Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[Si]([O:20][CH2:21][C:22]([CH3:58])([CH3:57])[O:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[C:35](=[O:36])[C:34]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([C:44]4[C:45]([C:50]#[N:51])=[CH:46][CH:47]=[CH:48][CH:49]=4)=[CH:40][CH:39]=3)=[C:33]([CH2:52][CH2:53][CH3:54])[N:32]=[C:31]2[CH2:55][CH3:56])=[CH:26][CH:25]=1)(C(C)(C)C)(C)C>O>[CH2:55]([C:31]1[N:30]([C:27]2[CH:26]=[CH:25][C:24]([O:23][C:22]([CH3:57])([CH3:58])[CH2:21][OH:20])=[CH:29][CH:28]=2)[C:35](=[O:36])[C:34]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=3[C:50]3[NH:3][C:4](=[O:7])[O:5][N:51]=3)=[CH:40][CH:39]=2)=[C:33]([CH2:52][CH2:53][CH3:54])[N:32]=1)[CH3:56]
Reactant: CCCc1nc(CC)n(-c2ccc(OC(C)(C)CO[Si](C)(C)C(C)(C)C)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCc1nc(CC)n(-c2ccc(OC(C)(C)CO)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 72.3 %

Procedure:
A mixture of hydroxylammonium chloride (0.93 g), sodium hydrogen carbonate (1.3 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-({1-[4-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethoxy)phenyl]-2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (0.5 g) was added, and the mixture was stirred at 90° C. for 24 hr. The mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the precipitated solid was collected by filtration. The obtained solid was dissolved in ethyl acetate. The solution was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.19 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.18 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL), tetrabutylammonium fluoride (2.1 mL, 1.0 M tetrahydrofuran solution) was added, and the mixture was stirred for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.33 g, 72%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([OH:9])=[C:4]([Cl:10])[N:3]=1.C([CH:13](O)[C:14]([O-:16])=[O:15])C.[C:18]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:19]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCOCC1>[CH2:18]([O:16][C:14](=[O:15])[CH2:13][O:9][C:5]1[C:4]([Cl:10])=[N:3][C:2]([Cl:1])=[N:7][C:6]=1[Cl:8])[CH3:19]
Reactant: CCC(O)C(=O)[O-]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Oc1c(Cl)nc(Cl)nc1Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: C1COCCO1
Product: CCOC(=O)COc1c(Cl)nc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.3 %

Procedure:
A mixture of 2,4,6-trichloro-pyrimidin-5-ol (3.0 g, 15.0 mmol), ethylglycolate (16.7 mL, 17.3 mmol), triphenylphosphine (4.5 g, 17.3 mmol) and DIAD (3.4 mL, 17.3 mmol) in dioxane (100 mL) was stirred at RT for 18 hours then concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, gradient 0-15% ethyl acetate in cyclohexane) affording (2,4,6-Trichloro-pyrimidin-5-yloxy)-acetic acid ethyl ester as a white solid (2.67 g, 62%). 1H NMR (400 MHz, CDCl3): δ 4.77 (2H, s), 4.28 (2H, q, J=7.14 Hz), 1.32 (3H, t, J=7.15 Hz).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]2[N:9]=[C:10]([N:13]([CH2:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][C:22]=3[O:31][CH2:32][CH3:33])[CH2:14][CH:15]([OH:19])[C:16](O)=[O:17])[N:11]=[CH:12][C:3]=12.CN([P+](Br)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:61]([NH2:64])[CH2:62][NH2:63]>CN(C=O)C>[NH2:63][CH2:62][CH2:61][NH:64][C:16](=[O:17])[CH:15]([OH:19])[CH2:14][N:13]([C:10]1[N:11]=[CH:12][C:3]2[C:4]([N:9]=1)=[N:5][C:6]([NH2:8])=[N:7][C:2]=2[NH2:1])[CH2:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]=1[O:31][CH2:32][CH3:33]
Reactant: NCCN
Reactant: CCOc1ccc2ccccc2c1CN(CC(O)C(=O)O)c1ncc2c(N)nc(N)nc2n1
Agent: CN(C)[P+](Br)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc2ccccc2c1CN(CC(O)C(=O)NCCN)c1ncc2c(N)nc(N)nc2n1
Reaction time: 0.5 h
Yield: 16 %

Procedure:
To 3-[(5,7-diamino-pyrimido[4,5-d]pyrimidin-2-yl)-(2-ethoxy-naphthalen-1-ylmethyl)-amino]-2-hydroxy-propionic acid (200 mg, 0.445 mmol) in dry DMF (2 ml) was added BroP (249 mg, 0.534 mmol). After the mixture was stirred for 30 min, DIEA (126 mg, 0.979 mmol) was added. After stirring for another 20 min, ethylene diamine (53.5 mg, 0.89 mmol) was added. The mixture was then stirred at room temperature for 16 hours and was directly purified by prep HPLC to yield 35 mg (16%) of the title compound: MS m/z (M+H) 492.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([CH3:12])[C:9]2[C:8](=[N:13][OH:14])[CH2:7][CH:6]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=3[C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[CH2:5][C:4]=2[N:3]=1.[H-].[Na+].[CH3:30][N:31]([CH3:62])[CH2:32][CH2:33][CH2:34]ON=C1CC(C2C=C(F)C=CC=2C2C=CC=CC=2)CC2N=C(N)N=C(C)C1=2>O>[CH3:30][N:31]([CH3:62])[CH2:32][CH2:33][CH2:34][O:14][N:13]=[C:8]1[CH2:7][CH:6]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[CH2:5][C:4]2[N:3]=[C:2]([NH2:1])[N:11]=[C:10]([CH3:12])[C:9]1=2
Reactant: Cc1nc(N)nc2c1C(=NO)CC(c1ccc(F)cc1-c1cccnc1)C2
Reactant: Cc1nc(N)nc2c1C(=NOCCCN(C)C)CC(c1cc(F)ccc1-c1ccccc1)C2
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: Cc1nc(N)nc2c1C(=NOCCCN(C)C)CC(c1ccc(F)cc1-c1cccnc1)C2

Procedure:
The title compound was prepared from 2-amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one oxime, compound 89, (100 mg, 0.275 mmol), 3-dimethyl-aminopropyl chloride hydrochloride (52 mg, 0.330 mmol) and sodium hydride (60% dispersion in oil) (35 mg, 0.881 mmol) following the same procedure used for 2-amino-7-(4-fluoro-biphenyl-2-yl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one O-(3-dimethylamino-propyl)-oxime (compound 88) except after addition of water the solvent was removed under reduced pressure. The crude material was then extracted with ethyl acetate (20 ml), filtered and the resulting organic phase was concentrated under reduced pressure. The resulting material was washed with diethyl ether yielding the title compound.
Reaction SMILES: [CH2:1]([P:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:10][CH3:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:20][Cl:21]>>[Cl-:21].[CH2:12]([P+:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])([CH2:10][CH3:11])[CH3:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCl
Reactant: CCCCCCCCP(CC)CCCCCCCC
Product: CCCCCCCC[P+](C)(CC)CCCCCCCC
Product: [Cl-]

Procedure:
Into 14.4 g (0.05 m) of dioctyl ethyl phosphine, placed in the bubbler reactor described in Example 2, methyl chloride was introduced at 130° C. for 4 hours. The degree of weight gain observed corresponded to a quantitative formation of the desired product; a colorless, waxy solid at room temperature. In the nmr spectrum of this product, the α-meythyl doublet appears at 1.93 ppm (JP-C 14 cps).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([O:10][CH3:11])=[N:6][CH:7]=[CH:8][CH:9]=1)[CH3:2].C([O-])(=O)C.[Na+].[Br:17]Br.[OH-].[Na+]>C(O)(=O)C>[Br:17][C:8]1[CH:9]=[C:4]([O:3][CH2:1][CH3:2])[C:5]([O:10][CH3:11])=[N:6][CH:7]=1
Reactant: BrBr
Reactant: CCOc1cccnc1OC
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCOc1cc(Br)cnc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
To a stirred mixture of 3-ethoxy-2-methoxy-pyridine (2.7 g, 17.6 mmol, 1.0 equiv) and sodium acetate (1.74 g, 21.2 mmol, 1.2 equiv) in acetic acid (50 mL) at 10° C. was slowly added a solution of bromine (1.09 mL, 3.38 g, 21.2 mmol, 1.2 equiv) in acetic acid (10 mL). After the addition was completed the reaction mixture was stirred for 1 h at rt. The reaction mixture was poured on ice, neutralized with NaOH and the solution extracted with diethylether (3×50 mL). The combined organic phases were dried over MgSO4 and the solvent removed by evaporation under reduced pressure yielding 3.86 g (94%) of a mixture of 5-bromo-3-ethoxy-2-methoxy-pyridine and 6-bromo-3-ethoxy-2-methoxy-pyridine in the ratio 3:2 as indicated by 1H NMR, which was used directly in the next reaction step. 1H NMR (300 MHz, CDCl3): δ 1.39 (t, J=7.0 Hz, 3H), 3.91 (s, 3H), 3.98 (q, J=7.0 Hz, 2H), 7.05 (d, J=1.9 Hz, 1H), 7.69 (d, J=1.9 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:4]=[C:3]1[N:15]1[CH2:20][CH2:19][NH:18][CH2:17][C@H:16]1[CH3:21].C(N(CC)CC)C.[N:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][C:30]=1[C:39](Cl)=[O:40]>ClCCl>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:4]=[C:3]1[N:15]1[CH2:20][CH2:19][N:18]([C:39]([C:30]2[CH:31]=[CH:32][C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:29]=2)=[O:40])[CH2:17][C@H:16]1[CH3:21]
Reactant: O=C(Cl)c1ccc2ccccc2n1
Reactant: C[C@@H]1CNCCN1c1nc(-c2ccncn2)cc(=O)n1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(C(=O)c2ccc3ccccc3n2)CCN1c1nc(-c2ccncn2)cc(=O)n1C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
To a solution of 1-methyl-2-((2R)-2-methyl-piperazin-1-yl)-1H-[4,4′]bipyrimidinyl-6-one (0.15 g, 0.52 mmol) and triethylamine (0.15 g, 1.48 mmol) in dichloromethane (2.5 ml) was added quinoline-2-carbonyl chloride (0.11 g, 0.57 mmol) at 0° C. and stirred for one hour at that temperature. The mixture was partitioned between water and dichloromethane, and the organic layer was washed with aqueous sodium hydrogen carbonate, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; chloroform/methanol=20/1) to afford 1-methyl-2-[(2R)-2-methyl-4-(quinoline-2-carbonyl)-piperazin-1-yl]-1H-[4,4′]bipyrimidinyl-6-one (0.18 g, 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([OH:7])=O.[CH3:12][Li]>C1COCC1>[Cl:11][C:9]1[CH:8]=[C:4]([C:5](=[O:7])[CH3:12])[CH:3]=[C:2]([Cl:1])[CH:10]=1
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1
Reactant: [Li]C
Solvent: C1CCOC1
Product: CC(=O)c1cc(Cl)cc(Cl)c1
Temperature: 0 °C

Procedure:
3,5-Dichlorobenzoic acid (19,10 g, 100 mmol) was dissolved in dry THF (165 mL) and cooled to 0° C. in an ice bath. With vigorous stirring, 138 mL (210 mmol) of methyl lithium (1.6 M in diethyl ether) was added dropwise over a period of 30 min via syringe. After 1 hour the mixture was poured into ice-water (500 mL). The aqueous phase was extracted with diethyl ether (4×50 mL). The combined organic phases were washed with saturated aqueous sodium hydrogen carbonate (2×50 mL) and saturated aqueous sodium chloride (2×50 mL). The organic phase was dried (magnesium sulphate), filtered and the solvent was removed in vacuo. This afforded 17.06 g of the title compound containing 18% by weight of 2-(3,5-dichlorophenyl)propan-2-ol. This compound was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[S:25]1[CH:29]=[CH:28][C:27]([C:30](Cl)=[O:31])=[CH:26]1>>[S:25]1[CH:29]=[CH:28][C:27]([C:30]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([C:11]4[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=5)[CH2:15][CH:16]=4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:31])=[CH:26]1
Reactant: O=C(Cl)c1ccsc1
Reactant: Nc1ccc2[nH]cc(C3=CCN(CCc4ccccc4)CC3)c2n1
Product: O=C(Nc1ccc2[nH]cc(C3=CCN(CCc4ccccc4)CC3)c2n1)c1ccsc1

Procedure:
Beginning with 0.015 gm (0.047 mMol) 5-amino-3-(1-(2-phenyleth-1-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[3,2-b]pyridine and 0.009 mL (0.061 mMol) 3-thiophenecarbonyl chloride, the title compound was prepared essentially by the procedure described in Example 7. MS(m/e): 429(M+)
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26](B5OC(C)(C)C(C)(C)O5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:40]1[CH:45]=[C:44]([CH3:46])[CH:43]=[CH:42][N:41]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O.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>[Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:24]=[CH:25][C:26]([C:40]5[CH:45]=[C:44]([CH3:46])[CH:43]=[CH:42][N:41]=5)=[CH:27][CH:28]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: Cc1ccnc(Br)c1
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(B5OC(C)(C)C(C)(C)O5)cc4)CC3)n2CCS1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccnc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)cc2)c1
Temperature: 25 °C
Yield: 20 %

Procedure:
A solution of the compound (555 mg, 1.0 mmol) obtained in Example 16-5), 2-bromo-4-picoline (344 mg, 2 mmol), tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.2 mmol), and potassium carbonate (276 mg, 2 mmol) in dimethoxyethane (4 mL) and water (1 mL) was stirred at 100° C. for 1 h under microwave irradiation. The reaction mixture was cooled to room temperature and purified by silica gel chromatography (Isco Combiflash, 40 g, methanol:ethyl acetate=0:100 to 20:80, gradient) to obtain the title compound (104 mg, 20%) as a light yellow oily substance.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][C:21]=1[F:29]>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)=[CH:22][C:21]=1[F:29]
Reactant: OB(O)c1ccc(Cl)c(F)c1
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccc(Cl)c(F)c4)cc(C#N)cc13)CCNC2=O

Procedure:
The title compound, off-white solid (63 mg, 71%), MS (ISP) m/z=354.5 [(M+H)+], mp 260° C., was prepared in accordance with the general method of example 1 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 16) (76 mg, 0.25 mmol) and commercially available 4-chloro-3-fluoro-phenylboronic acid (56.7 mg, 0.325 mmol).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[N:9]([O-])=[O:10].[Na+]>>[CH3:1][C:2]1[C:7](=[N:9][OH:10])[CH:6]=[CH:5][C:4](=[O:8])[CH:3]=1
Reactant: Cc1cccc(O)c1
Reactant: O=N[O-]
Agent: [Na+]
Product: CC1=CC(=O)C=CC1=NO

Procedure:
3-Methyl-1,4-benzoquinone-4-oxime was prepared by reaction of 3-methylphenol with sodium nitrite under basic conditions by the method of T. Ishikawa et al. described in Tetrahedron 31, 1995, page 8454.
Reaction SMILES: Cl.COC(=O)[C@@H](N)COCC1C=CC(C2C=CC=CC=2)=CC=1.FC(F)(F)C1C=CC(C2C=CC(C(O)=O)=CC=2)=CC=1.C[O:43][C:44](=[O:80])[C@@H:45]([NH:61][C:62]([C:64]1[CH:69]=[CH:68][C:67]([C:70]2[CH:75]=[CH:74][C:73]([C:76]([F:79])([F:78])[F:77])=[CH:72][CH:71]=2)=[CH:66][CH:65]=1)=[O:63])[CH2:46][O:47][CH2:48][C:49]1[CH:54]=[CH:53][C:52]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)=[CH:51][CH:50]=1>>[C:52]1([C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)[CH:51]=[CH:50][C:49]([CH2:48][O:47][CH2:46][C@H:45]([NH:61][C:62]([C:64]2[CH:69]=[CH:68][C:67]([C:70]3[CH:75]=[CH:74][C:73]([C:76]([F:77])([F:78])[F:79])=[CH:72][CH:71]=3)=[CH:66][CH:65]=2)=[O:63])[C:44]([OH:80])=[O:43])=[CH:54][CH:53]=1
Reactant: COC(=O)[C@H](COCc1ccc(-c2ccccc2)cc1)NC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: COC(=O)[C@@H](N)COCc1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: O=C(O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Product: O=C(N[C@@H](COCc1ccc(-c2ccccc2)cc1)C(=O)O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Yield: 80 %

Procedure:
(2S)-Amino-3-(biphenyl-4-ylmethoxy)-propionic acid methyl ester hydrochloride (0.150 g, 0.483 mmol) was reacted with 4′-trifluoromethyl-biphenyl-4-carboxylic acid (0.136 g, 0.483 mmol) as described in general procedure A yielding the 3-(biphenyl-4-ylmethoxy)-(2S)-[(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid methyl ester. The resulting compound was then hydrolyzed by following the general procedure C to yield the title compound (0.200 g, 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:19])[CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[S:20]1[CH2:24][C:23](=[O:25])[NH:22][C:21]1=[O:26].N1CCCCC1>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:19])[CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=[C:24]3[S:20][C:21](=[O:26])[NH:22][C:23]3=[O:25])=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1ccc(OCC(O)c2cccc(Cl)c2)cc1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1NC(=O)C(=Cc2ccc(OCC(O)c3cccc(Cl)c3)cc2)S1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.4 %

Procedure:
To a stirring solution of 4-[2-(3-chlorophenyl)-2-hydroxyethoxy]benzaldehyde (1.08 g, 3.90 mmol) in absolute EtOH (50 ml) was added 2,4-thiazolidinedione (0.50 g, 4.29 mmol) and piperidine (0.42 mL, 4.3 mmol), and the resulting solution was heated to reflux and then stirred overnight at room temperature. The reaction mixture was evaporated in vacuo and the residue was dissolved in EtOAc. This solution was washed with aqueous HOAc (pH 5-6), brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was adsorbed onto silica gel and chromatographed eluting with 10-20% EtOAc/DCM. Fractions containing product were combined and evaporated in vacuo to give 1.31 g (89%) of the product as a light yellow solid. MS (ESI+) for C18H14ClNO4S m/z 375.0 (M+H)+. MS (ESI−) for C18H14ClNO4S m/z 374.1 (M−H)−.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][CH:3]=1.[CH2:10]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[CH3:11]>CN(C=O)C.O>[CH2:10]([N:12]1[CH2:17][CH2:16][N:15]([C:2]2[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][CH:3]=2)[CH2:14][CH2:13]1)[CH3:11]
Reactant: CCN1CCNCC1
Reactant: O=Cc1ccc(Cl)nc1
Solvent: CN(C)C=O
Solvent: O
Product: CCN1CCN(c2ccc(C=O)cn2)CC1
Yield: 89 %

Procedure:
6-chloropyridine-3-carbaldehyde (5.0 g, 35.32 mmol) and 1-ethylpiperazine (20.16 g, 176.60 mmol, 22.42 mL) were heated overnight in a mixture of DMF/water (1:1, 40 mL) at 100° C. The reaction mixture was extracted with ethyl acetate (2×100 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated to dryness to provide 6-(4-ethylpiperazin-1-yl)pyridine-3-carbaldehyde, which was used in the next reaction without any further purification (6.91 g, 89% yield); 1H NMR (400 MHz, DMSO-d6): δ 0.99 (t, 3H), 2.31 (q, 2H), 2.39 (m, 4H), 3.66 (m, 4H), 6.91 (d, J=9.2 Hz, 1H), 7.82 (d, J=9.2 Hz, 1H), 8.55 (s, 1H), 9.7 (s, 1H); LRMS (ES+) m/z 219.8.
Reaction SMILES: C([O:8][C:9](=[O:23])[C@H:10]([O:15][C:16]([C:18]1[O:19][CH:20]=[CH:21][CH:22]=1)=[O:17])[CH2:11][CH:12]([CH3:14])[CH3:13])C1C=CC=CC=1.[H][H]>[Pd]>[O:19]1[CH:20]=[CH:21][CH:22]=[C:18]1[C:16]([O:15][C@H:10]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:9]([OH:23])=[O:8])=[O:17]
Reactant: CC(C)C[C@@H](OC(=O)c1ccco1)C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Product: CC(C)C[C@@H](OC(=O)c1ccco1)C(=O)O

Procedure:
A total of 55.5 g. of benzyl-(R)-2-(2-furoyloxy)-isocaproate were hydrogenated in 400 ml. of alcohol after the addition of 5 g. of palladium-on-charcoal (5%) until the theoretical amount of hydrogen had been taken up. The catalyst was filtered off by suction and the filtrate evaporated under reduced pressure at 40°. The oil thus obtained was dissolved in 250 ml. of 8% sodium bicarbonate solution and the resulting solution washed twice with 80 ml. portions of ether. The pH of the bicarbonate solution was adjusted to pH 2 with concentrated hydrochloric acid and extracted three times with 100 ml. portions of ethyl acetate. The ethyl acetate solutions were washed twice with 50 ml. portions of water, dried with magnesium sulphate and evaporated under reduced pressure at 45°. The residual oil was dried for 2 hours at 0.4 Torr and 40° to give (R)-2-(2-furoyloxy)-isocaproic acid; [α]D25 =+7.0 (c = 4.0 in alcohol).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]([OH:13])[CH3:12])[CH:7]=[CH:8][C:9]=1[Cl:10].[F:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19](F)[C:16]=1[C:17]#[N:18]>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]([O:13][C:19]2[CH:20]=[CH:21][CH:22]=[C:15]([F:14])[C:16]=2[C:17]#[N:18])[CH3:12])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: N#Cc1c(F)cccc1F
Reactant: CC(O)c1ccc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(Oc1cccc(F)c1C#N)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.4 %

Procedure:
To a cold (ice water) suspension of sodium hydride (316 mg; 7.9 mmol) in anhydrous DMF (10 mL) is added a solution of 1-(3,4-dichlorophenyl)-ethanol (1.40 g; 7.3 mmol) in anhydrous DMF (5 mL) over 30 minutes. After allowing to room temperature over 30 minutes, this solution is added to a cold (ice water) stirred solution of 2,6-difluorobenzonitrile (1.0 g; 7.2 mmol) in anhydrous DMF (15 mL), and allowed to room temperature over 2 hours. The reaction mixture is poured into ice water with vigorous stirring and extracted with ethyl acetate. The organics are separated and dried over magnesium sulfate. The solvent is removed and the resulting oil is dried under vacuum at 30° C. overnight to give 1.93 gm of 2-[1-(3,4-dichlorophenyl)-ethoxy]-6-fluorobenzonitrile.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:32])[C:17]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:34]1[C:39]([C:40]#[N:41])=[CH:38][C:37]([CH:42]=[O:43])=[CH:36][N:35]=1.C(=O)([O-])O.[Na+]>COCCOC>[CH3:20][CH2:19][CH2:18][CH:17]([CH3:22])[CH3:16].[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:32])[C:17]1[CH:18]=[CH:19][C:20]([C:34]2[C:39]([C:40]#[N:41])=[CH:38][C:37]([CH:42]=[O:43])=[CH:36][N:35]=2)=[CH:21][CH:22]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1cc(C=O)cnc1Cl
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(-c2ncc(C=O)cc2C#N)cc1
Product: CCCC(C)C
Reaction time: 7.5 h
Yield: 101.5 %

Procedure:
N-(2-t-butoxycarbonylaminophenyl)-4-(4,4,5,5,tetramethyl-1,3,2,-dioxaborolan-2-yl)benzamide (1.2 g, 2.74 mmol; prepared as described in international patent publication number wo03/087057, method 13, page 60), 2-chloro-3-cyano-5-formylpyridine [prepared as described in de 4429465 a1 (1996)] (456 mg, 2.74 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(ii)dichloride dichloromethane complex 112 mg, 0.137 mmol), 1,2-dimethoxyethane (12 ml) and a saturated aqueous solution of sodium hydrogen carbonate (6 ml) were stirred at 60° c. under an atmosphere of nitrogen for 7.5 hours. the mixture was allowed to cool before being partitioned between dichloromethane and water. the organics were separated, dried over sodium sulfate, filtered and evaporated. the crude product was purified by chromatography on silica eluting with 30:70 to 40:60 ethyl acetate: isohexane to afford the title compound as a cream solid (615 mg, 51%); nmr spectrum: (dmso-d6) 1.45 (s, 9h), 7.18 (m, 2h), 7.56 (m, 2h), 8.10 (d, 2h), 8.17 (d, 2h), 8.70 (s, 1h), 8.90 (d, 1h), 9.39 (d, 1h), 9.97 (s, 1h), 10.18 (s, 1h); mass spectrum: m+na+ 465.