Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[Mg][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1.[C:13]1([C:19]2[C:28]([CH:29]=[O:30])=[C:27]([CH:31]([CH3:33])[CH3:32])[CH:26]=[C:25]3[C:20]=2[C:21](=[O:36])[CH2:22][C:23]([CH3:35])([CH3:34])[O:24]3)[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=1.C(=O)(O)[O-].[Na+]>O1CCCC1>[C:13]1([C:19]2[C:28]([CH:29]([OH:30])[C:3]3[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=3)=[C:27]([CH:31]([CH3:32])[CH3:33])[CH:26]=[C:25]3[C:20]=2[C:21](=[O:36])[CH2:22][C:23]([CH3:34])([CH3:35])[O:24]3)[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=1
Reactant: FC(F)(F)c1ccc([Mg]Br)cc1
Reactant: CC(C)c1cc2c(c(C3=CCCCC3)c1C=O)C(=O)CC(C)(C)O2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)c1cc2c(c(C3=CCCCC3)c1C(O)c1ccc(C(F)(F)F)cc1)C(=O)CC(C)(C)O2
Reaction time: 0.75 h

Procedure:
At −78° C., 2.03 ml (1.02 mmol) of a freshly prepared 0.5 M solution of bromo[4-(trifluoromethyl)phenyl]magnesium in tetrahydrofuran are slowly added dropwise to a solution of 255 mg (780 μmol) of 5-cyclohex-1-en-1-yl-7-isopropyl-2,2-dimethyl-4-oxochroman-6-carbaldehyde (Example 33A) in 6 ml of tetrahydrofuran. The mixture is then allowed to thaw slowly to −20° C. and stirred at this temperature for 45 min. A further 300 μl (193 μmol) of the above Grignard solution are added and stirring is continued for a further hour, the solution slowly thawing to 0° C. 10% strength sodium bicarbonate solution is then added, the mixture is extracted three times with ethyl acetate and the combined organic phases are washed with saturated sodium chloride solution. The organic phases are dried over magnesium sulfate and the solvent is then removed under reduced pressure. The residue is dissolved in a mixture of cyclohexane and ethyl:acetate (10:1), whereupon the target product crystallizes and is filtered off. The filtrate is concentrated and the residue is purified by column chromatography on silica gel (mobile phase: gradient cyclohexane→cyclohexane/ethyl acetate 20:1→10:1). The resulting target product is combined with the crystals. The compound is present in the form of atropisomers (1:1).
Reaction SMILES: C([O:3][C:4](=[O:41])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH3:35])[CH:14]([C:18]2[C:19]([CH3:34])=[N:20][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=[CH:22][CH:23]=2)[CH2:15][CH2:16][CH3:17])=[CH:9][C:8]=1[CH2:36][CH2:37][CH2:38][O:39][CH3:40])C.[OH-].[Na+].Cl>C1COCC1.CCO>[CH3:40][O:39][CH2:38][CH2:37][CH2:36][C:8]1[CH:9]=[C:10]([N:13]([CH3:35])[CH:14]([C:18]2[C:19]([CH3:34])=[N:20][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=[CH:22][CH:23]=2)[CH2:15][CH2:16][CH3:17])[CH:11]=[CH:12][C:7]=1[O:6][CH2:5][C:4]([OH:41])=[O:3]
Reactant: CCCC(c1ccc(-c2cccc(C(F)(F)F)c2)nc1C)N(C)c1ccc(OCC(=O)OCC)c(CCCOC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCC(c1ccc(-c2cccc(C(F)(F)F)c2)nc1C)N(C)c1ccc(OCC(=O)O)c(CCCOC)c1
Reaction time: 2 h

Procedure:
0.082 g (0.143 mmol) of the above prepared [rac]-[2-(3-methoxy-propyl)-4-(methyl-{1-[2-methyl-6-(3-trifluoromethyl-phenyl)-pyridin-3-yl]-butyl}-amino)-phenoxy]-acetic acid ethyl ester was dissolved in 1.64 ml of THF/EtOH=1/1, treated at 0° C. with 0.43 ml (3 eq.) of 1N NaOH, and kept at ambient temperature for 2 h. The reaction mixture was then neutralized with HCl dil. to pH 7, extracted with AcOEt, the organic layer was washed with water, dried over sodium sulfate, and evaporated to dryness to leave 0.070 g of the title compound as light brown oil.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([O:19][CH3:20])=[CH:7][C:8]([CH:17]=[O:18])=[C:9]([CH:16]=1)[CH:10]=[CH:11][C:12]([O:14][CH3:15])=[O:13])(=[O:3])[CH3:2]>[Pd].C(OCC)(=O)C>[C:1]([O:4][C:5]1[C:6]([O:19][CH3:20])=[CH:7][C:8]([CH:17]=[O:18])=[C:9]([CH:16]=1)[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])(=[O:3])[CH3:2]
Reactant: COC(=O)C=Cc1cc(OC(C)=O)c(OC)cc1C=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)CCc1cc(OC(C)=O)c(OC)cc1C=O
Reaction time: 18 h

Procedure:
A mixture of methyl 5-acetoxy-2-formyl-4-methoxycinnamate (10.8 g) and 10% palladium on carbon (3 g) in ethyl acetate (100 ml) is hydrogenated at 45 psi for about 18 hours and filtered. The filtrate is concentrated in vacuo and the residue purified by HPLC, eluting 50% ethyl acetate in hexanes, to give the desired product.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[CH:27]=[CH:26][C:7]([CH2:8][O:9][C:10]([NH:12][C@H:13]([C:22](OC)=[O:23])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[O:11])=[CH:6][CH:5]=1>CO>[CH3:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([NH:12][C@H:13]([CH2:22][OH:23])[CH2:14][C:15]2[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=2)=[O:11])=[CH:26][CH:27]=1
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccc(C)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(COC(=O)N[C@H](CO)Cc2ccc(O)cc2)cc1
Temperature: 25 °C
Yield: 73.5 %

Procedure:
In 150 ml of 50% aqueous methanol, 13.1 g of sodium borohydride was added with stirring while cooling with ice. To the mixture was added dropwise 250 ml of a methanol solution containing 26.5 g of methyl N-(4-methylbenzyloxycarbonyl)-tyrosinate. The mixture was stirred while cooling with ice for two hours at room temperature for four hours. After neutralization with 10% hydrochloric acid, the mixture was concentrated in vacuo and extracted with ethyl acetate. The extrac was washed with water, dried and concentrated to dryness. The residue was crystallized from ethyl acetate-petroluem ether to give 17.9 g of N-(4-methylbenzyloxycarbonyl)-tyrosinol: yield 74%; mp. 128°-129° C. Analysis, calculated for C18H21O4N, C 68.55, H 6.72, N 4.44, found C 68.51, H 6.84, N 4.29.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:30][CH2:31][CH2:32][O:33][CH3:34])=[CH:5][C:6]([NH:9][C:10]([N:12]2[C:21]3[C:16](=[CH:17][C:18]([CH2:27][NH:28][CH3:29])=[C:19]([CH:22]([O:25][CH3:26])[O:23][CH3:24])[N:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])=[N:7][CH:8]=1)#[N:2].CCN(CC)CC.[CH3:42][O:43][CH2:44][C:45](Cl)=[O:46]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[C:1]([C:3]1[C:4]([NH:30][CH2:31][CH2:32][O:33][CH3:34])=[CH:5][C:6]([NH:9][C:10]([N:12]2[C:21]3[C:16](=[CH:17][C:18]([CH2:27][N:28]([CH3:29])[C:45](=[O:46])[CH2:44][O:43][CH3:42])=[C:19]([CH:22]([O:25][CH3:26])[O:23][CH3:24])[N:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])=[N:7][CH:8]=1)#[N:2]
Reactant: COCC(=O)Cl
Reactant: CNCc1cc2c(nc1C(OC)OC)N(C(=O)Nc1cc(NCCOC)c(C#N)cn1)CCC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCNc1cc(NC(=O)N2CCCc3cc(CN(C)C(=O)COC)c(C(OC)OC)nc32)ncc1C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-6-((methylamino)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 188, 230 mg, 0.490 mmol) in DCM (4 ml) at 0° C. was added NEt3 (0.100 ml, 0.721 mmol) and 2-methoxyacetyl chloride (50 μl, 0.548 mmol) and the reaction mixture was allowed to warm to room temperature and stirred for approximately 2 h. The reaction mixture was diluted with saturated aqueous NaHCO3 and DCM. Phases were separated and the water phase was extracted with DCM (2×), organic phases were combined and dried using Na2SO4, filtered and concentrated. The crude product was purified using silica gel column chromatography eluting with a gradient of MeOH (2-5%) in DCM. Fractions containing the product were combined and evaporated to yield the title compound as a colorless resin. (UPLC-MS 3) tR 0.91 min, ESI-MS 542.4 [M+H]+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:26]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[C:8]([NH2:28])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH:30]([CH3:32])[CH3:31]>>[NH2:28][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:26])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]1[CH2:25][CH2:24][N:23]([CH:30]([CH3:32])[CH3:31])[CH2:22][CH2:21]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCCC3CCNCC3)c2n1
Reactant: CC(C)I
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCCC3CCN(C(C)C)CC3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[5-(4-piperidinyl)pentyl]-9H-purin-6-amine and 2-iodopropane.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:19]([NH:21][NH:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24])=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:19]([NH:21][N:22]([CH2:6][C@@H:8]([CH3:18])[CH2:9][CH3:10])[S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24])=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)NNC(=O)[C@H](CC(C)C)[C@H](C/C=C/c2ccccc2)C(=O)OC(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC[C@H](C)CN(NC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.9 %

Procedure:
A mixture of 0.323 g of (E)-2(R)-[1(S)-(tert.-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methyl-2′-(p-toluenesulphonyl)valerohydrazide, 0.111 g of S(+)-1-bromo-2-methylbutane and 0.053 g of anhydrous potassium carbonate in 5 ml of dry dimethylformamide was stirred at room temperature overnight. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulphate and evaporated. The residue was purified by flash chromatography on silica gel using hexane/ethyl acetate (5:1) for the elution. There was obtained 0.187 g of (E)-2(R)-[1(S)-(tert.-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methyl-2′-(2(S)-methylbutyl)-2′-(p-toluenesulphonyl)valerohydrazide in the form of a gum. MS: 585 (M+H)+. Continued elution of the column gave 0.21 g of the hydrazide used in the reaction.
Reaction SMILES: [ClH:1].C([C:9]1[N:19]2[C:20]3[C:15]([CH2:16][CH2:17][CH2:18]2)=[CH:14][CH:13]=[CH:12][C:11]=3[C:10]=1CCN1CCN(C2C=C(C)C=CN=2)CC1)C1C=CC=CC=1>>[ClH:1].[ClH:1].[CH:10]1[C:11]2=[C:20]3[C:15](=[CH:14][CH:13]=[CH:12]2)[CH2:16][CH2:17][CH2:18][N:19]3[CH:9]=1
Reactant: Cc1ccnc(N2CCN(CCc3c(Cc4ccccc4)n4c5c(cccc35)CCC4)CC2)c1
Agent: Cl
Product: c1cc2c3c(c1)ccn3CCC2

Procedure:
The title base obtained above was converted into the corresponding hydrochloride as described in Example 13C). 1.5 g of 2-benzyl-5,6-dihydro-1-{2-[4-(4-methylpyridin-2-yl)-piperazin-1-yl]ethyl}-4H-pyrrolo[3,2,1-ij]quinoline.2.4 HCl 2 H2O were obtained as a pale grey powder having a melting point of 186°-208° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([C:12]([NH:14][C@H:15]([C:19]([NH:21][CH:22]([C:31](=[O:44])[CH2:32][O:33][C:34]1[C:39]([F:40])=[C:38]([F:41])[CH:37]=[C:36]([F:42])[C:35]=1[F:43])[CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])=[CH:5]2.C(O)(C(F)(F)F)=O>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([C:12]([NH:14][C@H:15]([C:19]([NH:21][CH:22]([C:31](=[O:44])[CH2:32][O:33][C:34]1[C:39]([F:40])=[C:38]([F:41])[CH:37]=[C:36]([F:42])[C:35]=1[F:43])[CH2:23][C:24]([OH:26])=[O:25])=[O:20])[CH:16]([CH3:17])[CH3:18])=[O:13])=[CH:5]2
Reactant: CC(C)[C@H](NC(=O)c1cc2cc(F)ccc2n1C)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)COc1c(F)c(F)cc(F)c1F
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](NC(=O)c1cc2cc(F)ccc2n1C)C(=O)NC(CC(=O)O)C(=O)COc1c(F)c(F)cc(F)c1F
Yield: 42 %

Procedure:
Treatment of the product from Example 114 with TFA as described in Example 80 gave the titled product (43 mg, 42%) as a white powder. MS C26H24F5N3O6, [M+Na]+ =592, [M−H]− =568.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH:8](C(C(OCC)=O)C(OCC)=O)[CH3:9])=[CH:3][CH:2]=1.[C:21](=[O:24])(O)[O-:22].[Na+]>Cl>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH:8]([CH3:9])[C:21]([OH:22])=[O:24])=[CH:3][CH:2]=1
Reactant: O=C([O-])O
Reactant: CCOC(=O)C(C(=O)OCC)C(C)Cc1ccncc1
Agent: Cl
Agent: [Na+]
Product: CC(Cc1ccncc1)C(=O)O
Yield: 76.9 %

Procedure:
Compound diethyl 2-(1-(pyridin-4-yl)propan-2-yl)malonate (2.50 g, 9.43 mmol) was refluxed in conc. HCl (30 ml) for 16 h. The pH of the reaction mixture was adjusted to 6 by adding solid sodium bicarbonate and extracted with ethyl acetate. The combined ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to afford 1.20 g (76.9%) of 2-((pyridin-4-yl)methyl)propanoic acid as an off-white solid.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Br:11][C:12]1[CH:17]=[CH:16][C:15]([C@H:18]2[CH2:23][NH:22][CH2:21][CH2:20][NH:19]2)=[CH:14][CH:13]=1>O1CCCC1>[CH2:1]([N:19]1[CH2:20][CH2:21][N:22]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:23][C@@H:18]1[C:15]1[CH:14]=[CH:13][C:12]([Br:11])=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: Brc1ccc([C@H]2CNCCN2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Brc1ccc([C@H]2CN(Cc3ccccc3)CCN2Cc2ccccc2)cc1
Reaction time: 1 h
Yield: 64 %

Procedure:
Hydrogen chloride in ethyl acetate solution (4N) was added to a solution of di-tert-butyl (2S)-2-(4-bromophenyl)piperazine-1,4-dicarboxylate (10 g, 22.7 mmol) in methanol (50 ml). The mixture was stirred for one hour at room temperature and the solvent was evaporated under reduced pressure to give white solid. The mixture was partitioned between saturated aqueous sodium bicarbonate and chloroform. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo to afford (2S)-2-(4-bromophenyl)piperazine as white crystals. Benzylbromide (9.7 g, 56.7 mmol) was added to a solution of sodium hydride (60% in oil, 2.0 g, 50 mmol) and (2S)-2-(4-bromophenyl)piperazine in tetrahydrofuran (50 ml) at room temperature and the mixture was stirred for one hour. The mixture was partitioned between water and chloroform. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting 5-10% methanol in chloroform to furnish (2S)-1,4-Dibenzyl-2-(4-bromophenyl)piperazine (6.1 g, 64%) as a colorless oil.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH:4]([C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=1)[O:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[CH:9]=[C:8]([O:15][CH2:16][CH3:17])[CH:7]=1.O.C(=O)([O-])[O-].[K+].[K+]>CO>[Br:24][C:21]1[CH:20]=[CH:19][C:18]([CH:4]([O:5][C:6]2[CH:7]=[C:8]([O:15][CH2:16][CH3:17])[CH:9]=[C:10]([O:12][CH2:13][CH3:14])[CH:11]=2)[C:3]([OH:25])=[O:2])=[CH:23][CH:22]=1
Reactant: CCOc1cc(OCC)cc(OC(C(=O)OC)c2ccc(Br)cc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCOc1cc(OCC)cc(OC(C(=O)O)c2ccc(Br)cc2)c1

Procedure:
16.9 g (41.3 mmol) of methyl(4-bromophenyl)-(3,5-diethoxyphenoxy)acetate are dissolved in 80 ml of methanol and 8 ml of water under argon at RT, and 7.99 g (57.8 mmol) of potassium carbonate are added. The mixture is heated under RF for 4 h. After cooling, the precipitate is filtered off, the filtrate is concentrated, the residue is taken up in water and the solution is extracted four times with diethyl ether. The aqueous phase is adjusted to a pH of 2 by adding 10% strength hydrochloric acid and is extracted three times with ethyl acetate, and the combined ethyl acetate phases are washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. 16.1 g (99% of theory) of the product are obtained.
Reaction SMILES: [C:1]1([CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1.[C:23](OC=C)(=O)[CH3:24]>C1(C)C=CC=CC=1>[C:1]1([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH:23]=[CH2:24])=[O:21])[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1
Reactant: O=C(O)CCCc1ccc2ccc3cccc4ccc1c2c34
Reactant: C=COC(C)=O
Solvent: Cc1ccccc1
Product: C=COC(=O)CCCc1ccc2ccc3cccc4ccc1c2c34
Temperature: 60 °C
Reaction time: 62 h

Procedure:
To a 500 mL, two neck flask equipped with a stir bar, argon inlet, and stopper is added 4-(1-Pyrenyl)butyric acid (10.0 grams, 34.7 mmol, obtained from Sigma-Aldrich, Milwaukee, Wis.), palladium acetate 1,10-phenanthroline complex (403 milligrams, 1 mmol) and vinyl acetate (128 milliliters, 1.39 mol, obtained from Sigma-Aldrich, Milwaukee, Wis.). Next, toluene (200 milliliters) is added, the solution is purged with argon and stirred magnetically at 60° C. for 62 hours. The excess vinyl acetate, along with acetic acid (co-product) is removed, an additional vinyl acetate (32 mL, 0.35 mol) is added, and the reaction is continued for 48 hours at 60° C. under argon to complete the reaction. The excess vinyl ester is removed, and the crude product is filtered to remove suspended catalyst residue, and the toluene is removed in vacuo to famish vinyl 4-(pyren-1-yl)butanoate.
Reaction SMILES: C([O:4][C:5]([CH3:10])([CH3:9])[C:6](Cl)=[O:7])(=O)C.[F:11][C:12]1[CH:18]=[C:17]([S:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=[CH:15][C:13]=1[NH2:14].N1C=CC=CC=1>C(Cl)Cl>[F:11][C:12]1[CH:18]=[C:17]([S:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=[CH:15][C:13]=1[NH:14][C:6](=[O:7])[C:5]([OH:4])([CH3:9])[CH3:10]
Reactant: Nc1ccc(Sc2ccccc2)cc1F
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(O)C(=O)Nc1ccc(Sc2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2-Acetoxy-2-methylpropanoyl chloride (0.47 ml) was added to a solution of 2-fluoro-4-phenylsulphanylaniline (Method 7) (0.64 g) and pyridine (0.28 ml) in DCM (10 ml). The solution was stirred at ambient temperature for 90 minutes then volatile material was removed by evaporation. The residue was dissolved in methanol (20 ml) and a solution of lithium hydroxide monohydrate (0.378 g) in water (2.5 ml) was added. Stirring was continued for another 1 hour then the mixture was acidified to pH 1 with 2M hydrochloric acid and concentrated by evaporation to about 5 ml. Water (10 ml) was added and the product was extracted with ethyl acetate. Organic layers were washed with brine then combined and dried. Volatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column eluting with 10-20% ethyl acetate/hexane to yield the title compound (0.784 g) as a solid. Mp 91-92.5° C.; NMR: 1.34 (s, 6H), 5.96 (s, 1H), 7.15 (d, 1H), 7.23 (dd, 1H), 7.27-7.4 (m, 5H), 8.02 (t, 1H), 9.3 (s, 1H); MS (ESP−): 304; EA: found: C, 62.8; H, 5.3; N. 4.5; S. 10.5%; C16H16FNO2S requires: C, 62.9; H, 5.3; N, 4.6; S, 10.5%.
Reaction SMILES: [C:1]1(=[N:9][OH:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([BH3-])#N.[Na+].[OH-].[Na+]>C(O)(=O)C>[CH:1]1([NH:9][OH:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: ON=C1CCCCCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: ONC1CCCCCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution containing cyclooctanone oxime (9.0 g, 64 mmol) in glacial acetic acid (90 mL) was slowly charged with sodium cyanoborohydride (6.0 g, 95 mmol). The reaction mixture was stirred at ambient temperature for 18 hours then adjusted to pH=9 by the slow addition of cold 2N sodium hydroxide. The resulting precipitate was collected and dried to provide cyclooctyl hydroxylamine as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([CH3:12])[CH:10]=2)[CH:5]=[C:4]([C:13]2[CH:18]=[C:17]([NH:19]/[C:20](/SC)=[CH:21]/[C:22](=[O:28])[C:23]3[S:24][CH:25]=[CH:26][N:27]=3)[CH:16]=[CH:15][C:14]=2[CH3:31])[C:3]1=[O:32].O1CCCCC1O[NH2:40].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([CH3:12])[CH:10]=2)[CH:5]=[C:4]([C:13]2[CH:18]=[C:17]([NH:19][C:20]3[CH:21]=[C:22]([C:23]4[S:24][CH:25]=[CH:26][N:27]=4)[O:28][N:40]=3)[CH:16]=[CH:15][C:14]=2[CH3:31])[C:3]1=[O:32]
Reactant: CS/C(=C\C(=O)c1nccs1)Nc1ccc(C)c(-c2cc3cnc(C)cc3n(C)c2=O)c1
Reactant: NOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1cc2c(cn1)cc(-c1cc(Nc3cc(-c4nccs4)on3)ccc1C)c(=O)n2C
Temperature: 150 °C

Procedure:
The mixture of (Z)-1,7-dimethyl-3-(2-methyl-5-(1-(methylthio)-3-oxo-3-(thiazol-2-yl)prop-1-enylamino)phenyl)-1,6-naphthyridin-2(1H)-one 32 (462 mg, 1.0 mmol), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (293 mg, 2.5 mmol) and K2CO3 (415 mg, 3.0 mmol) in 1,4-dioxane (5 mL) in a sealed vial was heated at 150° C. for 30 h. The mixture was purified by preparative LC/MS to give 1,7-dimethyl-3-(2-methyl-5-(5-(thiazol-2-yl)isoxazol-3-ylamino)phenyl)-1,6-naphthyridin-2(1H)-one (D9). 1H NMR (400 MHz, d6-DMSO) δ 10.73 (s, 1H), 9.19 (s, 1H), 8.11 (s, 1H), 7.93 (s, 1H), 7.87 (d, J=3.2 Hz, 1H), 7.74 (d, J=3.2 Hz, 1H), 7.65 (d, J=2.4 Hz, 1H), 7.61 (s, 1H), 7.53 (dd, J=2.4, 8.0 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 3.72 (s, 3H), 2.78 (s, 3H), 2.10 (s, 3H). MS m/z 430.2 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]([N:5]1[CH2:9][CH:8]2[CH2:10][C:11](=O)[CH2:12][CH:7]2[CH2:6]1)=[O:4].C1(C)C=CC(S([CH2:24][N+:25]#[C-])(=O)=O)=CC=1.CC(C)([O-])C.[K+].C(O)CCC>COCCOC.O.[Cl-].[Na+].O>[CH3:1][N:2]([CH3:14])[C:3]([N:5]1[CH2:9][CH:8]2[CH2:10][CH:11]([C:24]#[N:25])[CH2:12][CH:7]2[CH2:6]1)=[O:4]
Reactant: CN(C)C(=O)N1CC2CC(=O)CC2C1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Solvent: CCCCO
Product: CN(C)C(=O)N1CC2CC(C#N)CC2C1
Temperature: 25 °C
Yield: 51.2 %

Procedure:
N,N-dimethyl-5-oxo-hexahydro-cyclopenta[c]pyrrole-2-carboxamide 1g (12.9 g, 0.066 mol) and 4-toluenesulfonylmethyl isocyanide (14.2 g, 0.0727 mol) were dissolved in 240 mL of 1,2-dimethoxyethane with stirring upon cooling by an ice-water bath, followed by dropwise addition of a solution of potassium tert-butoxide (14.8 g, 0.132 mol) in tent-butanol. Upon completion of the addition, the ice-water bath was removed. The reaction mixture was warmed up to room temperature and reacted overnight. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was diluted with 100 mL of water and 50 mL of saturated brine and extracted with ethyl acetate (200 mL×3). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 5-cyano-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid dimethylamide 12a (7.0 g, yield 51%) as a light yellow oil.