Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:14][CH:15]([CH3:17])[CH3:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[CH3:19][N:20]1[CH:24]([CH2:25][CH2:26]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:23][N:22]([CH2:38][C:39]2[CH:44]=[CH:43][C:42](C(F)(F)F)=[CH:41][CH:40]=2)[C:21]1=[O:49].CN(C=[O:54])C>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:14][CH:15]([CH3:17])[CH3:16])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:26][CH2:25][CH:24]2[CH2:23][N:22]([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([OH:54])=[CH:41][CH:40]=3)[C:21](=[O:49])[N:20]2[CH3:19])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CN(C)C=O
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OC(C)C
Reactant: Cc1ccc(S(=O)(=O)OCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2C)cc1
Product: CCOC(=O)C(Cc1ccc(OCCC2CN(Cc3ccc(O)cc3)C(=O)N2C)cc1)OC(C)C
Temperature: 65 °C
Yield: 67 %

Procedure:
A mixture of 3-(4-hydroxy-phenyl)-2-isopropoxy-propionic acid ethyl ester (0.034 g, 0.134 mmol), toluene-4-sulfonic acid 2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethyl ester (0.068 g, 0.149 mmol) and CS2CO3 (0.066 g, 0.202 mmol) in DMF (6 mL) was heated to 65° C. under N2 for 16 h. The reaction was cooled and quenched with 1 N HCl (10 mL) and worked up extractively with Et2O and water. The organic layer was dried (MgSO4) and the solvent removed in vacuo to afford crude product that was purified by flash chromatography using 4:1 hexanes:acetone to afford 0.048 g (67%) 3-(4-{2-[1-(4-hydroxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-isopropoxy-propionic acid ethyl ester. Rf=0.36 (1:1 hexanes:acetone). 1H NMR (500 MHz, CDCl3)δ 1H NMR (500 MHz, CDCl3) □ 7.56 (d, 2H, J=8.07 Hz), 7.36 (d, 2H, J=8.07 Hz), 7.13 (d, 2H, J=8.80 Hz), 6.72 (d, 2H, J=8.80 Hz), 4.47, 4.36 (ABq, 2H, J=15.16 Hz), 4.20-4.12 (m, 2H), 4.00-3.94 (m, 3H), 3.66-3.59 (m, 1H), 3.48 (hp, 1H, J=5.87 Hz), 3.37 (t, 1H, J=8.80 Hz), 2.98 (t, 1H, J=8.80 Hz), 2.90-2.85 (m, 2H), 2.84 (s, 3H), 2.27-2.23 (m, 1H), 1.93-1.84 (m, 1H), 1.23 (t, 3H, J=6.85 Hz), 1.14 (d, 3H, J=5.87 Hz), 0.97 (d, 3H, J=5.87 Hz). MS (ES+) Calc'd for C28H36N2O5F3 (M+1) 537. Found m/z 537 (100%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:12]3([CH2:15][OH:16])[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[Si:24](OS(C(F)(F)F)(=O)=O)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Si:24]([O:16][CH2:15][C:12]1([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]3)[CH2:14][CH2:13]1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: Cc1ccc2cccc(C3(CO)CC3)c2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2cccc(C3(CO[Si](C)(C)C(C)(C)C)CC3)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
To a solution of (1-(2-methylquinolin-8-yl)cyclopropyl)methanol (0.050 g, 0.234 mmol) and triethylamine (0.065 mL, 0.47 mmol) in DCM (5 mL) was added TBSOTf (0.065 mL, 0.28 mmol) at ambient temperature and the reaction was stirred at ambient temperature for 1 hour. Saturated sodium bicarbonate (10 mL) and DCM (20 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (10:1 hexane/ethyl acetate) to give 8-(1-((tert-butyldimethylsilyloxy)methyl)cyclopropyl)-2-methylquinoline (0.071 g, 92.5%) as an oil.
Reaction SMILES: N1C=CC=CC=1.[SH2:7].[F:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1.C(N(CC)CC)C>O>[F:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]([NH2:14])=[S:7])=[CH:11][CH:10]=1
Reactant: S
Reactant: N#Cc1ccc(F)cc1
Solvent: c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Product: NC(=S)c1ccc(F)cc1
Reaction time: 4 h

Procedure:
Eighty-five ml of dry pyridine was saturated with hydrogen sulfide. To this was added 25 g of p-fluorobenzonitrile and 33 ml of triethylamine. Hydrogen sulfide was passed through the solution at room temperature, with good stirring. After 4 hours a sample on thin layer chromatography showed no nitrile. The solution was poured into water (600 ml) and ice. The solid product was filtered, washed with water and dried. Yield of 27.3 g, mp 143°--145° C.
Reaction SMILES: [C:1]1([CH:11]=[CH:12][C:13]([OH:15])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C([O:19][CH2:20][CH3:21])(=O)C>Cl>[OH:19][C:20]1[CH:21]=[C:3]2[C:2]([CH:11]([C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)[CH2:12][C:13](=[O:15])[O:14]2)=[CH:1][CH:10]=1
Reactant: CCOC(C)=O
Reactant: O=C(O)C=Cc1cccc2ccccc12
Agent: Cl
Product: O=C1CC(c2cccc3ccccc23)c2ccc(O)cc2O1
Reaction time: 8 h

Procedure:
A mixture of 3-(1-naphthyl)acrylic acid (50.0 g., 0.25 moles) in concentrated hydrochloric acid (1500 ml.) was stirred at reflux while a vigorous stream of hydrogen chloride was passed through the reaction for 6 hours. The solution was allowed to stand overnight at room temperature, then filtered to give a white solid which was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution (3×). The ethyl acetate solution was dried and removal of solvent gave the dihydrocoumarin as a white solid (43.5 g., 85% based on consumed starting material) m.p. 193°-196° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:7]=[C:8]=[S:9])=[CH:4][S:5][CH:6]=1.[Cl:10][C:11]1[C:12]([NH2:18])=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=1>>[NH2:18][C:12]1[C:11]([Cl:10])=[CH:16][CH:15]=[CH:14][C:13]=1[NH:17][C:8]([NH:7][C:3]1[C:2]([Cl:1])=[CH:6][S:5][CH:4]=1)=[S:9]
Reactant: S=C=Nc1cscc1Cl
Reactant: Nc1cccc(Cl)c1N
Product: Nc1c(Cl)cccc1NC(=S)Nc1cscc1Cl

Procedure:
was obtained as described in example 1 b) by reaction of 4-chloro-3-thienyl-isothiocyanate and 3-chloro-1,2-diaminobenzene. The compound crystallizes after stirring in diisopropylether. Solid crystalline material with 2 melting points: 1st m.p. 152-155° C.; 2nd m.p. (after recrystallization of molten material)>310° C.
Reaction SMILES: Br[CH:2]1[CH2:20][CH2:19][C:5]2=[CH:6][C:7]3[C:8]4[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:9]=4[CH2:10][O:11][C:12]=3[CH:13]=[C:4]2[C:3]1=[O:21].[C:22]([O:26][C:27]([N:29]1[C@@H:33]([CH3:34])[CH2:32][CH2:31][C@H:30]1[C:35]([OH:37])=[O:36])=[O:28])([CH3:25])([CH3:24])[CH3:23].CCN(C(C)C)C(C)C>CC#N.CCOC(C)=O>[CH3:34][C@@H:33]1[N:29]([C:27]([O:26][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:28])[C@H:30]([C:35]([O:37][CH:2]2[CH2:20][CH2:19][C:5]3=[CH:6][C:7]4[C:8]5[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:9]=5[CH2:10][O:11][C:12]=4[CH:13]=[C:4]3[C:3]2=[O:21])=[O:36])[CH2:31][CH2:32]1
Reactant: O=C1c2cc3c(cc2CCC1Br)-c1ccc(Cl)cc1CO3
Reactant: C[C@H]1CC[C@@H](C(=O)O)N1C(=O)OC(C)(C)C
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CC[C@@H](C(=O)OC2CCc3cc4c(cc3C2=O)OCc2cc(Cl)ccc2-4)N1C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 18 h
Yield: 82.1 %

Procedure:
To a solution of 9-bromo-3-chloro-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (1.41 g, 3.88 mmol) in MeCN (17 mL) was added (2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-carboxylic acid (980 mg, 4.27 mmol) and DIPEA (1.49 mL, 8.54 mmol). After stirring for 18 h at 50° C., the solution was diluted with EtOAc and washed successively with 1N HCl, saturated aqueous NaHCO3 and brine. The organics were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (10% to 30% EtOAc/hexanes) to afford (2S,5S)-1-tert-butyl 2-(3-chloro-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-9-yl) 5-methylpyrrolidine-1,2-dicarboxylate (1.63 g, 81%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([O:15]C)=O)=[C:10](/[N:17]=[CH:18]/[N:19]([CH3:21])C)[CH:9]=2)=[CH:4][CH:3]=1.[N:22]12[CH2:29][CH2:28][CH:25]([CH2:26][CH2:27]1)[C@@H:24]([O:30][C:31]1[CH:32]=[C:33](CN)[CH:34]=[CH:35][CH:36]=1)[CH2:23]2>CO>[N:22]12[CH2:29][CH2:28][CH:25]([CH2:26][CH2:27]1)[C@@H:24]([O:30][C:31]1[CH:36]=[C:35]([CH:34]=[CH:33][CH:32]=1)[CH2:21][N:19]1[C:13](=[O:15])[C:11]3[S:12][C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)=[CH:9][C:10]=3[N:17]=[CH:18]1)[CH2:23]2
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1/N=C/N(C)C
Reactant: NCc1cccc(O[C@H]2CN3CCC2CC3)c1
Solvent: CO
Product: O=c1c2sc(-c3ccc(Cl)cc3)cc2ncn1Cc1cccc(O[C@H]2CN3CCC2CC3)c1
Temperature: 120 °C

Procedure:
Methyl 5-(4-chlorophenyl)-3-{[(1E)-(dimethylamino)methylene]amino}thiophene-2-carboxylate (177 mg, 0.548 mmol) and 1-{3-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]phenyl}methanamine (140 mg, 0.603 mmol) were dissolved in MeOH (2 ml). The reaction was heated in a microwave at 120° C. for 30 minutes. The solvent was evaporated in vacuo. Purification by flash silica gel chromatography using a 40 g Biotage column with 100% EtOAc/MeOH/TEA 100:10:1 yielded the title compound as a white solid. Yield: 0.175 g (67%). 1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.56 (m, 2H), 7.40 (s, 1H), 7.37 (m, 2H), 7.22 (t, 1H, J=7.9 Hz), 6.88 (d, 1H, J=7.9 Hz), 6.86 (m, 1H), 6.75 (dd, 1H, J=8.1 Hz, J=2.1 Hz), 5.15 (s, 2H), 4.33 (m, 1H), 3.24 (m, 1H), 2.97-2.88 (m, 1H), 2.86-2.69 (m, 4H), 2.08 (m, 1H), 1.99-1.88 (m, 1H), 1.70 (m, 1H), 1.57-1.47 (m, 1H), 1.34 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 158.3, 157.7, 157.1, 151.4, 148.2, 137.5, 135.7, 131.7, 130.4, 129.6, 127.8, 123.2, 121.0, 120.4, 115.8, 115.2, 73.6, 55.8, 49.5, 47.5, 46.8, 25.3, 24.6, 19.4. MS (ESI+) 478.00 (M+1H+).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[C:4]([NH:6][C:7]1[C:8]([C:12]2[NH:16][C:15]3[CH:17]=[CH:18][CH:19]=[C:20]([CH2:21][OH:22])[C:14]=3[N:13]=2)=[N:9][NH:10][CH:11]=1)=[O:5]>C(Cl)Cl.CO.O=[Mn]=O>[F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[C:4]([NH:6][C:7]1[C:8]([C:12]2[NH:16][C:15]3[CH:17]=[CH:18][CH:19]=[C:20]([CH:21]=[O:22])[C:14]=3[N:13]=2)=[N:9][NH:10][CH:11]=1)=[O:5]
Reactant: O=C(Nc1c[nH]nc1-c1nc2c(CO)cccc2[nH]1)c1c(F)cccc1F
Agent: O=[Mn]=O
Solvent: CO
Solvent: ClCCl
Product: O=Cc1cccc2[nH]c(-c3n[nH]cc3NC(=O)c3c(F)cccc3F)nc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 15.1 %

Procedure:
A mixture of 2,6-difluoro-N-[3-(4-hydroxymethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-benzamide (200 mg, 0.54 mmol) and MnO2 (500 mg) in CH2Cl2/MeOH (5:1, 12 ml) was stirred at ambient temperature for 18 h, then filtered through Celite and reduced in vacuo. The residue was purified by flash column chromatography [SiO2, EtOAc-hexane (1:3, 1:2)] to give 2,6-difluoro-N-[3-(4-formyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-benzamide (30 mg) as a cream solid.
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][NH:6][C:7]1[C:12]([NH:13][C:14]([C:16]2[O:17][C:18]([Br:21])=[CH:19][CH:20]=2)=O)=[CH:11][CH:10]=[CH:9][N:8]=1)C.O.[OH-].[K+]>C(O)CO.CO>[Br:21][C:18]1[O:17][C:16]([C:14]2[N:6]([CH2:5][C:4]([OH:3])=[O:22])[C:7]3=[N:8][CH:9]=[CH:10][CH:11]=[C:12]3[N:13]=2)=[CH:20][CH:19]=1
Reactant: CCOC(=O)CNc1ncccc1NC(=O)c1ccc(Br)o1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: CO
Solvent: O
Product: O=C(O)Cn1c(-c2ccc(Br)o2)nc2cccnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 1.6 %

Procedure:
A solution of N-[3-[(5-bromo-2-furanylcarbonyl)amino]-2-pyridinyl]glycine ethyl ester (110 g, 0.30 mole) in ethylene glycol (510 ml) was refluxed under nitrogen for two hours. The solution was cooled to room temperature and water (100 ml) and potassium hydroxide pellets (23.25 g, 0.41 mole) were added. The solution was refluxed for an additional 1.5 hours and then filtered, while hot, into ice water (2 liters). A 3N hydrochloric acid solution was added until the suspension was acidic. After stirring overnight, the solid was collected by filtration and rinsed with water. Most of the wet material was dried at 56° C. overnight under high vacuum to give 79.5 g of crude material (82%) yield). A portion (3.0 g of wet material) was dissolved in hot methanol, filtered, and cooled to room temperature. Addition of water caused a solid to precipitate which was collected by filtration, rinsed with water, and dried at high vacuum at 56° C. to give 1.59 g of title compound, mp 229°-231° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]([CH2:19]Cl)=[CH:7]2.[N-:21]=[N+]=[N-].[Na+]>CS(C)=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]([CH2:19][NH2:21])=[CH:7]2
Reactant: [N-]=[N+]=[N-]
Reactant: ClCc1cc2cccc(Cl)c2nc1Oc1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: NCc1cc2cccc(Cl)c2nc1Oc1ccccc1
Reaction time: 4 h

Procedure:
To a solution of 8-chloro-3-(chloromethyl)-2-phenoxyquinoline (1 eq) in DMSO (0.25 M) was added NaN3 (3 eq) at rt and the mixture was stirred for 4 h at it. The mixture was diluted with water, extracted with EtOAc (2 times) and the combined organic layers were washed with water (2 times), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was dissolved in MeOH and treated with 10% Pd—C (5 wt %) and the mixture was then stirred under H2 balloon over night. The mixture was filtered through a Celite™ pad followed by removal of solvents to give (8-chloro-2-phenoxyquinolin-3-yl)methanamine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:13]=[N:14][C:15]([O:18]C)=[CH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1.Cl>O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[NH:14][CH:13]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)C[C@@H](c2ccc(Br)cc2)c2ccccc2C)cn1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccccc1[C@@H](CC(=O)c1ccc(=O)[nH]c1)c1ccc(Br)cc1

Procedure:
In analogy to example 162, step 2, (S)-3-(4-bromophenyl)-1-(6-methoxypyridin-3-yl)-3-o-tolyl-propan-1-one was reacted with 37% aqueous hydrochloric acid solution in 1,4-dioxane to give the title compound as a light yellow foam, MS (ESI+): m/z=396.0 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:10]=[C:9]([CH:11]([C:14]2[S:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)[C:12]#[N:13])[CH:8]=[CH:7][N:6]=1.[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1.C(N(CC)CC)C>C(Cl)Cl.CN(CC1C=C(CN(C)C)C(O)=C(CN(C)C)C=1)C>[S:15]1[C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=[C:14]1[CH:11]([C:12]#[N:13])[C:9]1[CH:8]=[CH:7][N:6]=[C:5]([NH:4][CH2:3][CH2:2][NH:1][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][C:24]([Cl:23])=[CH:25][CH:26]=2)[N:10]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: N#CC(c1ccnc(NCCN)n1)c1nc2ccccc2s1
Agent: CN(C)Cc1cc(CN(C)C)c(O)c(CN(C)C)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#CC(c1ccnc(NCCNC(=O)c2ccc(Cl)cc2)n1)c1nc2ccccc2s1
Reaction time: 8 h
Yield: 68.2 %

Procedure:
To a solution of 46 (0.1 g, 0.32 mmol) in DCM/DMF 3/1 (4 ml) was added p-chloro benzoylchloride (0.056 g, 0.32 mmol) and triethylamine (0.09 ml, 0.64 mmol) and the solution was shaken overnight at r.t then at 40° C. for 3 h. After cooling down to r.t, the precipitate formed was filtered off then washed with DCM then water. After recrystallization in acetonitrile, 98 mg (68%) of the title compound (base) was obtained as a yellow powder.
Reaction SMILES: [C:1]([N:5]1[CH2:8][CH:7]([OH:9])[CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CS(OCl)(=O)=O.[Br:23][C:24]1[CH:25]=[CH:26][C:27]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=2)=[C:28](O)[CH:29]=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=2)=[C:26]([CH:25]=1)[O:9][CH:7]1[CH2:8][N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:6]1
Reactant: CC(C)(C)N1CC(O)C1
Reactant: Oc1cc(Br)ccc1OCc1cccc(F)c1
Agent: CS(=O)(=O)OCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)N1CC(Oc2cc(Br)ccc2OCc2cccc(F)c2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.6 %

Procedure:
To a solution of the title compound of Step A (3 mmol), and triethylamine (6 mmol) in CH2Cl2 (50 mL), was added MeSO3Cl (4 mmol). The mixture was stirred at 25° C. for 16 h. After concentration, ⅓ of the residue was dissolved in MeCN (20 mL). Next, 5-bromo-2-(3-fluoro-benzyloxy)-phenol (0.5 mmol) and K2CO3 (2 mmol) were added. The mixture was stirred at 100° C. for 16 h, concentrated and purified via PTLC providing the title compound (189 mg). MS (ESI): mass calcd. for C20H23BrFNO2, 407.1; m/z found, 408.0 [M+H]+. 1H NMR (CDCl3): 7.37-7.28 (m, 1H), 7.19-7.12 (m, 2H), 7.04-6.95 (m, 2H), 6.84-6.63 (m, 2H), 5.08 (s, 2H), 4.78-4.48 (m, 1H), 3.68-3.62 (m, 2H), 3.35-3.26 (m, 2H), 1.00 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]([O:5][CH:6]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:7]([O:9]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:8])=[S:4].FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1>[CH3:1][O:2][C:3]([O:5][CH:6]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:7]([OH:9])=[O:8])=[S:4]
Reactant: COC(=S)OC(C(=O)OC(c1ccccc1)c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: COC(=S)OC(C(=O)O)c1ccccc1
Reaction time: 0.08 h

Procedure:
3.92 g. (10 mM) of the benzhydryl ester from Example 2 are stirred together with 30 ml. of trifluoroacetic acid and a few drops of anisole at 0° for 10 minutes. After distilling the solvent off in vacuum, the residue is treated with petroleum ether until it becomes solid. The solid is then stirred for five minutes in 50 ml. of sodium bicarbonate and filtered. After acidification with 2 N hydrochloric acid and extraction twice, each time with 20 ml. of ether and then drying from the organic phase, 1.2 g. of α-[(methoxycarbonothioyl)oxy]benzeneacetic acid are obtained from the filtrate in the form of white crystals after crystallization from cyclohexane/benzol, m.p. 86°-87°.
Reaction SMILES: Cl.[C:2]([CH2:4][C@@H:5]1[CH2:13][C@@H:12]2[C@@H:8]([CH2:9][NH:10][CH2:11]2)[C@@:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])([OH:14])[CH2:6]1)#[N:3].ClCCl.[CH2:26]([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:40][C:41](O)=[O:42])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CN(C)CCCN=C=NCC>O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C>[C:2]([CH2:4][C@@H:5]1[CH2:13][C@@H:12]2[C@@H:8]([CH2:9][N:10]([C:41](=[O:42])[CH2:40][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[O:33][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:11]2)[C@@:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])([OH:14])[CH2:6]1)#[N:3]
Reactant: COc1ccccc1[C@]1(O)C[C@H](CC#N)C[C@H]2CNC[C@H]21
Reactant: O=C(O)Cc1ccccc1OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1[C@]1(O)C[C@H](CC#N)C[C@H]2CN(C(=O)Cc3ccccc3OCc3ccccc3)C[C@H]21
Yield: 55 %

Procedure:
The procedure is as described in Example 4, starting from 1.61 g of (3aS,4S,6S,7aR)-6-cyanomethyl-4-(2-methoxyphenyl)perhydroisoindol-4-ol hydrochloride, 50 cm3 of dichloromethane, 0.70 cm3 of triethylamine, 1.21 g of (2-benzyloxyphenyl) acetic acid, 0.02 g of hydroxybenzotriazole hydrate and 1.05 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. Purification by chromatography followed by recrystallization from ethyl acetate give 1.4 g of (3aS,4S,6S,7aR)-6-cyanomethyl-2-[(2-benzyloxyphenyl)acetyl]-4-(2-methoxyphenyl)perhydroisoindol-4-ol are obtained in the form of white crystals.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[NH:14][C:15]3[C:20]([CH:21]=2)=[C:19]([O:22][CH2:23][C:24]2[C:28]4[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:27]=4[O:26][CH:25]=2)[CH:18]=[CH:17][CH:16]=3)=[O:12])=[CH:6][CH:5]=1.[NH:34]1[CH2:39][CH2:38][CH:37]([O:40]C(=O)C(C)(C)C)[CH2:36][CH2:35]1>>[OH:40][CH:37]1[CH2:36][CH2:35][N:34]([CH2:2][CH2:3][C:4]2[CH:5]=[CH:6][C:7]([NH:10][C:11]([C:13]3[NH:14][C:15]4[C:20]([CH:21]=3)=[C:19]([O:22][CH2:23][C:24]3[C:28]5[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:27]=5[O:26][CH:25]=3)[CH:18]=[CH:17][CH:16]=4)=[O:12])=[CH:8][CH:9]=2)[CH2:39][CH2:38]1
Reactant: O=C(Nc1ccc(CCO)cc1)c1cc2c(OCc3coc4ccc(Cl)cc34)cccc2[nH]1
Reactant: CC(C)(C)C(=O)OC1CCNCC1
Product: O=C(Nc1ccc(CCN2CCC(O)CC2)cc1)c1cc2c(OCc3coc4ccc(Cl)cc34)cccc2[nH]1

Procedure:
This compound is synthesized analogously to example 154 from 4-(5-Chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid [4-(2-hydroxy-ethyl)-phenyl]-amide (193) and 2,2-dimethyl-propionic acid piperidin-4-yl ester, followed by removal of the protective group by sodium methylate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.I[CH2:18][C:19]([NH2:21])=[O:20].C(=O)([O-])[O-].[Cs+].[Cs+].C(#N)C>O>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:18][C:19]([NH2:21])=[O:20])[CH2:13][CH2:12]1
Reactant: NC(=O)CI
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: NC(=O)CN1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Temperature: 60 °C
Reaction time: 20 h
Yield: 101.9 %

Procedure:
1-(2-Fluoro-4-nitro-phenyl)-piperazine (0.438 g, 1.94 mmol), Iodoacetamide (0.401 g, 2.17 mmol), Cesium Carbonate (0.956 g, 2.93 mmol) and Acetonitrile (20 mL, 400 mmol) were combined and stirred at 60° C. for 20 hours. The mixture was cooled to room temperature. Water was added to the mixture and the product was extracted into ethyl acetate three times. The extracts were dried over sodium sulfate, filtered and concentrated to yield a yellow solid, 2-[4-(2-Fluoro-4-nitro-phenyl)-piperazin-1-yl]-acetamide (558 mg, 100%). LCMS: m/z=283.06 (M+H+); 1H NMR (400 MHz, DMSO-d6) δ 8.00 (d, 2H), 7.26 (br s, 1H), 7.17 (m, 2H), 2.94 (s, 2H), 2.60 (m, 2H), 2.50 (s, 6H).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH:33]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([N:24]([CH2:25][C:12]3[CH:13]=[CH:14][CH:15]=[C:16]([CH3:17])[CH:11]=3)[CH2:29][C:30]3[CH:37]=[CH:36][CH:35]=[C:32]([CH3:33])[CH:31]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(C=O)c1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: Cc1cccc(CN(Cc2cccc(C)c2)c2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c1

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 3-methylbenzaldehyde according to the procedure of Example 66. MS (ESI) m/z 587.
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[N:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([Cl:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1.C(N(CC)CC)C>C(Cl)Cl>[ClH:23].[CH3:12][C:8]1[CH:9]=[N:10][C:11]2[CH:2]([NH:1][S:20]([C:17]3[CH:18]=[CH:19][C:14]([CH3:13])=[CH:15][CH:16]=3)(=[O:22])=[O:21])[CH2:3][CH2:4][CH2:5][C:6]=2[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cnc2c(c1)CCCC2N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NC2CCCc3cc(C)cnc32)cc1
Product: Cl
Temperature: 25 °C
Yield: 42.3 %

Procedure:
8-Amino-5,6,7,8-tetrahydro-3-methyl-quinoline (3.07g) was dissolved in CH2Cl2 [(250ml) and 4-methylbenzenesulphonyl-chloride (2.68g) was added in CH2Cl2 (25ml) followed by triethylamine (25ml) in CH2Cl2 (25ml). The reaction mixture was stirred at room temperature until t.l.c. showed all the starting material to have reacted. The solvent was removed under reduced pressure and the residue was dissolved in 2N.HCl (200ml) and extracted with Et2O (2×100ml). The acid solution was then basified with solid K2CO3 and was extracted with CH2Cl2 (3×100ml). The extracts were dried (MgSO4) and evaporated to low volume under reduced pressure. The residue was treated with Et2O/HCl to give a white solid which was recrystallised from EtOH to give 5,6,7,8-tetrahydro-3-methyl-8-(4-methylbenzenesulphonylamino) quinoline hydrochloride (2.1g). mp. 214° C. decomp. (Found: C,58.3; H,6.2; N,7.7. C17H21N 2 SO2Cl requires: C,58.0; H,6.0; N,7.8%).