.1 mL) followed by 15% NaOH (2.1 mL) and water (6.3 mL). The reaction mixture was stirred at ambient temperature for 15 minutes and then filtered through Celite®. The filtrate was concentrated under reduced pressure and purified by flash chromatography on silica gel (4% MeOH in DCM) to give tert-butyl 1-benzyl-3-(hydroxymethyl)pyrrolidin-3-ylcarbamate (11.2 g, 56%) as a colorless oil.
Reaction SMILES: [F:1][CH2:2][C:3]([N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20])([CH2:6][CH2:7][CH2:8]I)[C:4]#[N:5].[C:21]1(=[O:31])[NH:25][C:24](=[O:26])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12.[K]>CN(C=O)C>[F:1][CH2:2][C:3]([N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20])([CH2:6][CH2:7][CH2:8][N:25]1[C:24](=[O:26])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]2[C:21]1=[O:31])[C:4]#[N:5]
Reactant: N#CC(CF)(CCCI)N1C(=O)c2ccccc2C1=O
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: N#CC(CF)(CCCN1C(=O)c2ccccc2C1=O)N1C(=O)c2ccccc2C1=O
Yield: 51.7 %

Procedure:
A mixture of 2-fluoromethyl-2-phthalimido-5-iodopentanenitrile (34.1 g), potassium phthalimide (16.6 g), and dry DMF (230 ml) is stirred and heated at 70°-80° C. for 5 hours. The DMF is removed under reduced pressure, the residue is dissolved in chloroform, and the chloroform solution is washed with water (2×), 1N KOH (2×), 1N HCl, and water again (3×). The washed chloroform solution is dried and solvent is removed to give an oil which is evaporated twice with chloroform/ether to give a solid. Recrystallization from ether (500 ml) gives pure 2-fluoromethyl-2,5-diphthalimidopentanenitrile (18.5 g).
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.[CH3:13][O:14][C:15](=[O:33])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]=[C:24](Cl)[C:25]3[CH:30]=[C:29]([Cl:31])[S:28][C:26]=3[N:27]=2)=[CH:18][CH:17]=1>>[CH3:13][O:14][C:15](=[O:33])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]=[C:24]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:1][O:2][C:3]=4[CH:4]=3)[C:25]3[CH:30]=[C:29]([Cl:31])[S:28][C:26]=3[N:27]=2)=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3cc(Cl)sc3n2)cc1
Reactant: NCCc1ccc2c(c1)OCO2
Product: COC(=O)c1ccc(-c2nc(NCCc3ccc4c(c3)OCO4)c3cc(Cl)sc3n2)cc1

Procedure:
The reaction procedure as above wherein 3,4-methylenedioxyphenethylamine is reacted with 4-(4-chloro-6-chloro-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(3,4-methylenedioxyphenethylamino)-6-chloro-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: Cl[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:13]=[C:14]([C:17]([O:19]C)=[O:18])[CH:15]=[CH:16][C:4]=2[N:3]=1.ClC1C2C=CC(C(OC)=O)=CC=2SC2C=CC=CC=2N=1>>[CH:9]1[C:8]2[CH:2]=[N:3][C:4]3[CH:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][C:5]=3[S:6][C:7]=2[CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)c1ccc2c(c1)Sc1ccccc1C(Cl)=N2
Agent: COC(=O)c1ccc2c(c1)Sc1ccccc1N=C2Cl
Product: O=C(O)c1ccc2c(c1)Sc1ccccc1C=N2

Procedure:
Repeat the procedures of Examples 9 and 10, substituting an equivalent quantity of methyl 11-chlorodibenzo[b,f][1,4]thiazepin-7-carboxylate for the methyl 11-chlorodibenzo[b,f][1,4]thiazepin-3-carboxylate employed in Example 9, in order to obtain the title product.
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH:9]=O)[C:5]([CH2:11][OH:12])=[CH:4][N:3]=1.[ClH:13].[C:14]([CH:19]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:16][CH2:17][CH3:18])=[O:15]>C(O)C>[ClH:13].[OH:8][C:7]1[C:2]([CH3:1])=[N:3][CH:4]=[C:5]([CH2:11][OH:12])[C:6]=1[CH:9]=[CH:19][C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: Cc1ncc(CO)c(C=O)c1O
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C=Cc1c(CO)cnc(C)c1O
Temperature: 25 °C
Reaction time: 17 h
Yield: 23.8 %

Procedure:
To a suspension of 10.0 g of pyridoxal hydrochloride in 400 ml of ethanol, 17.2 g of (carbethoxymethylene)triphenylphosphorane is added under cooling in an ice-water bath, and the mixture is stirred at room temperature for 17 hours. The reaction mixture is concentrated to half in volume and cooled in an ice-water bath. The precipitate is collected and washed with a small amount of cold ethanol to give 3.2 g of ethyl 3-(3-hydroxy-5-hydroxymethyl-2-methyl-4-pyridyl)acrylate hydrochloride.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([NH2:10])=[CH:8][CH:9]=1.C(O[CH:14]=[C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])C.C(O)C>CCCCCC>[CH2:19]([O:18][C:16](=[O:17])[C:15](=[CH:14][NH:10][C:7]1[CH:8]=[CH:9][C:4]([O:3][CH2:2][CH3:1])=[CH:5][CH:6]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH3:20]
Reactant: CCOc1ccc(N)cc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CCO
Solvent: CCCCCC
Product: CCOC(=O)C(=CNc1ccc(OCC)cc1)C(=O)OCC

Procedure:
The preparation was the same as in example 1. But one equivalent of p-Phenetidine was used instead of p-Anisidine and one equivalent of diethyl ethoxymethylenemalonate was used instead of dimethyl methoxymethylenemalonate. Ethanol was replaced by hexane. 21 g of the title compound was obtained which is a white solid melting at 55-56° C., UV 329 nm (E=802).
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH:18]3[CH2:20][O:19]3)=[CH:12][CH:11]=2)[CH2:4][C:3]1([CH3:22])[CH3:21].[N:23]#[C:24][NH2:25].[Na]>>[CH3:1][N:2]1[C:3]([CH3:21])([CH3:22])[CH2:4][CH:5]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH:18]3[O:19][C:24]([NH2:25])=[N:23][CH2:20]3)=[CH:14][CH:15]=2)[CH2:6][C:7]1([CH3:8])[CH3:9]
Reactant: CN1C(C)(C)CC(c2ccc(OCC3CO3)cc2)CC1(C)C
Reactant: N#CN
Agent: [Na]
Product: CN1C(C)(C)CC(c2ccc(OCC3CN=C(N)O3)cc2)CC1(C)C

Procedure:
The title compound was prepared from 1,2,2,6,6-pentamethyl-4-(4-oxiranylmethoxy-phenyl)-piperidine and sodium hydrogen cyanamide according to the procedures employed for the preparation of the compound in Step 2 of Example 1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C1COCC1.CC([O-])(C)C.[K+].CS([C:31]1[CH:36]=[CH:35][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:33][N:32]=1)(=O)=O>O>[CH3:40][S:37]([C:34]1[CH:35]=[CH:36][C:31]([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[O:15])=[CH:6][CH:7]=2)=[N:32][CH:33]=1)(=[O:39])=[O:38]
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: CS(=O)(=O)c1ccc(S(C)(=O)=O)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1ccc(Oc2ccc(C(=O)c3ccccc3)cc2)nc1

Procedure:
To 5.5 g of p-hydroxybenzophenone in a 25 ml THF/25 ml DMSO mixture was added 3.6 g of t-BuOK and then 6.51 g of 2,5-bis(methylsulfonyl)pyridine, and the resulting mixture was heated at 62° C. for 11/2 hrs. The reaction mixture was cooled and added to approximately 3 to 4 volumes of water and stirred. The crude product which formed was filtered and dried. Recrystallization from ethanol gave purified (4-((5-(methylsulfonyl)-2-pyridinyl)oxy)phenyl)phenylmethanone, m.p. 130°-131.5° C.
Reaction SMILES: I[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Br:12])=[CH:4][CH:3]=1.[CH2:13]([C:16]1[CH:21]=[CH:20][C:19]([C:22]#[CH:23])=[CH:18][CH:17]=1)[CH2:14][CH3:15].O.CCCCCCC>CCN(CC)CC.[Cu]I.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>[Br:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([C:23]#[C:22][C:19]2[CH:20]=[CH:21][C:16]([CH2:13][CH2:14][CH3:15])=[CH:17][CH:18]=2)=[CH:3][CH:4]=1
Reactant: C#Cc1ccc(CCC)cc1
Reactant: Brc1ccc(I)c2ccccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCCCCCC
Solvent: CCN(CC)CC
Solvent: O
Product: CCCc1ccc(C#Cc2ccc(Br)c3ccccc23)cc1

Procedure:
15.3 g (43.6 mmol) of 1-iodo-4-bromonaphthalene and 7.25 g (5.3 mmol) of 4-n-propylphenylacetylene are initially introduced in 200 ml of NEt3, 170 mg (0.9 mmol) of copper(I) iodide and 600 mg (0.9 mmol) of bis(triphenylphosphine)palladium(II) chloride are added, and the mixture is refluxed for 30 minutes. The batch is cooled, water and heptane are added, and the phases are separated. The organic phase is washed with saturated sodium chloride soln., dried over sodium sulfate, filtered and evaporated in a rotary evaporator. The residue is purified by column chromatography (SiO2, heptane), and the further purification is carried out by recrystallisation from isopropanol.
Reaction SMILES: [C:1]1([C:7]2([C:13]#[N:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.[Ni]>[C:1]1([C:7]2([CH2:13][NH2:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CC1(c2ccccc2)CCCCC1
Agent: [Ni]
Solvent: CO
Product: NCC1(c2ccccc2)CCCCC1

Procedure:
1-Phenylcyclohexane carbonitrile is reduced with H2 in methanol containing 16% ammonia with a Raney nickel catalyst. The catalyst is filtered off and (1-phenylcyclohexyl)methylamine is precipitated as its hydrochloride salt m.p. 230°-33° C., by treatment with methanolic HCl and isopropyl ether.
Reaction SMILES: [C:1](Cl)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:19]([N:36]([C@@H:42]1[C@H:46]([OH:47])[C@@H:45]([CH2:48][OH:49])[O:44][C@H:43]1[N:50]1[CH:57]=[CH:56][C:54](=[O:55])[NH:53][C:51]1=[O:52])[C:37](=[O:41])[CH2:38][CH2:39][NH2:40])([O:21][CH2:22][CH:23]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:20]>N1C=CC=CC=1>[C:1]([C@@:46]1([OH:47])[C@@H:45]([CH:48]([C:1](=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[OH:49])[O:44][C@@H:43]([N:50]2[CH:57]=[CH:56][C:54](=[O:55])[NH:53][C:51]2=[O:52])[C@@H:42]1[N:36]([C:19]([O:21][CH2:22][CH:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:30]2[C:35]1=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:20])[C:37](=[O:41])[CH2:38][CH2:39][NH2:40])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: NCCC(=O)N(C(=O)OCC1c2ccccc2-c2ccccc21)[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(=O)[nH]c1=O
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCC(=O)C(O)[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](N(C(=O)CCN)C(=O)OCC2c3ccccc3-c3ccccc32)[C@@]1(O)C(=O)CCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
Palmitoyl chloride (1.55 mL, 1.8 mmol) was added to a solution of nucleoside 28 in abs pyridine and the reaction mixture was stirred overnight at room temperature. The solution was then quenched with MeOH, evaporated to dryness, dissolved in dichloromethane and washed with saturated aq sodium bicarbonate and brine. The organic phase was dried over sodium sulfate and evaporated to dryness. The residue was purified by flash chromatography on silica (EtOAc-Hexanes 1:1) affording 0.5 g of 29 (yield, 65%).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[C:10]([C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:34][C:35]1([CH3:48])[O:47][C:39]2[C:40]([CH3:46])=[N:41][CH:42]=[C:43]([CH:44]=O)[C:38]=2[CH2:37][O:36]1.[BH4-].[Na+].[OH-].[Na+]>ClCCl.C1(C)C=CC=CC=1>[C:1]([NH:5][S:6]([C:9]1[C:10]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:44][C:43]3[CH:42]=[N:41][C:40]([CH3:46])=[C:39]4[O:47][C:35]([CH3:48])([CH3:34])[O:36][CH2:37][C:38]=34)=[CH:17][CH:16]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(N)cc1
Reactant: Cc1ncc(C=O)c2c1OC(C)(C)OC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ncc(CNc2ccc(-c3ccccc3S(=O)(=O)NC(C)(C)C)cc2)c2c1OC(C)(C)OC2
Temperature: 120 °C
Reaction time: 7 h
Yield: 23.1 %

Procedure:
To a 250 mL three neck flask fitted with a condenser and Dean-Stark apparatus was added 4′-amino-biphenyl-2-sulfonic acid tert-butylamide (1.22 g, 4.0 mmol), p-toluenesulfonic acid monohydrate (152 mg, 0.8 mmol), 2,2,8-trimethyl-4H-[1,3]dioxino [4,5-c]pyridine-5-carbaldehyde (995 mg, 4.8 mmol) and toluene (120 ml). The reaction mixture was stirred at 120° C. under nitrogen atmosphere for 7 hours before concentrating to dryness. The resulting solid was then dissolved in acetic acid (20 mL), cooled to 0° C., followed by a slow addition of sodium borohydride (529 mg, 14 mmol). After the addition of sodium borohydride, dichloromethane (30 mL) was then added to the reaction mixture and stirring was continued at room temperature for an additional 3 hours. Sodium hydroxide (5 N) was added to neutralize the solution, and the reaction mixture was extracted with ethyl acetate, dried over MgSO4, filtered and evaporated. The crude mixture was purified by column chromatography on silica gel using a mixture of ethyl acetate and hexane (1:1) as eluant, to give 4′-[(2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridin-5-ylmethyl)-amino]-biphenyl-2-sulfonic acid tert-butylamide (1) (0.457 g, 24% yield) as a colorless solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[N:13]2[C:8]([C:9]([NH2:14])=[N:10][CH:11]=[N:12]2)=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]3[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=3[F:35])=[O:23])=[CH:17][CH:16]=2)[CH:6]=1)=[O:4].[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>C1COCC1.CCOC(C)=O.C1(C)C=CC=CC=1>[NH2:14][C:9]1[C:8]2=[C:7]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=4[F:35])=[O:23])=[CH:17][CH:16]=3)[CH:6]=[C:5]([C:3](=[O:4])[CH2:2][N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[N:13]2[N:12]=[CH:11][N:10]=1
Reactant: Nc1ncnn2c(C(=O)CBr)cc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)cc3)c12
Reactant: C1COCCN1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Nc1ncnn2c(C(=O)CN3CCOCC3)cc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)cc3)c12
Reaction time: 0.25 h

Procedure:
A solution of N-[4-(7-bromoacetyl-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea (65 mg, 0.12 mmol) in 2 mL THF was treated with morpholine (53 uL, 0.59 mmol) and allowed to stir for 15 min. The reaction was then diluted with 50 mL EtOAc and 5 mL toluene & washed with sodium carbonate solution (1×). The organic layer dried with sodium sulfate and concentrated to give a yellow oil. Trituration with Et2O:hexanes (1:1) gave the title compound as a fainly yellow powder (52.4 mg, 79% Yield). 1H-NMR (DMSO-d6) 9.28 (s, 1H), 8.84 (s, 1H), 8.43 to 8.47 (m, 1H). 7.95 (s, 1H), 7.42 (d, J=8.7 Hz, 2H), 7.19 to 7.31 (m, 3H) 7.25 (d, J=8.7 Hz, 2H), 7.17 (s, 1H), 3.76 (s, 2H), 3.38 to 3.43 (m, 4H), 2.35 to 2.41 (m, 4H); MS [M+H]+=557.9; LCMS RT=2.57.