Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH:9]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:21][C:22]([CH3:24])=O.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C>[C:14]([CH:9]1[CH2:10][NH:11][CH2:12][CH2:13][N:8]1[C:3]1[C:2]([NH:1][CH:22]([CH3:24])[CH3:21])=[CH:7][CH:6]=[CH:5][N:4]=1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: CC(C)(C)OC(=O)C1CNCCN1c1ncccc1N
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)Nc1cccnc1N1CCNCC1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3-amino-2-(Boc-piperazine)pyridine 7 (3.813 g, about 11.16 mmol, crude) was dissolved in dichloroethane (75 mL). Acetone (1.7 mL, 23.12 mmol) was added, followed by an addition of HOAc (1.0 mL, 17.45 mmol) at room temperature. After about 10 min, NaBH(OAc)3 (7.46 g, 33.44 mmol) was added. An additional amount of dichloroethane (25 mL) was added. The resulting mixture was stirred at room temperature for 64 h. 5% aqueous NaHCO3 was added to quench the reaction. The organic phase was separated and the aqueous phase was extracted with dichloromethane (2×50 mL). The combined organic solution was washed with brine, dried over anhydrous Na2SO4, concentrated. The residue was purified via flash column chromatography over silica gel with 5-35% ethyl acetate in hexane to afford the product as solid in quantitative yield. 1H-NMR (CDCl3): 7.673 (dd, J=5.0 Hz and 1.5 Hz, 1H, Ar—H), 6.904 (dd, J=8.0 Hz and 5.0 Hz, 1H, Ar—H), 6.812 (dd, J=8.0 Hz and 1.5 Hz, 1H, Ar—H), 4.150 (d, J=7.5 Hz, 1H, NH), 3.569-3.517 (m, 5H, 2CH2 and CH), 2.997 (t, J=5.0 Hz, 4H, 2 CH2), 1.477 (s, 9H, 3 CH3), 1.23 (d, J=6.0 Hz, 6H, 2 CH3). (ref. Romero D. L. et al. J. Med. Chem. 37, 999-1014, 1994.)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][C@@H:14]3[CH2:18][CH2:17][N:16]([C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[CH2:15]3)=[N:11][NH:10][C:9]2=[O:24])=[CH:4][CH:3]=1.[N:25]1[CH:26]=[CH:27][N:28]2[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][C:29]=12.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(O)C.O.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>[CH:21]1([C:19]([N:16]2[CH2:17][CH2:18][C@@H:14]([CH2:13][C:12]3[N:8]([C:5]4[CH:6]=[CH:7][C:2]([C:31]5[CH:32]=[CH:33][N:28]6[CH:27]=[CH:26][N:25]=[C:29]6[CH:30]=5)=[CH:3][CH:4]=4)[C:9](=[O:24])[NH:10][N:11]=3)[CH2:15]2)=[O:20])[CH2:23][CH2:22]1
Reactant: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(Br)cc2)C1
Reactant: OB(O)c1ccn2ccnc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3ccn4ccnc4c3)cc2)C1
Temperature: 95 °C
Yield: 51.1 %

Procedure:
A vial was charged with a slurry of 4-(4-bromophenyl)-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (100 mg, 0.256 mmol), imidazo[1,2-a]pyridin-7-ylboronic acid (83 mg, 0.511 mmol), tetrakis(triphenylphosphine)palladium(0) (29.5 mg, 0.026 mmol) and tripotassium phosphate (217 mg, 1.022 mmol) in absolute ethanol (5.0 mL) and water (5.00 mL) then purged with nitrogen and sealed with a standard teflon septa (crimped aluminum seal). The reaction was then heated in an aluminum block at 95° C. for 6 h. The resulting yellow solution was evaporated in vacuo to a residue that was triturated in DMSO, filtered through a nylon syringe adapter, then purified by reverse phase HPLC (LUNA C-18: 30×50 mm column; 10-40% acetonitrile w/0.1% TFA/water w/0.1% TFA). The desired product fractions were combined, treated with saturated aqueous sodium bicarbonate and evaporated to a residue that was slurried in 5% MeOH in dichloromethane and filtered through a short pad of silica (˜2 g). The filtrate was evaporated in vacuo to afford the title compound as a tan solid (56 mg, 48.6%). MS(ES)+ m/e 429.0 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:20]([OH:22])=[O:21])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][C:24]1C=CC(S(OC(C)C)(=O)=O)=C[CH:25]=1>>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH:24]([CH3:25])[CH3:23])[CH:12]=1)[C:20]([OH:22])=[O:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)OC(C)C)cc1
Product: CC(C)n1cc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)O)c2ccccc21
Yield: 43.3 %

Procedure:
The procedure of Referential Example 1(a) was repeated, except that N-tert-butoxycarbonyl-D-tryptophan (3.0 g) and isopropyl 4-methylbenzenesulfonate (3.17 g) were used, whereby the title compound (1.48 g) was yielded.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[CH2:26][C:27](=[O:38])[C@@H:28]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH3:29].[I-].[Na+].C(=O)(O)[O-].[Na+]>CN(C)C=O>[C:33]([O:32][C:31]([NH:30][C@@H:28]([CH3:29])[C:27](=[O:38])[CH2:26][NH:1][C@H:2]([C:10]([NH:12][C@H:13]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:37])([CH3:36])([CH3:34])[CH3:35]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)CCl
Reactant: CC(C)C[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NCC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 15 h
Yield: 73.4 %

Procedure:
To a stirred solution of L-phenylalanyl-L-leucine, t-butyl ester (2.18 g, 6 mmol) in 10 ml of dimethylformamide (under argon) was added a solution of [(S)-3-chloro-1-methyl-2-oxopropyl]carbamic acid, 1,1-dimethylethyl ester (1.33 g, 6 mmol) in 20 ml of dimethylformamide, followed by sodium iodide (450 mg, 3 mmol) and sodium bicarbonate (504 mg, 6 mmol). The reaction mixture was allowed to stir for 15 hours, then the solvent was evaporated (<25C° C., vacuum pump). The yellow residue was taken up into ethyl acetate (250 ml) and washed with water (4×25 ml) and brine (25 ml), then dried (sodium sulfate) and evaporated to a yellow residue (3.44 g). Flash chromatography on silica gel (Merck, 230-400 mesh, 250 g) with hexane-ethyl acetate (1.25:1) yielded 2.29 g of a colorless oil. Rapid recrystallization from ethyl acetate-hexane afforded 1.61 g of a powdery white solid.
Reaction SMILES: CCO[C:4]([C:6]([O:8]CC)=O)=[O:5].[CH2:11]([NH:13][CH2:14][CH2:15][NH2:16])[CH3:12]>C(O)C>[CH2:11]([N:13]1[CH2:14][CH2:15][NH:16][C:6](=[O:8])[C:4]1=[O:5])[CH3:12]
Reactant: CCNCCN
Reactant: CCOC(=O)C(=O)OCC
Solvent: CCO
Product: CCN1CCNC(=O)C1=O
Yield: 76.1 %

Procedure:
Into a mixture comprising 8 g of a diethyl ester of oxalic acid and 8 ml of ethanol was dropped at room temperature 4.4 g of N-ethyl ethylenediamine. The resulting mixture was allowed to react for 3 hours, and then heated to remove the ethanol. Subsequently, the residue was recrystallized from 10 ml of dioxane to obtain 5.4 g of 1-ethyl-2,3-dioxo-piperazine, m.p. 124° C., yield 76.0%.
Reaction SMILES: [C-:1]#[N:2].[Na+].[C:4]1([CH:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:11]2[CH2:16][CH2:15][CH:14]([CH2:17]Cl)[CH2:13][CH2:12]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O-])(O)=O.[Na+]>CS(C)=O>[C:1]([CH2:17][CH:14]1[CH2:15][CH2:16][N:11]([CH:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:12][CH2:13]1)#[N:2]
Reactant: ClCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: [C-]#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 60 °C
Yield: 61.4 %

Procedure:
Step 3): NaCN (2.5 g, 51 mmol) was added to a solution of 1-diphenylmethyl-4-chloromethyl-piperidine (8.9 g, 29.7 mmol) in dimethyl sulfoxide (DMSO) (100 ml). The mixture was heated at 60° C. for 20 hours and then poured into 3% NaHCO3 solution and extracted with ethyl acetate. The organic layer was dried (MgSO4) and concentrated. The residue was purified by column chromatography on silica gel (10% ethyl acetate in hexane) to give 4-cyanomethyl-1-diphenylmethylpiperidine (61.4%): mp 103°-104° C. and 3-(2-cyanoethyl)-1-diphenylmethyl pyrrolidine (20.9%):oil.
Reaction SMILES: [C:1]1([CH:7]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:33]4[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=4)=[O:26])=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)[C:8]([O:10]C)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[ClH:44]>O1CCOCC1>[ClH:44].[C:1]1([CH:7]([CH:12]2[CH2:13][CH2:14][N:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:33]4[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:40])[F:41])=[CH:35][CH:34]=4)=[O:26])=[CH:20][CH:19]=3)[CH2:16][CH2:17]2)[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C(c1ccccc1)C1CCN(c2ccc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)cc2)CC1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: O=C(Nc1ccc(N2CCC(C(C(=O)O)c3ccccc3)CC2)cc1)c1ccccc1-c1ccc(C(F)(F)F)cc1

Procedure:
A mixture of intermediate (23) (0.0014 mol) in concentrated HCl (25 ml) and dioxane (20 ml) was stirred and refluxed for 4 hours, cooled and poured out into water. The mixture was extracted with DCM. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was triturated in DIPE. The precipitate was filtered off and dried, yielding 0.48 g of α-phenyl-1-[4-[[[4′-(trifluoromethyl)[1,1′-biphenyl]-2-yl]carbonyl]amino]phenyl]-4-piperidineacetic acid monohydrochloride (intermediate 24, mp. 196° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:19][CH2:20][CH:21]=O)[CH:9]=2)=[CH:4][CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:19][CH2:20][CH2:21][N:33]3[CH2:32][CH2:31][N:30]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[F:23])[CH2:35][CH2:34]3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=CCCc1cc(-c2ccc(Cl)cc2)n(-c2ccccc2)n1
Reactant: Fc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccccc1N1CCN(CCCc2cc(-c3ccc(Cl)cc3)n(-c3ccccc3)n2)CC1

Procedure:
108 mg (83%) of target compound was obtained by using a method same as in Example 1 by using 3-(5-(4-chlorophenyl)-1-phenyl-1H-pyrazol-3-yl)-propanal (80 mg, 0.257 mmol), 1-(2-fluorophenyl)piperazine (46 mg, 0.257 mmol), DIPEA (0.070 mL, 0.386 mmol) and NaBH(OAc)3 (163 mg, 0.771 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.[OH-].[K+].[I:15]I>CO>[I:15][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[C:6]=1[OH:9]
Reactant: COc1ccc(O)c([N+](=O)[O-])c1
Reactant: II
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(I)c(O)c([N+](=O)[O-])c1
Yield: 57.3 %

Procedure:
A solution of 4-Methoxy-2-nitrophenol (5 g, 29.6 mmol) in MeOH (100 mL) was cooled to 0° C. and treated with KOH (1.8 g, 32.6 mmol) followed by portionwise addition of I2 (8.2 g, 32.6 mmol). The reaction was worked-up by quenching the excess I2 by adding a 10% Na2SO3 aq solution. The MeOH was stripped off and 2 N HCl aq. was added and the aqueous extracted with EtOAc. The EtOAc was washed with saturated NaHCO3, brine and dried over MgSO4. The solution was concentrated and triturated twice with MeOH to yield 5 g of material that consisted of a 2:1 mixture of product to starting material that was used as is for the next step.
Reaction SMILES: Br[CH:2]([CH2:6][S:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[C:3]([OH:5])=[O:4].[CH3:17][SH:18].[OH-].[Na+]>C(O)C>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][S:7][CH2:6][CH:2]([S:18][CH3:17])[C:3]([OH:5])=[O:4])=[CH:10][CH:11]=1
Reactant: COc1ccc(CSCC(Br)C(=O)O)cc1
Reactant: CS
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(CSCC(SC)C(=O)O)cc1

Procedure:
A solution of 2-bromo-3-(4-methoxybenzylmercapto)propanoic acid (15 g.), methylmercaptan (3 g.) and sodium hydroxide (4.6 g.) in 95% ethanol (25 ml.) is refluxed for twelve hours. The sodium bromide is filtered off and the filtrate is concentrated to dryness in vacuo. The residue is dissolved in water, acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer is dried and concentrated to dryness to yield 3-(4-methoxybenzylmercapto)-2-(methylthio)propanoic acid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([O:14][CH2:15][CH:16]([F:18])[F:17])=[CH:4][N:3]=1.[F-:19].[Cs+]>CS(C)=O>[F:17][CH:16]([F:18])[CH2:15][O:14][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=2)[C:2]([F:19])=[N:3][CH:4]=1
Reactant: [F-]
Reactant: COc1ccc2c(Cl)ncc(OCC(F)F)c2c1
Agent: [Cs+]
Solvent: CS(C)=O
Product: COc1ccc2c(F)ncc(OCC(F)F)c2c1
Temperature: 140 °C

Procedure:
To a solution of 1-chloro-4-(2,2-difluoroethoxy)-6-methoxyisoquinoline (538 mg, 1.966 mmol) in DMSO (5 mL) was added CsF (597 mg, 3.93 mmol) and heated to 140° C. for 2 hrs. LC/MS showed the desired product. The reaction was diluted with ethyl acteate and washed with water, and brine. The organic phase was collected, dried over MgSO4, and concentrated under vacuum to give the crude product as a reddish brown solid. The crude material was purified via silica gel chromatography (5-50% EtOAc:Hex) to give the product 4-(2,2-difluoroethoxy)-1-fluoro-6-methoxyisoquinoline (237 mg, 0.921 mmol, 46.9% yield) as a light yellow solid. MS: MS m/z 258.2(M++1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([O:19][CH3:20])=[N:7][C:8]([CH3:18])=[C:9]([N+:15]([O-])=O)[C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[O:4]>C(OCC)(=O)C.[Pd]>[NH2:15][C:9]1[C:8]([CH3:18])=[N:7][C:6]([O:19][CH3:20])=[C:5]([C:3]([O:2][CH3:1])=[O:4])[C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1c(OC)nc(C)c([N+](=O)[O-])c1C(=O)OC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1c(OC)nc(C)c(N)c1C(=O)OC
Reaction time: 4.5 h

Procedure:
In 5 ml of ethyl acetate was dissolved 350 mg of 3,4-dimethoxycarbonyl-2-methoxy-6-methyl-5-nitropyridine, and 300 mg of 10% Pd-C (50% wet) was added to the solution. Catalytic reduction reaction was conducted for 4.5 hours. After the reaction mixture was dried over magnesium sulfate, the solvent was distilled off to afford an oily product.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:33]([O:37][C:38](=[O:49])[NH:39][CH2:40][C:41]1[CH:46]=[CH:45][C:44]([CH2:47][NH2:48])=[CH:43][CH:42]=1)([CH3:36])([CH3:35])[CH3:34].CN1CCOCC1>CN(C)C=O>[C:33]([O:37][C:38](=[O:49])[NH:39][CH2:40][C:41]1[CH:42]=[CH:43][C:44]([CH2:47][NH:48][C:4]([C:3]2[C:2]([Cl:1])=[N:10][CH:9]=[CH:8][CH:7]=2)=[O:6])=[CH:45][CH:46]=1)([CH3:36])([CH3:34])[CH3:35]
Reactant: O=C(O)c1cccnc1Cl
Reactant: CC(C)(C)OC(=O)NCc1ccc(CN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)NCc1ccc(CNC(=O)c2cccnc2Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.1 %

Procedure:
2-Chloro-nicotinic acid (2.86 g, 18.2 mmol), 1-hydroxybenzotriazole (3.0 g, 21.8 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.18 g, 21.8 mmol) were dissolved in N,N-dimethylformamide (50 ml) at room temperature and (4-aminomethyl-benzyl)-carbamic acid tert-butyl ester (4.29 g, 18.2 mmol) (see Preparation 1) added followed by addition of N-methyl morpholine (4 ml, 36.3 mmol). The reaction mixture was stirred under an atmosphere of nitrogen at room temperature for 18 hours, then partitioned between ethyl acetate (100 ml) and water (100 ml) and the organic layer separated. The organic layer was then washed with a saturated aqueous solution of sodium chloride (100 ml), dried over anhydrous magnesium sulphate and the solvent removed in vacuo. The residue was then triturated with diethylether (2-fold 10 ml) to give (4-{[(2-chloro-pyridine-3-carbonyl)-amino]-methyl}-benzyl)-carbamic acid tert-butyl ester (6.71 g) as a white solid.
Reaction SMILES: [CH2:1]([C:3]1([CH2:24][CH3:25])[O:7][C:6]([C:9]2[CH:10]=[C:11]([S:14][C:15]3[CH:20]=[CH:19][C:18]([C:21](=O)[CH3:22])=[CH:17][CH:16]=3)[S:12][CH:13]=2)([CH3:8])[CH2:5][O:4]1)[CH3:2].Cl.[NH2:27][OH:28]>>[CH2:1]([C:3]1([CH2:24][CH3:25])[O:7][C:6]([C:9]2[CH:10]=[C:11]([S:14][C:15]3[CH:20]=[CH:19][C:18](/[C:21](=[N:27]/[OH:28])/[CH3:22])=[CH:17][CH:16]=3)[S:12][CH:13]=2)([CH3:8])[CH2:5][O:4]1)[CH3:2]
Reactant: NO
Reactant: CCC1(CC)OCC(C)(c2csc(Sc3ccc(C(C)=O)cc3)c2)O1
Agent: Cl
Product: CCC1(CC)OCC(C)(c2csc(Sc3ccc(/C(C)=N/O)cc3)c2)O1
Yield: 80 %

Procedure:
Using an analogous procedure to that described in Example 68, 4'-[4-(2,2-diethyl-4-methyl-1,3-dioxolan-4-yl)thien-2-ylthio]acetophenone was reacted with hydroxylamine hydrochloride to give (E)-4'-[4-(2,2-diethyl-4-methyl-1,3-dioxolan-4-yl)thien-2-ylthio]actophenone oxime in 80% yield as a gum.
Reaction SMILES: [C:1](=[O:19])(SCC)[O:2][O:3][CH:4]([O:8][C:9]([CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])[CH2:5][CH2:6][CH3:7].S(Cl)([Cl:23])(=O)=O>C(Cl)Cl>[Cl:23][C:1]([O:2][O:3][CH:4]([O:8][C:9]([CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])[CH2:5][CH2:6][CH3:7])=[O:19]
Reactant: CCCC(OOC(=O)SCC)OC(=O)C1CCCC1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CCCC(OOC(=O)Cl)OC(=O)C1CCCC1

Procedure:
A solution of (67) (1.83 g, 6.34 mmol) in CH2Cl2 at 0° C. was treated with sulfuryl chloride (0.62 mL, 7.61 mmol) under N2 for 10 min, then the reaction mixture was concentrated to dryness in vacuo to afford crude (1-cyclopentanecarbonyloxy-butoxy) chloroformate in quantitative yield. The chloroformate was dissolved in CH2Cl2, and was added to a mixture of N-hydroxysuccinimide (1.09 g, 9.51 mmol) and pyridine (1.28 mL, 15.8 mmol) in CH2Cl2 at 0° C. The reaction mixture was stirred at 0° C. for 1 h, then was washed with water, dilute HCl and brine and dried over Na2SO4. After removal of solvent in vacuo the title N-hydroxysuccinimidyl carbonate (68) was obtained in quantitative yield, and was used in the subsequent step without further purification.
Reaction SMILES: [CH2:1]([C:9]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:10]=1[C:11]([O:13]C)=[O:12])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+]>CO>[NH2:19][C:16]1[CH:17]=[CH:18][C:9]([CH2:1][CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[C:10]([CH:15]=1)[C:11]([OH:13])=[O:12]
Reactant: COC(=O)c1cc(N)ccc1CCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1ccc(CCc2ccccc2)c(C(=O)O)c1
Yield: 99.6 %

Procedure:
A mixture of compound 77(8.5 g), 2N. aqueous sodium hydroxide (50 ml) and methanol (100 ml) was stirred at ambient temperature for 18 hours and then heated at reflux for 2 hours. The mixture was cooled and evaporated under reduced pressure. The product was redissolved in water (1 L) and washed with diethyl ether (250 ml). The aqueous solution was acidified to pH 5-6 with glacial acetic acid . The resulting precipitate was isolated by filtration and dried under vacuum at 60° C. to give a powder which was azeotroped with toluene (3×50 ml) and then dried under high vacuum to give 5-amino-2-phenethylbenzoic acid (compound 78) (8.0 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][S:10][C:11]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:12]=2[NH2:13])=[C:6]([CH:8]=1)[NH2:7].[O:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH:21]=[C:20]1[S:28](Cl)(=[O:30])=[O:29]>>[Cl:18][C:15]1[CH:16]=[CH:17][C:11]([S:10][S:9][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:8][C:6]=2[NH:7][S:28]([C:20]2[O:19][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH:21]=2)(=[O:29])=[O:30])=[C:12]([NH:13][S:28]([C:20]2[O:19][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH:21]=2)(=[O:30])=[O:29])[CH:14]=1
Reactant: Nc1cc(Cl)ccc1SSc1ccc(Cl)cc1N
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Product: O=S(=O)(Nc1cc(Cl)ccc1SSc1ccc(Cl)cc1NS(=O)(=O)c1cc2ccccc2o1)c1cc2ccccc2o1

Procedure:
Following General Procedure F, the title compound was prepared from 2,2′-dithiobis(5-chloroaniline) and 1-benzofuran-2-sulfonyl chloride.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[C:5](Br)([CH3:7])[CH3:6])[CH3:2].[C:10]([C:12]1([C:18]2[N:23]=[CH:22][C:21]([NH:24][C:25]([C:27]3[CH:28]=[N:29][N:30]([C:33]4[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][N:34]=4)[C:31]=3[CH3:32])=[O:26])=[CH:20][CH:19]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)#[N:11].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:9])[C:5]([N:15]1[CH2:14][CH2:13][C:12]([C:10]#[N:11])([C:18]2[CH:19]=[CH:20][C:21]([NH:24][C:25]([C:27]3[CH:28]=[N:29][N:30]([C:33]4[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][N:34]=4)[C:31]=3[CH3:32])=[O:26])=[CH:22][N:23]=2)[CH2:17][CH2:16]1)([CH3:7])[CH3:6])[CH3:2]
Reactant: Cc1c(C(=O)Nc2ccc(C3(C#N)CCNCC3)nc2)cnn1-c1ccc(C(F)(F)F)cn1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)(C)N1CCC(C#N)(c2ccc(NC(=O)c3cnn(-c4ccc(C(F)(F)F)cn4)c3C)cn2)CC1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
2-Bromo-2-methylpropanoic acid ethyl ester (193 μl) was added to a suspension of N-[6-(4-cyanopiperidin-4-yl)pyridin-3-yl]-5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (455 mg) described in Reference Example 169 and potassium carbonate (276 mg) in N,N-dimethylformamide (3.3 ml) and stirred at 50° C. for 12 hours. Then, 2-bromo-2-methylpropanoic acid ethyl ester (100 μl) and potassium carbonate (276 mg) were added and stirred at 50° C. for 5 hours and at 80° C. for 3 hours. Further, 2-bromo-2-methylpropanoic acid ethyl ester (100 μl) was added and stirred at 80° C. for 3 hours. Water was added to the reaction solution, the precipitated solid was purified with silica gel chromatography (chloroform/methanol) to give 2-{4-cyano-4-[5-({5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carbonyl}amino)pyridin-2-yl]piperidin-1-yl}-2-methylpropanoic acid ethyl ester (320 mg) as a white solid. MS (ESI) m/z: 570 (M+H)+. (2) Lithium borohydride (25 mg) was added to a solution of 2-{4-cyano-4-[5-({5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carbonyl}amino)pyridin-2-yl]piperidin-1-yl}-2-methylpropanoic acid ethyl ester (320 mg) in tetrahydrofuran (3.7 ml) and stirred at room temperature for 1.5 hours. Then, lithium borohydride (25 mg) was added and stirred at 80° C. for 2 hours. To the reaction solution, were added methanol (1.5 ml) and sodium borohydride (85 mg), and stirred at room temperature for an hour. A saturated aqueous solution of ammonium chloride was added to the reaction solution, extracted with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified with silica gel chromatography (chloroform/methanol) to give the titled compound (35 mg) as a white solid.