Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1CNC(C2C=CN=C(NC(=O)C3C=CC=CC=3)C=2)=N1.[F:22][C:23]1[CH:24]=[C:25]([CH:47]=[C:48]([F:50])[CH:49]=1)[CH2:26][CH:27]1[CH2:31][NH:30][C:29]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([NH:38][C:39](=[O:46])[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH:33]=2)=[N:28]1>>[F:50][C:48]1[CH:47]=[C:25]([CH:24]=[C:23]([F:22])[CH:49]=1)[CH2:26][C:27]1[N:28]=[C:29]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([NH:38][C:39](=[O:46])[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH:33]=2)[NH:30][CH:31]=1
Reactant: O=C(Nc1cc(C2=NC(Cc3cc(F)cc(F)c3)CN2)ccn1)c1ccccc1
Agent: CC1CNC(c2ccnc(NC(=O)c3ccccc3)c2)=N1
Product: O=C(Nc1cc(-c2nc(Cc3cc(F)cc(F)c3)c[nH]2)ccn1)c1ccccc1
Yield: 32 %

Procedure:
Following the procedure as described in Example 10, making variations as required to replace N-(4-(4-methyl-4,5-dihydro-1H-imidazol-2-yl)pyridin-2-yl)benzamide with N-(4-(4-(3,5-difluorobenzyl)-4,5-dihydro-1H-imidazol-2-yl)pyridin-2-yl)benzamide, N-(4-(4-(3,5-difluorobenzyl)-1H-imidazol-2-yl)pyridin-2-yl)benzamide was obtained as a colorless solid in 32% yield: 1H NMR (300 MHz, CDCl3) δ 8.98 (br s, 1H), 8.67 (s, 1H), 8.22 (d, J=3.6 Hz, 1H), 7.88-7.81 (m, 2H), 7.73 (d, J=4.8 Hz, 1H), 7.61-7.40 (m, 3H), 6.82 (s, 1H), 6.78-6.70 (m, 1H), 6.66-6.57 (m, 2H), 3.94 (s, 2H); MS (ES+) m/z 391.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:17][CH2:18][CH2:19][O:20]C3CCCCO3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][O:9]2)=[CH:4][CH:3]=1>Cl.C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:17][CH2:18][CH2:19][OH:20])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][O:9]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(C2(CCCOC3CCCCO3)OCc3ccccc32)cc1
Agent: Cl
Solvent: CCO
Product: OCCCC1(c2ccc(F)cc2)OCc2ccccc21

Procedure:
39.6 Parts of 1-(4-fluorophenyl)-1,3-dihydro-1-[3-(tetrahydro-2H-pyran-2-yloxy)propyl]isobenzofuran were dissolved in 9.8 parts of a hydrochloric acid solution 0.1M and 788 parts of ethanol and the whole was stirred and refluxed for 1 hour. The solvent was evaporated and the residue was taken up in methylbenzene and water. The organic phase was separated, washed with water, dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (99:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 24.2 parts of 1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-1-propanol as a residue (intermediate 94).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[C:15]([O:22][C:23]1[CH:28]=[CH:27][C:26](N)=[CH:25][CH:24]=1)[CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].N([O-])=O.[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+].[Cl-:41].[Na+]>O.Cl.S([O-])([O-])(=O)=O.[Cu+2]>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[C:15]([O:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:41])=[CH:25][CH:24]=1)[CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: [Cl-]
Reactant: CCOC(=O)c1ncc2[nH]c3cccc(Oc4ccc(N)cc4)c3c2c1COC
Agent: [Cu+2]
Agent: Cl
Agent: O=N[O-]
Solvent: O
Product: CCOC(=O)c1ncc2[nH]c3cccc(Oc4ccc(Cl)cc4)c3c2c1COC
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 63.5 %

Procedure:
195 mg 5-(4-aminophenoxy)-4-methoxymethyl-beta-carboline-3-carboxylic acid ethyl ester is suspended in a mixture of 2 ml of water and 2 ml of concentrated hydrochloric acid and, after cooling to 0° C., is mixed drop by drop with a solution of 35 mg of sodium nitrite in 0.5 ml of water. After the addition is completed, it is stirred for 45 minutes at 0° C., whereby a bright yellow solution results. To this is added at 0° C. drop by drop a solution which was previously prepared by addition of 69 mg of sodium sulfate in 0.5 ml of water to 250 mg of copper(II) sulfate, 5 H2O and 87 mg of sodium chloride in 1 ml of water, suctioning off of the precipitate and dissolution in 0.5 ml of concentrated hydrochloric acid. After the addition is completed, a yellow precipitation has occurred and the mixture is then heated to the end of the development of gas on the steam bath. Then it is diluted with water, alkalized with ammonia solution and extracted with ethyl acetate. After evaporation of the organic phase, it is chromatographed over silica gel with methylene chloride: ethanol=10:1 as eluant. 130 mg (55% of theory) of 5-(-4-chlorophenoxy)-4-methoxymethyl-beta-carboline-3-carboxylic acid ethyl ester with a melting point of 207° C. is obtained.
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].CC(C)([O-])C.[K+].[Cl:12][C:13]1[C:14]([O:30][C:31]2[CH:32]=[N:33][C:34]([O:38][C@H:39]([CH3:44])[C:40]([F:43])([F:42])[F:41])=[C:35]([Cl:37])[CH:36]=2)=[CH:15][C:16]([F:29])=[C:17]([CH:28]=1)[C:18](OC1C=CC(C)=CC=1)=[O:19]>C1COCC1>[Cl:12][C:13]1[C:14]([O:30][C:31]2[CH:32]=[N:33][C:34]([O:38][C@H:39]([CH3:44])[C:40]([F:42])([F:43])[F:41])=[C:35]([Cl:37])[CH:36]=2)=[CH:15][C:16]([F:29])=[C:17]([CH:28]=1)[C:18]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[O:19]
Reactant: CS(N)(=O)=O
Reactant: Cc1ccc(OC(=O)c2cc(Cl)c(Oc3cnc(O[C@H](C)C(F)(F)F)c(Cl)c3)cc2F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C[C@@H](Oc1ncc(Oc2cc(F)c(C(=O)NS(C)(=O)=O)cc2Cl)cc1Cl)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 47.7 %

Procedure:
To a solution of methanesulfonamide (105 mg, 1.1 mmol) in THF (4 mL) was added potassium tert-butoxide (126 mg, 1.1 mmol) and the mixture was stirred for 10 minutes at room temperature. A solution of 4-methylphenyl 5-chloro-4-({5-chloro-6-[(1R)-2,2,2-trifluoro-1-methylethoxy]pyridin-3-yl}oxy)-2-fluorobenzoate (Preparation 234, 429 mg, 0.85 mmol) in THF (4 mL) was added and the resulting mixture was stirred at 50° C. for 3 hours. The reaction mixture was allowed to cool to room temperature. The reaction was quenched with water and acidified with 1N aqueous citric acid solution. The mixture was partitioned between water and DCM (3×5 mL) and filtered through a phase separation cartridge. The filtrate was concentrated in vacuo to give a crude solid that was purified using trituration with heptanes/acetone 9/1 to give the title compound (199 mg, 48%) as a white solid.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.[O:18]1[C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:21]2[C:20]([C:27](OC)=[O:28])=[CH:19]1>O1CCCC1>[OH:28][CH2:27][C:20]1[C:21]2[C:22](=[N:23][CH:24]=[CH:25][CH:26]=2)[O:18][CH:19]=1
Reactant: COC(=O)c1coc2ncccc12
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OCc1coc2ncccc12
Temperature: -75 °C
Reaction time: 0.67 h
Yield: 92.6 %

Procedure:
Diisobutylaluminium hydride in toluene (1.5M; 2.4 ml, 3.6 mmol) was added dropwise to a solution of methyl furo[2,3-b]pyridine-3-carboxylate (0.28 g, 1.58 mmol) in tetrahydrofuran (10 ml) at -75° C. The resulting solution was stirred at -75° C. for 40 minutes, the cooling bath removed and the mixture allowed to warm to room temperature. The reaction mixture was stirred at room temperature for 15 minutes, recooled to -40° C. and quenched by sequential addition of methanol (0.5 ml), water (0.25 ml) and 2M sodium hydroxide (0.25 ml). The mixture was allowed to warm up to produce a gel (exotherm observed), which was filtered off and washed with dichloromethane (8×10 ml). The filtrate was evaporated, the residue redissolved in dichloromethane and the solution dried (MgSO4). The solution was concentrated in vacuo to afford the title compound (0.2182 g, 93%) as a colourless solid; δH (CDCl3) 1.94 (1H, br s, CH2OH), 4.85 (2H, s, CH2OH), 7.26 (1H, dd, J 7.6, 4.9 Hz, 5-H), 7.69 (1H, s, 2-H), 8.05 (1H, dd, J 7.6, 1.7 Hz, 4-H), 8.34 (1H, dd, J 4.9, 1.7 Hz, 6-H).
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[S:8][CH:7]=1)=[O:5].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[C:11]1([C:9]2[S:8][CH:7]=[C:6]([CH:4]=[O:5])[CH:10]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CON(C)C(=O)c1csc(-c2ccccc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1csc(-c2ccccc2)c1
Reaction time: 1 h

Procedure:
At −78° C., to a solution of 38f (2.5 mmol) in 5 mL THF under argon protection was added a solution of LiAlH4 in THF (1 N, 1.42 mL) and stirring continued at 1 h at −20° C. The reaction mixture was placed on an ice bath and quenched by 20% H2SO4 solution, extracted with ethyl acetate and dried over MgSO4. The solvent was removed under reduced pressure and purified by column chromatography to yield 5-phenylthiophene-3-carbaldehyde (not shown) (84.8%). 1H NMR (CDCl3) δ 9.98 (s, 1H), 8.04 (d, 1H, J=1.5 Hz), 7.86 (br, 1H), 7.61-7.58 (br, 2H), 7.47-7.33 (m, 3H), 7.35-7.32 (m, 1H), 6.78 (d, 1H, J=4.0 Hz); MS (ESI) m/z 210.9 (M+Na)+. To a solution of 5-phenylthiophene-3-carbaldehyde (0.195 g, 1.04 mmoL) in 5 mL THF was added a THF solution of 3,4,5-trimethoxyphenylmagnesiumbromide (0.5 N, 2.3 mL, 1.14 mmol) at 0° C. The mixture was allowed to stir for 30 min and quenched with satd. NH4Cl, extracted with ethyl ether, dried with MgSO4. The solvent was removed under reduced pressure to yield a crude product, which was purified by column chromatography to obtain pure compound 40f. (70.5%). 1H NMR (CDCl3) δ 7.55-7.52 (m, 2H), 7.40-7.35 (m, 3H), 7.30 (br, 1H), 7.20 (br, 1H), 6.72 (s, 2H), 6.01 (d, 1H, J=3.9 Hz), 3.86 (s, 6H), 3.85 (s, 3H), 2.42 (d, 1H, J=3.9 Hz); MS (ESI) m/z 339.1 (M-OH)−.
Reaction SMILES: P(OCC)(OCC)([S-])=[S:2].[CH3:10][O:11][C:12]([C:14]1[C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N+:28]([O-:30])=[O:29])=[CH:16][CH:17]=[C:18]([C:20]#[N:21])[CH:19]=1)=[O:13]>C1COCC1.O>[CH3:10][O:11][C:12]([C:14]1[C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N+:28]([O-:30])=[O:29])=[CH:16][CH:17]=[C:18]([C:20](=[S:2])[NH2:21])[CH:19]=1)=[O:13]
Reactant: CCOP(=S)([S-])OCC
Reactant: COC(=O)c1cc(C#N)ccc1-c1ccccc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 45 h
Yield: 51.8 %

Procedure:
O,O′-Diethyl dithiophosphate (available from Aldrich Chemical Company, Inc.; 6.85 g, 36.8 mmol) was added to a solution of compound 4-cyano-2′-nitro-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 3; 8.62 g, 30.5 mmol) in a mixture of THF (96 mL) and water (24 mL). The resulting mixture was stirred at 80° C. for 45 h and then evaporated to a small volume. Ethyl acetate (500 mL) was added and the mixture was washed with water (250 mL) and sat. NaHCO3 (250 mL), dried over anhydrous sodium sulfate, filtered, evaporated, and purified by silica gel chromatography, using 17-50% ethyl acetate/petroleum ether as eluent, to give 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (5.0 g, 52%). 1H NMR (300 MHz, CDCl3) δ 8.50 (d, J=2.1 Hz, 1H), 8.18-8.15 (m, 2H), 7.70-7.54 (m, 3H), 7.32 (s, 1H), 7.30 (s, 1H), 7.24 (d, J=1.2 Hz, 1H), 3.69 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C@H:5](O)[CH2:4][C@H:3]1[CH2:8][O:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1.CCN(S(F)(F)[F:22])CC>C(Cl)Cl>[F:22][C@@H:5]1[CH2:6][N:2]([CH3:1])[C@H:3]([CH2:8][O:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH2:4]1
Reactant: CN1C[C@H](O)C[C@H]1COc1cccnc1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CN1C[C@@H](F)C[C@H]1COc1cccnc1
Temperature: -78 °C
Reaction time: 4 h

Procedure:
A 100 mg (0.5 mmol) sample of 3-((trans-1-methyl-4-hydroxy-2(S)-pyrrolidinyl)methoxy)pyridine, from Example 23 above, above was dissolved in 10 mL of methylene chloride and cooled to -78° C. To this was added 0.165 mL (1.25 mmol) of DAST, and the mixture was stirred for 4 hours while allowing the reaction mixture to warm to room temperature. The reaction was quenched by addition of satd NaHCO3 solution, and the mixture was extracted with chloroform. The solvent was removed, and the residue was purified by chromatography on silica gel, eluting with 20:1 CHCl3 :methanol, to give 30 mg of title compound.
Reaction SMILES: [Br-:1].[NH2:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[CH2:10][P+:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:30](Cl)(=[O:33])[CH:31]=[CH2:32].N1C=CC=CC=1>C(Cl)Cl>[Br-:1].[F:9][C:7]1[CH:6]=[CH:5][C:4]([CH2:10][P+:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[C:3]([NH:2][C:30](=[O:33])[CH:31]=[CH2:32])[CH:8]=1
Reactant: C=CC(=O)Cl
Reactant: Nc1cc(F)ccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CC(=O)Nc1cc(F)ccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 80.9 %

Procedure:
A suspension of 89 g (0.19 mol) of [(2-amino-4-fluorophenyl)methyl]-triphenylphosphonium bromide in 1.5 L CH2Cl2 was stirred and 17 mL (0.21 mol) of acryloyl chloride was added dropwise. A 22.8 mL sample of pyridine was added dropwise. The mixture was heated under reflux for 45 min. The mixture was cooled, washed with K2CO3 solution, dilute hydrochloric acid and brine. It was dried (Na2SO4), concentrated and triturated with Et2O to give 80 g (81%) of [[4-fluoro-2-[(1-oxo-2-propenyl)amino]phenyl]methyl]triphenylphosphonium bromide as a yellowish solid: 1H NMR (CDCl3) δ 8.0-7.4 (m, 15H); 6.9 (m, 2H); 6.4 (m, 1H); 6.1 (d, 1H); 5.9 (d, 2H); 5.5 (d, 1H). ##STR18##
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)=[N:17][O:18][C:19]=3[C:20]([F:23])([F:22])[F:21])[N:12]=[CH:11]2)=[N:6][CH:5]=1.[F:32][C:33]([F:37])([F:36])[CH2:34][NH2:35]>>[F:30][C:27]1[CH:28]=[CH:29][C:24]([C:16]2[C:15]([C:13]3[N:12]=[CH:11][N:10]([C:7]4[CH:8]=[CH:9][C:4]([C:3]([NH:35][CH2:34][C:33]([F:37])([F:36])[F:32])=[O:2])=[CH:5][N:6]=4)[CH:14]=3)=[C:19]([C:20]([F:23])([F:21])[F:22])[O:18][N:17]=2)=[CH:25][CH:26]=1
Reactant: NCC(F)(F)F
Reactant: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccc(F)cc4)noc3C(F)(F)F)c2)nc1
Product: O=C(NCC(F)(F)F)c1ccc(-n2cnc(-c3c(-c4ccc(F)cc4)noc3C(F)(F)F)c2)nc1
Yield: 95.8 %

Procedure:
As described for Example 38b, 6-{4-[3-(4-fluoro-phenyl)-5-trifluoromethyl-isoxazol-4-yl]-imidazol-1-yl}-nicotinic acid methyl ester (100 mg, 0.23 mmol), was converted, using 2,2,2-trifluoroethylamine (74.19 μL, 0.9 mmol) instead of cyclopropanemethylamine, to the title compound (110 mg, 95%) which was obtained as a white solid. MS: m/e=499.8 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][CH2:12][CH:11]([OH:15])[CH2:10]2)[C:5]([F:16])=[CH:4][N:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[CH2:10]2)[C:5]([F:16])=[CH:4][N:3]=1
Reactant: OC1CCC[C@H](Nc2nc(Cl)ncc2F)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=C1CCC[C@H](Nc2nc(Cl)ncc2F)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 93 %

Procedure:
To 700 ml DCM solution of 7.9 g (32.16 mmol) (3S)-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]cyclohexanol, 29a, (7.90 g, 32.16 mmol) in CH2Cl2 (700 mL) was added Dess-Martin reagent (17.73 g, 41.81 mmol). The reaction mixture was stirred at room temperature for 20 hours until TLC chromatography indicated reaction was complete. The reaction mixture was filtered through a pad of celite, and the resulting filtrate was washed with 200 mL of aqueous saturated NaHCO3 solution and 200 mL brine. The organic phase was dried with MgSO4, filtered and the solvent was removed under reduced pressure. The product was purified by silica gel chromatography (50% EtOAc/hexanes) to afford 7.3g of the desired product, 29b (93% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:11])=[CH:9][CH:10]=1)=[O:5])[CH3:2].[F:12][C:13]([F:25])([F:24])[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21](Cl)=[O:22])=[CH:16][CH:15]=1>ClCCCl>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:11])=[C:9]([C:21](=[O:22])[CH2:20][C:17]2[CH:16]=[CH:15][C:14]([C:13]([F:24])([F:12])[F:25])=[CH:19][CH:18]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: O=C(Cl)Cc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)c1ccc(C)[nH]1
Solvent: ClCCCl
Product: CCOC(=O)c1cc(C(=O)Cc2ccc(C(F)(F)F)cc2)c(C)[nH]1
Yield: 33 %

Procedure:
5-Methyl-4-[2-(4-trifluoromethyl-phenyl)-acetyl]-1H-pyrrole-2-carboxylic acid ethyl ester (117) was synthesized from 5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (107) and (4-trifluoromethylphenyl)-acetyl chloride following the procedure described in Example 32. Reaction Conditions: 1,2-dichloroethane/−40° C. Purification: prep/HPLC. Yield: 33%. 1H (CDCl3, 400 MHz): δ 10.5 (NH, broad s), 7.56 (2H, d), 7.34 (2H, d), 7.32 (1H, s), 4.37 (2H, q), 4.15 (2H, s), 2.59 (3H, s), 1.38 (3H, t) ppm. 13C (CDCl3, 100 MHz): δ 193.3, 161.5, 141.0, 139.0, 130.9, 125.5, 128.6, 121.4, 120.6, 114.0 61.0, 46.5, 14.5, 14.0 ppm. LC/MS: 98%.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[F:28][C:29]1[CH:30]=[C:31]([S:36](Cl)(=[O:38])=[O:37])[CH:32]=[C:33]([F:35])[CH:34]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[S:36]([C:31]2[CH:30]=[C:29]([F:28])[CH:34]=[C:33]([F:35])[CH:32]=2)(=[O:38])=[O:37])=[CH:4][CH:3]=1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccccc21
Reactant: O=S(=O)(Cl)c1cc(F)cc(F)c1
Product: O=C1OC2(CCN(C(=O)c3cn(S(=O)(=O)c4cc(F)cc(F)c4)c4cc(Cl)ccc34)CC2)c2ccccc21

Procedure:
Following the general procedure VII as described above, the sulphonylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 16 above) with commercially available 3,5-difluorobenzenesulfonyl chloride gave the title compound.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:16]=[N:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[BH4-].[Na+]>CO>[N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: C(=NCCc1ccccc1)c1ccccc1OCCN1CCOCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: c1ccc(CCNCc2ccccc2OCCN2CCOCC2)cc1
Yield: 78.4 %

Procedure:
N-[[2-[2-(4-Morpholinyl)ethoxy]phenyl]methylene]benzeneethanamine (68.5 g) is reduced with 22.5 g of sodium borohydride in 350 ml of methanol following the procedure described in Example 1B to yield 54 g of product as an oil, boiling point 216°-220° C at 0.2-0.3 mm of Hg.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([C:9]2[CH:14]=[C:13]([O:15][C:16]3[C:21]([CH3:22])=[CH:20][C:19]([N+:23]([O-:25])=[O:24])=[CH:18][C:17]=3[CH3:26])[CH:12]=[CH:11][C:10]=2[O:27][CH3:28])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C.O>C(Cl)Cl>[CH:1]1([CH2:6][CH2:7][C:9]2[CH:14]=[C:13]([O:15][C:16]3[C:17]([CH3:26])=[CH:18][C:19]([N+:23]([O-:25])=[O:24])=[CH:20][C:21]=3[CH3:22])[CH:12]=[CH:11][C:10]=2[O:27][CH3:28])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1C(=O)CC1CCCC1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1CCC1CCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.8 %

Procedure:
To a solution of 2-cyclopentyl-1-[5-(2,6-dimethyl-4-nitro-phenoxy)-2-methoxy-phenyl]-ethanone (200 mg, 0.52 mmol) and trifluoroacetic acid (0.34 mL) in CH2Cl2 (0.5 mL) was added triethylsilane (212 mg, 1.83 mmol). After stirring at RT for 18 h, the reaction mixture was poured into water (15 mL) and extracted with EtOAc (20 mL). The EtOAc extract was washed with sat'd sodium bicarbonate (2×15 mL), brine (15 mL), dried and concentrated. The residue was purified by preparative TLC (CH2Cl2:Hexanes=2:3) to give the title compound of Step B (186 mg) as an oil. MS (APCl−) Calc.: 369.2. Found: 468.3 (M−1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([NH2:12])[N:3]=1.[N+:13]([O-])([OH:15])=[O:14].[NH4+].[OH-]>OS(O)(=O)=O>[NH2:12][C:4]1[C:5]([N+:13]([O-:15])=[O:14])=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:7]=[C:2]([NH2:1])[N:3]=1
Reactant: Nc1cc(C(F)(F)F)cc(N)n1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: Nc1cc(C(F)(F)F)c([N+](=O)[O-])c(N)n1
Temperature: 25 °C

Procedure:
To a mixture of 2,6-diamino-4-trifluoromethylpyridine (173 mg) in H2SO4 (3 mL) at 0° C. was added HNO3 (0.048 mL, d=1.40). The stirred mixture was sequentially warmed to RT, aged 1.5 hours, poured onto 50 g ice, neutralized with NH4OH, extracted with EtOAc, filtered through 20 g SiO2 (washed with EtOAc until yellow color eluted), and concentrated to give 70 mg of 2,6-diamino-3-nitro-4-trifluoromethylpyridine as a yellow solid. A 1:1 THF/MeOH solution of the nitro compound (65 mg) was hydrogenated (1 atm H2, Ra-Ni, 16 hours at RT), filtered, concentrated, and converted to the title compound by the method outlined in Example 21. FAB MS (M+ +1)=465; 1H NMR (300 MHz, CD3OD) δ7.61 (t, 2H, J=7.8 Hz), 7.54-7.48 (m, 2H), 7.13-7.04 (AB q, 4H), 6.74 (s, 1H), 5.41 (s, 2H), 2.79 (q, 2H, J=7.5 Hz), 1.16 (t, 3H, J=7.5 Hz).
Reaction SMILES: [F:1][C:2]1[C:3]([C:10]2[C:14]([Cl:15])=[C:13]([O:16][CH:17]([F:19])[F:18])[N:12]([CH3:20])[N:11]=2)=[N:4][C:5](Cl)=[C:6]([Cl:8])[CH:7]=1.[CH:21]([Sn](CCCC)(CCCC)CCCC)=[CH2:22]>CN(C)C=O>[F:1][C:2]1[C:3]([C:10]2[C:14]([Cl:15])=[C:13]([O:16][CH:17]([F:19])[F:18])[N:12]([CH3:20])[N:11]=2)=[N:4][C:5]([CH:21]=[CH2:22])=[C:6]([Cl:8])[CH:7]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Cn1nc(-c2nc(Cl)c(Cl)cc2F)c(Cl)c1OC(F)F
Solvent: CN(C)C=O
Product: C=Cc1nc(-c2nn(C)c(OC(F)F)c2Cl)c(F)cc1Cl
Temperature: 67 °C
Reaction time: 24 h
Yield: 287 %

Procedure:
30 g of 3-(3-fluoro-5,6-dichloro-2-pyridyl)-4-chloro-5-difluoromethoxy-1-methyl-[1H]-pyrazole (Example H21) are dissolved in 200 ml of N,N-dimethylformamide (DMF). After addition of 32.9 g of vinyltributyltin, the mixture is twice evacuated and gassed with argon. A little (i.e. a spatula-tip) 2,6-di-tert-butyl-p-cresol and 3.0 g of bistriphenylphosphinepalladium dichloride (PdCl2(PPh3)2) are then added and the mixture is stirred at a temperature of 67° C. for 24 hours. After cooling to 22° C., the reaction mixture is filtered over Hyflo and partitioned between dilute hydrochloric acid and diethyl ether. The ether phase which has been separated off is washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. 84 g of a black oil are obtained, and this is purified over a silica gel flash column (eluting agent: n-hexanelethyl acetate 6/1). The resulting solid is stirred with 100 ml of n-hexane for a further 2 hours, filtered off, washed and dried. 16.4 g of the desired title compound are obtained as a white solid of melting point 75-77° C.
Reaction SMILES: [CH2:1](Cl)[CH:2]=[CH:3][CH3:4].[Mg].[Cl:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1>O1CCCC1>[CH3:4][CH:3]([CH:12]([C:11]1[CH:14]=[CH:15][C:8]([Cl:7])=[CH:9][CH:10]=1)[OH:13])[CH:2]=[CH2:1]
Reactant: CC=CCCl
Reactant: O=Cc1ccc(Cl)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CC(C)C(O)c1ccc(Cl)cc1
Temperature: 0 °C
Yield: 70.5 %

Procedure:
Crotyl chloride (154.7 g, 1.71 mol) in dry tetrahydrofuran (530 ml) was added to magnesium turnings (46.0 g, 1.89 mol) in dry tetrahydrofuran (130 ml) at such a rate so as to maintain steady reflux. After addition was complete the mixture was heated under reflux for a further hour and then cooled to 0° C. 4-Chlorobenzaldehyde (120.0 g, 0.854 mol) in dry tetrahydrofuran (780 ml) was added over a period of 2 hours. After a further hour the solution was decanted from the excess magnesium into saturated aqueous ammonium chloride solution and the magnesium washed with ether. 2M Hydrochloric acid was added to dissolve the precipitate and the mixture extracted with ether. The combined extracts were washed with water, dried and evaporated in vacuo. Partial purification was achieved by chromatography [SiO2, hexane-ethyl acetate mixtures] to give 3-methyl-4-(4-chlorophenyl)-but-1-en-4-ol (118.45 g, approximately 90% pure, approximately 64%).