Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[S:6][C:5]([N:7]=[C:8]=[O:9])=[N:4][CH:3]=1.C1C=CC=CC=1.[CH2:16]([NH:19][CH2:20][CH:21]=[O:22])[C:17]#[CH:18]>C(O)C.O>[CH2:16]([N:19]([CH2:20][CH:21]=[O:22])[C:8]([NH:7][C:5]1[S:6][C:2]([I:1])=[CH:3][N:4]=1)=[O:9])[C:17]#[CH:18]
Reactant: O=C=Nc1ncc(I)s1
Reactant: C#CCNCC=O
Solvent: c1ccccc1
Solvent: CCO
Solvent: O
Product: C#CCN(CC=O)C(=O)Nc1ncc(I)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Iodothiazol-2-yl isocyanate dimer (17.0 grams), benzene (70 ml) and the dimethyl acetal of 2-propargylaminoacetaldehyde (13.5 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is then stirred at room temperature for a period of about one hour. After this time the reaction mixture is filtered, and the filtrate is stripped of solvent under reduced pressure, leaving an oil. This oil is dissolved in an ethanol-water mixture, and the solution is filtered. The filtrate is then stripped of solvents under vacuum to yield the desired product the dimethyl acetal of 2-[1-propargyl-3-(5-iodothiazol-2-yl)ureido]acetaldehyde.
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[N:13][CH:14]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:17]1[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[O:23])[CH2:18]1>>[OH:1][C:2]1([C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[N:13][CH:14]=2)[CH2:7][CH2:6][CH:5]([N:17]2[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=3)=[O:23])[CH2:18]2)[CH2:4][CH2:3]1
Reactant: COc1ncc(C2(O)CCC(=O)CC2)cn1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: COc1ncc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cn1

Procedure:
The title compounds were prepared as white solids from reductive amination of 4-hydroxy-4-(2-methoxy-pyrimidin-5-yl)-cyclohexanone, as prepared in the previous step, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step E of Example 1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)[N:8]([CH3:22])[C:7]2=[O:23].[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30](O)=[O:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOCC.O>[CH3:22][N:8]1[C:7](=[O:23])[C:6]2[C:11](=[C:2]([NH:1][C:30](=[O:31])[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=3)[CH:3]=[CH:4][CH:5]=2)[N:10]=[C:9]1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1
Reactant: Cn1c(-c2cccc(C(F)(F)F)c2)nc2c(N)cccc2c1=O
Reactant: O=C(O)c1ccccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(-c2cccc(C(F)(F)F)c2)nc2c(NC(=O)c3ccccn3)cccc2c1=O
Temperature: 55 °C
Yield: 92.8 %

Procedure:
A mixture of 8-amino-3-methyl-2-(3-(trifluoromethyl)phenyl)quinazolin-4(3H)-one 5 (106 mg, 0.33 mmol), pyridine-2-carboxylic acid 6 (84 mg, 0.68 mmol), HATU (263 mg, 0.69 mmo) and DIPEA (208 mg) in DMF were heated at 55° C. for 2.5 h then poured into H2O. The resulting precipitate was collected by filtration, rinsed with H2O, then Et2O to give Compound 239 as a yellow solid (130 mg, 93% yield). MS (ESI) calc. for C22H15F3N4O2: 424.11. found: 425 [M+H].
Reaction SMILES: C([N:8]1[C:12]2[CH:13]=[C:14]([O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:23][CH:22]=3)[C:15]([N+:17]([O-])=O)=[CH:16][C:11]=2[O:10][C:9]1=[O:31])C1C=CC=CC=1.C([O-])=O.[K+].NC1C(OC2C=CC(C(C)(C)C)=CC=2)=CC2NC(=O)OC=2C=1.[C:58]([C:63]1[CH:77]=[C:76]([C:78]([CH2:81][CH3:82])([CH3:80])[CH3:79])[CH:75]=[CH:74][C:64]=1[O:65][CH:66]([CH2:70][CH2:71][CH2:72][CH3:73])[C:67](Cl)=[O:68])([CH2:61][CH3:62])([CH3:60])[CH3:59]>O.C1(C)C=CC=CC=1.[Pd].C(O)(C)C>[C:58]([C:63]1[CH:77]=[C:76]([C:78]([CH2:81][CH3:82])([CH3:79])[CH3:80])[CH:75]=[CH:74][C:64]=1[O:65][CH:66]([CH2:70][CH2:71][CH2:72][CH3:73])[C:67]([NH:17][C:15]1[C:14]([O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([CH3:28])([CH3:30])[CH3:29])=[CH:23][CH:22]=2)=[CH:13][C:12]2[NH:8][C:9](=[O:31])[O:10][C:11]=2[CH:16]=1)=[O:68])([CH2:61][CH3:62])([CH3:59])[CH3:60]
Reactant: CCCCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Cl
Reactant: CC(C)(C)c1ccc(Oc2cc3c(cc2[N+](=O)[O-])oc(=O)n3Cc2ccccc2)cc1
Agent: [Pd]
Agent: CC(C)(C)c1ccc(Oc2cc3[nH]c(=O)oc3cc2N)cc1
Agent: O=C[O-]
Solvent: O
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: CCCCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1cc2oc(=O)[nH]c2cc1Oc1ccc(C(C)(C)C)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 69.2 %

Procedure:
In a 500-ml flask, place 17.4 g (0.04 m) of 3-N-benzyl-5-(-t-butylphenoxy)-6-nitro-benzoxazol-2-one (5b), 70 ml of isopropyl alcohol and 35 ml of toluene. Heat the mixture to 60° C. Add 0.8 g of 5% Pd/C wet with 1 ml of water and 16.8 g (0.2 m) of potassium formate in 30 ml of water. Stir the reaction mixture vigorously at 60°-70° C. for 3 hrs under nitrogen. Cool the reaction mixture containing 6-amino-5-(4-t-butylphenoxy)-benzoxazol-2-one (6b; Y=4-t-butylphenoxy) to 15° C. and add 16.2 g (0.04 m×1.05 @95%) of 2-(2,4-di-t-pentylphenoxy)hexanoyl chloride (R′COZ; R′=1-(2,4-di-t-pentylphenoxy)pentyl and Z=Cl) in 60 ml of toluene slowly in drop wise over 1 hr period. Stir the mixture at 15° C. for another 30 min. Filter off catalyst and wash with a small volume of toluene and water. Separate toluene solution, wash with 100 ml of 1N HCl twice, and concentrate under a reduced pressure to a thick oil. Add 180 ml of heptane to the oil with gentle stirring. Cool in an ice-water bath for 1 hr. Collect solid, wash with heptane, and dry in a vacuum oven to give 18.1 g (72%) of 6-{2-(2,4-di-t-pentylphenoxy)hexanoyl}amino-5-(4-t-butylphenoxy)-benzoxazol-2-one (Formula I, Y=4-t-butylphenoxy and R′=1-(2,4-di-t-pentylphenoxy)pentyl).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:40])=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:36])([CH3:35])[CH2:32][CH2:33][OH:34])[NH:17][CH:16]2[C:37](O)=[O:38])[CH:12]=[CH:13][CH:14]=1.[NH2:41][C:42]1[CH:47]=[CH:46][N:45]([CH3:48])[C:44](=[O:49])[CH:43]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:48][N:45]1[CH:46]=[CH:47][C:42]([NH:41][C:37]([CH:16]2[CH:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=3[F:40])[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:36])([CH3:35])[CH2:32][CH2:33][OH:34])[NH:17]2)=[O:38])=[CH:43][C:44]1=[O:49]
Reactant: CC(C)(CCO)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: Cn1ccc(N)cc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ccc(NC(=O)C2NC(CC(C)(C)CCO)C(C#N)(c3ccc(Cl)cc3F)C2c2cccc(Cl)c2F)cc1=O
Yield: 5.2 %

Procedure:
In a manner similar to the method described in Examples 1e, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(4-hydroxy-2,2-dimethyl-butyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 116c (0.5 g, 0.8 mmol) was reacted with 4-amino-1-methyl-1H-pyridin-2-one (Molbridge) (0.18 g, 1.5 mmol), HATU (0.62 g, 1.6 mmol) and iPr2NEt (0.71 mL, 4.1 mmol) in CH2Cl2 at room temperature for 20 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(4-hydroxy-2,2-dimethyl-butyl)-pyrrolidine-2-carboxylic acid (1-methyl-2-oxo-1,2-dihydro-pyridin-4-yl)-amide as a white solid (25 mg, 5.1%).
Reaction SMILES: O=[C:2]([CH2:6][CH2:7][CH3:8])[C:3]([OH:5])=[O:4].[CH3:9][C:10]1([CH3:16])[CH2:12][CH:11]1[C:13]([NH2:15])=[O:14].O.N#N>C1(C)C=CC=CC=1>[CH3:9][C:10]1([CH3:16])[CH2:12][CH:11]1[C:13]([NH:15]/[C:2](=[CH:6]\[CH2:7][CH3:8])/[C:3]([OH:5])=[O:4])=[O:14]
Reactant: CC1(C)CC1C(N)=O
Reactant: CCCC(=O)C(=O)O
Agent: N#N
Solvent: Cc1ccccc1
Solvent: O
Product: CC/C=C(\NC(=O)C1CC1(C)C)C(=O)O
Reaction time: 20 h

Procedure:
A solution of 1.74 g (15 mmole) of 2-ketovaleric acid and 1.13 g (10 mmole) of 2,2-dimethylcyclopropanecarboxamide in 20 ml of toluene was refluxed with stirring with collection of H2O in a small Dean-Stark trap. After 20 hrs. the solution was cooled and treated with a gentle stream of N2. Before much of the solvent had evaporated, crystallization was induced by scratching. After standing, the solid was collected on a filter and washed with toluene and some Et2O. Yield of white crystals=0.63 g (30%), mp 154.5°-155.5° (slight prelim. softening). Tlc (4:1 toluene-AcOH) showed only an extremely faint trace of the other isomer. NMR was consistent with the Z-configuration.
Reaction SMILES: [OH:1][NH:2]/[C:3](=[N:14]\[H])/[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=1.[O:16]=[C:17]1[CH:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:21][CH2:20][CH2:19][N:18]1[CH2:29][C:30](O)=O.Cl.C(N=C=NCCCN(C)C)C>ClC(Cl)C>[C:23]1([CH:22]2[CH2:21][CH2:20][CH2:19][N:18]([CH2:29][C:30]3[O:1][N:2]=[C:3]([C:4]4[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=4)[N:14]=3)[C:17]2=[O:16])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: [H]/N=C(\NO)c1ccc(C(F)(F)F)cc1
Reactant: O=C(O)CN1CCCC(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(Cl)Cl
Product: O=C1C(c2ccccc2)CCCN1Cc1nc(-c2ccc(C(F)(F)F)cc2)no1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
A solution of (Z)—N-hydroxy-4-(trifluoromethyl)benzimidamide (0.142 g, 0.698 mmol), 2-(2-oxo-3-phenylpiperidin-1-yl)acetic acid (0.148 g, 0.634 mmol; Example 91D) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.158 g, 0.825 mmol) were stirred together in dichloroethane (0.5 mL) at room temperature for 2 hours. The reaction was then heated to 85° C. and stirred overnight. The reaction was cooled, loaded onto a SF15-12 column (Analogix®) and the product eluted using a gradient of 5% ethyl acetate/hexanes to 100% ethyl acetate over 25 minutes (Flow=30 mL/minute). The residue was dissolved in ethyl acetate and concentrated to give the title compound. 1H NMR (300 MHz, CDCl3) δ 8.23 (d, J=8.2, 2H), 7.77 (d, J=8.3, 2H), 7.42-7.15 (m, 5H), 5.19 (d, J=16.7, 1H), 4.73 (d, J=16.7, 1H), 3.84-3.76 (m, 1H), 3.70 (ddd, J=5.3, 7.6, 12.7, 1H), 3.59 (dt, J=5.5, 11.2, 1H), 2.43-2.18 (m, 1H), 2.18-1.82 (m, 3H); MS (ESI+) m/z 402.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[C:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1>[Ir].C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:8]=1
Reactant: CCOC(=O)C(C)=Cc1ccc(OC)cc1
Agent: [Ir]
Solvent: ClCCl
Product: CCOC(=O)C(C)Cc1ccc(OC)cc1
Yield: 96.4 %

Procedure:
According to the general procedure, a solution of ethyl 3-(4-methoxyphenyl)-2-methylacrylate (30 mg, 0.14 mmol) and iridium catalyst (S)-32 (4.5 mg, 0.0029 mmol, 2.0 mol %) in CH2Cl2 (1.4 mL) was hydrogenated. Removal of the solvent in vacuo and standard purification gave 37 (30 mg, 96%) as a colorless oil. [α]20D +24.5 (c 1.25, CHCl3); CSP HPLC analysis (Chiralcel OB-H; eluent: 99.5:0.5 hexanes/i-PrOH, 0.5 mL/min) determined a 90:10 er (80% ee) [tR(minor) 9.01 min, tR(major) 9.76 min]; 1H NMR (300 MHz, CDCl3) 7.08 (d, 2H, J=8.7 Hz), 6.81 (d, 2H, J=8.7 Hz), 4.09 (q, 2H, J=7.2 Hz), 3.78 (s, 3H), 3.01-2.90 (m 1H), 2.73-2.57 (m, 2H), 1.19 (t, 3H, J=7.2 Hz), 1.13 (d, 3H, J=6.6 Hz) ppm; 13C NMR (75 MHz, CDCl3) 176.2, 158.1, 131.4, 129.9, 113.7, 60.2, 55.2, 41.7, 38.8, 16.7, 14.2 ppm.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:11])=[C:7]([CH:10]=1)[CH:8]=[O:9])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>>[C:25]([Si:22]([CH3:24])([CH3:23])[O:21][CH2:20][CH2:19][O:11][C:6]1[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:10][C:7]=1[CH:8]=[O:9])([CH3:28])([CH3:27])[CH3:26]
Reactant: CCc1ccc(O)c(C=O)c1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCc1ccc(OCCO[Si](C)(C)C(C)(C)C)c(C=O)c1
Yield: 92 %

Procedure:
In a manner similar to the method described in example 130a, 5-ethyl-2-hydroxy-benzaldehyde (4.75 g, 31.7 mmol) was reacted with K2CO3 (13.1 g, 95.1 mmol) and (2-bromo-ethoxy)-tert-butyl-dimethyl-silane (9.09 g, 38.0 mmol) to give 2-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-5-ethyl-benzaldehyde as dark brown oil (9.0 g, 92.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]=[C:8]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])[CH:7]=[CH:6][C:5]2=1.ClC1C=C2C(=CC=1)NC1C=C(C(O)(C)C(O)=O)C=CC2=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]=[C:8]([C:15](=[CH2:19])[C:16]([OH:18])=[O:17])[CH:7]=[CH:6][C:5]2=1
Reactant: CC(C(=O)O)c1ccc2c(c1)[nH]c1ccc(Cl)cc12
Agent: CC(O)(C(=O)O)c1ccc2c(c1)[nH]c1ccc(Cl)cc12
Product: C=C(C(=O)O)c1ccc2c(c1)[nH]c1ccc(Cl)cc12

Procedure:
In yet another aspect, the invention relates to the process of preparing 6-chloro-α-methylcarbazole-2-acetic acid by a process which comprises the steps of (a) treating 6-chloro-α-hydroxy-α-methylcarbazole-2-acetic acid with a dehydrating agent to yield 6-chloro-α-methylene-2-carbazole acetic acid; (b) hydrogenating the reaction product of step (a) to obtain the desired 6-chloro-α-methylcarbazole-2-acetic acid. Alternatively, the 6-chloro-α-hydroxy-α-methylcarbazole-2-acetic acid can be treated with stannous chloride in the presence of an alkanoic and mineral acid to yield the desired 6-chloro-α-methylcarbazole-2-acetic acid.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([CH3:8])[CH:4]=1.[CH2:9]([NH2:11])[CH3:10]>C1COCC1>[CH2:9]([NH:11][CH2:2][C:3]1[O:7][N:6]=[C:5]([CH3:8])[CH:4]=1)[CH3:10]
Reactant: CCN
Reactant: Cc1cc(CCl)on1
Solvent: C1CCOC1
Product: CCNCc1cc(C)no1

Procedure:
prepared by reaction of 5-chloromethyl-3-methyl-isoxazole (Li W.-T. et al J. Med. Chem. 2003, 46, 9, 1706-1715) with 2M ethylamine in THF.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:14])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-:3])=[O:2].O[CH:16]1[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OCC)=O)=NC(OCC)=O.C([O-])(O)=O.[Na+]>C1COCC1.O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1)[O:14][CH:16]1[CH2:17][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19]1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc(O)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(Oc2cc([N+](=O)[O-])cc(C(F)(F)F)c2)C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 87.4 %

Procedure:
Dissolve 3-nitro-5-(trifluoromethyl)phenol (500 mg, 2.4 mmol), tert-butyl 3-hydroxyazetidine-1-carboxylate (500 mg, 2.9 mmol), PPh3 (9.5 g, 3.6 mmol) in THF (8 mL) and cool to 0° C. on ice bath. Add slowly diethyl azodicarboxylate (630 mg, 3.6 mmol). Stir the mixture at 35° C. for 16 hrs. Pour the mixture into water (50 mL), adjust pH to neutral with saturated NaHCO3 solution. Extract with EtOAc (15 mL×3), combine the organic layers; wash with brine (100 mL), dry over anhydrous Na2SO4. Concentrate under reduced pressure to give the crude product. Purification by chromatography (silica gel, EtOAc:PE=15:85) affords the target compound (760 mg, 87%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:15][N:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:21]#[N:22]>>[CH3:15][N:16]1[C:20]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([C:10]3[S:11][CH:12]=[CH:13][CH:14]=3)=[O:9])=[CH:4][CH:3]=2)=[CH:19][CH:18]=[C:17]1[C:21]#[N:22]
Reactant: Cn1cccc1C#N
Reactant: O=C(c1ccc(Br)cc1)c1cccs1
Product: Cn1c(C#N)ccc1-c1ccc(C(=O)c2cccs2)cc1

Procedure:
The title compound was prepared from (4-bromophenyl)(thien-2-yl)methanone and 1-methyl-2-cyanopyrrole according to the coupling procedure as described in example 1. MS (ES) m/z 293.1; HRMS: calcd for C17H12N2OS+H+, 293.0743; found (ESI, [M+H]+), 293.0744.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][C:13]([F:16])([F:15])[F:14])[CH:8]=2)[CH:3]=1.[B:17]1(B2OC(C)(C)C(C)(C)O2)[O:21]C(C)(C)C(C)(C)[O:18]1.CC([O-])=O.[K+].N#N.Cl>CS(C)=O.CCCCCC.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].CC(C)=O>[F:14][C:13]([F:16])([F:15])[O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([B:17]([OH:21])[OH:18])[CH:11]=[CH:10]2
Reactant: FC(F)(F)Oc1ccc2cc(Br)ccc2c1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CS(C)=O
Solvent: CC(C)=O
Solvent: CCCCCC
Product: OB(O)c1ccc2cc(OC(F)(F)F)ccc2c1
Temperature: 80 °C

Procedure:
2-Bromo-6-(trifluoromethoxy)naphthalene (428 mg, 1.47 mmol), bis(pinacolato)diboron (410 mg, 1.62 mmol), and KOAc (433 mg, 4.41 mmol) were suspended in DMSO (12 ml). The mixture was de-oxygenated by vacuum-N2 fill cycles, followed by the addition of catalyst PdCl2(dppf) (30 mg, 2.5 mol %). The reaction was heated under N2 atmosphere to 80° C. for 2 hr. The reaction was diluted with hexane (100 ml), washed with water, brine, and dried over Na2SO4. After evaporation of solvent, the residue obtained was treated with acetone (20 ml) and 2N HCl (5 ml) for 24 h. The crude boronic acid was purified by reverse phase HPLC to give [6-(trifluoromethoxy)-2-naphthyl]boronic acid as a white powder. NMR (500 MHz, CDCl3) δ: 7.44 (dd, J=2.3, 9.0 Hz, 1H); 7.74 (br s, 1H); 7.98 (d, J=8.2 Hz, 1H); 8.11 (d, J=9.0 Hz, 1H); 8.35 (dd, J=1.1 8.2 Hz, 1H); 8.85 (br s, 1H).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]([OH:13])=[O:12])[CH:8]=2)[NH:3]1.[N:14]1([CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[NH:27][C:26]([CH:31]=O)=[CH:25]3)[CH2:18][CH2:17][CH2:16][CH2:15]1>>[O:1]=[C:2]1[C:10](=[CH:31][C:26]2[NH:27][C:28]3[C:24]([CH:25]=2)=[CH:23][C:22]([O:21][CH2:20][CH2:19][N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:30][CH:29]=3)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]([OH:13])=[O:12])[CH:8]=2)[NH:3]1
Reactant: O=C1Cc2cc(C(=O)O)ccc2N1
Reactant: O=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1
Product: O=C1Nc2ccc(C(=O)O)cc2C1=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1

Procedure:
2-Oxo-2,3-dihydro-1H-indole-5-carboxylic acid was condensed with 5-(2-pyrrolidin-1-yl-ethoxy)-1H-indole-2-carbaldehyde to give the title compound.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.C[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[CH:24]([OH:28])[CH2:23][CH2:22]3)=[C:15]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][N:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)=[CH:32][CH:31]=2)[CH:14]=1.C(N(CC)CC)C>ClCCl.O>[OH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[C:24](=[O:28])[CH2:23][CH2:22]3)=[C:15]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][N:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)=[CH:32][CH:31]=2)[CH:14]=1
Reactant: COc1ccc(-c2ccc3c(c2)CCC3O)c(Nc2ccc(OCCN3CCCCC3)cc2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C1CCc2cc(-c3ccc(O)cc3Nc3ccc(OCCN4CCCCC4)cc3)ccc21
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 7.9 %

Procedure:
To dichloromethane (2 ml) was added oxalyl chloride (0.22 ml) under a nitrogen atmosphere, the solution was cooled at −78° C., a solution of dimethylsulfoxide (245 mg) in dichloromethane (2 ml) was added dropwise thereto over 10 minutes, and then solution was stirred for 45 minutes. A solution of 5-{4-methoxy-2-[4-(2-piperidin-1-ylethoxy)phenylamino]phenyl}indan-1-ol (552 mg) in dichloromethane (4 ml) was added dropwise thereto over 25 minutes, the solution was stirred for 40 minutes, then triethylamine (0.85 ml) was added dropwise thereto followed by stirring for 20 minutes while warming from −78° C. to room temperature. Water was added thereto followed by stirring, the solution was extracted with ethyl acetate, then sequentially washed with water and brine, and the solvent was evaporated in vacuo. Obtained by purifying the residue by NH silica gel column chromatography (hexane-ethyl acetate system), to a solution of the resulting 5-{4-methoxy-2-[4-(2-piperidin-1-ylethoxy)phenylamino]phenyl}indan-1-one (118 mg) in methanesulfonic acid (3 ml) was added DL-methionine (110 mg), the solution was stirred for 5 hours at 80° C., then water was added thereto, the solution was stirred, and neutralized with aqueous ammonia. The solution was extracted with ethyl acetate, then sequentially washed with water and brine, and the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (ethyl acetate-methanol system) to provide the title compound (42 mg).
Reaction SMILES: C(OC1C=CC(C(C2C=CC(OC(=O)C=C)=CC=2)(C2C=CC(OC(=O)C=C)=CC=2)C)=CC=1)(=O)C=C.[C:36]1([C:42]2[CH:51]=[CH:50][CH:49]=[C:48]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[C:43]=2[O:44][CH:45](O)[CH3:46])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[C:58]([OH:62])(=[O:61])[CH:59]=[CH2:60].CS(O)(=O)=O>C1(C)C=CC=CC=1>[C:58]([O:62][CH2:46][CH2:45][O:44][C:43]1[C:48]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)=[CH:49][CH:50]=[CH:51][C:42]=1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(=[O:61])[CH:59]=[CH2:60]
Reactant: CC(O)Oc1c(-c2ccccc2)cccc1-c1ccccc1
Reactant: C=CC(=O)O
Agent: C=CC(=O)Oc1ccc(C(C)(c2ccc(OC(=O)C=C)cc2)c2ccc(OC(=O)C=C)cc2)cc1
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: C=CC(=O)OCCOc1c(-c2ccccc2)cccc1-c1ccccc1
Reaction time: 3 h

Procedure:
To a 50 ml 1 neck round bottom equipped with a dean stark trap was added 2,6-diphenylphenoxyethanol (5 g, 1 eq), toluene (21 ml), acrylic acid (2.7 g, 2.2 eq), methane sulfonic acid (0.3 g, 0.18 eq), Prostab 5198 (0.003 g) and heated to reflux. After 3 hours the reaction was complete. The reaction was washed with 20 ml sodium carbonate and 20 ml sodium chloride brine. The toluene mixture was filtered through thin layer of silica gel and eluted with 30 ml toluene. The filtrate was treated with the “Prostab 5198” (0.003 g) and concentrated invacuo to recover a viscous oil. >97% by GC. RI=1.6062 at 25° C.
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:9]1[N:10]=[C:11]([NH:14][C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:12][CH:13]=1)\[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].[C:40]([O:44][C:45](=[O:50])[C:46](Br)([CH3:48])[CH3:47])([CH3:43])([CH3:42])[CH3:41]>CS(C)=O>[C:40]([O:44][C:45]([C:46]([O:1]/[N:2]=[C:3](/[C:9]1[N:10]=[C:11]([NH:14][C:15]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:12][CH:13]=1)\[C:4]([O:6][CH2:7][CH3:8])=[O:5])([CH3:48])[CH3:47])=[O:50])([CH3:43])([CH3:42])[CH3:41]
Reactant: CCOC(=O)/C(=N\O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 74.8 %

Procedure:
To ethyl (Z)-2-(hydroxyimino)-2-[2-(triphenylmethyl)aminothiazol-4-yl]acetate (46 g) were added potassium carbonate (27.6 g), tert-butyl-2-bromo-2-methylpropionate(24.1 g) and dimethylsulfoxide (300 ml), and then the solution was stirred for 6 hours at room temperature. Afterwards distilled water (100 ml) was added therein, the solution was stirred again for an hour. The precipitates were filtered, washed with distilled water(500 ml), and dried under reduced pressure to give the above-indicated compound(45.1 g) as a white solid.