Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[NH:8][CH:9]=[N:10][C:4]=2[CH:3]=1.[H-].[Na+].Cl[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1.O>C1COCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[N:8]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH:9]=[N:10][C:4]=2[CH:3]=1
Reactant: Clc1cc2nc[nH]c2cn1
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Cn2cnc3cc(Cl)ncc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
To a solution of 6-chloro-3H-imidazo[4,5-c]pyridine (3.50 g, 22.79 mmol) in THF (50 mL) at 0° C. was slowly added sodium hydride (60% dispersion in mineral oil, 1.82 g, 45.58 mmol) in several portions. After stirring at RT for 30 min, 1-(chloromethyl)-4-methoxybenzene (4.30 g, 27.48 mmol) was added and the mixture was stirred at RT for 2 h. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (100 mL×2). The combined extracts were washed with water (100 mL) and brine (50 mL), dried (MgSO4), filtered and evaporated under reduced pressure. The residue was purified by SiO2 chromatography eluting with hexane/EtOAc (1:1) to afford 5.0 g (80%) of 6-chloro-3-(4-methoxybenzyl)-3H-imidazo[4,5-c]pyridine as a white solid. MS (ESI): m/z=274.2 [M+1]+.
Reaction SMILES: Br[CH:2]([CH2:7][CH2:8]Br)[C:3]([O:5][CH3:6])=[O:4].[CH:10]1([NH2:15])[CH2:14][CH2:13][CH2:12][CH2:11]1>>[CH3:6][O:5][C:3]([CH:2]1[CH2:7][CH2:8][N:15]1[CH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:4]
Reactant: COC(=O)C(Br)CCBr
Reactant: NC1CCCC1
Product: COC(=O)C1CCN1C1CCCC1
Yield: 33 %

Procedure:
The reaction of methyl 2,4-dibromobutanoate 17 with cyclopentylamine 18I yielded 1-cyclopentyl-azetidine-2-carboxylic acid methyl ester as a light brown solid (33%). MS ISP (m/e): 184.2 (100) [(M+H)]+.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:9][CH2:10][CH2:11][CH2:12][C:13]1[NH:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1.C(N(CC)CC)C.O>CN(C=O)C>[Si:1]([O:9][CH2:10][CH2:11][CH2:12][C:13]1[NH:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: OCCCc1nc2ccccc2[nH]1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCCc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.2 %

Procedure:
To this end, tert-butyldimethylsilyl chloride (TBDMSCI) (14.68 g, 97.37 mmol) was added a little at a time to a solution of 2-(3-hydroxypropyl)-benzimidazole (15.60 g, 88.52 mmol) in DMF (265 ml) and triethylamine (20.27 ml, 145.41 mmol). The mixture was stirred at RT overnight and then admixed with water (800 ml) and extracted with diethyl ether. The organic phase was dried over sodium sulphate and chromatographed over silica gel (mobile phase: cyclohexane/ethyl acetate=6:1), giving 25 g (97%) of colourless crystals. MS (DCI): 291 (M+H)+
Reaction SMILES: C=[O:2].[CH2:3]([CH:6]([CH2:10][CH2:11][CH3:12])[C:7](Cl)=[O:8])[CH2:4][CH3:5].[CH2:13]([Cl:15])Cl>[Cl-].[Zn+2].[Cl-]>[Cl:15][CH2:13][O:8][C:7](=[O:2])[CH:6]([CH2:10][CH2:11][CH3:12])[CH2:3][CH2:4][CH3:5]
Reactant: CCCC(CCC)C(=O)Cl
Reactant: C=O
Reactant: ClCCl
Agent: [Cl-]
Agent: [Zn+2]
Product: CCCC(CCC)C(=O)OCCl
Temperature: 25 °C
Reaction time: 16 h
Yield: 58 %

Procedure:
Para-formaldehyde (1 g) and zinc chloride (catalytic amount) were mixed together at 0° C. 2,2-Di-n-propylacetyl chloride (30 mole, 4.88 g) was added dropwise over 1 hour. The reaction was warmed to ambient temperature, then was heated to 50-55° C. for 6 hours. The reaction mixture continued stirring at room temperature for 16 hours. The reaction mixture was taken up with methylene chloride (5 mL) and flash chromatographed on 150 g silica gel. Elution with 1 to 5% ethyl acetate/hexane gave 3.3 g (58%) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][C:15](=[O:18])[CH2:16][NH2:17])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C1CCNCC1.[CH:27]([C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1)([CH3:29])[CH3:28].N.S(Cl)(Cl)(=O)=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[CH2:8][CH2:9][CH:10]([CH2:13][NH:14][C:15](=[O:18])[CH2:16][NH:17][S:36]([C:33]3[CH:34]=[CH:35][C:30]([CH:27]([CH3:29])[CH3:28])=[CH:31][CH:32]=3)(=[O:38])=[O:37])[CH2:11][CH2:12]2)=[CH:4][CH:3]=1
Reactant: NCC(=O)NCC1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: N
Solvent: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: C1CCNCC1
Product: CC(C)c1ccc(S(=O)(=O)NCC(=O)NCC2CCN(Cc3ccc(Cl)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 1-(4-chlorobenzyl)-4-{(glycylamino)methyl}piperidine (14.8 mg, 0.05 mmol) in CHCl3 (2 mL) was treated with (piperidinomethyl)polystyrene resin (28 mg, 2.8 mmol/g), 4-isopropylbenzenesulfonyl chloride (1.5 equiv.) and stirred at 25° C. for 16 h. (Aminomethyl)polystyrene was added to scavenge the residual sulfonyl chloride and the reaction mixture was stirred at 25° C. for 16 h. Filtration and concentration afforded 1-(4-chlorobenzyl)-4-[{(4-isopropylphenylsulfonyl)glycyl}aminomethyl]piperidine (compound No. 869) (22.1 mg, 92%): The purity was determined by RPLC/MS (86%); ESI/MS m/e 478 (M++H, C24H32ClN3O3 S).
Reaction SMILES: O=[C:2]([CH2:8][CH3:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].Cl.[F:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18]N)=[CH:14][CH:13]=1.S(=O)(=O)(O)O.[CH3:25]O>>[F:11][C:12]1[CH:17]=[C:16]2[C:15](=[CH:14][CH:13]=1)[NH:18][C:2]([CH2:3][CH2:4][C:5]([O:7][CH3:25])=[O:6])=[C:8]2[CH3:9]
Reactant: NNc1ccc(F)cc1
Reactant: CCC(=O)CCC(=O)O
Reactant: CO
Agent: Cl
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1[nH]c2ccc(F)cc2c1C
Temperature: 120 °C
Yield: 46 %

Procedure:
A stirred mixture of 88.8 mg (0.68 mmol) of 4-oxohexanoic acid,* 100 mg (0.62 mmol) of (4-fluorophenyl)hydrazine hydrochloride, 3 mL of methanol and 80 μL of concentrated sulfuric acid in a 5 mL microwave process vial was heated for 10 min at 120° C. under argon in a microwave synthesizer. The alcoholic solution was concentrated to about one-third of its original volume and then transferred to a phase separator syringe filled with cold water (4 mL). The organic compound was repeatedly extracted with dichloromethane (3×5 mL) and the combined organic phases were washed with brine (4 mL), dried over Na2SO4 and filtered. Removal of the organic solvent and treatment of the residue with a little hexane afford the title compound in 46% yield (67 mg) as viscous mass. C13H14FNO2, Mr=235.25; 1H NMR (400 MHz, DMSO-d6) d: 2.12 (s, 3H), 2.66 (t, J=8.0 Hz, 2H), 2.93 (t, J=7.6 Hz, 2H), 3.58 (s, 3H), 6.80 (td, J=2.8/9.2 Hz, 1H), 7.10 (dd, J=2.4/10.2 Hz, 1H), 7.20 (dd, J=4.6/8.6 Hz, 1H), 10.74 (bs, 1H); 19F NMR (282 MHz, DMSO-d6) d: −124.03 (d, 5′-F); LCMS (ESI) tR: 2.58 min (>99%, UV220), m/z: 236.2 [M+1]+. [* instead of the acid one could also use the methyl ester with the same outcome.]
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=O)=O)=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.CCCCCCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[C:4]([C:12]([F:15])([F:13])[F:14])[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1C(F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Solvent: O
Product: FC(F)(F)c1cc(Br)ccc1S
Temperature: 2.5 °C
Yield: 97.7 %

Procedure:
4-Bromo-2-trifluoromethyl-benzenesulfonyl chloride (375 g, 1.16 mol) was dissolved in toluene (1.5 L) and a solution of triphenylphosphine (994 g, 3.79 mol) in toluene (1.5 L) was added at 5-10° C. within 45 min. The yellow suspension was stirred at 0-5° C. for min, then water (360 mL) was added at 5-12° C. (strongly exothermic) and the resulting colorless suspension was stirred for 20 min at room temperature. After filtration, the precipitate was washed with toluene (1 L). The combined organics were extracted with a potassium hydroxide solution (1M in water, 2.8 L). During extraction, 3 layers were formed. The upper layer was discarded, the other two were washed with toluene (1 L). The aqueous phase was acidified to pH 3-4 by addition of citric acid (280 g, 1.46 mol). After addition of n-heptane (1 L), the precipitate was filtered off and washed with n-heptane (500 mL). The layers of the combined filtrate were separated and the aqueous phase was extracted with n-heptane (1.5 L). The combined organic extracts were dried over sodium sulfate. Silica gel (250 g) was then added, the slurry was stirred for 10 min at room temperature, filtered and the filtered silica gel washed with n-heptane (1 L). The combined filtrate was concentrated and dried in vacuo at 45° C. to afford 291.2 g (98%) of the title compound as a colorless liquid that was used without further purification in the next step. MS (EI): m/z=256.9, 254.9 [M+H]+. 1H NMR (CDCl3, 400 MHz): δ 3.76 (q, J=2.8 Hz, 1H), 7.26 (d, J=8.3 Hz, 1H), 7.48 (dd, J=2.0 Hz, 8.5 Hz, 1H), 7.75 (d, J=1.9 Hz, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@@H:4]1[CH2:6][C@@H:5]1[CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:9][CH2:8]1.[H-].[Na+].Cl[C:26]1[C:31]([CH3:32])=[CH:30][C:29]([N+:33]([O-:35])=[O:34])=[CH:28][N:27]=1>CS(C)=O>[CH3:32][C:31]1[C:26]([O:1][CH2:2][CH2:3][C@@H:4]2[CH2:6][C@@H:5]2[CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:14])[CH2:9][CH2:8]2)=[N:27][CH:28]=[C:29]([N+:33]([O-:35])=[O:34])[CH:30]=1
Reactant: O=C(OCc1ccccc1)N1CCC([C@H]2C[C@H]2CCO)CC1
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc([N+](=O)[O-])cnc1OCC[C@@H]1C[C@@H]1C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 45 °C
Reaction time: 0.25 h

Procedure:
To the solution of benzyl 4-[(1R,2S)-2-(2-hydroxyethyl)cyclopropyl]piperidine-1-carboxylate (Intermediate 10, 1.84 g, 6.06 mmol) in 15 ml of DMSO was added NaH and the resulting solution was stirred at 45° C. for 15 min. The mixture was then cooled to 0° C. via an ice/water bath and 2-chloro-3-methyl-5-nitropyridine (1.05 g, 6.06 mmol) was added in portions. The reaction mixture turned dark and became a slurry. After 10 minutes, the ice/water bath was removed and 20 ml of DMSO was added. The resulting mixture was stirred for 40 minutes allowing to warm to room temperature. The reaction was quenched by water and extracted with ethyl acetate (3×100 mL). The organics were combined and washed with brine, dried on sodium sulfate, filtered and the filtrate concentrated under reduced pressure. The residue was purified via Biotage column (65M silica gel) using ethyl acetate in hexane (0-60%, 1000 ml) to afford the title compound. MS (ESI) m/z 440 [M+H]+.
Reaction SMILES: CCCCC[C@H:6]([OH:25])/[CH:7]=[CH:8]/[C@@H:9]1[C@@H:13]([CH2:14]/C=C\CCCC(O)=O)[C@@H](O)[CH2:11][C@H:10]1[OH:24].C(OC(Cl)=O)C(C)C>C(N(CC)CC)C>[OH:25][C:6]1[CH:7]=[CH:8][C:9]([C:10](=[O:24])[CH3:11])=[CH:13][CH:14]=1
Reactant: CCCCC[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H](O)C[C@H]1O
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(O)cc1

Procedure:
Following the procedure of Example 1 but using 0.738 g. of PGF2α, 0.306 ml. of triethylamine, 0.288 ml. of isobutylchloroformate, and 0.299 g. of p-hydroxyacetophenone, there is obtained a crude residue. This residue is subjected to silica gel chromatography, eluting with ethyl acetate-water (99:1) followed by ethyl acetate-acetonitrile (1:1). The residue obtained by concentration of selected fractions, 0.589 g. is crystallized from ethyl acetate diluted with an equal volume of hexane as the title compound, white free-flowing crystals, m.p. 85.3°-86.5° C. having Rf 0.4 (TLC on silica gel in ethyl acetate-acetonitrile (4:1)).
Reaction SMILES: [C:1]([N:24]1[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]1)(=[O:23])[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH:7]=[CH:8][CH2:9][CH:10]=[CH:11][CH2:12][CH:13]=[CH:14][CH2:15][CH:16]=[CH:17][CH2:18][CH:19]=[CH:20][CH2:21][CH3:22].C(C(O)=O)(F)(F)F.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[N:24]1([C:1](=[O:23])[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH:7]=[CH:8][CH2:9][CH:10]=[CH:11][CH2:12][CH:13]=[CH:14][CH2:15][CH:16]=[CH:17][CH2:18][CH:19]=[CH:20][CH2:21][CH3:22])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1
Reactant: CCC=CCC=CCC=CCC=CCC=CCC=CCCC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC=CCC=CCC=CCC=CCC=CCC=CCCC(=O)N1CCNCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.3 %

Procedure:
To a mixture of tert-butyl 4-docosa-4,7,10,13,16,19-hexaenoylpiperazine-1-carboxylate (1.5 g, 3 mmol) in CH2Cl2 (20 mL) at 0° C. was added CF3CO2H (7 mL, 91 mmol). The mixture solution was stirred (0° C., 2 h) and then 10% Na2CO3 was added to adjust pH=10. The mixture was extracted with CH2Cl2 (3×30 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by silica chromatography (CH2Cl2:CH3OH, 20:1) to afford 1-(piperazin-1-yl)docosa-4,7,10,13,16,19-hexaen-1-one (1.17 g, 97.5%) as a colorless oil. Mass calculated for C26H40N2O=396.61. found: [M+H]+=396.7, 398.2.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[CH2:3].[N+:7]([C:10]1[CH:17]=[CH:16][C:13]([CH2:14][OH:15])=[CH:12][CH:11]=1)([O-:9])=[O:8]>C(N(CC)CC)C>[C:1]([O:15][CH2:14][C:13]1[CH:12]=[CH:11][C:10]([N+:7]([O-:9])=[O:8])=[CH:17][CH:16]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Reactant: C=C(C)C(=O)Cl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCc1ccc([N+](=O)[O-])cc1
Yield: 64.6 %

Procedure:
From the reaction of 52.3 g (0.5 m) methacryloyl chloride and 76.6 g (0.5 m) of p-nitrobenzyl alcohol and 50.6 g triethylamine was isolated 71.5 g (34.5%) of p-nitrobenzyl methacrylate as pale-yellow crystals, mp--87°-88° C.
Reaction SMILES: [C:1]1([NH2:15])[N:2]=[C:3]([NH2:14])[N:4]=[C:5]2[C:10]=1[C:9]1[CH:11]=[CH:12][NH:13][C:8]=1[CH:7]=[CH:6]2.CN(C)C=O.[H-].[Na+].[CH2:23](Cl)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(O)(=O)C>[C:24]1([CH2:23][N:13]2[C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[C:1]([NH2:15])[N:2]=[C:3]([NH2:14])[N:4]=4)[C:9]=3[CH:11]=[CH:12]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: ClCc1ccccc1
Reactant: Nc1nc(N)c2c(ccc3[nH]ccc32)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Nc1nc(N)c2c(ccc3c2ccn3Cc2ccccc2)n1
Reaction time: 1.5 h

Procedure:
A suspension of 13.95 g. 7H-pyrrolo[3,2-f]quinazoline-1,3-diamine in 600 ml. dry dimethylformamide is stirred under nitrogen as 3.70 g. ca. 50% sodium hydride-mineral oil dispersion is added carefully. After stirring for 1.5 hours, a solution of 9.30 g. benzyl chloride (8.5 ml.) in 20 ml. dry dimethylformamide is added during ca. 10 min. Stirring is continued for 5 hours and then 120 ml. gl. acetic acid is added to the reaction mixture. After removal of solvent (in vacuo), the residue is stirred thoroughly with excess aqueous potassium carbonate solution and filtered. The solids are collected, washed with water, and dried. The crude product is dissolved in 1.4 l. boiling methanol, treated with charcoal, and filtered through Celite. The filtrate is concentrated to ca. 125 ml. and chilled. The crystalline solid is collected, washed with acetone, and again recrystallized from methanol to afford 11.76 g. title compound, m.p. 228°, NMR (dDMSO): δ 5.53 (singlet, N-CH2C6H5), 7.12 (doublet, J-3Hz, 9H), 7.23 (doublet, 8Hz, 5 or 6H), 7.63 (doublet, J=3Hz, 8H), 7.77 (doublet, J=9Hz, 5 or 6H) p.p.m.; λmax95%EtOH 235 (ε 26,900), 260 (ε 28,620), 317 (ε 9,640), 345 sh (ε 7,520) nm; λmin95%EtOH 243 (ε 26,020), 281 (ε 2,430) nm.
Reaction SMILES: [Al].[H-].[Li+].[CH2:4]([O:6][CH2:7][CH2:8][N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([CH3:39])([CH3:38])[C:33](OCC)=[O:34])=[CH:28][CH:27]=2)[CH2:20][CH2:19]1)[CH3:5].[H-]>C1COCC1.O>[CH2:4]([O:6][CH2:7][CH2:8][N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]([C:32]([CH3:38])([CH3:39])[CH2:33][OH:34])=[CH:30][CH:31]=2)[CH2:20][CH2:19]1)[CH3:5]
Reactant: CCOCCn1c(C2CCN(CCc3ccc(C(C)(C)C(=O)OCC)cc3)CC2)nc2ccccc21
Agent: [Al]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCOCCn1c(C2CCN(CCc3ccc(C(C)(C)CO)cc3)CC2)nc2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.7 %

Procedure:
1 g of aluminium and lithium hydride was dissolved in 30 ml of THF and 3 g of ethyl 2-[4-(2-(4-(1-(2-ethoxyethyl)benzimidazole-2-yl)piperidine-1-yl)ethyl)phenyl]-2-methylpropanoate were added dropwise thereto. This was stirred for four hours at room temperature and some milliliters of water were added to eliminate excess hydride. The solution was filtered and the filtrate was washed with a saturated sodium chloride solution. This was dried and concentrated. The residue was redissolved in chloroform and washed with water, dried and concentrated. The residue was purified by flash-chromatography using a hexane/ether/isopropyl-amine mixture (2/7.5/0.5) as an eluent, to yield 1.5 g of 1-(2-ethoxyethyl)-2-[1-(2-(4-(1,1-dimethyl-2-hydroxyethyl)phenyl)ethyl)piperidine-4-yl]-1H-benzimidazole.
Reaction SMILES: OO.[ClH:3].[CH2:4]([N:7]1[C:11]2=[C:12]([N:16]3[CH2:25][CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17]3)[N:13]=[CH:14][CH:15]=[C:10]2[C:9]([S:26]([CH3:28])=[O:27])=[C:8]1[CH3:29])[CH:5]=[CH2:6].C(=O)([O-])[O-:31].[K+].[K+]>C(O)(=O)C>[ClH:3].[CH2:4]([N:7]1[C:11]2=[C:12]([N:16]3[CH2:25][CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17]3)[N:13]=[CH:14][CH:15]=[C:10]2[C:9]([S:26]([CH3:28])(=[O:31])=[O:27])=[C:8]1[CH3:29])[CH:5]=[CH2:6]
Reactant: O=C([O-])[O-]
Reactant: C=CCn1c(C)c(S(C)=O)c2ccnc(N3CCc4ccccc4C3)c21
Agent: Cl
Agent: OO
Agent: [K+]
Solvent: CC(=O)O
Product: C=CCn1c(C)c(S(C)(=O)=O)c2ccnc(N3CCc4ccccc4C3)c21
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Hydrogen peroxide (50 wt. %, 100 μl) was added to a solution of 2-(1-allyl-3-methylsulfinyl-2-methyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (30 mg, 0.07 mmol) prepared in Example 632 in acetic acid (3 ml). The reaction mixture was stirred for 1 hour at 60° C., cooled to room temperature, basified with a potassium carbonate solution, and then extracted with dichloromethane. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography. The resulting product was dissolved in ethyl ether, saturated with hydrochloric acid gas, and then filtered to give 8 mg of the titled compound as a white solid.
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([C:13]([CH3:17])([CH3:16])[C:14]#[N:15])=[C:8]([Cl:18])[CH:7]=1.C([O-])(=O)C.[Na+].[CH2:24]([O:26][C:27](=[O:40])[NH:28][C:29](=[O:39])[CH2:30][C:31]([NH:33][C:34](=[O:38])[O:35][CH2:36][CH3:37])=[O:32])[CH3:25]>O.C(O)(=O)C.Cl>[Cl:18][C:8]1[CH:7]=[C:6]([NH:5][N:1]=[C:30]([C:31]([NH:33][C:34](=[O:38])[O:35][CH2:36][CH3:37])=[O:32])[C:29]([NH:28][C:27](=[O:40])[O:26][CH2:24][CH3:25])=[O:39])[CH:11]=[C:10]([Cl:12])[C:9]=1[C:13]([C:14]#[N:15])([CH3:16])[CH3:17]
Reactant: O=N[O-]
Reactant: CCOC(=O)NC(=O)CC(=O)NC(=O)OCC
Reactant: CC(C)(C#N)c1c(Cl)cc(N)cc1Cl
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)NC(=O)C(=NNc1cc(Cl)c(C(C)(C)C#N)c(Cl)c1)C(=O)NC(=O)OCC
Temperature: 10 °C
Yield: 83.8 %

Procedure:
A solution of NaNO2 (0.36 mole) in H2O (50 ml) was added to a solution of intermediate (3) (0.34 mole) in acetic acid (700 ml) and HCl (102 ml), stirred at 10° C. The reaction mixture was stirred for 80 minutes at 10° C. A powdered mixture of sodium acetate (1.02 mole) and diethyl(1,3-dioxo-1,3-propanediyl)biscarbamate (0.374 mole) was added and the reaction mixture was stirred for 40 minutes. The reaction mixture was poured out onto crushed ice. The precipitate was filtered off, washed with water, taken up into CH2Cl2, and the layers were separated. The organic layer was dried, filtered and the solvent evaporated, yielding 138.5 g (84%) of diethyl N,N′-[2-[[3,5-dichloro-4-(1-cyano-1-methylethyl)phenyl]hydrazono]-1,3-dioxo-1,3-propanediyl]dicarbamate (intermediate 4).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([F:11])[CH:3]=1.Cl.[CH:13]1([C:16]2[C:17]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[N:18][CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=2)[CH2:15][CH2:14]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:29]2[CH2:30][CH2:31][N:26]([C:17]3[C:16]([CH:13]4[CH2:15][CH2:14]4)=[CH:21][C:20]([C:22]([F:25])([F:23])[F:24])=[CH:19][N:18]=3)[CH2:27][CH2:28]2)=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: FC(F)(F)c1cnc(N2CCNCC2)c(C2CC2)c1
Reactant: O=C(Cl)c1ccc(Br)cc1F
Agent: Cl
Product: O=C(c1ccc(Br)cc1F)N1CCN(c2ncc(C(F)(F)F)cc2C2CC2)CC1
Yield: 85.5 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 8 and using 4-bromo-2-fluorobenzoyl chloride (2.5 g) and 1-(3-cyclopropyl-5-trifluoromethylpyridin-2-yl)piperazine hydrochloride (3.2 g) described in Preparation Example 76, the title compound (4.2 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:29]#[N:30])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][C:21]3([C:24]([F:27])([F:26])[F:25])[CH2:23][CH2:22]3)[C:17](O)=[O:18])[C:10](=[O:28])[CH:9]=2)[CH:7]=1.[NH2:31][C:32]1[CH:44]=[CH:43][C:35]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[CH:34][CH:33]=1.CC(C)N=C=NC(C)C.C(#N)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:29]#[N:30])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][C:21]3([C:24]([F:26])([F:27])[F:25])[CH2:22][CH2:23]3)[C:17]([NH:31][C:32]3[CH:44]=[CH:43][C:35]([C:36]([O:38][C:39]([CH3:40])([CH3:41])[CH3:42])=[O:37])=[CH:34][CH:33]=3)=[O:18])[C:10](=[O:28])[CH:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: COc1cn(C(CC2(C(F)(F)F)CC2)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1cn(C(CC2(C(F)(F)F)CC2)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
188 mg (426 μmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[1-(trifluoromethyl)cyclopropyl]propanoic acid (racemate), 82.4 mg (426 μmol) of tert-butyl 4-aminobenzoate, 6.1 mg (43 μmol) of Oxima and 66 μl (0.43 mmol) of DIC in 4 ml of dimethylformamide were reacted according to General Method 5B. Following preparative HPLC [column: Chromatorex C18, 10 μm, 125 mm×30 mm, mobile phase: acetonitrile/0.1% formic acid gradient (0 to 3 min 10% acetonitrile, to 35 min 90% acetonitrile and a further 3 min 90% acetonitrile)], the title compound was obtained. Yield: 157 mg (59% of theory)
Reaction SMILES: [C:1]([O:4]C(=O)C)(=[O:3])[CH3:2].[C:8]1(=[O:18])[O:13][C:11](=O)[C:10]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]12.C([O-])(=O)C.[K+]>C1(C)C=CC=CC=1>[O:18]=[C:8]1[C:9]2[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=2)/[C:11](=[CH:2]/[C:1]([OH:4])=[O:3])/[O:13]1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C(O)/C=C1\OC(=O)c2ccccc21
Temperature: 30 °C
Reaction time: 1 h
Yield: 52.1 %

Procedure:
To 402 ml (4.26 moles) of acetic anhydride was added 150.0 g (1.01 moles) of phthalic anhydride and 124 g (1.26 moles) of potassium acetate in a 2 liter 3 neck flask. The resulting slurry was heated to 130°-135° C. for 1 hour and 20 minutes then cooled to 75°-80° C. and 1500 ml of toluene were added. The slurry was allowed to cool to 30° C. and granulate for 1 hour. The solids were recovered by filtration, washed with 300 ml of methylene chloride and air dried. The dried solids were repulped in 1500 ml H2O at 20°-25° C., allowed to granulate for 1 hour and oven dried at 50° C. overnight with an air bleed to give a yield of 52% (100.0 g) of the title compound: