Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:56])[NH:4][CH:5]([C:9]([N:11]1[CH:17]([C:18]2[NH:19][C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][C:32]([C:35]5[NH:36][C:37]([CH:40]6[CH2:44][CH2:43][CH2:42][N:41]6[C:45](=[O:55])[CH:46]([NH:50][C:51]([O:53][CH3:54])=[O:52])[CH:47]([CH3:49])[CH3:48])=[N:38][CH:39]=5)=[CH:31][CH:30]=4)=[CH:25][CH:24]=3)=[CH:21][N:22]=2)C[C:13]2(CC2)[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7].[S:57]1CCNC1>>[CH3:1][O:2][C:3](=[O:56])[NH:4][CH:5]([C:9]([N:11]1[CH2:12][CH2:13][S:57][CH:17]1[C:18]1[NH:19][C:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][C:32]([C:35]4[NH:36][C:37]([CH:40]5[CH2:44][CH2:43][CH2:42][N:41]5[C:45](=[O:55])[CH:46]([NH:50][C:51]([O:53][CH3:54])=[O:52])[CH:47]([CH3:49])[CH3:48])=[N:38][CH:39]=4)=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)=[CH:21][N:22]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: C1CSCN1
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CC6(CC6)CN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)[nH]1)C(C)C
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5SCCN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)[nH]1)C(C)C

Procedure:
(Example DX) was prepared in a similar fashion to (1-{6-[5-(4′-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (Example DW), replacing the cyclopropyl proline carboxylic acid with the corresponding thiazolidine derivative.
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]([CH3:8])=[C:5]([C:9]([OH:11])=O)[C:4]=1[CH3:12])=[O:2].[CH:13]1([NH:16][CH2:17][C@@H:18]2[CH2:22][CH2:21][CH2:20][NH:19]2)[CH2:15][CH2:14]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH:13]1([NH:16][CH2:17][C@@H:18]2[CH2:22][CH2:21][CH2:20][N:19]2[C:9]([C:5]2[C:4]([CH3:12])=[C:3]([CH:1]=[O:2])[NH:7][C:6]=2[CH3:8])=[O:11])[CH2:15][CH2:14]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)O
Reactant: C1CN[C@H](CNC2CC2)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCC[C@H]1CNC1CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (270 mg, 1.61 mmol), cyclopropyl-(S)-1-pyrrolidin-2-ylmethyl-amine (220 mg, 1.57 mmol), HOBt (199 mg, 1.47 mmol), EDAC (344 mg, 1.8 mmol) and TEA (0.5 mL) in DMF (7 mL) was stirred at rt for 48 hours. The reaction was concentrated, diluted with sodium bicarbonate and extracted with DCM. The combined DCM was dried, concentrated and filtered through silica gel to give 4-((S)-2-cyclopropylaminomethyl-pyrrolidine-1-carbonyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde.
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[NH2:21][C:22]1[CH:36]=[CH:35][C:25]([CH2:26][P:27](=[O:34])([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30])=[CH:24][CH:23]=1>ClCCl.N1C=CC=CC=1>[CH2:32]([O:31][P:27]([CH2:26][C:25]1[CH:24]=[CH:23][C:22]([NH:21][C:1](=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](=[O:13])[NH:21][C:22]2[CH:36]=[CH:35][C:25]([CH2:26][P:27]([O:31][CH2:32][CH3:33])([O:28][CH2:29][CH3:30])=[O:34])=[CH:24][CH:23]=2)=[CH:36][CH:35]=1)(=[O:34])[O:28][CH2:29][CH3:30])[CH3:33]
Reactant: CCOP(=O)(Cc1ccc(N)cc1)OCC
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOP(=O)(Cc1ccc(NC(=O)c2ccccc2SSc2ccccc2C(=O)Nc2ccc(CP(=O)(OCC)OCC)cc2)cc1)OCC
Temperature: 23 °C
Reaction time: 72 h
Yield: 59.2 %

Procedure:
This compound was prepared according to the general method of Example 77 using 2,2'-dithiobisbenzoyl chloride (2.00 g, 5.83 mmol) in 50 mL of dichloromethane and diethyl 4-aminobenzylphosphonate (2.90 g, 11.6 mmol) in 23 mL of pyridine. The reaction mixture was stirred for 3 days at 23° C. under nitrogen atmosphere. The crude product was recrystallized from acetonitrile-DMF to yield 2.60 g of the title compound, mp 237°-238° C. (dec.).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:27])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH:18]([OH:25])[C:19]4[N:23]([CH3:24])[N:22]=[CH:21][CH:20]=4)=[C:13]([C:15]([OH:17])=O)[N:14]=[C:7]3[C:6]=2[CH:26]=1.[Cl-].[NH4+:29]>>[Br:1][C:2]1[C:3]([F:27])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH:18]([OH:25])[C:19]4[N:23]([CH3:24])[N:22]=[CH:21][CH:20]=4)=[C:13]([C:15]([NH2:29])=[O:17])[N:14]=[C:7]3[C:6]=2[CH:26]=1
Reactant: Cn1nccc1C(O)c1c(C(=O)O)nc2n1CCOc1cc(F)c(Br)cc1-2
Reactant: [NH4+]
Agent: [Cl-]
Product: Cn1nccc1C(O)c1c(C(N)=O)nc2n1CCOc1cc(F)c(Br)cc1-2
Yield: 50 %

Procedure:
10-bromo-9-fluoro-3-(hydroxy(1-methyl-1H-pyrazol-5-yl)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxylic acid was reacted with ammonium chloride and purified by flash chromatography to afford 79 mg (50% yield) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([CH3:15])[C:10]([O:12]CC)=[O:11].[OH-].[K+].O.Cl>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([CH3:15])[C:10]([OH:12])=[O:11]
Reactant: CCOC(=O)C(C)Cc1ccccc1Br
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(Cc1ccccc1Br)C(=O)O
Yield: 64 %

Procedure:
65.5 g of ethyl 3-(2-bromophenyl)-2-methylpropionate (243 mmole) and 20.5 g of potassium hydroxide (364 mmole) were dissolved in 250 ml of ethanol and heated under reflux for 6 hours, and 500 ml of water was added. After 50 ml of concentrated hydrochloric acid was added, and the product was then extracted with toluene, dried and concentrated to give 37.8 g of 3-(2-bromophenyl)-2-methylpropionic acid as a yellow oil (yield, 89%).
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([CH:16]=[CH:17][C:18]([OH:20])=[O:19])[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1>C(O)C.[Pd]>[CH:11]1[C:12]2[C:13]3([CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH2:15][CH:6]([C:5]4[C:14]3=[CH:1][CH:2]=[CH:3][CH:4]=4)[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(O)C=CC12CC(c3ccccc31)c1ccccc12
Agent: [Pd]
Solvent: CCO
Product: O=C(O)CCC12CC(c3ccccc31)c1ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of β-(9,10-dihydro-9,10-methano-9-anthryl)acrylic acid (612 mg) and 5% palladium-charcoal (120 mg) in ethanol was stirred under hydrogen atmosphere at room temperature for 2 hours. The catalyst was removed by filtration, and the solution was evaporated to dryness to give β-(9,10-dihydro-9,10-methano-9-anthryl)propionic acid, M.P. 185° - 189° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][O:7][CH2:8][CH2:9][C:10]([CH2:21][P:22]([O:28]C(C)C)([O:24]C(C)C)=[O:23])=[CH:11][CH:12]([NH:18]C=O)[C:13]([O:15]CC)=[O:14])=[O:5])[CH3:2].C[Si](C)(C)Br.C(O)C>C(Cl)Cl>[NH2:18][CH:12]([CH:11]=[C:10]([CH2:21][P:22]([OH:28])([OH:24])=[O:23])[CH2:9][CH2:8][O:7][CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)COCCC(=CC(NC=O)C(=O)OCC)CP(=O)(OC(C)C)OC(C)C
Agent: C[Si](C)(C)Br
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)COCCC(=CC(N)C(=O)O)CP(=O)(O)O
Reaction time: 24 h

Procedure:
5.5 g (11.8 mmol) of ethyl 6-ethoxycarbonylmethoxy-2-formylamino-4-diisopropylphosphonomethyl-hex-3-enoate are dissolved in 55 ml of CH2Cl2 and 6.1 ml (42.3 mmol) of trimethylbromosilane are then added dropwise at room temperature to this solution. The reaction mixture is allowed to stand for 24 hours at room temperature and, after the dropwise addition of 55 ml of ethanol, allowed to stand for a further 24 hours. The reaction mixture is concentrated by evaporation, the residue is dissolved in 24 ml of ethanol, and a mixture of 55 ml of propylene oxide and 55 of ethanol is added dropwise to this solution. The suspension so obtained is stirred for 1 hour and then filtered with suction. The filter product is dried giving 2-amino-6-ethoxycarbonylmethoxy-4-phosphonomethyl-hex-3-enoic acid with a melting point of 213°-215° C. (decomp.) as a white oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[CH:3]=1.[Li]CCCC.CN([CH:18]=[O:19])C>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[CH:18]=[O:19]
Reactant: Clc1cc(Cl)cc(Cl)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1c(Cl)cc(Cl)cc1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 92.7 %

Procedure:
2,4,6-Trichlorobenzaldehyde was prepared according to the procedure outlined in Synthesis 2008, 279. To a solution of 1,3,5-trichlorobenzene (10.0 g, 55.1 mmol) in THF (200 ml) at −78° C. was slowly added n-BuLi (1.6 M in hexanes, 34.4 ml, 55.1 mmol) over 20 min. The reaction mixture was stirred at −78° C. for 30 min then DMF (7.5 ml, 96.4 mmol) was added dropwise. The reaction was stirred at −78° C. for an additional 1.5 h then quenched with 3 N HCl (200 ml) and warmed to room temperature. The mixture was extracted with EtOAc. The organic layer was washed with sat NaHCO3 and brine then dried over MgSO4 and concentrated to afford 10.7 g (93%) of 2,4,6-trichlorobenzaldehyde as a white solid.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][O:6][C:7]([C:9]1[S:28][C:12]2[C:13]3[CH:14]=[CH:15][CH:16]=[C:17]([NH:20][CH2:21][CH:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)[C:18]=3[S:19][C:11]=2[C:10]=1[O:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:8]>>[CH3:5][O:6][C:7]([C:9]1[S:28][C:12]2[C:13]3[CH:14]=[CH:15][CH:16]=[C:17]([N:20]([C:1](=[O:3])[CH3:2])[CH2:21][CH:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)[C:18]=3[S:19][C:11]=2[C:10]=1[O:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:8]
Reactant: CCOC(=O)COc1c(C(=O)OC)sc2c1sc1c(NCC3CCCCC3)cccc12
Reactant: CC(=O)Cl
Product: CCOC(=O)COc1c(C(=O)OC)sc2c1sc1c(N(CC3CCCCC3)C(C)=O)cccc12
Yield: 58 %

Procedure:
Step B Amide Formation: Addition of acetyl chloride (0.05 mL, 0.65 mmol) to 7-(Cyclohexylmethyl-amino)-1-ethoxycarbonylmethoxy-3,8-dithia-cyclopenta[a]indene-2-carboxylic acid methyl ester (60 mg, 0.13 mmol) was carried out following a procedure similar to that delineated in Step B, Example 27, affording 38 mg of 7-(Acetyl-cyclohexylmethyl-amino)-1-ethoxycarbonylmethoxy-3,8-dithia-cyclopenta[a]indene-2-carboxylic acid methyl ester as a yellow solid. (58% yield).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][N:5]([CH:7]([F:9])[F:8])[N:6]=1.[C:10]1([CH:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17](Cl)=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[F:8][CH:7]([F:9])[N:5]1[N:4]=[N:3][C:2]([NH:1][C:17](=[O:18])[CH:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:6]1
Reactant: Nc1nnn(C(F)F)n1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: O=C(Nc1nnn(C(F)F)n1)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p. 143-145° and MS: (neg. ions): m/e=328.1 (M+−H) was prepared in accordance with the general method of example 1 from 5-amino-2-difluoromethyl-2H-tetrazole and diphenylacetyl chloride.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:18]=[N:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[CH3:19][O:20][C:21]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:22]=1[C:23](O)=[O:24]>>[CH3:19][O:20][C:21]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:22]=1[C:23]([N:7]1[CH2:8][CH:4]2[CH:5]([CH2:1][N:2]([C:9]3[CH:18]=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)[CH2:3]2)[CH2:6]1)=[O:24]
Reactant: c1ccc2nc(N3CC4CNCC4C3)cnc2c1
Reactant: COc1ccc(C(=O)O)c(OC)c1
Product: COc1ccc(C(=O)N2CC3CN(c4cnc5ccccc5n4)CC3C2)c(OC)c1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 35 and 2,4-dimethoxybenzoic acid. MS (ESI): mass calculated for C23H24N4O3, 404.47; m/z found 405.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:12]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[N:11]=[C:10]([C:21]3[CH:22]=[C:23]([CH2:26][C:27]#[N:28])[S:24][CH:25]=3)[C:4]=2[C:5]([O:8]C)=[N:6][CH:7]=1.[I-].[Na+].Cl[Si](C)(C)C.C(=O)([O-])O.[Na+]>C(#N)C>[Cl:1][C:2]1[C:3]2[N:12]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[N:11]=[C:10]([C:21]3[CH:22]=[C:23]([CH2:26][C:27]#[N:28])[S:24][CH:25]=3)[C:4]=2[C:5](=[O:8])[NH:6][CH:7]=1
Reactant: COc1ncc(Cl)c2c1c(-c1csc(CC#N)c1)nn2-c1c(F)cccc1F
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CC#N
Product: N#CCc1cc(-c2nn(-c3c(F)cccc3F)c3c(Cl)c[nH]c(=O)c23)cs1
Temperature: 50 °C
Reaction time: 1 h
Yield: 56.2 %

Procedure:
To a mixture of (4-(7-chloro-1-(2,6-difluorophenyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-thienyl)acetonitrile (70.2 mg) and sodium iodide (50.5 mg) in acetonitrile (3 mL) was added chloro(trimethyl)silane (0.108 mL) at room temperature, and the mixture was stirred at 50° C. for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, methanol/ethyl acetate) to give the title compound (38.1 mg).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([NH2:10])=[N:5][C:6]([CH3:9])=[N:7][CH:8]=1.C(N(CC)CC)C.[CH2:18]([C:20]1[CH2:21][CH2:22][NH:23][CH2:24][CH:25]=1)[CH3:19]>CN(C)C=O>[CH2:18]([C:20]1[CH2:25][CH2:24][N:23]([CH2:2][C:3]2[C:4]([NH2:10])=[N:5][C:6]([CH3:9])=[N:7][CH:8]=2)[CH2:22][CH:21]=1)[CH3:19]
Reactant: Cc1ncc(CCl)c(N)n1
Reactant: CCC1=CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC1=CCN(Cc2cnc(C)nc2N)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.7 %

Procedure:
A suspension of 0.95 g (0.0050 mol) of 5-chloromethyl-2-methyl-pyrimidin-4-ylamine in 13 ml of dimethylformamide was treated with 3.5 ml (0.025 mol) of triethylamine and 1.16 g (0.010) of 4-ethyl-1,2,3,6-tetrahydropyridine and the mixture was stirred at room temperature under argon for 18 hours. The solvent was distilled off in a high vacuum. The residue was partitioned between dichloromethane/water, extracted and dried over MgSO4. After removing the solvent the residue was chromatographed on silica gel with ethyl acetate as the eluent. 0.60 g (52%) of 5-(4-ethyl-3,6-dihydro-2H-pyridin-1-ylmethyl)-2-methyl-pyrimidin-4-ylamine were obtained as a beige solid; m.p. 75°-76°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH2:7][C:8]([OH:10])=O)[CH:6]=1.C(Cl)(C(Cl)=O)=O.[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:32]3[CH2:31][CH2:30][CH2:29][NH:28][C:27]=3[CH:26]=[N:25]2)=[CH:20][CH:19]=1.CCN(CC)CC>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH2:7][C:8]([N:28]2[CH2:29][CH2:30][CH2:31][C:32]3[N:24]([C:21]4[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=4)[N:25]=[CH:26][C:27]2=3)=[O:10])[CH:6]=1
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Reactant: O=C(O)Cn1cc(Cl)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Cn1cc(Cl)cn1)N1CCCc2c1cnn2-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.3 %

Procedure:
A mixture of 2-[(4-chloro-pyrazol-1-yl)]acetic acid (0.050 g, 0.31 mmol), (COCl)2 (0.060 mL, 0.70 mmol) and DMF (1 drop) in CH2Cl2 (1 mL) was stirred for 30 min at rt. It was then evaporated to dryness on a high vacuum pump. The obtained oil was added to a mixture containing 1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine (0.020 g, 0.092 mmol) and NEt3 (0.070 mL, 0.50 mmol) in CH2Cl2 (1 mL). The resulting mixture was then stirred at rt for 30 min. It was then quenched with water and partitioned between EtOAc (50 mL) and sat. NaHCO3 (30 mL). The organic layer was separated, dried over Na2SO4, concentrated in vacuo, and purified by reverse phase HPLC to afford the desired product (0.012 g, 36%). 1H NMR (400 MHz, CDCl3) δ 8.41 (s, 1H), 7.60 (s, 1H), 7.51 (s, 1H), 7.44 (dd, J=8.8, 4.6 Hz, 2H), 7.17 (dd, J=9.2, 8.8 Hz, 2H), 5.16 (s, 2H), 3.82 (m, 2H), 2.85 (t, J=6.2 Hz, 2H), 2.09 (m, 2H); MS: (ES) m/z calculated for C17H15ClFN5O [M+H]+ 360.1, found 360.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[F:21])[C:11](O)=[O:12])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCCC(F)(F)C(O)CC[C@@H]1[C@@H](CCCCCCC(O)=O)C(=O)C[C@H]1O.C1CC[CH:52]([NH:55]C2CCCCC2)CC1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CN.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[N:8]([C@@H:10]([C:11](=[O:12])[NH:55][CH3:52])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[F:21])[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccccc1F)C(=O)O
Reactant: C1CCC(NC2CCCCC2)CC1
Agent: CCCCC(F)(F)C(O)CC[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CNC(=O)[C@@H](Cc1ccccc1F)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(2R)-2-(N-tert-Butoxycarbonyl-N-methylamino)-3-(2-fluorophenyl)propionic acid as a dicyclohexylammonium salt (5.57 9; 18.73 mmol) was dissolved in methylene chloride (30 mL) and washed with an aqueous solution of sodium hydrogen sulfate (10%; 30 mL). The organic phase was dried (magnesium sulfate) and filtered. 1-Hydroxybenzotriazole hydrate (2.53 g; 18.73 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (3.75 g; 19.6 mmol) were added to the filtrate and the mixture was stirred for 15 min at room temperature. Methylamine (40% in methanol; 0.53 g; 17.0 mmol) and diisopropylethylamine (3.2 mL; 18.7 mmol) were added and the reaction mixture was stirred for 12 hours at room temperature. The reaction mixture was washed with an aqueous solution of sodium hydrogen carbonate (50 mL) and an aqueous solution of sodium hydrogen sulfate (10%; 50 mL) and dried (magnesium sulfate). The solvent was removed in vacuo and the residue was chromatographed on silica (3.5×40 cm) using ethyl acetate/heptane (2:1) as eluent to afford 2.4 g of N-((1R)-2-(2-Fluorophenyl)-1-(methylcarbamoyl)ethyl)-N-methylcarbamic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:9])=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[C:10]1([C:20](Cl)=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1>N1C=CC=CC=1>[Cl:1][C:2]1[C:3]([O:9][C:20]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[O:21])=[CH:4][C:5]([O:8][C:20]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[O:21])=[N:6][CH:7]=1
Reactant: O=c1cc(O)c(Cl)c[nH]1
Reactant: O=C(Cl)c1cccc2ccccc12
Solvent: c1ccncc1
Product: O=C(Oc1cc(OC(=O)c2cccc3ccccc23)c(Cl)cn1)c1cccc2ccccc12
Yield: 81.9 %

Procedure:
The general procedure of Example 45 was followed using 2.00 g of 5-chloro-4-hydroxy-2-pyridone, 3.93 g of α-naphthoyl chloride and 100 ml of pyridine, thereby producing 3.83 g of the title compound in a yield of 61%.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[Cl:20])[NH2:16]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:16][C:15]1[CH:17]=[CH:18][C:19]([Cl:20])=[C:13]([Cl:12])[CH:14]=1)=[O:9]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1cc(Br)ccc1O
Product: O=C(Nc1ccc(Cl)c(Cl)c1)c1cc(Br)ccc1O
Yield: 58.2 %

Procedure:
Using 5-bromosalicylic acid and 3,4-dichloroaniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[C:5]([O:15][CH3:16])[N:4]=1.[F:17][C:18]([F:28])([C:24]([F:27])([F:26])[F:25])/[CH:19]=[CH:20]/[C:21](O)=[O:22].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:10][CH2:11][N:12]([C:21](=[O:22])/[CH:20]=[CH:19]/[C:18]([F:17])([F:28])[C:24]([F:25])([F:26])[F:27])[CH2:13][CH2:14]2)[CH:6]=[C:5]([O:15][CH3:16])[N:4]=1
Reactant: O=C(O)/C=C/C(F)(F)C(F)(F)F
Reactant: COc1cc(N2CCNCC2)cc(OC)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(N2CCN(C(=O)/C=C/C(F)(F)C(F)(F)F)CC2)cc(OC)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.7 %

Procedure:
1-(2,6-Dimethoxy-4-pyridyl)piperazine (30 mg, 0.13 mmol) was dissolved in anhydrous dichloromethane (2 ml) together with (E)-4,4,5,5,5-pentafluoropent-2-enoic acid (35 mg, 0.18 mmol), triethylamine (31 mg, 44 μl, 0.32 mmol), HBTU (74 mg, 0.15 mmol) and stirred at room temperature for two hours. The mixture was evaporated to dryness under reduced pressure and the residue was purified by preparative HPLC (gradient of water containing 0.1% NH3 and acetonitrile) to yield 9 mg of a solid (0.023 mmol, 15%).
Reaction SMILES: C(P(CCCC)CCCC)CCC.[CH3:14][O:15][C:16](=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=1.[CH:26]([C:29]1[N:30]=[C:31]([C:38]2[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=2)[O:32][C:33]=1[CH:34]([CH3:37])[CH2:35]O)([CH3:28])[CH3:27]>C1(C)C=CC=CC=1.CCOCC>[CH3:14][O:15][C:16](=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:37][CH:34]([C:33]2[O:32][C:31]([C:38]3[CH:43]=[CH:42][C:41]([C:44]([F:45])([F:46])[F:47])=[CH:40][CH:39]=3)=[N:30][C:29]=2[CH:26]([CH3:28])[CH3:27])[CH3:35])[CH:19]=1
Reactant: COC(=O)Cc1cccc(O)c1
Reactant: CC(C)c1nc(-c2ccc(C(F)(F)F)cc2)oc1C(C)CO
Agent: CCCCP(CCCC)CCCC
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COC(=O)Cc1cccc(OCC(C)c2oc(-c3ccc(C(F)(F)F)cc3)nc2C(C)C)c1

Procedure:
Azodicarboxylic dipiperidide (0.31 g, 1.23 mmol) is stirred in 5 mL toluene at −30 to −20 deg C. Tri-n-butyl phosphine (0.31 mL, 1.23 mmol) is added dropwise and the mixture is stirred at −30 to −20 deg C. 10–15 min. An intimate mixture of (3-hydroxy-phenyl)-acetic acid methyl ester (0.13 g, 0.77 mmol) and 2-[4-isopropyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-propan-1-ol (0.20 g, 0.701 mmol) in toluene (5 mL) is added dropwise and the resulting mixture is stirred 18 hr at room temperature. The thick suspension is diluted with 25 mL ether and cooled on ice/water for 30 min. The mixture is filtered, concentrated, and purified via silica gel chromatography eluting with 98:2 hexanes:acetone to afford the title compound as a colorless thick oil, 0.10 g, 31%. MS M++1 462. The structure is confirmed by 1H NMR spectroscopy.
Reaction SMILES: [NH:1]1[C:10]2[N:9]=[C:8]3[CH2:11][CH:12]([CH2:15][CH2:16][C:17]([OH:19])=O)[CH2:13][CH2:14][C:7]3=[CH:6][C:5]=2[CH2:4][CH2:3][CH2:2]1.[CH2:20]([O:22][C:23](=[O:36])[CH2:24][C@H:25]([NH2:35])[C:26]1[CH:34]=[CH:33][C:29]2[CH2:30][CH2:31][O:32][C:28]=2[CH:27]=1)[CH3:21].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C>[CH2:20]([O:22][C:23](=[O:36])[CH2:24][C@@H:25]([C:26]1[CH:34]=[CH:33][C:29]2[CH2:30][CH2:31][O:32][C:28]=2[CH:27]=1)[NH:35][C:17](=[O:19])[CH2:16][CH2:15][CH:12]1[CH2:11][C:8]2=[N:9][C:10]3[NH:1][CH2:2][CH2:3][CH2:4][C:5]=3[CH:6]=[C:7]2[CH2:14][CH2:13]1)[CH3:21]
Reactant: CCOC(=O)C[C@H](N)c1ccc2c(c1)OCC2
Reactant: O=C(O)CCC1CCc2cc3c(nc2C1)NCCC3
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@H](NC(=O)CCC1CCc2cc3c(nc2C1)NCCC3)c1ccc2c(c1)OCC2

Procedure:
A solution of 14-4 (0.110 g, 0.39 mmol), β-aminoester 6-6 (0.106 g 0.39 mmol), EDC (0.075 g, 0.39 mmol), HOBT (0.053 g, 0.39 mmol) and N-methylmorpholine (0.164 mL, 1.17 mmol) in degassed DMF (5 mL) was stirred at room temperature for 12 h. The solution was concentrated. The residue was purified by flash chromatography to give 14-5.