Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([N+:16]([O-])=O)[CH:14]=2)[NH:9][N:8]=1.[Sn](Cl)Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([NH2:16])[CH:14]=2)[NH:9][N:8]=1
Reactant: O=[N+]([O-])c1cnc2[nH]nc(-c3ccccn3)c2c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1cnc2[nH]nc(-c3ccccn3)c2c1
Yield: 60 %

Procedure:
A 50 ml, round bottom flask was charged with 3-(pyridin-2-yl)-5-nitro-1H-pyrazolo[3,4-b]pyridine (0.10 g, 0.41 mmol) and tin dichloride (1.0 g, 5.2 mmol) in ethyl acetate (10 mL) and methanol (10 mL) and was heated to reflux for 3 hours. The reaction mixture was cooled and poured into saturated aqueous sodium bicarbonate and filtered through celite. The organic layer was separated, dried (MgSO4), and concentrated. The residue was purified by silica gel chromatography eluting with 10-60% methanol in methylene chloride to afford 3-(pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-amine (52 mg, 59% yield) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[CH2:11]([N:13](CC)[CH2:14]C)C.Cl.CNC>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:13]([CH3:14])[CH3:11])=[O:7])=[CH:4][N:3]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: CCN(CC)CC
Agent: CNC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)C(=O)c1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
6-Chloronicotinoyl chloride (500 mg, 2.76 mmol) and triethylamine (0.576 ml, 4.13 mmol) were taken-up in THF (13.8 ml) under argon and cooled to 0° C. Dimethylamine hydrochloride (337 mg, 4.13 mmol) was dissolved in THF (2 ml) and added dropwise to the reaction mixture over 15 minutes. The mixture was maintained at 0° C. for 1 hour, warmed to room temperature, and stirred for 15 minutes. The reaction was then diluted with ethyl acetate and washed twice with brine. The aqueous layers were combined and back-extracted twice with ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated to afford the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](=[O:9])[N:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:4]=1[S-:16])#[N:2].[Na+].Cl[CH2:19][C:20]#[N:21].O>CC#N>[NH2:2][C:1]1[C:3]2[CH:8]=[CH:7][C:6](=[O:9])[N:5]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:4]=2[S:16][C:19]=1[C:20]#[N:21]
Reactant: N#Cc1ccc(=O)n(-c2ccccc2)c1[S-]
Reactant: N#CCCl
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: N#Cc1sc2c(ccc(=O)n2-c2ccccc2)c1N

Procedure:
A mixture of Example 1 (100 g at 100%) and chloracetonitrile (30.4 mL) in MeCN (500 mL) was heated at reflux for 2 h. The mixture was cooled, initially to 40° C. when water (300 mL) was added, and then to +10° C. The reaction was maintained at +10° C. for at least 1 h when the product was recovered by filtration. The filter cake was washed with cold (+10° C.) H2O (500 mL) followed by a cold (+10° C.) mixture of MeCN and H2O (1:1, 300 mL). The product was dried under vacuum at 50° C. to constant weight to give the title compound as an off-white solid (100.9 g). δH (DMSO-d6) 7.90 (1H, d, J 9.6 Hz), 7.46-7.33 (3H, m), 7.25 (2H, m), 6.95 (2H, br s), 6.35 (1H, d, J 9.6 Hz). LCMS (ES+) RT 2.69 minutes, 268 (M+H)+.
Reaction SMILES: Cl[C:2]([O:4][C:5]([CH3:7])=[CH2:6])=[O:3].[F:8][C:9]1[CH:15]=[C:14]([CH3:16])[C:13]([C:17]2[C:28]([CH3:29])=[N:27][C:20]3[N:21]=[C:22]([S:25][CH3:26])[N:23]=[CH:24][C:19]=3[CH:18]=2)=[CH:12][C:10]=1[NH2:11]>CCOC(C)=O.C([O-])(O)=O.[Na+]>[F:8][C:9]1[CH:15]=[C:14]([CH3:16])[C:13]([C:17]2[C:28]([CH3:29])=[N:27][C:20]3[N:21]=[C:22]([S:25][CH3:26])[N:23]=[CH:24][C:19]=3[CH:18]=2)=[CH:12][C:10]=1[NH:11][C:2](=[O:3])[O:4][C:5]([CH3:7])=[CH2:6]
Reactant: CSc1ncc2cc(-c3cc(N)c(F)cc3C)c(C)nc2n1
Reactant: C=C(C)OC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: C=C(C)OC(=O)Nc1cc(-c2cc3cnc(SC)nc3nc2C)c(C)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
Add isopropenyl chloroformate (146 mg, 1.207 mmol) to a bi-phasic mixture of 2-fluoro-4-methyl-5-(7-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-6-yl)aniline (345 mg, 1.097 mmol) in EtOAc (15 mL) and saturated NaHCO3 (20 mL) and stir at RT for 2 h. Add EtOAc, separate the layers, wash the organic layer with brine, dry over Na2SO4 and concentrate to dryness to afford the title compound as an amorphous solid (434 mg, 99%). MS (m/z): 399.1 (M+1).
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5]1.I[CH3:16].O>O1CCCC1>[CH3:16][O:3][CH:4]1[CH2:5][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7]1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC1CN(C(=O)OC(C)(C)C)C1
Yield: 33.3 %

Procedure:
A suspension of sodium hydride (2.89 g) in tetrahydrofuran (50 ml) was stirred with cooling in an ice bath. A solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (5.00 g) in tetrahydrofuran (50 ml) was gradually added, followed by stirring at the same temperature for 30 minutes. Then, the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was stirred with cooling in an ice bath again for 15 minutes. Iodomethane (3.09 ml) was added dropwise to the reaction mixture, followed by stirring for 2 hours. Water was gradually added to the reaction mixture. When bubbling stopped, the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=3:1, 2:1, 1:1, then ethyl acetate). The fractions containing the target compound were concentrated to give the title compound (1.80 g, 33.3%) as a colorless oil. The fractions containing the starting material were concentrated and collected (2.10 g, 42.0%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]([CH3:15])([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1)[CH3:5].C([O-])=O.[NH4+]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:16])[C:4]([C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[CH:10][CH:11]=1)([CH3:15])[CH3:5]
Reactant: COC(=O)C(C)(C)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)C(C)(C)c1ccc(N)cc1
Temperature: 25 °C

Procedure:
To a solution of 2-methyl-2-(4-nitrophenyl)-propionic acid methyl ester (932.2 mg, 4.16 mmol) and ammonium formate (1.58 g, 25.1 mmol) in MeOH was added Pd/C (10%, 441.2 mg, 0.414 mmol). The reaction mixture was stirred at rt until gas evolution ceased, then filtered through a plug of diatomaceous earth and concentrated. The residue was redissolved in H2O and extracted with EtOAc. The organic layers were combined, dried, and concentrated to provide the title compound which was used without further purification.
Reaction SMILES: [NH3:1].[CH3:2][N:3]1[C:8]([CH3:9])=[CH:7][C:6](=[O:10])[CH2:5][S:4]1(=[O:12])=[O:11]>CO>[NH2:1][C:8]([CH3:9])=[CH:7][C:6](=[O:10])[CH2:5][S:4]([NH:3][CH3:2])(=[O:12])=[O:11]
Reactant: CC1=CC(=O)CS(=O)(=O)N1C
Reactant: N
Solvent: CO
Product: CNS(=O)(=O)CC(=O)C=C(C)N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A moderately rapid stream of dry ammonia was introduced at 20°-25° during 3 hours into a suspension of 10 g of 2,3-dimethyl-1,2-thiazin-5(6H)-one 1,1-dioxide in 100 ml of methanol, whereby a clear pale yellow solution resulted after about 10-15 minutes. Thereupon, the mixture was stirred further at room temperature overnight. The crystallized-out product was filtered off and washed with a small amount of methanol, whereby there were obtained 9.8 g of 4-amino-N-methyl-2-oxo-3-pentenesulfonamide in the form of colorless crystals, m.p. 158°-162°. From the filtrate there were obtained by concentration to about 50 ml an additional 2.2 g of product, mp. 158°-162°, total yield: 12 g.
Reaction SMILES: [S:1]=[C:2]1[N:13]([CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[C:12]2[C:4](=[CH:5][C:6]3[O:7][CH:8]=[CH:9][C:10]=3[N:11]=2)[S:3]1.[N+:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([O-:22])=[O:21].CCCCCC.O>C(#N)C.C(OCC)(=O)C>[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([C:8]2[O:7][C:6]3[CH:5]=[C:4]4[C:12]([N:13]([CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[C:2](=[S:1])[S:3]4)=[N:11][C:10]=3[CH:9]=2)=[CH:25][CH:24]=1)([O-:22])=[O:21]
Reactant: O=C(O)CCCn1c(=S)sc2cc3occc3nc21
Reactant: O=[N+]([O-])c1ccccc1
Solvent: CC#N
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(O)CCCn1c(=S)sc2cc3oc(-c4ccc([N+](=O)[O-])cc4)cc3nc21
Temperature: -10 °C
Reaction time: 1 h

Procedure:
4-(2-Thioxo-7-oxa-1-thia-3,4-diaza-s-indacen-3-yl)-butyric acid (0.2 mmol) was dissolved in dry acetonitrile (2 ml) under nitrogen atmosphere, and the solution was cooled to −10° C. Nitrosyltetrafluoroborate (NOBF4, 0.24 mmol) mixed in dry acetonitrile (1 ml) was added thereto, and the mixture turned red immediately. The resulting mixture was stirred for one hour at −10° C., and a mixture of nitrobenzene (0.4 mmol) and a solution of CuCl2 dihydrate (15 mmol) in acetonitrile (1 ml) was added dropwise. The reaction mixture was allowed to warm-up to 0° C., and TLC analysis using a 1:1 hexane:ethyl acetate mixture as eluent indicated complete conversion after 0.5-1.0 hours. Thereafter ethyl acetate and water were added, the organic and aqueous layers were separated, the organic layer was dried over Na2SO4 and the solvent was evaporated under reduced pressure to give the crude product 4-[6-(4-nitro-phenyl)-2-thioxo-7-oxa-1-thia-3,4-diaza-s-indacen-3-yl]-butyric acid which was further purified by column chromatography using fine silica and a 4:1 hexane:ethyl acetate mixture as eluent.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2[N:13]=[N:14][N:15]3[C:20]4[CH:21]=[CH:22][S:23][C:19]=4[C:18](=O)[NH:17][C:16]=23)(=[O:11])=[O:10])=[CH:5][CH:4]=1)[CH3:2].[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[CH2:30][NH2:31].C1CCN2C(=NCCC2)CC1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.Cl.C([O-])([O-])=O.[Na+].[Na+]>C(#N)C.C(Cl)(Cl)Cl>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2[N:13]=[N:14][N:15]3[C:20]4[CH:21]=[CH:22][S:23][C:19]=4[C:18]([NH:31][CH2:30][C:26]4[S:25][CH:29]=[CH:28][CH:27]=4)=[N:17][C:16]=23)(=[O:11])=[O:10])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(S(=O)(=O)c2nnn3c2[nH]c(=O)c2sccc23)cc1
Reactant: NCc1cccs1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: ClC(Cl)Cl
Solvent: C1CCC2=NCCCN2CC1
Product: CCc1ccc(S(=O)(=O)c2nnn3c2nc(NCc2cccs2)c2sccc23)cc1
Temperature: 100 °C
Yield: 55 %

Procedure:
Pyrimidin-5-one 15m (560 mg, 1.55 mmol) was treated with 2-thiophenemethylamine (0.48 mL, 4.66 mmol, 3 equivalent), DBU (0.70 mL, 4.66 mmol, 3 equivalent) and PyBOP (2.43 g, 4.66 mmol, 3 equivalent) in anhydrous acetonitrile (5.1 mL), and placed in a microwave vessel. The mixture was heated in a microwave synthesizer at 100° C. for 30 min. The reaction mixture was treated with aqueous HCl (1 M, 20 mL) and stirred for 30 min before Na2CO3 was added to adjust pH to approximately 9. The reaction mixture was dissolved in CHCl3 (75 mL), washed with aqueous HCl (1 M, 3×75 mL). The organic product layer was concentrated in vacuo and UTBinh-14 was purified by flash column chromatography: dichloromethane+1% acetic acid→dichloromethane:methanol (100:1+1% acetic acid). The residue was re-crystallized from ethanol to yield UTBinh-14 (392 mg, 55% yield) as a white solid. 1H NMR (CDCl3, 500 MHz): δ 1.21 (t, 3H, J=10 Hz), 2.67 (q, 2H, J=10 Hz), 5.15 (d, 2H, J=5 Hz), 5.86 (t, 1H, J=5 Hz), 7.01 (dd, 1H, J=5 Hz), 7.23 (d, 1H, J=5 Hz), 7.26 (d, 1H, J=5 Hz), 7.28 (d, 2H, J=5 Hz), 7.88 (d, 1H, J=5 Hz), 7.95 (d, 1H, J=5 Hz), 8.12 (d, 2H, J=10 Hz). 13C NMR (CDCl3, 125 Hz): δ 15.73, 29.55, 41.04, 118.13, 126.42, 127.89, 128.07, 128.64, 129.08, 133.84, 153.22. HR-ESI-MS (M+H)+ calc 456.0622. found 456.0583 for C20H17N5O2S3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])[CH2:13][CH2:12]1>CCO.[Pt]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:21])[CH:18]([CH3:19])[CH3:20])[CH2:13][CH2:12]2)=[C:2]([Cl:1])[CH:7]=1
Reactant: CC(C)C(=O)N1CCN(c2ccc([N+](=O)[O-])cc2Cl)CC1
Agent: [Pt]
Solvent: CCO
Product: CC(C)C(=O)N1CCN(c2ccc(N)cc2Cl)CC1
Yield: 100 %

Procedure:
According to Scheme 4 Step 2: A solution of 1-(4-(2-chloro-4-nitrophenyl)piperazin-1-yl)-2-methylpropan-1-one (0.62 mmol, 195 mg) in EtOH (120 mL) was passed through a Pt/C 5% column in an H-Cube equipment (mode: Full). Then the solution was concentrated under reduced pressure to yield 1-(4-(4-amino-2-chlorophenyl)piperazin-1-yl)-2-methylpropan-1-one (0.62 mmol, 175 mg, 99%). The product was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([O:26][CH3:27])[CH:20]=3)[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:18])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[N:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[N:30][CH:29]=1>>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[C:10]([NH2:18])=[N:9][C:8]2([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[C:21]([O:26][CH3:27])[CH:20]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:32]2[CH:33]=[N:28][CH:29]=[N:30][CH:31]=2)[CH:3]=1
Reactant: OB(O)c1cncnc1
Reactant: COc1cc(C2(c3cccc(Br)c3)N=C(N)c3c(F)cccc32)ccc1F
Product: COc1cc(C2(c3cccc(-c4cncnc4)c3)N=C(N)c3c(F)cccc32)ccc1F
Yield: 20 %

Procedure:
The title compound was synthesized as described for Example 45 in 20% yield starting from 1-(3-bromophenyl)-4-fluoro-1-(4-fluoro-3-methoxyphenyl)-1H-isoindol-3-amine (210 mg, 0.49 mmol) and pyrimidine-5-boronic acid (72.7 mg, 0.59 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([S:13][CH2:14][CH2:15][C:16](OCC(CC)CCCC)=O)=[CH:11][C:10]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N:9]1.[O-]CC.[Na+].[Br:36][C:37]1[CH:42]=CC=C(I)[CH:38]=1.C(N(C(C)C)C(C)C)C>C(O)C.C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:36][C:37]1[CH:38]=[C:14]([S:13][C:12]2[N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[N:9]=[C:10]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:11]=2)[CH:15]=[CH:16][CH:42]=1
Reactant: CCCCC(CC)COC(=O)CCSc1cc(C(=O)OCC)nn1-c1ccccc1Cl
Reactant: Brc1cccc(I)c1
Agent: [Pd]
Agent: CC[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc(Sc2cccc(Br)c2)n(-c2ccccc2Cl)n1
Temperature: 25 °C
Yield: 60.8 %

Procedure:
A mixture of ethyl 1-(2-chlorophenyl)-5-({3-[(2-ethylhexyl)oxy]-3-oxopropyl}thio)-1H-pyrazole-3-carboxylate (1.21 g), sodium ethoxide (362 mg), 1-bromo-3-iodobenzene (775 mg), tris(dibenzylideneacetone)dipalladium (0) (97 mg), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthine (123 mg) and N-ethyldiisopropylamine (0.88 mL) was stirred at 80° C. for 12 hr in ethanol (10 mL) and toluene (15 mL). The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=4:1) to give the title compound as a yellow oil (yield 689 mg, yield 61%).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.O[CH:33]1[CH2:38][CH2:37][CH:36]([N:39]2[C:47](=[O:48])[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40]2=[O:49])[CH2:35][CH2:34]1.[CH3:50][C:51]([SH:53])=[O:52]>C1COCC1.O.CC(=O)OCC>[C:51](=[O:52])([S:53][CH:33]1[CH2:38][CH2:37][CH:36]([N:39]2[C:47](=[O:48])[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40]2=[O:49])[CH2:35][CH2:34]1)[CH3:50]
Reactant: CC(=O)S
Reactant: O=C1c2ccccc2C(=O)N1C1CCC(O)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)SC1CCC(N2C(=O)c3ccccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
To a solution of PPh3 (1.28 g, 4.9 mmol) in THF (12 mL) was added dropwise DEAD (852 mg, 4.9 mmol) at −10° C. After the white solid was appeared, compound 2-(4-hydroxycyclohexyl)isoindoline-1,3-dione (600 mg, 2.45 mmol) was added, followed by CH3COSH (0.35 mL, 4.9 mmol) at −10° C. The mixture was stirred at room temperature overnight. TLC (PE:EA=1:1) showed the reaction was complete. The mixture was poured into water (200 mL) and extracted with EtOAc (100 mL). The aqueous layer was extracted with EtOAc (100 mL×3). The combined extracts were dried over Na2SO4, filtered and concentrated in vacuo to give S-(4-(1,3-dioxoisoindolin-2-yl)cyclohexyl) ethanethioate (600 mg, 81%) as a white solid.
Reaction SMILES: C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.[CH3:18][C:19]1[O:23][C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=2)=[N:21][C:20]=1[CH2:31][CH2:32][O:33][C:34]1[CH:46]=[CH:45][C:37](/[CH:38]=[CH:39]/[C:40](OCC)=[O:41])=[CH:36][CH:35]=1.CO>ClCCl.O>[CH3:18][C:19]1[O:23][C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=2)=[N:21][C:20]=1[CH2:31][CH2:32][O:33][C:34]1[CH:35]=[CH:36][C:37](/[CH:38]=[CH:39]/[CH2:40][OH:41])=[CH:45][CH:46]=1
Reactant: CCOC(=O)/C=C/c1ccc(OCCc2nc(-c3cccc(C)c3)oc2C)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CO
Product: Cc1cccc(-c2nc(CCOc3ccc(/C=C/CO)cc3)c(C)o2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
A toluene solution of diisobutylaluminum hydride (1.5M, 9.3 ml) was added dropwise at 0° C. to a suspension of ethyl (E)-4-[2-[5-methyl-2-(3-methylphenyl)-4-oxazolyl]ethoxy]cinnamate (2.48 g) in dichloromethane (50 ml). The mixture was stirred for 2 hours at room temperature, to which were then added, under ice-cooling, methanol (3 ml) and, then, water (30 ml). The mixture was subjected to filtration through a celite layer. The organic layer was washed with water, dried (MgSO4) and, then, concentrated. The concentrate was purified by means of a column chromatography. From the fractions eluted with ethyl acetate--hexane (1:1) was obtained (E)-3-[4-[2-[5-methyl-2-(3-methylphenyl)-4-oxazolyl]ethoxy]phenyl]-2-propen-1-ol (1.44 g, 65%). Recrystallization from dichloromethane--isopropyl ether gave colorless prisms, m.p.116°-117° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]1[CH2:39][CH2:38][CH:37]([C:40]#[N:41])[CH2:36][CH2:35]1)(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31]([N:34]3[CH2:35][CH2:36][CH:37]([C:40]#[N:41])[CH2:38][CH2:39]3)(=[O:32])=[O:33])=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: N#CC1CCN(S(=O)(=O)c2ccccc2Br)CC1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: N#CC1CCN(S(=O)(=O)c2ccccc2-c2ccc(-c3cnc(N)cn3)c(F)c2)CC1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and 1-((2-bromophenyl)sulfonyl)piperidine-4-carbonitrile. MS (ESI): mass calcd. for C22H20FN5O2S, 437.13; m/z found, 438.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.35 (s, 1H), 8.29 (d, J=1.1, 1H), 8.12-8.09 (m, 1H), 7.99 (m, 1H), 7.74-7.69 (m, 1H), 7.65-7.60 (m, 1H), 7.45-7.42 (m, 1H), 7.34 (s, 1H), 7.32-7.30 (m, 1H), 3.10-3.02 (m, 2H), 2.86-2.73 (m, 3H), 1.82-1.73 (m, 2H), 1.64-1.53 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([N:25]3[CH2:28][CH2:27][CH2:26]3)=[O:24])=[CH:19][CH:18]=2)[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4].N1(C(C2C=CC(Br)=CC=2[F:42])=O)CCC1.COC(C1C=C(O)C=C2OC(C)(C)CC=12)=O>>[CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([N:25]3[CH2:28][CH2:27][CH2:26]3)=[O:24])=[C:19]([F:42])[CH:18]=2)[CH:8]=[C:7]2[O:11][C:10]([CH3:9])([CH3:12])[CH2:13][C:6]=12)=[O:4]
Reactant: COC(=O)c1cc(Oc2ccc(C(=O)N3CCC3)cc2)c2c(c1)OC(C)(C)C2
Reactant: O=C(c1ccc(Br)cc1F)N1CCC1
Agent: COC(=O)c1cc(O)cc2c1CC(C)(C)O2
Product: COC(=O)c1cc(Oc2ccc(C(=O)N3CCC3)c(F)c2)cc2c1CC(C)(C)O2

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 35b, from azetidin-1-yl-(4-bromo-2-fluoro-phenyl)-methanone and 6-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-carboxylic acid methyl ester (197e). 1H NMR (400 MHz, CDCl3) δ 7.42 (d, J=7.07 Hz, 1 H) 7.37 (d, J=1.77 Hz, 1 H) 7.29 (dd, J=9.35, 1.52 Hz, 1 H) 7.15 (d, J=2.27 Hz, 1 H) 6.62 (d, J=2.27 Hz, 1 H) 4.16-4.25 (m, 2 H) 4.07-4.16 (m, 2 H) 3.87-3.88 (m, 3 H) 3.33 (s, 2 H) 2.29-2.39 (m, 2 H) 1.51 (s, 6 H); LCMS for C22H22FNO5 m/z 441.30 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:19][C:20]([CH3:24])=[CH:21][CH2:22]Cl>C(#N)C>[CH3:19][C:20]([CH3:24])=[CH:21][CH2:22][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: CC(C)=CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1ccc(OCC=C(C)C)cc1
Yield: 95.2 %

Procedure:
Ethyl 4-hydroxybenzoate (1.66 g, 10.0 mmol) and anhydrous potassium carbonate (2.07 g, 15.0 mmol) in acetonitrile (30 ml) was treated with 3-methyl-2-butenyl chloride (1.35 ml, 12.0 mmol) and the mixture was stirred and held at reflux for 3 hours. Upon cooling the solvent was removed in vacuo and the mixture partitioned between dichloromethane and water. The organics were separated and the solvent removed in vacuo to afford ethyl 4-(3-methyl-but-2-enyloxy)-benzoate (2.23 g, 95%) as a pale yellow liquid which was used without further purification. 1H NMR (DMSO-d6) 7.89 (2H, d), 7.04 (2H, d), 5.44 (1H, t), 4.62 (2H, d), 4.28 (2H, q), 1.77 (3H, s), 1.73 (3H, s), 1.31 (3H, t). MS: [M+H]+ 235.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[CH:3]([OH:10])[CH:4]([N+:7]([O-])=O)[CH2:5][CH3:6]>CO.[Ni]>[NH2:7][CH:4]([CH2:5][CH3:6])[CH:3]([OH:10])[C:2]([F:12])([F:11])[F:1]
Reactant: CCC(C(O)C(F)(F)F)[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: CCC(N)C(O)C(F)(F)F
Reaction time: 24 h

Procedure:
1,1,1-trifluoro-3-nitropentan-2-ol (3 g, 16 mmol) was dissolved in methanol (40 ml). Raney Nickel catalyst was added and the reaction vigorously stirred under an atmosphere of hydrogen for 24 h. The catalyst was filtered and the filtrate was concentrated in vacuo to give the amine relatively pure (2.35 g, 94%). δH (CDCl3, 500 MHz) 1.05 (3 H, t, J 5, CHCH2CH3), 1.55-1.45 (1 H, m, CHCHHCH3), 1.8-1.7 (1 H, m, CHCHHCH3), 2.95-2.9 (1 H, m, CHEt), 3.95-3.85 (1 H, m, CHOHCF3); δC (CDCl3, 500 MHz) 124.5 (C), 71.5 (CH), 54.03 (CH), 25.5 (CH2), 11.05 (CH3)