Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([CH2:21][CH:22]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:23]([O:25]C)=[O:24])=[CH:15]2.[OH-].[Na+]>CO.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([CH2:21][CH:22]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:23]([OH:25])=[O:24])=[CH:15]2
Reactant: CCCCCCC(Cc1cc2cc(OCCCNc3ccccn3)ccc2[nH]1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCCC(Cc1cc2cc(OCCCNc3ccccn3)ccc2[nH]1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 891.9 %

Procedure:
To a solution of methyl 2-({5-[3-(2-pyridylamino)propoxy]indolyl}methyl)octanoate (0.04 g, 0.09 mmol), as prepared in the preceding step, in methanol (5.0 mL) was added a solution of NaOH (0.1 g, 2.5 mmol) in H2O (0.3 mL), and the reaction was stirred at ambient temperature overnight. After evaporating the solvent in vacuo, the residue is taken up in H12O (5 mL) and acidified to pH 4–5 with 10% HCl, and extracted with ethyl acetate (2×15 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography on silica gel (4% methanol in methylene chloride) to give the title compound as an oil (0.34 g, 90%). 1H-NMR (400 MHz, CDCl3) δ 7.72 (m, 1H), 7.48 (m, 1H), 7.26 (d, 8.9 Hz, 1H), 7.02 (d, J=2.7 Hz, 2H), 6.77 (dd, J=8.9, 2.4 Hz, 1H), 6.50 (m, 2H), 6.28 (d, J=2.9 Hz, 1H), 4.27 (dd, J=14.2, 8.6 Hz, 1H), 3.99 (m, 3H), 3.32 (t, J=6.7 Hz, 2H), 2.85 (br s, 1H), 1.95 (m, 2H), 1.67 (m, 1H), 1.30 (m, 9H), 0.84 (t, J=6.6 Hz, 3H). Mass spectrum (LCMS, ESI pos.) Calcd. for C25H33N3O3 424.2 (M+H); Found: 424.7.
Reaction SMILES: Cl[CH:2]([CH2:12][C:13]([Cl:16])([Cl:15])Cl)[C:3]([CH3:11])([CH3:10])[CH:4]([C:8]#[N:9])C(O)=O.C1(C)C=CC=CC=1>CN(C)C=O>[Cl:16][C:13]([Cl:15])=[CH:12][CH:2]1[C:3]([CH3:10])([CH3:11])[CH:4]1[C:8]#[N:9]
Reactant: CC(C)(C(Cl)CC(Cl)(Cl)Cl)C(C#N)C(=O)O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC1(C)C(C#N)C1C=C(Cl)Cl
Temperature: 145 °C
Reaction time: 6 h
Yield: 86.8 %

Procedure:
A solution of 4-chloro-2-cyano-3,3-dimethyl-6,6,6-trichlorohexanoic acid (6.14 g) in dimethyl formamide (12 ml) was stirred at 145° C. for 4 hours under an ammonia atmosphere at initially 5 bar pressure. After release of the pressure the mixture was stirred for another 6 hours at 145° C. After cooling, over 90% of the solvent was flashed off (bath temperature max. 60° C., pressure 12 mmHg). The residue was mixed with toluene and subsequently washed with aqueous hydrochloric acid and aqueous sodium bicarbonate. After drying of the organic phase the solvent was removed under reduced pressure to yield 3.3 g of the required 2-(2,2-dichlorovinyl)-3,3-dimethylcyclopropane nitrile (97% pure, 89% yield).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]([CH2:25][CH2:26][N:27]([CH2:33][C@H:34]([OH:37])[CH2:35][OH:36])[CH2:28][C@H:29]([OH:32])[CH2:30][OH:31])[CH2:20][C@H:21]([OH:24])[CH2:22][OH:23])=[CH:15][CH:14]=1)=O)(C)(C)C.[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]>ClCCl>[F:41][C:40]([F:43])([F:42])[C:38]([OH:44])=[O:39].[F:41][C:40]([F:43])([F:42])[C:38]([OH:44])=[O:39].[OH:32][C@H:29]([CH2:30][OH:31])[CH2:28][N:27]([CH2:26][CH2:25][N:19]([C:16]1[CH:17]=[CH:18][C:13]([CH2:12][CH2:11][CH2:10][CH2:9][NH2:8])=[CH:14][CH:15]=1)[CH2:20][C@H:21]([OH:24])[CH2:22][OH:23])[CH2:33][C@H:34]([OH:37])[CH2:35][OH:36]
Reactant: CC(C)(C)OC(=O)NCCCCc1ccc(N(CCN(C[C@H](O)CO)C[C@H](O)CO)C[C@H](O)CO)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCCCc1ccc(N(CCN(C[C@H](O)CO)C[C@H](O)CO)C[C@H](O)CO)cc1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 80 %

Procedure:
Dichloromethane (2 mL) was added to the protected amine 670 (0.27 g, 0.5 mmol) followed by addition of TFA (5 mL). The mixture was stirred at room temperature for 25 min. The solvent was removed under reduced pressure. The residue was dissolved in methanol and the solvent was removed again under reduced pressure. The residue was dried under vacuum overnight to afford the compound 680 (0.31 g, 80%) as a clear oil. 1H NMR (300 MHz, CD3OD) δ 1.66 (m, 4H), 2.59 (m, 2H), 2.92 (m, 2H), 3.15-4.10 (m, 20H), 6.78 (d, 2H), 6.98 (d, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)=[CH:4][C:3]=1[O:14][CH3:15].Cl.[CH3:17][NH:18][O:19][CH3:20].CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([N:18]([O:19][CH3:20])[CH3:17])=[O:11])=[CH:4][C:3]=1[O:14][CH3:15]
Reactant: CNOC
Reactant: COc1cc(C(C)(C)C(=O)O)ccc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(C)(C)C(=O)N(C)OC)ccc1F
Reaction time: 5 h

Procedure:
To a solution of 2-(4-fluoro-3-methoxyphenyl)-2-methylpropanoic acid (114.75 g, 4.71 mmol) in DCM (2 L) was added N,O-dimethylhydroxylamine hydrochloride (79 g, 0.81 mol), EDCI (145 g, 0.72 mol), DMAP (33 g, 0.27 mol), and DIPEA (471 mL, 2.7 mol). The resulting mixture was stirred 5 h and quenched with H2O (1 L). The organic layer was washed with 1N HCl (1 L×2), satd NaHCO3 (1 L), and brine (1 L) successfully. The organic phase was dried over MgSO4 and concentrated at reduced pressure to afford 2-(4-fluoro-3-methoxyphenyl)-N-methoxy-N,2-dimethylpropanamide as yellow color oil (123 g, 89%). 1H NMR (400 MHz, CDCl3): δ 7.03 (t, 1H), 6.83 (d, 1H), 6.80 (m, 1H), 3.89 (s, 3H), 3.12 (s, 3H), 2.77 (s, 3H), 1.53 (s, 6H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](/[C:7](/[CH3:14])=[CH:8]\[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:2]=1>C(O)C.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([CH3:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:2]=1
Reactant: CCOC(=O)/C=C(/C)c1cccnc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC(C)c1cccnc1
Yield: 95.5 %

Procedure:
Ethyl 3-(3-pyridyl)crotonate (13.2 g) was hydrogenated in ethanol (130 ml) at 270 kPa with 10% palladium on charcoal catalyst for 3 hours at room temperature to give ethyl 3-(3-pyridyl)butyrate (12.74 g), b.p. 74°-80°/0.15 mmHg.
Reaction SMILES: P(Cl)(Cl)Cl.[F:5][C:6]1[CH:23]=[CH:22][C:9]([CH2:10][O:11][C:12]2[CH:13]=[N+:14]([O-])[CH:15]=[CH:16][C:17]=2[N+:18]([O-:20])=[O:19])=[CH:8][CH:7]=1.[OH-].[Na+]>C(OCC)(=O)C>[F:5][C:6]1[CH:23]=[CH:22][C:9]([CH2:10][O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][C:17]=2[N+:18]([O-:20])=[O:19])=[CH:8][CH:7]=1
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1OCc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClP(Cl)Cl
Product: O=[N+]([O-])c1ccncc1OCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Phosphorus trichloride (3.65 ml, 41.80 mmol) was slowly added at 0° C. to a solution of 3-(4-fluorobenzyloxy)-4-nitropyridin-N-oxide (7.72 g, 27.87 mmol) prepared in Step 3 in 500 ml of ethyl acetate. The reaction mixture was stirred for 1 hour at room temperature and then alkalized with 2N sodium hydroxide solution. The separated organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was used in the subsequent step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:17][C@H:16]([S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]([F:30])([F:29])[F:28])(=[O:20])=[O:19])[CH2:15][C@H:14]3[C:31]([OH:33])=O)=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:34][C@@H:35]([CH2:44][CH2:45][CH3:46])[C@H:36]([OH:43])[C:37]([NH:39][CH:40]1[CH2:42][CH2:41]1)=[O:38]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]([N:13]3[CH2:17][C@H:16]([S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]([F:28])([F:29])[F:30])(=[O:19])=[O:20])[CH2:15][C@H:14]3[C:31]([NH:34][C@@H:35]([CH2:44][CH2:45][CH3:46])[C:36](=[O:43])[C:37]([NH:39][CH:40]3[CH2:42][CH2:41]3)=[O:38])=[O:33])=[O:12])[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: CCC[C@H](N)[C@H](O)C(=O)NC1CC1
Reactant: O=C(O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=O)C1(c2ccc(Cl)cc2)CC1
Product: CCC[C@H](NC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=O)C1(c2ccc(Cl)cc2)CC1)C(=O)C(=O)NC1CC1

Procedure:
The title compound was prepared in analogy to Example 1, using (2S,4R)-1-[1-(4-chloro-phenyl)-cyclopropanecarbonyl]-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid and (2S,3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide in step 1. MS (m/e)=668.18 [M+H+].
Reaction SMILES: O=[C:2]1[NH:7][CH:6]=[N:5][C:4]2[S:8][C:9]3[CH2:13][N:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:11][C:10]=3[C:3]1=2.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:2]1[C:3]2[C:10]3[CH2:11][N:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)N1Cc2sc3nc[nH]c(=O)c3c2C1
Product: CCOC(=O)N1Cc2sc3ncnc(Cl)c3c2C1
Yield: 67 %

Procedure:
In analogy to Example 11A, ethyl 4-oxo-3,4,5,7-tetrahydro-6H-pyrrolo[3′,4′:4,5]thieno[2,3-d]pyrimidine-6-carboxylate from Example 20A (1.70 g, 6.41 mmol) was reacted with phosphoryl chloride to yield 1.23 g (67%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:14]O>Cl>[F:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([O:6][CH3:14])=[O:5]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Reactant: CO
Agent: Cl
Product: COC(=O)c1cc([N+](=O)[O-])ccc1F
Yield: 99 %

Procedure:
A solution of 2-fluoro-5-nitrobenzoic acid (200 mg, 1.08 mmol) in 0.7 M HCl in methanol was stirred for 5 h. The mixture was concentrated yielding 210 mg (99%) of the title compound; which was used without further purification.
Reaction SMILES: [OH-].[K+].[CH:3]1[C:8]([NH2:9])=[CH:7][CH:6]=[C:5]([OH:10])[CH:4]=1.[CH3:11][N:12]1[C:16](S(C)(=O)=O)=[N:15][C:14]([C:21]([F:24])([F:23])[F:22])=[N:13]1>CS(C)=O>[CH3:11][N:12]1[C:16]([O:10][C:5]2[CH:6]=[CH:7][C:8]([NH2:9])=[CH:3][CH:4]=2)=[N:15][C:14]([C:21]([F:24])([F:23])[F:22])=[N:13]1
Reactant: Nc1ccc(O)cc1
Reactant: Cn1nc(C(F)(F)F)nc1S(C)(=O)=O
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Cn1nc(C(F)(F)F)nc1Oc1ccc(N)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
8 g of pulverised KOH are added to 10.9 g of p-aminophenol in 120 ml of dimethyl sulfoxide, and the mixture is stirred for 1/2 hour. Then 22.9 g of 1-methyl-3-trifluoromethyl-5-methylsulfonyl-1H-1,2,4-triazole are added, the reaction mixture is stirred for a further 2 hours and subsequently poured into 1 liter of ice water. The precipitated product is isolated by filtration, washed with water and dried. Yield: 19.6 g (76% of theory). Melting point: 111°14 112° C.
Reaction SMILES: CCN(C(C)C)C(C)C.F[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:14]([NH:20][C:21]2[N:26]=[C:25]([C:27]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:29]([CH3:36])[CH:28]=3)[CH:24]=[CH:23][N:22]=2)=[C:13]([O:37][CH3:38])[CH:12]=1.[CH3:39][N:40]1[CH2:44][C@@H:43]2[NH:45][CH2:46][CH2:47][C@@H:42]2[CH2:41]1>FC(F)(F)CO>[CH3:39][N:40]1[CH2:41][C@@H:42]2[C@@H:43]([N:45]([C:11]3[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:14]([NH:20][C:21]4[N:26]=[C:25]([C:27]5[C:35]6[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=6)[N:29]([CH3:36])[CH:28]=5)[CH:24]=[CH:23][N:22]=4)=[C:13]([O:37][CH3:38])[CH:12]=3)[CH2:46][CH2:47]2)[CH2:44]1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Reactant: CN1C[C@H]2CCN[C@H]2C1
Solvent: CCN(C(C)C)C(C)C
Solvent: OCC(F)(F)F
Product: COc1cc(N2CC[C@@H]3CN(C)C[C@@H]32)c([N+](=O)[O-])cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Temperature: 140 °C
Yield: 84.3 %

Procedure:
DIPEA (0.411 mL, 2.36 mmol) was added to a suspension of N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3-yl)pyrimidin-2-amine (Intermediate 129, 425 mg, 0.94 mmol) and (3aR,6aR)-5-methyl-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-b]pyrrole (Intermediate 37, 250 mg, 1.98 mmol) in 2,2,2-trifluoroethanol (4 mL). The mixture was heated in a microwave at 140° C. for 1 h. The cooled mixture was then purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M methanolic ammonia and concentrated in vacuo. Further purification by FCC, eluting with 0-5% 7N methanolic ammonia in CH2Cl2 gave impure title compound (396 mg, 84%) as an orange/red solid. This solid was dissolved in the minimum amount of CH2Cl2 and the resulting solution was triturated with methanol. The resulting solid was collected by filtration to give the title compound (272 mg, 58%) as a red solid which was used without further purification; 1H NMR: 1.86 (1H, dd), 1.94-2.06 (1H, m), 2.12 (3H, s), 2.23 (1H, dd), 2.36-2.45 (2H, m), 2.52-2.58 (1H, m) partially obscured by DMSO peak, 2.91-3.04 (1H, m), 3.18 (1H, t), 3.49 (1H, td), 3.87 (3H, s), 3.95 (3H, s), 4.40 (1H, t), 6.61 (1H, s), 7.11 (1H, t), 7.18 (1H, d), 7.24 (1H, t), 7.51 (1H, d), 8.02 (1H, s), 8.27-8.31 (2H, m), 8.34 (1H, d), 8.51 (1H, s); m/z: ES+ MH+ 500.17.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C@@H:7]2[N:22]([CH3:23])[C@H:11]([CH2:12][C:13]=1OS(C(F)(F)F)(=O)=O)[CH2:10][N:9]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:8]2)=[O:5])[CH3:2].[Cl:31][C:32]1[C:37]([F:38])=[CH:36][CH:35]=[C:34]([F:39])[C:33]=1[C:40]1[CH:44]=[C:43]([CH2:45][O:46][C:47]2[CH:52]=[CH:51][C:50](B3OC(C)(C)C(C)(C)O3)=[CH:49][N:48]=2)[O:42][N:41]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=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>[CH2:1]([O:3][C:4]([C:6]1[C@@H:7]2[N:22]([CH3:23])[C@H:11]([CH2:12][C:13]=1[C:50]1[CH:49]=[N:48][C:47]([O:46][CH2:45][C:43]3[O:42][N:41]=[C:40]([C:33]4[C:34]([F:39])=[CH:35][CH:36]=[C:37]([F:38])[C:32]=4[Cl:31])[CH:44]=3)=[CH:52][CH:51]=1)[CH2:10][N:9]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:8]2)=[O:5])[CH3:2]
Reactant: CC1(C)OB(c2ccc(OCc3cc(-c4c(F)ccc(F)c4Cl)no3)nc2)OC1(C)C
Reactant: CCOC(=O)C1=C(OS(=O)(=O)C(F)(F)F)C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]1N2C
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: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CCOC(=O)C1=C(c2ccc(OCc3cc(-c4c(F)ccc(F)c4Cl)no3)nc2)C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]1N2C
Temperature: 80 °C
Reaction time: 1 h
Yield: 81.4 %

Procedure:
(rac.)-(1R*,5S*)-9-Methyl-7-trifluoromethanesulfonyloxy-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6-dicarboxylic acid 3-tert-butyl ester 6-ethyl ester (WO 2003/093267; 1.00 g, 2.18 mmol) and 2-[3-(2-chloro-3,6-difluoro-phenyl)-isoxazol-5-ylmethoxy]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (1.41 g, 3.27 mmol) were dissolved in DME (14.5 mL), and aq. 2M Na2CO3 (11.0 mL) was added. The mixture was degassed with N2 (5 min). Pd(PPh3)4 (126 mg, 0.109 mmol) was added, and the mixture was rapidly heated to 80° C. The mixture was stirred at this temperature for 1 h, and was allowed to cool to rt. The mixture was diluted with EtOAc (100 mL), and was washed with water (100 mL). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC(CH2Cl2/MeOH 95:5) yielded the title compound (1.12 g, 81%). LC-MS: tR=0.91 min; ES+: 631.34.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[H][H]>CC(O)C>[C:4]1([C@@H:1]([OH:3])[CH3:2])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Reactant: [H][H]
Solvent: CC(C)O
Product: C[C@H](O)c1ccccc1
Reaction time: 14 h
Yield: 97 %

Procedure:
Chiral hydrogenation of acetophenone was carried out (see formula (8) below). That is, a reaction was carried out in accordance with the procedures of Example 4 using the (R,RR)-ruthenium hydride complex (45.3 mg; 0.0425 mmol) synthesized in Example 1 and using acetophenone (102.1 g; 0.85 mol) as the substrate and 2-propanol (100 mL) as the solvent. However, the hydrogen pressure was set to 10 atmosphere, the reaction temperature was set to 22˜41° C., and the reaction time was set to 14 hours. As a result, (S)-1-phenylethanol was obtained at a conversion rate of 99.8%, isolation yield of 97% (100.7 g; 0.82 mol), and enantiomeric excess of 81%.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[C:15]([CH2:17][OH:18])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[C:19]([F:22])([F:21])[F:20].[Br-].[CH2:24]([Zn+])[CH:25]([CH3:27])[CH3:26].C1COCC1>Cl>[CH2:24]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[C:15]([CH2:17][OH:18])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[C:19]([F:22])([F:21])[F:20])[CH:25]([CH3:27])[CH3:26]
Reactant: OCc1ccc2nc(-c3ccc(Cl)c(C(F)(F)F)c3)oc2c1
Reactant: CC(C)C[Zn+]
Agent: Cl
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(C)Cc1ccc(-c2nc3ccc(CO)cc3o2)cc1C(F)(F)F
Temperature: 100 °C

Procedure:
A mixture of [2-(4-chloro-3-trifluoromethyl-phenyl)-benzooxazol-6-yl]-methanol (1 eq) and Pd(PBut3)2 (0.05 eq) is treated with isobutyl zinc bromide in THF (0.5 M, 3 eq). The resulting mixture is heated at 100° C. in microwave for 30 minutes. The reaction mixture is diluted with aqueous HCl (5%) and extracted with EtOAc. The organic solution is washed with brine and dried over Na2SO4. After concentration, the residue is purified by flash column chromatography (30% EtOAc in hexane) to give the desired intermediate [2-(4-isobutyl-3-trifluoromethyl-phenyl)-benzooxazol-6-yl]-methanol. MS: (ES+): 350.1 (M+1)+.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([O:22]C(C)(C)C)=[O:21])=[CH:14][CH:13]=3)=[C:9]([C:27]3[CH:32]=[CH:31][C:30]([O:33]C)=[CH:29][CH:28]=3)[S:8][C:7]=2[CH:35]=1.B(Br)(Br)Br>C(Cl)Cl.CO>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([OH:22])=[O:21])=[CH:14][CH:13]=3)=[C:9]([C:27]3[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=3)[S:8][C:7]=2[CH:35]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2Oc2ccc(/C=C/C(=O)OC(C)(C)C)cc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: O=C(O)/C=C/c1ccc(Oc2c(-c3ccc(O)cc3)sc3cc(O)ccc23)cc1
Temperature: 0 °C
Reaction time: 1.67 h
Yield: 50 %

Procedure:
To a solution of (E)-tert-butyl 3-(4-((6-methoxy-2-(4-methoxyphenyl)-benzo[b]thiophen-3-yl)oxy)phenyl)acrylate (40 mg, 0.08 mmol) in DCM (2.5 mL) at 0° C. was added BBr3 (1.0 M in DCM, 0.33 mL, 0.33 mmol) dropwise, a solid immediately precipitated from the solution. The resulting mixture was stirred at 0° C. for 100 min after which the reaction was quenched by addition of sat. aq. NaHCO3 (4 mL) solution and a white precipitate was observed. The aqueous layer was then extracted with 5% MeOH/EtOAc (4×12 mL) and the combined organic layers were passed through a phase separator to remove water and concentrated in vacuo to afford the crude product which was dissolved in MeOH (2 mL) and purified by reverse phase HPLC (neutral condition, 3% 1-propanol in 1-100% CH3CN/H2O) to afford (E)-3-(4-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (17.5 mg, 0.04 mmol, 53% yield). LC/MS (m/z, MH+): 405.0790.
Reaction SMILES: Cl.Cl.Cl.[N:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][NH2:19])[CH2:12][CH2:11]1.[F:20][C:21]1[CH:22]=[C:23]([C@@H:28]2[C:33]([C:34](O)=[O:35])=[C:32]([CH3:37])[NH:31][C:30](=[O:38])[NH:29]2)[CH:24]=[CH:25][C:26]=1[F:27]>>[N:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][NH:19][C:34]([C:33]2[C@@H:28]([C:23]3[CH:24]=[CH:25][C:26]([F:27])=[C:21]([F:20])[CH:22]=3)[NH:29][C:30](=[O:38])[NH:31][C:32]=2[CH3:37])=[O:35])[CH2:14][CH2:15]1
Reactant: NCCCN1CCC(c2ccccn2)CC1
Reactant: CC1=C(C(=O)O)[C@@H](c2ccc(F)c(F)c2)NC(=O)N1
Agent: Cl
Product: CC1=C(C(=O)NCCCN2CCC(c3ccccn3)CC2)[C@@H](c2ccc(F)c(F)c2)NC(=O)N1

Procedure:
3-(3′,4′,5′,6′-Tetrahydro-2′H-[2,4′]bipyridinyl-1′-yl)-propylamine trihydrochoride was used in place of 2-[1-(3-amino-propyl)-piperidine-4-yl]-5-fluoro-benzonitrile dihydrochloride and (4R)-4-(3,4-difluorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid was used in place of (4R)-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[NH:13]1[CH:17]=[CH:16][N:15]=[C:14]1CCCN>C1(C)C=CC=CC=1>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:6][CH2:7][CH2:1][CH2:11][N:15]1[CH:16]=[CH:17][N:13]=[CH:14]1)=[O:4]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: NCCCc1ncc[nH]1
Solvent: Cc1ccccc1
Product: Nc1ccccc1C(=O)NCCCn1ccnc1
Temperature: 90 °C

Procedure:
A mixture of 2.93 g of isatoic anhydride, 2.50 g of 1H-imidazole-propanamine and 30 ml of toluene was heated at 90° C. for 45 minutes and cooled. The toluene layer was decanted and the residue was dissolved in methylene chloride, washed with dilute sodium hydroxide solution, water and dried over magnesium sulfate. The organic layer was concentrated to obtain the desired product, mp 107°-110° C.
Reaction SMILES: [C:1]([C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Cl:17][C:18]1[CH:19]=[C:20]([CH2:24][CH2:25][NH2:26])[CH:21]=[CH:22][CH:23]=1>>[Cl:17][C:18]1[CH:19]=[C:20]([CH2:24][CH2:25][NH:26][CH2:13][C:12]2[CH:15]=[CH:16][C:9]([C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:10][CH:11]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: NCCc1cccc(Cl)c1
Reactant: CCCCCCC#Cc1ccc(C=O)cc1
Product: CCCCCCC#Cc1ccc(CNCCc2cccc(Cl)c2)cc1
Yield: 62 %

Procedure:
The same procedure as employed in the preparation of Example 1 (step a) but using 4-oct-1-ynylbenzaldehyde and [2-(3-chlorophenyl)ethyl]amine gave the title compound as a colorless oil (62%). 1H NMR (CDCl3, 300 MHz) δ 7.26 (d, J=8.3 Hz, 2H), 7.19-7.08 (m, 5H), 7.03-6.96 (m, 1H), 3.71 (s, 2H), 2.83-2.67 (m, 2H), 2.32 (t, J=7.2 Hz, 2H), 1.63-1.44 to (m, 2H), 1.44-1.31 (m, 2H), 1.31-1.15 (m, 6H), 0.83 (t, J=8.3 Hz, 3H). M+(LC/MS(ESI)): 354.4. HPLC (Condition A), Rt: 4.31 min (HPLC purity: 97.5%).
Reaction SMILES: [C:1]([N:3]=[C:4](OCC)[CH3:5])#[N:2].Cl.[NH2:10][CH2:11][CH2:12][C:13]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:17]([C:18](=[O:23])[C@@H:19]([O:21][CH3:22])[CH3:20])[N:16]=[C:15]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[F:31])[S:14]1.C(N(C(C)C)CC)(C)C>CCO.C([O-])([O-])=O.[Na+].[Na+]>[C:1]([N:3]=[C:4]([NH:10][CH2:11][CH2:12][C:13]1([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:17]([C:18](=[O:23])[C@@H:19]([O:21][CH3:22])[CH3:20])[N:16]=[C:15]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[F:31])[S:14]1)[CH3:5])#[N:2]
Reactant: CO[C@@H](C)C(=O)N1N=C(c2cc(F)ccc2F)SC1(CCN)c1ccccc1
Reactant: CCOC(C)=NC#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CO[C@@H](C)C(=O)N1N=C(c2cc(F)ccc2F)SC1(CCNC(C)=NC#N)c1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 73 %

Procedure:
Preparation of N′-cyano-N-(2-(5-(2,5-difluorophenyl)-3-((S-2-methoxypropanoyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)ethyl)acetamidine: To a solution of ethyl N-cyanoacetimidate (0.025 g, 0.22 mmol) and (2S)—(2-(2-aminoethyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one hydrochloride (0.018 g, 0.038 mmol) in EtOH (0.3 mL) was added diisopropylethylamine (0.033 mL, 0.19 mmol). After stirring at room temperature for 14 hours, the mixture was diluted with 10% Na2CO3 (30 mL) and extracted with dichloromethane. The combined organics were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was chromatographed (3% MeOH in dichloromethane) to provide the product as a mixture of diastereomers (13.0 mg, 73% yield). MS ESI (+) m/z 472 (M+1) detected; 1H NMR (400 MHz, CDCl3) δ 7.51 (m, 2H), 7.37 (m, 6H), 7.33 (m, 4H), 7.16 (m, 4H), 6.93 (br. t, 1H, J=4.7 Hz), 6.73 (br. t, 1H, J=4.7 Hz), 4.73 (m, 2H), 4.00 (m, 2H), 3.45-3.29 (m, 9H), 3.21 (m, 1H), 2.82 (m, 1H), 2.75 (m, 1H), 2.16 (s, 3H), 2.15 (s, 3H), 1.46 (d, 3H, J=6.3 Hz), 1.43 (d, 3H, J=7.0 Hz).