Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:23]=[CH:22][C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=2)[C:3]=1[CH2:24][C:25]([O:27][CH3:28])=[O:26].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:39]1[CH2:43]OC[CH2:40]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:23]=[CH:22][C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=2)[C:3]=1[CH:24]([CH2:40][CH2:39][CH3:43])[C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc2c(c1)OCO2)CCCC3
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCI
Solvent: CN(C)C=O
Product: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccc2c(c1)OCO2)CCCC3
Yield: 82.6 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-(benzo[d][1,3]dioxol-5-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.328 g; 0.83 mmol), LHMDS 1N in THF (1.24 mL; 1.24 mmol), 1-iodopropane (0.162 mL; 1.66 mmol) in DMF (4.1 mL) for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (3-40%) in heptane furnished 0.300 g (83%) of the title compound as a yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:31])[C:10]([NH:12][CH2:13][C:14]2[C:15]([C:24]3[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=3)=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=2)=[O:11])=[CH:5][C:4]=1[F:32])#[N:2].[BH4-].[Na+]>C(O)C.[NiH6-5]Cl>[NH2:2][CH2:1][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:31])[C:10]([NH:12][CH2:13][C:14]2[C:15]([C:24]3[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=3)=[N:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=2)=[O:11])=[CH:5][C:4]=1[F:32]
Reactant: Cc1cccc(-c2nc(C(F)(F)F)ccc2CNC(=O)C(C)c2ccc(C#N)c(F)c2)c1
Agent: Cl[NiH6-5]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cccc(-c2nc(C(F)(F)F)ccc2CNC(=O)C(C)c2ccc(CN)c(F)c2)c1
Reaction time: 2 h

Procedure:
Nickel(II) chloride hexahydride (1 equiv.) and 2-(4-cyano-3-fluorophenyl)-N-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide are stirred in anhydrous ethanol during 15 minute for activation. Sodium borohydrid (7 equiv.) is added on it and mixture stirred for 2 h. Adding celite to the reaction and filter it using celite packed filter, washing with ethanol. The reaction mixture is purified after concentration to obtain 2-(4-(aminomethyl)-3-fluorophenyl)-N-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide.
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[CH:11]=2)[N:9]=1)[C:2]([NH2:4])=[NH:3].[N:17]#[C:18][NH2:19].[CH2:20](O)C>>[C:18]([NH:19][CH:20]=[N:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:8]2[N:9]=[C:5]([NH:1][C:2]([NH2:4])=[NH:3])[S:6][CH:7]=2)[CH:11]=1)#[N:17]
Reactant: N=C(N)Nc1nc(-c2cccc(N)c2)cs1
Reactant: CCO
Reactant: N#CN
Product: N#CNC=Nc1cccc(-c2csc(NC(=N)N)n2)c1
Temperature: 120 °C

Procedure:
A mixture of 23.3 gm of 2-guanidino-4-(3-amino-phenyl)-thiazole, 18.5 gm of ethyl ortoformate and 4.2 gm of cyanamide was heated at 120° C. for 15 minutes, cooled to room temperature, treated with ethanol and filtered, yielding 23 gm of the title compound, m.p. 214°-216° C. (dec.).
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C@@H:12]2[CH2:14][C@H:13]2[CH2:15]OS(C)(=O)=O)=[O:11])[CH2:5][CH2:4]1)[CH3:2].Cl.[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.Cl.ClC1C=C(N2CCNCC2)C=CC=1>>[CH2:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C@@H:12]2[CH2:14][C@H:13]2[CH2:15][N:33]2[CH2:34][CH2:35][N:30]([C:24]3[CH:25]=[C:26]([CH3:29])[CH:27]=[CH:28][C:23]=3[CH3:22])[CH2:31][CH2:32]2)=[O:11])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CC[C@H]1CC[C@H](NC(=O)[C@@H]2C[C@H]2COS(C)(=O)=O)CC1
Reactant: Cc1ccc(C)c(N2CCNCC2)c1
Agent: Cl
Agent: Clc1cccc(N2CCNCC2)c1
Product: CC[C@H]1CC[C@H](NC(=O)[C@@H]2C[C@H]2CN2CCN(c3cc(C)ccc3C)CC2)CC1

Procedure:
Follow the procedure of Example 1e, and substitute methane sulfonic acid 2-(trans-4-ethyl-cyclohexylcarbamoyl)-trans-cyclopropylmethyl ester (Example 13d) for 2-(trans-4-methyl-cyclohexylcarbamoyl)-trans-cyclopropylmethyl ester and 4-(2,5-dimethylphenyl)-piperazine hydrochloride for 1-(3-chloro-phenyl)-piperazine hydrochloride therein, to obtain the title compound LC/MS, m/z=398 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:12])=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([NH:9][NH2:10])=[O:8].[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([OH:23])=[C:18]([C:20](=O)[CH3:21])[CH:19]=1>CO.C(O)(=O)C>[Br:1][C:2]1[C:3]([Cl:12])=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([NH:9]/[N:10]=[C:20](/[C:18]1[CH:19]=[C:14]([Cl:13])[CH:15]=[CH:16][C:17]=1[OH:23])\[CH3:21])=[O:8]
Reactant: CC(=O)c1cc(Cl)ccc1O
Reactant: NNC(=O)c1cnc(Cl)c(Br)c1
Solvent: CO
Solvent: CC(=O)O
Product: C/C(=N\NC(=O)c1cnc(Cl)c(Br)c1)c1cc(Cl)ccc1O
Temperature: 120 °C
Yield: 33.1 %

Procedure:
5-Bromo-6-chloronicotinohydrazide (15 mg, 0.060 mmol) and 1-(5-chloro-2-hydroxyphenyl)ethanone (10.22 mg, 0.060 mmol) were dissolved in methanol (4 mL) in the presence of acetic acid as a catalyst and the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. The reaction was monitored by TLC. Upon completion of the reaction and following cooling, the solvent was removed by vacuum, and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) affording the title compound as a solid (8 mg). 1H NMR (400 MHz, DMSO-d6): δ 8.39 (d, 1H, J=2.4 Hz), 8.28 (s, 1H), 7.63 (d, 1H, J=2.4 Hz), 7.32 (dd, 1H, J=2.4 & 8.8 Hz), 7.06 (d, 1H, J=6.8 Hz), 6.92 (d, 1H, J=9.2 Hz), 6.81 (d, 1H, J=6.8 Hz), 2.47 (s, 3H). ESI-MS: 404.0 [M+H]+.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[NH2:8][C:9]1[C:17]([CH3:18])=[C:16]([Br:19])[CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12]>C(OCC)(=O)C.C(O)C>[NH2:8][C:9]1[C:17]([CH3:18])=[C:16]([Br:19])[CH:15]=[CH:14][C:10]=1[C:11]([O:13][CH3:1])=[O:12]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Cc1c(Br)ccc(C(=O)O)c1N
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)c1ccc(Br)c(C)c1N
Reaction time: 16 h
Yield: 87.9 %

Procedure:
Add (trimethylsilyl)diazomethane (16.5 mL, 33 mmol, 2 M in hexane) to a solution of 2-amino-4-bromo-3-methyl-benzoic acid (3.8 g, 16.5 mmol) in ethyl acetate (50 mL) and ethanol (50 mL) at room temperature and stir the solution for 16 h. Remove the solvent under reduced pressure. Chromatograph the residue over silica gel, eluting with hexanes/ethyl acetate, to afford the title compound (3.54 g, 88%). MS (ES+): 245 (M+H).
Reaction SMILES: C1(N[C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:24][C@H:25]5[CH2:29][CH2:28][NH:27][CH2:26]5)[CH:20]=4)[N:15]=[CH:14]3)[CH:7]=2)CC1.C(OCC)(=[O:33])C>Br>[CH3:12][C:9]1[CH:10]=[CH:11][C:6]([C:5]([OH:33])=[O:30])=[CH:7][C:8]=1[N:13]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:24][C@H:25]3[CH2:29][CH2:28][NH:27][CH2:26]3)[CH:20]=2)[N:15]=[CH:14]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(O[C@H]3CCNC3)cc2c1=O
Reactant: CCOC(C)=O
Agent: Br
Product: Cc1ccc(C(=O)O)cc1-n1cnc2ccc(O[C@H]3CCNC3)cc2c1=O

Procedure:
A solution of N-Cyclopropyl-4-methyl-3-[4-oxo-6-[(3S)-pyrrolidin-3-yloxy]quinazolin-3(4H)-yl]benzamide (0.5 g) in 48% hydrobromic acid (5 ml) was heated to 130° C. for 30 minutes in a microwave (Personal Chemistry Emrys Optimizer with 300 W magnetron). The reaction mixture was diluted with ethyl acetate and extracted with water. The aqueous extracts were combined and purified by column chromatography on an ion exchange column (isolute SCX column from International Sorbent Technology Limited, Henoed, Mid-Glamorgan, UK) using initially methanol and then a 99:1 mixture of methanol and aqueous ammonia solution to give 4-methyl-3-[4-oxo-6-[(3S)-pyrrolidin-3-yloxy]quinazolin-3(4H)-yl]benzoic acid as a solid (224 mg); NMR Spectrum: (DMSOd6) 2.13 (m, 7H), 3.30 (m, 2H), 4.89 (s, 1H), 5.26 (s, 1H), 7.45 (m, 2H), 7.58 (t, 1H), 7.70 (d, 1H), 7.80 (s, 1H), 7.92 (m, 1H), 8.15 (s, 1H); Mass Spectrum: M+H+ 366.
Reaction SMILES: [C:1]([O:4][CH:5]=[CH:6][CH:7]=[CH2:8])(=[O:3])[CH3:2].[C:9]([NH2:13])(=[O:12])[CH:10]=[CH2:11].ClCCl>C1(C)C=CC=CC=1.C1(C=CC(O)=CC=1)O>[C:9]([CH:10]1[CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH:6]=[CH:7][CH2:8][CH2:11]1)(=[O:12])[NH2:13]
Reactant: C=CC(N)=O
Reactant: C=CC=COC(C)=O
Agent: Oc1ccc(O)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(=O)OC1C=CCCC1C(N)=O
Temperature: 110 °C
Reaction time: 24 h
Yield: 70.7 %

Procedure:
1-Acetoxy-1,3-butadiene (20.79 g, 0.185 mol) was dissolved in toluene (21 mL). To this was added acrylamide (11.98 g, 0.168 mol) and hydroquinone (0.111 g). The colourless solution was heated at 110° C. for 116 h under argon. More 1-acetoxy-1,3-butadiene (5.67 g, 0.051 mol) was then added, and heating continued for a further 24 h. The solution was cooled then dichloromethane added. This solution was purified by Biotage 75 chromatography twice on silica (2×400 g) to give the title compound as a viscous oil (21.76 g, 71%), which solidified on standing;
Reaction SMILES: Cl.[CH2:2]([C:7]1[S:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1)[CH2:3][CH2:4][CH2:5][CH3:6].FC(F)(F)S(O)(=O)=O.[N+:24]([O-])([OH:26])=[O:25].O>C(Cl)Cl>[CH2:2]([C:7]1[S:8][C:9]2[CH:15]=[C:14]([N+:24]([O-:26])=[O:25])[CH:13]=[CH:12][C:10]=2[N:11]=1)[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=[N+]([O-])O
Reactant: CCCCCc1nc2ccccc2s1
Agent: Cl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CCCCCc1nc2ccc([N+](=O)[O-])cc2s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-Pentylbenzothiazole hydrochloride (20.5 g, 0.084 mol) is added, at 0° C., to trifluoromethanesulfonic acid (44.6 ml 0.504 mol) and 100% nitric acid (10.6 ml, 0.215 mol) in methylene chloride (270 ml), and the mixture is stirred at 0° C. for 1.5 hours and at room temperature for one hour. Water (150 ml) is added dropwise and the phases are separated. The organic phase is washed with 0.5M NaHCO3 and with water. The resulting solution is dried, filtered and concentrated. The solid obtained is recrystallized from petroleum ether. Yield: 10.6 g (50%); Rf (8/2 petroleum ether/ethyl acetate): 0.71; 1H-NMR (d6-DMSO) 9.05 (d, 1H); 8.25 (dd, 1H); 8.15 (d, 1H); 3.13 (t, 2H); 1.28-1.36 (m, 4H); 0.85 (t, 3H).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:23](O)=[O:24]>>[OH:10][C:6]1[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:9]=[CH:8][C:7]=1[CH:23]=[O:24]
Reactant: CC(C)c1cccc(O)c1
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Product: CC(C)c1ccc(C=O)c(O)c1
Temperature: 60 °C

Procedure:
To 100 mL of trifluoroacetic acid were added 25.39 g of 3-isopropylphenol and 26.14 g of hexamethylenetetramine. After being stirred at 60° C. for an hour, the reaction mixture was concentrated under reduced pressure. To the residue was added diluted hydrochloric acid, and the mixture was stirred at room temperature for 30 minutes. After the reaction mixture was extracted with ethyl acetate, the organic layer was washed with saturated aqueous sodium bicarbonate solution, and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate-hexane) to give 6.69 g of 2-hydroxy-4-isopropylbenzaldehyde.
Reaction SMILES: FC(F)(F)S(O[CH2:7][C@H:8]1[CH2:13][CH2:12][C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[O:9]1)(=O)=O.C([Mg]Br)[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1.O.[Cl-].[NH4+]>O1CCCC1.C(Cl)Cl>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:7][C@H:8]2[CH2:13][CH2:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[O:9]2)=[CH:22][CH:23]=1
Reactant: O=S(=O)(OC[C@H]1CCc2ccccc2O1)C(F)(F)F
Reactant: COc1ccc(C[Mg]Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C[C@H]2CCc3ccccc3O2)cc1
Temperature: -10 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
(R)-(-)-3,4-Dihydro-2-trifluoromethanesulfonyloxymethyl-2H-benzopyran (23.0 g, 78 mmol) and copper (I) bromide dimethyl sulfide complex (2.8 g, 13 mmol) were dissolved in tetrahydrofuran (400 ml) under a nitrogen atmosphere and cooled to -10° C., 4-Anisylmagnesium bromide (215 ml of a 1M solution in tetrahydrofuran, 0.215 mol) was added dropwise over 30 minutes, keeping the temperature below -5° C. The solution was stirred for 3 hours at 0° C. and then slowly poured into a mixture of water (800 ml) containing ammonium chloride (96 g, 1.8 mol) and methylene chloride (400 ml). The layers were separated and the aqueous portion was extracted with methylene chloride (400 ml). The combined organics were washed with 10% ammonium chloride (2×400 ml), water (250 ml), and brine (250 ml). The methylene chloride layer was dried (MgSC4), filtered and concentrated in vacuo. The residue was purified on silica gel using hexanes/methylene chloride (1:1) as eluent to afford 18.5 g (92% yield) of the title product as an oil. [α]D -99.2° (c 1.7, MeOH); 1H NMR (300 MHz, CDCl3) δ1.6-1.7 (m, 1H), 1.9-2.0 (m, 1H), 2.7-2.8 (m, 3H), 3.1 (dd, 1H), 3.8 (s, 3H), 4.1 (m, 1H), 6.8 (m, 3H), 7.0 (m, 2H), 7.2 (m, 2H) .
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10](=[CH:11][CH:12]=1)[C:8](=[O:9])O[C:6]([C:13]([OH:15])=[O:14])=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>CO>[CH2:22]([N:29]1[C:6]([C:13]([OH:15])=[O:14])=[C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:4]2[C:10](=[CH:11][CH:12]=[C:2]([F:1])[CH:3]=2)[C:8]1=[O:9])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)c1oc(=O)c2ccc(F)cc2c1-c1ccccc1
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(O)c1c(-c2ccccc2)c2cc(F)ccc2c(=O)n1Cc1ccccc1
Temperature: 50 °C
Reaction time: 36 h
Yield: 76.1 %

Procedure:
A mixture of 6-fluoro-4-phenylisocoumarin-3-carboxylic acid (300 mg), benzylamine (230 mg), triethylamine (0.3 ml) and methanol (3 ml) was stirred at 50° C. for 36 hrs. The reaction mixture was concentrated, 1N-hydrochloric acid was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. 4N-Hydrochloric acid-ethyl acetate solution (3 ml) was added to the residue at room temperature, and the mixture was stirred for 12 hrs. The reaction mixture was concentrated under reduced pressure and the obtained crystals were washed with (diisopropyl ether) to give the title compound, 2-benzyl-6-fluoro-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (300 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:6](I)=[C:7]([CH2:25][C:26]([N:28]([CH2:33][CH2:34][OH:35])[CH2:29][CH2:30][O:31][CH3:32])=[O:27])[C:8]([C:15](=[O:24])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:10]=1.[CH2:37]([O:39]C=C[Sn](CCCC)(CCCC)CCCC)[CH3:38].[F-].[NH4+]>C1(C)C=CC=CC=1.CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd][P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[C:37]([C:6]1[C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:10][C:9]([O:11][CH2:12][O:13][CH3:14])=[C:8]([C:15](=[O:24])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:7]=1[CH2:25][C:26]([N:28]([CH2:33][CH2:34][OH:35])[CH2:29][CH2:30][O:31][CH3:32])=[O:27])(=[O:39])[CH3:38]
Reactant: COCCN(CCO)C(=O)Cc1c(I)c(OCOC)cc(OCOC)c1C(=O)c1ccc(OC)cc1
Reactant: CCCC[Sn](C=COCC)(CCCC)CCCC
Agent: Cc1ccccc1[P]([Pd][P](c1ccccc1C)(c1ccccc1C)c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: [F-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: COCCN(CCO)C(=O)Cc1c(C(C)=O)c(OCOC)cc(OCOC)c1C(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.5 %

Procedure:
2-[3,5-Bis(methoxymethoxy)-2-iodo-6-(4-methoxybenzoyl)phenyl]-N-(2-hydroxyethyl)-N-(2-methoxyethyl)acetamide (0.56 g, 0.91 mmol) obtained in Example 135, Step 2 was dissolved in toluene (10 mL), and ethoxyvinyl tributyltin (0.46 mL, 1.4 mmol) and bis(triphenylphosphine)palladium (II) dichloride (0.05 g, 0.071 mmol) were successively added thereto in an atmosphere of argon. The reaction mixture was stirred for 3 hours under heating and reflux, and then cooled to room temperature. To the mixture was added a saturated aqueous solution of ammonium fluoride, followed by stirring at room temperature for 6 hours. The reaction mixture was filtered through Celite, and the resulting filtrate was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was dissolved in tetrahydrofuran (10 mL) and a 1 mol/L hydrochloric acid was added thereto with stirring under ice-cooling, followed by stirring at room temperature for 1 hour. The reaction mixture was ice-cooled and neutralized with a saturated aqueous solution of sodium hydrogencarbonate, followed by liquid separation. After the aqueous layer was extracted with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate (20 mL), and activated carbon (400 mg) was added thereto, followed by stirring at room temperature for 15 hours. The reaction mixture was filtered through Celite, and the obtained filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/methanol=10/0-9/1 to obtain 2-[2-acetyl-3,5-bis(methoxymethoxy)-6-(4-methoxybenzoyl)phenyl]-N-(2-hydroxyethyl)-N-(2-methoxyethyl)acetamide (0.25 g, 51%).
Reaction SMILES: C=[C:2]1[CH2:15][CH2:14][C:5]2([C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][O:6]2)[CH2:4][C:3]1=O.[CH3:17]SC.B.[OH-:21].[Na+].[O-]O>O1CCCC1.O>[CH3:17][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[C:7](=[O:6])[O:21][C:5]12[CH2:4][CH2:3][CH2:2][CH2:15][CH2:14]1
Reactant: CSC
Reactant: C=C1CCC2(CC1=O)OCc1ccccc12
Reactant: [OH-]
Agent: B
Agent: [Na+]
Agent: [O-]O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc2c1C(=O)OC21CCCCC1
Reaction time: 1.5 h

Procedure:
A solution of 4-methylenespiro[cyclohexane-1,1′(3′H)-isobenzofuran]-3-one (196 mg) in anhydrous tetrahydrofuran (5.0 mL) was cooled to 0° C., to which borane-dimethyl sulfide complex (2M tetrahydrofuran solution, 690 μL) was added and the mixture was stirred at that temperature for 1.5 hours, then additional 20 minutes together with aqueous 2M sodium hydroxide (5.0 mL) and aqueous 30% hydroperoxide (5.0 mL). The reaction mixture was diluted with water, extracted with ethyl acetate, washed with saturated saline solution, then dried over anhydrous Na2SO4 and evaporated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=2/1) to give the subject compound (190 mg) as diastereomers.
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([CH2:10][O:11][CH:12]([C:17]2[S:21][C:20]([C:22]3[CH:23]=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=3)=[N:19][C:18]=2[CH3:32])[C:13]([F:16])([F:15])[F:14])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].FC(F)(F)C(C1S[C:40]([C:42]2[CH:43]=NC(C(F)(F)F)=CC=2)=NC=1C)O.BrC1C=C(CBr)C=CC=1C#N.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C1(B(O)O)CC1>C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[CH:43]1([C:2]2[CH:9]=[C:8]([CH2:10][O:11][CH:12]([C:17]3[S:21][C:20]([C:22]4[CH:23]=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=4)=[N:19][C:18]=3[CH3:32])[C:13]([F:14])([F:16])[F:15])[CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:42][CH2:40]1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)nc2)sc1C(OCc1ccc(C#N)c(Br)c1)C(F)(F)F
Reactant: Cc1nc(-c2ccc(C(F)(F)F)nc2)sc1C(O)C(F)(F)F
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: N#Cc1ccc(CBr)cc1Br
Agent: OB(O)C1CC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nc(-c2ccc(C(F)(F)F)nc2)sc1C(OCc1ccc(C#N)c(C2CC2)c1)C(F)(F)F
Temperature: 100 °C
Reaction time: 3 h

Procedure:
309 mg 2-Bromo-4-{2,2,2-trifluoro-1-[4-methyl-2-(6-trifluoromethyl-pyridin-3-yl)-thiazol-5-yl]-ethoxymethyl}-benzonitrile (derived from 2,2,2-Trifluoro-1-[4-methyl-2-(6-trifluoromethyl-pyridin-3-yl)-thiazol-5-yl]-ethanol and 2-Bromo-4-bromomethyl-benzonitrile according to the method described in example 30), 32 mg tricyclohexylphosphine, 148 mg cyclopropylboronic acid and 470 mg K3PO4 mono hydrate were dissolved in a mixture of 4 ml toluene and 0.4 ml water. The reaction mixture was purged with argon, then 130 mg palladium (II) acetate were added. The reaction mixture was stirred at 100° C. for three hours. The cooled reaction mixture was diluted by addition of 100 ml ethyl acetate and filtered through a celite pad. The filtrate was washed twice with 25 ml water, then dried over MgSO4. The solvent was removed in vacuo. The resulting residue was purified by reversed phase HPLC to obtain 185 mg 2-Cyclopropyl-4-{2,2,2-trifluoro-1-[4-methyl-2-(6-trifluoromethyl-pyridin-3-yl)-thiazol-5-yl]-ethoxymethyl}-benzonitrile.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[S:20](Cl)([CH3:23])(=[O:22])=[O:21]>C(Cl)Cl>[CH:1]1([N:6]2[CH2:7][CH2:8][CH:9]([O:12][S:20]([CH3:23])(=[O:22])=[O:21])[CH2:10][CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCN(C2CCCC2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CCN(C2CCCC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
1-Cyclopentyl-4-hydroxypiperidine (1 g, 5.91 mmol), DCM (10 ml) and triethylamine (0.91 ml, 6.5 mmol) were cooled to 0-5° C. and mesyl chloride (0.46 ml, 5.91 mmol) was added dropwise under N2. The reaction was allowed to warm to room temperature and stirred for 1 hour. The reaction was quenched with sat. NaHCO3 (20 ml) and the aqueous phase extracted with DCM (2×5 ml). The combined organic extracts were dried over MgSO4, filtered, washed with DCM and concentrated in vacuo to give the title compound (1.38 g, 95%) as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[Br:17]Br>C(Cl)Cl>[NH2:1][C:2]1[C:14]([Br:17])=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: BrBr
Reactant: COc1ccc(N)c(CN2CCCCC2)c1
Solvent: ClCCl
Product: COc1cc(Br)c(N)c(CN2CCCCC2)c1

Procedure:
N-(2-Amino-3-bromo-5-methoxy-benzyl)-piperidine was prepared from N-(2-amino-5-methoxy-benzyl)-piperidine and bromine analogous to Example 9. Proof of structure by IR-, UV- and NMR-spectra. IR-spectrum (methylenechloride):
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Mg]Br.[CH2:11]([N:18]1[CH2:26][CH:25]2[CH:20]([CH2:21][CH2:22][CH2:23][C:24]2=[O:27])[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[NH4+]>O1CCCC1.C(OCC)C>[CH2:11]([N:18]1[CH2:26][CH:25]2[CH:20]([CH2:21][CH2:22][CH2:23][C:24]2([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[OH:27])[CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C1CCCC2CN(Cc3ccccc3)CC12
Reactant: COc1ccccc1[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccccc1C1(O)CCCC2CN(Cc3ccccc3)CC21
Yield: 84.1 %

Procedure:
To a suspension of 55.63 g of 2-methoxyphenylmagnesium bromide in 250 cm3 of tetrahydrofuran is added dropwise, at room temperature and with stirring, a solution of 20.16 g of (3aRS,7aSR)-2-Benzyl-4-perhydroisoindolone in 250 cm3 of tetrahydrofuran. The reaction mixture is stirred at room temperature for 18 hours, treated with 300 cm3 of saturated aqueous ammonium chloride solution, taken up in 200 cm3 of ethyl ether and washed with 300 cm3 of saturated aqueous sodium chloride solution. The organic phase is separated out after settling has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (particle size 0.04-0.06 mm, diameter 8.8 cm, height 41 cm), eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (80/20 by volume) and collecting 1000 cm3 fractions. Fractions 4 to 27 are combined and then concentrated to dryness under reduced pressure (2.5 kPa). 24.96 g of (3aRS,4RS,7aSR)-2-benzyl-4-(2-methoxyphenyl)-4-perhydroisoindolol are obtained in the form of white crystals melting at 106° C.