Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]([CH3:22])[C:16]([C:19]([OH:21])=O)=[CH:17][N:18]=3)[S:13][C:6]=12.[O:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][NH2:38])[CH2:32][CH2:31]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C([O-])(O)=O.[Na+]>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]([CH3:22])[C:16]([C:19]([NH:38][CH2:37][CH2:36][N:33]4[CH2:34][CH2:35][O:30][CH2:31][CH2:32]4)=[O:21])=[CH:17][N:18]=3)[S:13][C:6]=12
Reactant: Cn1c(C(=O)O)cnc1-c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Reactant: NCCN1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1c(C(=O)NCCN2CCOCC2)cnc1-c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.8 %

Procedure:
To a solution of acid 214 (180 mg, 0.434 mmol) in DMF (8 mL) was added 2-morpholinoethanamine (0.114 mL, 0.869 mmol), DIPEA (0.266 mL, 1.520 mmol) and HATU reagent (1.303 mmol). The reaction mixture was stirred at RT for 4 hr. NaHCO3 saturated solution (5 mL) and EtOAc (5 mL) were added to form a precipitate that was collected by filtration. The organic layer of the filtrate was separated, dried over anhydrous sodium sulfate, concentrated and the residue was combined with the collected precipitate to give title compound 215 (180 mg, 0.342 mmol, 79% yield) as a white solid. MS: 527.5 (MH)+.
Reaction SMILES: [F:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([O:13]C)=[O:12])=[CH2:3].[Li+].[OH-].O>O.C1COCC1>[F:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([OH:13])=[O:12])=[CH2:3]
Reactant: C=C(F)c1ccccc1CC(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C=C(F)c1ccccc1CC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
A suspension of methyl 2-(2-(1-fluorovinyl)phenyl)acetate (334, 770.8 mg, 4.015 mmol) (Hakamoto T.; Kobavashi T. J. Org. Chem. 2003, 68, 6354-6359) and LiOH×H2O (185 mg, 4.41 mmol) in H2O/THF (1:1, 11 mL) was stirred overnight at room temperature. The THF was evaporated off under reduced pressure; the aqueous residue was diluted with water, washed with EtOAc, acidified to pH˜3 by addition of 1N HCl and extracted with DCM. The organic extract was dried over anhydrous Na2SO4 and concentrated under reduced pressure affording 335 (557.2 mg, 77% yield) as a white solid. LCMS: (M−1) 187.1 (100%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[C:18](=[O:19])[CH:17]=[CH:16][N:15]([C:20]4[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=4)[N:14]=3)=[CH:11][CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[C:26]([Si:28]([CH3:31])([CH3:30])[CH3:29])#[CH:27].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CNC>C(O)C.CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:23]1[CH:24]=[CH:25][C:20]([N:15]2[CH:16]=[CH:17][C:18](=[O:19])[C:13]([C:12]3[N:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([C:27]#[C:26][Si:28]([CH3:31])([CH3:30])[CH3:29])[CH:3]=4)[N:9]=[CH:10][CH:11]=3)=[N:14]2)=[CH:21][CH:22]=1
Reactant: O=c1ccn(-c2ccncc2)nc1-c1ccnn1-c1cccc(Br)c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CNC
Solvent: CCO
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1cccc(-n2nccc2-c2nn(-c3ccncc3)ccc2=O)c1
Temperature: 120 °C
Yield: 38.2 %

Procedure:
A mixture of 3-[2-(3-Bromo-phenyl)-2H-pyrazol-3-yl]-1-pyridin-4-yl-1H-pyridazin-4-one (example 97, 81 mg, 0.21 mmol), ethynyltrimethylsilane (44 ul, 0.31 mmol), CuI (2 mg, 0.01 mmol), (PPh3)2PdCl2 (9 mg, 0.01 mmol), PPh3 (113 mg, 0.41 mmol) and dimethylamine (421 ul, 3.1 mmol of a solution in ethanol) in DMF (1.0 ml) is heated at 120° C. for 20 minutes under microwave irradiation. After purification of the crude product by preparative HPLC 33 mg (39% yield) of the product is obtained as solid material. MS: M=412.3 (M+H)+
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[CH3:13][C:14]1([CH3:21])[C:19](=[O:20])[CH2:18][CH2:17][NH:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([N:16]2[CH2:17][CH2:18][C:19](=[O:20])[C:14]([CH3:21])([CH3:13])[CH2:15]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: CC1(C)CNCCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(N2CCC(=O)C(C)(C)C2)ccc1[N+](=O)[O-]
Yield: 43.6 %

Procedure:
4-Fluoro-2-methoxy-1-nitrobenzene (1.550 g, 9.06 mmol), 3,3-dimethylpiperidin-4-one (INTERMEDIATE 38) (2.17 g, 9.06 mmol, TFA salt), and potassium carbonate (2.504 g, 18.12 mmol) in DMF (20 ml) were heated at 70° C. overnight. The reaction mixture was concentrated in vacuo to remove the solvent. The residue was partitioned between CH2Cl2 (100 mL) and water (30 mL). The organic phase was dried over MgSO4 and concentrated in vacuo. The residue was purified using silica gel column (50%-100% CH2Cl2/Hexane) to obtain the title product (1.100 g, 43.6%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:32][C@@H:33]([C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([Cl:47])[CH:42]=1)[O:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][O:36]1)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:25]=[C:24]3[C:20]([C:21]([C:29]([OH:31])=O)=[CH:22][N:23]3[CH:26]([CH3:28])[CH3:27])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:60][S:61]([NH2:64])(=[O:63])=[O:62].C1CCN2C(=NCCC2)CC1.Cl>CN(C)C=O>[Cl:47][C:43]1[CH:42]=[C:41]([C@@H:33]([O:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][O:36]2)[CH2:32][N:8]([CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:25]=[C:24]4[C:20]([C:21]([C:29]([NH:64][S:61]([CH3:60])(=[O:63])=[O:62])=[O:31])=[CH:22][N:23]4[CH:26]([CH3:28])[CH3:27])=[CH:19][CH:18]=3)=[CH:15][CH:16]=2)[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH:46]=[CH:45][CH:44]=1
Reactant: CS(N)(=O)=O
Reactant: CC(C)n1cc(C(=O)O)c2ccc(-c3ccc(CCN(C[C@H](OC4CCCCO4)c4cccc(Cl)c4)C(=O)OC(C)(C)C)cc3)cc21
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)n1cc(C(=O)NS(C)(=O)=O)c2ccc(-c3ccc(CCN(C[C@H](OC4CCCCO4)c4cccc(Cl)c4)C(=O)OC(C)(C)C)cc3)cc21
Reaction time: 2.5 h
Yield: 91.6 %

Procedure:
To a solution of 6-[4-[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-amino]ethyl]phenyl]-1-isopropyl-1H-indole-3-carboxylic acid (131 mg) in N,N-dimethylformamide (2 mL) was added 1,1′-carbonyldiimidazole (35 mg) at room temperature under nitrogen, and the mixture was stirred at the same temperature for 2.5 hours. To this one were added methanesulfonamide (46 mg) and 1,8-diazabicyclo[5.4.0]-7-undecene (72 mg) at room temperature, and the mixture was stirred at 60° C. for 10 hours. The resulting mixture was poured into 0.1N hydrochloric acid and the aqueous layer was extracted with ethyl acetate. The organic layer was washed successively with 0.1N hydrochloric acid three times and brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform/methanol=200/1 to 100/1) to give tert-butyl [(2R)-2-(3-chlorophenyl)-2-(tetrahydro-2H-pyran-2-yloxy)ethyl][2-[4-[1-isopropyl-3-[[(methylsulfonyl)amino]-carbonyl]-1H-indol-6-yl]phenyl]ethyl]carbamate (134 mg).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:31])[C:5]([C:26]([O:28]CC)=[O:27])=[CH:6][N:7]2[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH:23]=[CH:22][C:21]([CH2:24]O)=[N:20]2)=[CH:15][CH:14]=1.COCCN(S(F)(F)[F:42])CCOC.[OH-].[Na+]>O1CCCC1>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:31])[C:5]([C:26]([OH:28])=[O:27])=[CH:6][N:7]2[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]2[CH:23]=[CH:22][C:21]([CH2:24][F:42])=[N:20]2)=[CH:17][CH:18]=1
Reactant: CCOC(=O)c1cn(Cc2ccc(-n3ccc(CO)n3)cc2)c2cccc(F)c2c1=O
Reactant: COCCN(CCOC)S(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cn(Cc2ccc(-n3ccc(CF)n3)cc2)c2cccc(F)c2c1=O
Reaction time: 0.5 h

Procedure:
A solution of ethyl 5-fluoro-1-{4-[3-(hydroxymethyl)-1H-pyrazol-1-yl]benzyl}-4-oxo-1,4-dihydroquinoline-3-carboxylate (0.050 g, 0.119 mmol) in 2 mL of tetrahydrofuran was cooled to −40° C. under nitrogen, and [bis(2-methoxyethyl)-amino]sulfur trifluoride (0.029 g, 0.13 mmol) was added. The reaction mixture was warmed to room temperature and after 4 hours 1 N NaOH (0.50 mL, 0.50 mmol) was added. After 30 minutes, the tetrahydrofuran was removed in vacuo, and 1 mL DMSO and 0.5 mL 40% NaOH were added. After 3 hours, the reaction mixture was acidified with 6 N HCl to pH ˜2, filtered, and purified via reverse phase HPLC to provide the title compound which gave a proton NMR spectrum consistent with theory and a mass ion (ES+) of 395.9 for M+H+: 1H NMR (400 MHz, d6-DMSO) δ 9.30 (s, 1H), 8.50 (s, 1H), 7.87-7.80 (m, 3H), 7.66 (d, J=8.8 Hz, 1H), 7.43 (d, J=8.6 Hz, 2H), 7.40-7.35 (m, 1H), 6.67 (s, 1H), 6.52 (s, 1H), 5.88 (s, 2H), 5.62 (d, J=10.2 Hz, 2H).
Reaction SMILES: [C:1]([N:8]([CH2:10][C:11]([OH:13])=O)[CH3:9])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.Cl.[CH3:22][O:23][C:24](=[O:27])[CH2:25][NH2:26]>C(Cl)Cl>[CH3:22][O:23][C:24](=[O:27])[CH2:25][NH:26][C:11](=[O:13])[CH2:10][N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH3:9]
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Reactant: COC(=O)CN
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)CNC(=O)CN(C)C(=O)OC(C)(C)C
Temperature: -10 °C
Reaction time: 1 h

Procedure:
To a suspension of Boc-sarcosine (9.0 g, 048 mol) in 70 ml of CH2Cl2 at −20° C. was added isobutyl chlorofomate (7.1 g, 0.052 mol) and N-Methylmorpholine (4.8 g, 0.047 mol). After 2 min glycine methyl ester, hydrochloride (7.19g, 0.057 mol) and N-methylmorpholine (5.76g, 0.057 mol) in CH2Cl2 (60 ml) was added. The reaction was stirred at −10° C. for 1 h and allowed to warm to room temperature. After 4h at room temperature, the reaction was filtered and washed with salt. NaHCO3 (100 ml), 1N NaHCO3 100 ml, twice with 1N KHSO4 (100 ml), water (100 ml) and brine (70 ml). The organic phase was dried with Na2SO4 and evaporated. The yield of Boc sarcosyl-glycine methyl ester was 89%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11](=[S:19])[C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[CH:10]=1)[NH:7][C:6](=[O:20])[CH2:5]2.Cl.[OH-:22].[Na+:23]>O>[OH2:20].[NH2:7][C:8]1[C:9]([C:11](=[S:19])[C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=1[CH2:5][C:6]([O-:20])=[O:22].[Na+:23]
Reactant: [OH-]
Reactant: Cc1ccc(C(=S)c2cc(Cl)cc3c2NC(=O)C3)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1ccc(C(=S)c2cc(Cl)cc(CC(=O)[O-])c2N)cc1
Temperature: 100 °C
Reaction time: 22 h
Yield: 39 %

Procedure:
A mixture of 6.4 g (20.0 mmol) of 5-chloro-7-(4-methylthiobenzoyl)indolin-2-one in 110 ml of 3N sodium hydroxide was heated at 100° C. in an oil bath and stirred under a nitrogen atmosphere for 22 hrs. The reaction mixture was diluted to 600 ml with water and then titrated to a pH of 7.5 with concentrated hydrochloric acid. The mixture was then filtered and the filter cake was extracted with 1.5 liter of hot water. The filtrate obtained was concentrated to a solid residue. This residue was dissolved in hot absolute ethyl alcohol and filtered. The filtrate obtained was concentrated to a solid which was dissolved in 300 ml of 2-propanol and filtered. The filtrate obtained was concentrated to 200 ml and cooled to 0° C., whereby a gel was obtained. This gel was left at room temperature and a crystalline solid was collected therefrom by filtration and dried to give 2.9 g (39%) of the titled compound as a yellow solid, m.p. 259°-260° C.
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([CH2:9][N:10]=[N+]=[N-])=[CH:5][CH:4]=1)#[N:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O>[C:1]([C:3]1[N:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(CN=[N+]=[N-])cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: N#Cc1ccc(CN)cn1
Reaction time: 8 h

Procedure:
The compound obtained in (a) was dissolved in 45 ml of TEF and 1.2 ml of water and, while stirring, 11.2 g of triphenylphosphine were added in portions. The reaction mixture was left to stand at RT overnight.
Reaction SMILES: [CH3:1][C:2]1([CH2:8][CH2:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)SCCCS1.C(=O)([O-])[O-:28].[Ca+2]>C1COCC1.CO.O.[Hg](Cl)Cl>[N:22]1([C:19]2[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][CH2:9][CH2:8][C:2](=[O:28])[CH3:1])=[CH:17][CH:18]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CC1(CCCCOCCCc2ccc(N3CCCC3)cc2)SCCCS1
Reactant: O=C([O-])[O-]
Agent: Cl[Hg]Cl
Agent: [Ca+2]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(=O)CCCCOCCCc1ccc(N2CCCC2)cc1

Procedure:
A solution of the product of stage (iv) (3.2 g) in THF (50 ml) was added to a stirred suspension of mercury (II) chloride (8.5 g) and calcium carbonate (3.2 g) in methanol-water (9:1, 50 ml) and the mixture was stirred at reflux for 1 h. The reaction was filtered through hyflo, the filtrate was concentrated in vacuo and the resulting oil was dissolved in chloroform (50 ml). The resulting precipitate was removed by filtration, the solvent was evaporated and the residue was purified by FCC (System D 19:1→4:1) to give the title compound as a crystalline mass (1.4 g) m.p. 30°-31°.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][CH:10]=[C:9]([CH3:12])[C:8]=2[CH:13]=1)N.C(Cl)Cl.[CH3:17][N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1.[OH-].[Na+]>O>[CH3:12][C:9]1[C:8]2=[C:13]3[C:4](=[CH:5][CH:6]=[C:7]2[S:11][CH:10]=1)[NH:2][C:21]1[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][C:20]3=1
Reactant: Cc1csc2ccc(NN)cc12
Reactant: CN1CCC(=O)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Cc1csc2ccc3[nH]c4c(c3c12)CN(C)CC4
Temperature: 200 °C
Reaction time: 0.5 h

Procedure:
15,75 g of 5-hydrazino-3-methylbenzothiophene hydrochloride are suspended in 500 ml of water, a layer of methylene chloride is introduced under the suspension and 10.5 g of 1-methyl-4-piperidone are added at about 0° C. The mixture is then adjusted to pH 9.5 with N NaOH and is stirred for 30 minutes. The organic phase is separated off and washed with saturated NaCl solution, dried and mixed with 500 ml of ethylene glycol and the methylene chloride is distilled off under a vacuum of 12 mm. Some of the glycol is then distilled off under 0.01 mm and at 100° C. and the concentrated solution is heated to 200° C. (bath temperature) in an N2 atmosphere for 1/2 hour. The crystals which precipitate on cooling the mixture are filtered off, washed and recrystallised from ethyl acetate. Melting point: 224°-227° C.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([NH2:5])=[O:4].[CH3:9][C@H:10]([NH:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[C:11](OC1C=CC([N+]([O-])=O)=CC=1)=[O:12]>CN(C)C=O>[NH:23]([C:24]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25])[C@H:10]([C:11]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([NH2:5])=[O:4])=[O:12])[CH3:9]
Reactant: NC(=O)[C@@H]1CCCN1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(N)=O
Reaction time: 18 h
Yield: 86.2 %

Procedure:
2.28 g of H-Pro-NH2 and 7.57 g of Z-Ala-ONP are dissolved in 20 ml of dimethylformamide and the yellow solution is allowed to stand for 18 hours at room temperature. It is then evaporated to dryness in a high vacuum, the residue is mixed with ethyl acetate and the resulting powder is thoroughly triturated. After filtering off and drying, 5.5 g of Z-Ala-Pro-NH2 of melting point 164°-165° C. are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][C@H:12]([CH3:14])[O:11][C@H:10]([CH3:15])[CH2:9]2)=[C:6]([CH2:16][OH:17])[N:5]=[C:4]2[C:18]([C:21]([NH:23][CH3:24])=[O:22])=[N:19][O:20][C:3]=12>C(Cl)Cl>[Cl:1][C:2]1[C:7]([N:8]2[CH2:13][C@H:12]([CH3:14])[O:11][C@H:10]([CH3:15])[CH2:9]2)=[C:6]([CH:16]=[O:17])[N:5]=[C:4]2[C:18]([C:21]([NH:23][CH3:24])=[O:22])=[N:19][O:20][C:3]=12
Reactant: CNC(=O)c1noc2c(Cl)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO)nc12
Solvent: ClCCl
Product: CNC(=O)c1noc2c(Cl)c(N3C[C@@H](C)O[C@@H](C)C3)c(C=O)nc12

Procedure:
Starting material: 7-chloro-6-((2R,6S)-2,6-dimethylmorpholino)-5-(hydroxymethyl)-N-methylisoxazolo[4,5-b]pyridine-3-carboxamide (Intermediate 293) in 20 ml CH2Cl2.
Reaction SMILES: C([O:9][CH2:10][C@@H:11]1[C:15]([O:17]C(=O)C)([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:28]=[C:27]([CH3:29])[C:26](=[O:30])[NH:25][C:24]2=[O:31])[O:12]1)(=O)C1C=CC=CC=1.CO>N>[F:22][C:14]1([CH3:21])[C@@:15]([OH:17])([CH3:16])[CH:11]([CH2:10][OH:9])[O:12][C@H:13]1[N:23]1[CH:28]=[C:27]([CH3:29])[C:26](=[O:30])[NH:25][C:24]1=[O:31]
Reactant: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cc(C)c(=O)[nH]c2=O)[C@]1(C)F
Agent: N
Solvent: CO
Product: Cc1cn([C@@H]2OC(CO)[C@@](C)(O)C2(C)F)c(=O)[nH]c1=O
Yield: 23.5 %

Procedure:
A solution of ((2R,4R)-3-acetoxy-4-fluoro-3,4-dimethyl-5-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-tetrahydrofuran-2-yl)methyl benzoate (about 0.11 g, 0.29 mmol) in methanolic ammonia (25% w/w 10 ml) was stirred at room temperature for overnight. Completion of the reaction mixture monitored by thin-layer chromatography and methanol was removed under reduced pressure. Water added to the crude and extracted with ethyl acetate and the organic layer was dried over sodium sulphate. Concentration under reduced pressure and purification by silica gel column chromatography using 5% methanol in dichloromethane to elude title compound (0.020 g). Yield: 23.5%; 1H-NMR: 1H NMR (300 MHz, CDCl3): δ 8.18 (s, 1H), 7.18 (bs, 1H), 6.45 (d, 1H, J=21 Hz), 4.53-4.15 (m, 4H), 2.67-2.38 (m, 1H), 2.38 (s, 3H), 1.68-1.42 (m, 6H); ES Mass: [M+Na]+ 311 (100%);
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH2:11]([NH:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[C:18]#N)[CH:12]=[CH2:13].C[OH:24]>C1(C)C=CC=CC=1>[CH2:11]([NH:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[O:24])[CH:12]=[CH2:13]
Reactant: CO
Reactant: C=CCNc1cccc(C#N)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: C=CCNc1cccc(C=O)c1
Temperature: 0 °C

Procedure:
Di-isobutylaluminum hydride (54 ml., 25% solution in toluene) is added with stirring to a solution of 12.1 g. of 3-(allylamino)benzonitrile under a nitrogen atmosphere. After addition is completed, the solution is stirred for one hour. A solution of methanol in toluene (50 ml., 1:1) is added over 30 minutes and the mixture is poured into 500 ml. vigorously stirred ice-cold 50% aqueous sulfuric acid. The mixture is filtered and the organic layer separated. The aqueous solution is extracted twice with toluene (100 ml.) and the combined organic layers are washed with aqueous sodium bicarbonate, dried over magnesium sulfate, decolorized with charcoal, filtered and evaporated in vacuo to give a light yellow crystalline solid. The product is recrystallized from dichloromethane/hexane giving colorless needles.
Reaction SMILES: [ClH:1].C([O:4][C:5]([C:7]1[CH:8]=[N:9][N:10]([C:13]2[CH:18]=[CH:17][C:16](N)=[C:15]([CH3:20])[N:14]=2)[C:11]=1[CH3:12])=[O:6])C.N([O-])=O.[Na+].C(=O)(O)[O-].[Na+]>[Cu]Cl.O>[Cl:1][C:16]1[CH:17]=[CH:18][C:13]([N:10]2[C:11]([CH3:12])=[C:7]([C:5]([OH:4])=[O:6])[CH:8]=[N:9]2)=[N:14][C:15]=1[CH3:20]
Reactant: Cl
Reactant: CCOC(=O)c1cnn(-c2ccc(N)c(C)n2)c1C
Agent: Cl[Cu]
Agent: O=C([O-])O
Agent: O=N[O-]
Solvent: O
Product: Cc1nc(-n2ncc(C(=O)O)c2C)ccc1Cl
Reaction time: 0.5 h

Procedure:
Water (4 ml) and concentrated hydrochloric acid (1 ml) were added to 1-(5-amino-6-methylpyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (260 mg) described in Reference Example 31(3), and then sodium nitrite (83 mg) was added therein at 0° C. After stirring for 0.5 hour, sodium nitrite (83 mg) was added again and stirred for an hour. Then copper (I) chloride (485 mg) was added and stirred in a water bath for 20 minutes. The reaction solution was added to a saturated aqueous solution of sodium bicarbonate and filtered through Celite. Water was added to the filtrate, extracted with ethyl acetate and the organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was reacted and treated in a similar manner as Reference Example 24(3) to give the titled compound (112 mg) as a brown solid.
Reaction SMILES: [I:1][C:2]1[CH:12]=[N:11][C:5]2[NH:6][CH2:7][C:8](=O)[NH:9][C:4]=2[CH:3]=1.[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:22]([F:25])([F:24])[F:23])=[C:18]([CH:21]=1)[CH2:19]Br.ClC1C=CC(C(F)(F)F)=CC=1CN1C(=O)CNC2N=CC(I)=CC1=2>>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:22]([F:23])([F:24])[F:25])=[C:18]([CH:21]=1)[CH2:19][N:9]1[CH2:8][CH2:7][NH:6][C:5]2[N:11]=[CH:12][C:2]([I:1])=[CH:3][C:4]1=2
Reactant: O=C1CNc2ncc(I)cc2N1
Reactant: FC(F)(F)c1ccc(Cl)cc1CBr
Agent: O=C1CNc2ncc(I)cc2N1Cc1cc(C(F)(F)F)ccc1Cl
Product: FC(F)(F)c1ccc(Cl)cc1CN1CCNc2ncc(I)cc21
Yield: 17 %

Procedure:
7-Iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (968 mg) was reacted with 5-chloro-2-(trifluoromethyl)benzyl bromide as in General Procedure 1. The resulting 1-(2-chloro-5-trifluoromethylbenzyl)-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one was reduced as in General Procedure 2 to give the title compound as an orange solid (17% yield). M.p. 189-191° C., LCMS: m/z=454.08 (M+H+), 1H-NMR (DMSO-d6, 400 MHz) δ 3.28-3.34 (m, 2H), 3.41-3.46 (m, 2H), 4.53 (s, 2H), 6.52 (s, 1H), 6.75 (s, 1H), 7.44 (s, 2H), 7.59 (d, J=8.4 Hz, 1H), 7.82 (d, J=8.6 Hz, 1H).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)[CH3:3].CC([O-])(C)C.[K+].Cl[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][N:20]=1>CS(C)=O>[CH3:3][CH:2]([O:4][C:5]1[CH:6]=[C:7]([O:11][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][N:20]=2)[CH:8]=[CH:9][CH:10]=1)[CH3:1]
Reactant: CC(C)Oc1cccc(O)c1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)Oc1cccc(Oc2ccc([N+](=O)[O-])cn2)c1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 81.5 %

Procedure:
To a solution of 3-[(1-methylethyl)oxy]phenol (Intermediate 27, 456 mg) in DMSO (8 mL) was added t-BuOK (336 mg, 3 mmol, Acros). The reaction mixture was stirred at 20° C. for 30 minutes. 2-chloro-5-nitropyridine (474 mg, 3 mmol, Aldrich) was added and the resulting mixture was stirred at 120° C. for 2 hours. The reaction mixture was cooled to room temperature, poured into ice-water (50 mL) and extracted with dichloromethane (3 times 50 mL). The combined organic layers were dried over sodium sulphate, filtered and concentrated. The residue was purified by column chromatography on silica gel eluting with (PE:EtOAc=50:1) to afford the title compound as a light yellow solid (670 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][O:6][C:7]1[CH:19]=[CH:18][C:10]([CH:11]=[N:12][C@@H:13]([CH3:17])[C:14]([NH2:16])=[O:15])=[CH:9][CH:8]=1.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][NH:12][C@@H:13]([CH3:17])[C:14]([NH2:16])=[O:15])=[CH:18][CH:19]=1
Reactant: C[C@H](N=Cc1ccc(OCc2cccc(F)c2)cc1)C(N)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[C@H](NCc1ccc(OCc2cccc(F)c2)cc1)C(N)=O
Temperature: 3.5 °C
Yield: 89.2 %

Procedure:
A mixture of (S)-2-[4-(3-fluorobenzyloxy)benzylideneamino]propanamide (III a) (150 g), prepared as described in Example 16a), and methanol (900 mL) is cooled under stirring to 2-5° C. Sodium borohydride (19.0 g) is added in small portions in 2 hours to the previously prepared cold mixture keeping the temperature below 5° C. The mixture is then stirred for additional 20 min at 5° C. The reaction mixture is concentrated under vacuum and worked up as described in Example 2 to give 135 g (89.2% yield) of (5)-2-[4-(3-fluorobenzyloxy)benzylamino]propanamide (Ia) with a HPLC purity of 98.8 (area % determined according to the method of Example 25A and a C,O-dialkylated (S)-2-[3-(3-fluorobenzyl)-4-(3-fluorobenzyloxy)-benzylamino]propanamide content of 0.005% by weight determined by HPLC, according to the method of Example 25B.