Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].[CH3:9][C:10]([CH:14]1[NH:17][C:16](=[O:18])[CH2:15]1)([CH3:13])[CH:11]=[CH2:12].C(N(CC)CC)C>CN(C)C=O>[Si:5]([N:17]1[CH:14]([C:10]([CH3:13])([CH3:9])[CH:11]=[CH2:12])[CH2:15][C:16]1=[O:18])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:8])[CH3:7]
Reactant: C=CC(C)(C)C1CC(=O)N1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=CC(C)(C)C1CC(=O)N1[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
t-Butyldimethylchlorosilane (7.51 g) is added in one portion to an ice-cold, stirred solution of 4-(1,1-dimethyl-prop-2-enyl)-azetidin-2-one (6.54 g) and triethylamine (5.04 g) in anhydrous dimethylformamide (100 ml). The reaction mixture is stirred at 0°-5° C. for 1 hour and then allowed to warm to room temperature. Most of the solvent is removed under vacuum to give a residue which is partitioned between diethyl ether (250 ml) and water. The ethereal phase is washed with 2.5 N hydrochloric acid (50 ml), water (3×50 ml), and brine, dried with magnesium sulfate, filtered and evaporated under vacuum to provide crude product which is purified by chromatography on silica gel (20% ether in petroleum ether) to yield 2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:21])[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:21])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)c(Cl)c2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OC1(c2ccc(Cl)c(Cl)c2)CCNC1
Reaction time: 12 h

Procedure:
Preparation according to Preparation 2: tert-butyl 3-(3,4-dichlorophenyl)-3-hydroxypyrrolidin-1-carboxylate (1.0 g, 3.0 mmol), dichloromethane (2 mL) and trifluoroacetic acid (1 mL). Stirred for 12 h. Yield: 0.34 g. MS m/z (rel. intensity, 70 eV) 233 (M+, 66), 231 (M+, bp), 173 (59), 145 (47), 75 (40).
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][C:11]([NH2:13])=[CH:12][C:7]=2[N:6]=[CH:5]1)([CH3:3])[CH3:2].[Br:14]Br.N.CO.C(Cl)Cl>CC(O)=O>[CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][C:11]([NH2:13])=[C:12]([Br:14])[C:7]=2[N:6]=[CH:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1cnc2cc(N)ccc21
Reactant: BrBr
Agent: N
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)n1cnc2c(Br)c(N)ccc21
Yield: 35 %

Procedure:
To a solution of 1-isopropyl-5-aminobenzimidazole (2.4 g, 14 mmol) in 20 ml of AcOH was added solution of Br2 in AcOH until it produces a precipitation. The reaction mixture was concentrated in vacuo to provide a brown solid which was subjected to column chromatography (5% NH3 sat'd MeOH/CH2Cl2) to provide 1.2 g (4.5 mmol, 35%) of the product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[O:11][CH3:12].CO/[CH:15]=[CH:16]/[C:17]([O:19][CH3:20])=[O:18].C(O)(=O)C.Cl>C(OCC)(=O)C.O>[CH3:1][O:2][C:3]1[C:4]([O:11][CH3:12])=[C:5]([O:9][CH3:10])[CH:6]=[CH:7][C:8]=1/[CH:15]=[CH:16]/[C:17]([O:19][CH3:20])=[O:18]
Reactant: COc1cccc(OC)c1OC
Reactant: CO/C=C/C(=O)OC
Agent: Cl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)/C=C/c1ccc(OC)c(OC)c1OC
Reaction time: 16 h
Yield: 25 %

Procedure:
1.68 g of 1,2,3-trimethoxybenzene, 1.34 g of methyl trans-3-methoxyacrylate and 6 mL of glacial acetic acid were mixed, 313 mg of 35 wt % hydrochloric acid was added into the mixture at an inner temperature of 25° C., the added mixture was stirred for 16 hours at the same temperature to cause a reaction. After completion of the reaction, 30 ml, of water and 50 mL of ethyl acetate were added into the reaction liquid, and extraction treatment was conducted. The resultant organic layer was washed with water, then, concentrated, and the resultant concentrated residue was purified by silica gel column chromatography (developing liquid: n-heptane/ethyl acetate=6/1 to 5/1), to obtain 0.63 g of methyl trans-3-(2,3,4-trimethoxyphenyl)acrylate (white solid). 0.92 g of the raw material 1,2,3-trimethoxybenzene was recovered. The yield of methyl 3-(2,3,4-trimethoxyphenyl)acrylate based on the converted 1,2,3-trimethoxybenzene was 55%.
Reaction SMILES: C[Si](C)(C)[C:3](=[O:16])[C:4]([F:15])([F:14])[CH:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:6]=[CH2:7].[N+](=[CH:21][CH2:22][CH2:23][CH2:24][CH3:25])=[N-].C(N(N=O)C(N[N+]([O-])=O)=N)CCCC.[OH-].[K+]>C(OCC)C>[F:14][C:4]([F:15])([C:3](=[O:16])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:6]=[CH2:7]
Reactant: CCCCC=[N+]=[N-]
Reactant: C=CC(c1ccccc1)C(F)(F)C(=O)[Si](C)(C)C
Agent: CCCCCN(N=O)C(=N)N[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: C=CC(c1ccccc1)C(F)(F)C(=O)CCCCC
Temperature: 0 °C
Reaction time: 12 h
Yield: 24 %

Procedure:
Trimethyl-(2,2-difluoro-3-phenyl-4-pentenoyl)silane (400 mg, 1.5 mmol) was dissolved in diethyl ether (10 ml). The resulting solution was cooled to 0° C. and etheral 1-diazopentane [prepared from 1-pentyl-3-nitro-1-nitrosoguanidine (0.6 g) added slowly to a two-phase mixture of aqueous KOH (0.67 g in 2 ml of water) and ethyl ether (10 ml)] was added dropwise. The mixture was then stirred at room temperature for 12 hours, refluxed for 0.5 hours and allowed to cool to room temperature. Excess diazopentane was destroyed and the enol ether hydrolyzed by the addition of excess aqueous acetic acid. The mixture was concentrated in vacuo to give 731 mg of crude product. This material was purified by flash chromatography using 1:4 chloroform:hexane as eluant. Pure fractions were combined and concentrated to provide 99 mg (24% yield) of title product as a viscous yellow oil. 1H-NMR(CDCl3)delta(ppm): 7.32 (m, 5H), 6.16 (ddd, 10 12 and 20 Hz, 1H), 5.32 (d, 12 Hz, 1H), 5.24 (d, 20 Hz, 1H), 4.06 (dt, 10 and 16 Hz, 1H), 2.50 (dt, 7 and 17 Hz, 1H), 2.28 (dt, 5 and 17 Hz, 1H), 1.45 (m, 2H), 1.16 (m, 4H), 0.84 (t, 6 Hz, 3H). 13C-NMR(CDCl3)delta(ppm): 134.87, 132.03, 129.51, 128.70, 127.93, 120,62, 120.40, 117.25, 114.00, 53.27, 52.98, 52.67, 37.86, 30.85, 22.24, 21.93, 13.79. IR (CDCl3) cm-1 : 2925, 1739. Mass spectrum m/e (relative intensity): M+ 276.1 (1).
Reaction SMILES: Br.[NH2:2][C@H:3]1[CH2:7][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C@H:5](/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:4]1.C(N(CC)CC)C.[C:31]1([CH3:41])[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1>ClCCl>[CH3:23][O:22][C:20]([CH2:19][CH2:18][CH2:17]/[CH:16]=[CH:15]\[C@@H:5]1[CH2:4][C@@H:3]([NH:2][S:37]([C:34]2[CH:35]=[CH:36][C:31]([CH3:41])=[CH:32][CH:33]=2)(=[O:39])=[O:38])[CH2:7][N:6]1[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:21]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)CCC/C=C\[C@@H]1C[C@@H](N)CN1Cc1ccccc1
Agent: Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCC/C=C\[C@@H]1C[C@@H](NS(=O)(=O)c2ccc(C)cc2)CN1Cc1ccccc1
Reaction time: 1.5 h
Yield: 56.3 %

Procedure:
To a solution of (2S,4R)-4-amino-2-[(Z)-5-methoxycarbonyl-1-pentenyl]-1-(phenylmethyl)pyrrolidine hydrobromide (371 mg) in dichloromethane (4 ml) were added triethylamine (0.67 ml) and p-toluenesulfonyl chloride (200 mg) at 0° C. and the mixture was stirred at the same temperature for 1.5 hours. The solution was washed successively with water and brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was chromatographed on a silica gel column with a mixture of ethyl acetate and n-hexane (1:2) as an eluent to give (2S,4R)-2-[(Z)-5-methoxycarbonyl-1-pentenyl]-4-(4-methylphenylsulfonylamino)-1-(phenylmethyl)pyrrolidine (249 mg) as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:18]=[C:17]([O:19]C)[C:16]([O:21]C)=[CH:15][C:4]=2[S:5][C:6]=1[C:7]([N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:8].B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[C:3]2[CH:18]=[C:17]([OH:19])[C:16]([OH:21])=[CH:15][C:4]=2[S:5][C:6]=1[C:7]([N:9]1[CH2:10][CH2:11][O:12][CH2:13][CH2:14]1)=[O:8]
Reactant: COc1cc2sc(C(=O)N3CCOCC3)c(Cl)c2cc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(c1sc2cc(O)c(O)cc2c1Cl)N1CCOCC1
Temperature: -20 °C
Reaction time: 8 h

Procedure:
(3-Chloro-5,6-dimethoxy-benzo[b]thiophen-2-yl)-morpholin-4-yl-methanone (8.6 g) was suspended in dichloromethane (50 ml) under nitrogen, cooled to −20° C. and treated dropwise with 1M boron tribromide (100 ml) in dichloromethane. The resultant suspension was stirred at −20° C. for 30 min and then in cool overnight. The mixture was poured into ice-cold water and stirred for 30 min at room temperature. The product was filtered and washed with water.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=O)[NH:8][C:4]=2[CH:3]=1.P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:7]1[NH:8][C:4]2[CH:3]=[C:2]([F:1])[CH:11]=[CH:10][C:5]=2[N:6]=1
Reactant: O=c1[nH]c2ccc(F)cc2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Fc1ccc2nc(Cl)[nH]c2c1
Yield: 81.7 %

Procedure:
4-Fluorobenzene-1,2-diamine (2 g, 15.86 mmol) was dissolved in THF (49.4 ml) and 1,1′-Carbonyldiimidazole (2.83 g, 17.44 mmol) was added at RT. The reaction mixture was stirred overnight at RT. To this was added concentrated ammonia solution (1.5 ml) and the mixture stirred for 30 minutes and then diluted with water (100 ml). The resultant solid was collected by filtration, washed with water, followed by Et2O and then dried in vacuo to afford 5-fluoro-1H-benzo[d]imidazol-2(3H)-one (1.250 g, 52%); 1H NMR (400 MHz, DMSO-d6) 6.66-6.79 (2H, m), 6.81-6.94 (1H, m), 10.64 (1H, s), 10.76 (1H, s); m/z: (ES+) MH+, 151.19. b) A solution of 5-fluoro-1H-benzo[d]imidazol-2(3H)-one (1.25 g, 8.22 mmol) in phosphorus oxychloride (25.2 ml, 270.34 mmol) was heated for 18 hours at 100° C. The reaction mixture was cooled to RT and excess of POCl3 was evaporated in vacuo. The residue was neutralized with saturated NaHCO3 solution (10 ml) and extracted with EtOAc (3×20 ml). The organic phase was washed with brine and then dried over MgSO4, filtered and concentrated under reduced pressure to afford 2-chloro-6-fluoro-1H-benzo[d]imidazole (1.146 g, 82%); 1H NMR (400 MHz, DMSO-d6) 7.09 (1H, ddd), 7.36 (1H, dd), 7.53 (1H, dd); m/z: (ES+) MH+, 171.34. c) 2-Chloro-6-fluoro-1H-benzo[d]imidazole (1.146 g, 6.72 mmol) was charged to high pressure autoclave PV10832 (Parr 160 ml) with methylamine 40% EtOH solution (50 ml, 6.72 mmol) and sealed on its trolley and the resulting solution heated to 160° C. in high pressure blast cell 60 for 16 hours. The pressure in the autoclave reached 13 bar. The reaction mixture was evaporated and the residue dissolved in MeOH and added to an SCX column. The desired product was eluted from the column using 7M NH3/MeOH. Fractions containing product were evaporated and the residue was purified by flash chromatography on silica, eluting with a gradient of 0 to 10% MeOH in DCM. Pure fractions were evaporated to afford 6-fluoro-N-methyl-1H-benzo[d]imidazol-2-amine (0.707 g, 64%); 1H NMR (400 MHz, DMSO-d6) 2.27 (3H, d), 6.38-6.44 (2H, m), 6.67 (1H, dd), 6.79-6.84 (1H, m); m/z: (ES+) MH+, 166.31.
Reaction SMILES: C[O:2][C:3](=[O:16])[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][CH:7]=1)[CH3:5].[OH-].[Li+]>CO.O>[C:12]([C:9]1[CH:8]=[CH:7][C:6]([CH:4]([CH3:5])[C:3]([OH:16])=[O:2])=[CH:11][CH:10]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: COC(=O)C(C)c1ccc(C(C)(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C(=O)O)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83 %

Procedure:
2-(4-Tert-butylphenyl)propionic acid methyl ester (946 mg, 4.29 mmol) was dissolved in MeOH (10 ml) and mixed with a solution of lithium hydroxide (154 mg, 6.44 mmol) in water (5 ml). The reaction mixture was stirred for 18 h at RT. The solvent was removed under vacuum and the aqueous residue mixed with diethyl ether (30 ml). The phases were separated. The aqueous phase was reextracted with diethyl ether (20 ml). The aqueous phase was adjusted to a pH of 3 using 1 N hydrochloric acid solution. There formed a clouding or precipitation which was extracted from the aqueous phase by the addition of EtOAc (2×20 ml). The organic phase was washed with sat. NaCl solution (20 ml), dried and concentrated. 2-(4-Tert-butylphenyl)propionic acid was obtained as a colourless solid in a yield of 83% (735 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:21]([CH3:23])[CH3:22])[C:6]2[O:10][C:9]([C:11]3[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:20]=1)#[N:2].[O:24]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[O:28][CH2:27][CH:26]([CH2:35][NH2:36])[CH2:25]1>>[C:1]([C:3]1[CH:4]=[C:5]([CH:21]([CH3:22])[CH3:23])[C:6]2[O:10][C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:15]([NH:36][CH2:35][CH:26]4[CH2:25][O:24][C:30]5[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=5[O:28][CH2:27]4)=[O:17])=[CH:18][CH:19]=3)=[N:8][C:7]=2[CH:20]=1)#[N:2]
Reactant: NCC1COc2ccccc2OC1
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)O)cc3)oc12
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4COc5ccccc5OC4)cc3)oc12

Procedure:
The title compound was prepared, as a mixture, from 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzoic acid (INTERMEDIATE 2), and 1-(3,4-dihydro-2H-1,5-benzodioxepin-3-yl)methanamine as described in EXAMPLE 1. Mass spectrum (ESI) 468.0 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.31 (d, J=8.5 Hz, 2H), 7.96 (d, J=8.5 Hz, 2H), 7.93 (d, J=1.5 Hz, 1H), 7.51 (d, J=1 Hz, 1H), 6.90-7.02 (m, 4H), 4.29 (m, 4H), 3.75 (t, J=6 Hz, 2H), 3.47 (septet, J=7 Hz, 1H), 2.65 (m, 1H), 1.46 (d, J=6.5 Hz, 6H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C[O-].[Na+].Cl[CH2:10][CH:11]([OH:22])[CH2:12][NH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21].O>CO.CN(C)C=O>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[NH:13][CH2:12][CH:11]([OH:22])[CH2:10][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: OC(CCl)CNc1ccc(Cl)cc1Cl
Reactant: c1c[nH]cn1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: OC(CNc1ccc(Cl)cc1Cl)Cn1ccnc1
Yield: 90.5 %

Procedure:
108 Grams (1.586 mol) of imidazole and 283 g (1.574 mol) of sodiummethylate solution 30% in methanol are mixed and the solution is then concentrated to dryness under reduced pressure at 50° C. The crystalline residue is dissolved in 400 ml dimethylformamide at 110° C. A solution of 259 g (1.017 mol) of N-(3-chloro-2-hydroxypropyl)-2,4-dichloroaniline in 500 ml of dimethylformamide is added dropwise at 110° C. within 30 minutes. Upon completion the reaction mixture is refluxed for 2 hours and then cooled down. The solution is now added dropwise to 3400 ml of water at room temperature within 30 minutes and stirred for another hour. The precipitated granular substance is filtered off, washed with water and dried in vacuum at 50° C. to yield 263.5 g 1-[3-(2,4-dichloroanilino)-2-hydroxypropyl]-imidazole, M.P. 107°-109° C.
Reaction SMILES: [Br:1][C:2]1[C:6]([S:7][C:8]([F:11])([F:10])[F:9])=[C:5]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[NH:4][C:3]=1[C:19]([F:22])([F:21])[F:20].CC(C)([O-])C.[K+].[CH2:29]([O:31][CH2:32]Cl)[CH3:30]>O1CCCC1.CCOCC.O>[Br:1][C:2]1[C:6]([S:7][C:8]([F:10])([F:9])[F:11])=[C:5]([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[N:4]([CH2:32][O:31][CH2:29][CH3:30])[C:3]=1[C:19]([F:22])([F:21])[F:20]
Reactant: CCOCCl
Reactant: FC(F)(F)Sc1c(-c2ccc(Cl)cc2)[nH]c(C(F)(F)F)c1Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CCOCn1c(-c2ccc(Cl)cc2)c(SC(F)(F)F)c(Br)c1C(F)(F)F
Reaction time: 0.5 h

Procedure:
A solution of 3-bromo-5-(p-chlorophenyl)-2-(trifluoromethyl)-4-[(trifluoromethyl)thio]pyrrole (0.6 g, 1.4 mmol) and potassium tert-butoxide (0.19 g, 1.7 mmol) in tetrahydrofuran is stirred for 15 minutes, treated with chloromethyl ethyl ether (0.16 g, 1.7 mmol), stirred for 30 minutes and diluted with an ether/water mixture. The organic phase is separated, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a residue. Chromatography of the residue using silica gel and a 1:9 ethyl acetate/hexanes solution gives the title product as an amber oil which is identified by 1HNMR and 13CNMR spectral analyses.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:13]([OH:15])=O.[CH2:16]([N:18]1[CH:22]=[C:21]([CH2:23][NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH:31]([CH3:33])[CH3:32])=[CH:27][CH:26]=2)[CH:20]=[N:19]1)[CH3:17]>>[CH2:16]([N:18]1[CH:22]=[C:21]([CH2:23][N:24]([C:25]2[CH:26]=[CH:27][C:28]([CH:31]([CH3:32])[CH3:33])=[CH:29][CH:30]=2)[C:13]([CH:6]2[C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[O:9][CH2:8][CH2:7]2)=[O:15])[CH:20]=[N:19]1)[CH3:17]
Reactant: CCn1cc(CNc2ccc(C(C)C)cc2)cn1
Reactant: COc1ccc2c(c1)C(C(=O)O)CCO2
Product: CCn1cc(CN(C(=O)C2CCOc3ccc(OC)cc32)c2ccc(C(C)C)cc2)cn1
Yield: 60.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 6-methoxychroman-4-carboxylic acid (0.31 g) and [(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.37 g) as starting materials, N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-6-methoxychroman-4-carboxamide (0.39 g) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[C:13]([CH3:15])[C:12]([O:16][CH3:17])=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH2:7][CH2:8][C:9]=1[CH:10]2[CH2:18][CH:19]=O.Cl.[CH3:22][NH:23][CH3:24].C(N(CC)CC)C.[BH4-].[Na+]>CO.C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:14]=[C:13]([CH3:15])[C:12]([O:16][CH3:17])=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH2:7][CH2:8][C:9]=1[CH:10]2[CH2:18][CH2:19][N:23]([CH3:24])[CH3:22]
Reactant: COc1c(C)cc(C)c2c1C(CC=O)C1=C2CCCC1
Reactant: CNC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1c(C)cc(C)c2c1C(CCN(C)C)C1=C2CCCC1
Reaction time: 3 h
Yield: 63.2 %

Procedure:
A methanol solution containing 1.0 g of 5,7-dimethyl-8-methoxy-9-formylmethyl-1,2,3,4-tetrahydro-9H-fluorene in 10 ml of methanol was added dropwise to a methanol solution containing 3.0 g of dimethylamine hydrochloride and 5.2 ml of triethylamine in 30 ml of methanol at 0° C. After stirring at the same temperature for 3 hours, 100 mg of sodium borohydride was added, followed by further stirring at the same temperature for 2 hours. The reaction mixture was diluted with chloroform, washed successively with water and saturated aqueous sodium chloride solution and then dried with magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by a silica gel column chromatography (eluent: methanol:chloroform=1:1) to obtain 700 mg of 5,7-dimethyl-8-methoxy-9-(2-dimethylaminoethyl)-1,2,3,4-tetrahydro-9H-fluorene. This was dissolved in ethanol and to the solution were added ethanol.hydrochloric acid. The solvent was distilled off and the residue was recrystallized from diethyl ether-diisopropyl ether to obtain 220 mg of 5,7-dimethyl- 8-methoxy-9-(2-dimethylaminoethyl)-1,2,3,4-tetrahydro-9H-fluorene hydrochloride.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([F:17])[CH:11]=2)[CH2:8][N:7]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:6]1)=[O:4].O[Li].O>O.CO>[CH2:18]([N:7]1[CH2:8][C@@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([F:17])[CH:11]=2)[C@H:5]([C:3]([OH:4])=[O:2])[CH2:6]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)c(F)c1
Agent: [Li]O
Solvent: O
Solvent: CO
Product: O=C(O)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)c(F)c1
Temperature: 80 °C
Yield: 80.8 %

Procedure:
A mixture of 19.5 g (56 mmol) (3S,4R)-1-Benzyl-4-(4-chloro-3-fluoro-phenyl)-pyrrolidine-3-carboxylic acid methyl ester and 14.1 g (337 mmol) LiOH.H2O in water (100 mL) and methanol (10 mL) was heated to 80° C. for 45 min. The organic solvents were removed under vacuum and the aqueous phase acidified with 2N HCl tp pH=1-2. The precipitate was filtered off, washed with acetonitrile and dried to yield 15.1 g (73%) of the title compound as off-white solid. MS m/e: 334.1 [M+H]+.
Reaction SMILES: N[C:2]([C:4]1([NH:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)=[O:3].C([OH:30])C>[Pd]>[CH2:21]([O:20][C:18]([NH:17][C:4]1([C:2]([OH:30])=[O:3])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])[CH2:6][CH2:5]1)=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)OCc2ccccc2)(C(N)=O)CC1
Reactant: CCO
Agent: [Pd]
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)OCc2ccccc2)(C(=O)O)CC1
Reaction time: 18 h

Procedure:
Palladium (10% on carbon; 210 mg) was added to a solution of tert-butyl 4-(aminocarbonyl)-4-{[(benzyloxy)carbonyl]amino}piperidine-1-carboxylate (0.43 g, 1.14 mmol) in ethanol (20 mL). The reaction vessel was evacuated and back-filled with nitrogen (3×), then back-filled with hydrogen (1 atm). After 18 h, the mixture was filtered and concentrated to give the title compound (290 mg).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([CH2:13][CH2:14][CH3:15])[CH2:11][OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>>[CH:1]1([CH2:7][CH2:8][CH2:9][CH:10]([CH2:13][CH2:14][CH3:15])[CH2:11][OH:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: CCCC(CO)CCCc1ccccc1
Product: CCCC(CO)CCCC1CCCCC1
Reaction time: 6 h
Yield: 91.8 %

Procedure:
365 g of 5-Phenyl-2-n-propyl-pentanol of Synthesis Example 1.2 were combined with 10 g Ru on activated carbon (Ru content: 5 wt. %) and hydrogenated at a hydrogen pressure of 20 bar and at a temperature of 120° C. After 5-7 hours the reaction was finished. The catalyst was removed and the product distilled. 345 g (content: 98.2%) of 5-cyclohexyl-2-n-propyl-pentanol are obtained. Yield: 90.8% of theoretical.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:10]2[C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=3[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[C:10]3[C:15]4[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=4[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: Fc1ccc(CNc2nc(Cl)nc3sc4c(c23)CCCC4)cc1
Product: Fc1ccc(CNc2nc(-n3cncn3)nc3sc4c(c23)CCCC4)cc1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-5,6,7,8-tetrahydro-4-(4-fluorobenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-5,6,7,8-tetrahydro-4-(4-fluorobenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine.
Reaction SMILES: C[O:2][C:3](=[O:13])[CH:4]=[CH:5][C:6]1[CH:7]=[N:8][C:9]([Br:12])=[CH:10][CH:11]=1.[Li+].[OH-]>C1COCC1.O>[Br:12][C:9]1[N:8]=[CH:7][C:6]([CH:5]=[CH:4][C:3]([OH:13])=[O:2])=[CH:11][CH:10]=1
Reactant: COC(=O)C=Cc1ccc(Br)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C=Cc1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.6 %

Procedure:
To 3-(6-bromo-pyridin-3-yl)-acrylic acid methyl ester (120 mg, 0.495 mmol) in THF was added a solution of 0.5 N-LiOH (2 eq) and the mixture was stirred for 3 hrs at room temperature. The resulting residue was dissolved in H2O, then washed three times with Et2O, and neutralized with 1N HCl to pH 5˜7. The resulting solid filtered and washed with H2O and then dried in vacuo to give 3-(6-bromo-pyridin-3-yl)-acrylic acid (100 mg, 88%).