Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([NH2:19])[CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]=O>CO>[CH3:18][O:17][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][C:12]=1[O:15][CH3:16])[CH2:20][NH:19][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:8]2
Reactant: C=O
Reactant: COc1ccc(CC(N)c2ccccc2)cc1OC
Solvent: CO
Product: COc1cc2c(cc1OC)CC(c1ccccc1)NC2

Procedure:
Heat a mixture of the amine from step C, 36% formaldehyde (1 mL) and 1.5 mL of methanol at reflux for 2 h. Distill off the solvent, add 3 mL of benzene to the residue and concentrate in vacuo to a residue. Add 3 mL of benzene and again concentrate to a residue. Add 2 mL of methanolic HCl (1.5N) and heat the mixture at reflux for 2 h. Pour the mixture into water, neutralize with NH4OH and extract with ethyl acetate. Concentrate the extract to give 286 mg of the title compound. 1H NMR (CDCl3): δ7.53-7.23 (5H, m); 6.6 (2H, d, J=2 Hz); 4.3-3.72 (3H, m); 3.87 (3H, s); 3.85 (3H, s); 2.9 (2H, d, J=7 Hz).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]Br.[OH-].[Na+]>C(O)C>[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Reactant: BrCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: BrCCCCCSc1ccccc1
Reaction time: 8 h

Procedure:
A solution of 20 ml (0.2 mol) of thiophenol and 50.6 g (0.22 mol) of 1,5-dibromopentane in 200 ml of ethanol is heated to 40° C whilst stirring and 40 ml (0.2 mol) of 5N NaOH are added dropwise. Thereafter the mixture is stirred for 2 hours and after standing overnight the alcohol is evaporated in vacuo, the residue is extracted with methylene chloride and the extract is washed 3 to 4 times with water, dried and evaporated. A yellow oil is obtained in quantitative yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6](O)=[O:7].S(Cl)([Cl:18])=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([Cl:18])=[O:7]
Reactant: COc1cc(C(=O)O)cc(OC)c1OC
Reactant: O=S(Cl)Cl
Product: COc1cc(C(=O)Cl)cc(OC)c1OC

Procedure:
10 g of (0.047 mole) of 3,4,5-trimethoxybenzoic acid are suspended in 120 ml of thionyl chloride and refluxed for 2 hours. The solution is concentrated under reduced pressure. The residual oil crystallizes immediately after the addition of petroleum ether. The crystals are spun and washed with petroleum ether.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:7]([OH:8])[CH2:6][C@@H:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.CCN(CC)CC.[CH2:23]([O:30][C:31](ON1C(=O)CCC1=O)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[OH:8][C@H:7]1[C@@H:3]([CH2:2][NH:1][C:31]([O:30][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:32])[CH2:4][C@H:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6]1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CC(C)(C)OC(=O)[C@H]1C[C@H](CN)[C@H](O)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@H]1C[C@H](CNC(=O)OCc2ccccc2)[C@H](O)C1
Reaction time: 18 h
Yield: 89.7 %

Procedure:
To a solution of (±)-1,1-dimethylethyl (1S,3R,4R)-3-(aminomethyl)-4-hydroxycyclopentanecarboxylate (7.9 g, 37.0 mmole) in DCM (100 mL) at RT was added Et3N (6.7 mL, 48.4 mmole) and N-(benzyloxycarbonyloxy)succinimide (12.1 g, 48.4 mmole). After 18 h, the DCM was removed under vacuum and the residue purified on silica (1:1, hexanes/EtOAc) to give the title compound (11.6 g, 89%) as a white solid: LC-MS (ES) m/e 350 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C:3](=[NH:18])[N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:6][CH2:5]1.[Cl:19][C:20]([SH:23])(Cl)Cl.[OH-].[Na+]>ClCCl.O>[Cl:19][C:20]1[S:23][N:2]=[C:3]([N:4]2[CH2:5][CH2:6][CH:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:15])([CH3:14])[CH3:16])[CH2:8][CH2:9]2)[N:18]=1
Reactant: SC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=N)N)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(c2nsc(Cl)n2)CC1
Temperature: 25 °C
Yield: 34.4 %

Procedure:
To a solution of tert-butyl {1-[amino(imino)methyl]piperidin-4-yl}carbamate hydrochloride (1.50 g, 5.38 mmol) and perchloromethyl mercaptan (0.578 ml, 5.38 mmol) in dichloromethane (20 ml) was added dropwise a solution of sodium hydroxide (0.861 g, 21.5 mmol) in water (2.5 ml) under ice-cooling. Then, the reaction mixture was stirred under ice-cooling for 1 hour and at room temperature for 1 hour. The organic layer was separated, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give 590 mg (34.3%) of the desired product as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[N:7][CH:8]=1.[H-].[Na+].[Cl:12][CH2:13][CH2:14][CH2:15]I.[Na+].[Cl-]>CN(C=O)C.O>[Cl:12][CH2:13][CH2:14][CH2:15][O:9][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[N:7][CH:6]=1
Reactant: COc1cncc(O)c1
Reactant: ClCCCI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cncc(OCCCCl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
Under a nitrogen atmosphere, a solution of 5-methoxypyridin-3-ol (0.50 g, 4.01 mmol) in DMF (10 mL) was slowly added over 10 min to a cold (0-5° C.), stirring slurry of sodium hydride (0.19 g of an 80% dispersion in mineral oil, 6.33 mmol) in DMF (15 mL). The mixture was allowed to warm to ambient temperature and further stirred for 1 h. To this slurry was added drop-wise over 5 min, 1-chloro-3-iodopropane (0.98 g, 4.81 mmol), and the resulting dark brown mixture was stirred at ambient temperature for 4 h. Cold water (25 mL) was carefully added, followed by saturated NaCl solution (25 mL). The resulting mixture was extracted with ether (4×50 mL). The combined ether extracts were dried (MgSO4), filtered, and concentrated by rotary evaporation producing a dark-brown oil (0.75 g, 92.8%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[Cl:9].[H-].[Na+].[CH2:12](Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][C:3]=1[Cl:9]
Reactant: Oc1ccc(Br)c(Cl)c1
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1cc(OCc2ccccc2)ccc1Br

Procedure:
2 g of 4-bromo-3-chlorophenol dissolved in 20 cm3 of dimethylformamide are added to 480 mg of sodium hydride at 60% in oil, in 10 cm3 of dimethylformamide, followed by addition of a solution of 1.38 cm3 of benzyl chloride dissolved in 5 cm3 of dimethylformamide. The reaction medium is concentrated under reduced pressure and taken up in 100 cm3 of ethyl acetate. The organic phase is washed successively with 2×50 cm3 of water and with 50 cm3 of saturated sodium chloride solution, separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 50° C.) to give 3 g of crude product, which is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2.5 cm), eluting with a cyclohexane/ethyl acetate mixture (90/10 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.). 2.63 g of 1-bromo-2-chloro-4-(phenylmethoxy)benzene are obtained in the form of an orange-coloured oil which crystallizes.
Reaction SMILES: [H-].[Na+].[C:3]([C:6]1[C:7]2[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=2[S:9][C:10]=1[NH:11][S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])(=[O:5])[CH3:4].[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][C:23]=1[C:30]([F:33])([F:32])[F:31].C1OCCOCCOCCOCCOC1>CN(C=O)C.O>[C:3]([C:6]1[C:7]2[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=2[S:9][C:10]=1[N:11]([CH2:26][C:25]1[CH:28]=[CH:29][C:22]([F:21])=[C:23]([C:30]([F:33])([F:31])[F:32])[CH:24]=1)[S:12]([CH2:15][CH3:16])(=[O:13])=[O:14])(=[O:5])[CH3:4]
Reactant: CCS(=O)(=O)Nc1sc2ccccc2c1C(C)=O
Reactant: Fc1ccc(CBr)cc1C(F)(F)F
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCS(=O)(=O)N(Cc1ccc(F)c(C(F)(F)F)c1)c1sc2ccccc2c1C(C)=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Sodium hydride (60% in oil, 46 mg, 1.15 mmol) was added to a solution of N-(3-acetyl-benzo[b]thiophen-2-yl)-ethanesulfonamide (310 mg, 1.09 mmol) in DMF (4 mL), at 0° C. The resulting mixture was stirred at 0° C. for 15 min, to which was added 4-fluoro-3-trifluoromethylbenzyl bromide (253 μL, 1.33 mmol) and the resulting mixture stirred at ambient temperature for 2 h. 15-Crown-5 ether (220 μL, 1.33 mmol) and an additional equivalent of 4-fluoro-3-trifluoromethylbenzyl bromide was then added. The resulting solution was stirred at ambient temperature overnight, water was then added, and the desired product extracted into ethyl acetate. The organic phase was washed with water (3×), brine, dried over sodium sulfate, filtered, and the solvent evaporated in vacuo to yield a residue. The residue was purified by flash column chromatography (SiO2), eluting with an ethyl acetate-heptane gradient to yield N-(3-acetyl-benzo[b]thiophen-2-yl)-N-(4-fluoro-3-trifluoromethyl-benzyl)-ethanesulfonamide as an off-white solid. 1H-NMR (DMSO-d6): δ 1.32 (t, 3H), 2.29 (s, 3H), 3.49 (q, 2H), 5.08 (s, 2H), 7.41-7.52 9m, 3H), 7.70-7.77 (m, 2H), 7.93-8.03 (m, 2H); MS: m/z 460.2 (MH+).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].FC(F)(F)S(O[C:23]1[CH:24]=[CH:25][C:26]2[N:32]3[C:33]([CH3:36])=[N:34][N:35]=[C:31]3[C@H:30]([CH2:37][C:38]([NH:40][CH2:41][CH3:42])=[O:39])[N:29]=[C:28]([C:43]3[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=3)[C:27]=2[CH:50]=1)(=O)=O.O>COCCOC.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>[Cl:49][C:46]1[CH:47]=[CH:48][C:43]([C:28]2[C:27]3[CH:50]=[C:23]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=4[CH3:10])[CH:24]=[CH:25][C:26]=3[N:32]3[C:33]([CH3:36])=[N:34][N:35]=[C:31]3[C@H:30]([CH2:37][C:38]([NH:40][CH2:41][CH3:42])=[O:39])[N:29]=2)=[CH:44][CH:45]=1
Reactant: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(OS(=O)(=O)C(F)(F)F)ccc2-n2c(C)nnc21
Reactant: Cc1ccccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(-c3ccccc3C)ccc2-n2c(C)nnc21
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
o-Tolylboronic acid (30.1 mg), sodium carbonate (43.0 mg) and bis(triphenylphosphine)palladium(II) chloride (12.95 mg) were added to a 2-5 ml microwave vial. A solution of (4S)-6-(4-chlorophenyl)-4-[2-(ethylamino)-2-oxoethyl]-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-8-yl trifluoromethanesulfonate (for a preparation see intermediate 3) (100 mg) in DME (3 ml) and water (1 ml) was added and the reaction mixture was heated at 120° C. for 20 min (microwave) and then at 120° C. for a further 30 min (microwave). Bis(triphenylphosphine)palladium(II) chloride (12.7 mg) was added and the reaction mixture was heated at 120° C. for 30 min (microwave). The reaction mixture was partitioned between ethyl acetate (10 ml) and water (10 ml). The organic phase was separated and washed with water (10 ml) and brine (10 ml), dried and the solvent evaporated. The residue was chromatographed (0-5% methanol:DCM). The resulting mixture was repurified by MDAP (formate modifier) to give 2-[(4S)-6-(4-chlorophenyl)-1-methyl-8-(2-methylphenyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide as a white oil (16.8 mg). LCMS (formate): MH+ 484/486, RT 1.14 min
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:13]2[NH:14][S:15](=[O:29])(=[O:28])[C:16]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=[CH:20][C:17]=3[C:18]=2[OH:19])=[O:12])[CH:7]=[CH:8][CH:9]=1.[CH3:30]I>CO>[Cl:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:13]2[N:14]([CH3:30])[S:15](=[O:28])(=[O:29])[C:16]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=[CH:20][C:17]=3[C:18]=2[OH:19])=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(Nc1cccc(Cl)c1)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN1C(C(=O)Nc2cccc(Cl)c2)=C(O)c2ccc3ccccc3c2S1(=O)=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 64.3 %

Procedure:
3.15 ml of 1 N sodium hydroxide (3.15 millimols) were added dropwise to a suspension of 1.2 gm (3 millimols) of N-(3-chloro-phenyl)-4-hydroxy-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxamide-1,1-dioxide in 100 ml of methanol and 1.7 gm (12 millimols) of methyl iodide. The resulting mixture was stirred at room temperature for 72 hours, and was then evaporated to dryness in vacuo. The residue was washedwith a small quantity of water, and the remaining solid matter was recrystallized from ethylene chloride, yielding 0.8 gm (64% of theory) of N-(3-chloro-phenyl)-4-hydroxy-2-methyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxamide-1,1-dioxide, m.p. 248°-249° C (decomp.).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([O:15][CH2:16][O:17][C:18](=[O:39])[C@H:19]([OH:38])[CH2:20][C@H:21]([NH2:37])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=2[F:36])=[CH:25][CH:24]=1)(=[O:14])[CH2:11][CH2:12][CH3:13].[OH:40][N:41]1[CH:45]=[C:44]([C:46](O)=[O:47])[N:43]=[N:42]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C=O)C>>[C:10]([O:15][CH2:16][O:17][C:18](=[O:39])[C@H:19]([OH:38])[CH2:20][C@H:21]([NH:37][C:46]([C:44]1[N:43]=[N:42][N:41]([OH:40])[CH:45]=1)=[O:47])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=2[F:36])=[CH:25][CH:24]=1)(=[O:14])[CH2:11][CH2:12][CH3:13]
Reactant: CCCC(=O)OCOC(=O)[C@H](O)C[C@H](N)Cc1ccc(-c2cc(Cl)ccc2F)cc1
Reactant: O=C(O)c1cn(O)nn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(=O)OCOC(=O)[C@H](O)C[C@@H](Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1cn(O)nn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.9 %

Procedure:
DIPEA (35.8 μL, 206 μmol) was added to a solution of (2R,4R)-4-amino-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxypentanoic acid butyryloxymethyl ester (30.0 mg, 68.5 μmol), 1-hydroxy-1H-1,2,3-triazole-4-carboxylic acid (13.3 mg, 103 μmol) and HATU (39.1 mg, 103 μmol) in DMF (500 μL, 6.5 mmol). The resulting mixture was stirred at room temperature for 30 minutes, then concentrated in vacuo to yield a clear yellow liquid. The crude liquid was purified by preparative scale HPLC (C18 column chromatography, small column, using 30-90% MeCN in water with 0.05% TFA) to yield the title compound as a white solid (9.0 mg). MS m/z [M+H]+ calc'd for C25H26ClFN4O7, 549.15. found 549.1.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[N:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([OH:16])=O.C(N(CC)CC)C.CCCP(=O)=O.[CH:33]([C:36]1[CH:37]=[C:38]([CH:40]=[CH:41][CH:42]=1)[NH2:39])([CH3:35])[CH3:34]>CN(C1C=CN=CC=1)C.ClCCCl>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[N:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([NH:39][C:38]1[CH:40]=[CH:41][CH:42]=[C:36]([CH:33]([CH3:35])[CH3:34])[CH:37]=1)=[O:16]
Reactant: CC(C)c1cccc(N)c1
Reactant: O=C(O)c1cccc(N2CCc3ccncc3C2)c1
Agent: CCCP(=O)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(C)c1cccc(NC(=O)c2cccc(N3CCc4ccncc4C3)c2)c1
Temperature: 25 °C
Reaction time: 0.13 h
Yield: 59.3 %

Procedure:
To a mixture of 3-(3,4-dihydro-2,7-naphthyridin-2(1H)-yl)benzoic acid (15.0 mg, 0.059 mmol), triethylamine (0.016 mL, 0.12 mmol) and catalytic DMAP in 1.0 mL 1,2-dichloroethane at rt was added propylphosphonic anhydride solution (50 wt % in EtOAc, 0.046 mL, 0.077 mmol). After 8 min at rt, 3-isopropylaniline (0.015 mL, 0.106 mmol) was added and the reaction stirred at rt for 18 hours. Then additional 3-isopropylaniline (0.015 mL) and propylphosphonic anhydride solution (0.030 mL) was added and the reaction continued for an additional 3 hours. The reaction was quenched into brine/dilute aqueous Na2CO3 solution, extracted with EtOAc, the EtOAc layer washed with H2O, brine/dilute aqueous Na2CO3 solution, dried with anhydrous Na2SO4 and rotary evaporated to an oil. The oil was chromatographed eluting with CHCl3/EtOAc to give the title compound as a light yellow solid (13 mg, 57%). 1H NMR (CDCl3) δ: 8.42 (s, 1H), 8.38 (d, J=5.0 Hz, 1H), 7.94 (s, 1H), 7.55-7.57 (m, 2H), 7.47 (ddd, J=8.1, 2.2, 1.2 Hz, 1H), 7.34-7.40 (m, 1H), 7.29 (t, J=7.8 Hz, 1H), 7.21-7.26 (m, 1H), 7.08-7.14 (m, 2H), 7.01-7.05 (m, 1H), 4.46 (s, 2H), 3.63 (t, J=5.9 Hz, 2H), 2.85-3.02 (m, 3H), 1.27 (d, J=7.0 Hz, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[O:5][C:6]1[C:15]2[N:14]=[C:13]([CH3:16])[C:12](=[O:17])[NH:11][C:10]=2[N:9]=[CH:8][CH:7]=1.[C:21]([C:25]1[CH:29]=[C:28]([N:30]=[C:31]=[O:32])[N:27]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)[N:26]=1)([CH3:24])([CH3:23])[CH3:22]>>[C:21]([C:25]1[CH:29]=[C:28]([NH:30][C:31]([NH:1][C:2]2[CH:20]=[CH:19][CH:18]=[C:4]([O:5][C:6]3[C:15]4[N:14]=[C:13]([CH3:16])[C:12](=[O:17])[NH:11][C:10]=4[N:9]=[CH:8][CH:7]=3)[CH:3]=2)=[O:32])[N:27]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)[N:26]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2N=C=O)cc1
Reactant: Cc1nc2c(Oc3cccc(N)c3)ccnc2[nH]c1=O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2cccc(Oc3ccnc4[nH]c(=O)c(C)nc34)c2)cc1
Yield: 57 %

Procedure:
Method F2 was used with 8-(3-aminophenoxy)-2-methylpyrido[2,3-b]pyrazin-3(4H)-one and 3-tert-butyl-5-isocyanato-1-p-tolyl-1H-pyrazole to afford the title compound as a white solid (89 mg, 57%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:21][C:22]([C:24]2[C:25](=[O:40])[N:26]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:27]([CH2:30][CH:31]([OH:33])[CH3:32])[C:28]=2[CH3:29])=[O:23])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1.[C:41]([NH:51][C@H:52]([C:54](O)=[O:55])[CH3:53])([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([NH:21][C:22]([C:24]2[C:25](=[O:40])[N:26]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:27]([CH2:30][C@H:31]([O:33][C:54](=[O:55])[C@@H:52]([NH:51][C:41]([O:43][CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[O:42])[CH3:53])[CH3:32])[C:28]=2[CH3:29])=[O:23])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COc1ccc2c(Oc3ccc(NC(=O)c4c(C)n(CC(C)O)n(-c5ccccc5)c4=O)cc3F)ccnc2c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1ccc2c(Oc3ccc(NC(=O)c4c(C)n(C[C@@H](C)OC(=O)[C@H](C)NC(=O)OCc5ccccc5)n(-c5ccccc5)c4=O)cc3F)ccnc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 76.3 %

Procedure:
To a mixture of (R)—N-(3-fluoro-4-(7-methoxyquinolin-4-yloxy)phenyl-1-(2-hydr-oxypropyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (2.0 g, 3.68 mmol), (S)—N-Cbz-alanine (1.647 g, 7.36 mmol, Shanghai Hanhong Chemical CO., LTD.) and DMAP (0.90 g, 7.36 mmol, Aladdin) in CH2Cl2 (30 mL) was added EDC solid (2.116 g, 11.04 mmol, Aladdin) in portions at 0° C. After stirring at 0° C. for 2 hrs, the reaction mixture was warmed up to room temperature and continued to stir at rt for 20 hrs. The mixture was diluted with 180 mL of CH2Cl2. The resulted mixture was washed with 30 mL of 0.1 N HCl, followed by 50 mL of saturated NaHCO3 solution. The aqueous phase was extracted with EtOAc (50 mL×3), and the combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc) to give the desired compound as a pale yellow solid (2.1 g, 73.1%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5](=O)[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=O)[CH3:2].C(O)(=O)C.O.[NH2:30][NH2:31].C([O-])(O)=O.[Na+]>O>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:31][N:30]=1)=[O:24])[CH3:2]
Reactant: NN
Reactant: CCOC(=O)C(=O)CC(=O)c1ccccc1OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1cc(-c2ccccc2OCc2ccccc2)[nH]n1
Yield: 100 %

Procedure:
To a solution of 1-(2-hydroxy-phenyl)-ethanone (5 g, 0.03672 mole) in DMF (75 mL) was added NaH (60% w/w dispersion in oil) (1.66 g, 0.0416 mole) and the resulting mixture was stirred at ambient temperature for 15 minutes. Benzyl bromide (7.23 g, 0.0422 mole) was then added and the mixture as stirred for an additional 4 hours. The reaction mixture was then quenched with cold aqueous NH4Cl solution and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with water, brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 8.4 g (100%) of 1-(2-benzyloxy-phenyl)-ethanone. LCMS: 227.1 (M+1)+, 84.14%. To a mixture of THF (200 mL) and NaH (60% w/w dispersion in oil) (4.4 g, 0.11 mole) cooled to 0° C. was added diethyl oxalate (10.73 g, 0.07345 mole). The resulting mixture was heated to reflux for 15 minutes. After cooing to ambient temperature, 1-(2-benzyloxy-phenyl)-ethanone (8.3 g, 0.0376 mole) was added dropwise over a period of 45 minutes. The resulting mixture was heated to 55° C. for 30 minutes. The reaction mixture was then quenched with cold aqueous NH4Cl solution and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with water, brine solution, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography using silica gel 60-120 mesh (4% ethyl acetate in hexane) to afford 8.7 g (71%) of 4-(2-benzyloxy-phenyl)-2,4-dioxo-butyric acid ethyl ester. LCMS: 327.12 (M+1)+, 78.6%. A solution of 4-(2-benzyloxy-phenyl)-2,4-dioxo-butyric acid ethyl ester (3.75 g, 0.01149 mole), acetic acid (20 mL) and hydrazine hydrate (0.632 g, 0.01264 mole) was heated to reflux for 3 hours. The reaction mixture was then poured into iced water basified with saturated aqueous NaHCO3 solution and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 3.703 g (100%) of 5-(2-benzyloxy-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester. LCMS: 323.13 (M+1)+, 97.14%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][CH3:16])[N:13]=[C:12]([CH3:17])[C:11]=2[CH:18]=[O:19])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[BH4-].[Na+].O>CO>[Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][CH3:16])[N:13]=[C:12]([CH3:17])[C:11]=2[CH2:18][OH:19])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCn1nc(C)c(C=O)c1Sc1cc(Cl)cc(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCn1nc(C)c(CO)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81.5 %

Procedure:
A mixture of 1.1 g of 5-(3,5-dichloro-phenylsulphanyl)-1-ethyl-3-methyl-1H-pyrazole-4-carbaldehyde and 0.53 g of sodium borohydride in 25 ml of anhydrous methanol was stirred under nitrogen at room temperature for 15 minutes. Water (25 ml) was added and the mixture was extracted three times with 20 ml of diethyl ether. The combined extracts were dried over magnesium sulphate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using ethyl acetate/petroleum ether (bp 40-60° C.) (1:3) for the elution to give 902 mg of [5-(3,5-dichloro-phenylsulphanyl)-1-ethyl-3-methyl-1H-pyrazol-4-yl]-methanol as a yellow oil. Mass spectrum (ES) m/z 317 [M+H]+.