Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:22])([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][CH:10]=1)C1C=CC=CC=1>O.[Pd].C(OCC)(=O)C>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([CH3:21])([CH3:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:13][CH:14]=1
Reactant: CCOC(=O)C(C)(C)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C)c1ccc(O)cc1
Yield: 62.1 %

Procedure:
Under inert atmosphere, a round bottom flask was charged with ethyl 2-(4-benzyloxyphenyl)-2-methyl-propanoate (15 g, mmol) and ethyl acetate (200 mL). To above reaction mixture 2-3 drops of water was added followed by Pd/C. Reaction mixture allowed to stir and evacuated the flask until solvent begins to bubble and then carefully backfill with nitrogen gas (repeated twice). Nitrogen balloon was replaced by hydrogen bladder and flask was again evacuated and refilled with hydrogen (repeated twice). The reaction mixture thus maintained under hydrogen atmosphere was allowed to stir overnight at room temperature. The reaction mixture was filtered through cellite pad and the filtrate was concentrated under reduced pressure to afford 6.5 g of product.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9]([O:15][CH:16]([CH3:21])[C:17]([F:20])([F:19])[F:18])=[C:10]([CH:14]=1)[C:11]([OH:13])=O)(=[O:5])=[O:4])[CH3:2].Cl.[F:23][C:24]([F:37])([F:36])[C:25]1[S:29][C:28]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[N:27][CH:26]=1>>[CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9]([O:15][CH:16]([CH3:21])[C:17]([F:20])([F:19])[F:18])=[C:10]([C:11]([N:33]2[CH2:34][CH2:35][N:30]([C:28]3[S:29][C:25]([C:24]([F:37])([F:23])[F:36])=[CH:26][N:27]=3)[CH2:31][CH2:32]2)=[O:13])[CH:14]=1)(=[O:4])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)c1ccc(OC(C)C(F)(F)F)c(C(=O)O)c1
Reactant: FC(F)(F)c1cnc(N2CCNCC2)s1
Agent: Cl
Product: CCS(=O)(=O)c1ccc(OC(C)C(F)(F)F)c(C(=O)N2CCN(c3ncc(C(F)(F)F)s3)CC2)c1
Yield: 82 %

Procedure:
Prepared in analogy to example 1 (b) from 5-ethanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (Example A17) and 1-(5-trifluoromethyl-thiazol-2-yl)-piperazine hydrochloride (Example 58(c)). The crude material was purified by reversed phase HPLC (acetonitrile/water) followed by trituration in ether to yield the title compound as an off-white crystalline solid (yield 82%). MS (m/e): 546.4 (M+H+, 100%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][CH3:17])[C:11]([C:18]([F:21])([F:20])[F:19])=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].C([O:28][C:29](=O)[CH2:30][C:31](=[O:44])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=2)[CH:33]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][CH3:17])[C:11]([C:18]([F:21])([F:20])[F:19])=[CH:10][C:9]=1[NH:22][C:29](=[O:28])[CH2:30][C:31](=[O:44])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=2)[CH:33]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Reactant: CCCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CCCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cccnc3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-propoxy-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J35) (251 mg, 0.75 mmol) and 3-oxo-3-(3-pyridin-3-yl-phenyl)-propionic acid tert-butyl ester (Example K1) (223 mg, 0.75 mmol) according to the general procedure M. Obtained as a yellow foam (369 mg, 88%).
Reaction SMILES: C=C[C:3]1[CH:8]=[CH:7]C=CC=1.BrC1C=CC(C=C)=CC=1.C(C1C=CC=CC=1C=C)=C.C1OCC1.[I-:32].II.[C:35]1([P:41]([C:48]2C=CC=C[CH:49]=2)[C:42]2C=CC=C[CH:43]=2)C=CC=C[CH:36]=1.C(P(CC)CC)C>>[I-:32].[CH2:35]([P+:41]([CH2:48][CH3:49])([CH2:42][CH3:43])[CH2:7][CH2:8][CH3:3])[CH3:36]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: C=Cc1ccccc1
Agent: C1COC1
Agent: C=Cc1ccc(Br)cc1
Agent: C=Cc1ccccc1C=C
Product: CCC[P+](CC)(CC)CC

Procedure:
The catalyst of this example was prepared from a cross-linked copolymer of a 2:1 molar ratio of styrene and p-bromo styrene and 2% by weight, based on the above monomers, of divinyl monomers. The latter in this instance was divinyl benzene. The Br of the polymer was replaced with Li and then the Li was converted to --(CH2)3OH by reaction with trimethylene oxide. The OH of the --(CH2)3OH was converted to the iodide with I2 in the presence of triphenyl phosphine. The cross-linked polymer having a plurality of --(CH2)3I groups was then reacted with triethyl phosphine to form the corresponding triethyl n-propyl phosphonium iodide. The iodide was converted to the acetate with sodium acetate and the acetate was converted to --OC2H5 /OH- by reaction with an 80-20 ethanol-water mixture (by volume) containing 3.7 g. Na in 200 ml. of the ethanol-water mixture. This catalyst had a plurality of ##STR3##
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].[CH2:9]([N+]1C2C=CC=CC=2[Te]C=1C)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH3:26][O:27][C:28]1[C:29]([O:38][CH3:39])=[CH:30][C:31]2[Te:35][C:34]([CH3:36])=[N:33][C:32]=2[CH:37]=1>>[F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].[CH2:9]([N+:33]1[C:32]2[CH:37]=[C:28]([O:27][CH3:26])[C:29]([O:38][CH3:39])=[CH:30][C:31]=2[Te:35][C:34]=1[CH3:36])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1[te]c2ccccc2[n+]1Cc1ccccc1
Reactant: COc1cc2nc(C)[te]c2cc1OC
Agent: O=S(=O)([O-])C(F)(F)F
Product: COc1cc2[te]c(C)[n+](Cc3ccccc3)c2cc1OC

Procedure:
This compound was prepared in the same way and on the same scale as the compound of Example 52, except that 5,6-dimethoxy-2-methylbenzotellurazole (Example 19) was used in place of 2-methylbenzotellurazole. Yield 0.50 g of a pale gray powder, m.p. 179°-182° C. (dec). The infrared, nuclear magnetic resonance, and mass spectra were in agreement with that expected for a mixture of desired compound and the hydro salt 5,6-dimethoxy-2-methylbenzotellurazole.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:42])[C@H:4]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1)[NH:5][C:6](=[O:33])[C@H:7]([CH:30]([CH3:32])[CH3:31])[NH:8][C:9](=[O:29])[C@H:10]([CH2:22][CH2:23][CH2:24][NH:25][C:26](=[NH:28])[NH2:27])[N:11](C(OC(C)(C)C)=O)[N+:12]([O-:14])=[O:13].[ClH:43]>C(O)(=O)C.O1CCOCC1>[ClH:43].[CH3:1][O:2][C:3](=[O:42])[C@H:4]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1)[NH:5][C:6](=[O:33])[C@H:7]([CH:30]([CH3:32])[CH3:31])[NH:8][C:9](=[O:29])[C@H:10]([CH2:22][CH2:23][CH2:24][NH:25][C:26](=[NH:27])[NH2:28])[NH:11][N+:12]([O-:14])=[O:13]
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(=N)N)N(C(=O)OC(C)(C)C)[N+](=O)[O-])C(C)C
Agent: Cl
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(=N)N)N[N+](=O)[O-])C(C)C
Reaction time: 0.08 h

Procedure:
30.9 g of t-butoxycarbonylnitroarginylvalyltyrosine methyl ester is dissolved in 177 ml of acetic acid. To this solution is added 88.5 ml of 6 N hydrochloric acid in dioxane. The reaction is allowed to stand for five minutes and the solvent is removed under vacuum. The residue is triturated with ethyl ether. The resultant precipitate is filtered, washed with ethyl ether and dried in a vacuum oven at 55° C. to afford nitroarginylvalyltyrosine methyl ester hydrochloride.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([CH2:19][CH2:20][CH2:21][N:22]([CH2:24][C:25]([N:27]3[CH2:32][CH2:31][CH:30]([O:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[F:40])[CH2:29][CH2:28]3)=O)[CH3:23])[O:18][CH2:17][CH2:16][O:15]2)=[CH:10][CH:9]=1.C([O-])(=O)C([O-])=O.[OH-].[Na+].C(=O)([O-])[O-].[Na+].[Na+].C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:67].Cl>C1COCC1.O>[ClH:67].[ClH:67].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([CH2:19][CH2:20][CH2:21][N:22]([CH2:24][CH2:25][N:27]3[CH2:28][CH2:29][CH:30]([O:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[F:40])[CH2:31][CH2:32]3)[CH3:23])[O:15][CH2:16][CH2:17][O:18]2)=[CH:10][CH:9]=1
Reactant: CN(CCCC1(c2ccc(F)cc2)OCCO1)CC(=O)N1CCC(Oc2ccccc2F)CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: O=C([O-])C(=O)[O-]
Solvent: O
Solvent: C1CCOC1
Product: CN(CCCC1(c2ccc(F)cc2)OCCO1)CCN1CCC(Oc2ccccc2F)CC1
Temperature: 25 °C

Procedure:
To a stirred suspension of 7.38 g (0.503 mol) of lithium aluminum hydride (50% in oil; washed 3 times with hexanes) in 250 ml of dry THF at 0° was added dropwise a solution of 1-{N-{3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl}-N-methylaminoacetyl}-4-(2-fluorophenoxy)piperidine (liberated from 28.6 g, 50.6 mmol, of the oxalate) in 250 ml of THF. The mixture was allowed to warm to room temperature and subsequently heated at reflux for 24 hours under nitrogen. The mixture was allowed to cool to room temperature and subsequently cooled in an ice bath. To the mixture were added dropwise, slowly, 4 ml water, 4 ml 15% sodium hydroxide and 12 ml water. The suspension was filtered and the residue washed with THF. Evaporation of the solvent provided an oil which was shaken with saturated sodium carbonate, extracted twice with ether, washed with saturated sodium chloride and dried over potassium carbonate. Filtration followed by evaporation of the solvent provided an oil. The yield of the dihydrochloride was 20.26 g (44.0 mmol, 87%).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13](B(O)O)=[CH:12][C:11]=3[CH:18]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1.C(N(CC)CC)C>C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13]([C:20]4[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=4)=[CH:12][C:11]=3[CH:18]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OB(O)c1cc2cc(N3CCCCC3)ccc2o1
Reactant: O=Cc1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=Cc1ccc(-c2cc3cc(N4CCCCC4)ccc3o2)cc1
Yield: 30.8 %

Procedure:
A mixture of 5-(piperidin-1-yl)benzofuran-2-ylboronic acid (90 mg, 0.367 mmol), 4-bromobenzaldehyde (62 mg, 0.330 mmol), triethylamine (1.0 mL, 7.3 mmol) and bis(triphenylphosphine)palladium(II) chloride (12.8 mg, 0.02 mmol) in ethanol (9 mL) was irradiated in a microwave instrument at 100° C. for 20 min. The reaction mixture was cooled, and the solvent was removed. The residue was purification by silica gel chromatography on ISCO system yielding the title compound (31 mg, 28% yield). ESI-MS: 306.4 (M+H)+, 1H NMR (400 MHz, CDCl3) δ 10.02 (s, 1H), 7.95 (dd, 4H), 7.42 (d, 1H), 7.11 (m, 2H), 7.07 (dd, 1H), 3.13 (t, 4H), 1.78-1.74 (m, 4H), 1.62-1.56 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:27]2[CH:28]=[CH:29][C:30]([Cl:42])=[C:31]3[C:35]=2[N:34]([CH3:36])[N:33]=[C:32]3[NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[C:5]([C@@H:9]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:10][C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=2)=[N:6][C:7]=1Br.[C:43]([O-])([O-])=O.[K+].[K+].CB1OB(C)OB(C)O1>O1CCOCC1.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]>[NH2:1][C:2]1[CH:3]=[C:4]([C:27]2[CH:28]=[CH:29][C:30]([Cl:42])=[C:31]3[C:35]=2[N:34]([CH3:36])[N:33]=[C:32]3[NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[C:5]([C@@H:9]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:10][C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=2)=[N:6][C:7]=1[CH3:43]
Reactant: O=C([O-])[O-]
Reactant: Cn1nc(NS(C)(=O)=O)c2c(Cl)ccc(-c3cc(N)c(Br)nc3[C@H](Cc3cc(F)cc(F)c3)NC(=O)OC(C)(C)C)c21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CB1OB(C)OB(C)O1
Solvent: C1COCCO1
Product: Cc1nc([C@H](Cc2cc(F)cc(F)c2)NC(=O)OC(C)(C)C)c(-c2ccc(Cl)c3c(NS(C)(=O)=O)nn(C)c23)cc1N
Temperature: 100 °C

Procedure:
To a flask of 47A (255 mg, 0.37 mmol) in dioxane, K2CO3 (179 mg, 1.30 mmol), PdCl2(dppf) (27 mg, 0.037 mmol) and trimethyl boroxine (0.052 mL, 0.37 mmol) was added to the mixture. The reaction mixture was heated at 100° C. for 3 h. The reaction was cooled down and the solution partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc and the combined extracts dried, filtered and concentrated in vacuo. The crude product was purified by flash chromatography to provide the title compound. MS (m/z) 621 [M+H]+.
Reaction SMILES: Br[C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=2)[N:3]=1.[CH3:18][C:19]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22].C(=O)(O)[O-].[Na+].O1CCOCC1>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.O>[CH3:18][C:19]1[CH:28]=[C:27]([C:2]2[N:6]=[CH:5][N:4]([C:7]3[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=3)[N:3]=2)[CH:26]=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1C
Reactant: FC(F)(F)Oc1ccc(-n2cnc(Br)n2)cc1
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: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
To 3-bromo-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (0.496 g, 1.609 mmol), methyl 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (0.466 g, 1.689 mmol), sodium bicarbonate (0.405 g, 4.83 mmol) and tetrakis(triphenylphosphine)palladium (0.186 g, 0.161 mmol) in a 2.0 mL microwave vial was added dioxane (6 mL) and water (1.5 mL). The reaction was capped and placed on a Biotage® Initiator microwave reactor for 30 min at 140° C. The reaction mixture was then diluted with EtOAc and washed with water. The aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated. Purification by flash column chromatography provided the title compound as a white solid (0.376 g, 0.997 mmol, 62%): 1H NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 8.10 (dt, J=1.6, 0.7 Hz, 1H), 8.09-8.00 (m, 2H), 7.84-7.78 (m, 2H), 7.44-7.37 (m, 2H), 3.93 (s, 3H), 2.70 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −58.02; ESIMS m/z 378 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][C:35]=1[Cl:36])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13](=[O:32])[CH2:14][S:15][C:16]2[S:17][CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N:27]=[CH:28][N:29](C)C)[CH:22]=3)[N:20]=2)[CH2:8][CH2:7]1.Cl.[OH:38]N>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][C:35]=1[Cl:36])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13](=[O:32])[CH2:14][S:15][C:16]2[S:17][CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][CH:28]=[N:29][OH:38])[CH:22]=3)[N:20]=2)[CH2:8][CH2:7]1
Reactant: NO
Reactant: CN(C)C=Nc1cccc(-c2csc(SCC(=O)NC3CCN(Cc4ccc(Cl)c(Cl)c4)CC3)n2)c1
Agent: Cl
Solvent: CO
Product: O=C(CSc1nc(-c2cccc(NC=NO)c2)cs1)NC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Reaction time: 30 h
Yield: 92 %

Procedure:
The product (100 mg) of Example 173 was dissolved in methanol (10 mL), and hydroxyamine hydrochloride (15 mg) was added to the solution. The mixture was stirred for 30 hrs. The solvent was evaporated under reduced pressure, and the obtained residue was extracted with chloroform, then washed with saturated brine, and dried. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform:methanol=100:1–20:1) to give the title compound (90 mg) as a white amorphous solid.
Reaction SMILES: [S:1](=[O:31])(=[O:30])([O:3][CH2:4][C@@H:5]1[C@@H:9]([OH:10])[CH2:8][C@H:7]([N:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:14]=3[C:13]([C:28]#[CH:29])=[CH:12]2)[O:6]1)[NH2:2].O>CCO.[Pd]>[S:1](=[O:30])(=[O:31])([O:3][CH2:4][C@@H:5]1[C@@H:9]([OH:10])[CH2:8][C@H:7]([N:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:14]=3[C:13]([CH2:28][CH3:29])=[CH:12]2)[O:6]1)[NH2:2]
Reactant: C#Cc1cn([C@H]2C[C@H](O)[C@@H](COS(N)(=O)=O)O2)c2ncnc(CCc3ccccc3)c12
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: CCc1cn([C@H]2C[C@H](O)[C@@H](COS(N)(=O)=O)O2)c2ncnc(CCc3ccccc3)c12
Yield: 11.8 %

Procedure:
A suspension of {(2R,3S,5R)-5-[5-ethynyl-4-(2-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-3-hydroxytetrahydrofuran-2-yl}methyl sulfamate (0.0824 g, 0.190 mmol) and Pd/C (10% wt, ˜50% H2O, 0.01 g) in EtOH (10 mL) was stirred under an atmosphere of H2 (1 atm) for 5 h at r.t. The reaction mixture was filtered through celite and the filtrate was concentrated. The residue was purified by flash chromatography (0 to 10% MeOH/DCM) to give the title compound (0.010 g, 11%).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([C:9]2[N:18]=[C:17]([C:19]([OH:21])=O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1.Cl.[OH:25][C:26]1[C:35]([CH3:36])=[CH:34][CH:33]=[C:32]2[C:27]=1[CH2:28][CH2:29][NH:30][CH2:31]2>>[F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([C:9]2[N:18]=[C:17]([C:19]([N:30]3[CH2:29][CH2:28][C:27]4[C:32](=[CH:33][CH:34]=[C:35]([CH3:36])[C:26]=4[OH:25])[CH2:31]3)=[O:21])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1ccc2c(c1O)CCNC2
Reactant: O=C(O)c1nc(-c2cccc(C(F)(F)F)c2)nc2ccccc12
Agent: Cl
Product: Cc1ccc2c(c1O)CCN(C(=O)c1nc(-c3cccc(C(F)(F)F)c3)nc3ccccc13)C2
Yield: 14 %

Procedure:
Reaction of 2-(3-(trifluoromethyl)phenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 56 (14% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 2.25 and 2.28 (2s, 3H), 2.82 and 3.06 (2t, 2H), 3.61 and 4.25 (2t, 2H), 4.48 and 5.11 (2s, 2H), 6.34 and 6.83 (2d, 1H), 6.90 and 7.09 (2d, 1H), 7.63-7.71 (m, 2H), 7.79-7.81 (m, 1H), 7.98-8.09 (m, 2H), 8.25-8.30 (m, 1H), 8.88-8.97 (m, 2H); MS (ESI) m/z 464 ([M+H]+).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:8]([CH2:14][C:15]3[CH:34]=[CH:33][C:18]4/[C:19](=[C:29](/[CH3:32])\[C:30]#[N:31])/[C:20]5[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:21]=5[O:22][CH2:23][C:17]=4[CH:16]=3)=[C:9]([CH:11]3[CH2:13][CH2:12]3)[N:10]=2)[CH:5]=[CH:6][N:7]=1.[CH3:35][NH:36][CH3:37].C1COCC1.O>C1COCC1>[CH:11]1([C:9]2[N:10]=[C:3]3[C:2]([N:36]([CH3:37])[CH3:35])=[N:7][CH:6]=[CH:5][N:4]3[C:8]=2[CH2:14][C:15]2[CH:34]=[CH:33][C:18]3/[C:19](=[C:29](/[CH3:32])\[C:30]#[N:31])/[C:20]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:21]=4[O:22][CH2:23][C:17]=3[CH:16]=2)[CH2:12][CH2:13]1
Reactant: CNC
Reactant: C/C(C#N)=C1/c2ccc(Cc3c(C4CC4)nc4c(Cl)nccn34)cc2COc2cc(F)ccc21
Solvent: O
Solvent: C1CCOC1
Product: C/C(C#N)=C1/c2ccc(Cc3c(C4CC4)nc4c(N(C)C)nccn34)cc2COc2cc(F)ccc21
Temperature: 100 °C
Yield: 87.3 %

Procedure:
[step 6] (E)-2-{8-[(8-chloro-2-cyclopropylimidazo[1,2-a]pyrazin-3-yl)methyl]-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene}propanenitrile (0.2 g, 0.43 mmol) obtained in step 5 was dissolved in THF (1.4 mL), and 2 mol/L dimethylamine THF solution (1.7 mL, 3.4 mmol) was added. The mixture was stirred with heating at 100° C. for 1.5 hr in an Emrys Optimizer microwave synthesizer. Water was added to the mixture, and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane/ethyl acetate=100/0 v/v-50/50 v/v) to give the title compound (0.18 g, 87%).
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:14]=[C:15]([C:19]2[O:23][N:22]=[C:21]([OH:24])[CH:20]=2)[CH:16]=[CH:17][CH:18]=1.[B:25](OC(C)C)([O:30]C(C)C)[O:26]C(C)C.Cl>C1(C)C=CC=CC=1.C1COCC1>[OH:24][C:21]1[CH:20]=[C:19]([C:15]2[CH:14]=[C:13]([B:25]([OH:30])[OH:26])[CH:18]=[CH:17][CH:16]=2)[O:23][N:22]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Oc1cc(-c2cccc(Br)c2)on1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OB(O)c1cccc(-c2cc(O)no2)c1
Temperature: -20 °C
Reaction time: 1.5 h

Procedure:
Add a 2.5 M solution of n-butyllithium in hexane (0.60 mL, 1.10 mmol) to a solution of 5-(3-bromophenyl)isoxazol-3-ol (120 mg, 0.50 mmol) and triisopropyl borate (113 mg, 0.60 mmol) in a mixture of toluene (2.5 mL) and THF (2.5 mL) at −78° C. After 1.5 h, warm the mixture to −20° C. and add a 2.0 N aqueous HCl solution (1 mL). Extract the mixture with EtOAc after warm to room temperature. Dry, filter and concentrate the organic layer to a white solid.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].C([Li])CCC.[CH3:12][C:13]1[O:17][N:16]=[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14]=1C(Cl)=O>C1COCC1>[CH3:12][C:13]1[O:17][N:16]=[C:15]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:14]=1[C:4](=[O:6])[CH2:3][C:1]#[N:2]
Reactant: N#CCC(=O)O
Reactant: Cc1onc(-c2ccccc2)c1C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1onc(-c2ccccc2)c1C(=O)CC#N
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.5 %

Procedure:
To cyanoacetic acid (0.43 g, 5.12 mmol) in THF at −78° C., containing one crystal of 1,1′-bipyridyl was added n-butyl lithium (6.4 mL, 10.24 mmol). The temperature was allowed to warm to 0° C. resulting in a pink colored solution. After cooling to −78° C., 5-Methyl-3-phenyl-isoxazole-4-carbonyl chloride (0.567 g, 2.56 mmol) in THF (5 mL) was added dropwise. The mixture was stirred at −78° C. for 1 hr. and at ambient temperature for an addition 1 hr. The reaction was quenched with 1N HCl (13 mL0 and extracted twice with CH2Cl2. Combined extracts were washed with saturated NaHCO3, brine, dried over MgSO4 to give the title compound (0.391 g, 67% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:18]([CH3:23])([CH3:22])[C:19](F)=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH3:28].O>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:18]([CH3:22])([CH3:23])[C:19]([NH2:28])=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: N
Reactant: CC(C)CC(c1ccc2c(cnn2-c2ccc(F)cc2)c1)C(C)(C)C(=O)F
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CC(c1ccc2c(cnn2-c2ccc(F)cc2)c1)C(C)(C)C(N)=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2,5-trimethylhexanoyl fluoride (1.65 g, 4.23 mmol) in anhydrous THF (30 mL) at −78° C. was bubbled NH3 (g) for 10 minutes. The reaction mixture was sealed and stirred at −78° C. for 15 min and at rt for 1 hr. Water (100 mL) was added, the reaction mixture was extracted with ethyl acetate (100 mL), dried (Na2SO4), and concentrated to give 1.62 g (100% yield) of 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2,5-trimethylhexanamide, the NMR spectrum of which was consistent with the desired structure.
Reaction SMILES: C([O:5][C:6](=[O:40])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][C:15]([N:17]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]#[N:36])[S:18]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)(=[O:20])=[O:19])=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:37][CH2:38][CH3:39])(C)(C)C.C(O)(C(F)(F)F)=O>>[C:35]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH2:28][N:17]([S:18]([C:21]1[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=1)(=[O:19])=[O:20])[C:15]1[CH:14]=[CH:13][C:12]2[N:8]([CH2:7][C:6]([OH:40])=[O:5])[C:9]([CH2:37][CH2:38][CH3:39])=[N:10][C:11]=2[CH:16]=1)#[N:36]
Reactant: CCCc1nc2cc(N(Cc3ccccc3C#N)S(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2cc(N(Cc3ccccc3C#N)S(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)O

Procedure:
{5-[(2-Cyano-benzyl)-(4-fluoro-benzenesulfonyl)-amino]-2-propyl-benzoimidazol-1-yl}-acetic acid tert-butyl ester was treated with TFA (2 mL) for 2 hours, concentrated, and purified by preparative LCMS to give the title compound. MS calculated for C26H23FN4O4S+H: 507, observed: 507.