Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC(C(F)(F)F)=O.[CH3:8][N:9]1[CH:13]([C:14]([OH:16])=O)[CH2:12][N:11]([C:17]2[CH:18]=[N:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)[C:10]1=[O:25].C(N1CCOCC1)C.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl:57][C:58]1[CH:63]=[C:62]([Cl:64])[CH:61]=[CH:60][C:59]=1[CH2:65][NH2:66]>ClCCl>[Cl:57][C:58]1[CH:63]=[C:62]([Cl:64])[CH:61]=[CH:60][C:59]=1[CH2:65][NH:66][C:14]([CH:13]1[CH2:12][N:11]([C:17]2[CH:18]=[N:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)[C:10](=[O:25])[N:9]1[CH3:8])=[O:16]
Reactant: NCc1ccc(Cl)cc1Cl
Reactant: COc1ccc(N2CC(C(=O)O)N(C)C2=O)cn1
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(N2CC(C(=O)NCc3ccc(Cl)cc3Cl)N(C)C2=O)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.1 %

Procedure:
To a solution of 3-methyl-1-[6-(methyloxy)-3-pyridinyl]-2-oxo-4-imidazolidinecarboxylic acid TFA salt (145 mg, 0.404 mmol) and N-ethylmorpholine (0.307 ml, 2.424 mmol) in dichloromethane (5 ml) was added 1-hydroxybenzotriazole hydrate (61.9 mg, 0.404 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (77 mg, 0.404 mmol) and the reaction mixture was stirred for 10 minutes at room temperature. 1-(2,4-Dichlorophenyl)methanamine (71.1 mg, 0.404 mmol) was added and the reaction was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and the solution was washed with saturated sodium hydrogen carbonate solution, water and brine, separated through a hydrophobic frit and the organic layer was reduced under vacuum. The residue was purified by SP4 automated silica gel chromatography eluting with 10-100% ethyl acetate in isohexane to give N-[(2,4-dichlorophenyl)methyl]-3-methyl-1-[6-(methyloxy)-3-pyridinyl]-2-oxo-4-imidazolidinecarboxamide (101 mg, 59.9% yield). LC/MS [M+H]+=409, retention time=2.34 minutes.
Reaction SMILES: C([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[NH:21][N:20]=[C:19]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:18]=2)=[CH:9]1)(OC(C)(C)C)=O>C(O)(C(F)(F)F)=O>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[NH:21][N:20]=[C:19]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:18]=2)=[CH:9]1
Reactant: CC(C)(C)OC(=O)n1cc(-c2cc(Nc3ccccc3)n[nH]2)c2ccccc21
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(Nc2cc(-c3c[nH]c4ccccc34)[nH]n2)cc1
Yield: 74.5 %

Procedure:
[5-(N-BOC-indol-3-yl)-1H-pyrazol-3-yl]-phenyl-amine (332 mg, 0.89 mmol) was stirred in 50% TFA/CH2C12 (8 mL) at r.t. for 1 h, at which point material had precipitated to a solid block. Solvents were removed in vacuo, and the solid was dissolved in EtOAc (50 mL), washed with saturated NaHCO3 (25 mL) and brine (25 mL), dried (MgSO4) and concentrated in vacIto. Purification by silica gel chromatography (50% to 70% EtOAc/hexanes) gave 182 mg (75%) of [5-(1H-indol-3-yl)-1H-pyrazol-3-yl]-phenyl-amine as a white solid. 1H NMR (300 MHz, DMSO-d6) δ12.06 (s, 1H), 11.41 (s, 1H), 8.38 (s, 1H), 7.80 (d, 1H, J=6.3 Hz), 7.74 (d, 1H, J=2.7 Hz), 7.36-7.47 (m, 3H), 7.11-7.21 (m, 4H), 6.70 (t, 1H, J=7.2 Hz), 6.14 (s, 1H). Anal. (C17H14N4.0.05 H2O) C, H, N. Calculated C=74.19; H=5.16; N=20.36; found C=74.25; H=5.17; N=20.24.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][C:8]#[N:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(OCC)(=O)C>[CH2:26]([O:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][C:8]#[N:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCc1ccccc1
Reactant: N#CCOc1ccc(O)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#CCOc1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Temperature: 70 °C
Reaction time: 22 h
Yield: 80.4 %

Procedure:
A heterogeneous mixture of 6.0 g of (4-hydroxy-3-nitro-phenoxy)-acetonitrile, 50 ml N,N-dimethylformamide, 12.8 g of potassium carbonate, and 5.8 g of benzyl bromide was heated with stirring at 70° C. for 22 hours. The mixture was cooled to room temperature, poured into ethyl acetate, washed with water, washed with 1N sodium hydroxide, again with water, dried (MgSO4), evaporated, and obtained 7.06 g of (4-benzyloxy-3-nitro-phenoxy)-acetonitrile as a tan solid.
Reaction SMILES: C[C:2]1[N:3]([C:20]2[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=2[CH3:28])[C:4]2[C:9]([N:10]=1)=[C:8]([NH:11]CC1C=CC=CC=1)[CH:7]=[C:6]([CH3:19])[N:5]=2>C(O)(=O)C.[OH-].[Pd+2].[OH-]>[CH3:19][C:6]1[N:5]=[C:4]2[N:3]([C:20]3[C:21]([CH3:28])=[CH:22][C:23]([CH3:27])=[CH:24][C:25]=3[CH3:26])[CH:2]=[N:10][C:9]2=[C:8]([NH2:11])[CH:7]=1
Reactant: Cc1cc(C)c(-n2c(C)nc3c(NCc4ccccc4)cc(C)nc32)c(C)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1cc(C)c(-n2cnc3c(N)cc(C)nc32)c(C)c1
Reaction time: 20 h

Procedure:
Add palladium hydroxide (0.05 g) to a solution of [2,5-dimethyl-3-(2,4,6-trimethylphenyl)imidazolo[5,4-b]pyridin-7-yl]benzylamine (0.15 g, 0.42 mmol) in acetic acid (10 mL). Hydrogenate the mixture at a pressure of 50 psi for 20 hr. Filter the reaction mixture through celite, evaporate to dryness under reduced pressure, dilute with EtOAc and successively wash with aq NaHCO3 and aq NaCl. Dry the organic layer over Na2SO4, filter, and concentrate. Purify by flash column chromatography (3% MeOH in CH2Cl2) to obtain the title compound as a brown solid.
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[N:17]([CH3:18])[C:16]2[C:19]([CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[CH:20][CH:21]=[CH:22][C:15]=2[N:14]=1.[C:28]1([CH3:38])[CH:33]=[C:32]([CH3:34])[CH:31]=[C:30]([CH3:35])[C:29]=1[CH:36]=[O:37]>C(OCC)C>[CH2:24]([CH:23]([C:19]1[C:16]2[N:17]([CH3:18])[C:13]([CH:36]([C:29]3[C:28]([CH3:38])=[CH:33][C:32]([CH3:34])=[CH:31][C:30]=3[CH3:35])[OH:37])=[N:14][C:15]=2[CH:22]=[CH:21][CH:20]=1)[CH2:26][CH3:27])[CH3:25]
Reactant: CCC(CC)c1cccc2nc(Br)n(C)c12
Reactant: Cc1cc(C)c(C=O)c(C)c1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CCC(CC)c1cccc2nc(C(O)c3c(C)cc(C)cc3C)n(C)c12
Reaction time: 0.5 h
Yield: 15.8 %

Procedure:
A solution of n-butyllithium in n-hexane (1.6M solution, 0.25 mL, 0.40 mmol) was added dropwise to a solution of 2-bromo-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole (100 mg, 0.36 mmol) in diethyl ether (4 mL) at 0° C. To the reaction mixture was added a solution of mesitaldehyde (74 mg, 0.50 mmol) in diethyl ether (1 mL) at 0° C. The reaction mixture was stirred for 0.5 hr, and the reaction was quenched by the addition of 1N hydrochloric acid to the mixture, and the mixture was extracted with ethyl acetate. The organics were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC eluting with a 10-100% water/acetonitrile gradient mixture containing 0.1% trifluoroacetic acid. The fractions containing the title compound were concentrated in vacuo, and the residue was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution. The organics were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The resulting solid was recrystallized from ethanol/water to give the title compound (20 mg, 0.057 mmol, 16%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:5]([CH:6]=O)=[C:4](F)[CH:3]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][NH2:21])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1>[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:4]3[C:5](=[CH:8][C:9]([O:10][CH3:11])=[C:2]([Cl:1])[CH:3]=3)[CH:6]=[N:21]2)=[CH:16][CH:15]=1
Reactant: COc1cc(C=O)c(F)cc1Cl
Reactant: NNc1ccc(F)cc1
Agent: CN1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1cc2cnn(-c3ccc(F)cc3)c2cc1Cl
Temperature: 150 °C

Procedure:
4-Chloro-2-fluoro-5-methoxy benzaldehyde (204 mg, 1.1 mmol) and 4-fluorophenylhydrazine (176 mg, 1.1 mmol) were dissolved in N-methylpyrrolidine (5 mL). After addition of cesium carbonate (1.15 g, 3.3 mmol) the mixture was heated in a microwave reactor (CEM Discovery, 150 Watt) to 150° C. for 20 min. After dilution with DCM the mixture was washed with sat. NaHCO3, brine and the organic phase was evaporated. After purification of the crude by flash chromatography on silica gel 253 mg (84%) of the subtitle compound were obtained.
Reaction SMILES: [CH2:1]([CH:3]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:4][O:5][C:6]([N:8]1[C:12](=[O:13])[CH:11]=[CH:10][C:9]1=[O:14])=[O:7])[CH3:2].[CH2:19]([OH:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25]>>[OH:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][O:26][C:12]([CH:11]=[CH:10][C:9]([NH:8][C:6](=[O:7])[O:5][CH2:4][CH:3]([CH2:1][CH3:2])[CH2:15][CH2:16][CH2:17][CH3:18])=[O:14])=[O:13]
Reactant: CCCCC(CC)COC(=O)N1C(=O)C=CC1=O
Reactant: OCCCCCCO
Product: CCCCC(CC)COC(=O)NC(=O)C=CC(=O)OCCCCCCO

Procedure:
According to the same manner as described in Example 1 except for reacting N-(2-ethylhexyloxycarbonyl)maleimide with 1,6-hexanediol under conditions shown in Table 20, 2-Ethylhexyl N-{3-(6-hydroxyhexyloxycarbonyl)propenoyl)carbamate was obtained. Characteristics and identified structure of the resulting compound are shown in Table 18.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:27](O)=[O:28])[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.[Cl:30][C:31]1[CH:32]=[C:33]([C:37](=[N:39]O)[NH2:38])[CH:34]=[CH:35][CH:36]=1>>[Cl:30][C:31]1[CH:32]=[C:33]([C:37]2[N:39]=[C:27]([CH:12]3[CH2:13][CH:14]([C:16]4[CH:21]=[CH:20][C:19]([O:22][C:23]([F:24])([F:25])[F:26])=[CH:18][CH:17]=4)[CH2:15][N:10]([C:8]([N:5]4[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]4)=[O:9])[CH2:11]3)[O:28][N:38]=2)[CH:34]=[CH:35][CH:36]=1
Reactant: NC(=NO)c1cccc(Cl)c1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCC(O)CC2)C1
Product: O=C(N1CCC(O)CC1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(-c3cccc(Cl)c3)no2)C1

Procedure:
100 mg (0.24 mmol) of 1-[(4-hydroxypiperidin-1-yl)carbonyl]-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 63A) and 61 mg (0.36 mmol, 1.5 eq.) of 3-chloro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 2. Yield: 69 mg (52% of theory)
Reaction SMILES: [CH2:1]([Si:19]([CH3:22])([CH3:21])O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].CN(C)C=O.C(Cl)([Cl:30])=O>ClCCCl>[CH2:1]([Si:19]([CH3:22])([CH3:21])[Cl:30])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=C(Cl)Cl
Reactant: CCCCCCCCCCCCCCCCCC[Si](C)(C)O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCC[Si](C)(C)Cl
Yield: 87 %

Procedure:
To the same reactor as used in Example 1 were added 82.2 g (0.25 mole) of octadecyldimethylsilanol, 330 g of 1,2-dichloroethane and 1.83 g (0.025 mole) of N,N-dimethylformamide, and 27.2 g (0.275 mole) of phosgene was introduced into the resulting mixture at a temperature of from 40° to 45° C. over 2 hours with stirring. After completion of the introduction, the same procedure as in Example 7 was carried out to obtain 75.5 g of octadecyldimethylchlorosilane.
Reaction SMILES: [CH:1]1([C@:4]([OH:32])([CH3:31])[CH2:5][NH:6][C:7]([C:9]2[CH:14]=[N:13][C:12]([C:15]#[C:16][Si](CC)(CC)CC)=[C:11]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[N:10]=2)=[O:8])[CH2:3][CH2:2]1.[F-].[NH4+]>CO>[CH:1]1([C@:4]([OH:32])([CH3:31])[CH2:5][NH:6][C:7]([C:9]2[CH:14]=[N:13][C:12]([C:15]#[CH:16])=[C:11]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[N:10]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: CC[Si](C#Cc1ncc(C(=O)NC[C@](C)(O)C2CC2)nc1-c1ccc(Cl)cc1)(CC)CC
Agent: [F-]
Agent: [NH4+]
Solvent: CO
Product: C#Cc1ncc(C(=O)NC[C@](C)(O)C2CC2)nc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.40 g 6-(4-chloro-phenyl)-5-triethylsilanylethynyl-pyrazine-2-carboxylic acid ((R)-2-cyclopropyl-2-hydroxy-propyl)-amide in 10 ml methanol was added at room temperature 0.40 g ammonium fluoride and the mixture was stirred at room temperature for 30 min. The orange reaction mixture was partitioned between water and ethyl aceate, the phases were separated and the organic phase was purified by chromatography on silica gel with heptane:ethyl acetate=1:1 to yield 6-(4-chloro-phenyl)-5-ethynyl-pyrazine-2-carboxylic acid ((R)-2-cyclopropyl-2-hydroxy-propyl)-amide as light yellow foam.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:11]([C:12]([N:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:15])=[O:13])[N:10]=[C:9]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[S:8]1)=[N+]=[N-].Cl>CO.[Pt]=O>[NH2:1][CH2:4][CH2:5][CH2:6][C:7]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:11]([C:12]([N:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:15])=[O:13])[N:10]=[C:9]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[S:8]1
Reactant: CN(OC(C)(C)C)C(=O)N1N=C(c2cc(F)ccc2F)SC1(CCCN=[N+]=[N-])c1ccccc1
Agent: O=[Pt]
Agent: Cl
Solvent: CO
Product: CN(OC(C)(C)C)C(=O)N1N=C(c2cc(F)ccc2F)SC1(CCCN)c1ccccc1
Reaction time: 1 h

Procedure:
To a solution of 2-(3-azidopropyl)-N-tert-butoxy-5-(2,5-difluorophenyl)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide (0.032 g, 0.065 mmol) and platinum oxide (15 mg) in methanol (3 mL) was added HCl (5.3 M solution in dioxane, 0.05 mL). After stirring under a hydrogen balloon for 1 hour, the mixture was filtered and the filtrate was concentrated under reduced pressure to provide the product.
Reaction SMILES: [C-]#N.[Na+].Br[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[C:7]([F:15])[CH:6]=1.[CH3:16][NH:17]CCNC.[OH-].[NH4+]>[Cu]I.O.C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:16]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[C:7]([F:15])[CH:6]=1)#[N:17]
Reactant: CC(=O)Nc1ccc(Br)cc1F
Reactant: CNCCNC
Agent: [Cu]I
Agent: [C-]#N
Agent: [NH4+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(C#N)cc1F
Temperature: 110 °C
Reaction time: 24 h
Yield: 89.6 %

Procedure:
An oven dried screw cap test tube was charged with NaCN (137 mg, 2.796 mmol) dried KI (77 mg, 0.464 mmol, 20 mol %) and CuI (44 mg, 0.231 mmol, 10 mol %), N-(4-Bromo-2-fluoro-phenyl)-acetamide (540 mg, 2.330 mmol), evacuated and backfilled with argon three times. Anhydrous toluene (1.550 mL) and N,N′-dimethylethylenediamine (250 μl, 2.348 mmol) were added under argon. The tube was sealed and the reaction mixture was stirred magnetically at 110° C. for 24 h. The resulting yellow color suspension was cooled to room temperature, 2 mL of ethyl acetate, 1 mL of ammonium hydroxide 30% and 1 mL of water were added. The mixture was stirred at 25° C. for 10 min then the organic layer was separated and the aqueous layer was extracted three times with ethyl acetate (3×2 mL). The organic layers combined were washed with 5 mL of water and dried over MgSO4. The solvent was removed at reduced pressure. Purification of the residue by flash chromatography on silica gel (2×15 cm; hexane/ethyl acetate 10:1) provided 372 mg (90% yield) of the title compound as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:15])([CH3:14])[C:9](OCC)=[O:10])[CH:5]=[N:6][CH:7]=1.[BH4-].[Li+]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:15])([CH3:14])[CH2:9][OH:10])[CH:5]=[N:6][CH:7]=1
Reactant: CCOC(=O)C(C)(C)c1cncc(Br)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCO
Product: CC(C)(CO)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the title compound from Example 53 Step D (93 g, 0.34 mol) in ethanol (1.2 L) was added lithium borohydride (16.6 g, 0.75 mol). The resulting mixture was heated to reflux and stirred overnight. The reaction was then cooled to room temperature and poured onto ice. The mixture was extracted with ethyl acetate, and the organic layer washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatograph on silica gel (petroleum ether/ethyl acetate=40/1-8/1) provided the title compound: LCMS m/z 230 [M+H]+; 1H NMR (300 MHz, CDCl3) δ 8.58 (s, 1H), 8.52 (s, 1H), 7.97 (s, 1H), 4.82-4.86 (m, 1H), 3.44-3.46 (m, 2H), 1.24 (s, 6H).
Reaction SMILES: C[O:2][P:3]([CH2:23][NH:24][C:25]([C@@H:27]([NH:32][C:33]([C@@H:35]1[CH2:39][CH2:38][CH2:37][N:36]1[C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41])=[O:34])[CH2:28][CH:29]([CH3:31])[CH3:30])=[O:26])([CH2:5][CH:6]([C:11](=[O:22])[NH:12][C@H:13]([C:18](=[O:21])[NH:19][CH3:20])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:7][CH:8]([CH3:10])[CH3:9])=[O:4].Br[Si](C)(C)C>ClCCl>[CH2:43]([O:42][C:40]([N:36]1[CH2:37][CH2:38][CH2:39][C@H:35]1[C:33]([NH:32][C@H:27]([C:25]([NH:24][CH2:23][P:3]([CH2:5][CH:6]([C:11](=[O:22])[NH:12][C@H:13]([C:18](=[O:21])[NH:19][CH3:20])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:7][CH:8]([CH3:9])[CH3:10])(=[O:2])[OH:4])=[O:26])[CH2:28][CH:29]([CH3:30])[CH3:31])=[O:34])=[O:41])[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: CNC(=O)[C@H](CC(C)C)NC(=O)C(CC(C)C)CP(=O)(CNC(=O)[C@H](CC(C)C)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)OC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: CNC(=O)[C@H](CC(C)C)NC(=O)C(CC(C)C)CP(=O)(O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.7 %

Procedure:
0.11 g of benzyl(S)-2-[[(S)-1-[[[methoxy[(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinyl]methyl]carbamoyl]-3-methylbutyl]carbamoyl]-1-pyrrolidinecarboxylate was dissolved in 4 ml of dichloromethane and 0.5 ml of bromotrimethylsilane was added. The mixture was stirred at room temperature for 1.5 hours and the solvent was removed by evaporation. The residue was dissolved in 5 ml of acetone and there were then added 1 ml of water and 0.5 g of sodium hydrogen carbonate followed by 50 mg of benzyl chloroformate. After stirring at room temperature for 2.5 hours, the solvent was removed by evaporation. The residue was dissolved in 15 ml of 1M sodium hydroxide solution and the resulting solution was extracted three times with 15 ml of diethyl ether each time. The aqueous solution was acidified with 10% sulfuric acid, saturated with sodium chloride solution and extracted five times with 20 ml of 5% methanol in dichloromethane each time. The organic extracts were dried over anhydrous sodium sulfate and evaporated to give 0.1 g of [[[N-[1-[(benzyloxy)carbonyl]-L-prolyl]-L-leucyl]amino]methyl][(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid in the form of a white foam.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](C#CP(OC)(C[C@@H](O)CC(OC)=O)=O)=[C:10]([CH:17]([CH3:19])[CH3:18])[N:11]3[C:16]=2[CH:15]=[CH:14][CH:13]=[CH:12]3)=[CH:4][CH:3]=1.CO.[CH3:36][CH2:37][O:38][C:39](C)=[O:40]>[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:39]([O:38][CH2:37][CH3:36])=[O:40])=[C:10]([CH:17]([CH3:19])[CH3:18])[N:11]3[C:16]=2[CH2:15][CH2:14][CH2:13][CH2:12]3)=[CH:6][CH:7]=1
Reactant: COC(=O)C[C@H](O)CP(=O)(C#Cc1c(-c2ccc(F)cc2)c2ccccn2c1C(C)C)OC
Reactant: CCOC(C)=O
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1c(-c2ccc(F)cc2)c2n(c1C(C)C)CCCC2
Reaction time: 20 h
Yield: 96 %

Procedure:
To a solution of Example 1, Part C compound 6.50 g, 20.0 mmol) in EtOAc (35 mL)-CH3OH (70 mL) was added 10% Pd-C (1.5 g) and the resulting mixture hydrogenated in a Parr apparatus at 50 psi for 20 hours. The catalyst was removed by filtration through Celite and the filtrate evaporated to a colorless, viscous oil. The crude product was crystallized from hexane to give pure title compound (6.292 g, 96%) as white crystals, mp 85.5°-86.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[C:11]([C:13](OC)=[O:14])[C:10]([CH3:17])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[C:11]([CH:13]=[O:14])[C:10]([CH3:17])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cn(-c2cccc(Cl)c2)nc1C
Agent: [Mn+4]
Agent: [Al+3]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1nn(-c2cccc(Cl)c2)cc1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.9 %

Procedure:
A solution (20 mL) of methyl 1-(3-chlorophenyl)-3-methyl-1H-pyrazole-4-carboxylate (1.9 g) synthesized in the above-mentioned (1) in tetrahydrofuran was added to an ice-cooled solution (80 mL) of lithium aluminum hydride (0.29 g) in tetrahydrofuran. The ice bath was removed, and the reaction mixture was stirred at room temperature for 1 hr. The mixture was ice-cooled again, and water (0.80 mL), 1N aqueous sodium hydroxide solution (4.0 mL) and water (0.80 mL) were successively added dropwise to quench the reaction. The residue was filtered through celite, and the filtrate was concentrated under reduced pressure to give a crude product (0.65 g) of 1-(3-chlorophenyl)-3-methyl-1H-pyrazole-4-methanol as a pale-yellow oil. This was dissolved in toluene (30 mL), manganese dioxide (2.0 g) was added, and the mixture was heated for 30 min with a Dean-Stark trap. The reaction mixture was allowed to cool to room temperature, and manganese dioxide was collected by filtration. The solvent was evaporated under reduced pressure to give the title object compound (0.35 g, 23%) as a colorless solid.
Reaction SMILES: [O:1]=[C:2]1[NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[C:4]2([CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]2)[O:3]1.FC(F)(F)C(O)=O>ClCCl>[NH:7]1[CH2:6][CH2:5][C:4]2([O:3][C:2](=[O:1])[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]2=3)[CH2:9][CH2:8]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)OC(=O)Nc1ccccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1Nc2ccccc2C2(CCNCC2)O1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
tert-Butyl 2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,4′-piperidine]-1′-carboxylate (6.71 g, 21.1 mmol) (A3) was dissolved in dichloromethane (50 mL), treated with trifluoroacetic acid (20 mL) and stirred at room temperature for 45 min. The reaction was concentrated under reduced pressure, re-dissolved in acetonitrile and re-concentrated under reduced pressure. The crude TFA salt was cooled in an ice water bath, dissolved in ice-cold saturated brine (20 mL) and H2O (50 mL) and basified with ice-cold 35% NaOH (aq). A small amount of product (obtained from extraction with 50 mL ethyl acetate) was added to the aqueous layer to initiate crystallization. The suspension obtained was cooled in an ice-H2O bath, filtered, rinsed with ice-cold H2O and dried to afford spiro[benzo[d][1,3]oxazine-4,4′-piperidin]-2(1H)-one (A4) free base as a white crystalline solid. Additional free base was obtained via extraction of the mother liquor with ethyl acetate (10×50 mL) and subsequent trituration of the crude free base with acetonitrile (overall yield=84%). LC/MS m/z 219.2 [M+H]+, retention time 0.58 min (RP-C18, 10-99% CH3CN/0.05% TFA); 1H-NMR (400 MHz, DMSO-d6) δ 10.17 (br s, 1H), 7.23 (m, 2H), 7.02 (m, 1H), 6.87 (dd, J=8.2, 1.2 Hz, 1H), 2.89 (m, 2H), 2.82 (m, 2H), 1.84 (m, 4H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][Si:8]([CH3:18])([CH3:17])[C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Br)=[CH:11][CH:10]=1.[Cl:19][C:20]1[C:21](=[O:29])[N:22]([CH2:27][CH3:28])[N:23]=[CH:24][C:25]=1[OH:26].O>CN(C)C=O>[Cl:19][C:20]1[C:21](=[O:29])[N:22]([CH2:27][CH3:28])[N:23]=[CH:24][C:25]=1[O:26][CH2:13][C:12]1[CH:15]=[CH:16][C:9]([Si:8]([CH3:18])([CH3:17])[CH3:7])=[CH:10][CH:11]=1
Reactant: CCn1ncc(O)c(Cl)c1=O
Reactant: C[Si](C)(C)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1ncc(OCc2ccc([Si](C)(C)C)cc2)c(Cl)c1=O
Temperature: 25 °C
Yield: 58.7 %

Procedure:
1.8 g of anhydrous potassium carbonate and 2.1 g of p-trimethylsilylbenzylbromide were added to 1.5 g of 4-chloro-2-ethyl-5-hydroxy-3(2H)-pyridazinone dissolved in 10 ml of N,N-dimethylformamide, and the resulting mixture was heated in an oil bath of 120°-130° C. for 2 hours. After the reaction mixture was allowed to cool to room temperature, 100 ml of water was added thereto and the mixture was stirred vigorously. Precipitate was filtered, washed with water and dried to obtain 1.7 g of a crude product. The product was recrystallized from a mixed solvent of isopropyl ether and ethyl acetate to obtain the intended compound (Compound No. 4.6) having m.p. 122°-125° C. (yield: 44.8%).