Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1(/[C:6](/[N:10]2[CH:14]=[C:13]([C:15]3[C:16]4[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:17]=4[N:18]=[CH:19][N:20]=3)[CH:12]=[N:11]2)=[CH:7]/[C:8]#[N:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.O=O.[H][H]>>[CH:1]1([CH:6]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]4[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:31])[CH3:30])[C:17]=4[N:18]=[CH:19][N:20]=3)[CH:12]=[N:11]2)[CH2:7][C:8]#[N:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(/C(=C\C#N)C4CCCC4)c3)ncnc21
Reactant: [H][H]
Agent: O=O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)C4CCCC4)c3)ncnc21
Temperature: 25 °C

Procedure:
General screening procedure for asymmetric hydrogenation using the substrate, (Z)-3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)acrylonitrile (19), to afford optically enriched product, 3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile ((R)-20 or (S)-20): A 300 mL-volume autoclave with glass vial (20 mL) was charged with the substrate (19), the catalyst (metal, ligand, and catalyst precursor), and oxygen-free solvent (4-6 mL) under nitrogen. This autoclave was charged with hydrogen gas to the desired pressure and stirred at room temperature or heated with oil bath. After hydrogen gas was released, the reaction mixture was concentrated under reduced pressure. The residue was purified by eluting through a silica gel pad using a mixture of ethyl acetate and methanol (v/v=9/1) to afford product, 3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile ((R)-20 or (S)-20), for chemical conversion (HPLC and chiral HPLC), LC/MS and NMR spectroscopy and enantiomeric excess (% ee by chiral HPLC) determination.
Reaction SMILES: [N+](=[C:3]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1)[C:4]([O:6][CH3:7])=[O:5])=[N-].[OH:23][CH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>C(Cl)Cl.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[O:27]1[CH2:28][CH2:29][CH:24]([O:23][CH:3]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)(=[O:16])=[O:15])=[CH:10][CH:9]=2)[C:4]([O:6][CH3:7])=[O:5])[CH2:25][CH2:26]1
Reactant: COC(=O)C(=[N+]=[N-])c1ccc(S(=O)(=O)C2CCOCC2)cc1
Reactant: OC1CCOCC1
Agent: [Rh]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)C(OC1CCOCC1)c1ccc(S(=O)(=O)C2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.4 %

Procedure:
Methyl 2-diazo-2-(4-tetrahydropyran-4-ylsulfonylphenyl)acetate (4.0 g, 12.34 mmol) was dissolved in DCM (40 mL) under argon atmosphere. To this solution, 4-hydroxy tetrahydropyran (1.5 g, 14.8 mmol) was added followed by rhodium (II) acetate dimer (0.109 g, 0.24 mmol). Mixture was stirred at 25° C. for 30 min. Reaction mixture was diluted with DCM (10 mL), organic layer was washed with water followed by brine solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product as methyl 2-tetrahydropyran-4-yloxy-2-(4-tetrahydropyran-4-ylsulfonylphenyl)acetate (4.1 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]([O:15][C@@H:16]3[O:33][C@H:32]([CH2:34][O:35][C:36](=[O:38])[CH3:37])[C@@H:27]([O:28][C:29](=[O:31])[CH3:30])[C@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]3[O:18][C:19](=[O:21])[CH3:20])=[N:11][NH:12][C:13]=2[CH3:14])=[CH:4][CH:3]=1.[F:39][C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1.[F-].[Cs+]>COCCOC.C(O)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>[F:39][C:40]1[CH:45]=[CH:44][C:43]([C:2]2[CH:3]=[CH:4][C:5]([CH2:8][C:9]3[C:10]([O:15][C@@H:16]4[O:33][C@H:32]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[C@@H:34]([O:35][C:36](=[O:38])[CH3:37])[C@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]4[O:18][C:19](=[O:21])[CH3:20])=[N:11][NH:12][C:13]=3[CH3:14])=[CH:6][CH:7]=2)=[CH:42][CH:41]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C)c2Cc2ccc(Br)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C)c2Cc2ccc(-c3ccc(F)cc3)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 85 °C
Reaction time: 18 h
Yield: 60.1 %

Procedure:
A mixture of 4-[(4-bromophenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole (0.099 g), 4-fluorophenylboronic acid (0.046 g), cesium fluoride (0.050 g) and tetrakis(triphenylphosphine)palladium(0) (0.0038 g) in 1,2-dimethoxyethane (1.3 mL), ethanol (0.3 mL) and water (0.3 mL) was stirred at 85° C. for 18 hours. The reaction mixture was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=1/1-1/2-1/5) to give 4-{[4-(4-fluorophenyl)phenyl]methyl}-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole (0.061 g).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[C:11]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])=[CH:12][S:13][CH:14]=1>C(O)(=O)C>[Cl:1][C:12]1[S:13][CH:14]=[C:10]([Cl:9])[C:11]=1[NH:15][C:16](=[O:21])[C:17]([F:18])([F:20])[F:19]
Reactant: O=C(Nc1cscc1Cl)C(F)(F)F
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Product: O=C(Nc1c(Cl)csc1Cl)C(F)(F)F
Reaction time: 0.58 h

Procedure:
A solution of 1.4 g of N-chlorosuccinimide in 25 ml of glacial acetic acid was added dropwise with stirring to a solution of 2.3 g of 4-chloro-3-trifluoroacetylaminothiophene in 60 ml of glacial acetic acid, the mixture was stirred at 40–45° C. for a further 35 minutes and the solvent was distilled off. The residue was admixed with water and extracted with ethyl acetate, the organic phase was washed with water and dried over sodium sulfate, and the solvent was distilled off. The residue was purified by column chromatography on silica gel using a mixture of 10 parts by volume of toluene and 2 parts by volume of n-heptane, and removed from the still unconverted monochloro compound.
Reaction SMILES: [CH3:1][O:2]C(OC)OC.[CH3:8][C:9]1[NH:13][C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][CH:10]=1>C(O)(C(F)(F)F)=O>[CH:1]([C:10]1[CH:11]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[NH:13][C:9]=1[CH3:8])=[O:2]
Reactant: CCOC(=O)c1ccc(C)[nH]1
Reactant: COC(OC)OC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc(C=O)c(C)[nH]1
Reaction time: 0.17 h

Procedure:
Trimethoxymethane (1.18 ml, 10.78 mmol) was added to a solution of ethyl 5-methyl-1H-pyrrole-2-carboxylate (Intermediate 20) (0.5 g, 3.26 mmol) in TFA (2.5 ml) at 0° C. The reaction was stirred at that temperature for 10 mins then quenched with cold water (20 ml). The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were dried over magnesium sulfate and concentrated to give yellow solid which was purified by flash chromatography (10% to 20% EtOAc in hexanes, 0.25 g).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].Cl[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1>CN(C=O)C>[N:1]1([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(-n2ccnc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.7 %

Procedure:
9.5 g of imidazole were dissolved in 100 ml of DMF, and the resultant solution was further added with 6.1 g of 60% NaH while cooling it with ice. The solution was then stirred for 30 min. and further for 1 hour at room temperature. Then, the solution was added with 20.0 g of 4-chloronitrobenzene and then stirred for 2 hours at a temperature of from 80 to 85° C. The solution reacted was poured into ice water, and the crystals precipitated was filtered and then dried to obtain 22.5 g of 4-(imidazole-1-yl)nitrobenzene.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[C:25]([F:31])[C:26]([Cl:30])=[CH:27][CH:28]=4)[NH:23][C:22]3=[O:32])[CH:13]2[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=2[F:40])=[O:11])=[CH:5][CH:4]=1)#[N:2].[OH:41]O.[OH-].[Na+]>CS(C)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[C:25]([F:31])[C:26]([Cl:30])=[CH:27][CH:28]=4)[NH:23][C:22]3=[O:32])[CH:13]2[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=2[F:40])=[O:11])=[CH:7][CH:8]=1)(=[O:41])[NH2:2]
Reactant: OO
Reactant: CC(C)(C)CC1NC(C(=O)Nc2ccc(C#N)cc2)C(c2cccc(Cl)c2F)C12C(=O)Nc1c2ccc(Cl)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C(N)=O)cc2)C(c2cccc(Cl)c2F)C12C(=O)Nc1c2ccc(Cl)c1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
To the solution of rac-(2′S,3′S,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-7-fluoro-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-phenyl)-amide (0.12 g, 0.2 mmol) prepared in Example 175 in DMSO (2 mL) at 0° C. was added an aqueous solution (30% Aldrich) of H2O2 (0.34 g, 3 mmol), then aqueous solution (1N) of NaOH (1 mL, 1 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 1 h. The mixture was partitioned between ethyl acetate and saturated aqueous Na2SO3 solution. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-7-fluoro-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-carbamoyl-phenyl)-amide as a light yellow solid (Yield 0.11 g, 93%)
Reaction SMILES: C[O:2][C:3]1[C:12]([CH3:13])=[C:11]2[C:6]([CH:7]=[C:8]([C:18]([O:20][CH2:21]C)=[O:19])[CH:9]([C:14]([F:17])([F:16])[F:15])[O:10]2)=[CH:5][CH:4]=1.B(Br)(Br)Br.CO>C(Cl)Cl>[OH:2][C:3]1[C:12]([CH3:13])=[C:11]2[C:6]([CH:7]=[C:8]([C:18]([O:20][CH3:21])=[O:19])[CH:9]([C:14]([F:17])([F:15])[F:16])[O:10]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)C1=Cc2ccc(OC)c(C)c2OC1C(F)(F)F
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C1=Cc2ccc(O)c(C)c2OC1C(F)(F)F
Temperature: -78 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
The ethyl 7-methoxy-8-methyl-2-(trifluoromethyl)-2H-chromene-3-carboxylate from Example 3a, Step 2 (3.0 g, 9.49 mmole) was dissolved in methylene chloride (120 mL). The solution was chilled to −78° C. and BBr3 (94.9 mL, 1 M solution in CH2Cl2) was added slowly to the above solution. The reaction was slowly warmed to room temperature and stirred overnight. The reaction was cooled to −78° C. and MeOH (30 mL) added in. After the solution was stirred at room temperature for 2 h, the reaction was evaporated to dryness to give a brownish solid having ca.90% purity. The crude product was further purified by passing through a silica plug to give a yellow solid (2.7 g, 80%): LCMS m/z 311.05 (M+Na). 1H NMR (acetone-d6/400 MHz) 9.11 (s, 1H), 7.75 (s, 1H), 7.11(d, 1H, J=8.4 Hz), 6.59 (d, 1H, J=8.4 Hz), 5.78 (q, 1H, J=6 Hz), 3.79 (s, 3H), 2.09(s, 3H).
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([C:6]([NH2:11])=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)O1.ClCCl.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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]>[NH2:11][C:6]1[C:5]2=[CH:4][CH:3]=[C:2]([C:20]3[CH:21]=[CH:22][C:23]([N:26]4[CH2:27][CH2:28][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:30][CH2:31]4)=[CH:24][CH:25]=3)[N:10]2[N:9]=[CH:8][N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Nc1ncnn2c(Br)ccc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3ccc4c(N)ncnn34)cc2)CC1
Temperature: 80 °C
Yield: 82.3 %

Procedure:
To a stirred suspension of 7-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine (801 mg, 3.76 mmol), tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]tetrahydro-1(2H)-pyrazinecarboxylate (2.19 g, 5.64 mmol), and [1,1′-bis(diphenylphosphino)-ferrocene]dichloro palladium(II)-complex with dichloromethane (275 mg, 0.38 mmol) in degassed DME (25 mL) was added aqueous Na2CO3 solution (2 M, 5.6 mL). The reaction was heated at 80° C. for 17 h and then cooled to rt. The mixture was filtered through a pad of Celite® using ethyl acetate. The filtrate was washed with water (75 mL), dried (Na2SO4), and concentrated. The crude material was purified by ISCO® chromatography using a gradient of 50 to 75% ethyl acetate in hexanes to afford 1.22 g (74%) of the desired product as an off-white solid, which contained trace impurities. 1H NMR (300 MHz, DMSO-d6) δ 7.94-7.88 (m, 2 H), 7.86 (s, 1 H), 7.65 (br s, 2 H), 7.03-6.97 (m, 1 H), 6.94 (d, 1 H), 6.89 (d, 1 H), 3.51-3.42 (m, 4 H), 3.19-3.11 (m, 4 H), 1.42 (s, 9 H); ES-MS m/z 395.1 [M+H]+, HPLC RT (min) 2.52.
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13]([C:15]4[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=4)=[CH:12][C:11]=3[CH:23]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(=O)C.[NH:28]1[CH2:33][CH2:32][CH:31]([C:34]([OH:36])=[O:35])[CH2:30][CH2:29]1.C([BH3-])#N.[Na+]>C(Cl)Cl.CO.CS(C)=O>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13]([C:15]4[CH:16]=[CH:17][C:18]([CH2:19][N:28]5[CH2:33][CH2:32][CH:31]([C:34]([OH:36])=[O:35])[CH2:30][CH2:29]5)=[CH:21][CH:22]=4)=[CH:12][C:11]=3[CH:23]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)C1CCNCC1
Reactant: O=Cc1ccc(-c2cc3cc(C4CCCCC4)ccc3o2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CS(C)=O
Product: O=C(O)C1CCN(Cc2ccc(-c3cc4cc(C5CCCCC5)ccc4o3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.7 %

Procedure:
A mixture of 4-(5-cyclohexylbenzofuran-2-yl)benzaldehyde (22 mg, 0.07 mmol), acetic acid (7 μL, 0.11 mmol) and piperidine-4-carboxylic acid (14 mg, 0.11 mmol) in DCM/MeOH (1:1, 1.6 mL) was stirred at room temperature for 1 h. Sodium cyanoborohydride (2.3 mg, 0.05 mmol) was added and the reaction mixture was stirred for 4 h at room temperature. After concentration of solvent under reduced pressure, the resulting residue was dissolved in DMSO, filtered and purified by reverse phase preparative HPLC (Phenomenex reverse phase Luna 5μ C18(2) column, 60×21.2 mm ID) to yield the desired final product (15.4 mg, 51%) [hS1P1 EC50=1600 nM, >25000 nM]: >95% purity by LCMS, ESI-MS: 418.1 (M+H)+, 1H NMR (400 MHz, CD3OD) δ 8.00 (d, J=8.0 Hz, 2H), 7.59 (d, J=8.0 Hz, 2H), 7.45 (d, J=1.6 Hz, 1H), 7.43 (d, J=8.4 Hz, 1H), 7.26 (s, 1H), 7.21 (dd, J=8.4 Hz, J=1.6 Hz), 4.35 (s, 2H), 3.57 (d, J=11.6 Hz, 2H), 3.07 (t, J=12 Hz, 2H), 2.64-2.53 (m, 2H), 2.24 (d, 2H), 1.19-1.86 (m, 4H), 1.79 (t, 2H), 1.58-1.42 (m, 4H), 1.38-1.26 (m, 2H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][CH2:26][C:27]1[C:28]([F:44])=[C:29]([O:34][C:35]2[CH:36]=[C:37]([CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:38]#[N:39])[C:30]([Cl:33])=[CH:31][CH:32]=1.[CH3:45][C:46]([O:49][C:50]([NH:52][C:53]1[CH:54]=[C:55]2[C:59](=[CH:60][CH:61]=1)[NH:58][C:57]([C:62](O)=[O:63])=[CH:56]2)=[O:51])([CH3:48])[CH3:47].C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][NH:25][C:62]([C:57]2[NH:58][C:59]3[C:55]([CH:56]=2)=[CH:54][C:53]([NH:52][C:50](=[O:51])[O:49][C:46]([CH3:47])([CH3:45])[CH3:48])=[CH:61][CH:60]=3)=[O:63])=[C:28]([F:44])[C:29]=1[O:34][C:35]1[CH:36]=[C:37]([C:38]#[N:39])[CH:40]=[C:41]([Cl:43])[CH:42]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc2[nH]c(C(=O)O)cc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc2[nH]c(C(=O)NCc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4)c3F)cc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.6 %

Procedure:
HATU (2.75 g, 7.23 mmol) was added to a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (1.50 g, 4.82 mmol), 5-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-1H-indole-2-carboxylic acid (1.33 g, 4.82 mmol) and diisopropylethylamine (1.26 mL, 7.23 mmol) in DMF (10 mL). The mixture was stirred at RT overnight. The reaction mixture was extracted with EtOAc and water and the organic layer was washed with water, dried over sodium sulfate and concentrated. The residue was purified by silica gel flash chromatography (5-50% EtOAc:hexane) to give an off-white solid which was triturated with EtOAc:hexane, filtered and dried to afford the title compound (1.36 g, 49%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.44 (s, 1H), 9.07 (br. s., 1H), 8.95 (t, 1H), 7.78 (s, 1H), 7.71 (br. s., 1H), 7.41-7.55 (m, 3H), 7.36 (t, 1H), 7.21-7.30 (m, 1H), 7.15 (d, 1H), 7.03 (s, 1H), 4.37-4.68 (m, 2H), 1.44 (s, 9H). ES-LCMS: m/z 569 (M+H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:30]=[CH:29][C:18]([CH2:19][O:20][C:21]2[C:26]([CH2:27]O)=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:17][CH:16]=1.[CH2:31]([N:33](CC)CC)C.CS(Cl)(=O)=O.[C-]#N.[Na+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)C1C=CC=CC=1.O.C(#N)C.C(OCC)(=O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][O:20][C:21]2[C:26]([CH2:27][C:31]#[N:33])=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:29][CH:30]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ncccc2CO)cc1
Reactant: CCN(CC)CC
Agent: CCCC[N+](CCCC)(CCCC)Cc1ccccc1
Agent: CS(=O)(=O)Cl
Agent: [C-]#N
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ncccc2CC#N)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 35.9 %

Procedure:
To a mixture of [2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]methanol (1.50 g), triethylamine (0.75 g) and ethyl acetate (150 mL) was dropwise added methanesulfonyl chloride (0.85 g) at room temperature and the mixture was stirred at room temperature for 15 hrs. The reaction mixture was washed successively with water, saturated aqueous sodium hydrogencarbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give an oil. A mixture of this oil, sodium cyanide (0.72 g), benzyltributylammonium chloride (0.59 g), acetonitrile (20 mL) and water (10 ml) was stirred at room temperature for 15 hrs. The reaction mixture was concentrated, and ethyl acetate was added to the residue. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (0.55 g, 36%) of 2-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]acetonitrile from a fraction eluted with ethyl acetate-hexane (1:4, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 149-150° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(O)(=O)C.S(Cl)([Cl:19])(=O)=O>C(OCC)C>[NH2:1][C:2]1[C:10]([OH:11])=[CH:9][C:8]([Cl:19])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Nc1c(O)cccc1C(=O)O
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Solvent: CCOCC
Product: Nc1c(O)cc(Cl)cc1C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 47.7 %

Procedure:
A 25-mL round bottomed flask equipped with a magnetic stirrer was charged with 2-amino-3-hydroxybenzoic acid (0.852 g, 5.59 mmol), acetic acid (0.4 mL) and diethyl ether (0.4 mL). After cooling to 0° C. sulfuryl chloride (0.754 g, 5.59 mmol) was added and the reaction stirred at ambient temperature for 4 h. Dilution with ether (15 mL), filtration and purification by preparative HPLC afforded 0.500 g (48% yield) of 2-amino-5-chloro-3-hydroxybenzoic acid as a white solid: 1H NMR (500 MHz, CD3OD) δ 7.29 (d, J=9.5 Hz, 1H), 6.76 (d, 1H, J=9.5 Hz, 1H) MS (ESI) m/z 186 (M−H).
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[C:7]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH2:18][CH:19]2[O:21][CH2:20]2)[O:6][N:5]=1)([CH3:3])[CH3:2].[C:22]([NH2:26])([CH3:25])([CH3:24])[CH3:23]>>[CH:1]([C:4]1[CH:8]=[C:7]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH2:18][CH:19]([OH:21])[CH2:20][NH:26][C:22]([CH3:25])([CH3:24])[CH3:23])[O:6][N:5]=1)([CH3:2])[CH3:3]
Reactant: CC(C)c1cc(C=Cc2ccccc2OCC2CO2)on1
Reactant: CC(C)(C)N
Product: CC(C)c1cc(C=Cc2ccccc2OCC(O)CNC(C)(C)C)on1

Procedure:
7 g (0.025 mole) of 3-isopropyl-5-[2-(2,3-epoxypropoxy)-styryl]-isoxazole and 3.6 g (0.05 mole) of tert.-butylamine are reacted by the method described in Example 4. 5.8 g (59% of theory) of colorless crystals are obtained. Melting point 191°-193° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]>[Pd].CO>[C:1]([O:5][C:6](=[O:33])[N:7]([CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)=[CH:14][CH:15]=1)[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1)Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N(CCc1ccc(Oc2ccc(N)cc2)cc1)Cc1ccccc1
Yield: 98.6 %

Procedure:
Combine benzyl-{2-[4-(4-nitro-phenoxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester (2.5 g), 5% Pd/C (200 mg), and methanol (100 mL) then hydrogenated at 40 PSIG at room temperature for 2 hours. Filter off catalyst then concentrate on a rotary evaporator to yield {2-[4-(4-amino-phenoxy)-phenyl]-ethyl}-benzyl-carbamic acid tert-butyl ester (2.3 g): 1H NMR (CDCl3, 300.00 MHz): 7.42-6.70 (m, 13H), 4.41 (m, 2H), 3.39 (m, 2H), 2.77 (m, 2H), 1.52 (s, 9H). Step 5 4-[4-(2-Benzylamino-ethyl)-phenoxy]-phenylamine
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=O)[CH2:13][CH3:14].C[O-].[Na+].Cl>CO.O>[CH3:1][O:2][C:3]([C:4]1[O:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]=1[CH2:13][CH3:14])=[O:16]
Reactant: CCC(=O)c1ccccc1OCC(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCc1c(C(=O)OC)oc2ccccc12
Temperature: 60 °C
Yield: 38 %

Procedure:
(2-Propionyl-phenoxy)-acetic acid methyl ester (432 mg, 1.94 mmol, 1 eq.) was added to a solution of sodium methoxide (105 mg, 0.94 mmol, 1 eq.) in methanol (10 mL) and the reaction was heated at 60° C. for 4 h. The reaction was acidified using 1N HCl, diluted with water, extracted twice with ethyl acetate, and the combined organic layers were washed with saturated aqueous NaHCO3. The aqueous layers were extracted with ethyl acetate. The organic layers were combined, dried over magnesium sulfate, and concentrated in vacuo. 3-Ethyl-benzofuran-2-carboxylic acid methyl ester is obtained in 38% yield after flash column chromatography purification (1-5% ethyl acetate/hexanes). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.2 (t, J=7.6 Hz, 3 H) 3.1 (q, J=7.6 Hz, 2 H) 3.9 (s, 3 H) 7.4 (m, 1 H) 7.5 (m, 1 H) 7.7 (m, 1 H) 7.9 (dd, J=7.8, 0.8 Hz, 1 H).