Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]#N)=[CH:5][CH:4]=1.CC(C[AlH]CC(C)C)C.Cl.[OH2:25]>C1(C)C=CC=CC=1>[Br:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH:13]=[O:25])=[CH:5][CH:4]=1
Reactant: O
Reactant: N#Cc1ccc(CBr)c2ccccc12
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: O=Cc1ccc(CBr)c2ccccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a stirred solution of 4-(bromomethyl)-1-naphthonitrile (8 g, 33 mmol) in toluene (100 mL) at 0° C. was added dropwise DIBAL-H (1.0 M solution in toluene; 43 mL), and the reaction mixture was stirred at 0° C. for 1 h. 3 N HCl in H2O (50 mL) was added to the mixture until it became a white slurry and then additional 1 N HCl (20 mL) was added. The organic layer was collected and the aqueous layer was extracted with EtOAc (3×100 mL). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; 5% EtOAc in petroleum ether) afforded the title compound as a white solid (7 g, 88%): mp 115-116° C.; 1H NMR (400 MHz, CDCl3) δ 10.41 (s, 1H), 9.35 (m, 1H), 8.22 (m, 1H), 7.90 (d, J=8.0 Hz, 1H), 7.75 (m, 3H), 4.95 (s, 2H); ESIMS m/z 248.88 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:17]([C:22]2[C:40]([CH:41]3[CH2:43][CH2:42]3)=[CH:39][C:25]3[C:26]([C:36]([OH:38])=[O:37])=[C:27]([C:29]4[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=4)[O:28][C:24]=3[CH:23]=2)[S:18]([CH3:21])(=[O:20])=[O:19])[CH:5]=[CH:6][C:7]=1[B:8]1[O:12]C(C)(C)C(C)(C)[O:9]1.I([O-])(=O)(=O)=O.[Na+].Cl.O>C1COCC1.CCOC(C)=O>[B:8]([C:7]1[CH:6]=[CH:5][C:4]([N:17]([C:22]2[C:40]([CH:41]3[CH2:42][CH2:43]3)=[CH:39][C:25]3[C:26]([C:36]([OH:38])=[O:37])=[C:27]([C:29]4[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=4)[O:28][C:24]=3[CH:23]=2)[S:18]([CH3:21])(=[O:20])=[O:19])=[CH:3][C:2]=1[Cl:1])([OH:9])[OH:12]
Reactant: CC1(C)OB(c2ccc(N(c3cc4oc(-c5ccc(Cl)cc5)c(C(=O)O)c4cc3C3CC3)S(C)(=O)=O)cc2Cl)OC1(C)C
Agent: Cl
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CS(=O)(=O)N(c1ccc(B(O)O)c(Cl)c1)c1cc2oc(-c3ccc(Cl)cc3)c(C(=O)O)c2cc1C1CC1
Yield: 24 %

Procedure:
A solution of 6-(N-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylsulfonamido)-2-(4-chlorophenyl)-5-cyclopropylbenzofuran-3-carboxylic acid (110 mg, 0.171 mmol) and sodium periodate (183 mg, 0.856 mmol) in THF (14 mL) and aqueous 1N HCl (7 mL) was stirred at RT for 4 h then water and EtOAc were added. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by Reverse Phase HPLC (water/ACN+0.1% formic acid) to give 6-(N-(4-borono-3-chlorophenyl)methylsulfonamido)-2-(4-chlorophenyl)-5-cyclopropylbenzofuran-3-carboxylic acid (24 mg, 0.041 mmol, 24% yield) as a white powder. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.31 (br. s., 1H), 8.33 (s, 2H), 8.16 (s, 1H), 8.03 (d, 2H), 7.52-7.70 (m, 3H), 7.37-7.48 (m, 2H), 7.34 (dd, 1H), 3.40 (s, 3H), 2.09-2.22 (m, 1H), 0.64-1.11 (m, 3H), 0.47 (br. s., 1H). LCMS (m/z, ES+)=558.1 (M−H).
Reaction SMILES: [C:1]1(=[O:23])[N:5]([CH:6]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][PH:8](=[O:10])[OH:9])[C:4](=[O:18])[C:3]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:2]12.P(Cl)(Cl)(Cl)(Cl)Cl.[CH2:30](O)[CH3:31].C(N(CC)CC)C.[NH2:40][CH:41]1[CH2:46][S:45][C@H:44]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[N:43]([CH2:53][C:54]([O:56][CH2:57][CH3:58])=[O:55])[C:42]1=[O:59]>C1C=CC=CC=1.C(Cl)Cl>[C:4]1(=[O:18])[N:5]([CH:6]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][P:8]([NH:40][CH:41]2[CH2:46][S:45][C@H:44]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[N:43]([CH2:53][C:54]([O:56][CH2:57][CH3:58])=[O:55])[C:42]2=[O:59])([O:9][CH2:30][CH3:31])=[O:10])[C:1](=[O:23])[C:2]2=[CH:22][CH:21]=[CH:20][CH:19]=[C:3]12
Reactant: CCO
Reactant: O=C1c2ccccc2C(=O)N1C(Cc1ccccc1)C[PH](=O)O
Reactant: CCOC(=O)CN1C(=O)C(N)CS[C@@H]1c1ccccc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: c1ccccc1
Product: CCOC(=O)CN1C(=O)C(NP(=O)(CC(Cc2ccccc2)N2C(=O)c3ccccc3C2=O)OCC)CS[C@@H]1c1ccccc1
Temperature: 25 °C

Procedure:
A suspension of (2-phthalimido-3-phenylpropyl)phosphinic acid in dry benzene is treated with phosphorus pentachloride and stirred at room temperature under argon for an hour. The mixture is then refluxed for 15 minutes, cooled and evaporated to dryness at room temperature (0.5 mm. of Hg). The residue is taken up in dry methylene chloride and reacted successively with a mixture of ethanol (1 eq.) and triethylamine (1 eq.) in methylene chloride and (R)-dihydro-5-amino-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, ethyl ester in the presence of triethylamine according to the procedure of Example 1(f). Work up of the reaction mixture according to the procedure of Example 1(f) yields (R)-dihydro-5-[[[2-phthalimido-3-phenylpropyl]ethoxyphosphinyl]amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:31])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH2:17][CH:18]2[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]2)=[N:6][CH:7]=1.FC(F)(F)C([O-])=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:31])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH2:17][CH:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccccc2C(=O)Nc2ccc(Cl)cn2)CC1
Agent: O=C([O-])C(F)(F)F
Product: O=C(Nc1ccc(Cl)cn1)c1ccccc1OCC1CCNCC1
Yield: 187.8 %

Procedure:
Using a similar procedure to that described in Example 9-B, N-(5-chloropyridin-2-yl)-2-(1-tert-butoxycarbonylpiperidin-4-ylmethoxy)benzamide (240 mg, 0.539 mmol) yielded 350 mg of the title compound as a trifluoroacetate salt which was used without further purification.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5]([O:7][C:8](=[O:13])[CH2:9][C:10](C)=O)C.[CH3:14]N(C)C=O>>[CH3:5][O:7][C:8](=[O:13])[C@@H:9]([CH3:14])[CH2:10][N:1]=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CN(C)C=O
Reactant: CCOC(=O)CC(C)=O
Agent: [Na+]
Product: COC(=O)[C@@H](C)CN=[N+]=[N-]
Temperature: 60 °C
Reaction time: 24 h
Yield: 96 %

Procedure:
4.97 g (25.3 mmol) of (S)-3-methanesulfonyloxy-2-methyl-propionic acid methyl ester obtained in the above step (2) was dissolved in 40 mL of dimethylformamide, and then 5 g (76.8 mmol) of sodium azide was added thereto, followed by stirring at 60° C. for 24 hours. 200 mL of ethylacetoacetate was added to the solution, and the reaction solution was washed with water, then an organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, then the residue was purified by column chromatography to give 3.5 g (24.4 mmol) of the title compound in a yield of 96%.
Reaction SMILES: C1CCCC([O:7][C:8]2[CH:17]=[C:16]([NH:18][C:19](=[O:21])[CH3:20])[C:15]([Cl:22])=[CH:14][C:9]=2[C:10]([O:12][CH3:13])=[O:11])C=1.CCN([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)CC>C(OC(=O)C)C.CCCCCC>[CH2:30]([C:17]1[C:16]([NH:18][C:19](=[O:21])[CH3:20])=[C:15]([Cl:22])[CH:14]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[C:8]=1[OH:7])[CH2:29][CH:28]=[CH:33][CH2:32][CH3:31]
Reactant: COC(=O)c1cc(Cl)c(NC(C)=O)cc1OC1C=CCCC1
Reactant: CCN(CC)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCC=CCCc1c(O)c(C(=O)OC)cc(Cl)c1NC(C)=O
Temperature: 220 °C

Procedure:
A mixture of 0.6 g of methyl 2-(cyclohexen-3-yloxy)-4-acetylamino-5-chlorobenzoate and 0.5 ml diethylaniline is placed under house vaccum and heated to 220° C. for 2 hours. This reaction mixture is then diluted with 40% ethylacetate/hexane and purified by dry column chromatography using the same solvent system as eluent. Three fractions are separated: 1. diethylaniline; 2. starting benzoate compound and 3. methyl 3-(3-hexenyl)-4-acetylamino-5-chlorosalicylate. The latter is used directly in the next step.
Reaction SMILES: [F:1][C:2]([F:13])([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][N:7]=1)[C:3]([O-])=O.[Na+].[NH2:15][C:16]1[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([NH2:20])=[O:19]>O>[F:1][C:2]([F:13])([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][N:7]=1)[C:3]1[NH:20][C:18](=[O:19])[C:17]2[C:16](=[C:24]([F:25])[CH:23]=[CH:22][CH:21]=2)[N:15]=1
Reactant: O=C([O-])C(F)(F)c1ccc(F)cn1
Reactant: NC(=O)c1cccc(F)c1N
Agent: [Na+]
Solvent: O
Product: O=c1[nH]c(C(F)(F)c2ccc(F)cn2)nc2c(F)cccc12
Temperature: 115 °C
Yield: 97 %

Procedure:
Sodium 2,2-difluoro-2-(5-fluoropyridin-2-yl)acetate from Example 2 Step B (51 mg, 0.24 mmol) and 2-amino-3-fluorobenzamide (31 mg, 0.2 mmol) were combined with polyphosphoric acid (1.0 g) and the mixture was heated at 115° C. for 20 h with vigorous stirring. The mixture was allowed to cool to rt, then water (3 mL) was added, resulting in a precipitate that was separated washing with DCE (2×8 mL). The combined DCE extracts were washed with brine (3 mL) and separated using Biotage Phase Separators. The organic fraction was concentrated using a Savant Speed Vac to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-8-fluoroquinazolin-4(3H)-one as an off-white solid (60 mg). LCMS (ESI) m/z 310 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[CH2:9]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[CH3:10]>C1(C)C=CC=CC=1>[CH2:9]([N:11]1[CH2:16][CH2:15][N:14]([C:6]2[N:5]=[CH:4][N:3]=[C:2]([NH2:1])[CH:7]=2)[CH2:13][CH2:12]1)[CH3:10]
Reactant: Nc1cc(Cl)ncn1
Reactant: CCN1CCNCC1
Solvent: Cc1ccccc1
Product: CCN1CCN(c2cc(N)ncn2)CC1
Temperature: 110 °C

Procedure:
A mixture of 1 g (7.7 mmol) 4-amino-6-chloropyrimidine (commercially available) and 1.75 g (15.4 mmol) 1-ethyl piperazine (commercially available) in 10 mL toluene was heated to 110° C. for 16 h. After evaporation of all volatiles the residue was purified by flash column chromatography on silica eluting with a gradient formed from DCM (0.5% NEt3) and methanol. The combined product fractions were evaporated to dryness to yield the title compound. MS (m/e): 208.3 (MH+).
Reaction SMILES: C(O[C:4](=[O:12])[CH2:5][C:6](=O)[C:7]([F:10])([F:9])[F:8])C.Cl.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][NH2:22]>C(O)C>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[C:4]([OH:12])=[CH:5][C:6]([C:7]([F:8])([F:9])[F:10])=[N:22]1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: NNc1ccccc1Cl
Agent: Cl
Solvent: CCO
Product: Oc1cc(C(F)(F)F)nn1-c1ccccc1Cl

Procedure:
Into a 250 mL flask was weighed 5.01 g of 4,4,4-trifluoro-3-oxo-butyric acid ethyl ester, 4.88 g of 2-chlorophenylhydrazine hydrochloride, and 100 mL of ethanol. The resulting solution was heated at 90-950C for 18 h then was concentrated in vacuo to remove ethanol. The residue was washed into a separatory funnel with ethyl acetate and 1 M HCl. The ethyl acetate was separated, washed with brine, was dried, and concentrated in vacuo. The residue was partially purified by silica gel flash chromatography (Jones Flashmaster, 70 g Silica gel, gradient elution from 100% hexanes to 20% ethyl acetate over 30 minutes). Appropriate fractions were combined and concentrated and product was precipitated by addition of excess hexanes. The solid precipitate was collected by filtration and was dried under high vacuum to afford the intermediate 2-(2-Chlorophenyl)-5-trifluoromethyl-2H-pyrazol-3-ol as a tan powder, yield: 3.73 g (52%). 1H NMR (DMSO-d6): δ 12.25 (br s, 1H), 7.72 (d, J=8 Hz, 1H), 7.5-7.65 (m, 3H), 5.94 (s, 1H).
Reaction SMILES: Br[CH:2]1[CH2:8][NH:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]2[C:13]([CH3:16])=[N:14][N:15]=[C:3]12.CC1(C)C(C)(C)OB([C:25]2[CH:26]=[CH:27][C:28]([NH2:31])=[N:29][CH:30]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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>[CH3:16][C:13]1[N:4]2[C:5]3[CH:12]=[CH:11][C:10]([C:25]4[CH:26]=[CH:27][C:28]([NH2:31])=[N:29][CH:30]=4)=[CH:9][C:6]=3[NH:7][CH2:8][CH2:2][C:3]2=[N:15][N:14]=1
Reactant: Cc1nnc2n1-c1ccccc1NCC2Br
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nnc2n1-c1ccc(-c3ccc(N)nc3)cc1NCC2
Yield: 65.3 %

Procedure:
A solution of bromo-1-methyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine (30 mg, 0.11 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (48 mg, 0.22 mmol), Tetrakis(triphenylphosphine)palladium(0) (10 mg) and Cs2CO3 (72 mg, 0.22 mmol) in dioxane (5 mL) and water (1 mL) was heated at 120° C. under microwave for 20 min. The reaction mixture was concentrated to give the crude product, which was purified by prep-TLC (DCM:MeOH=10:1) to afford 5-(1-methyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-8-yl)pyridin-2-amine (21 mg, yield 55%).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35](Cl)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35]([N:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)=[O:36])[C@@:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C@@:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: C1CCNCC1
Product: CCOc1nc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCCCC1

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with piperidine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C33H40Cl2N5O2 [(M+H)+] 608.2554, observed 608.2551.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[C:14]([O:15][CH:16]2[CH2:21][CH2:20][N:19]([CH:22]3[CH2:25][O:24][CH2:23]3)[CH2:18][CH2:17]2)=[CH:13][C:12]([C:26]#[N:27])=[CH:11][C:10]=1[NH:28][C:29]1[N:34]=[C:33]([N:35]([CH:45]2[CH2:47][CH2:46]2)CC2C=CC(OC)=CC=2)[C:32]2=[N:48][CH:49]=[C:50]([C:51]#[N:52])[N:31]2[N:30]=1.C1(OC)C=CC=CC=1>ClCCCl>[Cl:8][C:9]1[C:14]([O:15][CH:16]2[CH2:21][CH2:20][N:19]([CH:22]3[CH2:25][O:24][CH2:23]3)[CH2:18][CH2:17]2)=[CH:13][C:12]([C:26]#[N:27])=[CH:11][C:10]=1[NH:28][C:29]1[N:34]=[C:33]([NH:35][CH:45]2[CH2:46][CH2:47]2)[C:32]2=[N:48][CH:49]=[C:50]([C:51]#[N:52])[N:31]2[N:30]=1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(OC4CCN(C5COC5)CC4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Solvent: COc1ccccc1
Product: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(Cl)c(OC2CCN(C3COC3)CC2)c1
Temperature: 45 °C
Yield: 66.7 %

Procedure:
TFA (25% in DCE, 2 ml, 6.49 mmol) was added to a solution of 2-((2-chloro-5-cyano-3-((1-(oxetan-3-yl)piperidin-4-yl)oxy)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (50 mg, 0.080 mmol) and anisole (0.035 ml, 0.319 mmol) in DCE (1 mL) and the reaction mixture was heated at 45° C. for 3 hours. Solvent was evaporated in vacuo and the residue was dried under vacuum overnight. The residue was washed with hexane (2×2 ml), dissolved in acetonitrile (2 ml) and 2N ammonia in methanol was added to give a suspension. Solvent was evaporated until a very small amount and the precipitate was collected by filtration. 2-((2-chloro-5-cyano-3-((1-(oxetan-3-yl)piperidin-4-yl)oxy)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (27 mg) was obtained as a white solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][NH:6][C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])[CH2:3]1.[NH2:23][C:24]1[S:25][C:26]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[CH:33]=2)=[C:27]([C:29](O)=[O:30])[N:28]=1>>[CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][N:6]([C:29]([C:27]3[N:28]=[C:24]([NH2:23])[S:25][C:26]=3[C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[CH:33]=3)=[O:30])[C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])[CH2:3]1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CC(C)C[C@@H]21
Reactant: Cc1cccc(-c2sc(N)nc2C(=O)O)c1
Product: Cc1cccc(-c2sc(N)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-7-methyl-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 2-amino-5-(3-methyl-phenyl)-thiazole-4-carboxylic acid.
Reaction SMILES: O1[C:5]2[CH:6]=[CH:7]C=[CH:9][C:4]=2[N:3]=C1C=CC1C(=O)NC(C)=C(CC)C=1.CO.[CH2:24]([OH:26])C.[CH2:27]1[CH2:31][O:30][CH2:29][CH2:28]1>[Pd]>[CH3:29][O:30][C:31]1[N:3]=[C:4]([CH3:9])[C:5]([CH2:6][CH3:7])=[CH:28][C:27]=1[CH:24]=[O:26]
Reactant: C1CCOC1
Reactant: CCc1cc(C=Cc2nc3ccccc3o2)c(=O)[nH]c1C
Reactant: CCO
Agent: [Pd]
Solvent: CO
Product: CCc1cc(C=O)c(OC)nc1C

Procedure:
A solution of 80% pure 3-[2-(benzoxazol-2-yl)ethenyl]-5-ethyl-6-methyl-2-(1H)-pyridinone (200 mg) in methanol/ethanol/THF (25 mL, 1:1:1) was hydrogenated at atmospheric pressure over 5% palladium/charcoal for four hours. After filtering off the catalyst, the solvents were evaporated and the residue flash chromatographed over silica gel. Elution with 2% methanol-98% chloroform gave 75 mg of analytically pure product, mp 155°-156.5° C.
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:4]([NH:6][CH2:7][C:8]([OH:10])=O)=[O:5])C.[NH2:28][C@H:29]([CH:37]=[O:38])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[CH3:39]N(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN(C)C=O.ClCCl>[NH2:28][C@H:29]([C:37]([NH:1][CH2:2][C:4]([NH:6][C@H:7]([CH:8]=[O:10])[CH3:39])=[O:5])=[O:38])[CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: N[C@H](C=O)Cc1ccccc1
Reactant: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCC(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](C=O)NC(=O)CNC(=O)[C@@H](N)Cc1ccccc1

Procedure:
Similar to comparative example 4, CTC-phenylalanine (Phe)-H was synthesized by the solid phase reaction method using CTC as a solid phase carrier. Furthermore, similar to Example 7, Fmoc-Ala-Gly-OH was synthesized. Then, to dichloromethane (2 ml) were added CTC-Phe-H (110 mg (0.145 mmol)), Fmoc-Ala-Gly-OH (160 mg (0.4 mmol)), HBTU (165 mg (0.4 mmol)), HOBt (60 mg (0.4 mmol)), dimethylformamide (1 ml) and diisopropylethylamine (75 μl (0.4 mmol)), respectively, and the mixture was stirred to react at room temperature for 2 hours. After the reaction, the solid phase was washed with dimethylformamide (3×2 ml), methanol (3×2 ml) and dichloromethane (3×2 ml), respectively. Subsequently, to the above solid phase was added the previously prepared Fmoc deprotection solution (dimethylformamide:piperidine:DBU=96:2:2) (2 ml), and the mixture was stirred to react at room temperature for 1 hour to obtain CTC-Phe-Gly-Ala-H.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:14]([O:16]CC)=O)[C:11]([NH:12][NH2:13])=[C:6]2[CH:5]=[N:4]1)[CH3:2].C(O[CH:22]=[N:23][C:24]#[N:25])C>O1CCOCC1>[CH2:1]([N:3]1[C:7]2[N:8]=[CH:9][C:10]3[C:14](=[O:16])[NH:25][C:24]4[N:12]([N:13]=[CH:22][N:23]=4)[C:11]=3[C:6]=2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1NN
Reactant: CCOC=NC#N
Solvent: C1COCCO1
Product: CCn1ncc2c1ncc1c(=O)[nH]c3ncnn3c12
Temperature: 25 °C

Procedure:
249 g. of 1-ethyl-4-hydrazino-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester (1 mol.) are refluxed in 1.5 liters of dry dioxane together with 98 g. of ethoxymethylene cyanamide for 12 hours. After cooling to room temperature, the precipitated 8-ethyl-4H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidin-5(8H)-one is filtered off and recrystallized from dimethylformamide, yield 135 g. (53%); m.p. 355°-356°.
Reaction SMILES: C(O)(C(F)(F)F)=O.CC([N:12]([CH2:16][C@@H:17]([NH:25][C:26]([C:28]1[S:29][CH:30]=[C:31]([C:33]2[N:37]([CH3:38])[N:36]=[CH:35][N:34]=2)[CH:32]=1)=[O:27])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)C(=O)[O-])(C)C>C(Cl)Cl>[NH2:12][CH2:16][C@@H:17]([NH:25][C:26]([C:28]1[S:29][CH:30]=[C:31]([C:33]2[N:37]([CH3:38])[N:36]=[CH:35][N:34]=2)[CH:32]=1)=[O:27])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cn1ncnc1-c1csc(C(=O)N[C@@H](Cc2ccccc2)CN(C(=O)[O-])C(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1ncnc1-c1csc(C(=O)N[C@H](CN)Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 116.6 %

Procedure:
TFA (1 ml) was added to a solution of 1,1-dimethylethyl[(2S)-2-({[4-(1-methyl-1H-1,2,4-triazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate (100 mg, 0.226 mmol) in DCM (5 ml). The reaction was stirred at RT for 30 min. The solvent was removed and the residue was purified by reverse phase HPLC (10% org˜60% org) to give the title compound as a white solid (90 mg, 87%). LC-MS (ES) m/z 342.2 (M+H)+, 1H NMR (d4-MeOH, 400 MHz) δ 8.23 (s, 1H), 8.03 (m, 2H), 7.22-7.31 (m, 5H), 4.60 (m, 1H), 4.08 (s, 3H), 3.10-3.20 (m, 2H), 3.00 (m, 2H).
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[F:9][C:10]([C:13]1[CH:18]=[CH:17][C:16](B2OC(C)(C)C(C)(C)O2)=[CH:15][CH:14]=1)([F:12])[CH3:11]>O.[Ru](=O)=O>[F:9][C:10]([C:13]1[CH:18]=[CH:17][C:16]([C@H:2]2[O:6][C@@H:5]([CH2:7][OH:8])[CH2:4][CH2:3]2)=[CH:15][CH:14]=1)([F:12])[CH3:11]
Reactant: O=Cc1ccc(Br)o1
Reactant: CC(F)(F)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: O=[Ru]=O
Solvent: O
Product: CC(F)(F)c1ccc([C@@H]2CC[C@H](CO)O2)cc1

Procedure:
The requisite {cis-5-[4-(1,1-difluoroethyl)phenyl]tetrahydrofuran-2-yl}methanol was prepared via Suzuki reaction of 5-bromofuran-2-carbaldehyde with 2-[4-(1,1-difluoroethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, followed by hydrogenation in the presence of ruthenium(IV) oxide hydrate.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][N:4]([C@@H:7]2[CH2:12][CH2:11][CH2:10][NH:9][C@@H:8]2[CH3:13])[C:3]1=[O:14].[Cl:15][C:16]1[C:17]([C:23]#[N:24])=[N:18][CH:19]=[C:20](Cl)[N:21]=1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[Cl:15][C:16]1[C:17]([C:23]#[N:24])=[N:18][CH:19]=[C:20]([N:9]2[CH2:10][CH2:11][CH2:12][C@@H:7]([N:4]3[CH2:5][CH2:6][N:2]([CH3:1])[C:3]3=[O:14])[C@H:8]2[CH3:13])[N:21]=1
Reactant: N#Cc1ncc(Cl)nc1Cl
Reactant: C[C@H]1NCCC[C@H]1N1CCN(C)C1=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1[C@H](N2CCN(C)C2=O)CCCN1c1cnc(C#N)c(Cl)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
Compound 356 from above was dissolved in 10 mL DMF. To it were added 3,5-dichloropyrazine-2-carbonitrile (250 mg, 1.42 mmol) and DIEA (500 μL, 2.84 mmol). The mixture was stirred at RT for 2 hours, diluted with 150 mL EtOAc, washed with water ×3, dried, concentrated in vacuo, and subjected to silica flash column using 0 to 3% MeOH in DCM to isolate 3-chloro-5-((2R,3R)-2-methyl-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carbonitrile (357, 200 mg, 42% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=[C:4]([CH:11]([C:14](=O)[C:15]([F:18])([F:17])[F:16])[C:12]#[N:13])[CH:3]=1.O=P(Cl)(Cl)[Cl:22].C(N(CC)CC)C>O>[Cl:22][C:14]([C:15]([F:18])([F:17])[F:16])=[C:11]([C:4]1[CH:3]=[C:2]([Cl:1])[C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=1)[C:12]#[N:13]
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#CC(C(=O)C(F)(F)F)c1cc(Cl)c2c(c1)OCO2
Solvent: CCN(CC)CC
Solvent: O
Product: N#CC(=C(Cl)C(F)(F)F)c1cc(Cl)c2c(c1)OCO2
Temperature: 90 °C
Yield: 79.5 %

Procedure:
2-(7-chloro-1,3-benzodioxol-5-yl)-4,4,4-trifluoro-3-oxo-butanenitrile (23.9 g, 82 mmol) was treated with POCl3 (62.0 g, 0.41 mol) and then triethylamine (11.4 mL, 82 mmol) was added. The reaction mixture was heated for 3 h at 80-100° C. and then carefully poured into warm water. The product was then extracted ethyl acetate, washed with water and brine, dried, filtered and concentrated to give the title compound (20.2 g; 80%) and used for the next step directly.