Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([NH:16][CH3:17])=[O:15])=[CH:12][N:11]=[C:10]([CH3:18])[CH:9]=2)=[C:4](F)[CH:3]=1.[H-].[Na+]>O1CCCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:13](=[CH:12][N:11]=[C:10]([CH3:18])[CH:9]=3)[C:14](=[O:15])[N:16]([CH3:17])[C:4]=2[CH:3]=1
Reactant: CNC(=O)c1cnc(C)cc1-c1ccc(Cl)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc2c(cn1)c(=O)n(C)c1cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 81.2 %

Procedure:
To a solution of 4-(4-chloro-2-fluorophenyl)-N,6-dimethylnicotinamide (520 mg, 1.86 mmol) in tetrahydrofuran (20 mL) at 0° C. was added NaH (224 mg, 5.60 mmol). The reaction mixture was brought to room temperature gradually and stirred at room temperature for 15 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (100 mL). The organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure to afford product, 8-chloro-2,6 dimethylbenzo[c][2,7]naphthyridin-5(6H)-one (480 mg, 1.51 mmol, 81% crude yield) as a red solid. The material was carried forward without further purification. LC/MS (ESI) m/e 259.0 [(M+H)+, calcd for C14H12ClN2O 259.0]; LC/MS retention time (Method C): tR=1.74 min. 1H NMR (300 MHz, METHANOL-d4) δ ppm 9.41 (s, 1H), 8.48 (d, J=8.59 Hz, 1H), 8.23 (s, 1H), 7.69 (d, J=1.98 Hz, 1H), 7.44 (dd, J=8.64, 1.94 Hz, 1H), 3.78 (s, 3H), 2.75 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[N:7][CH:8]=1)#[N:2].[CH2:9]([Mg]Br)[CH3:10].B(F)(F)F>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C1COCC1>[N:5]1[CH:4]=[C:3]([C:1]2([NH2:2])[CH2:10][CH2:9]2)[CH:8]=[N:7][CH:6]=1
Reactant: N#Cc1cncnc1
Reactant: CC[Mg]Br
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: CC[Mg+]
Solvent: C1CCOC1
Product: NC1(c2cncnc2)CC1
Reaction time: 0.25 h

Procedure:
5-Cyano pyrimidine (5 g, 47.6 mmol, 1 eq) was taken in a Dry THF under Argon atmosphere, then Titanium isopropoxide (17 ml, 57.1 mmol, 1.2 eq) was added slowly at ambient temperature and the resulting mass was stirred for 15 mins. To the above stirred solution was added Ethyl magnesium bromide (1 M solution in THF, 107 ml, 809.3 mmol, 2.5 eq) slowly via syringe at ambient temperature. (During the addition of EtMgBr reaction mass turned black). Then the reaction mass was stirred for an hour, BF3.EtO (16.7 ml, 119.0 mmol, 2.5 eq) was added slowly through syringe at 0° C. Then the reaction was allowed to attain ambient temperature and the stirring was continued for another one hour. Finally the reaction was quenched by adding 50 ml of water and the reaction mass was passed through Celite and the bed was washed with water and Ethyl acetate. The filtrate was basified with 10% NaOH solution (pH=9) and then extracted with DCM and washed with brine solution. The required product was purified by silica gel (60-120) column chromatography using DCM/methanol as the eluent. Yield: 0.1 g (5%) 1H NMR (400 MHz, DMSO-d6): 1.04-1.08 (q, 2H, J=3.96 Hz), 1.18-1.25 (q, 2H, J=3.96 Hz), 8.26 (d, 2H), 9.05 (s, 1H). LCMS: (ES+) m/z=136 (M+H).
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][C@H:7]([OH:10])[CH2:6][C@@H:5]1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH3:25])([CH3:24])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:13][C:12]=1[O:26]CC1C=CC=CC=1)[CH2:2][CH3:3]>[Pd]>[CH2:1]([N:4]1[CH2:9][CH2:8][C@H:7]([OH:10])[CH2:6][C@@H:5]1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH3:24])([CH3:25])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:13][C:12]=1[OH:26])[CH2:2][CH3:3]
Reactant: CCCCCCC(C)(C)c1ccc([C@H]2C[C@@H](O)CCN2CCC)c(OCc2ccccc2)c1
Agent: [Pd]
Product: CCCCCCC(C)(C)c1ccc([C@H]2C[C@@H](O)CCN2CCC)c(O)c1
Yield: 94.2 %

Procedure:
Employing the procedure of Example 4, 535 mg (1.18 mmole) N-propyl-cis-2-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-piperidinol and 212 mg 5% palladium on carbon (50% wet) gives 402 mg (94%) of the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18](I)=[CH:17][C:16]=3[F:24])=[O:11])=[CH:4][CH:3]=1.[CH2:25]([O:28][CH3:29])[C:26]#[CH:27].CCN(CC)CC>CN(C=O)C.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18]([C:27]#[C:26][CH2:25][O:28][CH3:29])=[CH:17][C:16]=3[F:24])=[O:11])=[CH:4][CH:3]=1
Reactant: C#CCOC
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(I)cc2c1O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CO
Product: COCC#Cc1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Temperature: 25 °C

Procedure:
A solution of the title compound of Example 5 (540.3 mg), methyl propargyl ether (0.14 mL), PdCl2 (PPh3)2 (21.1 mg), and 0.75 mL Et3N in 3 mL DMF is heated at 90° C. for 1 hr. The reaction mixture is cooled to room temperature and partitioned between EtOAc and H2 0. The aqueous layer is washed with EtOAc (4×). The combined organic layers are dried over Na2SO4 and condensed to obtain a dark residue. The residue is diluted with MeOH, adsorbed onto silica, and chromatographed eluting with 2% MeOH in CH2Cl2. Fractions homogenous by TLC are combined, condensed and recrystallized from EtOAc/hexanes to yield 0.218 g of the desired product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([C:26]2[N:31]=[C:30]([NH:32][C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[CH:29]=[CH:28][CH:27]=2)[CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:13]([NH:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:27]=[CH:28][CH:29]=[C:30]([NH:32][C:33](=[O:37])[CH:34]([CH3:35])[CH3:36])[N:31]=4)[CH2:22][CH2:21]3)=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCCC1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)n1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(Cl)cc4)CCCC3)CC2)n1

Procedure:
Example 84 was prepared from 1-(4-chlorophenyl)cyclopentanecarboxylic acid and N-{6-[1-(3-aminopropyl)-4-piperidinyl]-2-pyridinyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 8.07 (d, 1H, J=8.4 Hz), 7.81 (s, 1H), 7.66 (t,1H, J=7.6 Hz), 7.36–7.33 (m, 2H), 7.30–7.27 (m, 2H), 6.90 (d, 1H, J=6.8 Hz), 6.60 (br s, 1H), 3.28 (dd, 2H, J=5.6, 12.0 Hz), 2.95 (d, 2H, J=11.6 Hz), 2.55–2.49 (m, 4H), 2.33 (t, 2H, J=6.4 Hz), 2.00–1.61 (m, 14H), 1.26 (d, 6H, J=6.8 Hz); ESMS m/e: 511.3 (M+H)+.
Reaction SMILES: [S:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[O:12])=[CH:6][CH:5]=1)[C:2]#[N:3].[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][OH:20])[CH:14]=1>C1C=CC=CC=1>[S:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:12])[O:20][CH2:19][C:15]2[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=2)=[CH:8][CH:9]=1)[C:2]#[N:3]
Reactant: OCc1cccnc1
Reactant: N#CSc1ccc(N=C=O)cc1
Solvent: c1ccccc1
Product: N#CSc1ccc(NC(=O)OCc2cccnc2)cc1
Yield: 47 %

Procedure:
To a solution of p-thiocyanophenyl isocyanate (5.25g., 0.0298 mole) in 100 ml. of benzene was added 3-pyridyl carbinol (3.25g., 0.0298 mole). An immediate exothermic reaction took place and a solid precipitated. After standing over the weekend 5.5g. of solid was isolated and after recrystallization from toluene this gave 4.0g. melting at 188°-191°C. This was a 47% yield of 3-pyridylmethyl N-(4'-thiocyanophenyl)carbamate.
Reaction SMILES: [CH:1](=[C:8]1[CH2:12][CH:11]([CH2:13][CH3:14])[O:10][C:9]1=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[H][H]>[Pd].C(O)C>[CH2:1]([CH:8]1[CH2:12][CH:11]([CH2:13][CH3:14])[O:10][C:9]1=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: [H][H]
Reactant: CCCCCCC=C1CC(CC)OC1=O
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCC1CC(CC)OC1=O
Yield: 94.2 %

Procedure:
The product prepared above was hydrogenated following the general procedure described in Example I. For the reaction, 2.1 g 3-heptylidene-5-ethyldihydro-2(3H)-furanone (0.010 mole) was combined with 0.1 g 5% palladium on carbon and 5 ml ethanol and hydrogen gas slowly introduced for 1.5 hours. Upon removal of the catalyst and evaporation of the solvent, 2.0g (97% assay by GLC; 95% yield) 3-heptyl-5-ethyldihydro-2(3H)-furanone was recovered.
Reaction SMILES: O[CH2:2][C:3]1[N:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:5][CH:4]=1.C(Br)(Br)(Br)[Br:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:19][CH2:2][C:3]1[N:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)CCc1cccc(CO)n1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCc1cccc(CBr)n1
Yield: 69.2 %

Procedure:
t-Butyl 3-(6-hydroxymethylpyridin-2-yl)propionate (16.13 g) was dissolved in 200 mL of dry methylene chloride, and 33.8 g of carbon tetrabromide was added to the above solution, additionally 21.5 g of triphenylphosphine was added thereto in small portions under stirring at ice temperature, and then the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was transferred to a separating funnel, washed with saturated aqueous sodium bicarbonate, then brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the residue, 200 mL of a mixture of hexane-ethyl acetate (2:1) was added, the insoluble portion precipitated was filtrated off, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel (hexane-ethyl acetate=5:1) to give 14.12 g of t-butyl 3-(6-bromomethylpyridin-2-yl)propionate as a light yellow oil.
Reaction SMILES: Cl.O1CCOCC1.[OH:8][C@@H:9]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=2)[CH:21]=1)[CH2:10][CH2:11][NH:12]C(=O)OC(C)(C)C>CO>[NH2:12][CH2:11][CH2:10][C@H:9]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=2)[CH:21]=1)[OH:8]
Reactant: Cc1cccc(COc2cccc([C@H](O)CCNC(=O)OC(C)(C)C)c2)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cccc(COc2cccc([C@H](O)CCN)c2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
HCl/dioxane (4M, 2 mL) was added at 0° C. to a solution of (R)-tert-butyl (3-hydroxy-3-(3-((6-methylpyridin-2-yl)methoxy)phenyl)propyl)carbamate (200 mg, 0.54 mmol) in MeOH (3 mL) and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure to give after purification by triturating in diethyl ether Example 12 hydrochloride as a white solid. Yield (0.15 g, 52%); 1H NMR (400 MHz, DMSO-d6) δ 7.92 (bs, 1H), 7.74 (bs, 3H), 7.47 (bs, 1H), 7.40 (bs, 1H), 7.28 (t, J=8.0 Hz, 1H), 7.02 (s, 1H), 6.95-6.90 (m, 2H), 5.20 (s, 2H), 4.68-4.65 (m, 1H), 2.84 (bs, 2H), 2.56 (s, 3H), 1.88-1.83 (m, 2H); MS: m/z 273.20 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[O:17][CH:16]([CH:18]4[CH2:20][CH2:19]4)[C:15](=[O:21])[NH:14][C:13]=3[CH:22]=2)[C:5]([F:23])=[CH:4][N:3]=1.[NH2:24][C:25]1[CH:33]=[C:32]2[C:28]([CH:29]=[N:30][NH:31]2)=[CH:27][CH:26]=1>>[CH2:19]1[CH2:20][CH:18]1[CH:16]1[C:15](=[O:21])[NH:14][C:13]2[CH:22]=[C:9]([NH:8][C:6]3[C:5]([F:23])=[CH:4][N:3]=[C:2]([NH:24][C:25]4[CH:33]=[C:32]5[C:28]([CH:29]=[N:30][NH:31]5)=[CH:27][CH:26]=4)[N:7]=3)[CH:10]=[CH:11][C:12]=2[O:17]1
Reactant: O=C1Nc2cc(Nc3nc(Cl)ncc3F)ccc2OC1C1CC1
Reactant: Nc1ccc2cn[nH]c2c1
Product: O=C1Nc2cc(Nc3nc(Nc4ccc5cn[nH]c5c4)ncc3F)ccc2OC1C1CC1

Procedure:
In like manner to the preparation of N4-[2-(2-cyclopropyl)-3-oxo-4H-benz[1,4]oxazin-6-yl]-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine, 2-chloro-N4-[2-(2-cyclopropyl)-3-oxo-4H-benz[1,4]oxazin-6-yl]-5-fluoro-4-pyrimidineamine and 6-aminoindazole were reacted to yield the desired product N4-[2-(2-cyclopropyl)-3-oxo-4H-benz[1,4]oxazin-6-yl]-5-fluoro-N2-(indazol-6-yl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 8.06 (m, 2H), 7.82 (s, 1H), 7.53 (d, 4H), 7.39 (dd, 1H), 7.22 (m, 2H), 6.83 (d, 1H), 1.19 (m, 4H); LCMS: retention time 9.29 min; purity 90%; MS (m/e): 418 (MH+).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCOCC1.Br[C:27]1[N:35]2[C:30]([CH:31]=[N:32][C:33]([S:36][CH3:37])=[N:34]2)=[CH:29][CH:28]=1.[CH3:38][S:39]([C:42]1[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=1)(=[O:41])=[O:40].CN(C)C=O.C(=O)([O-])[O-].[Na+].[Na+].O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:38][S:39]([C:42]1[CH:47]=[CH:46][C:45]([C:27]2[N:35]3[C:30]([CH:31]=[N:32][C:33]([S:36][CH3:37])=[N:34]3)=[CH:29][CH:28]=2)=[CH:44][CH:43]=1)(=[O:41])=[O:40]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CSc1ncc2ccc(Br)n2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ncc2ccc(-c3ccc(S(C)(=O)=O)cc3)n2n1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
Into a 30 ml, vial, Palladium Acetate (0.11 g, 0.00049 mol) and Triphenylphosphine (0.32 g, 0.0012 mol) were added and purged under an atmosphere of Nitrogen for 5 minutes 1,4-Dioxane (10.8 mL, 0.138 mol) was added and stirred for 10 minutes. 7-Bromo-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (0.600 g, 0.00246 mol), (4-Methylsulfonylphenyl)boronic acid (0.983 g, 0.00492 mol), N,N-Dimethylformamide (23.7 mL, 0.306 mol) and 1.50 M of Sodium carbonate in Water (4.92 mL, 0.00737 mol) were added, respectively. The reaction mixture was heated at 80° C. overnight. The solvent was removed under vacuum. The solid was washed with DCM. The organic was removed under vacuum. The reaction was purified via ISCO column chromatography with hexane and EtOAc as eluant (0 to 100% EtOAc). The collected fraction afforded 7-(4-Methanesulfonyl-phenyl)-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine a yellow solid (0.63 g, 83%). NMR 1H (DSMO-d6)-9.09 (s, 1H), 8.51 (d, 2H, J=8.48 Hz), 8.05 (d, 2H, J=8.49 Hz), 7.58 (d, 1H, J=4.84 Hz), 7.15 (d, 1H, J=4.84 Hz), 3.27 (s, 3H), 2.62 (s, 3H).
Reaction SMILES: [CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([OH:17])=O)=[CH:12][CH:13]=2)[CH:8]=[C:7]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[N:6]=1)([CH3:3])[CH3:2].[CH3:25][S:26]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)(=[O:28])=[O:27]>>[CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([N:32]3[CH2:33][CH2:34][N:29]([S:26]([CH3:25])(=[O:28])=[O:27])[CH2:30][CH2:31]3)=[O:17])=[CH:12][CH:13]=2)[CH:8]=[C:7]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[N:6]=1)([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: Cc1cc(Nc2cc3cc(C(=O)O)ccc3c(OC(C)C)n2)n[nH]1
Product: Cc1cc(Nc2cc3cc(C(=O)N4CCN(S(C)(=O)=O)CC4)ccc3c(OC(C)C)n2)n[nH]1

Procedure:
Similar procedure as described in example 384 was used, starting from 1-Isopropoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinoline-6-carboxylic acid and 1-Methanesulfonyl-piperazine to give [1-Isopropoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-yl]-(4-methanesulfonyl-piperazin-1-yl)-methanone. LC-MS: m/e 473 (MH+).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:9][C@H:8]1/[CH:32]=[CH:33]/[C:34]([NH:36][CH3:37])=[O:35])=[O:6])[CH:2]=[CH2:3].C([SiH](CC)CC)C>>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([SH:12])[CH2:9][C@H:8]1/[CH:32]=[CH:33]/[C:34]([NH:36][CH3:37])=[O:35])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1/C=C/C(=O)NC
Agent: CC[SiH](CC)CC
Product: C=CCOC(=O)N1C[C@@H](S)C[C@H]1/C=C/C(=O)NC
Yield: 76.3 %

Procedure:
The same operation as in Reference Example 4-2) was carried out by using (E)-3-[(2S,4S)-N-allyloxycarbonyl-4-tritylthiopyrrolidin-2-yl]-N-methylacrylamide (the compound obtained in Reference Example 5-1); 1.54 g, 3 mmol) and triethylsilane (0.49 ml, 3.15 mmol), followed by flash column chromatographic purification on silica gel (Wakogel® C-300, 40 ml, elution with acetone-methylene chloride 1:1) to give the title compound (620 mg, 76.3% yield).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:5]=[C:6]([N+:10]([O-])=O)[CH:7]=[CH:8][CH:9]=1>C(O)(=O)C.[Zn]>[CH3:1][O:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[NH2:10]
Reactant: COCc1cccc([N+](=O)[O-])c1
Agent: [Zn]
Solvent: CC(=O)O
Product: COCc1cccc(N)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.1 %

Procedure:
EX-514B) The 3-(methoxymethyl)nitrobenzene (4.18 g, 25 mmol) from EX-514A was dissolved in 160 mL of acetic acid. Zinc dust (5 g, 76.5 mmol) was added, and the solution was stirred at room temperature for 18 hours, at which time HPLC analysis indicated that no 3-(methoxymethyl)nitrobenzene starting material remained. The reaction mixture was filtered through celite and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with aqueous saturated sodium bicarbonate. The organic layer was washed with water, then dried over MgSO4, and concentrated in vacuo to give 3.4 g (99%) of the desired 3-(methoxymethyl)aniline as a brown oil. The crude product was used without further purification. HRMS calcd. for C8H12NO: 138.0919 [M+H]+, found: 138.0929. 1H NMR (CDCl3) δ 3.4 (s, 3H), 3.7 (s, 2H), 4.4 (s, 2H), 6.6 (d, 1H), 6.7 (m, 2H), 7.2 (t, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH3:21][O:22][C:23]1[C:46]([O:47][CH3:48])=[C:45]([O:49][CH3:50])[CH:44]=[CH:43][C:24]=1[CH2:25][CH:26]1[CH:31]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[C:35]([O:41][CH3:42])[CH:34]=2)[CH2:30][O:29][C:27]1=[O:28].B(F)(F)F.CCOCC.C([O-])(O)=O.[Na+]>ClCCl>[CH3:42][O:41][C:35]1[CH:34]=[C:33]2[CH2:32][C@H:31]3[CH2:30][O:29][C:27](=[O:28])[C@@H:26]3[CH2:25][C:24]3[C:23]([O:22][CH3:21])=[C:46]([O:47][CH3:48])[C:45]([O:49][CH3:50])=[CH:44][C:43]=3[C:38]2=[CH:37][C:36]=1[O:39][CH3:40]
Reactant: COc1ccc(CC2COC(=O)C2Cc2ccc(OC)c(OC)c2OC)cc1OC
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1cc2c(cc1OC)-c1cc(OC)c(OC)c(OC)c1C[C@H]1C(=O)OC[C@@H]1C2
Yield: 98 %

Procedure:
192 mg (1.44 mmole) of hydrated ruthenium oxide (soluble form) suspended in 12 ml of dichloromethane are placed in a 100 ml three-necked flask equipped with a magnetic stirrer, which is swept with argon. 1.5 ml (19 mmoles) of trifluoro acetic acid and 0.8 ml (5.7 mmoles) of trifluoro acetic anhydride are added at ambient temperature. 100 mg (0.24 mmole) of 2-(2,3,4-trimethoxybenzyl)-3-(3,4-dimethoxybenzyl)-4-butanolide dissolved in 8 ml of anhydrous dichloromethane, immediately followed by boron trifluoride etherate (0.2 ml, 1.6 mmole) are added, at ambient temperature, to the suspension which is vigorously stirred. After a few minutes, the supernatant of the solution becomes pale yellow in color. The suspension is thus maintained stirred at ambient temperature overnight, at the end of which time, monitoring by thin layer chromatography indicates the presence of a single product, with the complete disappearance of the starting product. The reaction mixture is treated with NaHCO3 and then filtered through filter paper in order to remove the solid products. The organic phase is then decanted and the aqueous phase extracted with ethyl acetate. The organic phases are then combined, dried over MgSO4 and evaporated to give a pale yellow solio which is chromatographically pure. After filtering through silica (dichloromethane), a white solid (m=98 mg, Yield: 98%) is obtained, which is comparable in all respects (chromatography, IR spectroscopy and 1H NMR spectroscopy) to the compound obtained from the plant species Steganotaenia araliacea Hochst (Umbelliferae), by high resolution analytical liquid chromatography of an ethanolic extract.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].Br[CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13]>C1C=CC=CC=1>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH:4][CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(C)Br
Reactant: Cc1cccc(C)c1N
Solvent: c1ccccc1
Product: CCOC(=O)C(C)Nc1c(C)cccc1C
Yield: 40 %

Procedure:
Chem. Soc. (1961), 3,303-3,308 discloses that 2,6-dimethylaniline and ethyl α-bromopropionate can be reacted in benzene to give ethyl α-(2,6-dimethylanilino)propionate. Though the reaction time is 96 hours, the yield achievable is only 37 percent. As is shown, however, in Chemische Berichte, 22 (1889), 1,792-1,795, the yield is virtually quantitative if the two sterically hindering substituents in the 2,6-position are absent, ie. if aniline is used as the starting material. A comparison of the reaction of aniline and of ortho-methylaniline with ethyl 2-chloropropionate for 12 hours at 120°-125° C. in the presence of sodium acetate (C.R. Acad. Sc. Paris, 264 (Series C, 1967), 1,864-1,865) shows a yield of 40 percent based on aniline and 20 percent based on ortho-methylaniline, and thus shows the effect of even one ortho-substituent. The same reaction with the methyl group in the meta-position or para-position instead of the ortho-position gives yields of 33 and 57 percent. Accordingly, the yield increases the more remote the substituent is from the amino group.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:3]=1.[CH3:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][C:22]=1B1OC(C)(C)C(C)(C)O1>COCCOC.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[O:11]1[CH2:12][CH2:13][N:8]([C:6]2[N:7]=[C:2]([C:22]3[CH:23]=[C:24]([CH:26]=[CH:27][C:21]=3[CH3:20])[NH2:25])[CH:3]=[C:4]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:5]=2)[CH2:9][CH2:10]1
Reactant: Cc1ccc(N)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Clc1cc(N2CCOCC2)nc(N2CCOCC2)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: Cc1ccc(N)cc1-c1cc(N2CCOCC2)nc(N2CCOCC2)n1
Temperature: 120 °C
Yield: 96 %

Procedure:
To a solution of 4,4′-(6-chloropyrimidine-2,4-diyl)dimorpholine (1.0 equiv.) and 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.5 equiv.) in DME and 2M sodium carbonate (3:1, 0.2 M) was added PdCl2(dppf)-DCM adduct (0.100 equiv.) in a microwave vial equipped with a stir bar. The reaction was heated to 120° C. for 20 min in the microwave. The reaction mixture qas quenched with water and the aqueous layer was separated and extracted with EtOAc (×3). The combined organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The material was purified via silica gel column chromatography eluting with 100% DCM to 10% MeOH/DCM to afford 3-(2,6-dimorpholinopyrimidin-4-yl)-4-methylaniline in 96% yield. LCMS (m/z) (M+H)=356.2, Rt=0.44 min.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH2:16][CH3:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH2:16][CH3:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][CH:9]=1
Reactant: CCOC(=O)C(CC)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(CC)c1ccc(N)cc1
Yield: 94.3 %

Procedure:
A solution of 9.13 g (0.0385 mole) of ethyl 2-(4-nitrophenyl)-n-butyrate in 150 ml of ethanol was subjected to hydrogenation in the presence of palladium black catalyst to give 7.51 g (0.0363 mole, 94% yield) of ethyl 2-(4-aminophenyl)-n-butyrate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:14]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].C([O-])([O-])=O.[K+].[K+].COCCOC>O>[C:14]([C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)[CH:3]=2)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: Brc1cccc(-c2ccccn2)c1
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)c1ccc(-c2cccc(-c3ccccn3)c2)cc1

Procedure:
13.7 g (0.058 mol) of 2-(3-bromophenyl)pyridine was added to 12.5 g (0.070 mol) of 4-tert-butylphenylboronic acid, 3.4 g (0.003 mol) of Pd(Ph3)4, 22.0 g (0.16 mol) of K2CO3, 50 mL of DME and 50 mL of water. The reaction mixture was refluxed for 20 hours and separated on silica gel column. MS confirmed the desired product.