Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:21]2[CH:22]=[N:23][N:24]3[CH:29]=[CH:28][C:27]([N:30]4[C@@H:34]([C:35]5[CH:40]=[CH:39][C:38]([F:41])=[CH:37][N:36]=5)[CH2:33][O:32][C:31]4=[O:42])=[N:26][C:25]=23)[CH:5]=[CH:6][C:7]=1[C:8]1[N:12]=[CH:11][N:10](COCC[Si](C)(C)C)[N:9]=1>C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:3]=[C:4]([C:21]2[CH:22]=[N:23][N:24]3[CH:29]=[CH:28][C:27]([N:30]4[C@@H:34]([C:35]5[CH:40]=[CH:39][C:38]([F:41])=[CH:37][N:36]=5)[CH2:33][O:32][C:31]4=[O:42])=[N:26][C:25]=23)[CH:5]=[CH:6][C:7]=1[C:8]1[N:12]=[CH:11][NH:10][N:9]=1
Reactant: C[Si](C)(C)CCOCn1cnc(-c2ccc(-c3cnn4ccc(N5C(=O)OC[C@@H]5c5ccc(F)cn5)nc34)cc2F)n1
Solvent: O=C(O)C(F)(F)F
Product: O=C1OC[C@H](c2ccc(F)cn2)N1c1ccn2ncc(-c3ccc(-c4nc[nH]n4)c(F)c3)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.5 %

Procedure:
To the solid (S)-3-(3-(3-fluoro-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-(5-fluoropyridin-2-yl)oxazolidin-2-one (5.8 g, 9.8 mmol) was added TFA (40 mL) and the reaction stirred at ambient temperature for 2 hours. The reaction was concentrated in vacuo and the residue was dissolved in acetonitrile/methanol (1:1, 70 mL). Water (30 mL) was added and the mixture was stirred at ambient temperature for 3 hours. The aqueous layer was made basic with NaHCO3 (saturated solution) and the organic layer was removed in vacuo. The solid that formed was filtered and dried in vacuo. The solid was taken up in acetone (100 mL) and water added (500 mL) slowly. After complete addition, the slurry was stirred for 1 hour at ambient temperature. The slurry was filtered and the solid dried in vacuo for 36 hours to yield (S)-3-(3-(3-fluoro-4-(1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-(5-fluoropyridin-2-yl)oxazolidin-2-one (3.4 g, 7.4 mmol, 75% yield). LCMS (APCI+) m/z 461 [M+H]+.
Reaction SMILES: Cl.C([O:4][C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[C:11]([F:28])[C:12]([F:27])=[C:13]([F:26])[C:14]=2[O:18]CC2C=CC=CC=2)[N:9]([C:29]2[C:34]([F:35])=[CH:33][C:32]([F:36])=[C:31]([NH:37]C(OCC3C=CC=CC=3)=O)[CH:30]=2)[CH:8]=1)=[O:6])C>C(O)(=O)C>[NH2:37][C:31]1[CH:30]=[C:29]([N:9]2[C:10]3[C:15](=[C:14]([OH:18])[C:13]([F:26])=[C:12]([F:27])[C:11]=3[F:28])[C:16](=[O:17])[C:7]([C:5]([OH:6])=[O:4])=[CH:8]2)[C:34]([F:35])=[CH:33][C:32]=1[F:36]
Reactant: CCOC(=O)c1cn(-c2cc(NC(=O)OCc3ccccc3)c(F)cc2F)c2c(F)c(F)c(F)c(OCc3ccccc3)c2c1=O
Agent: Cl
Solvent: CC(=O)O
Product: Nc1cc(-n2cc(C(=O)O)c(=O)c3c(O)c(F)c(F)c(F)c32)c(F)cc1F
Temperature: 100 °C
Reaction time: 4 h
Yield: 69.9 %

Procedure:
To 8 ml of acetic acid and 10 ml of 6N hydrochloric acid was added 1.3 g of the compound synthesized in Example 235. The solution was stirred at 100° C. for 4 hours. The solvent was distilled off in vacua. Water was added to the residue. The solid was collected by filtration and washed with water, ethanol, and isopropyl ether to give 0.55 g of the title compound as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]([CH3:13])[C:10](Cl)=[O:11])=[N:7][CH:8]=1)#[N:2].[Br:14][C:15]1[CH:16]=[N:17][N:18]2[CH2:23][CH2:22][NH:21][CH2:20][C:19]=12.C(N(CC)CC)C.O>C1COCC1.CN(C)C1C=CN=CC=1>[Br:14][C:15]1[CH:16]=[N:17][N:18]2[CH2:23][CH2:22][N:21]([C:10]([N:9]([C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][N:7]=3)[CH3:13])=[O:11])[CH2:20][C:19]=12
Reactant: CN(C(=O)Cl)c1ccc(C#N)cn1
Reactant: Brc1cnn2c1CNCC2
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CN(C(=O)N1CCn2ncc(Br)c2C1)c1ccc(C#N)cn1
Temperature: 60 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
To a solution of (5-cyanopyridin-2-yl)(methyl)carbamic chloride (I-28) in THF (2.0 mL) were added 3-bromo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (137 mg, 0.680 mmol), triethylamine (0.14 mL, 1.021 mmol) and 4-dimethylaminopyridine (2.0 mg, 0.017 mmol). The mixture was stirred at 60° C. for 1 h. Subsequently, water (25 mL) was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and the solvent was removed under reduced pressure. The resulting crude product was purified by preparative TLC to afford 60 mg (44%) of 3-bromo-N-(5-cyanopyridin-2-yl)-N-methyl-6,7-dihydropyrazolo-[1,5-a]pyrazine-5(4H)-carboxamide (I-29) as a off white solid. 1H NMR (400 MHz, DMSO) δ 8.64 (s, 1H), 8.07 (d, J=8.8 Hz, 1H), 7.60 (s, 1H), 7.18 (d, J=8.4 Hz, 1H), 4.53 (s, 2H), 4.16 (t, J=4.9 Hz, 2H), 3.84 (t, J=4.9 Hz, 2H), 3.26 (s, 3H); ESI-LC/MS (m/z): [M+H]+ 360.91, [(M+2)+H]+ 362.93, RT 1.63 min.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:34]([N:36]1[CH2:40][CH2:39][C@H:38]([F:41])[CH2:37]1)=[O:35])[C@H:10]([C:16]1[CH:21]=[CH:20][C:19]([N:22]([CH3:33])[C:23](=[O:32])[C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)=[CH:18][CH:17]=1)[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])=O)(C)(C)C.[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45]>ClCCl>[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45].[NH2:8][C@H:9]([C:34]([N:36]1[CH2:40][CH2:39][C@H:38]([F:41])[CH2:37]1)=[O:35])[C@H:10]([C:16]1[CH:21]=[CH:20][C:19]([N:22]([CH3:33])[C:23](=[O:32])[C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)=[CH:18][CH:17]=1)[C:11]([N:13]([CH3:14])[CH3:15])=[O:12]
Reactant: COc1ccc(C(=O)N(C)c2ccc([C@H](C(=O)N(C)C)[C@H](NC(=O)OC(C)(C)C)C(=O)N3CC[C@H](F)C3)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(C(=O)N(C)c2ccc([C@H](C(=O)N(C)C)[C@H](N)C(=O)N3CC[C@H](F)C3)cc2)cc1
Reaction time: 1 h

Procedure:
To a solution of 17.6 mg (0.0346 mmol) of N-(4-{(1S,2S)-2-[(tert-butoxycarbonyl)amino]-1-[(dimethylamino)carbonyl]-3-[(3S)-3-fluoropyrrolidin-1-yl]-3-oxopropyl}phenyl)-N-methyl-4-methoxybenzamide from Step H in 1 mL of dichloromethane was added 1 mL of trifluoroacetic acid. After 1 h at ambient temperature, the solution was concentrated in vacuo. Purification by reverse-phase preparative HPLC (10% to 80% acetonitrile in water) afforded the title compound as a foaming white solid. LC/MS 471.2 (M+1).
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:14]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])[CH:16]=[CH:17][CH:18]=2)[CH2:8][CH2:7]1)=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.O>[NH2:1][CH2:4][CH2:5][C:6]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:14]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])[CH:16]=[CH:17][CH:18]=2)[CH2:8][CH2:7]1
Reactant: [N-]=[N+]=NCCC1(c2ccccc2)CCN(c2cccc(-c3ccc(F)cc3F)c2)C(=O)O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCCC1(c2ccccc2)CCN(c2cccc(-c3ccc(F)cc3F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.9 %

Procedure:
To a solution of 6-(2-azidoethyl)-3-(2′,4′-difluorobiphenyl-3-yl)-6-phenyl-1,3-oxazinan-2-one (100 mg, 0.23 mmol) in 20:1 THF/H2O (3 mL) was added PPh3 (72 mg, 0.28 mmol). The reaction mixture was stirred at rt overnight. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel to afford 6-(2-aminoethyl)-3-(2′,4′-difluorobiphenyl-3-yl)-6-phenyl-1,3-oxazinan-2-one (30 mg, 31%). 1H NMR (400 MHz, CDCl3): δ=2.20-2.51 (m, 2H), 2.51-2.60 (m, 2H), 2.72 (m, 1H), 3.00 (m, 1H), 3.24 (m, 1H), 3.53 (m, 1H), 6.85-6.99 (m, 2H), 7.14 (m, 1H), 7.31-7.50 (m, 8H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([CH2:15][CH2:16][C:17]([OH:19])=O)(=[O:14])=[O:13])[CH:6]=[CH:5]2.S(Cl)([Cl:22])=O>CN(C=O)C.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([CH2:15][CH2:16][C:17]([Cl:22])=[O:19])(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: O=C(O)CCS(=O)(=O)c1ccc2cc(Cl)ccc2c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)CCS(=O)(=O)c1ccc2cc(Cl)ccc2c1

Procedure:
3-((6-Chloro-2-naphthyl)sulfonyl)propionic acid (14.9 g), thionyl chloride (4.4 mL) and DMF (2 drops) were added to toluene (100 mL), and the mixture was refluxed for 1.5 hours. The solvent was distilled off under reduced pressure, and the residue was washed with ether and hexane to give the title compound (15.5 g) as a brown solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.C([Li])CCC.[O:15]1[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]1.O>C1COCC1>[OH:21][C:18]1([C:2]2[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=2)[CH2:19][CH2:20][O:15][CH2:16][CH2:17]1
Reactant: O=C1CCOCC1
Reactant: Cc1cc(C)cc(Br)c1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C)cc(C2(O)CCOCC2)c1
Reaction time: 1 h
Yield: 63.1 %

Procedure:
To a solution of 5-bromo-m-xylene (5.55 g) in THF (60 ml) was added n-butyl lithium (17.8 ml) at −78° C. under an atmosphere of argon. The mixture was stirred for 1 hour. To the reaction solution was added tetrahydropyran-4-one (2.0 g) and the mixture was stirred for additional 3 hours. To the reaction solution was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:n-hexane=1:3) to give the title compound (2.6 g) having the following physical data.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9](Cl)(=[O:11])=[O:10].N1C=CC=CC=1.[CH2:21]([O:23][C:24](=[O:34])[CH2:25][NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH3:22]>ClCCl>[CH2:21]([O:23][C:24](=[O:34])[CH2:25][N:26]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[S:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:2]([F:14])([F:13])[F:1])(=[O:11])=[O:10])[CH3:22]
Reactant: CCOC(=O)CNCc1ccccc1
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)CN(Cc1ccccc1)S(=O)(=O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.8 %

Procedure:
To a stirred solution of 2-trifluoromethylbenzenesulfonyl chloride (3.8 g) in dichloromethane (100 mL) under argon was added pyridine (14 mL). A solution of N-benzylglycine ethylester (2 g) in dichloromethane (40 mL) was added slowly. The mixture was stirred at r.t. overnight and then concentrated under reduced pressure. The residue was dissolved in dichloromethane and washed with water. The organic phase was dried (MgSO4), filtered and concentrated under reduced pressure. The product was purified by chromatography (SiO2, cyclohexane to cyclohexane/ethyl acetate 1:1) to give [benzyl-(2-trifluoromethyl-benzenesulfonyl)-amino]-acetic acid ethyl ester (2.61 g) as a colorless oil. MS: 402.1 ([M+H]+)
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]2[C:14]([CH:19]=[O:20])=[N:15][C:16]([Cl:18])=[CH:17][C:12]=2[N:11]([C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[BH4-].[Na+]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[C:13]2[C:14]([CH2:19][OH:20])=[N:15][C:16]([Cl:18])=[CH:17][C:12]=2[N:11]([C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1nc(Cl)cc2c1c(OCc1ccccc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: OCc1nc(Cl)cc2c1c(OCc1ccccc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-(benzyloxy)-6-chloro-1-trityl-1H-pyrazolo[4,3-c]pyridine-4-carbaldehyde (2.8884 g, 5.45 mmol) in DCM (10 ml) was charged with MeOH (20 ml) and then sodium borohydride (0.309 g, 8.17 mmol). Stirred at RT for 2 hr. Quenched with water and extracted into DCM. Dried organics over MgSO4, filtered, concentrated in vacuo and used as-is. MS: [M+H]+ m/z 532.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8](Br)[CH:9](OC)OC)[N:3]=1.[Cl:15][C:16]1[C:17]([NH2:22])=[N:18][CH:19]=[CH:20][N:21]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>CC#N.O>[Br:1][C:2]1[N:3]=[C:4]([C:8]2[N:18]3[CH:19]=[CH:20][N:21]=[C:16]([Cl:15])[C:17]3=[N:22][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1nccnc1Cl
Reactant: COC(OC)C(Br)c1cccc(Br)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC#N
Product: Clc1nccn2c(-c3cccc(Br)n3)cnc12
Temperature: 25 °C

Procedure:
A mixture of 2-bromo-6-(1-bromo-2,2-dimethoxy-ethyl)-pyridine (from Example 37 supra) (5.267 g, 16.2 mmol), 3-chloropyrazin-2-amine (2.1 g, 16.2 mmol), and pTsOH.H2O (2.1 g, 11 mmol) in CH3CN (900 mL) and water (90 mL) was stirred and heated at reflux overnight. The reaction mixture was then cooled to room temperature, concentrated under reduced pressure. The crude product was purified by chromatography (CH2Cl2:CH3OH, 100:1) to give 3-(6-bromo-pyridin-2-yl)-8-chloro-imidazo[1,2-a]pyrazine. (Yield 4.86 g, 52%). LC-MS: [M+H]+ 309.
Reaction SMILES: Cl.[C:2]([C:6]1[N:10]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]=[CH:16][CH:15]=[CH:14]3)[N:9]=[C:8]([C:21]([O:23]CC)=[O:22])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[Li+].[OH-]>C1COCC1>[C:2]([C:6]1[N:10]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]=[CH:16][CH:15]=[CH:14]3)[N:9]=[C:8]([C:21]([OH:23])=[O:22])[CH:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CCOC(=O)c1cc(C(C)(C)C)n(-c2ccc3ncccc3c2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C(=O)O)nn1-c1ccc2ncccc2c1
Yield: 79.9 %

Procedure:
A suspension of ethyl 5-tert-butyl-1-(quinolin-6-yl)-1H-pyrazole-3-carboxylate hydrochloride (32 g, 0.089 mol) in THF (300 mL) was treated with aqueous LiOH (2 N, 100 mL, 0.20 mmol) and the resultant mixture was heated to 40° C. for 3 hours. The reaction was concentrated under reduced pressure and the remaining aqueous layer was washed with EtOAc. The aqueous phase was acidified to pH 3 and the resultant precipitate was collected by filtration, washed with cold ether and dried in vacuo to provide 5-tert-butyl-1-(quinolin-6-yl)-1H-pyrazole-3-carboxylic acid (21 g, 71% yield). 1H-NMR (400 MHz, DMSO-d6) δ 9.03 (m, 1H), 8.50 (d, J=8.7 Hz, 1H), 8.20 (d, J=2.4 Hz, 1H), 8.15 (d, J=8.8 Hz, 1H), 7.79 (dd, J=8.7 Hz, 2.4 Hz, 1H), 7.67 (dd, J=8.4, 4.4 Hz, 1H), 6.68 (s, 1H), 1.17 (s, 9H); MS (ESI) m/z: 296.3 (M+H+).
Reaction SMILES: [CH3:1][N:2]([C@H:33]([CH3:38])[C:34]([O:36]C)=[O:35])[C:3](=[O:32])[CH:4]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=2)=[CH:12][CH:11]=1)[CH2:5][C:6]([NH:8][CH3:9])=[O:7].[Li+].[OH-]>CO>[CH3:1][N:2]([C@H:33]([CH3:38])[C:34]([OH:36])=[O:35])[C:3](=[O:32])[CH:4]([C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:17][C:18]2[CH:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=[C:20]([C:28]([F:29])([F:30])[F:31])[CH:19]=2)=[CH:14][CH:15]=1)[CH2:5][C:6]([NH:8][CH3:9])=[O:7]
Reactant: CNC(=O)CC(C(=O)N(C)[C@H](C)C(=O)OC)c1ccc(OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CNC(=O)CC(C(=O)N(C)[C@H](C)C(=O)O)c1ccc(OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1
Reaction time: 1 h
Yield: 93.6 %

Procedure:
Methyl 2-{N-methyl-N-[(R/S)-α-methylaminocarbonylmethyl-4-(3,5-bistrifluoromethylbenzyloxy)phenylacetyl]amino}-(R)-propionate 48g (310 mg, 0.56 mmol) was dissolved in MeOH (5 mL) and 1 N LiOH (2 mL) was added. The solution was stirred for 1 hour and concentrated in vacuo. EtOAc was added and the solution was acidified with 1 N HCl, washed with brine, dried over MgSO4, and concentrated to afford the acid (280 mg, 92%) as a solid. MS (ESI): (M+H)+=535.8.
Reaction SMILES: Cl.C(OC(=O)C(=COCC)C(OCC)=O)C.CC[O-].[Na+].C(O[C:24]([C:26]1[C:27](O)=[N:28][C:29]([C:32]2[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][CH2:40][CH3:41])=[CH:34][CH:33]=2)=[N:30][CH:31]=1)=O)C.P(Cl)(Cl)(Cl)=O.C(OC(C1C(Cl)=[N:55]C(C2C=CC(CCCC)=CC=2)=NC=1)=O)C>C(O)C>[C:24]([C:26]1[CH:27]=[N:28][C:29]([C:32]2[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][CH2:40][CH3:41])=[CH:34][CH:33]=2)=[N:30][CH:31]=1)#[N:55]
Reactant: CCCCc1ccc(-c2ncc(C(=O)OCC)c(Cl)n2)cc1
Reactant: CCCCc1ccc(-c2ncc(C(=O)OCC)c(O)n2)cc1
Agent: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: CC[O-]
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCO
Product: CCCCc1ccc(-c2ncc(C#N)cn2)cc1

Procedure:
The starting material can be obtained according to the procedure of A. R. Todd and F. Bergel, J. Chem. Soc. 1937, 366 from p-n-butylbenzamindine hydrochloride and ethoxymethylenemalonic acid diethyl ester with sodium ethylate in ethanol and subsequent treatment of the obtained 2-(p-n-butylphenyl)-4-hydroxy-5-pyrimidinecarboxylic acid ethyl ester (melting point 198.0°-198.8° C) with phosphorus oxychloride. The melting point of 2-(p-n-butylphenyl)-4-chloro-5-pyrimidinecarboxylic acid ethyl ester is 64.9°-65.3° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[NH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:7]3[C:6]=2[C:5]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:4][CH:3]=1.Br[C:22]1[C:27]([Cl:28])=[CH:26][C:25]([C:29]([F:32])([F:31])[F:30])=[CH:24][N:23]=1.N1C=CC=CC=1C1C=CC=CN=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O.C(OCC)(=O)C.[Cu]I>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:22]4[C:27]([Cl:28])=[CH:26][C:25]([C:29]([F:32])([F:30])[F:31])=[CH:24][N:23]=4)[CH2:12][CH2:13][CH2:14][CH2:15][N:7]3[C:6]=2[C:5]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1cnc(Br)c(Cl)c1
Reactant: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1ncc(C(F)(F)F)cc1Cl
Temperature: 150 °C
Reaction time: 16 h
Yield: 43.3 %

Procedure:
A mixture of 10-chloro-7-(1-ethylpropyl)-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]benzimidazole (Reference Example 72; 150 mg, 0.51 mmol), 2-bromo-3-chloro-5-(trifluoromethyl)pyridine (401 mg, 1.54 mmol), copper(I) iodide (97 mg, 0.51 mmol), 2,2′-bipyridyl (159 mg, 1.02 mmol) and cesium carbonate (333 mg, 1.02 mmol) in 1-methyl-2-pyrrolidinone (2.0 mL) was stirred at 150° C. for 16 hr. The mixture was diluted with ethyl acetate, filtered through a pad of celite, washed with 2N hydrochloric acid, water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 5-20% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give a residue, which was purified by preparative HPLC to give a solid, which was recrystallized from n-hexane/ethyl acetate to give the title compound (104 mg, 0.221 mmol, 43%) as a colorless solid.
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[C:6]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:7]=2[N:8]=[CH:9][N:10]=1>CCO>[NH:2]([C:5]1[C:6]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:7]=2[N:8]=[CH:9][N:10]=1)[NH2:3]
Reactant: Clc1ncnc2c1CCCCCC2
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNc1ncnc2c1CCCCCC2
Temperature: 60 °C
Yield: 60 %

Procedure:
Hydrazine monohydrate (0.21 mL; 4.34 mmol; 1.2 equiv) was added to a suspension of 4-chloro-5,6,7,8,9,10-hexahydrocycloocta[d]-pyrimidine (0.71 g; 3.62 mmol; 1.0 equiv) in 8 mL of EtOH. The reaction was heated at 60° C. overnight. The solid was filtered, washed with H2O and dried to give 4-hydrazino-5,6,7,8,9,10-hexahydrocycloocta[d]-pyrimidine as an off-white solid (0.42 g; 60% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[C:21](=[O:22])[C:20]3=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=[C:19]3[C:18]2=[O:28])[CH2:13][C:14](O)=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:42][OH:43]>O1CCCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[C:21](=[O:22])[C:20]3=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=[C:19]3[C:18]2=[O:28])[CH2:13][C:14]([NH:42][OH:43])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc(C(CC(=O)O)N2C(=O)c3ccc(O)cc3C2=O)ccc1OC
Reactant: NO
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)NO)N2C(=O)c3ccc(O)cc3C2=O)ccc1OC
Yield: 43.2 %

Procedure:
3-(3-Ethoxy-4-methoxyphenyl)-N-hydroxy-3-(4-hydroxyphthalimido)propionamide was prepared by the procedure of Example 1 from 3-(3-ethoxy-4-methoxyphenyl)-3-(4-hydroxyphthalimido)propanoic acid (4.0 g, 10.4 mmol), carbonyldiimidazole (2.02 g, 12.46 mmol) and hydroxylamine hydrochloride (1.13 g, 16.3 mmol) in tetrahydrofuran (20 mL) to afford 3-(3-ethoxy-4-methoxyphenyl)-N-hydroxy-3-(4-hydroxyphthalimido)propionamide as a yellow solid (1.8 g, 44% yield): mp, 143.5-146.0° C.; 1H NMR (DMSO-d6) δ1.31 (t, J=6.9 Hz, 3H, CH3), 3.09 (d, J=7.9 Hz, 2H, CH2), 3.72 (s, 3H, CH3), 3.98 (q, J=6.9 Hz, 2H, CH2), 5.62 (t, J=7.9 Hz, 1H, NCH), 6.89 (br s, 2H, Ar), 7.01 (br s, 1H, Ar), 7.09-7.12 (m, 2H, Ar), 7.66-7.69 (m, 1H, Ar), 8.88 (br s, 1H, OH), 10.59 (br s, 1H, NH); 13C NMR (DMSO-d6) δ24.71, 44.39, 60.08, 65.47, 73.75, 119.72, 121.76, 122.36, 129.66, 130.53, 131.37, 135.32, 141.49, 144.08, 157.68, 158.51, 173.43, 176.09, 177.49; Anal Calcd for C20H20N2O7+0.35H2O: C, 59.07; H, 5.13; N, 6.89. Found: C, 58.84; H, 5.05; N, 7.26.
Reaction SMILES: C([N:4]1[CH2:9][C:8](=[O:10])[N:7]([C:11](=[O:13])[CH3:12])[CH2:6][C:5]1=[O:14])(=O)C.[N+:15]([C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=O)([O-:17])=[O:16].C(N(CC)CC)C>CN(C=O)C>[C:11]([N:7]1[CH2:6][C:5](=[O:14])[NH:4][C:9](=[CH:21][C:20]2[CH:23]=[CH:24][CH:25]=[C:18]([N+:15]([O-:17])=[O:16])[CH:19]=2)[C:8]1=[O:10])(=[O:13])[CH3:12]
Reactant: CC(=O)N1CC(=O)N(C(C)=O)CC1=O
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)N1CC(=O)NC(=Cc2cccc([N+](=O)[O-])c2)C1=O
Yield: 66 %

Procedure:
1,4-Diacetyl-2,5-piperazinedione (1 equivalent), prepared by the published procedure mentioned in Example 3, was treated with 3-nitrobenzaldehyde (1 equivalent) in the presence of triethylamine (1 equivalent) in DMF at room temperature for 18-20 hrs. The title compound was obtained in 9% yield together with 1-acetyl-3-(3-nitrobenzylidene)-2,5-piperazinedione (66% yield). Characterising data are set out in Example 16.
Reaction SMILES: C(OC(N1C2C(=CC=C([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:26]=4[O:33][CH3:34])=[CH:21][CH:20]=3)C=2)C=C1)=O)(C)(C)C.[C:35]([O:39][C:40]([N:42]1[C:50]2[C:45](=[C:46](CO)[CH:47]=[CH:48][CH:49]=2)[CH:44]=[CH:43]1)=[O:41])([CH3:38])([CH3:37])[CH3:36].FC1C(F)=CC(C2C=CC(O)=CC=2)=C(OC)C=1>>[C:35]([O:39][C:40]([N:42]1[C:50]2[C:45](=[C:46]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:26]=4[O:33][CH3:34])=[CH:21][CH:20]=3)[CH:47]=[CH:48][CH:49]=2)[CH:44]=[CH:43]1)=[O:41])([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(=O)n1ccc2c(CO)cccc21
Reactant: COc1cc(F)c(F)cc1-c1ccc(OCc2ccc3ccn(C(=O)OC(C)(C)C)c3c2)cc1
Agent: COc1cc(F)c(F)cc1-c1ccc(O)cc1
Product: COc1cc(F)c(F)cc1-c1ccc(OCc2cccc3c2ccn3C(=O)OC(C)(C)C)cc1

Procedure:
4-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-indole-1-carboxylic acid tert-butyl ester was synthesized by a procedure similar to 6-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-indole-1-carboxylic acid tert-butyl ester from starting materials 4-hydroxymethyl-indole-1-carboxylic acid tert-butyl ester and 4′,5′-difluoro-2′-methoxy-biphenyl-4-ol to yield the product as a white solid (880 mg, 70%). LC-MS (ES) calculated for C27H25F2NO2, 465.2; found m/z 466 [M+H]+.