Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)Cl.[CH2:4]([O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([F:16])[C:8]=1[F:17])[CH3:5].[F:18][CH:19]1[C:24]([F:26])([F:25])[C:23]2([CH2:29][CH2:30][CH3:31])[CH2:27][CH2:28][C:20]1(O)[CH2:21][CH2:22]2.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.O>[F:18][CH:19]1[C:24]([F:25])([F:26])[C:23]2([CH2:29][CH2:30][CH3:31])[CH2:22][CH2:21][C:20]1([O:12][C:11]([C:10]1[CH:14]=[CH:15][C:7]([O:6][CH2:4][CH3:5])=[C:8]([F:17])[C:9]=1[F:16])=[O:13])[CH2:28][CH2:27]2
Reactant: CCOc1ccc(C(=O)O)c(F)c1F
Reactant: CCCC12CCC(O)(CC1)C(F)C2(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CCCC12CCC(OC(=O)c3ccc(OCC)c(F)c3F)(CC1)C(F)C2(F)F

Procedure:
Methylene chloride solution containing 4-ethoxy-2,3-difluorobenzoic acid (7) (52.6 mg) and 2,3,3-trifluoro-1-hydroxy-4-n-propylbicyclo[2.2.2]octane (4) (39.0 mg) was added with N,N′-dicyclohexyl carbodiimide (53.0 mg) and 4-dimethylamino pyridine (7.0 mg), and the mixture was refluxed under heating for 11 hours. The mixture was then added with water to terminate the reaction, the organic layer was extracted three times with ethyl acetate, the organic layers were combined, and the combined organic layer was washed with saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was then vaporized off under reduced pressure to thereby obtain a crude product. The crude product was purified by silica gel column chromatography (hexane/ethyl acetate=8:2), to thereby obtain 2,3,3-trifluoro-1-(4′-ethoxy-2′,3′-difluorophenyl)carbonyloxy-4-n-propylbicyclo[2.2.2]octane (8) (yield=20.0 mg, yield ratio=28%) as a colorless clear crystal.
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]1[O:8][CH:7]1[CH2:9][OH:10].[OH-].[Na+].[CH2:13]([OH:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>>[CH2:13]([O:21][CH:7]([CH2:9][OH:10])[CH2:6][OH:8])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: OCC1CO1
Reactant: CCCCCCCCO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCOC(CO)CO
Temperature: 25 °C
Yield: 15.9 %

Procedure:
0.6 ml of concentrated sulfuric acid was added to 165 g of 1-octanol, the mixture was stirred at room temperature and 23.5 g of glycidol was added dropwise. The reaction mixture was poured on ice water, the mixture was neutralized with 1N aqueous sodium hydroxide solution and extracted with ether, and the ether layer was dried over anhydrous sodium sulfate. The solvent was distilled away, the most part of 1-octanol was removed by vacuum distillation, and the residue was distilled under a vacuum of 1 mmHg to give 10.3 g of the desired product containing a by-product 3-octyloxy-1,2-propanediol.
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[CH:7][C:8]([O:19][CH2:20][CH:21]([OH:28])[CH2:22][NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[C:9]([CH:18]=1)[C:10]([CH2:12][CH2:13][C:14](OC)=[O:15])=O)(=O)C.O.[NH2:30][NH2:31]>>[NH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:19][CH2:20][CH:21]([OH:28])[CH2:22][NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[C:9]([C:10]2[CH2:12][CH2:13][C:14](=[O:15])[NH:30][N:31]=2)[CH:18]=1
Reactant: COC(=O)CCC(=O)c1cc(NC(C)=O)ccc1OCC(O)CNC(C)(C)C
Reactant: NN
Solvent: O
Product: CC(C)(C)NCC(O)COc1ccc(N)cc1C1=NNC(=O)CC1

Procedure:
Methyl 3-[5-acetamido-2-(3-t-butylamino-2-hydroxypropoxy)benzoyl]propionate was hydrolysed by aqueous acid and the solution was neutralised and evaporated to dryness. 3-[5-Amino-2-(3-t-butylamino-2-hydroxypropoxy)benzoyl]propionic acid was extracted from the residue with hot ethanol and the combined extracts were evaporated to give the crude acid, which was cyclised by hydrazine hydrate as in Example 2(iv) to give 6-[5-amino-2-(3-t-butylamino-2-hydroxypropoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][C:2]21[CH2:18][C:10]1[CH:11]=[C:12]3[C:16](=[CH:17][C:9]=1[CH2:8][CH2:7][CH2:6]2)[NH:15][N:14]=[CH:13]3.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C@@H]1(N)[CH2:32][CH2:31][CH2:30][CH2:29][C@H:28]1[NH2:33].IC1C=CN=CC=1>[Cu]I.O1CCOCC1>[N:33]1[CH:32]=[CH:31][C:30]([N:15]2[C:16]3[C:12](=[CH:11][C:10]4[CH2:18][C:2]5([O:1][CH2:5][CH2:4][O:3]5)[CH2:6][CH2:7][CH2:8][C:9]=4[CH:17]=3)[CH:13]=[N:14]2)=[CH:29][CH:28]=1
Reactant: N[C@@H]1CCCC[C@H]1N
Reactant: c1n[nH]c2cc3c(cc12)CC1(CCC3)OCCO1
Agent: [Cu]I
Agent: Ic1ccncc1
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: c1cc(-n2ncc3cc4c(cc32)CCCC2(C4)OCCO2)ccn1
Temperature: 105 °C
Yield: 427.2 %

Procedure:
5,7,8,9-Tetrahydro-1H-spiro[cyclohepta[f]indazole-6,2′-[1,3]dioxolane] (28.283 g, 116 mmol), potassium phosphate (49.2 g, 232 mmol), copper(I) iodide (2.205 g, 11.58 mmol) and (1R,2R)-cyclohexane-1,2-diamine (2.64 g, 23.16 mmol) were added to a round bottomed flask, followed by the addition of 1,4-dioxane (300 mL). 4-Iodopyridine (35.6 g, 174 mmol) was added and the mixture was heated to about 105° C. for about 8 h. The reaction was cooled to rt and filtered. The filter cake was rinsed with excess EtOAc. The filtrate was washed with sat. a.q NH4Cl (100 mL) followed by brine (100 mL), dried over MgSO4, filtered and concentrated in vacuo to about ¼ the original volume. The resulting solids were collected by filtration to provide a first crop of product. The mother liquor was fully concentrated and then taken into DCM and sonicated to provide additional solids, which were collected by filtration to provide an additional crop of product. The filtrate was then purified on silica gel (120 g) eluting with a gradient of 10-100% EtOAc/DCM. The product containing fractions were concentrated in vacuo then combined with the previous collections to provide 1-(pyridin-4-yl)-5,7,8,9-tetrahydro-1H-spiro[cyclohepta[f]indazole-6,2′-[1,3]dioxolane] (82, R1=4-Pyridyl), (31.8 g, 85%); LC/MS, method 3, Rt=1.98 min, MS m/z 322 (M+H)+, 1H NMR (400 MHz, DMSO) δ 8.72-8.66 (m, 2H), 8.38-8.36 (m, 1H), 7.94-7.86 (m, 3H), 7.64 (s, 1H), 4.11-3.86 (m, 2H), 3.87-3.80 (m, 2H), 3.15 (s, 2H), 3.02-2.96 (m, 2H), 1.95-1.83 (m, 2H), 1.76-1.60 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([OH:7])[N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:3]=1.[OH-].[Ca+2].[OH-].Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].Cl>O1CCOCC1>[CH3:1][C:2]1[NH:3][N:4]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:5](=[O:7])[C:6]=1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]
Reactant: Cc1cc(O)n(-c2ccccc2)n1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Ca+2]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1[nH]n(-c2ccccc2)c(=O)c1C(=O)OCc1ccccc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 79.7 %

Procedure:
A suspension of 3-methyl-1-phenyl-1H-pyrazol-5-ol (10.0 g, 57 mmol) and calcium hydroxide (8.5 g, 115 mmol) in dry 1,4-dioxane (100 mL) was heated to 50° C. for 20 min. The suspension was chilled to 10° C. and benzyl chloroformate (8.2 ml, 57 mmol) was in dioxane (10 mL) added. The resultant was heated to 90° C. for 3 h, cooled to 25° C. and then, chilled (0° C.) 1 M HCl (200 mL) was added. The mixture was stirred at 25° C. overnight. A solid collected by filtration was washed with cold EtOH (2×25 mL) and ether (50 mL), dried at 80° C. (sand bath) exposed to air for 4 h to give the title compound (14.0 g, 79% yield) as an off-white solid. MS (ESI pos. ion) m/z: 309 (MH+). Calc'd exact mass for C18H16N2O3 308.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:9]=[CH:10][C:3]=12.[CH3:19][C:20]1[N:21]=[CH:22][N:23]([C:25]2[CH:30]=[CH:29][C:28]([Sn](CCCC)(CCCC)CCCC)=[CH:27][CH:26]=2)[CH:24]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>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.O>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:8]2[C:4]3=[N:5][CH:6]=[CH:7][C:2]([C:28]4[CH:29]=[CH:30][C:25]([N:23]5[CH:24]=[C:20]([CH3:19])[N:21]=[CH:22]5)=[CH:26][CH:27]=4)=[C:3]3[CH:10]=[CH:9]2)=[CH:13][CH:14]=1
Reactant: Fc1ccc(Cn2ccc3c(Cl)ccnc32)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(-n2cnc(C)c2)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: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: ClCCl
Product: Cc1cn(-c2ccc(-c3ccnc4c3ccn4Cc3ccc(F)cc3)cc2)cn1
Temperature: 25 °C
Yield: 10.8 %

Procedure:
To 4-chloro-1-(4-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine (36 mg, 0.14 mmol), 4-methyl-1-(4-(tributylstannyl)phenyl)-1H-imidazole (100 mg, 0.21 mmol) and Potassium carbonate (100 mg, 0.7 mmol) was added 3 ml Toluene followed by Pd(PPh3)4 (20 mg, 0.014 mmol) then heat to 120 C for 2 hrs. The reaction was worked up by cooling to RT then adding water and DCM. Extract aqueous layer 3×DCM, then dry over sodium sulfate and filter and concentrate to dryess. The residue was purified by chromatography over silica gel (eluted with DCM/MeOH 99:1 to 90:10) to provide 5.8 mg (10%) of product. 1H NMR (CDCl3 400 MHz): 8.4 (d, 1H), 8.01 (s, 2H), 7.78-7.8 (m, 1H), 7.4 (s, 2H), 7.26-7.27 (m, 3H), 6.95-7.02 (m, 3H), 6.65-6.72 (m, 1H), 5.53 (s, 1H), 3.93 (s, 3H), 2.33 (s, 3H). LCMS (MH+)=413; retention time=3.19 min.
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[OH:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]([CH3:23])[C:15](=[O:24])[C:14]=1[N+:25]([O-:27])=[O:26].CCN(CC)CC>C(#N)C.CN(C1C=CN=CC=1)C>[CH3:23][N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]([O:12][S:1]([C:4]2[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=2)(=[O:3])=[O:2])=[C:14]([N+:25]([O-:27])=[O:26])[C:15]1=[O:24]
Reactant: Cn1c(=O)c([N+](=O)[O-])c(O)c2ccccc21
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)Oc2c([N+](=O)[O-])c(=O)n(C)c3ccccc23)cc1
Temperature: 35 °C
Yield: 75.5 %

Procedure:
A solution of tosyl chloride (30.0 g, 160 mmol) in 100 mL of acetonitrile was added to a stirred solution of the 4-hydroxy-1-methyl-3-nitro-1H-quinolin-2-one (32.0 g, 145.0 mmol), Et3N (17.65 g, 174.4 mmol), and DMAP (0.178 g, 1.45 mmol) in 300 mL of MeCN at 0° C. After the addition was complete, the reaction mixture was heated at 35° C. for 3 h. After the solvent was evaporated under reduced pressure, water (35 mL) and CH2Cl2 (50 mL) were added to the residue. The resulting precipitate was removed by filtration, and the filtrate was extracted with CH2Cl2 (3×200 mL). The combined extracts were dried, filtered through a plug of SiO2, and concentrated. The resulting residue was combined with the solid isolated earlier, and was triturated with ether to give 41.0 g (75%) of toluene-4-sulfonic acid 1-methyl-3-nitro-2-oxo-1,2-dihydro-quinolin-4-yl ester. 1H-NMR (CDCl3): δ 8.16 (dd, 1H, J=7.6, 1.2 Hz), 7.90 (m, 2H), 7.79 (m, 1H), 7.44 (m, 4H), 3.79 (s, 3H), 2.51 (s, 3H). MS: calculated for C17H14N2O6S+H 375.1; found: 375.3.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[Cl:9][C:10]1[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([F:16])[C:10]=2[Cl:9])[CH:7]=1
Reactant: OB(O)c1cccc(F)c1Cl
Reactant: Brc1cncc(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: Fc1cccc(-c2cncc(Br)c2)c1Cl

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 3,5-dibromo-pyridine and 2-chloro-3-fluoro-phenylboronic acid. (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) was used in place of tetrakis(triphenylphosphine)palladium(0).
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:13]1([CH2:19][CH2:20][CH2:21][NH2:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[BH4-].[Na+].Cl>CO>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:22][CH2:21][CH2:20][CH2:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C=O)cc1
Reactant: NCCCc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1ccc(CNCCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.38 ml of 4-tert-butylbenzaldehyde (2.25 mmol) and 0.213 ml of 3-phenylpropylamine (1.5 mmol) were dissolved in 5 ml methanol at rt, and after stirring for 30 min at rt, were refluxed for 2 h. After cooling down to rt, 85 mg (2.25 mmol) of sodium borohydride were added and after 10 min stirring at rt, the reaction mixture was then refluxed for 3 h. After cooling down to rt, the reaction mixture was treated with 0.15 ml 1 N HCl and concentrated in vacuo. The residue was diluted with water/EtOAc. After separation of the organic phase, the aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried with magnesium sulfate, filtered off and concentrated in vacuo. The residue, 558 mg of a light brown oil, was not further purified and used directly in the next step.
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:18]([N+:19]([O-])=O)=[CH:17][CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Ni].C(OCC)(=O)C>[NH2:19][C:18]1[C:9]([S:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1SCc1ccccc1
Agent: [Ni]
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(N)c1SCc1ccccc1
Yield: 100 %

Procedure:
Under hydrogen atmosphere, a mixture of methyl 2-(benzylthio)-3-nitrobenzoate (28.5 g, 94.0 mmol) and a catalytic amount of Raney nickel in ethyl acetate (500 mL) was stirred at room temperature for 12 hr, and filtered through celite. The solvent was evaporated under reduced pressure to give the title compound (25.7 g, yield 96%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH:13]=2)=[CH:4][C:3]=1[C:21]([O:23][CH3:24])=[O:22].[H][H]>C(O)C.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]2)=[CH:4][C:3]=1[C:21]([O:23][CH3:24])=[O:22]
Reactant: [H][H]
Reactant: COC(=O)c1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)ccc1F
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1F
Reaction time: 4 h

Procedure:
A mixture of tert-butyl 4-[4-fluoro-3-(methoxycarbonyl)phenyl]-3,6-dihydropyridine-1(2H)-carboxylate (2.11 g, 6.29 mmol) and 10% Pd/C (525 mg) in ethanol (60 mL) was stirred under an hydrogen atmosphere using a hydrogen filled balloon for 6 h. The reaction mixture was filtered and the filtrate was concentrated. 1H NMR analysis revealed that approximately 5% of the starting olefin remained, so the mixture was resubmitted to the above conditions for 4 h. Filtration, and concentration of the filtrate gave tert-butyl 4-[4-fluoro-3-(methoxycarbonyl)phenyl]piperidine-1-carboxylate which was used without further purification. 1H NMR (500 MHz, CDCl3) δ 7.78 (dd, J=6.5, 2.0 Hz, 1H), 7.37 (m, 1H), 7.10 (dd, J=10.5, 8.0 Hz, 1H), 4.27 (br m, 2H), 3.95 (s, 3H), 2.82 (br m, 2H), 2.69 (tt, J=12.5, 3.5 Hz, 1H), 1.83 (br d, J=13 Hz, 2H), 1.62 (dq, J=4.5, 13 Hz, 2H), 1.50 (s, 9H).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([N+:13]([O-])=O)=[CH:9][C:10]=2[F:12])[CH2:5][C:4]1=[O:16])[CH3:2].[Cl-].[NH4+]>C(O)C.O.ClCCl.[Fe]>[NH2:13][C:8]1[CH:7]=[C:6]2[C:11](=[C:10]([F:12])[CH:9]=1)[N:3]([CH2:1][CH3:2])[C:4](=[O:16])[CH2:5]2
Reactant: CCN1C(=O)Cc2cc([N+](=O)[O-])cc(F)c21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: CCN1C(=O)Cc2cc(N)cc(F)c21
Temperature: 25 °C

Procedure:
Iron powder (3.84 g, 68.7 mmol) is added in small portions to 1-ethyl-7-fluoro-5-nitro-1,3-dihydro-indol-2-one (3.85 g, 17.2 mmol) and ammonium chloride (8.94 g, 171 mmol) in ethanol (150 ml) and water (75 ml) at 90° C. The reaction mixture is stirred vigorously and heated for 30 min, cooled to room temperature, and diluted with dichloromethane (600 ml). The mixture is filtered through celite, the organic layer separated and washed with water and brine, dried over sodium sulfate and evaporated to give the title compound as a yellow solid. HPLC r.t. 2.60 min; MS for C10H11FN2O m/z 195.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([N:8]2[CH2:13][CH:12]=[C:11]([C:14]#[N:15])[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C([OH:18])C.O>>[F:1][C:2]1[C:3]([N:8]2[CH2:9][CH:10]=[C:11]([C:14]([NH2:15])=[O:18])[CH2:12][CH2:13]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCO
Reactant: N#CC1=CCN(c2ncccc2F)CC1
Solvent: O
Product: NC(=O)C1=CCN(c2ncccc2F)CC1
Yield: 100 %

Procedure:
3′-Fluoro-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carbonitrile 20 (10.0 g, 49.2 mMol) was dissolved in ethanol:water (2:1, 150 mL) with stirring and heating. PtH(PMe2O)2(PMe2OH) (50 mg, 0.025 mol %) was added and the solution stirred under reflux for 2 h. LC/MS showed the reaction to be 100% complete after this time. The cooled solution was evaporated to dryness in vacuo to leave a white solid. The solid was filtered through a flash pad of silica gel to remove the catalyst to give the title compound as a white solid (10.9 g, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][N:4]=1>C(O)C.C(N(CC)CC)C.[Pd]>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][N:4]=1
Reactant: CCOC(=O)C=Cc1cnc(OC)nc1
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)CCc1cnc(OC)nc1

Procedure:
A suspension of ethyl 3-(2-methoxypyrimidin-5-yl)acrylate (52.4 g, 0.252 mol) in ethanol (400 ml) and triethylamine (50 ml) was treated with 10% palladium on carbon (3 g) and hydrogenated at 50 psi for 1.75 h. The catalyst was filtered off through hyflo and the filtrate evaporated. The residue was dissolved in dichloromethane, washed twice with saturated aqueous ammonium chloride, dried (MgSO4) and evaporated to an oil, yield 41.2 g (78%). 1H-NMR (CDCl3) δ 1.23 (3H, t), 2.61 (2H, t), 2.87 (2H, t), 3.99 (3H, s), 4.13 (2H, q), 8.39 (2H, s); MS (APCI+) found (M+H)=211; C10H14N2O3 requires 210.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21]([O:22][CH3:23])=[N:20][C:19](Br)=[CH:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][Zn]C.C1(C)C=CC=CC=1>O1CCCC1.O.C(OCC)(=O)C.[Ni](Cl)Cl.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21]([O:22][CH3:23])=[N:20][C:19]([CH3:25])=[CH:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1nc(Br)cnc1NCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: C[Zn]C
Agent: Cl[Ni]Cl
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1nc(C)cnc1NCC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 1.5 h

Procedure:
To 4-[(5-bromo-3-methoxy-pyrazin-2-ylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (EXAMPLE 131, STEP 1) (0.20 g, 0.0005 mol) in tetrahydrofuran (1 mL), under nitrogen, was added 1,3-bis(diphenylphosphino)propane nickel(II) chloride (0.034 g, 0.0625 mmol) followed by a dropwise addition of 2.0M dimethylzinc in toluene (0.313 mL, 0.000625 mol). The reaction mixture was stirred for 1.5 h, diluted with water (5 mL) and ethyl acetate (30 mL). The organic layer was removed, dried over sodium sulfate, filtered and concentrated to an oil. The oil was chromatographed on silica using a gradient of 20–50% ethyl acetate/hexane to give the title compound as a foam. M.S.(M+1): 337.
Reaction SMILES: [CH:1]([O:4][CH:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:3])[CH3:2].[CH:20]([Si:22]([O:29][CH2:30][CH3:31])([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25])=[CH2:21]>C1(C)C=CC=CC=1>[CH:1]([O:4][CH:5]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:6](=[O:13])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=1[CH2:21][CH2:20][Si:22]([O:23][CH2:24][CH3:25])([O:26][CH2:27][CH3:28])[O:29][CH2:30][CH3:31])([CH3:3])[CH3:2]
Reactant: C=C[Si](OCC)(OCC)OCC
Reactant: CC(C)OC(C(=O)c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCO[Si](CCc1ccccc1C(=O)C(OC(C)C)c1ccccc1)(OCC)OCC
Reaction time: 0.5 h
Yield: 55.1 %

Procedure:
10.2 g (40 mmol) of benzoin isopropyl ether, 9.2 ml (44 mmol) of vinyltriethoxysilane and 735 mg (0.8 mmol) of RuH2 (CO) (PPh3)3 were dissolved in 60 ml of anhydrous toluene and degassed by passing in argon for 1/2 hour. The mixture was then stirred with exclusion of light and under argon, at reflux, for 7 hours and left to stand overnight at room temperature, a further 370 mg (0.4 mmol) of RuH2 (CO) (PPh3)3 and 1 ml (5 mmol) of vinyltriethoxysilane were added, and heating at reflux was carried out for a further 6.5 hours. After the toluene had been distilled off, the mixture was chromatographed on silica gel (initially heptane/CH2Cl2 9:1, then CH2 Cl2, then CH2Cl2 /ethyl acetate, finally ethyl acetate) and purified by bulb-tube distillation. 9.8 g (55%) of a pale yellowish oil were obtained. 1H-NMR (CDCl3): 0.61-0.95 ppm (2H, mc, Et-H2); 1.21 ppm (6H, d, isopropyl-CH3, 3JH,H =6.0 Hz); 1.22 ppm (9H, t, ethoxy-CH3, 3JH,H =7.0 Hz); 2.61 ppm (2H, mc, Et-H1); 3.71 ppm (1H, hept, isopropyl-H); 3.79 ppm (6H, q, ethoxy-CH2); 5.55 ppm (1H, s, benzoin-H); 7.13-7.38 ppm (8H, m, Ph-H); 7.48 ppm (1H, dd, Ph-H6, 3JH5,H6 =7.6 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[C:28](Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.C(N1C=CC(N)=N1)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH3:28])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Agent: CCn1ccc(N)n1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CCn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
2(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 175 mg, 0.53 mmol) was dissolved in methylene chloride and a 2.0 M solution of oxalyl chloride in methylene chloride (193 mg, 0.58 mmol) was added. The reaction stirred at 25° C. for 1 h. The reaction was chilled to 0° C. under nitrogen and 2,6-lutidine (142 μL, 1.22 mmol) was added dropwise. The reaction became golden brown, the ice bath was removed and the reaction continued to stir at 25° C. for 30 min. 1-Ethyl-1H-pyrazol-3-ylamine (59 mg, 0.51 mmol) was dissolved in methylene chloride and added dropwise to the reaction. The solution continued to stir at 25° C. for 16 h. The reaction was diluted with methylene chloride, washed with water and saturated aqueous brine solution. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 10% ethyl acetate/hexanes to 70% ethyl acetate/hexanes) afforded 2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(1-ethyl-1H-pyrazol-3-yl)-propionamide as a white powder (139 mg, 62%) ESI-LRMS m/e calcd for C20H26ClN3O3S [M+] 423.1, found 424.1 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.07-1.21 (m, 2H, CH2), 1.44 (t, J=7.3 Hz, 3H, CH3), 1.47-1.96 (m, 8H, 4×CH2), 2.16-2.29 (m, 1H, CH), 3.26 (s, 3H, SO2CH3), 3.53 (t, J=7.5 Hz, 1H, CH), 4.03 (q, J=7.3 Hz, 2H, NCH2), 6.64 (d, J=2.3 Hz, 1H, Ar), 7.27 (d, J=2.3 Hz, 1H, Ar), 7.46 (dd, Jo=8.1, Jm=1.7 Hz. 1H, Ar), 7.59 (d, Jm=1.7 Hz, 1H, Ar), 7.94 (s, 1H, NH), 8.08 (d, Jo=8.1 Hz, 1H, Ar).