Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:3]1[CH2:9][CH2:8][C:7](=[O:10])[C:6]2[CH:11]=[CH:12][S:13][C:5]=2[CH2:4]1)=O.O>Cl.O1CCOCC1>[S:13]1[C:5]2[CH2:4][NH:3][CH2:9][CH2:8][C:7](=[O:10])[C:6]=2[CH:11]=[CH:12]1
Reactant: O=CN1CCC(=O)c2ccsc2C1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: O=C1CCNCc2sccc21
Temperature: 60 °C
Yield: 94.3 %

Procedure:
7-Formyl-5,6,7,8-tetrahydrothieno[2,3-c]azepin-4-one (2.6 g) prepared in the step 4 was dissolved in 4N hydrochloric acid/dioxane solution, 13.5 mL of water was added thereto and the mixture was heated at 60° C. for 6 hours with stirring. The solvent was evaporated from the reaction solution in vacuo, water was added to the residue and the mixture was subjected to extraction with diethyl ether. The resulting aqueous solution was slowly neutralized with an aqueous solution of sodium hydrogen carbonate with stirring and subjected to extraction with diethyl ether. The organic layer was separated, washed with water and a saturated solution of sodium chloride successively and dried over anhydrous magnesium sulfate and the solvent was evaporated therefrom in vacuo to give 2.1 g of the objective compound as a brown solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH:6]=[CH:5]2.Cl[C:24]1[C:33]2[C:28](=[CH:29][C:30]([O:36][CH3:37])=[C:31]([O:34][CH3:35])[CH:32]=2)[N:27]=[CH:26][N:25]=1>>[CH3:35][O:34][C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][C:30]=1[O:36][CH3:37])[N:27]=[CH:26][N:25]=[C:24]2[O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([NH:12][C:13](=[O:14])[O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH:6]=[CH:5]2
Reactant: O=C(Nc1ccc2cc(O)ccc2c1)OCc1ccccc1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Product: COc1cc2ncnc(Oc3ccc4cc(NC(=O)OCc5ccccc5)ccc4c3)c2cc1OC

Procedure:
N-(6-Hydroxy-2-naphthyl)(phenylmethoxy)carboxamide (180 mg, 0.61 mmol, Example 1a) was reacted with 4-chloro-6,7-dimethoxy-quinazoline (140 mg, 0.61 mmol, Oakwood) under the conditions of Example 4b to give the title compound as a white solid. MS (ESI, pos. ion) m/z: 482.5 (M+1). Mass Calc'd for C28H23N3O5: 481.16.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5](/[CH:6]=[CH:7]/[CH2:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][NH:10]2)=[CH:4][CH:3]=1.BrC[CH:19]1[CH2:21][CH2:20]1>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:6]=[CH:7]/[CH2:8][CH:9]2[CH2:14][CH2:13][CH2:12][N:10]2[CH2:11][CH:19]2[CH2:21][CH2:20]2)=[CH:15][CH:16]=1
Reactant: Fc1ccc(/C=C/CC2CCCCN2)cc1
Reactant: BrCC1CC1
Solvent: CC#N
Product: Fc1ccc(/C=C/CC2CCCN2CC2CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31 %

Procedure:
In a reactor protected from moisture, there are introduced 2.3 g (0.010 mol) of (E)-2-(p-fluorocinnamyl)piperidine (Preparation 2B) dissolved in 25.2 ml acetonitrile, followed, during 2 min, by 1.56 g (1.1 ml-0.012 mol) bromomethylcyclopropane. The medium is kept stirring at ambient temperature for 1 h 30 min, is raised to 60° C. for 4 h, and is then lowered to 20°±3° C. for 16 h. The solvent is evaporated under vacuum and on a water bath. The oily residue is dissolved in water, acidified and extracted with ether. After decanting, the cooled aqueous phase is alkalinized with soda, extracted with ether and washed with saturated NaCl solution. The organic phase is dehydrated over Na2SO4 and the solvent is then removed by distillation. The residue is purified by the Chromatoflash technique, elution being carried out with a 90:10 v/v mixture of methylene chloride and 10% ammoniacal MeOH, and is then subjected to a second acid-alkali treatment. (E) -2-(p-fluorocinnamyl)-1-(cyclopropylmethyl)pyrrolidine is obtained in the form of a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]([CH:9]=1)[C:7]#[N:8].Cl[C:20]1[C:25]([F:26])=[CH:24][CH:23]=[CH:22][N:21]=1.[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1COCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][N:21]=2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: CC1(C)OB(c2ccc(F)cc2C#N)OC1(C)C
Reactant: Fc1cccnc1Cl
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cc(F)ccc1-c1ncccc1F
Temperature: 70 °C
Yield: 62.2 %

Procedure:
To a degassed solution of 5-fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzonitrile (5.55 g, 22.46 mmol), 2-chloro-3-fluoropyridine (2.95 g, 22.46 mmol), potassium fluoride (4.3 g, 74.14 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.824 g, 0.89 mmol) in THF (80 ml) and water (8 ml) was added tri(tert-butyl)phosphine (0.51M solution in hexane; 3.52 ml, 1.79 mmol). The reaction was heated at 70° C. for 48 h, then allowed to cool to ambient temperature. The reaction mixture was filtered through a catalyst filter, and the filtrate diluted with ethyl acetate (400 ml) and washed with water (2×100 ml). The organic phase was separated, dried (MgSO4), filtered and adsorbed onto silica gel. The crude product was chromatographed on silica, eluting with 10% ethyl acetate in isohexane, to give 5-fluoro-2-(3-fluoropyridin-2-yl)benzonitrile as a white solid (3.02 g): δH (400 MHz, CDCl3) 7.40-7.45 (2H, m), 7.51-7.61 (2H, m), 7.72-7.76 (1H, m), 8.58-8.60 (1H, m); m/z (ES+) 217.
Reaction SMILES: [C:1]([NH:20][C@H:21]([C:24]([O:26][CH3:27])=[O:25])[CH2:22][OH:23])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl.[Cl-].C([N+](C)(C)C)C1C=CC=CC=1>[CH2:30]([O:23][CH2:22][C@@H:21]([C:24]([O:26][CH3:27])=[O:25])[NH:20][C:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)[C@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)[C@H](COCc1ccccc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 71.3 %

Procedure:
Methyl N-trityl-L-serinate (3.61 g, 10.0 mmol), prepared by the method of Baldwin, Tetrahedron, 49, pp. 6309-6330, (1993), was dissolved in 50 mL of CH2Cl2 followed by the addition of 25 mL of 50% aqueous NaOH solution. To the stirred mixture were added benzyltrimethylammonium chloride (186 mg, 1.00 mmol) and benzyl bromide (1.20 mL, 10.0 mmol). After stirring overnight, the mixture was treated with 100 mL of ice water. After all of the ice had melted, 100 mL of CH2Cl2 was added and the layers were separated. The aqueous portion was extracted with another 50 mL of CH2Cl2 and the combined organic layers were washed with H2O (2×100 mL) and brine (3×50 mL). The organic portion was dried over Na2SO4, filtered and concentrated. Chromatography (SiO2, 10-20% ethyl acetate/hexanes) gave 3.22 g of methyl O-benzyl-N-trityl-L-serinate as a colorless syrup.
Reaction SMILES: [F:1][C:2]([F:7])([CH3:6])[C:3](O)=[O:4].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.ClC1C=C(C=CC=1OC)C[N:34]1[CH2:39][CH2:38][CH:37]([NH:40][C:41]([N:43]2[CH2:48][CH2:47][C:46](=[CH:49][C:50]3[CH:55]=[C:54]([F:56])[CH:53]=[CH:52][C:51]=3[F:57])[CH2:45][CH2:44]2)=[O:42])[CH2:36][CH2:35]1.CCN(CC)CC>C(#N)C.O>[F:57][C:51]1[CH:52]=[CH:53][C:54]([F:56])=[CH:55][C:50]=1[CH:49]=[C:46]1[CH2:47][CH2:48][N:43]([C:41]([NH:40][CH:37]2[CH2:36][CH2:35][N:34]([C:3](=[O:4])[C:2]([F:7])([F:1])[CH3:6])[CH2:39][CH2:38]2)=[O:42])[CH2:44][CH2:45]1
Reactant: COc1ccc(CN2CCC(NC(=O)N3CCC(=Cc4cc(F)ccc4F)CC3)CC2)cc1Cl
Reactant: CC(F)(F)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: CC(F)(F)C(=O)N1CCC(NC(=O)N2CCC(=Cc3cc(F)ccc3F)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.7 %

Procedure:
2,2-Difluoropropionic acid (66.0 mg, 0.60 mmol) was dissolved in acetonitrile (2.0 mL), and then HOBt (75.0 mg, 0.60 mmol), WSC (115 mg, 0.60 mmol), the compound (150 mg, 0.40 mmol) obtained in Example 36 (1), and Et3N (167 μL, 1.2 mmol) were added thereto, followed by stirring at room temperature overnight. Water was added to the reaction mixture, and after extraction with chloroform, the extract was washed with water and a saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporation under reduced pressure was purified using medium pressure silica gel flash column chromatography (methanol:chloroform=1:30), thereby giving the title compound (20.0 mg, 12%) as a white solid.
Reaction SMILES: CC(C)=O.[CH3:5][O:6][C:7](=[O:39])[CH2:8][N:9]([S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26]([OH:38])[C:27]1[CH:35]=[C:34]([O:36][CH3:37])[C:30]2[O:31][CH2:32][O:33][C:29]=2[CH:28]=1)(=[O:19])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>C(OCC)(=O)C>[CH3:5][O:6][C:7](=[O:39])[CH2:8][N:9]([S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]([C:27]1[CH:35]=[C:34]([O:36][CH3:37])[C:30]2[O:31][CH2:32][O:33][C:29]=2[CH:28]=1)=[O:38])(=[O:18])=[O:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16]
Reactant: COC(=O)CN(c1ccccc1C)S(=O)(=O)c1ccccc1C(O)c1cc(OC)c2c(c1)OCO2
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COC(=O)CN(c1ccccc1C)S(=O)(=O)c1ccccc1C(=O)c1cc(OC)c2c(c1)OCO2
Reaction time: 0.25 h
Yield: 59 %

Procedure:
To acetone (225 mL) was added ({2-[hydroxy-(7-methoxy-benzo[1,3]dioxol-5-yl)-methyl]-benzenesulfonyl}-o-tolyl-amino)-acetic acid methyl ester (4.17 g, 8.35 mmol), and 8N Jones reagent (4 mL). The mixture was stirred 15 minutes giving a suspended solid. Isopropanol (20 mL) was added followed by stirring for 15 minutes. The mixture was filtered, saturated sodium bicarbonate solution was added, and the solvent was removed in vacuo giving a paste. The paste was resuspended in ethyl acetate and water, filtered, and washed with saturated sodium bicarbonate, brine and dried over anhydrous magnesium sulfate. The solution was filtered and evaporated to a solid which was crystallized from ethyl acetate and ethyl ether giving a white solid, 2.41 g, 59% yield, mp 159-170° C. NMR spectra and elemental analysis were consistent with the structure.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][CH:10]([CH3:12])[CH3:11])=[O:8])[N:6]=1.Cl.[NH:14]1[CH2:19][CH2:18][CH:17]([N:20]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[CH2:23][O:22][C:21]2=[O:30])[CH2:16][CH2:15]1>>[CH3:11][CH:10]([NH:9][C:7]([C:5]1[N:6]=[C:2]([N:14]2[CH2:15][CH2:16][CH:17]([N:20]3[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[CH2:23][O:22][C:21]3=[O:30])[CH2:18][CH2:19]2)[S:3][CH:4]=1)=[O:8])[CH3:12]
Reactant: CC(C)NC(=O)c1csc(Br)n1
Reactant: O=C1OCc2ccccc2N1C1CCNCC1
Agent: Cl
Product: CC(C)NC(=O)c1csc(N2CCC(N3C(=O)OCc4ccccc43)CC2)n1

Procedure:
The title compound was prepared from the product of step (i) (0.16 g) and 1-piperidin-4-yl-1,4-dihydro-2H-3,1-benzoxazin-2-one hydrochloride (0.15 g) using the method of example 115 step (ii). Yield 0.04 g.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:11][C:12]1[N:17]=[C:16]([CH3:18])[CH:15]=[CH:14][N:13]=1.[C:19]([C:21]1[CH:22]=[C:23]([CH:30]=[CH:31][CH:32]=1)[C:24]([N:26]([CH3:29])OC)=O)#[N:20]>C1COCC1>[Cl:11][C:12]1[N:17]=[C:16]([C:18]2[N:13]3[CH:14]=[CH:15][CH:16]=[CH:18][C:29]3=[N:26][C:24]=2[C:23]2[CH:22]=[C:21]([CH:32]=[CH:31][CH:30]=2)[C:19]#[N:20])[CH:15]=[CH:14][N:13]=1
Reactant: Cc1ccnc(Cl)n1
Reactant: CON(C)C(=O)c1cccc(C#N)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 39.3 %

Procedure:
Lithium bis(trimethylsilyl)amide (1M in THF, 36.0 mL, 36.0 mmol) was added to 100 mL of THF and cooled to −78° C. 2-Chloro-4-methylpyrimidine (3.07 g, 23.9 mmol) in 20 mL of THF was added dropwise over 10 minutes. The addition funnel was rinsed with 10 mL of THF. The reaction was stirred 20 minutes, and 3-cyano-N-methyl-N-(methyloxy)benzamide (see Organic Lett. 2006, 8, 4843-4846) (5.00 g, 26.3 mmol) in 25 mL of THF was added dropwise over 10 minutes. The addition funnel was rinsed with 10 mL of THF. The reaction was stirred for one hour and allowed to warm to 0° C. The reaction was quenched with saturated ammonium chloride solution and poured into H2O and EtOAc. The layers were separated, and the organic layer was washed with brine. The combined aqueous layers were extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford the product contaminated with 3-cyano-N-methyl-N-(methyloxy)benzamide. The mixture was triturated with 30% EtOAc in hexanes, filtered, and the solid washed with 30% EtOAc in hexanes followed by hexanes. The yellow solid was collected to provide 1.56 g (25%) of the title compound as an approximately 1:1 mixture of ketone and enol tautomers. 1H NMR (400 MHz, DMSO-d6) δ [Enol tautomer] 13.45 (s, 1H), 6.70 (s, 1H); [Ketone tautomer]-4.72 (s, 2H); [Aromatic protons] 8.72 (d, J=5.1 Hz, 1H), 8.62 (d, J=5.3 Hz, 1H), 8.47 (s, 1H), 8.30 (s, 1H), 8.26 (d, J=7.9 Hz, 1H), 8.16 (d, J=8.1 Hz, 1H), 8.13 (d, J=7.9 Hz, 1H), 7.96 (d, J=7.9 Hz, 1H), 7.76 (t, J=7.9 Hz, 1H), 7.70 (t, J=7.9 Hz, 1H), 7.56 (d, J=5.1 Hz, 1H), 7.33 (d, J=5.3 Hz, 1H).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH2:9]O)[CH2:4]1)[CH3:2].C(Br)(Br)(Br)[Br:12]>O1CCCC1>[Br:12][CH2:9][CH:5]1[CH2:6][CH2:7][CH2:8][N:3]([CH2:1][CH3:2])[CH2:4]1
Reactant: BrC(Br)(Br)Br
Reactant: CCN1CCCC(CO)C1
Solvent: C1CCOC1
Product: CCN1CCCC(CBr)C1
Reaction time: 8 h
Yield: 69.5 %

Procedure:
To mixture of (1-ethylpiperidin-3-yl)methanol (430 mg) and polymer bound triphenylphoshphine (2 g) in tetrahydrofuran (30 mL) was added carbon tetrabromide (1 g). The mixture was stirred for 8 hours before polymer bound triphenylphoshphine (1 g) and carbon tetrabromide (0.5 g) were added. The reaction was stirred overnight at room temperature. The mixture was filtered and evaporated and the residue was purified by silica column chromatography, eluting with a gradient of 0 to 5% 7M NH3/MeOH in dichloromethane to give the title compound as a yellow oil (430 mg, 69%).
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH:7]1[O:12][CH2:11][CH2:10][N:9]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:8]1)(=O)C.[OH-].[K+].C(O)C>O>[OH:4][CH2:5][CH2:6][CH:7]1[O:12][CH2:11][CH2:10][N:9]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:8]1
Reactant: CC(=O)OCCC1CN(C(=O)OCc2ccccc2)CCO1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(OCc1ccccc1)N1CCOC(CCO)C1
Yield: 70.9 %

Procedure:
A mixture of 2-(2-acetoxyethyl)-4-benzyloxycarbonylmorpholine (24.5 g), potassium hydroxide (8.9 g), ethanol (40 ml), and water (40 ml) is refluxed for 30 minutes and concentrated under reduced pressure. Water is added to the residue and the mixture is extracted with diethyl ether. The organic layer is washed with water, dried over sodium sulfate, and evaporated to give the title compound (15 g) as an oil.
Reaction SMILES: [C:1]1([P:7]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][C:20]=2[O:29]S(C(F)(F)F)(=O)=O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[SiH](Cl)Cl>C(N(CC)CC)C>[C:37]1([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][C:20]=2[OH:29])[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: O=P(c1ccccc1)(c1ccccc1)c1ccc2ccccc2c1-c1c(OS(=O)(=O)C(F)(F)F)ccc2ccccc12
Agent: Cl[SiH](Cl)Cl
Solvent: CCN(CC)CC
Product: Oc1ccc2ccccc2c1-c1c(P(c2ccccc2)c2ccccc2)ccc2ccccc12

Procedure:
More specifically, 1,1'-bi-2-naphthol 10 is reacted with trifluoromethanesulfonic acid anhydride to obtain 2,2'-bis(trifluoromethanesulfonyloxy)-1,1'-binaphthYl 11 which is then reacted with diphenylphosphine oxide in the presence of a palladium complex catalyst to obtain 2-diphenylphosphinyl-2'-trifluoromethanesulfonyloxy-1,1'-binaphthyl 12. The compound 12 is reduced by trichlorosilane in the presence of triethylamine and then hydrolyzed to obtain 2-diphenylphosphino-2'-hydroxy-l,l'-binaphthyl 13. The compound 13 is reacted with a separately synthesized chlorophosphite 14 in the presence of triethylamine to obtain phosphine compound 15 of the present invention.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[C@@H:6]3[C@@H:11]([CH2:12][CH2:13][C:4]=2[CH:3]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]3.[CH3:17]I>C1COCC1>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[C@@H:6]3[C@@H:11]([CH2:12][CH2:13][C:4]=2[CH:3]=1)[N:10]([CH3:17])[C:9](=[O:14])[CH2:8][CH2:7]3
Reactant: CI
Reactant: O=C1CC[C@@H]2c3ccc(Cl)cc3CC[C@H]2N1
Solvent: C1CCOC1
Product: CN1C(=O)CC[C@@H]2c3ccc(Cl)cc3CC[C@H]21
Reaction time: 13 h

Procedure:
Two hundred L of THF was added to a reactor, and 24.6 kg of (4aR)-(10bR)-8-chloro-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one was added. Then 35 kg of methyl iodide was added, rinsed in with 10 L of THF. A 79.6 kg portion of 50% aqueous sodium hydroxide was added in 13 minutes at 15°-25°, rinsed in with 40 L of THF. The mixture was stirred at 36°-39° for 13 hours, and was then cooled to 15°-25°. The layers were allowed to separate, and the water/THF phase was neutralized to pH 7 with hydrochloric acid and heated to reflux. Distillate was removed until the temperature reached 77°. A total of 154 kg of water was added from time to time. The solution was cooled over 3 hours to 3°-10°, and was then stirred vigorously at that temperature until solids began to form. Then the slurry was stirred gently at constant temperature for 3 hours. The slurry was filtered, and the vessel and filter cake were washed with cold water. The cake was air dried at 25°-35° for 75 hours no obtain 27.3 kg of the desired product, potency 85.1% by liquid chromatographic analysis.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([C:16]2[C:20]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[CH:19][N:18]([CH2:27][CH3:28])[N:17]=2)[C:10]=1[F:29])C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[CH2:27]([N:18]1[CH:19]=[C:20]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[C:16]([C:11]2[C:10]([F:29])=[C:9]([NH2:8])[CH:14]=[CH:13][C:12]=2[F:15])=[N:17]1)[CH3:28]
Reactant: CCn1cc(-c2ccncc2)c(-c2c(F)ccc(N(Cc3ccccc3)Cc3ccccc3)c2F)n1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCn1cc(-c2ccncc2)c(-c2c(F)ccc(N)c2F)n1
Reaction time: 7 h
Yield: 79 %

Procedure:
Dibenzyl-[3-(1-ethyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-2,4-difluoro-phenyl]-amine (2.35 g, 4.89 mmol) was dissolved in methanol (140 mL). 20% Palladium hydroxide on carbon (500 mg) was added and the reaction was stirred under hydrogen atmosphere (50 psi) for 7 h. A further addition of catalyst was made (500 mg) and hydrogenation was continued for 6 more hours. The reaction mixture was filtered over a Celite pad and then concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (DCM/methanol 95:5) to give 1.16 g of the desired product as a colourless foam (79% yield).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>C(#N)C.O>[N:10]1([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=2)[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: C1CNCCN1
Solvent: O
Solvent: CC#N
Product: N#Cc1ccc(N2CCNCC2)nc1
Temperature: 60 °C

Procedure:
6-Chloronicotinonitrile (500 mg, 3.61 mmole) and piperazine (930 mg, 10.8 mmole) were dissolved in 20 ml of acetonitrile and heated at 60° C. under N2 for 5 hours. The mixture was cooled to room temperature, diluted with water and extracted with dichloromethane (5×). The combined organics were dried over sodium sulfate, filtered, and concentrated to provide the title compound. 1H NMR (300 MHz, CDCl3) δ 8.40 (d, J=1.70 Hz, 1H) 7.60 (dd, J=8.81, 2.37 Hz, 1H) 6.59 (d, J=8.48 Hz, 1H) 3.57-3.75 (m, 4H) 2.91-3.05 (m, 4H); MS (M+H)+=189.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH:11]([C:13]1[O:14][C:15]([CH:18]2[CH2:20][CH2:19]2)=[N:16][N:17]=1)[OH:12])[CH2:9][CH3:10])(C)(C)C.[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25]>ClCCl>[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25].[NH2:7][CH:8]([CH2:9][CH3:10])[C@@H:11]([C:13]1[O:14][C:15]([CH:18]2[CH2:20][CH2:19]2)=[N:16][N:17]=1)[OH:12]
Reactant: CCC(NC(=O)OC(C)(C)C)C(O)c1nnc(C2CC2)o1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(N)[C@H](O)c1nnc(C2CC2)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of {1-[(5-cyclopropyl-[1,3,4]oxadiazol-2-yl)-hydroxy-methyl]-propyl}-carbamic acid tert-butyl ester (2.83 g, 9.95 mmol), trifluoro acetic acid (5 mL) in dichloromethane (20 mL) is stirred at room temperature for 2 hrs and concentrated to dryness under reduced pressure to give (S)-2-amino-1-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-butan-1-ol: compound with trifluoro-acetic acid.
Reaction SMILES: CO.[CH2:3]([O:10][C:11]([NH:13][C@H:14]([C:23]([OH:25])=[O:24])[CH2:15][S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.[C:27]1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH3:27][O:24][C:23](=[O:25])[C@H:14]([CH2:15][S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH:13][C:11]([O:10][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:12]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(N[C@@H](CSc1ccccc1)C(=O)O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)[C@H](CSc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 50 °C
Yield: 1974 %

Procedure:
In a nitrogen atmosphere, 150 ml of methanol was added to 30.01 g of N-benzyloxycarbonyl-S-phenyl-L-cysteine and 864 mg of p-toluenesulfonic acid monohydrate, and the reaction was allowed to proceed under reflux. After 6 reaction hours, the mixture was cooled to about 50° C., and the pH was adjusted to 5.5 by adding 8 ml of a 5% (by weight) aqueous solution of sodium hydrogen carbonate. Then, the methanol was replaced with toluene at about 50° C., to give 103.87 g of a toluene-substituted reaction mixture containing 30.97 g (concentration: 29.8% by weight; yield: 99%; optical purity: 99.7%) of N-benzyloxycarbonyl-S-phenyl-L-cysteine methyl ester (Example 4). Then, 15 ml of pure water was added to this toluene-substituted reaction mixture at room temperature, and the mixture was stirred for 15 minutes and then allowed to stand, whereupon the aqueous phase formed a large number of droplets, which remained dispersed or settled in the organic phase but did not unite with one another. This procedure thus failed to form two layers, namely the upper and lower layers, separable from each other, hence to enable phase separation (Reference Example 2).