Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C([Zn][C:33]#[N:34])#N.Cl[C:36]1[N:41]=[CH:40][C:39]([OH:42])=[CH:38][C:37]=1[CH3:43]>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:42][C:39]1[CH:38]=[C:37]([CH3:43])[C:36]([C:33]#[N:34])=[N:41][CH:40]=1
Reactant: N#C[Zn]C#N
Reactant: Cc1cc(O)cnc1Cl
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: Cc1cc(O)cnc1C#N
Temperature: 110 °C
Reaction time: 21 h
Yield: 36.2 %

Procedure:
A resealable vessel was charged with Pd2dba3 (0.893 g, 0.975 mmol, Strem), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (0.858 g, 2.090 mmol, Strem), dicyanozinc (1.636 g, 13.93 mmol), and 6-chloro-5-methylpyridin-3-ol (2.00 g, 13.93 mmol, step 3 intermediate 34). The solids were taken up in DMF (45 mL) and the reaction mixture was purged with Argon. The vessel was sealed and heated in a 110° C. oil bath. After 21 h, the reaction was filtered through Celite and the filter cake was rinsed with 5% MeOH-DCM. The filtrate was concentrated and the residue was purified by silica gel chromatography, eluting with 40% to 50% EtOAc-hexane to afford the title compound (676 mg, 32%). MS m/z=135 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4]([OH:16])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1.[C:17]1([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)CCC>Cl>[ClH:1].[ClH:1].[N+:13]([C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][CH:4]([OH:16])[CH2:3][CH2:2][N:26]2[CH2:27][CH2:28][N:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:24][CH2:25]2)=[CH:8][CH:9]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1ccc(OCC(O)CCCl)cc1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: O=[N+]([O-])c1ccc(OCC(O)CCN2CCN(c3ccccc3)CC2)cc1

Procedure:
This compound was prepared according to the procedure of Example 97. A mixture of 12.3 g (0.05 mole) of 4-chloro-1-(4-nitrophenoxy)-2-butanol, 8.1 g (0.05 mole) of 1-phenylpiperazine, and 26.0 g (0.25 mole) of anhydrous sodium carbonate in a total volume of 250 ml of 1-butanol gave a golden oil as residue. The hydrochloride was formed in ethereal hydrogen chloride and the collected solid was recrystallized thrice from methanol-water to give 1.1 g (5%) of white solid, m.p. 195°-200° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N1C=CN=C1)([N:23]1C=CN=C1)=O.NC[CH2:35][CH:36]1[CH2:40][CH2:39][CH2:38][N:37]1[CH2:41][CH3:42]>O1CCCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]([CH2:17][C:18]([NH:23][CH2:35][CH:36]3[CH2:40][CH2:39][CH2:38][N:37]3[CH2:41][CH3:42])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2cccc(Cl)c2)nc2cccnc21
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCN1CCCC1CCN
Solvent: C1CCOC1
Product: CCN1CCCC1CNC(=O)Cn1c(-c2cccc(Cl)c2)nc2cccnc21
Product: Cl
Temperature: 25 °C
Yield: 31.8 %

Procedure:
A solution of 2-(3-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.76 g, 0.020 mole), 1,1'-carbonyldiimidazole (3.24 g, 0.020 mole), and anhydrous tetrahydrofuran (250 ml) was stirred at room temperature with a stream of nitrogen bubbling through for 2 hrs. The nitrogen flow was stopped and a solution of 2-(aminoethyl)-1-ethyl pyrrolidine (2.56 g, 0.02 mole) in dry tetrahydrofuran (50 ml) was added. The solution was stoppered and stirred at room temperature over the weekend. The reaction was concentrated in vacuo and partitioned between ethyl acetate (100 ml) and 5% potassium hydroxide solution (50 ml). The layers were separated and the aqueous portion washed with ethyl acetate (50 ml), water (25 ml), brine (25 ml), dried over sodium sulfate, and concentrated in vacuo. The solid residue was converted to the dihydrochloride salt and crystallized from isopropyl alcohol-diethyl ether. Recrystallization from isopropyl alcohol-isopropyl ether gave 1.38 g (15%) of an off-white solid, mp 186°-190° C. with decomposition.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH3:13][CH:14]1[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[C:23]([F:26])([F:25])[F:24])[NH:15]1.[N:27]1([C:33]2[N:34]=[C:35]([CH2:40][C:41]([O-])=[O:42])[NH:36][C:37](=[O:39])[CH:38]=2)[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.[Na+]>CN(C)C=O.N1C=CC=CC=1.O>[CH3:13][CH:14]1[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[C:23]([F:24])([F:26])[F:25])[N:15]1[C:41](=[O:42])[CH2:40][C:35]1[NH:36][C:37](=[O:39])[CH:38]=[C:33]([N:27]2[CH2:28][CH2:29][O:30][CH2:31][CH2:32]2)[N:34]=1
Reactant: CC1Cc2c(cccc2C(F)(F)F)N1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: CC1Cc2c(cccc2C(F)(F)F)N1C(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 35 %

Procedure:
225 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride and 196 mg of 2-methyl-4-trifluoromethyl-2,3-dihydro-1H-indole are added to a solution of 259 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate (example 1d, step 2d) in 3 ml of N,N-dimethylformamide and 3 ml of pyridine. The reaction mixture is stirred at ambient temperature for 20 hours and then diluted with water and extracted with ethyl acetate. The extracts are washed successively with water, a hydrochloric acid solution (1M), water and a saturated sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered, and concentrated under reduced pressure, so as to give 144 mg of 2-[2-(2-methyl-4-trifluoromethyl-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one in the form of a white solid.
Reaction SMILES: Br[C:2]1[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=1.CC1(C)C(C)(C)OB([C:17]2[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH:22]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:8][C:3]1[C:2]([C:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]=2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Cc1ncccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ncccc1C1=CCN(C(=O)OC(C)(C)C)CC1
Yield: 76 %

Procedure:
3-Bromo-2-methylpyridine (172 mg, 1 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (309 mg, 1 mmol) were dissolved in THF (10 ml) and combined with a solution of sodium carbonate (425 mg, 4 mmol) in water (1 ml). The mixture was purged with argon, PdCl2(PPh3)2 (35 mg, 0.05 mmol) was added and the mixture was stirred under reflux for three days, diluted with ethyl acetate (30 ml), the phases were separated and the organic layer was washed with brine and dried (sodium sulfate). After concentration under reduced pressure the residue was purified with column chromatography (silica, gradient of 0 to 30% ethyl acetate in DCM) to yield 209 mg (0.76 mmol, yield 76%) MS (multi-mode) m/z=275.2 [M+1]+.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:11])[CH:4]1[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1.Cl.[NH2:13][OH:14].N1C=CC=CC=1>C(O)C>[CH3:2][N:3]([CH3:11])[CH:4]1[CH2:9][CH2:8][C:7](=[N:13][OH:14])[CH2:6][CH2:5]1
Reactant: NO
Reactant: CN(C)C1CCC(=O)CC1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CN(C)C1CCC(=NO)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.2 %

Procedure:
A mixture of 1.78 gm (10 mMol) of 4-dimethylaminocyclohexanone hydrochloride and 0.70 gm (10 mMol) of hydroxylamine hydrochloride in 25 mL ethanol was treated with 3 mL pyridine and then heated at reflux for 30 minutes. The reaction mixture was then cooled to room temperature and stored at 4° C. for 18 hours. The resulting crystalline solid was collected and washed with cold ethanol. The solid was then dissolved in water and the aqueous solution made basic by the addition of potassium carbonate. The aqueous phase was then extracted with dichloromethane which contained a small amount of isopropanol. The organic extracts were combined, dried over sodium sulfate and concentrated under reduced pressure to provide a crystalline solid. This solid was recrystallized from ethanol to provide 1.05 gm (67%) of the desired oxime.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=1.[Cl:11][C:12]([Cl:22])([Cl:21])[CH2:13][O:14][S:15]([N:18]=[C:19]=[O:20])(=[O:17])=[O:16].CCCCCC>ClCCl>[CH3:9][O:8][C:6]1[N:5]=[C:4]([CH3:10])[N:3]=[C:2]([NH:1][C:19]([NH:18][S:15]([O:14][CH2:13][C:12]([Cl:22])([Cl:21])[Cl:11])(=[O:16])=[O:17])=[O:20])[N:7]=1
Reactant: COc1nc(C)nc(N)n1
Reactant: O=C=NS(=O)(=O)OCC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCCCCC
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)OCC(Cl)(Cl)Cl)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.5 %

Procedure:
14.0 g (0.1 mole) of 2-amino-4-methoxy-6-methyl-1,3,5-triazine were suspended in 250 ml of dichloromethane, and a solution of 25.5 g (0.1 mole) of 2,2,2-trichloro-eth-1-oxysulfonyl isocyanate in 100 ml of dichloromethane was added dropwise at 0° to 5° C. The reaction mixture was further stirred for 18 hours at room temperature and cooled to 0° C., and n-hexane was added. The precipitated reaction product was filtered off under suction and recrystallized from absolute ethanol. 35.3 g (89.4% of theory) of N-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)-N'-(2,2,2-trichloro-eth-1-oxy-sulfonyl)-urea of melting point 128° C. were obtained.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH2:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]1>CN(C=O)C>[CH2:21]([O:20][C:18]([N:15]1[CH2:14][CH2:13][CH:12]([NH:11][C:2]2[O:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)[CH2:17][CH2:16]1)=[O:19])[CH3:22]
Reactant: CCOC(=O)N1CCC(N)CC1
Reactant: Clc1nc2ccccc2o1
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC(Nc2nc3ccccc3o2)CC1
Temperature: 25 °C

Procedure:
A mixture of 2-chloro-benzooxazole (8.00 g, 52.1 mmol, 1.0 equiv) and ethyl 4-amino-1-piperidine carboxylate (10.78 g, 62.5 mmol, 1.2 equiv) in anhydrous DMF (50 mL) was stirred at rt. A precipitate formed over night which was filtered off, the volume of the filtrate reduced and the residue taken up in ethyl acetate (10 mL). Precipitation of this solution from hexane provided an additional batch of the title compound as a white solid. Combined yield: 6.8 g (45%). 1H NMR (400 MHz, CDCl3): δ 1.27 (t, J=7.2 Hz, 3H), 1.48-1.52 (m, 2H), 2.14-2.18 (m, 2H), 3.09 (br t, 2H), 3.81-3.95 (m, 1H), 4.12-4.18 (m, 2H), 4.15 (q, J=7.2 Hz, 2H), 5.64 (br d, J=7.8 Hz, 1H), 7.04 (t, J=7.8 Hz, 1H), 7.17 (t, J=7.6 Hz, 1H), 7.25 (d, J=7.8 Hz, 1H), 7.36 (d, J=7.6 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 14.93, 32.53, 42.85, 50.66, 61.72, 109.00, 116.62, 121.24, 124.24, 143.10, 148.66, 155.72, 161.32. MS (ISP): 290.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:12]=[C:13]([CH:17]2[C:26]([CH3:28])([CH3:27])[CH:25](O)[C:24]3[C:19](=[C:20]([C:30]([O:32][CH3:33])=[O:31])[CH:21]=[CH:22][CH:23]=3)[NH:18]2)[CH:14]=[CH:15][CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([C:11]1[CH:12]=[C:13]([CH:17]2[C:26]([CH3:28])([CH3:27])[CH2:25][C:24]3[C:19](=[C:20]([C:30]([O:32][CH3:33])=[O:31])[CH:21]=[CH:22][CH:23]=3)[NH:18]2)[CH:14]=[CH:15][CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc2c1NC(c1cccc(C(=O)OCc3ccccc3)c1)C(C)(C)C2O
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cccc2c1NC(c1cccc(C(=O)OCc3ccccc3)c1)C(C)(C)C2
Temperature: 25 °C
Yield: 17 %

Procedure:
To a solution of methyl 2-(3-(benzyloxycarbonyl)phenyl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-8-carboxylate (0.66 g, 1.49 mmol), triethylsilane (0.5 g, 4.3 mmol) in dichloro methane (10 mL) was added a solution of trifluoroacetic acid (0.69 g, 6.1 mmol), which was placed in a drop funnel, under nitrogen with ice cooling. Upon completion of addition, the resulting mixture was allowed to warm back to room temperature naturally overnight. Thin layer chromatography (petroleum ether:ethyl acetate=20:1) showed the reaction was complete. The reaction mixture was basified with solid sodium carbonate to pH=6 and filtered. The filtrate was concentrated in vacuo and the residual was purified by column chromatography (petroleum ether:ethyl acetate=25:1) to give 109 mg of methyl 2-(3-(benzyloxycarbonyl)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-8-carboxylate as a off-yellow solid, yield: 39.6%.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SC)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH2:34]([O:36][CH2:37][CH2:38][N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)[CH3:35]>>[F:32][C:2]([F:33])([F:1])[C:3]1[CH:27]=[C:26]([C:28]([F:30])([F:29])[F:31])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:42]4[CH2:43][CH2:44][N:39]([CH2:38][CH2:37][O:36][CH2:34][CH3:35])[CH2:40][CH2:41]4)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: CCOCCN1CCNCC1
Product: CCOCCN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)CC1

Procedure:
5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-ethoxy-ethyl)-piperazin-1-yl]-thiazol-4-one was prepared from 5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and 1-(2-ethoxy-ethyl)-piperazine following General Procedure C.
Reaction SMILES: [C:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#N.[CH2:18]([OH:20])[CH3:19].Cl.CC[O:24]CC>>[CH2:18]([O:20][C:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)=[O:24])[CH3:19]
Reactant: N#Cc1ccc(OCc2ccc(F)cc2)cc1
Reactant: CCOCC
Reactant: CCO
Agent: Cl
Product: CCOC(=O)c1ccc(OCc2ccc(F)cc2)cc1
Reaction time: 24 h

Procedure:
A solution of 4-cyanophenoxy-(4'-fluorophenyl) methane (2.25g.; 0.1 mole) in dry ether (20ml) with ethanol (0.46g.; 0.1 mole) was cooled in an ice-bath and then saturated with dry hydrogen chloride gas then allowed to stand for 24 hrs. The resulting solid was filtered off and dried, m.p. 210° C (rearrangement at 135° C). The imino-ether (1.54g) was dissolved in water (30ml) neutralised with dilute sodium hydroxide solution then boiled under reflux for 3 hrs. Mixture cooled and the product extracted with ether to give 4-ethoxycarbonylphenoxy-(4'-fluorophenyl) methane m.p. 60°-2° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[S:6][CH2:7][CH2:8][S:9][C:4]=2[CH:3]=1.C([Li])CCC.CCCCCC.[CH:23](OCC)=[O:24].Cl>C(OCC)(=O)C.O1CCCC1>[S:6]1[C:5]2[CH:10]=[CH:11][C:2]([CH:23]=[O:24])=[CH:3][C:4]=2[S:9][CH2:8][CH2:7]1
Reactant: CCOC=O
Reactant: Brc1ccc2c(c1)SCCS2
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=Cc1ccc2c(c1)SCCS2
Reaction time: 0.5 h

Procedure:
To 5 mL of a tetrahydrofuran solution containing 500 mg of 6-bromo-2,3-dihydro-1,4-benzodithiin, 0.67 mL of a 2.67 mol/L butyllithium/hexane was added at −78° C., the mixture was stirred for 0.5 hour, then 300 mg of ethyl formate was added thereto, and the mixture was further stirred for 2 hours. Thereto was added 1 mol/L hydrochloric acid, and ethyl acetate was then added to the mixture. The organic layer was separated, washed with an aqueous saturated sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [silica gel; Silica gel 60N manufactured by Kanto Chemical Co., Inc., eluent; ethyl acetate:hexane 1:4] to obtain 121 mg of a brown oily substance, 2,3-dihydro-1,4-benzodithiin-6-carbaldehyde.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=2[F:17])[C:12]#[N:13])[CH:5]=[CH:4][CH:3]=1.[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1B(O)O.C(O)C.C([O-])([O-])=O.[Na+].[Na+]>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>[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[C:2]1[N:7]=[C:6]([CH2:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=2[F:17])[C:12]#[N:13])[CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(F)c(Cc2cccc(Br)n2)c1
Reactant: OB(O)c1ccc(F)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: N#Cc1ccc(F)c(Cc2cccc(-c3ccc(F)cc3F)n2)c1
Temperature: 95 °C
Yield: 75.8 %

Procedure:
To a solution of 3-[(6-bromopyridin-2-yl)methyl]-4-fluorobenzonitrile (from Step B above, 8.34 g, 28.6 mmol) in toluene (300 mL) was added (2,4-difluorophenyl)boronic acid (8.15 g, 34.4 mmol), tetrakis(triphenylphosphine)palladium (1.65 g, 1.40 mmol), ethanol (30 mL), and 2M Na2CO3 (30 mL). The resulting mixture was heated to 95° C. for 2 hours. The reaction was cooled to room temperature and filtered through celite and concentrated in vacuo. The crude residue was dissolved in EtOAc, washed with H2O, brine (2×), dried over MgSO4, and concentrated. The crude material was purified via silica gel chromatography (hexanes/ethyl acetate) to give the title compound as a white solid (7.03 g).
Reaction SMILES: [CH3:1][O:2][CH:3]1[O:8][CH2:7][C:6](=[O:9])[CH:5]=[CH:4]1.[Br:10]Br.C(N(CC)CC)C>C(Cl)Cl.C1(C)C=CC=CC=1>[Br:10][C:5]1[C:6](=[O:9])[CH2:7][O:8][CH:3]([O:2][CH3:1])[CH:4]=1
Reactant: COC1C=CC(=O)CO1
Reactant: BrBr
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1C=C(Br)C(=O)CO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.1 %

Procedure:
To a solution of 6-methoxy-2H-pyran-3(6H)-one 12.8 (0.1 mole) in 40 ml CH2Cl2 at 0° C. was added 16.0 g (0.1 mole) of bromine in 10 ml of CH2Cl2. Then 14 ml of triethylamine was added dropwise at 0° C. and the reaction was allowed to warm to room temperature and stir for two hours. The reaction was then diluted with 200 ml of toluene. After filtration, the organic solution was then washed with 5% NaHCO3 and brine, dried with Na2SO4, filtered and concentrated to yield the crude product as light brown solid Recrystallisation from ethyl acetate afforded the title compound (17 g, 82%) as a white crystalline solid. m.p. 74-75° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH3:17].[H-].[Na+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1>[CH2:20]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=2)[C:5]([CH2:11][C@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[CH3:17])=[CH:6]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccc(Br)cc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCC[C@@H]1Cc1cn(Cc2ccccc2)c2ccc(Br)cc12
Temperature: 25 °C
Yield: 62.7 %

Procedure:
To a stirred solution of (R)-5-bromo-3-(1-methyl-2-pyrrolidinylmethyl)-1H-indole (see Example 27, WO 92/06973) (21.44 g, 73.2 mmol) in tetrahydrofuran (110 ml) at 0° C. under a nitrogen atmosphere was added sodium hydride (60% dispersion in mineral oil, 3.51 g, 87.7 mmol) portionwise, maintaining the temperature below 5° C. Upon completion of the addition, the dark brown solution was stirred at 0-5° C. for 1 hr before benzyl bromide (10.4 ml, 87.4 mmol) was added dropwise maintaining the temperature below 5° C. The brown solution was then warmed to ambient temperature over a 1 hr period before being quenched into water (100 ml). The mixture was then extracted with ethyl acetate (3×25 ml) and the organic extracts were combined and evaporated in vacuo to yield a brown oil. This was purified by flash column chromatography (ethyl acetatehexane:diethylamine 1:1:0.1 as eluant) to give the subtitle compound (17.6 g, 63%) as a brown viscous oil.
Reaction SMILES: [NH4+].Cl[C:3]1[N:8]=[C:7]([OH:9])[C:6]([F:10])=[C:5]([CH2:11][CH3:12])[N:4]=1.C(O)C>[Pd].O>[CH2:11]([C:5]1[N:4]=[CH:3][N:8]=[C:7]([OH:9])[C:6]=1[F:10])[CH3:12]
Reactant: CCc1nc(Cl)nc(O)c1F
Agent: [Pd]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCc1ncnc(O)c1F
Temperature: 4 °C

Procedure:
To a mixture of the compound of part (iii) (34 kg), ethanol (170 L) and water (5 kg) was added 5% w/w palladium-on-carbon (50% w/w water content) (3.4 kg) and the mixture hydrogenated at 50° C. and 345 kPa (50 psi) until completion of the reaction. Water (10.5 L) w as added and the catalyst removed by filtration. The filtrate was concentrated under reduced pressure to a small volume and extracted with dichloromethane (2×58 L). The combined organic extracts were concentrated under reduced pressure and toluene (150 L) added. The mixture was concentrated under reduced pressure to 50 L in volume, toluene (50 L) added and cooled to 4° C. for 4 hours. The precipitated product was collected by filtration, washed with toluene (10 L) and dried (Yield=20 kg), m.p. 112-4° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5](=[O:18])[CH2:6][C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH3:17])([CH3:9])[CH3:8])[CH3:2].[F:20][C:21]([Si](C)(C)C)([F:26])[C:22]([F:25])([F:24])[F:23].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:1]([O:3][C:4](=[O:19])[C:5]([OH:18])([C:21]([F:26])([F:20])[C:22]([F:25])([F:24])[F:23])[CH2:6][C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH3:17])([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)C(=O)CC(C)(C)c1ccccc1OC
Reactant: C[Si](C)(C)C(F)(F)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)C(O)(CC(C)(C)c1ccccc1OC)C(F)(F)C(F)(F)F

Procedure:
Analogously to Example 7, 687 mg of ethyl-4-(2-methoxyphenyl)-4-methyl-2-oxopentanoate (WO 00/32584) with 1 g of (pentafluoroethyl)trimethylsilane and 0.5 ml of (tetrabutylammonium fluoride solution (1 M in THF)) in 18 ml THF are reacted to form g of ethyl-4-(2-methoxyphenyl)-2-hydroxy-4-methyl-2-(pentafluoroethyl)-pentanoate. 450 mg of the ester that is obtained in 12 ml of diethyl ether is mixed in portions at 0° C. with 66 mg of lithium aluminum hydride. After stirring for 11 hours, it is added to saturated bicarbonate solution and filtered through diatomaceous earth. The phases are separated, and the aqueous phase is extracted with ethyl acetate. The organic phase is washed with water and brine, dried (Na2SO4) and concentrated by evaporation. 420 mg of diol is obtained as a yellow oil. 400 mg of the diol is oxidized to the corresponding aldehyde with 0.11 ml of oxalyl chloride, 0.21 ml of DMSO and 1 ml of triethylamine. It is washed with water and brine, dried with sodium sulfate, and concentrated by evaporation in a vacuum. After chromatography on silica gel (hexane/ethyl acetate 0→5%), 268 mg of the title compound is obtained as a yellow oil.