Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(CC([NH:10][CH:11]2[C:31](=[O:32])[N:13]3[C:14]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=4)=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=O)C=CC=CC=1.N1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl.CO>ClCCl>[NH2:10][CH:11]1[C:31](=[O:32])[N:13]2[C:14]([C:18]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=3)=[O:19])=[CH:15][CH2:16][S:17][C@H:12]12
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12
Temperature: 10 °C
Reaction time: 0.75 h
Yield: 101.7 %

Procedure:
To a suspension of p-nitrobenzyl 7-phenylacetamido-3-cephem-4-carboxylate (10.50 g.) in dry dichloromethane (100 ml.) was added dry pyridine (2.14 g.). Phosphorus pentachloride (5.50 g.) was added to the solution at -10° C., and the mixture was stirred at -5° C. for 45 minutes and further at 10° C. for an hour. After adding methanol (520 g.) to the resultant mixture, the mixture was stirred at -20° C. for 1.5 hours. The precipitates were collected by filtration, washed with dichloromethane (120 ml.) and diethyl ether (130 ml.) in turn, and then dried to give p-nitrobenzyl 7-amino-3-cephem-4-carboxylate (7.90 g.), m.p. 182° C. (dec.).
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.[CH3:13][C@@H:14]([CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:15](OCC)=[O:16].OS([O-])(=O)=O.[K+]>C1COCC1>[CH3:13][C@@H:14]([CH2:20][CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:15](=[O:16])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COP(C)(=O)OC
Reactant: CCOC(=O)[C@@H](C)CCCc1ccccc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)[C@@H](C)CCCc1ccccc1)OC
Reaction time: 0.5 h
Yield: 42.3 %

Procedure:
To a stirring solution consisting of dimethyl methylphosphonate (23.37 g, 188.4 mmol) in THF (400 mL) at −78° C. was slowly added n-butyllithium solution (112 mL, 179 mmol, 1.6 M solution in hexane). The reaction mixture was stirred for 30 minutes, after which time, (S)-(+)-ethyl 2-methyl-5-phenylpentanoate (14mb(i), 28.1 g, 94.2 mmol) in THF (100 mL) was slowly added. The resulting reaction mixture was stirred at −78° C. for two hours and was then allowed to rise to room temperature overnight. The reaction mixture was treated with 5% KHSO4 and extracted with ethyl acetate three times. The organic layer was washed twice with 50:50 water-brine and the organic layer was dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography. Elution with ethyl acetate-heptane (60:40 v/v) afforded the title compound (11.9 g, 42%) as a clear oil, pure of unrelated components; TLC Rf 0.22 (solvent system: 60:40 v/v ethyl acetate-heptane); HPLC retention time 14.5 minutes, 5μ Chiralpak IA 250×4.6 mm, ultraviolet detector at 210 nm, 1 mL/min, chiral purity 97.8% (S), 2.19% (R); MS (ESI−) m/z 297.1 (M−H)−; 1H NMR (CDCl3) δ 7.28-7.21 (m, 2H), 7.17-7.12 (m, 3H), 3.76-3.71 (m, 6H), 3.10 (d, J=2.20 Hz, 1H), 3.04 (d, J=2.20 Hz, 1H), 2.79-2.70 (m, 1H), 2.54-2.62 (m, 2H), 1.74-1.54 (m, 3H), 1.42-1.24 (m, 1H), 1.07 (d, J=6.96 Hz, 3H); [α]Tλ=α/cl, [α]21.9D=+0.084/(0.0169 g/1.5 mL)(0.5)=+14.91° (c=1.13, CHCl3).
Reaction SMILES: [N:1]1([C@H:13]2[CH2:17][CH2:16][C@H:15]([NH2:18])[CH2:14]2)[C:12]2[C:4](=[CH:5][N:6]=[C:7]3[C:11]=2[CH:10]=[CH:9][NH:8]3)[N:3]=[N:2]1.[CH3:19][O:20][CH2:21][CH2:22]Br.C(=O)([O-])[O-].[K+].[K+].[ClH:30].CO>C(Cl)Cl.CN(C=O)C>[ClH:30].[CH3:19][O:20][CH2:21][CH2:22][NH:18][C@H:15]1[CH2:16][CH2:17][C@H:13]([N:1]2[C:12]3[C:4](=[CH:5][N:6]=[C:7]4[C:11]=3[CH:10]=[CH:9][NH:8]4)[N:3]=[N:2]2)[CH2:14]1
Reactant: COCCBr
Reactant: N[C@H]1CC[C@H](n2nnc3cnc4[nH]ccc4c32)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClCCl
Product: COCCN[C@H]1CC[C@H](n2nnc3cnc4[nH]ccc4c32)C1
Temperature: 135 °C

Procedure:
A mixture of racemic trans 3-(6H-1,2,3,5,6-pentaaza-as-indacen-1-yl)-cyclopentylamine (95.0 mg, 392 μmol), 2-bromoethyl methyl ether (59.9 mg, 431 μmol), potassium carbonate (108 mg, 780 μmol) and DMF (2 mL) was heated to 135° C. for 15 minutes using microwave irradiation. The mixture was filtered, concentrated in vacuo and purified by column chromatography on silica gel (gradient: DCM to 10% [2M NH3 in methanol] in DCM) followed by reverse phase HPLC (5 to 50% acetonitrile in water, +0.1% NH4OH). The colourless residue was treated with 1.25 M HCl in methanol (2 eq) in DCM and concentrated to afford 17.6 mg of racemic trans (2-methoxy-ethyl)-[3-(6H-1,2,3,5,6-pentaaza-as-indacen-1-yl)-cyclopentyl]-amine hydrochloride was isolated as a beige gum. LCMS (Method A, ESI): RT=1.92 min, m+H=301.3; 1H NMR (400 MHz, DMSO) δ: 12.35 (s, 1H), 8.99 (s, 1H), 7.60 (t, 1H), 7.00 (dd, 1H), 5.65 (m, 1H), 3.59 (m, 1H), 3.47 (t, 2H), 3.28 (s, 3H), 2.83 (t, 2H), 2.47 (m, 2H, partially obscured by DMSO), 2.29-2.17 (m, 3H), 1.72 (m, 1H).
Reaction SMILES: C(O[C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][C:16](=[O:18])[CH3:17])[O:11][CH:10]=[C:9]([C:19]([OH:21])=[O:20])[C:8]2=[O:22])(=[O:3])C.O[C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][C:33]=1[OH:34])[O:30][CH:29]=[C:28]([C:35]([OH:37])=[O:36])[C:27]2=[O:38]>>[C:16]([O:15][C:14]1[C:13]([O:37][C:35](=[O:36])[CH3:28])=[C:12]2[C:7]([C:8](=[O:22])[C:9]([C:19]([OH:21])=[O:20])=[CH:10][O:11]2)=[CH:6][CH:5]=1)(=[O:18])[CH3:17].[OH:34][C:33]1[C:32]([OH:3])=[C:31]2[C:26]([C:27](=[O:38])[C:28]([C:35]([OH:37])=[O:36])=[CH:29][O:30]2)=[CH:25][CH:24]=1
Reactant: CC(=O)Oc1cc2occ(C(=O)O)c(=O)c2cc1OC(C)=O
Reactant: O=C(O)c1coc2cc(O)c(O)cc2c1=O
Product: CC(=O)Oc1ccc2c(=O)c(C(=O)O)coc2c1OC(C)=O
Product: O=C(O)c1coc2c(O)c(O)ccc2c1=O

Procedure:
7,8-Diacetoxychromone-3-carboxylic acid and 7,8-dihydroxychromone-3-carboxylic acid were prepared by the processes according to (A) and (B), respectively.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:25]=[C:24]([O:26][C@H:27]3[C@H:31]4[O:32][CH2:33][C@@H:34]([OH:35])[C@H:30]4[O:29][CH2:28]3)[N:23]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=1.Br[C:45]1[CH:50]=[CH:49][C:48]([NH:51][S:52]([CH3:59])(=[N:54][CH:55]2[CH2:58][CH2:57][CH2:56]2)=[O:53])=[CH:47][CH:46]=1>>[OH:35][C@H:34]1[C@H:30]2[O:29][CH2:28][C@@H:27]([O:26][C:24]3[N:23]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:5]4=[N:6][C:7]([C:8]5[CH:13]=[CH:12][C:11]([C:45]6[CH:50]=[CH:49][C:48]([NH:51][S:52]([CH3:59])(=[N:54][CH:55]7[CH2:58][CH2:57][CH2:56]7)=[O:53])=[CH:47][CH:46]=6)=[CH:10][CH:9]=5)=[C:2]([Cl:1])[CH:3]=[C:4]4[N:25]=3)[C@H:31]2[O:32][CH2:33]1
Reactant: CC1(C)OB(c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O)n4COCC[Si](C)(C)C)cc2)OC1(C)C
Reactant: CS(=O)(=NC1CCC1)Nc1ccc(Br)cc1
Product: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2cc(Cl)c(-c3ccc(-c4ccc(NS(C)(=O)=NC5CCC5)cc4)cc3)nc21

Procedure:
The title compound is prepared from (3R,3aR,6R,6aR)-6-(6-chloro-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-b]pyridin-2-yloxy)hexahydrofuro[3,2-b]furan-3-ol and N-(4-bromophenyl)-N′-cyclobutyl-methanesulfonimidamide following a procedure analogous to that described for Intermediate 3 (Step 3). LC (method 1): tR=1.14 min; Mass spectrum (ESI+): m/z=726 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[C:13]([CH2:15][NH:16][CH:17]3[CH2:20][CH2:19][CH2:18]3)[N:14]=2)=[CH:6][CH:5]=1.[CH3:23][N:24]1[CH:28]=[C:27]([C:29](O)=[O:30])[N:26]=[CH:25]1.C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(#N)C.O>[CH:17]1([N:16]([CH2:15][C:13]2[N:14]=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=3)[S:11][CH:12]=2)[C:29]([C:27]2[N:26]=[CH:25][N:24]([CH3:23])[CH:28]=2)=[O:30])[CH2:20][CH2:19][CH2:18]1
Reactant: FC(F)(F)Oc1ccc(-c2nc(CNC3CCC3)cs2)cc1
Reactant: Cn1cnc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[NH3+]
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cn1cnc(C(=O)N(Cc2csc(-c3ccc(OC(F)(F)F)cc3)n2)C2CCC2)c1
Yield: 37.8 %

Procedure:
A solution of N-({2-[4-(trifluoromethoxy)phenyl]-1,3-thiazol-4-yl}methyl)cyclobutaneamine (430 mg), methyl-1H-imidazole-4-carboxylic acid (451 mg), 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (HATU) (598 mg) and diisopropylethylamine (0.69 mL) in acetonitrile (15 mL) was stirred at room temperature for 3 days. Water was added to the reaction mixture, followed by extraction with chloroform. The solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (NH silica gel cartridge, hexane:ethyl acetate=75:25-0:100) and PTLC (silica gel, chloroform:methanol=19:1). The resulting residue was re-crystalized with isopropyl ether to afford the title compound (216 mg).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.COC([C:14]1[C:15]2[CH:16]3[N:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:19]([CH2:20][C:21]=2[CH:22]=[CH:23][CH:24]=1)[CH2:18][CH2:17]3)=O>C(Cl)Cl>[CH3:29][O:28][C:26]([C:24]1[CH:23]=[C:22]([N+:1]([O-:4])=[O:2])[C:21]2[CH2:20][CH:19]3[N:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:16]([CH2:17][CH2:18]3)[C:15]=2[CH:14]=1)=[O:27]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)N1C2CCC1c1c(cccc1C(=O)OC)C2
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CCOC(=O)N1C2CCC1c1cc(C(=O)OC)cc([N+](=O)[O-])c1C2
Reaction time: 0.5 h
Yield: 23 %

Procedure:
Concentrated nitric acid (5 mL) was added dropwise to a mixture of concentrated sulfuric acid (5 mL), 12-aza-tricyclo[7.2.1.0*2,7*]dodeca-2(7),3,5-triene-3,12-dicarboxylic acid 12-ethyl ester 3-methyl ester (300 mg, 1.04 mmol) and CH2Cl2 (5 mL) at 0° C. The resulting brown solution was stirred at this temperature for 30 min before pouring onto ice-water and extracting with CH2Cl2 (2×5 mL). Drying over MgSO4, filtering and concentration gave a brown residue that was purified with silica gel chromatography (0-20% EtOAc in hexanes) to give 6-Nitro-12-aza-tricyclo[7.2.1.0*2,7*]dodeca-2(7),3,5-triene-4,12-dicarboxylic acid 12-ethyl ester 4-methyl ester as a clear oil (81 mg, 23%) 1HNMR (400 MHz, CDCl3) δ 8.5 (s, 1H), 8.0 (s, 1H), 5.2 (m, 1H), 4.7 (m, 1H), 4.1 (q, 2H, J=7.1 Hz), 4.0 (s, 3H), 3.6-3.5 (m, 1H), 3.0 (d, 1H, J=18.7), 2.3-2.2 (m, 2H), 1.9 (m, 1H), 1.7 (m, 1H), 1.3-1.2 (m, 3H); MS (m/e) 335 (M+1); and 5-Nitro-12-aza-tricyclo[7.2.1.0*2,7*]dodeca-2(7),3,5-triene-4,12-dicarboxylic acid 12-ethyl ester 4-methyl ester as a pale yellow solid (79 mg, 23%) as the 5-nitro compound. 1HNMR (400 MHz, CDCl3) δ 7.6 (s, 1H), 7.4 (s, 1H), 5.1 (m, 1H), 4.6 (m, 1H), 4.1 (q, 2H, J=7.3 Hz), 3.9 (s, 3H), 3.5-3.4 (m, 1H), 2.7 (d, 1H, J=17.4), 2.3-2.2 (m, 2H), 1.9 (m, 1H), 1.7 (m, 1H), 1.3-1.2 (m, 3H); MS (m/e) 335 (M+1); The regioisomers were distinguished by NOE and 1H-1H COSY
Reaction SMILES: Cl.[F:2][C:3]1[CH:27]=[CH:26][CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:10]([C:11]2[CH:15]=[CH:14][O:13][N:12]=2)=[CH:9][C:8]([C:16]2[N:21]=[C:20]([NH2:22])[C:19]([NH2:23])=[CH:18][N:17]=2)=[N:7]1.ClCCl.[CH2:31]([O:33]CC)[CH3:32]>C(O)(=O)C>[NH2:22][C:20]1[C:19]([NH:23][C:31](=[O:33])[CH3:32])=[CH:18][N:17]=[C:16]([C:8]2[CH:9]=[C:10]([C:11]3[CH:15]=[CH:14][O:13][N:12]=3)[N:6]([CH2:5][C:4]3[CH:24]=[CH:25][CH:26]=[CH:27][C:3]=3[F:2])[N:7]=2)[N:21]=1
Reactant: CCOCC
Reactant: Nc1cnc(-c2cc(-c3ccon3)n(Cc3ccccc3F)n2)nc1N
Agent: Cl
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(=O)Nc1cnc(-c2cc(-c3ccon3)n(Cc3ccccc3F)n2)nc1N
Temperature: 25 °C
Yield: 79 %

Procedure:
A solution of 2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidine-4,5-diamine hydrochloride (I-107) (30 mg, 0.077 mmol) in acetic acid (2 mL) was heated to 110° C. for 18 h. After cooling to room temperature, the solution was partitioned between ethyl actetate (50 mL) and saturated aqueous sodium carbonate. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The organics were dried over MgSO4, filtered, and the solvent was removed in vacuo to give the crude product as a tan residue. Dichloromethane (3 mL) and diethyl ether (5 mL) were added, and the resulting white solid was filtered and washed with additional diethyl ether ether to give N-(4-amino-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-5-yl)acetamide (24 mg, 0.061 mmol, 79% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.42 (d, 1H), 8.26 (s, 1H), 7.66 (br s, 1H), 7.34 (s, 1H), 7.18-7.13 (m, 1H), 7.01-6.96 (s, 1H), 6.92 (t, 1H), 6.77 (t, 1H), 6.56 (d, 1H), 5.96 (s, 2H), 5.57 (br s, 2H), 2.12 (s, 3H).
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.ClCCl.[N:21]1([C:27]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][C:28]=2[NH2:29])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>CN(C)C1C=CN=CC=1.O>[N:21]1([C:27]2[CH:33]=[CH:32][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:30][C:28]=2[NH:29][C:2](=[O:9])[C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: Nc1cc(C(F)(F)F)ccc1N1CCCCC1
Reactant: O=C(Cl)c1ccncc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Nc1cc(C(F)(F)F)ccc1N1CCCCC1)c1ccncc1
Temperature: 25 °C
Reaction time: 19.5 h
Yield: 33.9 %

Procedure:
Isonicotinoyl chloride hydrochloride (151 mg, 0.850 mmol, commercially available product), triethylamine (450 μl, 3.23 mmol), and a catalytic amount of 4-(dimethylamino)pyridine were sequentially added at 0° C. to a dichloromethane (5 ml) solution of 2-(1-piperidinyl)-5-(trifluoromethyl)aniline (173 mg, 0.708 mmol), obtained as described in Referential Example 1-2A. The resulting mixture was warmed to room temperature and stirred for 19.5 hours. Water was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated aqueous solution of sodium bicarbonate, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10 g, hexane/ethyl acetate=1.5/1) and recrystallization (hexane). Thus, N-[2-(1-piperidinyl)-5-(trifluoromethyl)phenyl]isonicotinamide (SRPIN-1, code name GIF-0340) (83.8 mg, 0.240 mmol, 33.9%) was yielded as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:22])[N:4]([CH2:8][C:9]([NH:11][CH:12]([CH:19]([CH3:21])[CH3:20])[C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[O:10])[CH:5]=[CH:6][CH:7]=1.[C:23]1([CH2:29][CH2:30][C:31](Cl)=[O:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>ClCCl>[C:23]1([CH2:29][CH2:30][C:31]([NH:1][C:2]2[C:3](=[O:22])[N:4]([CH2:8][C:9]([NH:11][CH:12]([CH:19]([CH3:20])[CH3:21])[C:13](=[O:18])[C:14]([F:16])([F:17])[F:15])=[O:10])[CH:5]=[CH:6][CH:7]=2)=[O:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)C(NC(=O)Cn1cccc(N)c1=O)C(=O)C(F)(F)F
Reactant: O=C(Cl)CCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(NC(=O)Cn1cccc(NC(=O)CCc2ccccc2)c1=O)C(=O)C(F)(F)F
Reaction time: 2 h

Procedure:
To a stirred suspension of 2-(3-amino-2-oxo-1,2-dihydro-1-pyridyl)-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide (0.399) in dichloromethane at 0° C. was added 3-phenylpropionyl chloride (0.247 g) and triethylamine (0.247 g). The mixture was allowed to stir for 2 h, was diluted with dichloromethane (100 mL), washed (1N hydrochloric acid, saturated aqueous sodium bicarbonate, brine), dried, and evaporated to give a residue which was purified by chromatography, using methanol:dichloromethane as an eluent (gradient, 0.5:99.5, 2:98), to yield the title compound; mp 154°-155° C.; NMR: 0.80-0.98 (m,6), 2.21 (m,1), 4.09(m, NHCH hydrate), 4.52-4.82 (m, NHCH keto, CH2CO), 6.23 (m), 7.15-7.34 (m), 7.91 (d, J=10, NH hydrate), 8.24 (dd,1, J=7.5, 1.5), 8.93 (d, NH keto), 9.26 (s, NH hydrate), 9.29 (s, NH keto).
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C@@H:9]([C:17]([N:19]1[CH2:33][CH2:32][CH2:31][C@H:20]1[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)C(C)C)(C)C.[CH2:43]([N:45]=[C:46]=[O:47])[CH3:44]>ClCCl>[CH2:43]([NH:45][C:46]([NH:8][C@@H:9]([C:17]([N:19]1[CH2:33][CH2:32][CH2:31][C@H:20]1[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:47])[CH3:44]
Reactant: N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reactant: CCN=C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCNC(=O)N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 16 h
Yield: 107 %

Procedure:
To a solution of TFA.D-Phe-Pro-OBzl (10 g, 21.4 mmol) in dichloromethane (150 mL) was added N,N-diisopropylethylamine (3.73 mL, 21.4 mmol) followed by ethyl isocyanate (1.86 mL, 23.5 mmol). After stirring for 16 h, the solution was washed three times with 1N HCl, dried over Na2SO4, filtered and concentrated in vacuo to give 9.7 g (107%) of white foam.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:10][CH2:9][N:8]([Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[C:5]2=[N:6][CH:7]=1.C([Li])(C)(C)C.CCCCC.[C:28](=[O:30])=[O:29]>CCOCC>[C:14]([Si:11]([CH3:13])([CH3:12])[N:8]1[C:5]2=[N:6][CH:7]=[C:2]([C:28]([OH:30])=[O:29])[CH:3]=[C:4]2[CH2:10][CH2:9]1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)N1CCc2cc(Br)cnc21
Reactant: O=C=O
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: CCCCC
Product: CC(C)(C)[Si](C)(C)N1CCc2cc(C(=O)O)cnc21
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a stirred and cooled (−78° C.) solution of the bromide 4 (205 mg, 0.65 mmol) in Et2O (4 mL) was added dropwise a 1.5 M solution of tert-butyllithium in pentane (0.92 mL, 1.37 mmol). After 40 min., dry gaseous CO2 was introduced into the reaction vessel. Progress of the reaction was followed by TLC analysis. After complete consumption of starting material 4 the reaction was quenched by the addition of saturated aqueous NaHCO3 solution. The mixture was allowed to warm to room temperature, and diluted with CH2Cl2. The aqueous layer was extracted with CH2Cl2 (2×), and the combined organic solutions were dried (MgSO4), filtered and concentrated. The residual yellow oil was dissolved in CH2Cl2:MeOH=20:1 and filtered through silicagel pad. The filtrate was concentrated and used directly in the next step.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:13][C@H:14]([C:18]([NH:20]C2(C#N)CC2)=O)[CH2:15][CH2:16]C)[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[CH3:26][S:27]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)(=[O:29])=[O:28].[C:39]([O-:42])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[C:18]([C:14]1([N:13]([C@@H:8]([C:5]2[CH:4]=[CH:3][C:2]([C:33]3[CH:34]=[CH:35][C:30]([S:27]([CH3:26])(=[O:29])=[O:28])=[CH:31][CH:32]=3)=[CH:7][CH:6]=2)[C:9]([F:10])([F:11])[F:12])[C:39](=[O:42])[C@H:8]([CH2:5][CH2:4][CH3:3])[NH2:13])[CH2:15][CH2:16]1)#[N:20]
Reactant: O=C([O-])[O-]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CCC[C@H](N[C@@H](c1ccc(Br)cc1)C(F)(F)F)C(=O)NC1(C#N)CC1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC[C@H](N)C(=O)N([C@@H](c1ccc(-c2ccc(S(C)(=O)=O)cc2)cc1)C(F)(F)F)C1(C#N)CC1
Temperature: 82.5 °C

Procedure:
A mixture of N2-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N1-(1-cyanocyclopropyl)-L-norvalinamide (6.46 g, 15.44 mmol), 4-methanesulfonylphenyl-boronic acid (3.40 g, 16.98 mmol), and 2M K2CO3 (19.3 mL) was dissolved in DMF (75 mL) in a thick-walled flask. The reaction mixture was degassed, and [1,1′-bis(diphenyl-phosphino)ferrocene]dichloropalladium(II), dichloromethane complex (0.678 g, 0.926 mmol) was added. The flask was sealed, heated at 80-85° C. for 3 hours, cooled, and diluted with ethyl acetate (300 mL). The solution was washed with 1:1 water/brine (200 mL), brine (200 mL), filtered through a three-layered plug of silica (bottom) DARCO, and MgSO4 (top), concentrated in vacuo, and purified on a plug of silica gel (50-70% ethyl acetate/hexane elution). The product was then further purified by recrystallization from ethyl acetate/hexanes to yield the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[CH:27]([CH3:29])[CH3:28])[O:23][CH2:22][C:21]2[N:16]3[CH:17]([CH3:31])[C:18](=[O:30])[NH:19][N:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1CC(OC2C=C3C(=CC=2Br)OCC2N3C(C)C(=O)NN=2)C1)=O)(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[CH:27]([CH3:28])[CH3:29])[O:23][CH2:22][C:21]2[N:16]3[C@@H:17]([CH3:31])[C:18](=[O:30])[NH:19][N:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[CH:27]([CH3:28])[CH3:29])[O:23][CH2:22][C:21]2[N:16]3[C@H:17]([CH3:31])[C:18](=[O:30])[NH:19][N:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)c1cc2c(cc1OC1CN(C(=O)OC(C)(C)C)C1)N1C(=NNC(=O)C1C)CO2
Agent: CC1C(=O)NN=C2COc3cc(Br)c(OC4CN(C(=O)OC(C)(C)C)C4)cc3N21
Product: CC(C)c1cc2c(cc1OC1CN(C(=O)OC(C)(C)C)C1)N1C(=NNC(=O)[C@@H]1C)CO2
Product: CC(C)c1cc2c(cc1OC1CN(C(=O)OC(C)(C)C)C1)N1C(=NNC(=O)[C@H]1C)CO2
Yield: 47 %
Yield: 50 %

Procedure:
Racemic 3-(7-isopropyl-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yloxy)-azetidine-1-carboxylic acid tert-butyl ester (prepared from the corresponding bromide (Example #65, Step G) with similar procedure as descried in Example #57, Step A-B, 0.090 g, 0.210 mmol) was separated by chiral SFC (Table 2, Method 7) to give 3-(7-isopropyl-4(S)-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yloxy)-azetidine-1-carboxylic acid tert-butyl ester (Enantiomer 1, SFC (Table 1, Method 13) Rt=1.572 min.; 0.045 g, 50%) and 3-(7-isopropyl-4(R)-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yloxy)-azetidine-1-carboxylic acid tert-butyl ester (Enantiomer 2, SFC (Table 1, Method 13) Rt=2.104 min, 0.042 g, 47%).
Reaction SMILES: [NH2:1][C@@H:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[C@H:3]1[OH:16].Cl.CN(C)CCC[CH2:23][CH2:24][N:25]=[C:26]=[NH:27].[CH3:29][N:30](C)C=O>>[C:29]([N:27]=[C:26]([NH:25][CH2:24][CH3:23])[NH:1][C@@H:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:14])([CH3:15])[C@H:3]1[OH:16])#[N:30]
Reactant: CN(C)C=O
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Reactant: CN(C)CCCCCN=C=N
Agent: Cl
Product: CCNC(=NC#N)N[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the title A compound (1.15 g, 8.9 mmol) and (trans)-4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (prepared according to Evans et al., J. Med. Chem., 1983, 26, 1582 and J. Med. Chem., 1986, 29, 2194). (1.5 g, 6.9 mmol) in dimethylformamide (5 mL) under argon was added 1-(3-dimethylaminopropyl)-2-ethylcarbodiimide hydrochloride (1.71 g, 8.9 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours and then partitioned between 1N HCl and ethyl acetate. The organic phase was separated and the aqueous phase was reextracted with ethyl acetate. The combined organic phase was washed with water, aqueous sodium bicarbonate and brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the residue was purified by flash chromatography on silica gel (25% acetone in dichloromethane). The fractions containing the desired product were combined and evaporated to yield a colorless solid (801 mg). This solid product was recrystallized from acetonitrile-ether to yield the title compound, m.p. 185°-188° C.