Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:16])[CH:11]=[C:12]([CH3:15])[NH:13][CH:14]=1)C1C=CC=CC=1.[H][H].[ClH:19]>CO.O.[Pd]>[ClH:19].[OH:8][C:9]1[C:10](=[O:16])[CH:11]=[C:12]([CH3:15])[NH:13][CH:14]=1
Reactant: Cc1cc(=O)c(OCc2ccccc2)c[nH]1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: Cc1cc(=O)c(O)c[nH]1

Procedure:
5-Benzyloxy-2-methyl-1H-pyridin-4-one (15.5 g, 72.0 mmol) was mixed with 10% Pd/C (1.60 g) in methanol (200 mL) and water (35 mL) in a Parr hydrogenator bottle. The mixture was hydrogenated on a Parr hydrogenator for 45 minutes at 50 psi hydrogen pressure. 6N HCl (12 mL) was added. A CELITE™ bed was prepared on a sintered glass, and washed with 6M HCl (100 mL), followed by water (7×50 mL) and then methanol (2×50 mL) under suction. The reaction mixture was filtered through the pre-treated CELITE™ bed. The filtrate was evaporated to dryness and the residue was triturated with acetone, then filtered to give 5-hydroxy-2-methyl-1H-pyridin-4-one hydrochloride 9.30 g as off-white solid. The mother liquor was diluted with hexane and placed at room temperature over night to give an additional 1.63 g of product. Thus, 10.9 g of the title compound was obtained (94% yield). 1H NMR (90 MHz, MeOD) δ (ppm) 7.93 (s, 1H, CH), 7.07 (s, 1H, CH) 2.56 (s, 3H, CH3,). MS-ESI (m/z): 126.1 [M+1]+, 108.2, 110.1.
Reaction SMILES: Cl.C([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]#[N:15])[CH:12]=2)[C:7]([CH3:22])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:6]1)(=O)C.C([O-])(O)=O.[Na+]>C(#N)C>[CH3:22][C:7]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[C:13](=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)[NH:5][CH2:6]1
Reactant: CC(=O)N1CC(C)(c2ccccc2)c2ccc(C#N)cc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC1(c2ccccc2)CNc2cc(C#N)ccc21
Temperature: 25 °C
Yield: 94.8 %

Procedure:
5 M aqueous HCl (3 mL) was added to a solution of 1-acetyl-3-methyl-3-phenyl-2,3-dihydro-1H-indole-6-carbonitrile (250 mg, 0.9 mmol) in acetonitrile (10 mL). The solution was stirred at reflux for 1 h and then cooled to room temperature. Saturated aqueous NaHCO3 was then added to the reaction mixture until the pH of the solution reached 8 and the product was then extracted with EtOAc. The organic phase was dried over MgSO4 and concentrated in vacuo to give the title compound (200 mg) as a light brown gum. MS: [M+H]+=235.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@@H:9]1[C:14]([OH:16])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.[NH2:27][CH:28]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH:29]([OH:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31].C(Cl)CCl.CCN(C(C)C)C(C)C>C1COCC1.CN(C=O)C>[CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@@H:9]1[C:14]([NH:27][CH:28]([CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[CH:29]([OH:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@H]1CCC(=O)N1Cc1ccccc1
Reactant: CCOC(=O)C(O)C(N)Cc1ccccc1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)C(O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-1-benzyl-5-oxopyrrolidine-2-carboxylic acid (2440 mg, 11.13 mmol) in a mixture of 24 ml THF and 4 ml DMF were successively added at 5° C. 1-hydroxybenzotriazole (1875 mg, 12.24 mmol), ethyl 3-amino-2-hydroxy-4-phenylbutanoate (2485 mg, 11.13 mmol; preparation described in WO 98/25883, example 8a on page 24), EDC (2347 mg, 12.24 mmol) and DIPEA (6.41 mL; 4750 mg, 36.7 mmol). After stirring overnight at room temperature the reaction mixture was concentrated under reduced pressure, water was added and the obtained mixture was extracted three times with ethyl acetate. The organic layer was washed successively with aq. saturated NaHCO3 (2×), 10% aq. citric acid solution (3×) and brine, dried over Na2SO4 and the solvent was then removed under reduced pressure. The title compound was obtained as a yellow oil (4550 mg, yield: 96%), which was used without further purification in the next step.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:22]=[CH:21][C:9]([C:10]([NH:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][S:18][CH2:17][CH2:16]2)=[O:11])=[CH:8][CH:7]=1)(=[O:4])=[O:3].Cl.OO.S([O-])([O-])=[O:27].[Na+].[Na+]>O.CO>[CH3:1][S:2]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:12][CH2:13][CH2:14][N:15]2[CH2:16][CH2:17][S:18](=[O:27])[CH2:19][CH2:20]2)=[O:11])=[CH:21][CH:22]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)Nc1ccc(C(=O)NCCN2CCSCC2)cc1
Reactant: O=S([O-])[O-]
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)Nc1ccc(C(=O)NCCN2CCS(=O)CC2)cc1
Temperature: 0 °C

Procedure:
To 50 ml of methanol add 1.0 g (2.93 mmole) of 4-[(methylsulfonyl)amino]-N-[2-(thiomorpholin-4-yl)ethyl]benzamide. Add dropwise 3.08 ml (3.08 mmole) of 1.0N hydrochloric acid. Cool the solution to 0° C. Slowly add 0.70 ml (6.16 mmole) of 30% w/v hydrogen peroxide. Stir the reaction at ambient temperature. Monitor the progress of the reaction by thin layer chromatography on silica gel (methanol:1M NaCl; 95:5). Upon the completion of the reaction, add 25 ml of 10% sodium sulfite to the stirring solution. Filter the resulting solid. Evaporate the filtrate in vacuo to yield a solid. Stir this solid in H2O overnight, then filter the solid and recrystallize it from methanol to yield the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:6](B(O)O)=[C:5]([CH3:10])[O:4][N:3]=1.Br[C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2([OH:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([O-])([O-])=O.[Na+].[Na+].CC(=O)OCC>O1CCOCC1.O.CC(P(C(C)(C)C)C1[CH-]C=CC=1)(C)C.CC(P(C(C)(C)C)C1[CH-]C=CC=1)(C)C.[Cl-].[Cl-].[Fe+2].[Pd+2]>[CH3:1][C:2]1[C:6]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16](=[O:21])[C:15]3([OH:28])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[C:5]([CH3:10])[O:4][N:3]=1
Reactant: Cc1noc(C)c1B(O)O
Reactant: O=C1Nc2ccc(Br)cc2C1(O)c1ccccc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(C)(C)P(c1ccc[cH-]1)C(C)(C)C
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: Cc1noc(C)c1-c1ccc2c(c1)C(O)(c1ccccc1)C(=O)N2
Yield: 65.5 %

Procedure:
Under N2, a mixture of 3,5-dimethylisoxazol-4-ylboronic acid (28 g, 200 mmol, 1.5 eq), dichloro[1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II) (4.5 g, 6.1 mmol, 0.05 eq), 5-bromo-3-hydroxy-3-phenylindolin-2-one (40 g, 132 mmol, 1.0 eq) and Na2CO3 (45 g, 425 mmol, 3.2 eq) in dioxane/H2O (500 mL/120 mL) was heated to reflux for 5 h. After cooled down, 500 mL EA was added, the mixture was filtered through a pad of celite, the filter was washed with brine (500 mL×2), dried over Na2SO4, concentrated, purified by sili-gel to give product 27.7 g (yield, 65.6%). 1H NMR (400 MHz, DMSO-d6): δH 10.51 (s, 1H), 7.25-7.34 (m, 6H), 7.10 (m, 1H), 6.99-7.01 (d, 1H, J=8.0 Hz), 6.72 (s, 1H), 2.33 (s, 31H), 2.16 (s, 3H). MS (ESI) m/e [M+1]+ 321.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[C:11]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)([C:20]#[N:21])[CH:10]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[NH:9]1)=[O:7].[CH3:34][S:35](Cl)(=[O:37])=[O:36].CN(C1C=CC=CN=1)C>C(Cl)Cl>[CH3:34][S:35]([NH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[C:11]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)([C:20]#[N:21])[CH:10]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[NH:9]1)=[O:7])(=[O:37])=[O:36]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)CC1NC(C(=O)NCCCN)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)NCCCNS(C)(=O)=O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.6 %

Procedure:
A mixture of rac (2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-amino-propyl)-amide (120 mg, 0.24 mmol), methane sulfonyl chloride (49 μL, 0.6 mmol) and dimethylaminopyridine (97.6 mg, 0.8 mmol) in CH2Cl2 (8 mL) was stirred for 5 h at rt. The mixture was then extracted with NaHCO3(s), water and the organic layer dried with MgSO4, filtered and the solvent was evaporated under reduced pressure. diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then purified by reverse phase chromatography (20-95% of ACN/water) to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-methanesulfonylamino-propyl)-amide (112.1 mg, 80.5%) as an off-white powder. HRMS (ES+) m/z Calcd for C27H34Cl2N4O3S+H [(M+H)+]: 565.1802. found: 565.1800.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1([C:17](O)=O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[CH3:20][NH:21][CH3:22]>>[CH3:20][N:21]([CH3:22])[CH2:17][C:11]1([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CNC
Reactant: O=C(O)C1(c2ccc3ccccc3c2)CCCCC1
Product: CN(C)CC1(c2ccc3ccccc3c2)CCCCC1
Yield: 11 %

Procedure:
The title compound was synthesized from 1-(naphthalen-2-yl)cyclohexane-carboxylic acid and dimethyl amine using General Procedure G, followed by General Procedure E and was obtained in 11% yield as a clear oil. LCMS Rt=6.47 min, m/z=268 (M+1). 1H NMR (CDCl3, δ): 7.80 (m, 4H), 7.55 (dd, J=1.7, 8.6 Hz, 1H), 7.45 (m, 2H), 2.2 (m, 2H), 1.97 (s, 6H), 1.8-1.3 (m, 8H). 13C NMR (CDCl3, δ, mult): 133.4, 131.6, 127.9, 127.4, 127.2, 126.2, 126.1, 125.8, 125.5, 125.1, 72.6, 56.6, 48.4, 34.3, 26.6, 22.3.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=O)[CH:3]=1.C(N(CC)C(C)C)(C)C.Cl.[NH2:29][OH:30]>CO>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8]/[C:9](/[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[N:29]/[OH:30])[CH:3]=1
Reactant: NO
Reactant: COc1ccc(C(=O)Cc2cc(Br)ccn2)cc1
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(/C(Cc2cc(Br)ccn2)=N\O)cc1
Temperature: 60 °C
Reaction time: 48 h
Yield: 67.8 %

Procedure:
To a stirred solution of 2-(4-bromopyridin-2-yl)-1-(4-methoxyphenyl)ethanone (3.8 g, 12.4 mmol) and N,N-diisopropylethylamine (5.4 mL, 31 mmol) in methanol (60 mL) at room temperature was added hydroxylamine hydrochloride (1.7 g, 24.8 mmol). The mixture was stirred at 60° C. for 2 days. After cooling to room temperature, the precipitate formed was filtered and dried under vacuum to afford white needles (2.7 g, 68%). The material was used as is in the next step. LCMS m/z 321.0; 323.0 (M+H)+, ret. time=2.37 min.
Reaction SMILES: [NH4+].[Cl-].[NH4+].[OH-].[Br:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[C:8]([N+:15]([O-])=O)[C:7]=1[OH:18]>O>[NH2:15][C:8]1[CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=[C:6]([Br:5])[C:7]=1[OH:18]
Reactant: O=[N+]([O-])c1cc(Br)c(O)c([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: Nc1cc([N+](=O)[O-])cc(Br)c1O
Temperature: 85 °C

Procedure:
10 g of NH4Cl and 2 mL of NH4OH were added to a solution of 4.7 g of 2-bromo-4,6-dinitro-phenol and 50 mL of water. The mixture was heated to 85° C., and then cooled to 70° C. At this point 5.2 g of Na2S-9H2O was added, keeping reaction between 80-85° C. After addition, reaction was heated for 2 h at 85° C. Solution was then cooled in ice bath, and resulting precipitate was collected via filtration. The solid was then placed in 30 mL of water, brought to a boil, acidified with AcOH, along with 170 mg of norit being added. The solution was filtered hot, then cooled with 1.97 g of title compound crystalizing out of solution. The compound was carried on without further purification.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[CH2:3][O:4][C:5]1[CH:10]=[C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:8]=[CH:7][C:6]=1[CH2:17][C:18]([O:20]C)=[O:19].O.O[Li].O.Cl>C1COCC1>[F:23][C:2]([F:1])([F:22])[CH2:3][O:4][C:5]1[CH:10]=[C:9]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[CH:8]=[CH:7][C:6]=1[CH2:17][C:18]([OH:20])=[O:19]
Reactant: COC(=O)Cc1ccc(N2CCOCC2)cc1OCC(F)(F)F
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cc1ccc(N2CCOCC2)cc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a stirred solution of methyl 2-(2,2,2-trifluoroethoxy)-4-(4-morpholinyl)phenylacetate (0.22 g, 0.67 mmol) from Step 2 above in THF (2 mL) and water (0.5 mL) was added LiOH.H2O (0.056 g, 1.3 mmol). The mixture was stirred at ambient temperature for 14 h. The solution was adjusted to pH 3 by the addition of 5 N aqueous HCl and the solvents were removed under reduced pressure and the residue was purified by pressurized silica gel column chromatography using a gradient elution of 0-50% MeOH:CH2Cl2 as eluant. 2-(2,2,2-Trifluoroethoxy)-4-(4-morpholinyl)phenylacetic acid was obtained as a gum (HPLC retention time=5.8 min (method A)).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:26]3[CH:31]=[C:30]([CH3:32])[C:29]([O:33][CH3:34])=[C:28]([CH3:35])[CH:27]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:9]2=[O:25])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:45](Cl)(=[O:47])[CH3:46]>C(Cl)Cl>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:45](=[O:47])[CH3:46])=[CH:3][CH:4]=2)([C:26]2[CH:27]=[C:28]([CH3:35])[C:29]([O:33][CH3:34])=[C:30]([CH3:32])[CH:31]=2)[C:9]1=[O:25]
Reactant: COc1c(C)cc(C2(c3ccc(N)cc3)C(=O)N(Cc3ccccc3Cl)c3ccccc32)cc1C
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1c(C)cc(C2(c3ccc(NC(C)=O)cc3)C(=O)N(Cc3ccccc3Cl)c3ccccc32)cc1C
Yield: 94.5 %

Procedure:
Combine 3-(4-amino-phenyl)-1-(2-chloro-benzyl)-3-(4-methoxy-3,5-dimethyl-phenyl)-1,3-dihydro-indol-2-one (126 mg, 0.26 mmol), N,N-diisopropylethylamine (0.068 mL, 0.39 mmol) and acetyl chloride (0.020 mL, 0.29 mmol) in CH2Cl2 (1 mL) and stirred at room temperature for 48 h. Dilute with CH2Cl2 and wash with water. Backwash water with CH2Cl2 and ethyl acetate. Combine all organics, dilute with more CH2Cl2 and wash with 1N HCl and brine. Dry (MgSO4), filter and concentrate in vacuo to give a residual foam. Purify by flash chromatography (gradient of 33% EtOAc/hexanes to 66% EtOAc/hexanes) to give 129 mg (67%) of the title compound as a white foam. MS (ES): m/z=525 (M+1), 523 (M−1); 1H NMR(DMSO-d6): δ9.99 (s, 1H), 7.53 (m, 3H), 7.41-7.26 (m, 4H), 7.12 (m, 3H), 6.98 (m, 2H), 6.82 (s, 2H), 5.08 (s, 2H), 3.64 (s, 3H), 2.15 (s, 6H).
Reaction SMILES: C([O:3][C:4](=[O:21])[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[N:7][C:6]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)C.O.[OH-].[Li+].Cl>O1CCCC1>[Cl:20][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[Cl:19])[O:12][C:6]1[N:7]=[CH:8][C:9]([F:11])=[CH:10][C:5]=1[C:4]([OH:21])=[O:3]
Reactant: CCOC(=O)c1cc(F)cnc1Oc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(F)cnc1Oc1ccc(Cl)c(Cl)c1
Reaction time: 7 h
Yield: 98.4 %

Procedure:
2-(3,4-Dichloro-phenoxy)-5-fluoro-nicotinic acid ethyl ester (4.9 g, 14.8 mmol, see preparation 72) was dissolved in tetrahydrofuran (50 ml). Water (27 ml) and lithium hydroxide (1.56 g, 37.1 mmol) were added and the mixture was stirred vigorously for 7 hours. The reaction mixture was acidified to pH5 by addition of 2 M hydrochloric acid and the mixture was partitioned between ethyl acetate (200 ml) and water (200 ml). The aqueous layer was acidified to pH 3 by addition of 2 M hydrochloric acid and the phases were separated. The aqueous phase was extracted with ethyl acetate (2-fold 50 ml) and the combined organic solutions were dried over magnesium sulphate and concentrated in-vacuo to give 2-(3,4-dichloro-phenoxy)-5-fluoro-nicotinic acid as a white solid (4.4 g).
Reaction SMILES: [CH2:1]([C:3]1[C:15]([CH2:16][C:17]#[N:18])=[C:6]2[C:7]3[CH:13]=[C:12]([CH3:14])[O:11][C:8]=3[CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2]>[Co].N.C(O)C>[CH2:1]([C:3]1[C:15]([CH2:16][CH2:17][NH2:18])=[C:6]2[C:7]3[CH:13]=[C:12]([CH3:14])[O:11][C:8]=3[CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nn2ccc3oc(C)cc3c2c1CC#N
Agent: [Co]
Agent: N
Solvent: CCO
Product: CCc1nn2ccc3oc(C)cc3c2c1CCN
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.3 %

Procedure:
A mixture of (2-ethyl-8-methylfuro[3,2-c]pyrazolo[1,5-a]pyridin-1-yl)acetonitrile (232 mg, 0.970 mmol), Raney cobalt (2.3 g) and 2M ammonia/ethanol solution (20 mL) was stirred at room temperature for 16 hr under a hydrogen atmosphere. The catalyst was filtered through celite, and the filtrate was concentrated under reduced pressure to give the title compound (225 mg, yield 95%).
Reaction SMILES: [NH2:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@H:3]1[OH:11].C(N(CC)CC)C.Cl[CH2:20][CH2:21][N:22]([CH2:33][CH2:34]Cl)[S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24]>CN(C)C=O>[CH3:32][C:29]1[CH:30]=[CH:31][C:26]([S:23]([N:22]2[CH2:21][CH2:20][N:1]([C@H:2]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH2:4][C@H:3]3[OH:11])[CH2:34][CH2:33]2)(=[O:25])=[O:24])=[CH:27][CH:28]=1
Reactant: N[C@H]1c2ccccc2C[C@H]1O
Reactant: Cc1ccc(S(=O)(=O)N(CCCl)CCCl)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2CCN([C@H]3c4ccccc4C[C@H]3O)CC2)cc1
Temperature: 80 °C

Procedure:
To 8 g of (1S,2R)-1-aminoindan-2-ol (53.6 mmol) dissolved in 80 ml of dimethyl-formamide there are added 15 ml of triethylamine (107.2 mmol) and 15.8 g of N,N-bis(2-chloroethyl)-p-toluenesulphonamide (53.6 mmol). The mixture is heated at 80° C. for 24 hours and then the dimethylformamide is evaporated off. The residue is taken up in dichloromethane, washed, dried, filtered and evaporated. The oil obtained is purified by flash chromatography on silica (eluant: dichloromethane/ethyl acetate 95/5) to yield the expected product in the form of a meringue.
Reaction SMILES: [CH3:1][N:2]([S:6][N:7]([CH2:18][CH:19]([CH3:21])[CH3:20])[P:8]1(=[S:17])[O:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[O:9]1)[C:3](F)=[O:4].[OH:22][N:23]=[C:24]([S:26][CH3:27])[CH3:25].[OH-].[Na+]>C(Cl)Cl.[Cl-].C([N+](CC)(CC)CC)C.O>[CH3:1][N:2]([S:6][N:7]([CH2:18][CH:19]([CH3:21])[CH3:20])[P:8]1(=[S:17])[O:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[O:9]1)[C:3]([O:22][N:23]=[C:24]([S:26][CH3:27])[CH3:25])=[O:4]
Reactant: CSC(C)=NO
Reactant: CC(C)CN(SN(C)C(=O)F)P1(=S)Oc2ccccc2O1
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CSC(C)=NOC(=O)N(C)SN(CC(C)C)P1(=S)Oc2ccccc2O1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of N-(2-methylpropyl)-2-thioxo-1,3,2-benzodioxaphosphol-2-amine (16.2 g, 66.6 mmol) and triethylamine (7.3 g, 72 mmol) in tetrahydrofuran (50 ml) is added dropwise over 10 minutes to a solution of sulfur dichloride (8.1 g, 78.7 mmol) in tetrahydrofuran (50 ml) with cooling to maintain a temperature of -5° to 0°. After the addition, the mixture is stirred for two hours then diluted with ether (100 ml). The reaction mixture is filtered under nitrogen and the filtrate concentrated in vacuo. The residue is dissolved in dimethyl formamide (50 ml) and N-methyl carbamoyl fluoride (5.8 g, 75.3 mmol) added at once followed by dropwise addition of triethylamine (7.3 g, 72 mmol) in dimethyl formamide (10 ml) over 10 minutes with cooling in a bath at -25°. After the addition the mixture is stirred for two hours in a bath at 0°. The mixture is diluted with ether, washed with ice cold water, dried and concentrated to leave a crude N-methyl[[(2-methylpropyl)(2-thioxo-1,3,2-benzodioxaphosphol-2-yl)amino]thio]carbamic fluoride II"'. The carbamic fluoride is dissolved in methylene chloride (50 ml) and a solution of methyl N-hydroxyethanimidothioate (7.00 g, 66.6 mmol), tetraethylammonium chloride (1.00 g, 6.04 mmol) and sodium hydroxide (3.20 g, 80 mmol) in water (50 ml) is added at once. The mixture is stirred for 20 hours at room temperature, the phases separated, and the organic phase washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residual oil is triturated with ether to precipitate the product methyl N-[[[methyl[[(2-methylpropyl)(2-thioxo-1,3,2-benzodioxaphosphol-2-yl)amino]thio]amino]carbonyl]oxy]ethanimidothioate I"'.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2([C:16]([OH:18])=[O:17])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)C>C1(C)C(C)=CC=CC=1>[O:6]1[C:7]2[CH:12]=[CH:11][C:10]([C:13]3([C:16]([OH:18])=[O:17])[CH2:15][CH2:14]3)=[CH:9][C:8]=2[CH:4]=[CH:5]1
Reactant: CCOC(COc1ccc(C2(C(=O)O)CC2)cc1)OCC
Solvent: Cc1ccccc1C
Product: O=C(O)C1(c2ccc3occc3c2)CC1
Temperature: 140 °C
Yield: 11.4 %

Procedure:
To a suspension of crude 1-[4-(2,2-diethoxy-ethoxy)-phenyl]-cyclopropanecarboxylic acid (20 g, ˜65 mmol) in xylene (100 mL) was added PPA (22.2 g, 64.9 mmol) at room temperature. The mixture was heated at reflux (140° C.) for 1 hour before it was cooled to room temperature and decanted from the PPA. The solvent was evaporated under vacuum to obtain the crude product, which was purified by preparative HPLC to provide 1-(benzofuran-5-yl)cyclopropanecarboxylic acid (1.5 g, 5%). 1H NMR (400 MHz, DMSO-d6) δ 12.25 (br s, 1H), 7.95 (d, J=2.8 Hz, 1H), 7.56 (d, J=2.0 Hz, 1H), 7.47 (d, J=11.6 Hz, 1H), 7.25 (dd, J=2.4, 11.2 Hz, 1H), 6.89 (d, J=1.6 Hz, 1H), 1.47-1.44 (m, 2H), 1.17-1.14 (m, 2H).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:10]=[N:9]2)[S:5][CH:6]=1.[F:18][C:19]1[C:24]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C(O)C>[F:18][C:19]1[C:24]([C:25]([F:26])([F:27])[F:28])=[CH:23][CH:22]=[CH:21][C:20]=1[C:2]1[N:3]=[C:4]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:10]=[N:9]2)[S:5][CH:6]=1
Reactant: CCOC(=O)c1cnn(Cc2nc(Br)cs2)c1
Reactant: OB(O)c1cccc(C(F)(F)F)c1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cnn(Cc2nc(-c3cccc(C(F)(F)F)c3F)cs2)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 84.3 %

Procedure:
Under a nitrogen atmosphere, to a mixed solution of the compound (300 mg, 0.95 mmol) obtained in Example 30c and 2-fluoro-3-(trifluoromethyl)phenylboronic acid (260 mg, 1.1 mmol) in 1,2-dimethoxyethane/ethanol (v/v=3/1, 4 mL) were added 2N aqueous sodium carbonate solution (0.57 mL, 1.1 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (78 mg, 0.095 mmol), and the mixture was stirred at 90° C. overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was purified by column chromatography (hexane-hexane/ethyl acetate=70/30) to give the title compound (320 mg, 84%) as colorless crystals.