Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[C:12]([O:18][CH:19]([CH3:22])[CH2:20][Cl:21])(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15].Cl>C1(C)C=CC=CC=1>[C:14]([C:13](=[CH:7][C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[C:12]([O:18][CH:19]([CH3:22])[CH2:20][Cl:21])=[O:17])(=[O:15])[CH3:16]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)CC(=O)OC(C)CCl
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)OC(C)CCl
Reaction time: 48 h
Yield: 82.9 %

Procedure:
A solution containing 12.2 g of 3-nitrobenzaldehyde and 14.3 g of 1-methyl-2-chloroethyl acetoacetate in 80 ml of toluene, maintained at 0°-5° C., was saturated with hydrogen chloride gas. After two days at 20°-25° C., the residual hydrogen chloride was removed by bubbling nitrogen through the solution. The toluene was then evaporated off in vacuo. The residual oil was dissolved in dichloromethane and the solution thus obtained was washed with water until it was neutral. The organic phase which was separated and dried, was then evaporated to dryness under vacuum at 20° C. The residue was crystallized from 200 ml of isopropanol to give 20.70 g of the title compound, melting at 95°-96° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1.[CH3:28][O:29][C:30]([CH:32]1[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]1)=[O:31]>>[CH3:28][O:29][C:30]([C:32]1([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH2:33][CH2:34][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:36][CH2:37]1)=[O:31]
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Clc1ncnc2ccc(I)cc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(c2ncnc3ccc(I)cc23)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Prepared essentially as described in Example 1c using 4-chloro-6-iodo-quinazoline, as prepared in the preceding step, 1.1 eq LiHMDS/THF and 1.1 eq piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester, as prepared in Example 1b, and stirring at rt for 14 h following enolate formation at −78° C. The homogeneous brown solution was worked up as described in Example 1c to provide the impure crude title compound as a very dark brown thick oil (14.97 g). 1H-NMR (300 MHz, CDCl3) δ 9.28 (s, 1H), 8.41 (d, 1H), 8.10 (dd, 1H), 7.80 (d, 1H), 3.8-3.5 (m, 4H), 3.66 (s, 3H), 2.45-2.35 (m, 4H), 1.46 (s, 9H). LC/MS (ESI): calcd mass 497.1, found 398.0 (MH-Boc)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].CS(C)=O.[OH-].[K+].[CH2:18](I)[CH:19]([CH3:21])[CH3:20]>>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH2:18][CH:19]([CH3:21])[CH3:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1O
Reactant: CC(C)CI
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)COc1ccccc1C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 60.1 g (0.40 mol) 2-tert-butylphenol in 600 ml of DMSO 89.6 g (1.60 mol) of KOH and 147 g (0.80 mol) of isobutyl iodide were added. This mixture was stirred for 2 h at room temperature, then 73.6 g (0.40 mol) of isobutyl iodide was added. The resulting mixture was stirred for 1 h, and, again, then 73.6 g (0.40 mol) of isobutyl iodide was added. The formed mixture was stirred overnight at room temperature. The top layer was separated. To the bottom layer 5 liters of water was added, and some product was extracted with 2×250 ml of dichloromethane. The combined organic extract (including the separated top layer) was washed with 5×1 liter of water, dried over Na2SO4, and evaporated to dryness. The crude product (free of 2-tert-butylphenol) was obtained from the residue by flash chromatography on silica gel 60 (40-63 um; eluent: hexanes). Further on, this crude product was distillated to give pure 1-tert-butyl-2-isobutoxybenzene, b.p. 85-95° C./4 mm Hg. This procedure gave 44.9 g (54%) of the title product.
Reaction SMILES: C([NH:8][C:9]1[C:17]2[C:12](=[N:13][CH:14]=[N:15][C:16]=2[NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[NH:11][N:10]=1)C1C=CC=CC=1>C1C=CC=CC=1>[NH2:8][C:9]1[C:17]2[C:12](=[N:13][CH:14]=[N:15][C:16]=2[NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[NH:11][N:10]=1
Reactant: Clc1cccc(Nc2ncnc3[nH]nc(NCc4ccccc4)c23)c1
Solvent: c1ccccc1
Product: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Temperature: 80 °C

Procedure:
Starting with a suspension of 75.8 g (216 mmol) of 3-benzylamino-4-(3-chlorophenylamino)-1H-pyrazolo[3,4-d]pyrimidine in 1.5 liters of benzene, some of the solvent is distilled off for the purpose of removing residual water. Then, with the exclusion of moisture, the suspension is added to 84 g of aluminium chloride (Fluka, Buchs/Switzerland) in 500 ml of benzene and heated at 80° C. for 2.5 hours. The reaction mixture is cooled to RT, the supernatant benzene phase is poured into 2 kg of ice-water (leaving behind a green oily residue), and the solid that separates out is filtered off with suction and washed thoroughly with water (→K1). Using a rotary evaporator, the benzene is evaporated off from the filtrate and the aqueous phase that remains behind is added to the green oily residue together with 1 kg of ice and hydrolyzed at 40° C. for 2 hours. The crystalline product is filtered off with suction and washed with water (K2). K1 and K2 are taken up in 1 liter of methanol, acidified with 4N aqueous HCl and partially concentrated by evaporation. Water is added and the methanol is evaporated off completely. The crystals are filtered off and washed with water. The same purification procedure is repeated using semi-saturated Na2CO3 solution/methanol and water/methanol. Stirring at 50° C. in methanol, precipitation with diethyl ether, filtration and drying yield 3-amino-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine; m.p. 232-234° C.; TLC: Rf=0.50 (ethyl acetate).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:25][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[OH-].[Na+].Cl.CC#N.O>O1CCCC1>[CH2:25]([C:19]1[CH:20]=[CH:21][C:22]([F:24])=[C:23]2[C:18]=1[CH2:17][CH2:16][C@H:15]2[O:14][C:12]1[CH:11]=[CH:10][C:9]2[C@H:5]([CH2:4][C:3]([OH:32])=[O:2])[CH2:6][O:7][C:8]=2[CH:13]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Cc5ccccc5)ccc(F)c43)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Cc5ccccc5)ccc(F)c43)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
{(S)-6-[(R)-4-Benzyl-7-fluoro-indan-1-yloxy]-2,3-dihydrobenzofuran-3-yl}-acetic acid methyl ester (18.6 mg) is dissolved in tetrahydrofuran (4 mL) and 1N aqueous sodium hydroxide solution (0.4 mL) is added. The mixture is stirred at room temperature overnight and then acidified with 1N aqueous hydrochloric acid (0.4 mL). The solution is submitted to HPLC on reversed phase (MeCN/water) to give the title compound. LC (method 6): tR=0.72 min; Mass spectrum (ESI−): m/z=417 [M−H]−.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7])#[N:2].C([Sn]([N:29]=[N+:30]=[N-:31])(CCCC)CCCC)CCC.Cl>CO>[C:10]1([CH:5]([CH2:4][CH2:3][C:1]2[NH:31][N:30]=[N:29][N:2]=2)[C:6]([O:8][CH3:9])=[O:7])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: COC(=O)C(CCC#N)c1ccccc1
Agent: Cl
Solvent: CO
Product: COC(=O)C(CCc1nnn[nH]1)c1ccccc1
Temperature: 160 °C
Reaction time: 18 h
Yield: 61 %

Procedure:
Methyl (RS)-4-cyano-2-phenylbutanoate (see Preparation 21) (1.8 g) and tri-n-butyltin azide (3.23 g were mixed and heated at 160° C. for 3 hours, dissolved in methanol (100 ml), treated by the addition of hydrogen chloride gas for 10 minutes and left for 18 hours. Evaporation gave a residue which was triturated three times with diisopropyl ether then partitioned between 10% aqueous sodium carbonate and ethyl acetate. The aqueous later was acidifed with 2 M hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over magnesium sulphate and evaporated to give the title compound (1.34 g, 61%) as a brown oil.
Reaction SMILES: [I-:1].[Na+].CS(O[CH2:8][CH2:9][CH2:10][C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])(=O)=O>CC(C)=O>[I:1][CH2:8][CH2:9][CH2:10][C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13]
Reactant: [I-]
Reactant: CS(=O)(=O)OCCCC(F)(F)C(F)(F)F
Agent: [Na+]
Solvent: CC(C)=O
Product: FC(F)(F)C(F)(F)CCCI
Yield: 9.4 %

Procedure:
Sodium iodide (35.1 g, 2.15 mol) was added to a solution of 1-methanesulfonyloxy-4,4,5,5,5-pentafluoropentane (20 g, 0.781 mol) in acetone (200 ml), followed by heating under reflux for 12 hours. After the reaction mixture was filtered, the filtrate was concentrated. Ethyl acetate was added to the residue, which was then filtered again. The filtrate was washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. The solvent was distilled off to give 1-iodo-4,4,5,5,5-pentafluoropentane (21.1 g, Yield 93.4%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7]1(=O)[CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH2:8]1>C(O)C>[OH:13][C:10]1[CH:11]=[CH:12][C:7]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:8][CH:9]=1
Reactant: O=C1CCC(=O)CC1
Reactant: C1CCNCC1
Solvent: CCO
Product: Oc1ccc(N2CCCCC2)cc1
Yield: 53.7 %

Procedure:
0.85 g of piperidine and 2.24 g of 1,4-cyclohexanedione were heated with stirring in 15 ml of ethanol at 50 to 60° C. and reacted in air for 8 hours. During the reaction, ethanol was added as needed. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure and the resultant was separated by silica gel column chromatography (n-hexane:ethyl acetate=2:1) and 0.95 g of 1-(4-hydroxyphenyl)piperidine was obtained (yield 53.7%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([NH2:14])=[C:9](CC)[C:10]=1[CH3:11])=[O:5])[CH3:2].[Cl:15][CH2:16][CH2:17][N:18]=[C:19]=[O:20]>C(#N)C>[Cl:15][CH2:16][CH2:17][NH:18][C:19](=[O:20])[NH:14][C:8]1[S:7][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:10]([CH3:11])[CH:9]=1
Reactant: CCOC(=O)c1sc(N)c(CC)c1C
Reactant: O=C=NCCCl
Solvent: CC#N
Product: CCOC(=O)c1sc(NC(=O)NCCCl)cc1C
Temperature: 70 °C
Reaction time: 20 h
Yield: 82 %

Procedure:
A mixture of ethyl 5-amino-3-methylthiophene-2-carboxylic acid ethyl ester (4.75 g, 25.6 mmol) and 2-chloroethyl-isocyanate (2.63 ml, 30.8 mmol) in anhydrous acetonitrile (50 mL) was stirred under nitrogen atmosphere at 70° C. for 20 h, then was cooled to ambient temperature and concentrated in vacuo. The residue was triturated with hexanes/ethyl acetate to afford an off-white solid. The filtrate was concentrated in vacuo, and the residue was triturated with hexanes/ethyl acetate to afford an off white solid. The combined solid was dried to afford the title compound in 82% yield (6.11 g): 1H NMR (300 MHz, CDCl3) δ 7.73 (br s, 1H), 6.31 (s, 1H), 5.60 (t, J=5.0 Hz, 1H), 4.27 (q, J=7.1 Hz, 2H), 3.69-3.59 (m, 4H), 2.44 (s, 3H), 1.33 (t, J=7.1 Hz, 3H); MS (ES+) m/z 291.2 (M+1).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([CH3:30])=[CH:10][N:11]([C:16]3[CH:17]=[C:18]([CH:26]=[CH:27][C:28]=3[CH3:29])[C:19]([NH:21][CH:22]3[CH2:25][CH2:24][CH2:23]3)=[O:20])[C:12]2=[O:15])=[CH:7][CH:6]=1.[I-].[K+].[CH3:33][NH:34][CH:35]([CH3:37])[CH3:36]>CC(N(C)C)=O.C(OCC)(=O)C>[CH:22]1([NH:21][C:19](=[O:20])[C:18]2[CH:26]=[CH:27][C:28]([CH3:29])=[C:16]([N:11]3[CH:10]=[C:9]([CH3:30])[C:8]4[C:13](=[CH:14][C:5]([O:4][CH2:3][CH2:2][N:34]([CH:35]([CH3:37])[CH3:36])[CH3:33])=[CH:6][CH:7]=4)[C:12]3=[O:15])[CH:17]=2)[CH2:23][CH2:24][CH2:25]1
Reactant: Cc1ccc(C(=O)NC2CCC2)cc1-n1cc(C)c2ccc(OCCCl)cc2c1=O
Reactant: CNC(C)C
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Cc1ccc(C(=O)NC2CCC2)cc1-n1cc(C)c2ccc(OCCN(C)C(C)C)cc2c1=O
Temperature: 150 °C

Procedure:
A mixture of 3-[7-(2-chloroethoxy)-4-methyl-1-oxoisoquinolin-2(1H)-yl]-N-cyclobutyl-4-methylbenzamide (131 mg), potassium iodide (102 mg), and N-methylisopropylamine (0.19 ml) were stirred in DMA (2 ml) and heated under microwave irradiation conditions (Personal Chemistry Emrys Optimizer with 300 W magnetron) at 150° C. for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with water (×5), brine (×2), dried (magnesium sulfate) and concentrated. Purification by column chromatography on a silica column eluting using initially 10% methanol/ethyl acetate and then a 99:1 mixture of 10% methanol/ethyl acetate and aqueous ammonia solution gave N-cyclobutyl-3-[7-{2-[isopropyl(methyl)amino]ethoxy}-4-methyl-1-oxoisoquinolin-2(1H)-yl]-4-methylbenzamide (74 mg) as a cream solid; NMR Spectrum: (DMSOd6) 0.98 (d, 6H), 1.68 (m, 2H), 2.06 (m, 2H), 2.11 (s, 3H), 2.21 (m, 2H), 2.25 (s, 3H), 2.28 (s, 3H), 2.77 (t, 2H), 2.84 (m, 1H), 4.15 (m, 2H), 4.43 (m, 1H), 7.09 (s, 1H), 7.45-7.51 (m, 2H), 7.71-7.74 (m, 2H), 7.80 (s, 1H), 7.89 (d, 1H), 8.60 (d, 1H); Mass Spectrum: M+H+ 462.
Reaction SMILES: C.[P:2]([CH2:6][N:7](CC(O)=O)[CH2:8][C:9]([OH:11])=[O:10])([OH:5])([OH:4])=[O:3].O=O>O>[P:2]([CH2:6][NH:7][CH2:8][C:9]([OH:11])=[O:10])([OH:5])([OH:4])=[O:3]
Reactant: O=C(O)CN(CC(=O)O)CP(=O)(O)O
Agent: C
Agent: O=O
Solvent: O
Product: O=C(O)CNCP(=O)(O)O
Temperature: 95 °C

Procedure:
To a 300 ml. autoclave as described above 100 ml. deionized water, 1 gram of Norit A activated carbon, and 4 grams N-phosphonomethyliminodiacetic acid are charged. There is also added a 0.15 gram amount of the 3.30% Pt/H--MOR catalyst of Example 1. The contents are heated to 90° C. with oxygen flowing at atmospheric pressure. The contents are heated to about 95° C. with agitation for approximately two hours, with yields of N-phosphonomethylglycine in excess of 95% expected to be obtainable. Because of the effectiveness of the noble metal catalyst in oxidizing the formaldehyde, the moles of CO2 generated may be expected to approach 1.9 or so for each mole of reactant, with the amount of formaldehyde remaining being less than 10% of theoretical and in concentrations possibly around 0.1% or lower by weight. Thus the tendency of formaldehyde to react with the N-phosphonomethylglycine product will be markedly diminished.
Reaction SMILES: Br[CH2:2][CH2:3][NH:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)=[O:6].[C:17]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:14][C:13]([F:16])([F:15])[C:10]1[CH:11]=[CH:12][C:7]([C:5]([NH:4][CH2:3][CH2:2][N:27]2[CH2:26][CH2:25][N:24]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:29][CH2:28]2)=[O:6])=[CH:8][CH:9]=1
Reactant: O=C(NCCBr)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(CCNC(=O)c2ccc(C(F)(F)F)cc2)CC1

Procedure:
A mixture of N-(2-bromoethyl)[4-(trifluoromethyl)phenyl]carboxamide (0.6 g, 2 mmol), BOC-piperazine (0.38 g, 2 mmol), and potassium carbonate (0.56 g, 4 mmol) in acetone was heated to reflux for 2 hours. The reaction was then cooled and concentrated. The product was isolated using column chromatography (EtOAc:Hexanes 1:1) to yield tert-butyl 4-(2-{[4-(trifluoromethyl)phenyl]carbonylamino}ethyl)piperazinecarboxylate (M+1=402.1)
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[O:8][CH2:9][CH2:10][CH2:11][NH2:12])[CH3:3].C1([NH:24][C:25](SC)=[CH:26][N+:27]([O-:29])=[O:28])CCCCCCC1>C(#N)C>[CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[O:8][CH2:9][CH2:10][CH2:11][NH:12][C:25]([NH2:24])=[CH:26][N+:27]([O-:29])=[O:28])[CH3:3]
Reactant: CSC(=C[N+](=O)[O-])NC1CCCCCCC1
Reactant: CN(C)Cc1cccc(OCCCN)c1
Solvent: CC#N
Product: CN(C)Cc1cccc(OCCCNC(N)=C[N+](=O)[O-])c1
Yield: 35.4 %

Procedure:
A solution of 3-[3-[(dimethylamino)methyl]phenoxy]-propylamine (0.28 g) and 1-cyclooctylamino-1-methylthio-2-nitroethene (0.36 g) in acetonitrile (5 ml) was heated at 80° for 10 days. The solvent was then evaporated in vacuo and the residue partitioned between water (15 ml) and chloroform (15 ml). The aqueous phase was then extracted with chloroform (2×25 ml) and the combined organic extracts were washed with brine (50 ml), dried (Na2SO4) and evaporated in vacuo. The residue was purified by column chromatography on alumina using pentane/chloroform mixtures as eluant to give N-[3-[3-[(dimethylamino)methyl]phenoxy]propyl]-2-nitro-1,1-ethenediamine (0.14 g) as an orange oil.
Reaction SMILES: I[C:2]1[C:3]([NH:17][CH2:18][CH2:19][CH3:20])=[N:4][C:5]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[CH2:21]([OH:26])[CH2:22][CH2:23][C:24]#[CH:25].C(OCC)(=O)C.O>CN(C)C=O.C(N(CC)CC)C.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.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:26][CH2:21][CH2:22][CH2:23][C:24]#[C:25][C:2]1[C:3]([NH:17][CH2:18][CH2:19][CH3:20])=[N:4][C:5]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)=[N:6][CH:7]=1
Reactant: CCCNc1nc(Nc2ccc(C#N)cc2)ncc1I
Reactant: C#CCCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCNc1nc(Nc2ccc(C#N)cc2)ncc1C#CCCCO
Reaction time: 3 h
Yield: 76.3 %

Procedure:
To a suspension of 4-((5-iodo-4-(propylamino)pyrimidin-2-yl)amino)benzonitrile (F25, 289 mg), bis(triphenylphosphine)palladium(II) dichloride (53 mg) and copper(I) iodide (28 mg) in N,N-dimethylformamide (4 mL), triethylamine (322 μL), 4-pentyn-1-ol (304 mg), and tetrakis(triphenylphosphine)palladium(0) (88 mg) were added at room temperature, and the mixture was stirred at the same temperature for 3 hours. To the reaction mixture, ethyl acetate and water were added, and the insoluble matter was removed by filtration through Cerite. The organic layer was separated, washed successively with water, saturated aqueous ammonium chloride and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 90 to 0% hexane in ethyl acetate) to obtain 4-((5-(5-hydroxy-1-pentyn-1-yl)-4-(propylamino)pyrimidin-2-yl)amino)benzonitrile (G11, 195 mg).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1/[CH:10]=[CH:11]/[CH2:12][C@H:13]([C:45]1[CH:50]=[CH:49][C:48]2[O:51][CH2:52][O:53][C:47]=2[CH:46]=1)[C@H:14]([N:16]([CH2:34][C:35]1[CH:44]=[CH:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=1)[C:17]([C@@H:19]([OH:33])[C@@H:20]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21][C:22]([O:24][CH3:25])=[O:23])=[O:18])[CH3:15].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1/[CH:10]=[CH:11]/[CH2:12][C@H:13]([C:45]1[CH:50]=[CH:49][C:48]2[O:51][CH2:52][O:53][C:47]=2[CH:46]=1)[C@H:14]([N:16]([CH2:34][C:35]1[CH:44]=[CH:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=1)[C:17]([C:19]([OH:33])=[C:20]([C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH2:21][C:22]([O:24][CH3:25])=[O:23])=[O:18])[CH3:15]
Reactant: COC(=O)C[C@H](C(=O)OC(C)(C)C)[C@H](O)C(=O)N(Cc1ccc2ccccc2c1)[C@H](C)[C@H](C/C=C/c1nc2ccccc2o1)c1ccc2c(c1)OCO2
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COC(=O)CC(C(=O)OC(C)(C)C)=C(O)C(=O)N(Cc1ccc2ccccc2c1)[C@H](C)[C@H](C/C=C/c1nc2ccccc2o1)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.9 %

Procedure:
36 mg of methyl (3S,4S)-4-[N-{(1R,2R,4E)-5-(2-benzoxazolyl)-1-methyl-2-(3,4-methylenedioxyphenyl)-4-pentenyl}-N-(2-naphthylmethyl)carbamoyl]-3-tert-butoxycarbonyl-4-hydroxybutanoate was dissolved in 2 ml of chloroform, and 42 mg of a Dess-Martin reagent (periodenane) was added thereto, followed by stirring at room temperature for 1 hour. The reaction solution was poured into a mixed solution of a saturated sodium hydrogencarbonate aqueous solution and a saturated sodium thiosulfate aqueous solution and extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The drying agent was filtered off, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel thin layer chromatography (Kieselgel™60F254, Art™5744; hexane/ethyl acetate=3/2) to obtain 14.7 mg (yield: 41%) of the above-identified compound as colorless oily substance.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7]([S:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)=[C:8]([CH3:20])[N:9]2[CH2:14][C:15]([O:17]CC)=[O:16])(=[O:3])[CH3:2].[OH-].[Na+].CC(CC(C)=O)C>C(O)CC>[C:1]([NH:4][CH:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]1=[C:7]([S:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[CH:8]([CH3:20])[N:9]2[CH2:14][C:15]([OH:17])=[O:16])(=[O:3])[CH3:2]
Reactant: CCOC(=O)Cn1c(C)c(Sc2ccc(Cl)cc2)c2c(NC(C)=O)cccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)CC(C)C
Solvent: CCCO
Product: CC(=O)NC1C=CC=C2C1=C(Sc1ccc(Cl)cc1)C(C)N2CC(=O)O
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
To a stirred slurry of ethyl [4-acetylamino-3-(4-chlorophenylsulfanyl)-2-methyl-1H-indol-1-yl]acetate (3.16 kg, 3.05 kg corrected for assay, 7.3 moles) in 1-propanol (15.3 L) was added aqueous NaOH (1M, 15.3 L). The mixture was then heated at 70° C. for 2 h, cooled to 40° C. then MIBK (30.5 L) was added and the mixture reheated to 80° C. Approximately 20% of the resulting biphasic mixture was removed from the reaction vessel to be processed separately. To the remainder, aqueous hydrochloric acid (1M, 13.4 L) was added to the solution over a period of 45 mins then the resulting slurry was cooled to 15° C. over 1 h and stirring continued at this temperature for a further 30 mins. The solid product was collected by filtration, washed with water (2×9.8 L) followed by EtOAc (7.3 L) then dried on the filter for 10 mins then in vacuo at 45° C. to give the title compound as a solid; 2.15 kg; assay by 1H NMR: 99.4% w/w; 2.14 kg corrected for assay (94%); purity: 99.5 area % by HPLC; m/z: 389 (MH+); 1H NMR: 1.86 (3H, s), 2.34 (3H, s), 5.11 (2H, s), 6.97-7.00 (2H, d), 7.08-7.11 (1H, m), 7.27-7.30 (3H, m), 7.47-7.50 (1H, d), 9.50 (1H, br s).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:2]1[O:4][CH2:3]1.[CH3:12][C:13]([NH2:25])([CH3:24])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([F:23])[CH:16]=1>>[OH:4][CH:2]([CH2:1][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][NH:25][C:13]([CH3:24])([CH3:12])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([F:23])[CH:16]=1
Reactant: COc1ccc(CC(C)(C)N)cc1F
Reactant: c1ccc(OCC2CO2)cc1
Product: COc1ccc(CC(C)(C)NCC(O)COc2ccccc2)cc1F

Procedure:
Using the method of Example 6, supra, phenyl glycidyl ether (150 mg, 1.1 mmol) and 1,1-dimethyl-2-(3-fluoro-4-methoxyphenyl)ethylamine (197 mg, 1 mmol) were used to prepare the title compound. The title compound crystallized on standing to yield 169 mg of small crystals: GC/EI-MS, m/z (rel. int.) 332 (M+−15, 0.1), 209 (16), 208 (100), 139 (13), 133 (5), 114 (7), 107 (6), 77 (11), 71 (12), 70 (20), 58 (9).