Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:11]2[C:10](=S)[NH:9][C:8]3[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:17][CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1.C(Cl)Cl>C(OCCO)C>[CH:1]1[C:11]2[C:10]([NH:17][CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[N:9][C:8]3[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: NCc1cccnc1
Reactant: S=C1Nc2ccccc2Nc2ccccc21
Solvent: ClCCl
Solvent: CCOCCO
Product: c1cncc(CNC2=Nc3ccccc3Nc3ccccc32)c1
Yield: 56.6 %

Procedure:
A solution of 0.6 g (2.7 mmol) of 5,10-dihydro-dibenzo[b,e][1,4]diazepin-11-thione [German Patent, DE-2,306,762, C.A. 79:126533a (1973)] in 10 mL 2-ethoxyethanol was treated with 0.6 mL (5.4 mmol) of 3-(aminomethyl)pyridine and heated at reflux overnight. The solvent was removed under reduced pressure and the residue taken up in EtOAc and washed three times with H2O, then saturated NaHCO3 solution and saturated NaCl solution. Drying over MgSO4 and removal of the solvent under reduced pressure left the crude product. Chromatography on silica gel, eluting with CHCl3 /MeOH (95/5) gave the product. On adding CH2Cl2, the product crystallized. There was obtained 459 mg (58.1% yield) of the pure product as a yellow solid, mp 150-152° C. The structure was confirmed by NMR and mass spectroscopy. (m+H)+ =301.
Reaction SMILES: C1([C@H](OC(=O)[NH:11][C@H:12]2[C@H:21]([O:22][CH3:23])[CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:24](=[O:26])[NH2:25])=[CH:17][CH:18]=3)[C:13]2([CH2:29][CH3:30])[CH2:27][CH3:28])C)C=CC=CC=1.Cl.O1CCOCC1>>[NH2:11][C@@H:12]1[C:13]([CH2:27][CH3:28])([CH2:29][CH3:30])[C:14]2[CH:15]=[C:16]([C:24]([NH2:25])=[O:26])[CH:17]=[CH:18][C:19]=2[CH2:20][C@H:21]1[O:22][CH3:23]
Reactant: CCC1(CC)c2cc(C(N)=O)ccc2C[C@@H](OC)[C@@H]1NC(=O)O[C@H](C)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: CCC1(CC)c2cc(C(N)=O)ccc2C[C@@H](OC)[C@@H]1N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
((2R,3R)-7-Carbamoyl-1,1-diethyl-3-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-carbamic acid (R)-1-phenyl-ethyl ester (1.7 g, 4.0 mmol) was treated with 4.0 N HCl in dioxane (20 mL, 80 mmol) and stirred at RT. After 24 h, the solvent was removed at reduced pressure and the residual solid was triturated with 50% dichloromethane in hexane (15 mL). The solid was collected on a Buchner funnel, rinsed with 50% dichloromethane in hexane (10 mL) and dried under vacuum to give the title compound as the hydrochloride salt (1.2 g). (m/z): [M+H]+ calcd for C16H24N2O2 277.19. found 277.4. 1H NMR (d6-DMSO, 400 mHz) δ (ppm) 8.19 (br s, 3H), 7.98 (s, 1H), 7.70 (m, 2H), 7.32 (s, 1H) 7.19 (d, J=7.8 Hz, 1H), 3.83 (m, 1H), 3.47 (m, 1H), 3.42 (s, 3H), 3.23 (m, 1H), 2.63 (dd, J=16.8 Hz, 9.7 Hz, 1H) 2.06 (m, 1H), 1.88 (m, 1H) 1.64 (guar, J=7.7 Hz, 2H), 0.62 (t, J=7.5 Hz, 3H), 0.50 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][N:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:15](=[NH:18])[NH:16][OH:17])[CH:12]=2)[C:7]1=[O:19])[CH3:2].[C:21](OC(=O)C)(=O)[CH3:22]>>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][N:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:15]3[N:18]=[C:21]([CH3:22])[O:17][N:16]=3)[CH:12]=2)[C:7]1=[O:19])[CH3:2]
Reactant: CCOC(=O)CN1Cc2cc(C(=N)NO)ccc2C1=O
Reactant: CC(=O)OC(C)=O
Product: CCOC(=O)CN1Cc2cc(-c3noc(C)n3)ccc2C1=O

Procedure:
The compound of example 66b (1 g; 3.8 mmol) in acetic anhydride (20 ml) was heated at 120° C. for 4 h. It was concentrated and purified using flash chromatography (silica gel, 5% CH3CN in dichloromethane) to obtain the title compound. Yield, 0.6 g (55%); mp, 155° C.; MS (ESI−): 286 (M−1), analysis: C14H13N3O4 requires C, 58.53; H, 4.56; N, 14.63; found: C, 58.13; H, 4.79; N, 14.14%.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][N:22]=1)[C:16]([O:18][CH3:19])=[O:17]>CO.[Pt](=O)=O>[ClH:1].[F:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:6]=[CH:5][C:4]=1[CH:13]1[CH2:14][CH:15]([C:16]([O:18][CH3:19])=[O:17])[CH2:20][CH2:21][NH:22]1
Reactant: COC(=O)c1ccnc(-c2ccc(C(F)(F)F)cc2F)c1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: COC(=O)C1CCNC(c2ccc(C(F)(F)F)cc2F)C1
Reaction time: 2 h
Yield: 92.8 %

Procedure:
Methyl 2-(2-fluoro-4-(trifluoromethyl)phenyl)isonicotinate hydrochloride (5.4 g, 16.09 mmol) was dissolved in MeOH (40 mL) and platinum(IV) oxide (0.365 g, 1.61 mmol) added. The resulting mixture was hydrogenated in a Büchi hydrogenator at room temperature and 5 bar for 2 h. The catalyst was filtered off and washed with MeOH and the eluate evaporated yielding methyl 2-(2-fluoro-4-(trifluoromethyl)phenyl)piperidine-4-carboxylate hydro-chloride (5.1 g, 93%) as a slightly brown solid. MS m/z 306 (M+H)+
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:11]([C:21]([CH3:23])=[CH2:22])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>CO.[Ni]>[Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:11]([CH:21]([CH3:23])[CH3:22])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: C=C(C)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Agent: [Ni]
Solvent: CO
Product: CC(C)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl (2S,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(prop-1-en-2-yl)pyrrolidine-1-carboxylate (90 g) dissolved in methanol (250 mL) was added Raney Nickel (24 g). The reaction mixture was stirred under hydrogen (40 atm) at 60° C. for 3 hours. The mixture was filtered and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with brine (2×50 mL), dried over magnesium sulfate, filtered and concentrated to give tert-butyl (2S,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(propan-2-yl)pyrrolidine-1-carboxylate. The residue was used directly without further purification.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.C[Al](C)C.[CH3:12][C:13]1[N:14]=[C:15]([CH2:21][CH2:22][C:23]2[C:24]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:25][O:26][C:27]=2[CH3:28])[S:16][C:17]=1[C:18](O)=[O:19]>O1CCOCC1.C1(C)C=CC=CC=1>[O:5]1[CH2:6][CH2:7][CH:2]([NH:1][C:18]([C:17]2[S:16][C:15]([CH2:21][CH2:22][C:23]3[C:24]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[N:25][O:26][C:27]=3[CH3:28])=[N:14][C:13]=2[CH3:12])=[O:19])[CH2:3][CH2:4]1
Reactant: NC1CCOCC1
Reactant: Cc1nc(CCc2c(-c3ccccc3)noc2C)sc1C(=O)O
Agent: C[Al](C)C
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: Cc1nc(CCc2c(-c3ccccc3)noc2C)sc1C(=O)NC1CCOCC1
Temperature: 90 °C
Reaction time: 1 h
Yield: 32.4 %

Procedure:
To a stirred suspension of 4-aminotetrahydropyran (123 mg, 1.2 mmol) in dioxane (5 mL) under argon at room temperature was added trimethylaluminium (0.6 mL of a 2M solution in toluene, 1.2 mmol). After 1 h, a solution of 4-methyl-2-[2-(5-methyl-3-phenyl-isoxazol-4-yl)-ethyl]-thiazole-5-carboxylic acid (100 mg, 0.3 mmol) in dioxane (5 mL) was added and the reaction mixture warmed to 90° C. After 3 h, the reaction mixture was cooled, quenched with ice water and extracted with dichloromethane. The combined extracts were washed with Seignette's salt solution then dried, filtered, and concentrated. Purification by chromatography (silica, 0 to 10% methanol in dichloromethane) gave the title compound (40 mg, 32%) as a colourless oil. MS: m/e=412.4 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:13])=[C:6]([C:11]#[N:12])[S:7][C:8]=1[S:9][CH3:10])(=[O:3])[CH3:2].[CH3:14][N:15]([CH:17](OC)OC)[CH3:16]>C(#N)C>[CH3:14][N:15]([CH3:17])[CH:16]=[CH:2][C:1]([C:4]1[C:5]([CH3:13])=[C:6]([C:11]#[N:12])[S:7][C:8]=1[S:9][CH3:10])=[O:3]
Reactant: CSc1sc(C#N)c(C)c1C(C)=O
Reactant: COC(OC)N(C)C
Solvent: CC#N
Product: CSc1sc(C#N)c(C)c1C(=O)C=CN(C)C

Procedure:
To a solution of 4-acetyl-3-methyl-5-methylsulfanyl-thiophene-2-carbonitrile (10 mmol) in acetonitrile (5 mL) was added DMF-DMA (2 mL) and the resulting mixture heated at reflux for 18 hours. The reaction was concentrated and the residue triturated with diethyl ether (20 mL). The suspension was filtered and washed with ether to afford the desired product as a yellow solid.
Reaction SMILES: C([NH:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[NH:21])[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:8][CH:7]=1)C=C>C(#N)C.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[C:17]([O:16][C:14]([NH:13][C:12]([C:9]1[CH:8]=[CH:7][C:6]([CH2:5][NH2:4])=[CH:11][CH:10]=1)=[NH:21])=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: C=CCNCc1ccc(C(=N)NC(=O)OC(C)(C)C)cc1
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC(=N)c1ccc(CN)cc1
Temperature: 25 °C

Procedure:
The N-allyl-4-(t-butoxycarbonylamidino)benzylamine (3.97 mmoles, 1.15 g) and chlorotris(triphenylphosphine)-rhodium(I) (0.21 mmoles, 195 mg) was stirred in acetonitrile/water (84:16, 92 mL) under nitrogen. The mixture was refluxed for 3 hr and allowed to cool to room temperature. Then the mixture was filtered through a pad of celite and the solvent removed in vacuo. The residue was dried on a high vacuum pump to yield an orange glassy product 4-(t-Butoxycarbonylamidino)benzylamine product was verified by HPLC/MS and used without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]([CH2:15][CH2:16][CH3:17])[C:12]([OH:14])=[O:13])=[CH:3]1.S(=O)(=O)(O)O.[CH3:23]O>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]([CH2:15][CH2:16][CH3:17])[C:12]([O:14][CH3:23])=[O:13])=[CH:3]1
Reactant: CO
Reactant: CCCC(C(=O)O)c1cn(C)c2ccccc12
Agent: O=S(=O)(O)O
Product: CCCC(C(=O)OC)c1cn(C)c2ccccc12
Yield: 70 %

Procedure:
A mixture of 2-(1-methyl-1H-indol-3-yl)pentanoic acid (12a) (1.22 g, 5.28 mmol) and concentrated sulfuric acid (1 mL) in methanol (40 mL) was refluxed for 3 hours. After concentration, the mixture was quenched with a saturated aqueous solution of sodium carbonate and the aqueous layer was extracted with dichloromethane (2×20 mL). The organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 93/7) to afford the desired ester (12b) as a white solid (910 mg, 3.71 mmol, 70%).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[O:4][N:3]=1.[C:11](Cl)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1C=CC=CC=1.N1C=CC=CC=1>[C:11]([NH:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[O:4][N:3]=1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)c1cc(N)no1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(NC(=O)c2ccccc2)no1

Procedure:
To a solution of 3-amino-5-t-butylisoxazole in benzene, benzoyl chloride and pyridine are added, whereby the reaction is carried out. Thus 3-benzoylamino-5-t-butylisoxazole is obtained as crystals melting at 192° to 193° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[O:1]([C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1cccc(O)c1
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.4 %

Procedure:
A mixture of ethyl 3-hydroxybenzoate (0.200 g; 1.20 mmol), benzeneboronic acid (0.294 g; 2.41 mmol), copper acetate (0.437 g; 2.41 mmol) and pyridine (0.195 mL; 2.42 mmol) in dichloromethane (8 mL) was stirred at room temperature overnight. The reaction mixture was filtered and concentrated in vacuo. The crude mixture was purified by flash chromatography on silica gel (eluent 5 to 35% ethyl acetate in heptane) to yield 0.222 g (76%) of the title compound as a colourless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:11]([Cl:19])=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27](=O)[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:42]=[CH:41][N:40]=[C:39]([CH3:43])[CH:38]=2)[CH:32]=1)=[O:30])(C)(C)C>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH2:15][CH:16]([CH3:17])[CH3:18])[C:11]([Cl:19])=[CH:10][C:9]=1[NH:20][C:27](=[O:26])[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:42]=[CH:41][N:40]=[C:39]([CH3:43])[CH:38]=2)[CH:32]=1)=[O:30])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)CNc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(Cl)c(NCC(C)C)cc3NC(=O)OC(C)(C)C)c2)ccn1

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-isobutylamino-phenyl)-carbamic acid tert-butyl ester (Example J16) (314 mg, 1.0 mmol) and 3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K12) (311 mg, 1.0 mmol) according to the general procedure M. Obtained as a yellow foam (480 mg, 87%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][N:11]=2)[C:5]([C:18]#[N:19])=[C:4]([C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)[N:3]=1.[Cl:25]N1C(=O)CCC1=O>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([C:20]2[O:21][C:22]([Cl:25])=[CH:23][CH:24]=2)[C:5]([C:18]#[N:19])=[C:6]([O:8][CH2:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][N:11]=2)[N:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cnc(COc2nc(N)nc(-c3ccco3)c2C#N)c(C)c1
Solvent: CN(C)C=O
Product: Cc1cnc(COc2nc(N)nc(-c3ccc(Cl)o3)c2C#N)c(C)c1

Procedure:
From 2-amino-4-(3,5-dimethyl-pyridin-2-ylmethoxy)-6-furan-2-yl-pyrimidine-5-carbonitrile and N-chlorosuccinimide in DMF. ES-MS m/e (%): 358 (M{37Cl}+H+, 30), 356 (M{35Cl}+H+, 100).
Reaction SMILES: [N:1]1[N:5]2[CH2:6][CH2:7][NH:8][CH2:9][C:4]2=[CH:3][C:2]=1[C:10]([O:12]CC)=[O:11].F[C:16](F)(F)C([O-])=O>>[CH3:16][N:8]1[CH2:7][CH2:6][N:5]2[N:1]=[C:2]([C:10]([OH:12])=[O:11])[CH:3]=[C:4]2[CH2:9]1
Reactant: O=C([O-])C(F)(F)F
Reactant: CCOC(=O)c1cc2n(n1)CCNC2
Product: CN1CCn2nc(C(=O)O)cc2C1

Procedure:
Prepared analogously to Example 45b starting from 2-ethyl 4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine-2-carboxylate (as the trifluoroacetate salt).
Reaction SMILES: [NH2:1][C@H:2]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)[CH2:3][C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:33](=[O:34])[C:32]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:31]2[C:30]1=[O:39])(OCC)=O>>[C:30]1(=[O:39])[N:1]([C@H:2]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=2)[CH2:3][C:4]([O:6][CH3:7])=[O:5])[C:33](=[O:34])[C:32]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:31]12
Reactant: COC(=O)C[C@H](N)c1ccc(OC)c(OC)c1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)C[C@@H](c1ccc(OC)c(OC)c1)N1C(=O)c2ccccc2C1=O

Procedure:
Methyl (S)-3-amino-3-(3,4-dimethoxyphenyl)propionate (0.45 g, 1.63 mmol), sodium carbonate (0.17 g, 1.63 mmol) and N-carboethoxyphthalimide (0.36 g, 1.63 mmol) were allowed to react according to the procedure of Example 85. Methyl (S)-3-phthalimido-3-(3,4-dimethoxyphenyl)propionate was obtained as a white powder, 0.51 g (85%); 1H NMR (DMSO-6, 250 MHz) δ7.87 (br s, 4H, Ar), 6.80-7.10 (m, 3H, Ar), 5.65 (dd, 1H, J1 =7 Hz, J2 =9 Hz), 3.73 (s, 3H, OCH3), 3.72 (s, 3H, OCH3), 3.55 (s 3H, OCH3), 3.30-3.67 (m, 2H); 13C NMR (DMSO-d6) δ170.8, 167.7, 148.6, 148.4, 134.7, 131.1, 131.0, 123.2, 119.3, 111.7, 111.0, 55.5, 51.6, 49.9, 35.6. Anal. Calcd for C20H19 NO6. Theoretical C, 65.03; H, 5.18; N, 3.79. Found C, 64.94; H, 5.29; N, 3.86. HPLC 97%.
Reaction SMILES: [C:1](=[O:23])([O:21][CH3:22])[O:2][C:3]1[CH:8]=[C:7]([NH2:9])[C:6]([C:10]#[C:11][CH2:12][N:13]([CH3:15])[CH3:14])=[CH:5][C:4]=1[CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[F:42][C:43]([F:59])([F:58])[O:44][C:45]1[CH:46]=[CH:47][C:48]2[O:53][CH:52]([C:54](O)=[O:55])[CH2:51][NH:50][C:49]=2[CH:57]=1>CC1CCCO1.C(OCC)(=O)C>[C:1](=[O:23])([O:21][CH3:22])[O:2][C:3]1[CH:8]=[C:7]([NH:9][C:54]([CH:52]2[O:53][C:48]3[CH:47]=[CH:46][C:45]([O:44][C:43]([F:59])([F:42])[F:58])=[CH:57][C:49]=3[NH:50][CH2:51]2)=[O:55])[C:6]([C:10]#[C:11][CH2:12][N:13]([CH3:15])[CH3:14])=[CH:5][C:4]=1[CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: COC(=O)Oc1cc(N)c(C#CCN(C)C)cc1C1CCCC1
Reactant: O=C(O)C1CNc2cc(OC(F)(F)F)ccc2O1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CC1CCCO1
Solvent: CCOC(C)=O
Product: COC(=O)Oc1cc(NC(=O)C2CNc3cc(OC(F)(F)F)ccc3O2)c(C#CCN(C)C)cc1C1CCCC1

Procedure:
5-Amino-2-cyclopentyl-4-(3-(dimethylamino)prop-1-ynyl)phenyl methyl carbonate (150 mg, 0.47 mmol) was dissolved in 2-methyltetrahydrofuran (3 mL) and T3P (754 mg, 705 μL of 50% w/w, 1.18 mmol). 6-(Trifluoromethoxy)-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid (125 mg, 0.47 mmol) was added portion-wise over 30 min. After 3 h the reaction was diluted with ethyl acetate, washed with 10% saturated NaHCO3 (2×20 mL) and brine. The solution was dried over Na2SO4, filtered, and dried down to an orange solid. Purification by silica gel chromatography (1% methanol/dichloromethane) provided 2-cyclopentyl-4-(3-(dimethylamino)prop-1-ynyl)-5-(6-(trifluoromethoxy)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamido)phenyl methyl carbonate as a colorless oil. LC/MS m/z 562.2 [M+H]+. The oil was dissolved in methanol (3 mL) and treated with NaOH (0.5 mL of 5 M, 2.4 mmol) and stirred for 5 min. Water (5 mL) and saturated NaHCO3 (2 mL) were added until a white precipitate formed. The product was extracted into ethyl acetate, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to provide N-(4-cyclopentyl-2-(3-(dimethylamino)prop-1-ynyl)-5-hydroxyphenyl)-6-(trifluoromethoxy)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamide as a off-white solid (90 mg, 34% yield). LC/MS m/z 504.2 [M+H]+. 1H NMR (400.0 MHz, DMSO-d6) δ 10.72 (s, 1H), 10.16 (s, 1H), 9.25 (s, 1H), 7.53 (s, 1H), 7.25 (s, 1H), 6.95 (d, J=8.7 Hz, 1H), 6.60 (d, J=2.0 Hz, 1H), 6.52-6.49 (m, 1H), 4.91 (dd, J=3.0, 6.3 Hz, 1H), 4.32 (t, J=3.8 Hz, 2H), 3.54 (dd, J=3.0, 12.2 Hz, 1H), 3.42 (dd, J=6.3, 12.3 Hz, 1H), 3.14 (quin, J=8.4 Hz, 1H), 2.85 (d, J=4.4 Hz, 6H), 1.91 (m, 2H), 1.72 (m, 2H), 1.63-1.60 (m, 2H), 1.48 (m, 2H).
Reaction SMILES: O[CH2:2][C:3]1[C:4]([I:13])=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:33]N1C(=O)CCC1=O.C([O-])(O)=O.[Na+]>CN(C=O)C>[Cl:33][CH2:2][C:3]1[C:4]([I:13])=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: OCc1cc2ccccc2nc1I
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: ClCc1cc2ccccc2nc1I
Temperature: -23 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
To a stirred mixture of 3-hydroxymethyl-2-iodoquinoline prepared in accordance with Example 10 above (350 mg, 1.23 mmol) and triphenylphosphine (483 mg, 1.84 mmol) in 10 mL of dry DMF at -23° C. was added N-chlorosuccinimide (246 mg, 1.84 mmol), and the mixture was stirred for 1 h at -23° C. After the addition of 40 mL of dilute aqueous NaHCO3, the mixture was extracted with ethyl acetate (20 mL) and then ether (2×15 mL). The combined organic extracts were washed successively with 20-mL portions of dilute NaHCO3, water and brine, and were dried over MgSO4. Concentration and purification of the residue by radial PLC (silica gel, 10% ethyl acetate/hexanes) afforded 312 mg (84%) of 3-chloromethyl-2-iodoquinoline as a white crystalline solid: mp 138°-140° C. Recrystallization from hexanes afforded an analytical sample as colorless needles: mp 139°-140° C. 1H NMR (300 MHz, CDC13) δ8.17 (s, 1H), 8.07 (d, 1H, J=9 Hz), 7.84 (d, 1H, J=9 Hz), 7.75 (t, 1H, J=9 Hz), 7.62 (t, 1H, J=9 Hz), 4.80 (s, 1H); IR (nujol) 1585, 1555, 1260, 1010, 780, 755, 710 cm-1.
Reaction SMILES: [CH:1]1([C:4]2[NH:5][N:6]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:7](=[O:9])[CH:8]=2)[CH2:3][CH2:2]1.[F:16][C:17]([F:25])([F:24])[C:18](=[O:23])[C:19]([O:21][CH3:22])=[O:20]>C(Cl)(Cl)Cl>[CH3:22][O:21][C:19](=[O:20])[C:18]([OH:23])([C:17]([F:25])([F:24])[F:16])[C:8]1[C:7](=[O:9])[N:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:5][C:4]=1[CH:1]1[CH2:3][CH2:2]1
Reactant: COC(=O)C(=O)C(F)(F)F
Reactant: O=c1cc(C2CC2)[nH]n1-c1ccccc1
Solvent: ClC(Cl)Cl
Product: COC(=O)C(O)(c1c(C2CC2)[nH]n(-c2ccccc2)c1=O)C(F)(F)F
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a chloroform solution (5 ml) of 3-cyclopropyl-1-phenyl-5-pyrazolone (100 mg, 0.5 mmol), methyl trifluoropyruvate (78 mg, 0.5 mmol) was added at room temperature and the mixture was stirred at 80° C. for 2 hours. After removing the solvent under reduced pressure, the title compound was obtained as a colorless solid (178 mg).
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:39])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=4)[C:25](O)=[O:26])[N:20]=3)[N:15]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].CN(C(ON1N=[N:55][C:50]2[CH:51]=CC=N[C:49]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N)(C)C>CN(C=O)C>[C:1]([CH:3]1[CH2:4][N:5]([C:7](=[O:39])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[CH:30]=[CH:29][CH:28]=[C:24]([C:25](=[O:26])[NH:55][CH:50]([CH3:51])[CH3:49])[CH:23]=4)[N:20]=3)[N:15]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:37])([CH3:36])[CH3:38])[CH:14]=2)=[O:12])[CH3:9])[CH2:6]1)#[N:2]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C(=O)O)c3)nc12)C(=O)N1CC(C#N)C1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CC(C)N
Product: CC(C)NC(=O)c1cccc(-c2cnc3c(n2)c(C(=O)N[C@H](C)C(=O)N2CC(C#N)C2)cn3COCC[Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.8 %

Procedure:
To a solution of 3-[7-[(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethylcarbamoyl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-benzoic acid (70 mg, 0.13 mmol) and HATU (53.4 mg, 0.14 mmol) in DMF (1.5 mL) was added isopropylamine (44 μL, 0.51 mmol). The reaction mixture was stirred at room temp for 4 h then quenched with water and extracted with EtOAc (2×). The combined organics were washed with water (3×) and brine then dried over MgSO4 and concentrated. The residue was chromatographed with 50% to 100% EtOAc/hexanes to isolate 52 mg (69%) of 2-(3-isopropylcarbamoyl-phenyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as an off-white foamy solid.