Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.Br[C:13]1[CH:14]=[C:15]([CH:19]2[CH2:21][CH:20]2[C:22]([O:24][CH3:25])=[O:23])[CH:16]=[N:17][CH:18]=1.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:13]1[CH:14]=[C:15]([CH:19]2[CH2:21][CH:20]2[C:22]([O:24][CH3:25])=[O:23])[CH:16]=[N:17][CH:18]=1
Reactant: OB(O)c1cccc(Cl)c1Cl
Reactant: COC(=O)C1CC1c1cncc(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)C1CC1c1cncc(-c2cccc(Cl)c2Cl)c1
Reaction time: 1 h
Yield: 74.6 %

Procedure:
A mixture of 2,3-dichlorophenylboronic acid (279 mg, 1.464 mmol), methyl 2-(5-bromopyridin-3-yl)cyclopropanecarboxylate (357 mg, 1.394 mmol), PdCl2(dppf).CH2Cl2 adduct (114 mg, 0.139 mmol) and Na2CO3 (2 M in water, 1.743 ml, 3.49 mmol) in DMF (7 ml) was heated at 100° C. under nitrogen atmosphere. After 1 h, the solvent was removed under vacuo. The residue was purified by flash column (EtOAc/Heptane=0-25%, v/v) to give methyl 2-(5-(2,3-dichlorophenyl)pyridin-3-yl)cyclopropanecarboxylate (335 mg, 1.040 mmol, 74% yield). ESI-MS m/z: 322[M+1]+; 1H NMR (CDCl3, 400 MHz) 1.38-1.41 (m, 1H), 1.68-1.73 (m, 1H), 1.97-2.01 (m, 1H), 2.58-2.63 (m, 1H), 3.75 (s, 3H), 7.21 (dd, J=7.6, 1.2 Hz, 1H), 7.30 (t, J=7.6 Hz, 1H), 7.43 (bs, 1H), 7.53 (dd, J=7.6, 1.2 Hz, 1H), 8.48 (d, J=1.6 Hz, 1H), 8.50 (d, J=1.6 Hz, 1H),
Reaction SMILES: C([O:8][CH2:9][CH2:10][N:11]1[CH2:17][CH2:16][CH2:15][C@H:14]([N:18]([CH2:25][C:26]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=2)[C:19]2[N:20]=[N:21][N:22]([CH3:24])[N:23]=2)[C:13]2[CH:40]=[C:41]([CH3:48])[C:42]([C:44]([F:47])([F:46])[F:45])=[CH:43][C:12]1=2)C1C=CC=CC=1>[Pd].C(O)C>[F:34][C:32]([F:33])([F:35])[C:30]1[CH:31]=[C:26]([CH:27]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:29]=1)[CH2:25][N:18]([C:19]1[N:20]=[N:21][N:22]([CH3:24])[N:23]=1)[C@H:14]1[CH2:15][CH2:16][CH2:17][N:11]([CH2:10][CH2:9][OH:8])[C:12]2[CH:43]=[C:42]([C:44]([F:45])([F:46])[F:47])[C:41]([CH3:48])=[CH:40][C:13]1=2
Reactant: Cc1cc2c(cc1C(F)(F)F)N(CCOCc1ccccc1)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc2c(cc1C(F)(F)F)N(CCO)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Yield: 95.9 %

Procedure:
Stir a mixture of (S)-[1-(2-Benzyloxy-ethyl)-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl]-(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amine (0.420 g, 0.612 mmol) and 10% palladium on charcoal (0.210 g) in ethanol (50 mL) under a hydrogen balloon at room temperature for 3 h. Filter the mixture through Celite® and remove the solvents under reduced pressure to provide the title compound as a colorless foam (0.350 g, 97%). MS (ES+): 597 (M+H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12](=[O:29])[CH2:13][CH2:14][CH:15]([NH:21]C(=O)OC(C)(C)C)[C:16]3[CH:20]=[CH:19][S:18][CH:17]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[ClH:30]>C(Cl)Cl>[ClH:30].[ClH:30].[NH2:21][CH:15]([C:16]1[CH:20]=[CH:19][S:18][CH:17]=1)[CH2:14][CH2:13][C:12]([NH:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[CH:1]=[N:2][CH:3]=[CH:4]2)=[O:29]
Reactant: CC(C)(C)OC(=O)NC(CCC(=O)Nc1ccc2cnccc2c1)c1ccsc1
Agent: Cl
Solvent: ClCCl
Product: NC(CCC(=O)Nc1ccc2cnccc2c1)c1ccsc1
Reaction time: 8 h

Procedure:
To tert-butyl 4-(isoquinolin-6-ylamino)-4-oxo-1-(thiophen-3-yl)butylcarbamate (E73E) in CH2Cl2 is added HCl (4N in dioxane), and the solution is stirred for 8 hours. The solvents are evaporated to give 4-amino-N-(isoquinolin-6-yl)-4-(thiophen-3-yl)butanamide dihydrochloride (E73).
Reaction SMILES: N.C(=O)(OC)[O:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([F:13])=[CH:6][C:5]=1[CH3:14]>CO>[F:13][C:7]1[C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]([OH:3])=[C:5]([CH3:14])[CH:6]=1
Reactant: COC(=O)Oc1cc([N+](=O)[O-])c(F)cc1C
Agent: N
Solvent: CO
Product: Cc1cc(F)c([N+](=O)[O-])cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Concentrated aqueous ammonia solution (30 ml) was added to a solution of (4-fluoro-2-methyl-5-nitrophenyl) methyl carbonate (6 g, 26 mmol), (prepared as described in EP 0307777 A2), in methanol (150 ml) and the mixture stirred for 1 hour at ambient temperature. Most of the organic solvent was removed by evaporation and the residue was partitioned between water and ethyl acetate. The organic layer was separated, dried (MgSO4) and the volatiles removed by evaporation to give 4-fluoro-2-methyl-5-nitrophenol (4.45 g, 100%).
Reaction SMILES: [OH:1][CH2:2][N:3]1[C:7](=[O:8])[CH2:6][N:5]([CH2:9][C:10]#[CH:11])[C:4]1=[O:12].[CH:13]([O:16][N:17]=[CH:18]/[C:19](/[CH3:29])=[CH:20]/[C@@H:21]1[C@@H:23]([C:24](O)=[O:25])[C:22]1([CH3:28])[CH3:27])([CH3:15])[CH3:14].C(Cl)(Cl)Cl.Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.[Cl-].[Na+].O>[CH:13]([O:16][N:17]=[CH:18]/[C:19](/[CH3:29])=[CH:20]/[C@@H:21]1[C@@H:23]([C:24]([O:1][CH2:2][N:3]2[C:7](=[O:8])[CH2:6][N:5]([CH2:9][C:10]#[CH:11])[C:4]2=[O:12])=[O:25])[C:22]1([CH3:27])[CH3:28])([CH3:15])[CH3:14]
Reactant: C#CCN1CC(=O)N(CO)C1=O
Reactant: C/C(C=NOC(C)C)=C\[C@@H]1[C@@H](C(=O)O)C1(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: C#CCN1CC(=O)N(COC(=O)[C@@H]2[C@@H](/C=C(\C)C=NOC(C)C)C2(C)C)C1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 50.8 %

Procedure:
Under nitrogen atmosphere, to a mixture of 0.17 g of 3-hydroxymethyl-1-(2-propynyl)imidazolidine-2,4-dione, 0.25 g of (1R)-trans-3-[(E)-3-isopropoxyimino-2-methyl-1-propenyl]-2,2-dimethylcyclopropanecarboxylic acid, catalytic amount of 4-dimethylaminopyridine and 5 ml of anhydrous chloroform was added 0.23 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and the mixture was stirred at room temperature for 5 hours. Thereafter, saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, then, filtrated, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.20 g of 2,5-dioxo-3-(2-propynyl)imidazolidin-1-ylmethyl (1R)-trans-3-[(E)-3-isopropoxyimino-2-methyl-1-propenyl]-2,2-dimethylcyclopropanecarboxylate (hereinafter, referred to as the present compound (5)) represented by the formula (5):
Reaction SMILES: [F:1][C:2]1[C:3]([O:26][CH3:27])=[CH:4][C:5]([CH3:25])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10](OS(C(F)(F)F)(=O)=O)[C:9]=2[N+:22]([O-:24])=[O:23])[CH:7]=1.[CH:28]1([C@H:31]([NH2:34])[CH2:32][CH3:33])[CH2:30][CH2:29]1>>[CH:28]1([C@H:31]([NH:34][C:10]2[C:9]([N+:22]([O-:24])=[O:23])=[C:8]([C:6]3[CH:7]=[C:2]([F:1])[C:3]([O:26][CH3:27])=[CH:4][C:5]=3[CH3:25])[CH:13]=[CH:12][N:11]=2)[CH2:32][CH3:33])[CH2:30][CH2:29]1
Reactant: COc1cc(C)c(-c2ccnc(OS(=O)(=O)C(F)(F)F)c2[N+](=O)[O-])cc1F
Reactant: CC[C@@H](N)C1CC1
Product: CC[C@@H](Nc1nccc(-c2cc(F)c(OC)cc2C)c1[N+](=O)[O-])C1CC1
Yield: 38.8 %

Procedure:
Trifluoro-methanesulfonic acid 4-(5-fluoro-4-methoxy-2-methyl-phenyl)-3-nitro-pyridin-2-yl ester (0.5 g, 1.22 mmol), prepared substantially as described in Part C of Example 19a, and (R)-1-cyclopropyl-propylamine (0.33 g, 2.44 mmol) were treated substantially as described in Part C of Example 19a to produce 0.17 g (43%) of crude (R)-(1-Cyclopropyl-propyl)-[4-(5-fluoro-4-methoxy-2-methyl-phenyl)-3-nitro-pyridin-2-yl]-amine.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:8][C:9]=1[NH:10][S:11]([C:14]1[CH:19]=[C:18]([CH3:20])[C:17]([Cl:21])=[CH:16][C:15]=1[CH3:22])(=[O:13])=[O:12])=[O:4].[I:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:8][C:9]=1[N:10]([S:11]([C:14]1[CH:19]=[C:18]([CH3:20])[C:17]([Cl:21])=[CH:16][C:15]=1[CH3:22])(=[O:13])=[O:12])[CH2:33][C:32]1[CH:35]=[CH:36][CH:37]=[C:30]([I:29])[CH:31]=1)=[O:4]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1NS(=O)(=O)c1cc(C)c(Cl)cc1C
Reactant: BrCc1cccc(I)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-c2ccccc2)cc1N(Cc1cccc(I)c1)S(=O)(=O)c1cc(C)c(Cl)cc1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 87.1 %

Procedure:
To a solution of 3-(4-Chloro-2,5-dimethyl-benzenesulfonylamino)-5-phenyl-thiophene-2-carboxylic acid methyl ester (100 mg, 0.229 mmol) in anhydrous DMF (6 mL), 3-iodobenzyl bromide (82 mg, 0.276 mmol) and cesium carbonate (88 mg, 0.276 mmol) were added and the reaction mixture was stirred at room temperature under a N2 atmosphere for 12 h. The reaction mixture was partitioned between water and ether. The ether layer was separated, dried (Na2SO4), concentrated. The residue was purified by silica gel column chromatography using ethyl acetate and hexane (1:3) as eluent to obtain 3-[(4-Chloro-2,5-dimethyl-benzenesulfonyl)-(3-iodo-benzyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (130 mg, 87%) as a syrup.
Reaction SMILES: [S:1]1[C:5]([C:6]23[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][CH:10]2[CH2:9][O:8][NH:7]3)=[CH:4][CH:3]=[N:2]1.C(O)(=O)C>C(OCC)(=O)C.[Zn]>[NH2:7][C:6]1([C:5]2[S:1][N:2]=[CH:3][CH:4]=2)[CH:10]([CH2:9][OH:8])[CH2:11][N:12]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CC2CONC2(c2ccns2)C1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(CO)C(N)(c2ccns2)C1
Temperature: 40 °C
Reaction time: 8 h
Yield: 64.8 %

Procedure:
tert-Butyl 6a-isothiazol-5-yl-3,3a,4,6-tetrahydro-1H-pyrrolo[3,4-c]isoxazole-5-carboxylate (400.0 g, 1.35 mol), acetic acid (4.00 L) and zinc (439.78 g, 6.73 mol) are added together. The reaction mixture is heated to 40° C. and stirred at 40° C. for 8 hours and then cooled to room temperature. The reaction mixture is diluted with ethyl acetate (4 L), filtered through diatomaceous earth, washed with ethyl acetate, and evaporated under reduced pressure. The yellow oily residue is dissolved in toluene (2 L) and concentrated. The dissolution process with toluene is repeated 3 times. The foamy oil residue is suspended in 10% w/w aq. citric acid (3.2 L), MTBE (4 L) is added and the mixture is stirred for 15 minutes at room temperature. The biphasic mixture is filtered through diatomaceous earth (slow filtration) to remove the gel-like solids. The layers are separated and the aqueous layer is washed with MTBE (4×600 mL). The aqueous layer (pH 4.0) is added to ethyl acetate (3.0 L), and the mixture is neutralized with NaOH 50% w/w to adjust the pH=9.0-9.5 and the mixture is vigorously stirred. The organic layer is separated and the aqueous layer is extracted with ethyl acetate (3×1 L). The organic layers are combined, dried over sodium sulfate, filtered, and evaporated under reduced pressure to give the title compound as a white solid, (262.00 g, 65.1%). ES/MS (m/e): 300 (M+H).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH2:25])=[O:24])[C:7]2[C:16]3[N:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].C1C=C(Cl)C=C(C(OO)=O)C=1.[OH-].[NH4+:38].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>>[NH2:38][C:9]1[C:8]2[N:17]=[C:5]([CH2:4][O:3][CH2:1][CH3:2])[N:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH2:25])=[O:24])[C:7]=2[C:16]2[N:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CCOCc1nc2cnc3cccnc3c2n1CCCCCC(N)=O
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Product: CCOCc1nc2c(N)nc3cccnc3c2n1CCCCCC(N)=O
Reaction time: 1 h

Procedure:
A modification of the methods described in Part F of Example 53 was used to treat 6-[2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)hexanamide (1.70 g, 5.0 mmol) with mCPBA (3.34 g of 70-77% purity) followed by ammonium hydroxide (5.5 mL), and p-toluenesulfonyl chloride (0.95 g). After the amination reaction was stirred for one hour, a precipitate was present and was isolated by filtration and washed with chloroform and water. The precipitate was triturated with 2-propanol (7.5 mL/g at 97° C.), and the mixture was filtered hot. The isolated solid was dried overnight under vacuum and then in a vacuum oven for six days at 65° C. The product was then sonicated in 1 M aqueous sodium hydroxide for 15 minutes, isolated by filtration, washed with deionized water, and dried in a vacuum oven for three days at 90° C. to provide 0.32 g of 6-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]hexanamide as a yellow solid, mp 215-217° C.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:8]=[C:9]([O:13][CH2:14][O:15][CH3:16])[CH:10]=[CH:11][CH:12]=2)[O:6][CH2:5][CH2:4][O:3]1.C([Li])(C)(C)C.[C:22](=[O:24])=[O:23]>CCOCC>[CH3:1][C:2]1([C:7]2[CH:12]=[CH:11][C:10]([C:22]([OH:24])=[O:23])=[C:9]([O:13][CH2:14][O:15][CH3:16])[CH:8]=2)[O:6][CH2:5][CH2:4][O:3]1
Reactant: O=C=O
Reactant: COCOc1cccc(C2(C)OCCO2)c1
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: COCOc1cc(C2(C)OCCO2)ccc1C(=O)O
Temperature: 10 °C

Procedure:
To a solution of methoxymethyl 3-(2-methyl-1,3-dioxolan-2-yl)phenyl ether (8.16 g, 36.4 mmol) in ether (200 mL) was added dropwise tert-butyl lithium (1.7 M solution, 26.8 mL, 1.25 equivalents) at −5 to −10° C. The reaction mixture was stirred 15 min before carbon dioxide gas was bubbled in for 5 min. The reaction mixture was allowed to warm slowly in the cold bath to about 10° C., then it was extracted with water. The aqueous layer was acidified with 5 N HCl and extracted with EtOAc. The organic phase was dried (MgSO4) and evaporated to afford a crude product which was triturated with hexane to afford the benzoic acid (4.54 g).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH2:11][CH2:10][C@H:9]2[NH2:15])=[O:5].C(N(CC)CC)C.[Cl:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>ClCCl.C([O-])(O)=O.[Na+]>[CH3:2][O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH2:11][CH2:10][C@H:9]2[NH:15][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=1[Cl:23])=[O:5]
Reactant: COC(=O)c1ccc2c(c1)[C@H](N)CC2
Reactant: O=C(Cl)c1ccccc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)[C@H](NC(=O)c1ccccc1Cl)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
Method 1 (3R)-3-Amino-2,3-dihydro-1H-indene-5-carboxylic acid methyl ester hydrochloride (A-01) (8.784 mmol, 1 eq) was dissolved in dichloromethane, and triethylamine (3 eq) and 2-chlorobenzoic acid chloride (1.2 eq) were added at 0° C. under a protecting gas atmosphere. The reaction mixture was stirred for 1 h at RT. Then the reaction mixture was diluted with sat. NaHCO3 solution and the aqueous phase was extracted with dichloromethane (3×50 ml). The organic phase was dried over sodium sulfate and concentrated to yield (3R)-3-[(2-chloro-benzoyl)amino]-2,3-dihydro-1H-indene-5-carboxylic acid methyl ester (B-01). Yield: 98%
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH:7]=[CH2:8].[CH:9]([C:12]([CH3:22])([N:15]1[C:19](=[O:20])[CH:18]=[CH:17][C:16]1=[O:21])[C:13]#[N:14])([CH3:11])[CH3:10]>C(Cl)(Cl)Cl>[CH:9]([C:12]([CH3:22])([N:15]1[C:19](=[O:20])[CH:18]2[CH2:8][CH2:7][C:3]3[N:2]([CH3:1])[CH:6]=[CH:5][C:4]=3[CH:17]2[C:16]1=[O:21])[C:13]#[N:14])([CH3:11])[CH3:10]
Reactant: C=Cc1cccn1C
Reactant: CC(C)C(C)(C#N)N1C(=O)C=CC1=O
Solvent: ClC(Cl)Cl
Product: CC(C)C(C)(C#N)N1C(=O)C2CCc3c(ccn3C)C2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 589.2 %

Procedure:
A mixture of 1-methyl-2-vinylpyrrole (3.90 g, 36.0 mmol), α-isopropyl-α-methyl-2,5-dioxo-3-pyrroline-1-acetonitrile (7.00 g, 36.0 mmol) and chloroform is stirred overnight at room temperature and concentrated in vacuo. The resultant residue is flash chromatographed (silica gel, 50% ether:hexanes eluent) to afford the title product as a clear yellow glass (63.5 g, 58.8%).
Reaction SMILES: [BH4-].[Li+].O1CCCC1.Cl.[F:9][C:10]1[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=1[C@H:17]1[CH2:22][CH2:21][C@H:20]([CH2:23][CH2:24][CH2:25][CH2:26][C:27](OCC)=[O:28])[CH2:19][CH2:18]1>>[F:9][C:10]1[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=1[C@H:17]1[CH2:18][CH2:19][C@H:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28])[CH2:21][CH2:22]1
Reactant: CCOC(=O)CCCC[C@H]1CC[C@H](c2cccc(F)c2F)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCCCC[C@H]1CC[C@H](c2cccc(F)c2F)CC1

Procedure:
First, 1.3 g of lithium borohydride and 45 ml of dry tetrahydrofuran were placed in a 200 ml flask. Then, 30 ml of a tetrahydrofuran solution in which 7.7 g of 2,3-difluoro-1-[trans-4-(4-ethoxycarbonylbutyl)cyclohexyl]benzene was dissolved was added dropwise to the mixture, and the resultant mixture was stirred under reflux for 1 hour. Cold diluted hydrochloric acid was added to the reaction mixture, and an organic layer was extracted with ether. The ether layer was washed with water and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away. The residue was purified by silica gel column chromatography (eluent: toluene/ethyl acetate=3/1) and recrystallized from hexane to obtain 4.77 g of 2,3-difluoro-1-[trans-4-(5-hydroxypentyl)cyclohexyl]benzene (Y: 71.2%). The compound thus obtained had a purity of 98.9% by GC and 98.5% by HPLC.
Reaction SMILES: [C:1]1([C:7]2[C:11]([CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])=[CH:10][N:9]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([NH:28][CH2:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=4)=[O:27])[CH:21]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].C(O)C.Cl>O1CCCC1>[C:1]1([C:7]2[C:11]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:10][N:9]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([NH:28][CH2:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=4)=[O:27])[CH:21]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCc1cn(Cc2cccc(C(=O)NCCc3ccccn3)c2)nc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)CCc1cn(Cc2cccc(C(=O)NCCc3ccccn3)c2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
A mixture of ethyl 3-[3-phenyl-1-[3-[2-(2-pyridyl)ethylaminocarbonyl]benzyl]-1H-pyrazol-4-yl]propionate (450 mg), 1 N aqueous sodium hydroxide solution (2 ml), ethanol (2 ml), and tetrahydrofuran (2 ml) was stirred at room temperature for one hour. After 1 N hydrochloric acid (2 ml) was added to the reaction mixture, the reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The obtained crystals were collected by filtration, and 3-[3-phenyl-1-[3-[2-(2-pyridyl)ethylaminocarbonyl]benzyl]-1H-pyrazol-4-yl]propionic acid (400 mg, yield: 95%) was obtained. This was recrystallized from tetrahydrofuran-hexane. Melting point: 166–167° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[C:35](Cl)[N:34]=[N:33][C:32]=2[CH2:38][CH2:39][CH3:40])=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:35]2[N:34]=[N:33][C:32]([CH2:38][CH2:39][CH3:40])=[C:31]([C:28]3[CH:27]=[CH:26][C:25]([O:24][CH2:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:30][CH:29]=3)[CH:36]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CCCc1nnc(Cl)cc1-c1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCc1nnc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OCc2ccccc2)cc1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.49 mmol, 0.1 g) in THF (1.5 mL) at room temperature was added NaH (50 mg) followed 4-(4-benzyloxy-phenyl)-6-chloro-3-propyl-pyridazine (0.44 mmol, 0.15 g). The mixture was stirred at 70° C. for 4 h. The reaction mixture was cooled to room temperature, quenched with methanol by drop-wise addition, and removed the volatiles under reduced pressure. The residue was purified by flash silica gel column chromatography by eluting with 20% ethyl acetate to provide 4-[5-(4-benzyloxy-phenyl)-6-propyl-pyridazin-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [N:1]([C@@H:4]1[C@H:8]([OH:9])[C@@H:7]([CH2:10][OH:11])[O:6][C@H:5]1[N:12]1[CH:19]=[CH:18][C:16](=[O:17])[NH:15][C:13]1=[O:14])=[N+:2]=[N-:3].[I:20]Cl.CCOCC>CO>[I:20][C:18]1[C:16](=[O:17])[NH:15][C:13](=[O:14])[N:12]([CH:19]=1)[C@@H:5]1[O:6][C@H:7]([CH2:10][OH:11])[C@@H:8]([OH:9])[C@H:4]1[N:1]=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=N[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(=O)[nH]c1=O
Reactant: ClI
Solvent: CO
Solvent: CCOCC
Product: [N-]=[N+]=N[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cc(I)c(=O)[nH]c1=O
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 76.5 %

Procedure:
To a solution of 2'-azido,2'-deoxyuridine (2.5 g, 9.3 mmoles) in methanol (20 ml) is added ICl (3.3 g, 20.5 mmoles, 2.2 eq.). The mixture is heated at 50° C. for 30 min. After cooling to room temperature, an equal volume of ether is added and the white precipitate is filtered off. The precipitate is stirred in methanolic ammonia (20 ml) at room temperature for 15 min, and then evaporated to dryness to yield 2.81 g (76%) of 5-iodo,2'-azido,2'-deoxyuridine. 1H NMR (300 MHz, methanol -d4) δ 8.58 (s, 1H, H6), 5.88 (d, 1H, H1', JH1'H2' =3.5 Hz), 4.46 (t, 1H, H3', J=5.8 Hz), 4.11 (dd, 1H, H2', JH1',H2' =3.9 Hz, J H2',H3' =5.3 Hz), 4.01 (m, 1H, H4'), 3.91 (dd, 1H, H5'AJgem =12.3 Hz, JH5',H4' =2.4 Hz) 3.76 (dd, 1H, H5'B, Jgem =12.3 Hz, JH5',H4' =2.4 Hz). 13C NMR (75 MHz, methanol-d4) δ 163.03, 152.17, 146.50, 88.88, 86.18, 71.21, 67/67, 61.00, 48.15. FAB mass spectrum, (M+H) m/z 396.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:24]([NH:26][C:27](=[O:45])[C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[C:31]([CH3:43])=[C:30]([F:44])[CH:29]=1)[CH3:25].C(=O)([O-])O.[Na+].O>C(O)(C)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)Cl>[CH2:24]([NH:26][C:27]([C:28]1[CH:29]=[C:30]([F:44])[C:31]([CH3:43])=[C:32]([C:2]2[CH:10]=[C:9]3[C:5]([C:6]([N:11]4[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:13][CH2:12]4)=[N:7][NH:8]3)=[CH:4][CH:3]=2)[CH:33]=1)=[O:45])[CH3:25]
Reactant: CCNC(=O)c1cc(F)c(C)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2n[nH]c3cc(Br)ccc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Solvent: O
Product: CCNC(=O)c1cc(F)c(C)c(-c2ccc3c(N4CCN(C(=O)OC(C)(C)C)CC4)n[nH]c3c2)c1
Temperature: 150 °C
Yield: 45.2 %

Procedure:
A mixture of 1,1-dimethylethyl 4-(6-bromo-1H-indazol-3-yl)-1-piperazinecarboxylate (Intermediate 6, 28 mg), N-ethyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (Intermediate 5, 27 mg), tetrakis(triphenylphosphine)palladium (2 mg) and aqueous sodium hydrogen carbonate (0.125 ml) in isopropanol (0.5 ml) was heated at 150° C. in a microwave oven for 15 min. Water and DCM were added and the organic phase was separated using a hydrophobic filter tube. The solvent was evaporated and the residue was purified by reverse phase preparative HPLC to give the title compound (16 mg).