Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][C:9]([C@H:11]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:12][C@@H:13]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[C@@H:14]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:10])(C(C)(C)C)(C)C.[Li+:42].[OH-]>O1CCOCC1>[Li+:42].[Si:31]([O:30][C@H:13]([CH2:12][C@H:11]([C:9]([O-:10])=[O:8])[CH2:38][CH:39]([CH3:40])[CH3:41])[C@@H:14]([NH:22][C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:34]([CH3:36])([CH3:35])[CH3:37])([CH3:33])[CH3:32]
Reactant: CC(C)C[C@H](C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)O[Si](C)(C)C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)C[C@H](C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 48.8 %

Procedure:
A solution of the crude resultant compound of Example 166 (0.075 mmol) in 2 mL of dioxane was treated with 0.6 mL (0.3 mmol) of LiOH (0.5M in H2O) and allowed to stir at ambient temperature for 2 days. After removal of the solvent, purification by flash column chromatography using 3% methanol/chloroform gave 18.3 mg (49%) of the desired compound (Rf 0.10, 2% methanol/chloroform).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:12]2[NH:13][C:14]([C:22]3[CH:31]=[CH:30][CH:29]=[C:28]4[C:23]=3[N:24]=[C:25]([NH:33][C:34]([CH3:37])(C)[CH3:35])[C:26]([CH3:32])=[N:27]4)=[CH:15][C:16]=2[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].BrCC(C1C([F:52])=CC=C2C=1N=C(NC(C)C)C(C)=N2)=O.C(OC(NC1(C(=O)CC(OCC)=O)CC1)=O)(C)(C)C>CCO.CC(O)=O>[C:1]([O:5][C:6]([NH:8][C:9]1([C:12]2[NH:13][C:14]([C:22]3[C:31]([F:52])=[CH:30][CH:29]=[C:28]4[C:23]=3[N:24]=[C:25]([NH:33][CH:34]([CH3:37])[CH3:35])[C:26]([CH3:32])=[N:27]4)=[CH:15][C:16]=2[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc2ccc(F)c(C(=O)CBr)c2nc1NC(C)C
Reactant: CCOC(=O)c1cc(-c2cccc3nc(C)c(NC(C)(C)C)nc23)[nH]c1C1(NC(=O)OC(C)(C)C)CC1
Agent: CCOC(=O)CC(=O)C1(NC(=O)OC(C)(C)C)CC1
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(-c2c(F)ccc3nc(C)c(NC(C)C)nc23)[nH]c1C1(NC(=O)OC(C)(C)C)CC1
Yield: 85 %

Procedure:
This compound (1.07 g, 85% yield) as a yellow amorphous solid was prepared according to the procedures described for Intermediate 324b, using 2-bromo-1-(6-fluoro-3-(isopropylamino)-2-methylquinoxalin-5-yl)ethanone (619) (840 mg, 2.47 mmol), ethyl 3-(1-((tert-butoxycarbonyl)amino)cyclopropyl)-3-oxopropanoate (604) (804 mg, 2.96 mmol) as the starting materials, followed by the subsequent treatment of the resulting 330a (m/z (ESI, +ve) 531.2 (M+H)+) with NH4OAc (952 mg, 12.35 mmol) in 3 mL of EtOH and 1.5 mL of HOAc at 50° C. for 4 h. m/z (ESI, +ve) 512.2 (M+H)+.
Reaction SMILES: [CH2:1]([CH:3]([CH:11]([OH:13])[CH3:12])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[CH3:2].C(OC=C)(=O)CCCCCCCCCCC>>[CH2:1]([CH:3]([C@@H:11]([OH:13])[CH3:12])[C:4]([O:6][C:7]([CH3:9])([CH3:8])[CH3:10])=[O:5])[CH3:2]
Reactant: CCC(C(=O)OC(C)(C)C)C(C)O
Agent: C=COC(=O)CCCCCCCCCCC
Product: CCC(C(=O)OC(C)(C)C)[C@H](C)O
Temperature: 35 °C
Reaction time: 48 h
Yield: 66 %

Procedure:
A mixture of 15.0 g of t-butyl 2-ethyl-3-hydroxybutanoate as racemate, 9.0 g of vinyl laurate and 8.0 g of Lipase P (trade name, supplied by Amano Pharmaceutical Co., Ltd.) was stirred at 35° C. for two days. After stopping the reaction, the enzyme was removed by filtration and the enzyme was washed with n-heptane on a filter paper. n-Heptane was distilled away from the filtrate and the residue was subjected to vacuum distillation to obtain 9.9 g of t-butyl (3S )-2-ethyl-3-hydroxybutanoate, b.p. 73.5°-75° C. (4.5 mm Hg), [α]D28 =+1.5° (C=1.22, CHCl3) of the following formula. ##STR73## The NMR chart is shown in FIG. 8.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][N:20]=[CH:19]2>>[ClH:1].[NH:21]1[C:22]2[C:18](=[CH:17][C:16]([NH:15][C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=4)[N:5]=[CH:4][N:3]=3)=[CH:24][CH:23]=2)[CH:19]=[N:20]1
Reactant: O=[N+]([O-])c1ccc2ncnc(Cl)c2c1
Reactant: Nc1ccc2[nH]ncc2c1
Product: Cl
Product: O=[N+]([O-])c1ccc2ncnc(Nc3ccc4[nH]ncc4c3)c2c1
Yield: 68 %

Procedure:
Using an analogous procedure to that described in Example 1, 4-chloro-6-nitroquinazoline was reacted with 5-amino-1H-indazole to give in turn 4-(1H-indazol-5-ylamino)-6-nitroquinazoline hydrochloride in 68% yield, m.p. 289°-291° C., and the free base in quantitative yield.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:12]([C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]>>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:9]=[CH:10][CH:11]=[C:2]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:17][CH:18]=2)[CH:3]=1
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: COC(=O)c1cccc(Br)c1
Product: COC(=O)c1cccc(Nc2ccc(C(C)(C)C)cc2)c1

Procedure:
Reaction of methyl 3-bromobenzoate with 4-tert-butylaniline according to general procedure A provided methyl ester of Compound 10 as a yellow oil (81% yield). 1H NMR (CDCl3, 500 MHz): δ=7.73 (s, 1H), 7.57 (d, J=7.6 Hz, 1H), 7.21-7.42 (m, 4H), 7.06-7.13 (m, 2H), 5.85 (s, 1H), 3.92 (s, 3H), 1.36 (s, 9H). 13C NMR (CDCl3, 125 MHz): δ=167.4, 145.1, 144.3, 139.8, 131.4, 129.4, 126.4, 121.3, 120.9, 118.9, 117.7, 52.3, 34.4, 31.6.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:11]=[C:12]3[N:17]([CH:18]=2)[CH:16]=[C:15]([C:19]([NH2:21])=[O:20])[CH:14]=[CH:13]3)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:24]I>CN(C=O)C.C1COCC1>[CH3:24][NH:21][C:19]([C:15]1[CH:14]=[CH:13][C:12]2[N:17]([CH:18]=[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[CH:11]=2)[CH:16]=1)=[O:20]
Reactant: CI
Reactant: NC(=O)c1ccc2cc(-c3cccc([N+](=O)[O-])c3)cn2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CNC(=O)c1ccc2cc(-c3cccc([N+](=O)[O-])c3)cn2c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 23.8 %

Procedure:
To a cooled solution of 2-(3-nitrophenyl)indolizine-6-carboxamide (0.4 g, 1.42 mmol) in DMF/THF (20/10 ml) was added NaH (60% in mineral oil, 58 mg, 1.45 mmol). The resulting mixture was stirred under Ar at 0° C. for 5 min, and then MeI (0.13 mL, 2.08 mmol) was added. The reaction mixture was stirred under Ar at 0° C. and warmed gradually to room temperature and stirred at room temperature overnight. It was concentrated in vacuo. The residue was recrystallized from CH2Cl2/acetone/EtOAc to give a white solid (0.1 g, 24%). 1H NMR (CDCl3, 400 MHz) δ: 8.78 (s, 1H), 8.48 (t, J=2.0 Hz, 1H), 8.42 (br s, 1H), 8.30 (d, J=1.6 Hz, 1H), 8.18 (d, J=7.6 Hz, 1H), 8.09 (dd, J=8.0, 1.6 Hz, 1H), 7.69 (t, J=8.0 Hz, 1H), 7.45 (d, J=9.2 Hz, 1H), 7.13 (dd, J=9.6, 1.6 Hz, 1H), 6.99 (s, 1H), 2.77 (d, J=4.4 Hz, 3H). MS: m/z=296 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCCC1>[F:12][C:8]1[CH:9]=[C:10]([F:11])[C:2]2[NH:1][C:14](=[O:16])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1c(F)cc(F)cc1C(=O)O
Solvent: C1CCOC1
Product: O=c1[nH]c2c(F)cc(F)cc2c(=O)o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94 %

Procedure:
2-Amino-3,5-difluoro-benzoic acid (2.44 g, 0.0141 mol) was dissolved in Tetrahydrofuran (100 mL). Triphosgene (4.18 g, 0.0141 mol) was dissolved in Tetrahydrofuran (10 mL) and added. The resulting solution was stirred for 4 h at rt. The reaction mixture was concentrated, and the resulting residue was sonicated in H2O. The peach ppt was filtered, taken up in acetone, and was concentrated under reduced pressure. It was then azeotroped in toluene to give 6,8-Difluoro-1H-3,1-benzoxazine-2,4-dione as tan solids (2.64 g, 94%). 1H-NMR (DMSO): 12.00 (s, 1H), 7.85 (m, 1H), 7.60 (m, 1H); 19F-NMR (DMSO): −116, −125.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10]CC)=[O:9])=[C:6]([F:13])[C:5]([CH2:14][NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:4][CH:3]=1.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CO.O>[Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([F:13])[C:5]([CH2:14][NH:15][C:16](=[O:21])[C:17]([CH3:19])([CH3:18])[CH3:20])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(Cl)ccc(CNC(=O)C(C)(C)C)c1F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.7 %

Procedure:
To a solution of ethyl 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoate (100 mg, 0.317 mmol) in THF:MeOH:H2O (3:2:1; 6 mL) was added NaOH (25 mg, 0.634 mmol). The reaction mass was stirred at rt for 3 h. The reaction mass was neutralized with citric acid and concentrated. The residue was diluted with EtOAc and was washed with water and brine. The organic layer was separated, dried, filtered and concentrated to afford 70 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 14.10 (s, 1H), 8.14 (br t, 1H), 7.38-7.26 (m, 2H), 4.25 (d, J=5.4 Hz, 2H), 1.11 (s, 9H).
Reaction SMILES: C1(NC(=NC2CCCCC2)O[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)CCCCC1.CN(C=O)C.[NH2:29][C:30]1[C:38]([N+:39]([O-:41])=[O:40])=[CH:37][CH:36]=[CH:35][C:31]=1[C:32]([OH:34])=[O:33]>C(OCC)(=O)C.CCCCCC>[NH2:29][C:30]1[C:38]([N+:39]([O-:41])=[O:40])=[CH:37][CH:36]=[CH:35][C:31]=1[C:32]([O:34][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:33]
Reactant: Nc1c(C(=O)O)cccc1[N+](=O)[O-]
Reactant: c1ccc(COC(=NC2CCCCC2)NC2CCCCC2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: Nc1c(C(=O)OCc2ccccc2)cccc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
Benzyl N,N′-dicyclohexylimidocarbamate (0.82 g) was added to a DMF (3 mL) solution of 2-amino-3-nitrobenzoic acid (0.36 g), followed by heating up to 70° C. and stirring for 2 hours. The reaction mixture was cooled to room temperature, then an ethyl acetate/ether (1/1) solution was poured into it, and the insoluble matter was separated by filtration. The filtrate was washed with aqueous sodium hydrogencarbonate solution and water in that order, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1) to obtain benzyl 2-amino-3-nitrobenzoate (0.42 g). FA: 273.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:11][CH2:10][NH:9][C:8]2=[O:12])[CH2:3][CH2:2]1.N1C=CC=CC=1.[C:19](Cl)(Cl)=[O:20].[CH2:23]([C:25]1[N:30]=[C:29]([NH2:31])[CH:28]=[CH:27][C:26]=1[O:32][C:33]1[CH:38]=[CH:37][N:36]=[C:35]([C:39]2[CH:44]=[CH:43][N:42]=[C:41]([CH3:45])[CH:40]=2)[CH:34]=1)[CH3:24]>C(Cl)Cl>[CH2:23]([C:25]1[N:30]=[C:29]([NH:31][C:19]([N:9]2[CH2:10][CH2:11][N:7]([CH:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)[C:8]2=[O:12])=[O:20])[CH:28]=[CH:27][C:26]=1[O:32][C:33]1[CH:38]=[CH:37][N:36]=[C:35]([C:39]2[CH:44]=[CH:43][N:42]=[C:41]([CH3:45])[CH:40]=2)[CH:34]=1)[CH3:24]
Reactant: O=C1NCCN1C1CCOCC1
Reactant: CCc1nc(N)ccc1Oc1ccnc(-c2ccnc(C)c2)c1
Reactant: O=C(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCc1nc(NC(=O)N2CCN(C3CCOCC3)C2=O)ccc1Oc1ccnc(-c2ccnc(C)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 3.8 %

Procedure:
A 0° C. solution of Example B1 (0.19 g, 1.116 mmol) and pyridine (0.26 mL, 3.21 mmol) in DCM (5 mL) was treated drop-wise with phosgene (20% in toluene, 1.4 mL, 2.65 mmol), warmed to RT over 0.5 h, then treated slowly with a solution of 6-ethyl-5-((2′-methyl-[2,4′-bipyridin]-4-yl)oxy)pyridin-2-amine (0.13 g, 0.424 mmol) and pyridine (0.16 mL, 1.978 mmol) in DCM (5 mL) and stirred at RT overnight. The mixture was treated with satd. NaHCO3, extracted with EtOAc (4×) and the combined organics were dried over MgSO4, concentrated to dryness, purified via silica gel chromatography (MeOH/DCM), then re-purified via reverse-phase chromatography (MeCN/H2O with 0.1% TFA). The organics were removed under reduced pressure, the aqueous residue treated with satd. NaHCO3, extracted with DCM (5×) and the combined organics were dried over MgSO4 and concentrated to dryness to afford N-(6-ethyl-5-((2′-methyl-[2,4′-bipyridin]-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide (8 mg, 4%). 1H NMR (400 MHz, DMSO-d6): δ 10.93 (s, 1 H), 8.56 (d, J=5.7 Hz, 1 H), 8.52 (d, J=5.3 Hz, 1 H), 7.93-7.89 (m, 2 H), 7.67 (d, J=2.4 Hz, 1 H), 7.68-7.66 (m, 1 H), 7.64 (s, 1 H), 6.86 (dd, J=5.7, 2.4 Hz, 1 H), 3.94-3.78 (m, 5 H), 3.49-3.34 (m, 4 H), 2.58 (q, J=7.5 Hz, 2 H), 2.53 (s, 3H), 1.78-1.66 (m, 2 H), 1.64-1.57 (m, 2 H), 1.12 (t, J=7.5 Hz, 3H); MS (ESI) m/z: 503.3 (M+H+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[CH3:20][C:21]1[O:25][CH2:24][N:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:22]=1[NH2:32]>>[CH2:17]1[CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6]3[C:5]([F:19])=[CH:4][N:3]=[C:2]([NH:32][C:22]4[N:23]([C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=5)[CH2:24][O:25][C:21]=4[CH3:20])[N:7]=3)=[CH:10][C:11]=2[O:18]1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Reactant: CC1=C(N)N(c2ccccc2)CO1
Product: CC1=C(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)N(c2ccccc2)CO1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine with 5-methyl-3-phenyl-4-oxazolylamine gave N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(5-methyl-3-phenyl-4-oxazolyl)-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.80–7.65 (m, 2H), 7.45 (bd, 1H), 7.20 (m, 1H), 7.00 (m, 1H), 6.65 (bd, 1H), 4.20 (s, 4H), 2.35 (s, 3H); LCMS: ret. time: 20.61 min.; purity: 78%; MS (m/e): 420 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>O1CCCC1.O>[CH2:22]([O:21][C:19]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=[O:6])=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Nc1cc(C(=O)O)ccc1F
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1cc(C(=O)O)ccc1F)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-amino-4-fluorobenzoic acid (30 g, 193 mmol) in a mixture of tetrahydrofuran (300 mL) and water (300 mL) was added cesium carbonate (157 g, 483 mmol) and benzyl chloroformate (30.4 mL, 213 mmol). This mixture was stirred at ambient temperature for 16 hours, and was concentrated to about 200 mL. The residue was acidified with 2N HCl to a pH 3, and was partitioned between ethyl acetate and brine. The precipitated solid was collected by filtration, washed with ethyl acetate and water, and dried to provide the title compound. MS (DCI/NH3) m/z 290 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=2)[C:10](=[O:11])[NH:9][C:8](=[O:12])[NH:7]1)[CH:2]=[CH2:3].Br[C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([C:29]([F:32])([F:31])[F:30])[CH:22]=1>CC(N(C)C)=O.[Cu-]=O>[O:12]=[C:8]1[NH:7][C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=2)([CH2:5][O:4][CH2:1][CH:2]=[CH2:3])[C:10](=[O:11])[N:9]1[C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([C:29]([F:30])([F:32])[F:31])[CH:22]=1
Reactant: N#Cc1ccc(Br)cc1C(F)(F)F
Reactant: C=CCOCC1(c2cccc(C)c2)NC(=O)NC1=O
Agent: O=[Cu-]
Solvent: CC(=O)N(C)C
Product: C=CCOCC1(c2cccc(C)c2)NC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Temperature: 130 °C

Procedure:
To a solution of 4-[(2-propenyloxy)methyl]-4-(3-methylphenyl)imidazolidine-2,5-dione (899 mg) and 4-bromo-2-(trifluoromethyl)benzonitrile (863 mg) in DMAC (5 mL) is added copper (I) oxide (395 mg). The mixture is refluxed overnight at 130° C. The mixture is concentrated, taken in ethyl acetate, washed with a 10% aqueous ammonia solution and brine. The organic phase is dried over magnesium sulfate, concentrated under vacuum and purified on silica gel (ethyl acetate/cyclohexane 0/100 to 50/50) to give the desired compound.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([CH:15]1[O:20][C:18](=[O:19])[CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16]1)[CH3:14].[Br:27][CH2:28]Br>CN(C)P(N(C)C)(N(C)C)=O.O1CCCC1>[Br:27][CH2:28][C:17]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][CH:15]([CH2:13][CH3:14])[O:20][C:18]1=[O:19]
Reactant: BrCBr
Reactant: CCC1CC(c2ccccc2)C(=O)O1
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCC1CC(CBr)(c2ccccc2)C(=O)O1
Temperature: -75 °C
Reaction time: 0.5 h

Procedure:
To a solution of 19.4 g. (0.19 m) diisopropylamine in 100 ml. of dry tetrahydrofuran is added dropwise 12.3 g. (0.19 m) n-butyl lithium at -75° C. under nitrogen. Stirring is continued for 1/2 hour when a solution of 30 g. (0.16 m) 4-ethyl-2-phenyl-gamma-butyrolactone in 50 ml. tetrahydrofuran is added dropwise in one hour. The resulting mixture is further stirred for 1/2 hour and a mixture of 33 g. (0.19 m) dibromomethane and 34 g. (0.19 m) hexamethylphosphoramide is added dropwise. The reaction temperature is maintained at -75° C. throughout the additions. The reaction mixture is stirred at room temperature overnite. It is then poured into 500 ml. of saturated ammonium chloride solution and extracted with ether. The combined ether extracts are dried over sodium sulfate and filtered. Solvent is removed under vacuum to give 39 g. of an oil which is further purified by bulb-to-bulb vacuum distillation to give 26 g. of pure product.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][NH2:6])[CH2:3][CH2:2]1.C1N=CN([C:12](N2C=NC=C2)=[O:13])C=1.[CH2:19]([C@H:21]1[CH2:25][NH:24][CH2:23][C@H:22]1[C:26]1[N:30]2[C:31]3[CH:37]=[CH:36][N:35]([S:38]([C:41]4[CH:47]=[CH:46][C:44]([CH3:45])=[CH:43][CH:42]=4)(=[O:40])=[O:39])[C:32]=3[N:33]=[CH:34][C:29]2=[N:28][N:27]=1)[CH3:20]>CN(C=O)C>[CH:1]1([CH2:4][CH2:5][NH:6][C:12]([N:24]2[CH2:23][C@H:22]([C:26]3[N:30]4[C:31]5[CH:37]=[CH:36][N:35]([S:38]([C:41]6[CH:42]=[CH:43][C:44]([CH3:45])=[CH:46][CH:47]=6)(=[O:40])=[O:39])[C:32]=5[N:33]=[CH:34][C:29]4=[N:28][N:27]=3)[C@H:21]([CH2:19][CH3:20])[CH2:25]2)=[O:13])[CH2:3][CH2:2]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC[C@H]1CNC[C@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Reactant: NCCC1CC1
Solvent: CN(C)C=O
Product: CC[C@@H]1CN(C(=O)NCCC2CC2)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Temperature: 65 °C
Reaction time: 2 h
Yield: 74.9 %

Procedure:
To a solution of 2-cyclopropylethanamine (0.068 g, 0.804 mmol, Oakwood) in DMF (3 mL) was added CDI (0.150 g, 0.926 mmol). The solution was stirred at about 65° C. for about 2 h. 1-((cis)-4-ethylpyrrolidin-3-yl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (0.250 g, 0.609 mmol, Example #36, step F) was added and the reaction mixture continued heating at about 65° C. After about 2 h, the reaction mixture was cooled to ambient temperature. The solvent was removed under reduced pressure. The crude material was purified by chromatography on silica gel eluting with a gradient of 0-10% MeOH in DCM to give (cis)-N-(2-cyclopropylethyl)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)pyrrolidine-1-carboxamide (0.238 g, 64%) as product: LC/MS (Table 1, Method a) Rt=2.17 min; MS m/z: 522 (M+H)+.
Reaction SMILES: [Br-].[NH2:2][C:3]1[C:12](Cl)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N+:4]=1[CH2:14][C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=O.C([OH:24])C>>[O:24]=[C:12]1[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[CH:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:2]=[C:3]12
Reactant: CCOC(=O)C(=O)C[n+]1c(N)c(Cl)nc2ccccc21
Reactant: CCO
Agent: [Br-]
Product: CCOC(=O)c1cn2c(n1)c(=O)[nH]c1ccccc12
Reaction time: 2 h

Procedure:
A suspension of 6.5 g of the product of Step A in 500 ml of ethanol was refluxed with stirring for 2 hours and the resulting clear yellow solution was concentrated and cooled in a refrigerator. The mixture was filtered and then 3.70 g of white crystalline product was crystallized from ethanol to obtain ethyl 4,5-dihydro-4-oxoimidazo-[1,2-a]-quinoxaline-2-carboxylate in the form of shiny crystals melting at 292°-293° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([C:16]2[O:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:19][N:20]=2)[OH:15])=[CH:4][CH:3]=1.[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)[CH2:34][CH2:33]1)=[O:31])[CH3:28]>>[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:15])[C:16]4[O:17][C:18]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)=[N:19][N:20]=4)=[CH:4][CH:3]=3)=[CH:37][CH:36]=2)[CH2:33][CH2:34]1)=[O:31])[CH3:28]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1nnc(-c2ccccc2)o1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)c4nnc(-c5ccccc5)o4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 17, Step 1, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-(5-phenyl-[1,3,4]oxadiazol-2-yl)-methanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[CH:10]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[N:11]([CH2:23][CH2:24][CH2:25][OH:26])[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I([O-])(=O)(=O)=[O:35].[Na+]>C(#N)C.C(Cl)(Cl)(Cl)Cl.O.O.[Ru](Cl)(Cl)Cl>[CH2:1]([O:8][C:9]([CH:10]([N:11]([S:12]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)(=[O:14])=[O:13])[CH2:23][CH2:24][C:25]([OH:35])=[O:26])[CH:27]1[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1)=[O:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(S(=O)(=O)N(CCCO)C(C(=O)OCc2ccccc2)C2CCCCC2)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(S(=O)(=O)N(CCC(=O)O)C(C(=O)OCc2ccccc2)C2CCCCC2)cc1
Reaction time: 4 h

Procedure:
Cyclohexyl[(3-hydroxypropyl)(4-methoxybenzenesulfonyl)amino]acetic acid benzyl ester (45.8 grams, 96 mmol) and sodium periodate (92.6 grams, 433 mmol) were dissolved in a mixture of acetonitrile (345 mL), carbon tetrachloride (345 mL) and water 460 mL). While cooling in an ice bath, ruthenium trichloride monohydrate (4.4 grams, 21 mmol) was then added. The resulting mixture was mechanically stirred with ice bath cooling for 30 minutes. The bath was removed and stirring was continued at room temperature for 4 hours. The reaction mixture was diluted with ethyl acetate and filtered through diatomaceous earth. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and saturated brine. After drying over magnesium sulfate, the solvents were evaporated to give a dark oil from which 3-[(benzyloxycarbonylcyclohexylmethyl)-(4-methoxybenzenesulfonyl) amino]propionic acid, a white foam (28.1 grams, 60%), was isolated by flash chromatography on silica gel eluting sequentially with chloroform and 1% methanol in chloroform.