Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])=[C:13]([CH:17]=1)[C:14](O)=[O:15].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O.O>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])=[C:13]([CH:17]=1)[C:14]([NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[O:15]
Reactant: O=C(O)c1cc(Br)ccc1OCc1ccccc1F
Reactant: Nc1cccnc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCCl
Product: O=C(Nc1cccnc1)c1cc(Br)ccc1OCc1ccccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Neat pyridin-3-amine (82 mg, 0.87 mmol) was added in one charge to a stirred solution of 5-bromo-2-{[(2-fluorophenyl)methyl]oxy}benzoic acid (may be prepared as described in Description 85; 200 mg, 0.58 mmol), EDC (223 mg, 1.16 mmol) and HOBT (178 mg, 1.16 mmol) in dimethylformamide (3 ml) in air at room temperature. The reaction mixture was stirred at 25° C. overnight. Water (25 ml) was added into the reaction mixture. The precipitate was filtered, washed with water (15 ml), and dried in vacuum to obtain crude product, which was purified with Prep-TLC (eluate: dichloromethane:methanol=25:1) to yield the title compound as a white solid. 67 mg.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[N:9][CH:8]=[C:7]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=1)[CH:6]=2.FC1C=[C:25]([CH2:30][OH:31])C=CC=1F.BrC1C=[N:35]C2C(C=1)=NC=C(Br)C=2.[H-].[Na+]>CN1C(=O)CCC1.O>[F:21][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=1[F:20])[CH2:13][O:12][C:7]1[CH:6]=[C:5]2[C:10]([CH:11]=[C:2]([CH2:25][C:30]([NH2:35])=[O:31])[CH:3]=[N:4]2)=[N:9][CH:8]=1
Reactant: Brc1cnc2cc(Br)cnc2c1
Reactant: Fc1ccc(COc2cnc3cc(Br)cnc3c2)cc1F
Reactant: OCc1ccc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: NC(=O)Cc1cnc2cc(OCc3ccc(F)c(F)c3)cnc2c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 53.3 %

Procedure:
3-Bromo-7-((3,4-difluorobenzyl)oxy)-1,5-naphthyridine. To a mixture of (3,4-difluorophenyl)methanol (119 μL, 1.04 mmol) and 3,7-dibromo-1,5-naphthyridine (Intermediate 3, 200 mg, 0.69 mmol) in NMP (1 mL) at 100° C. under a nitrogen atmosphere was added a slurry of sodium hydride (69.45 mg, 1.74 mmol) in NMP (1 mL) dropwise. The solution was allowed to stir at 100° C. for 3 h. Upon completion the reaction was cooled and water was added to afford a solid precipitate. The solid was collected by filtration to give the title compound (130 mg, 53.3%) as a crude brown solid, which used without further purification. 1H NMR (400 MHz, CDCl3) δ 8.93 (s, 1H), 8.82 (d, J=2.5 Hz, 1H), 8.54 (s, 1H), 7.66 (d, J=2.0 Hz, 1H), 7.41-7.31 (m, 1H), 7.27-7.16 (m, 2H), 5.19 (s, 2H). [M+H]=351.1.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][CH:21]=[CH:20]3)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>O1CCCC1>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[NH:22][CH:21]=[CH:20]4)=[CH:13][CH:12]=2)[C:3]([OH:26])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(-c2ccc3[nH]ccc3c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)C(CC1CCCC1)c1ccc(-c2ccc3[nH]ccc3c2)cc1
Temperature: 25 °C
Reaction time: 39 h
Yield: 57.3 %

Procedure:
A solution of 3-cyclopentyl-2-[4-(1H-indol-5-yl)-phenyl]-propionic acid methyl ester (310 mg, 0.89 mmol) in tetrahydrofuran (2 mL) was treated with a 0.8M aqueous lithium hydroxide solution (1.45 mL, 1.16 mmol). The resulting reaction mixture was stirred at 25° C. for 39 h and then heated at 80° C. for 4 h. The reaction mixture was then allowed to cool to 25° C. where it was stirred for 3 d. The reaction mixture was then concentrated in vacuo to remove tetrahydrofuran. The resulting aqueous layer was extracted with methylene chloride (2×40 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-[4-(1H-indol-5-yl)-phenyl]-propionic acid (170 mg, 58%) as a pale yellow foam: mp 62-65° C.; FAB-HRMS m/e calcd for C22H23NO2 (M+H)+ 333.1729, found 333.1731.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:18][CH2:19][C:20]([OH:22])=O)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH2:33][CH2:34][NH2:35])[CH:28]=[CH:29][C:30]=1[O:31][CH3:32]>>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH2:33][CH2:34][NH:35][C:20](=[O:22])[CH2:19][CH2:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:10]([NH:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:11])[CH:28]=[CH:29][C:30]=1[O:31][CH3:32]
Reactant: COc1ccc(CCN)cc1OC
Reactant: O=C(O)CCc1ccccc1C(=O)NCCc1ccccc1
Product: COc1ccc(CCNC(=O)CCc2ccccc2C(=O)NCCc2ccccc2)cc1OC

Procedure:
This was prepared from the product of step (c) and 3,4-dimethoxybenzeneethanamine using the procedure of Example 6(c) mp 122°-3°.
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:19][C:20]([O:22]C)=O)[C:7]([NH:9][C@H:10]([C:16]([OH:18])=[O:17])[CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])=[O:8])(=O)C.C(SCC(CC(OC)=O)C([NH:32][C@H](C(O)=O)CCCNC(=N)N)=O)(=O)C>>[C:20]([CH2:19][CH:6]([CH2:5][SH:4])[C:7]([NH:9][C@H:10]([C:16]([OH:18])=[O:17])[CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])=[O:8])(=[O:22])[NH2:32]
Reactant: COC(=O)CC(CSC(C)=O)C(=O)N[C@@H](CCCCN)C(=O)O
Reactant: COC(=O)CC(CSC(C)=O)C(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Product: NCCCC[C@H](NC(=O)C(CS)CC(N)=O)C(=O)O

Procedure:
By substituting Nα -[3-(acetylthio)-2-methoxycarbonylmethylpropanoyl]-L-lysine for the Nα -[3-acetylthio-2-methoxycarbonylmethylpropanoyl]-L-arginine in the procedure of Example 19, Nα -[2-(carbamoylmethyl)-3-mercaptopropanoyl]-L-lysine is obtained.
Reaction SMILES: [CH:1]1([NH2:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[Br:18][CH2:19][C:20](Br)=[O:21]>C(Cl)Cl.O>[Br:18][CH2:19][C:20]([NH:8][CH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:21]
Reactant: O=C(Br)CBr
Reactant: NC1CCCCCC1
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CBr)NC1CCCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.7 %

Procedure:
To a −20° C. solution of cycloheptylamine (6.37 mL, 50.0 mmol) and diisopropylethylamine (9.58 mL, 55.0 mmol) in CH2Cl2 (250 mL) was slowly added bromoacetyl bromide (4.78 mL, 55.0 mmol). The reaction mixture was warmed to room temperature over 20 minutes and stirred for an additional 30 minutes. The reaction mixture was diluted with water (100 mL) and stirred for an additional 30 minutes. The organic layer was separated, washed with water (3×100 mL), dried over magnesium sulfate and concentrated in vacuo to afford a beige solid (10.5 g). The crude material was further purified by silica gel flash column chromatography using hexane:ethyl acetate (1/1, v/v) as the eluent to give the purified title compound as an oil (9.77 g, 83%). 1H-NMR (Me2SO-d6): δ 8.20 (br d, 1H), 3.77 (s, 2H), 3.67 (m, 1H) and 1.8-1.3 (m, 12H). 13C-NMR (CDCl3): δ 164.01, 51.04, 34.59, 29.40, 27.80 and 23.87. Mass spectrum (FAB+) m/z 234/236 [M+H]+ and 256/258 [M+Na]+.
Reaction SMILES: [CH2:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][CH2:12]O)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].P(Br)(Br)[Br:15]>>[CH2:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][CH2:12][Br:15])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[C@H]1CC[C@H](CCO)CC1
Reactant: BrP(Br)Br
Product: CCCC[C@H]1CC[C@H](CCBr)CC1
Temperature: 25 °C
Yield: 144.4 %

Procedure:
31 g (0.17 mol) of 2-(trans-4'-butylcyclohexyl)ethanol was given dropwise addition of 23 g (0.09 mol) of PBr3 while stirring at room temperature, after which it was stirred for 1 hour on a 70° C. hot water bath. The reactant was cooled to room temperature, poured into ice water to decompose the excess PBr3, the oily layer was taken off, and the water layer was extracted with chloroform and combined with the oily layer and washed with water. The chloroform was removed, and the remaining oily substance was distilled under reduced pressure (b. p. 99° C./2 mmHg) to obtain 32 g (0.13 mol) of 2-(trans-4'-butylcyclohexyl)-1-bromoethane.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.[CH3:32][O:33][C:34]1[CH:35]=[CH:36][C:37]([CH2:40]O)=[CH:38][CH:39]=1.[C:42]1(=[O:48])[NH:46][C:45](=[O:47])[CH:44]=[CH:43]1>>[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][N:46]2[C:42](=[O:48])[CH:43]=[CH:44][C:45]2=[O:47])=[CH:36][CH:35]=1
Reactant: COc1ccc(CO)cc1
Reactant: O=C1C=CC(=O)N1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1ccc(CN2C(=O)C=CC2=O)cc1

Procedure:
Reagents: Ph3P (1.31 g, 5 mmol), DEAD (0.8 ml, 5 mmol), p-methoxybenzyl alcohol (0.93 ml, 7.5 mmol) and maleimide (0.48 g, 5 mmol).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([OH:13])[CH2:10][CH:9]1[CH3:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:34]([C:37]1[CH:45]=[CH:44][C:40]([C:41](O)=[O:42])=[CH:39][CH:38]=1)([O-:36])=[O:35].CCOC(/N=N/C(OCC)=O)=O.Cl>C1COCC1.CCCCCC.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:41](=[O:42])[C:40]2[CH:39]=[CH:38][C:37]([N+:34]([O-:36])=[O:35])=[CH:45][CH:44]=2)[CH2:10][CH:9]1[CH3:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: CC1CC(O)CN1C(=O)OC(C)(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1CC(OC(=O)c2ccc([N+](=O)[O-])cc2)CN1C(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
The 4-hydroxy-2-methyl-pyrrolidine-1-carboxylic acid t-butyl ester (300.00 mg, 1.49 mmol) and triphenyl phosphine (512.54, 1.95 mmol) were dissolved in anhydrous THF and added to a mixture of para-nitrobenzoic acid (249.00 mg, 1.49 mmol) and DEAD (268.00 mg, 1.54 mmol, 0.24 mL) in anhydrous THF at 0EC under argon. The mixture was stirred for 1 h at 0EC. After 1 h the TLC indicated no starting material remained and the reaction mixture was poured into a 1N HCl solution and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with water and brine then dried over MgSO4. The solution was filtered and the solvent removed under reduced pressure. The product was isolated by flash chromatography. (2:1 hexane-ethyl acetate) Yield 391.54 mg. 1H NMR (CDCl3, 300 MHz): δ 1.39 (d, J=9 Hz, 3H), 1.49 (s, 9H), 1.99 (d, J=15 Hz, 1H), 2.24-2.33 (m, 1H), 3.62-3.71 (m, 1H), 3.82 (dd, J=7, 12 Hz, 1H), 4.13 (bs, 1H), 5.52-5.56 (m, 1H), 8.20-8.35 (m, A2B2), 4H).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([N:5]([CH2:12][P:13]([O:17]Cl)([O:15]Cl)=[O:14])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:4].[CH3:21][OH:22].C(N(CC)CC)C.[C:30]1([SH:36])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CCOCC>[F:1][C:2]([F:20])([F:19])[C:3]([N:5]([CH:12]([O:22][CH3:21])[P:13]([OH:17])([O:15][S:36][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:14])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:4]
Reactant: CCOC(=O)CN(CP(=O)(OCl)OCl)C(=O)C(F)(F)F
Reactant: CO
Reactant: Sc1ccccc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)CN(C(=O)C(F)(F)F)C(OC)P(=O)(O)OSc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 11.6 %

Procedure:
Ethyl N-trifluoroacetyl-N-(dichlorophosphonomethyl)glycinate (6.6 g, 0.02 mole) was dissolved in 100 ml. of ether, cooled to 0° C. and treated with a solution of methanol (0.8 g, 0.02 mole) and triethylamine (2.78 g, 0.02 mole) in 50 ml. of ether. After two hours, the solution was filtered and the filtrate cooled to 0° C. and treated with a solution of thiophenol (2.05 ml, 0.02 mole) and triethylamine (2.78 ml, 0.02 mole) in 50 ml. of ether. After two hours, the solution was filtered and the filtrate was concentrated in vacuo. The residue was extracted into petroleum ether and the petroleum ether was removed by distillation in vacuo. The residue (1.5 g) was chromatographed on silica gel eluting with ether/benzene (7/3) to afford ethyl N-trifluoroacetyl-N-(methoxy(phenylthio)phosphonomethyl)glycinate as a colorless oil (1 g), ND =1.5047.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5](=[O:55])[C@@H:6]([NH:22][C:23]([C@@H:25]1[CH2:34][C:33]2[CH:32]=[C:31]3[O:35][CH2:36][C@H:37]([C:39]4[CH:44]=[CH:43][C:42]([O:45][CH2:46][C:47]5[CH:52]=[CH:51][C:50]([Cl:53])=[C:49]([Cl:54])[CH:48]=5)=[CH:41][CH:40]=4)[O:38][C:30]3=[CH:29][C:28]=2[CH2:27][NH:26]1)=[O:24])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[C:15]=2[CH3:21])=[CH:10][CH:9]=1.[CH3:56][C:57]1[N:62]=[C:61]([CH:63]=O)[CH:60]=[CH:59][CH:58]=1>>[CH3:3][O:4][C:5](=[O:55])[C@@H:6]([NH:22][C:23]([C@@H:25]1[CH2:34][C:33]2[CH:32]=[C:31]3[O:35][CH2:36][C@H:37]([C:39]4[CH:44]=[CH:43][C:42]([O:45][CH2:46][C:47]5[CH:52]=[CH:51][C:50]([Cl:53])=[C:49]([Cl:54])[CH:48]=5)=[CH:41][CH:40]=4)[O:38][C:30]3=[CH:29][C:28]=2[CH2:27][N:26]1[CH2:63][C:61]1[CH:60]=[CH:59][CH:58]=[C:57]([CH3:56])[N:62]=1)=[O:24])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[C:15]=2[CH3:21])=[CH:10][CH:9]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: Cc1cccc(C=O)n1
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1Cc1cccc(C)n1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3

Procedure:
(S)-2-({(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester dihydrochloride (30 mg) was reacted with 6-methyl-pyridine-2-carbaldehyde according to General Procedure D. The reaction mixture was directly purified over silica (hexanes to 1:1 hexanes EtOAc to 1:1 hexanes EtOAc+1% MeOH to 1:1 hexanes EtOAc+2% MeOH up to 1:1 hexanes EtOAc+5% MeOH) to give (S)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-(6-methyl-pyridin-2-ylmethyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester. This ester was hydrolyzed according to General Procedure B to give the title compound (15 mg). LCMS (m/z): 845.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([CH2:8][C@H:9]([OH:12])[CH2:10][OH:11])[C:6]=1[CH3:7].C1COCC1.C([Mg]Cl)(C)C.CO[B:25]1[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]1.[NH4+].[Cl-]>>[CH3:7][C:6]1[N:5]([CH2:8][C@H:9]([OH:12])[CH2:10][OH:11])[N:4]=[CH:3][C:2]=1[B:25]1[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]1
Reactant: COB1OC(C)(C)C(C)(C)O1
Reactant: Cc1c(I)cnn1C[C@H](O)CO
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1c(B2OC(C)(C)C(C)(C)O2)cnn1C[C@H](O)CO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (S)-3-(4-Iodo-5-methylpyrazol-1-yl)-propane-1,2-diol (20.0 mg, 0.0709 mmol) in THF (1 mL, 10 mmol) was added 2 M isopropylmagnesium chloride in THF (0.18 mL, 0.36 mmol) at 0° C., and the reaction was allowed to warm to rt over 30 min. 2-Methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.070 mL, 0.43 mmol) was then added, and the mixture was stirred at rt for 30 min. Sat. NH4Cl was added to quench, and the organic solvent was removed in vacuo. The material was extracted with DCM and water, and the organic layer was concentrated in vacuo to afford the title compound as a clear oil. It was used in the Suzuki coupling without further purification.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:24]([O:25]C)=[C:13]3[C:14](=[O:23])[N:15]([CH3:22])[C:16]4[C:21]([N:12]3[N:11]=2)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[O:9])=[CH:4][CH:3]=1.Br>CC(O)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:24]([OH:25])=[C:13]3[C:14](=[O:23])[N:15]([CH3:22])[C:16]4[C:21]([N:12]3[N:11]=2)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[O:9])=[CH:27][CH:28]=1
Reactant: COc1c(C(=O)NCc2ccc(F)cc2)nn2c1c(=O)n(C)c1ccccc12
Agent: Br
Solvent: CC(=O)O
Product: Cn1c(=O)c2c(O)c(C(=O)NCc3ccc(F)cc3)nn2c2ccccc21
Temperature: 50 °C

Procedure:
To a solution of N-(4-fluorobenzyl)-3-methoxy-5-methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxaline-2-carboxamide (85 mg, 0.22 mmol) in AcOH (1 mL) was added 30% HBr in AcOH (2 mL). The mixture was stirred and warmed to 50° C. for 8 hours. The solvent was removed under reduced pressure. The residue was triturated in AcOH to give the title compound as a white solid. 1H NMR (400 MHz, d6-DMSO) δ 9.82 (br s, 1H), 9.06 (t, J=6.0 Hz, 1H), 8.20 (d, J=8.0 Hz, 1H), 7.58 (d, J=7.8 Hz, 1H), 7.51 (t, J=7.8 Hz, 1H), 7.38-7.43 (m, 3H), 7.17 (t, J=9.0 Hz, 2H), 4.50 (d, J=6.2 Hz, 2H), 4.02 (s, 3H), 3.57 (s, 3H); ES MS (M+1)=367.
Reaction SMILES: [C:1]1([C:9]([CH2:11][C:12]2[CH:19]=[CH:18][C:15]([O:16][CH3:17])=[CH:14][CH:13]=2)=O)[CH:8]=[CH:7][C:4]([O:5][CH3:6])=[CH:3][CH:2]=1.Cl.[NH2:21][OH:22].[OH-].[Na+]>CO.O>[C:1]1([C:9](=[N:21][OH:22])[CH2:11][C:12]2[CH:19]=[CH:18][C:15]([O:16][CH3:17])=[CH:14][CH:13]=2)[CH:8]=[CH:7][C:4]([O:5][CH3:6])=[CH:3][CH:2]=1
Reactant: NO
Reactant: COc1ccc(CC(=O)c2ccc(OC)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(CC(=NO)c2ccc(OC)cc2)cc1
Reaction time: 0.25 h
Yield: 98.6 %

Procedure:
Desoxyanisoin (98%, 52.2 g., 0.2 mole) and hydroxylamine hydrochloride (15.3 g., 0.22 mole) are slurried in a mixture of methanol (300 ml) and water (200 ml) and sodium hydroxide (16 g., 0.4 mole) is added slowly. The mixture is stirred for 15 minutes, then placed in a hot water bath (70° C.) and stirred an additional hour. Methanol is then added to the hot mixture until solution is almost complete, the mixture is filtered and concentrated to remove most of the methanol, then cooled with the addition of ice-water. Filtered, dissolved the resulting solid in ethyl acetate, extracted with brine. Dried the organic layer (Na2SO4), filtered and concentrated to obtain 53.5 g (98.5%) of the oxime as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:14](=O)[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[C:9]([O:11]CC)=O)=[CH:4][CH:3]=1.[C:22]1([CH2:28][CH2:29][CH2:30][CH2:31][C:32]([NH2:34])=[NH:33])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CC1C=CC(C)=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9](=[O:11])[NH:34][C:32]([CH2:31][CH2:30][CH2:29][CH2:28][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[N:33][C:14]=2[C:15]2[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C(=O)c1ccncc1)c1ccc(F)cc1
Reactant: N=C(N)CCCCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccc(C)cc1
Product: O=c1[nH]c(CCCCc2ccccc2)nc(-c2ccncc2)c1-c1ccc(F)cc1
Reaction time: 16 h

Procedure:
Ethyl 2-(4-fluorophenyl)-3-oxo-3-(4-pyridyl)-propionate (293 mg, 1.02 mmol), 4-phenylbutanecarboxamidine (315 mg, 1.79 mmol) and pyridinium p-toluenesulfonate (10 mg) were suspended in p-xylene (10 ml). With efficient stirring, the mixture was heated to reflux using a Dean-Stark apparatus with continuous removal of water. After 16 h, the solvent was evaporated and the product purified by column chromatography on silica gel (3% methanol/dichloromethane) followed by recrystallization from acetone. MS (m/z): 400.3 (M+H)+; C25H22FN3O requir. 399.5.
Reaction SMILES: CO[CH:3]=[C:4]([CH3:8])[C:5](Cl)=[O:6].C1C=CC=CC=1.[OH:15][CH2:16][CH2:17][CH:18]1[CH2:20][CH:19]1[N:21]1C=CC(=O)[NH:24][C:22]1=[O:23].CN(C)C=O>[Ag]OC#N.C(OCC)C>[OH:15][CH2:16][CH2:17][CH:18]1[CH2:20][CH:19]1[N:21]1[CH:3]=[C:4]([CH3:8])[C:5](=[O:6])[NH:24][C:22]1=[O:23]
Reactant: O=c1ccn(C2CC2CCO)c(=O)[nH]1
Reactant: COC=C(C)C(=O)Cl
Agent: N#CO[Ag]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: Cc1cn(C2CC2CCO)c(=O)[nH]c1=O
Temperature: -15 °C

Procedure:
3-Methoxymethacrylic acid chloride (2.68 g) and 25 mL of benzene are combined in a round bottom flask. To this mixture is added 6.4 g of silver cyanate and the resultant mixture heated to reflux temperature. After 40 min at reflux temperature the mixture is cooled to -15° C. In a separate round bottom flask, 1.0 g of the product of Step A of Example 8, 30 mL of dimethyl formamide (DMF) and 10 mL of diethyl ether are combined and this second mixture cooled to -15° C. The acylisocyanate mixture is added to the amine and the resultant solution stirred at -15° C. for 2 h. and allowed to stand in the refrigerator overnight. The reaction mixture is concentrated and the crude material is purified by column chromatography. The material recovered from the column and 5 mL of 2N aqueous sulfuric acid solution are combined in a round bottom flask and this reaction mixture heated at reflux temperature for 2 h. The mixture is adjusted to pH 7 with aqueous barium hydroxide, filtered and the filtrate concentrated. The residue is purified by column chromatography to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([F:16])[F:15])[N:11]3[N:17]=[CH:18][C:19]([C:20]([OH:22])=O)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[N:23]1([S:29]([C:32]2[CH:33]=[C:34]([NH2:38])[CH:35]=[CH:36][CH:37]=2)(=[O:31])=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[N:23]1([S:29]([C:32]2[CH:33]=[C:34]([NH:38][C:20]([C:19]3[CH:18]=[N:17][N:11]4[C:12]([CH:14]([F:16])[F:15])=[CH:13][C:8]([C:5]5[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=5)=[N:9][C:10]=34)=[O:22])[CH:35]=[CH:36][CH:37]=2)(=[O:31])=[O:30])[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1
Reactant: Nc1cccc(S(=O)(=O)N2CCOCC2)c1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(Cl)cc3)nc12
Product: O=C(Nc1cccc(S(=O)(=O)N2CCOCC2)c1)c1cnn2c(C(F)F)cc(-c3ccc(Cl)cc3)nc12

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-difluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.3) and 3-(morpholine-4-sulfonyl)-phenylamine [CAS 22184-97-0; commercially available] according to general procedure II. Yellow solid. MS (ISP) 548.3 [(M+H)+]; mp 253° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C@H:11]([CH2:20][C@@H:21]([CH:29]([CH3:31])[CH3:30])[CH:22]=[CH:23][C:24]([O:26]CC)=[O:25])[O:10][C:9]1([CH3:33])[CH3:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].C(O)(=O)C>CO>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)[C@H:11]([CH2:20][C@@H:21]([CH:29]([CH3:30])[CH3:31])[CH:22]=[CH:23][C:24]([OH:26])=[O:25])[O:10][C:9]1([CH3:32])[CH3:33])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C=C[C@@H](C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC1CCCCC1)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)[C@@H](C=CC(=O)O)C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC1CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.1 %

Procedure:
1.7 g (3.7 mmol) of ethyl (S)-5-[(4S,5S)-3-(t-butoxycarbonyl)-4-(cyclohexylmethyl)-2,2-dimethyl-5-oxazolidinyl]-4-isopropyl-2-pentenoate are dissolved in 10 ml of methanol, treated with 2 ml (18 mmol) of 28% sodium hydroxide solution and stirred at room temperature for 16 hours. Thereafter, the reaction mixture is poured into ice-water, the pH value is adjusted to 5 with acetic acid and the mixture is extracted with ethyl acetate. The ethyl acetate extracts are dried over magnesium sulphate and evaporated under reduced pressure. Chromatography of the residue on 20 g of silica gel with a mixture of methylene chloride and isopropanol as the eluting agent yields 1.2 g of (S)-5-[(4S,5S)-3-(t-butoxycarbonyl)-4-(cyclohexylmethyl)-2,2-dimethyl-5-oxazolidinyl]-4-isopropyl-2-pentenoic acid as an oil, MS: 422 (M-CH3)+.