Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:9]1[C:17]2[CH:16]=[CH:15][C:14]([I:18])=[C:13]3[CH2:19][C@H:20]([N:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])[CH2:21][C@@H:11]([C:12]=23)[CH2:10]1)(=O)C1C=CC=CC=1.[OH-].[K+]>O>[I:18][C:14]1[CH:15]=[CH:16][C:17]2[NH:9][CH2:10][C@H:11]3[CH2:21][C@@H:20]([N:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])[CH2:19][C:13]=1[C:12]=23
Reactant: CCCN(CCC)[C@H]1Cc2c(I)ccc3c2[C@H](C1)CN3C(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCCN(CCC)[C@H]1Cc2c(I)ccc3c2[C@@H](CN3)C1
Yield: 96.7 %

Procedure:
A mixture of 100 g (0.21 mol) of (2aS,4R)-1-benzoyl-6-iodo-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole and 1 liter of 1M ethanolic potassium hydroxide was refluxed under nitrogen for 5 hours. The cooled mixture was diluted with two volumes of water, and the product was extracted into methylene chloride. After drying the extract over sodium sulfate the solvent was evaporated leaving 78 g of the debenzoylated product as a light brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH2:18](O)[CH3:19]>N1CCCCC1>[CH3:4][C:8]1[CH:9]=[C:13]([CH3:14])[NH:12][C:18]=1[CH:19]=[C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[CH:16][C:8]=2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[NH:12][C:11]1=[O:17]
Reactant: CCO
Reactant: O=C1Cc2c(cccc2-c2cccc(Cl)c2)N1
Solvent: C1CCNCC1
Product: Cc1cc(C)c(C=C2C(=O)Nc3cccc(-c4cccc(Cl)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 68 %

Procedure:
To a solution of 4-(3-chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 0.25 mmol) and 3,5-dimethyl-H-pyrrole-2-carbaldehyde (32 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-(3,5-Dimethyl-1H-pyrrol-2-ylmethylene)-4-(3-chloro-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (60 mg, 68%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1)=[O:5])[CH3:2].[Cl:16][C:17]1[CH:18]=[C:19]([CH:29]=[CH:30][C:31]=1[Cl:32])[O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClC(Cl)C>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:10]=[CH:11][C:12]([NH:15][CH2:24][C:23]2[CH:26]=[CH:27][CH:28]=[C:21]([O:20][C:19]3[CH:29]=[CH:30][C:31]([Cl:32])=[C:17]([Cl:16])[CH:18]=3)[CH:22]=2)=[CH:13][CH:14]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1ccc(N)cc1
Reactant: O=Cc1cccc(Oc2ccc(Cl)c(Cl)c2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: O
Product: CCOC(=O)[C@@H]1C[C@H]1c1ccc(NCc2cccc(Oc3ccc(Cl)c(Cl)c3)c2)cc1
Reaction time: 12 h
Yield: 85.8 %

Procedure:
To a mixture of (+)-(trans)-ethyl-2-(4-aminophenyl)cyclopropanecarboxylate (III-1b) (0.099 g, 0.482 mmol) in dichloroethane (3.0 mL) was added 3-(3,4-dichlorophenoxy)benzaldehyde (0.116 g, 0.434 mmol). The mixture was stirred for 12 h followed by addition of sodium triacetoxyborohydride (0.140 g, 0.660 mmol). The mixture was stirred for 6 h at RT. Water was added (10 mL), and the layers were separated. The aqueous phase was extracted with CH2Cl2 (2×10 mL). The combined organics were dried with MgSO4 and concentrated. The crude material was purified by chromatography (EtOAc/hexanes) to give the title compound (0.17 g, 85%, mixture of ethyl and methyl ester). 1H NMR (400 MHz, CDCl3) δ 7.35-7.31 (m, 2H), 7.14 (d, J=7.5 Hz, 1H), 7.05-7.00 (m, 2H), 6.92-6.87 (m, 3H), 6.81 (dd, J=8.8 Hz, 2.7 Hz, 1H), 6.52 (d, J=8.4 Hz, 2H), 4.31 (s, 2H), 4.14 (q, J=7.1 Hz, 2H), 2.42 (m, 1H), 1.77 (m, 1H), 1.51 (m, 1H), 1.28-1.20 (t+m, 4H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[S:11])=[CH:5][CH:4]=1)#[N:2].[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13]>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([NH:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[S:11])=[CH:7][CH:8]=1)#[N:2]
Reactant: CC(C)(C)N
Reactant: N#Cc1ccc(N=C=S)cc1
Solvent: C1CCOC1
Product: CC(C)(C)NC(=S)Nc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 94.1 %

Procedure:
To a solution of 4-cyanophenyl isothiocyanate (1.00 g, 6.24 mmol) in THF (25 mL) at room temperature was added a solution of tert-butylamine (1.31 mL, 12.5 mmol) and the reaction was stirred at room temperature for 6 hours. The mixture was concentrated in vacuo and the resulting residue was triturated with diethyl ether and filtered to afford 1.37 g (94%) of 1-(4-cyanophenyl)-3-(tert-butyl)-thiourea as a white solid which was used without further purification.
Reaction SMILES: [CH3:1][O:2][P:3]([C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][C:10]([C:16]([O:18][CH3:19])=[O:17])=[CH:9][C:8]=1[N+:20]([O-])=O)(=[O:6])[O:4][CH3:5]>CO.[Ni]>[CH3:1][O:2][P:3]([C:7]1[C:8]([NH2:20])=[CH:9][C:10]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][C:12]=1[NH2:13])(=[O:6])[O:4][CH3:5]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(P(=O)(OC)OC)c([N+](=O)[O-])c1
Agent: [Ni]
Solvent: CO
Product: COC(=O)c1cc(N)c(P(=O)(OC)OC)c(N)c1

Procedure:
45 g of (0.134 mol) of 2,6-dinitro-4-carbomethoxybenzene-phosphonic acid dimethylester are dissolved in 550 ml of methanol and hydrogenated at 35° C and 60 excess atmospheres after the addition of 10 g of Raney nickel. The catalyst is filtered off after 4 hours and the solvent is then evaporated off and the residue is freed from any remaining solvent in a high vacuum.
Reaction SMILES: [O:1]=[C:2]1[O:6][CH2:5][C:4]([N:7]2[CH2:12][CH2:11][CH2:10][C:9]3([CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)[CH2:8]2)=[CH:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:8]1[C:9]2([CH2:13][CH2:14][NH:15][CH2:16][CH2:17]2)[CH2:10][CH2:11][CH2:12][N:7]1[C:4]1[CH2:5][O:6][C:2](=[O:1])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCCN(C3=CC(=O)OC3)C2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1C=C(N2CCCC3(CCNCC3)C2)CO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To tert-butyl 2-(5-oxo-2,5-dihydrofuran-3-yl)-2,9-diazaspiro[5.5]undecane-9-carboxylate (266 mg, 0.792 mmol) in DCM (2 mL) was added TFA (2 mL, 26.0 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h, then concentrated under reduced pressure, then placed on the high vacuum. The residue was dissolved in MeOH and loaded onto a 2 g Bond Elut SCX column (pre-rinsed with MeOH). These were rinsed with MeOH, and the product was eluted via 2M NH3 in MeOH to afford 4-(2,9-diazaspiro[5.5]undecan-2-yl)furan-2(5H)-one. LC/MS: [(M+1)]+=237
Reaction SMILES: C(O[C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][N:6]=1)(C)C.P(Cl)(Cl)([Cl:17])=O>C(#N)C>[Cl:17][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][N:6]=1
Reactant: CC(C)Oc1nccc2ccccc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: Clc1nccc2ccccc12

Procedure:
Methyl ester 104 is coupled with compound 7, which is synthesized as described in Reaction Scheme 1, in the presence of palladium acetate coupling catalyst, tetrabutylammonium fluoride, sodium bicarbonate in dimethyl formamide at 100° C., to produce compound 105. Compound 105 is converted to isopropoxy isoquinoline compound 107 by one of two methods. In the first method, compound 105 is treated with phosphoryl chloride in refluxing acetonitrile to produce the 1-chloro isoquinoline compound 106, which is then reacted with isopropyl alcohol in the presence of sodium hydride base to product compound 107. Alternatively, compound 105 is converted directly to compound 107 by reaction with isopropyl bromide, in dimethylformamide at 80° C., in the presence of potassium tert-butoxide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]([OH:15])=O)[C:10]([CH3:16])=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:26][CH:27]([CH3:29])[CH3:28])=[C:22]([CH:25]=1)[C:23]#[N:24].C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>O.CN(C)C=O>[C:23]([C:22]1[CH:25]=[C:18]([NH:17][C:13]([C:11]2[C:10]([CH3:16])=[N:9][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH:12]=2)=[O:15])[CH:19]=[CH:20][C:21]=1[CH2:26][CH:27]([CH3:28])[CH3:29])#[N:24]
Reactant: CC(C)Cc1ccc(N)cc1C#N
Reactant: Cc1nn(-c2ccc(F)cc2)cc1C(=O)O
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1nn(-c2ccc(F)cc2)cc1C(=O)Nc1ccc(CC(C)C)c(C#N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.1 %

Procedure:
1-(4-Fluorophenyl)-3-methylpyrazole-4-carboxylic acid (1.5 g), 5-amino-2-isobutylbenzonitrile (1.2 g), triethylamine (2.0 g) and diethyl cyanophosphate (1.2 g) were added to dimethylformamide (15 ml) and the mixture was stirred at room temperature for 1 h. The reaction mixture was added into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. A mixed solvent of ethyl acetate-n-hexane was added to the residue to allow crystallization. The crystals were recrystallized from hydrous dimethylformamide to give the title compound (0.9 g), melting point: 178–179° C.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:18]=[CH:17][C:8]([C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].N.B.Cl>CCOCC>[OH:10][CH:9]([C:8]1[CH:7]=[CH:6][C:5]([O:4][C:1](=[O:3])[CH3:2])=[CH:18][CH:17]=1)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)CC(=O)c1ccc(OC(C)=O)cc1
Agent: B
Agent: Cl
Agent: N
Solvent: CCOCC
Product: CCOC(=O)CC(O)c1ccc(OC(C)=O)cc1
Temperature: 0 °C
Yield: 57.5 %

Procedure:
A 250 ml round bottom flask was charged with 11.25 grams (0.045 mol.) of ethyl 4-acetoxy-benzoylacetate and 150 ml of diethyl ether. The solution was stirred and ammonia-borane (1.39 gm., 0.045 mol., Alfa) was added in 4 portions. After being stirred 90 minutes at room temperature 50 ml of ether were added and the reaction mixture was slowly poured into a 400 ml beaker containing 20 ml of 3N HCl and 100 ml of crushed ice. After 15 minutes the organic phase was separated. The aqueous phase was extracted with ether (2×100 ml). The combined organic phase was washed with brine, dried over magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography, using a 7 cm. diameter column of 250 grams silica gel, packed and eluted with 25% ethyl acetate/petroleum ether. 6.53 grams of ethyl 3-hydroxy-3-(4-acetoxyphenyl)propionate was obtained. The product was identical to that obtained by method A as determined by NMR and elemental analysis.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:3]=1.C(N(CC)CC)C.Cl[C:22]([O:24][CH3:25])=[O:23]>CN(C1C=CN=CC=1)C.ClCCl>[C:22](=[O:23])([O:24][CH3:25])[O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Oc1ccc(Br)cc1C1CCCC1
Reactant: COC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Oc1ccc(Br)cc1C1CCCC1
Temperature: 25 °C
Yield: 84.6 %

Procedure:
4-Bromo-2-cyclopentylphenol (10.0 g, 41.47 mmol) and DMAP (253 mg, 2.07 mmol) was dissolved in dichloromethane (50 mL) and triethylamine (11.6 mL, 82.94 mmol), cooled to 0° C. and treated with methyl chloroformate (4.8 mL, 62.20 mmol). The reaction was allowed to warm to room temperature over 2 h. The reaction was quenched with water, the layers separated, and the aqueous layer re-extracted with dichloromethane. The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo to yield an oil that was purified by silica gel chromatography (20% ethyl acetate/hexane) to yield 4-bromo-2-cyclopentylphenyl methyl carbonate (10.5 g, 85% yield). 1H NMR (400.0 MHz, DMSO-d6) δ 7.52 (d, J=2.4 Hz, 1H), 7.44 (dd, J=2.4, 8.6 Hz, 1H), 7.22-7.17 (m, 1H), 3.84 (s, 3H), 3.07-2.98 (m, 1H), 1.95-1.88 (m, 2H), 1.79-1.71 (m, 2H), 1.66-1.46 (m, 4H).
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].[Cl:24][C:25]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:26]=1[NH2:27]>>[Cl:24][C:25]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:26]=1[NH:27][C:1]([C:4]12[CH2:5][CH2:6][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:10][CH2:11]2)=[O:2]
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: Nc1ccc(Cl)cc1Cl
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)Nc3ccc(Cl)cc3Cl)(CC1)CC2
Yield: 35.3 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 2,4-dichloroaniline (55.1 mg) were used to obtain (2S,4S)-1-[[N-[4-[N-(2,4-dichlorophenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (25.5 mg).
Reaction SMILES: [CH3:1][C:2]1[C:7](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])=[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[CH:4][N:3]=1>C(O)C.[Pd]>[CH3:1][C:2]1[C:7]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COC(=O)/C=C/c1c(-c2ccccc2)ccnc1C
Agent: [Pd]
Solvent: CCO
Product: COC(=O)CCc1c(-c2ccccc2)ccnc1C
Reaction time: 40 h
Yield: 100.4 %

Procedure:
(E)-Methyl 3-(2-methyl-4-phenyl-3-pyridinyl)-2-propenoate (7.10 g, 0.028 mol) was dissolved in 500 ml of ethanol under a nitrogen atmosphere. Palladium on activated charcoal (0.14 g, 10%) was added in one portion. The nitrogen atmosphere was evacuated, and hydrogen was introduced. After vigorous shaking for 40 hours, the reaction mixture was filtered under a stream of nitrogen and evaporated under reduced pressure to yield 7.18 g of methyl 2-methyl-4-phenyl-3-pyridinepropanoate.
Reaction SMILES: [Br:1][CH2:2][C:3](=[O:15])[CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].[BH4-].[Na+].C(OCC)(=O)C.Cl>O1CCCC1.CO>[OH:15][CH:3]([CH2:2][Br:1])[CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6]
Reactant: O=C(CBr)CC(=O)OCc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(CC(O)CBr)OCc1ccccc1
Temperature: 0 °C
Yield: 86.2 %

Procedure:
The product of step 1 (500 mg, 1.84 mmoles) was dissolved in a mixture of tetrahydrofuran (9 mL) and methanol (1 mL), the solution was cooled in an ice-bath, and sodium borohydride (72 mg, 1.90 mmoles) was added in one portion. Stirring was continued in the ice-bath for 15 min, and ethyl acetate (50 mL) and M hydrochloric acid (1.5 mL) were added. The aqueous layer was separated, extracted with ethyl acetate (20 mL), and the combined organic layers were washed with saturated sodium bicarbonate (40 mL), dried over anhydrous magnesium sulfate and evaporated to give benzyl 3-hydroxy-4-bromobutanoate (433 mg, 86%). 1HMR (CDCl3, δ): 7.36 (5H, s), 5.17 (2H, s), 4.26 (1H, m), 3.50 (1H, dd, 5.0, 10.5 Hz), 3.47 (1H, dd, 5.6, 10.5 Hz), 3.06 (1H, d, 541 Hz), 2.72 (1H, dd, 5.0, 16.6 Hz), 2.69 (1H, dd, 7.3, 16.6 Hz). IR (neat): 3443, 3064, 1731, 1624 cm−1. Mass spectum (CI,m/z): 273, 275 (M+1, M+3). Calcd. for C11H13BrO3.0.5H2O: C 53.75; H 5.88. Found: C 53.65; H 5.60.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C@H:17]2[O:19][CH2:18]2)=[CH:15][CH:14]=1>>[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C@@H:17]([OH:19])[CH2:18][N:8]([CH2:9][CH2:10][OH:11])[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:15][CH:14]=1
Reactant: OCCNCc1ccccc1
Reactant: Clc1ccc([C@@H]2CO2)cc1
Product: OCCN(Cc1ccccc1)C[C@H](O)c1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
N-Benzylethanolamine (1.36 g, 1.5 equivalents) was added to (R)-4-chloro-styrene oxide (928 mg, 6.0 mmol), and the mixture was stirred at 70° C. for 3 hours. By cooling to room temperature, 2.56 g of the reaction mixture including the title compound was obtained (yield: 86%, chemical purity: 69.0 area %, N-benzyl ethanolamine: 9.2 area %, 10.4 area % of regioisomer was contaminated). The retention time in the chemical purity analysis method was 3.8 min.
Reaction SMILES: [BH4-].[Na+].CO.[CH3:5][N:6]1[C:10](=[O:11])[CH2:9][CH:8]([C:12](OC)=[O:13])[CH:7]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[OH:13][CH2:12][CH:8]1[CH2:9][C:10](=[O:11])[N:6]([CH3:5])[CH:7]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)C1CC(=O)N(C)C1c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN1C(=O)CC(CO)C1c1ccccc1
Reaction time: 2 h

Procedure:
To 82.6 g. of sodium borohydride in 950 ml. of methanol at -5° to 0° C. was slowly added in portions 63 g. of methyl 1-methyl-5-oxo-2-phenylpyrrolidin-3-carboxylate. After the addition, the reaction mixture was then allowed to come to ambient temperature over 2 hours. Concentration in vacuo gave a semisolid which was suspended in water at 50° C. and stirred for 30 minutes. The solid was then dissolved in 3:1 chloroform-ether, dried (Na2SO4) filtered, and concentrated in vacuo to yield 40 g. of an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[NH:7][C:8]1([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:29]=[C:28]4[C:23]([CH:24]=[N:25][C:26]5[N:27]4[N:30]=[C:31]([CH3:33])[CH:32]=5)=[C:22](Cl)[C:21]=3[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:16][CH:15]=2)[CH2:11][C:10]([OH:13])([CH3:12])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:42]B(O)O.C([O-])([O-])=O.[Cs+].[Cs+]>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.O1CCOCC1>[C:1]([O:5][C:6](=[O:41])[NH:7][C:8]1([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:29]=[C:28]4[C:23]([CH:24]=[N:25][C:26]5[N:27]4[N:30]=[C:31]([CH3:33])[CH:32]=5)=[C:22]([CH3:42])[C:21]=3[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:16][CH:15]=2)[CH2:11][C:10]([OH:13])([CH3:12])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CB(O)O
Reactant: Cc1cc2ncc3c(Cl)c(-c4ccccc4)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CC(C)(O)C5)cc4)nc3n2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1cc2ncc3c(C)c(-c4ccccc4)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CC(C)(O)C5)cc4)nc3n2n1
Temperature: 80 °C

Procedure:
A 20 ml scintillation vial containing Compound (20-4) (40 mg, 0.07 mmol, 1 eq.), methylboronic acid (84 mg, 1.4 mmol, 2 eq.), Cs2CO3 (226 mg, 0.70 mmol, 1 eq.), and dioxane (5.0 ml) was evacuated and flushed three times with nitrogen. Then PdCl2(dppf)-CH2Cl2 (24 mg, 0.03 mmol, 0.5 eq.) was added and the resulting solution was evacuated and flushed three times with nitrogen. The mixture was heated at 80° C. for 2.5 h. Then it was allowed to cool. The solvent was removed in vacuo. The residue was dissolved in CH2Cl2 (10 mL). After filtration and concentration, it was purified by silica gel chromatography by using MeOH and CH2Cl2 as the mobile phases to furnish Compound (20-5) as a yellowish solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:6]([CH:9]=1)[C:7]#[N:8].[C:20]([O:24][C:25](=[O:37])[NH:26][C:27]1([C:35]#[CH:36])[CH2:32][O:31][C:30]([CH3:34])([CH3:33])[O:29][CH2:28]1)([CH3:23])([CH3:22])[CH3:21].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.CC#N.CC#N.Cl[Pd]Cl.O>[C:20]([O:24][C:25](=[O:37])[NH:26][C:27]1([C:35]#[C:36][C:2]2[CH:3]=[CH:4][C:5]([O:10][CH2:11][CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:6]([C:7]#[N:8])[CH:9]=2)[CH2:32][O:31][C:30]([CH3:34])([CH3:33])[O:29][CH2:28]1)([CH3:23])([CH3:22])[CH3:21]
Reactant: N#Cc1cc(Br)ccc1OCCCc1ccccc1
Reactant: C#CC1(NC(=O)OC(C)(C)C)COC(C)(C)OC1
Agent: Cl[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)NC1(C#Cc2ccc(OCCCc3ccccc3)c(C#N)c2)COC(C)(C)OC1

Procedure:
Compound 1-1 (0.720 g), (5-ethynyl-2,2-dimethyl-1,3-dioxan-5-yl)carbamic acid t-butyl ester (0.634 g) synthesized according to the known method (e.g., Tetrahedron vol.57 (2001) pages 6531-6538), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (0.050 g), bis(acetonitrile)palladium(II) dichloride (0.009 g) and cesium carbonate (0.855 g) were stirred in acetonitrile (8.7 ml) at 70° C. for 7 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give (5-{2-[3-cyano-4-(3-phenylpropoxy)phenyl]ethynyl}-2,2-dimethyl-1,3-dioxan-5-yl)carbamic acid t-butyl ester as a pale-brown solid. This solid was dissolved in ethyl acetate (5 ml), 10% palladium carbon (containing water about 50%, 0.044 g) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 3 hr. The solution was filtered, and the filtrate was concentrated to give the object product (0.408 g) as a brown oil.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][CH3:21])[N:12]=[CH:11][N:10]=1.[CH2:22]([S:26][C:27]1[CH:35]=[CH:34][C:30]([CH2:31][CH2:32][NH2:33])=[CH:29][CH:28]=1)[CH2:23][CH2:24][CH3:25].O>C1(C)C=CC=CC=1>[CH2:22]([S:26][C:27]1[CH:28]=[CH:29][C:30]([CH2:31][CH2:32][NH:33][C:9]2[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][CH3:21])[N:12]=[CH:11][N:10]=2)=[CH:34][CH:35]=1)[CH2:23][CH2:24][CH3:25]
Reactant: CCCCSc1ccc(CCN)cc1
Reactant: CCOC(=O)c1c(Cl)ncnc1CC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCSc1ccc(CCNc2ncnc(CC)c2C(=O)OCC)cc1
Temperature: 25 °C
Yield: 55.5 %

Procedure:
Triethylamine (0.19 g, 1.88 mmol) was added to a solution of ethyl 4-chloro-6-ethylpyrimidine-5-carboxylate (0.20 g, 0.93 mmol) in toluene (4 ml). The mixture was stirred at room temperature. Then, 4-butylthiophenethylamine (0.20 g, 0.96 mmol) was added. After stirring for 3 hours, water (20 ml) was added to the reaction mixture. The mixture was extracted with ethyl acetate and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (=8/2) to give the desired ethyl 4-(2-(4-butylthiophenyl)ethylamino)-6-ethylpyrimidine-5-carboxylate (0.20 g, 55%).
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)OC(C)C)#[N:2].Cl.[CH3:16][S:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1.C(N(CC)CC)C>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=1)=[N:23][CH2:22][C:21]1[CH:24]=[CH:25][C:18]([S:17][CH3:16])=[CH:19][CH:20]=1)#[N:2]
Reactant: CSc1ccc(CN)cc1
Reactant: CC(C)OC(=NC#N)c1ccncc1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CSc1ccc(CN=C(NC#N)c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.6 %

Procedure:
Isopropyl N-cyano-4-pyridinecarboximidate (0.40 g, 2.1 mmol) was dissolved in methanol (15 ml), and 4-methylthiobenzylamine hydrochloride (0.60 g, 3.2 mmol) and triethylamine (0.43 g, 4.2 mmol) were added. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was then concentrated under reduced pressure. The residual concentrate was extracted with ethyl acetate (50 ml×3). The ethyl acetate layer was washed with water (100 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residual concentrate was crystallized from methanol-diethyl ether to give the title compound (0.29 g, 1.0 mmol, yield: 49%) as colorless crystals.