Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH2:5][NH:6][C:7](=[O:31])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:21][C:22]2[CH:27]=[C:26]([CH3:28])[C:25](Br)=[C:24]([CH3:30])[CH:23]=2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:10][CH:9]=1.[F-].[K+].[F:35][C:36]([F:48])([F:47])[O:37][C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:28][C:26]1[CH:27]=[C:22]([O:21][CH:14]([C:11]2[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:32])=[O:31])=[CH:13][CH:12]=2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:23]=[C:24]([CH3:30])[C:25]=1[C:41]1[CH:40]=[CH:39][C:38]([O:37][C:36]([F:35])([F:47])[F:48])=[CH:43][CH:42]=1
Reactant: CCCCCCC(Oc1cc(C)c(Br)c(C)c1)c1ccc(C(=O)NCCC(=O)OC)cc1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Product: CCCCCCC(Oc1cc(C)c(-c2ccc(OC(F)(F)F)cc2)c(C)c1)c1ccc(C(=O)NCCC(=O)O)cc1
Yield: 91.8 %

Procedure:
3-{4-[1-(4-Bromo-3,5-dimethyl-phenoxyl)-heptyl]-benzoylamino}-propionic acid methyl ester (isomer 1, 100 mg, 0.2 mmol), potassium flouride (35 mg, 0.6 mmol), 4-trifluoromethoxylphenyl boronic acid (83 mg, 0.4 mmol) and tetrakis(triphenylphosphine)palladium (23 mg, 0.02 mmol) are place in a flask. After the reaction is purged with N2 for several times, Toluene/H2O (20 ml/5 ml) is added. The resulting solution is refluxed overnight, loaded on silica gel, eluted with hexane and ethyl acetate to give 3-{4-[1-(2,6-Dimethyl-4′-trifluoromethoxy-biphenyl-4-yloxy)-heptyl]-benzoylamino}-propionic acid, (105 mg).
Reaction SMILES: [CH3:1][Si:2]([CH3:41])([C:35]([CH3:40])([CH3:39])[CH:36]([CH3:38])[CH3:37])[O:3][C:4]1[C:21]2[CH2:20][S:19][CH2:18][C@@H:17]([C:22]3[O:26][N:25]=[C:24]([CH3:27])[N:23]=3)[NH:16][C:15](=[O:28])[CH2:14][CH2:13][C@H:12]([CH2:29]O)[CH2:11][O:10][C:9](=[O:31])[C:8]=2[C:7]([CH3:32])=[C:6]([O:33][CH3:34])[CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(P([N:87]=[N+:88]=[N-:89])(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCCC1>[N:87]([CH2:29][C@@H:12]1[CH2:11][O:10][C:9](=[O:31])[C:8]2[C:7]([CH3:32])=[C:6]([O:33][CH3:34])[CH:5]=[C:4]([O:3][Si:2]([CH3:1])([CH3:41])[C:35]([CH3:40])([CH3:39])[CH:36]([CH3:37])[CH3:38])[C:21]=2[CH2:20][S:19][CH2:18][C@@H:17]([C:22]2[O:26][N:25]=[C:24]([CH3:27])[N:23]=2)[NH:16][C:15](=[O:28])[CH2:14][CH2:13]1)=[N+:88]=[N-:89]
Reactant: COc1cc(O[Si](C)(C)C(C)(C)C(C)C)c2c(c1C)C(=O)OC[C@@H](CO)CCC(=O)N[C@H](c1nc(C)no1)CSC2
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(O[Si](C)(C)C(C)(C)C(C)C)c2c(c1C)C(=O)OC[C@@H](CN=[N+]=[N-])CCC(=O)N[C@H](c1nc(C)no1)CSC2
Temperature: 0 °C
Reaction time: 0.58 h

Procedure:
To a solution of 140 mg of (4R,9R)-16-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-9-hydroxymethyl-14-methoxy-13-methyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)-1,3,4,5,6,7,8,9,10,12-decahydro-11,2,5-benzoxathiaazacyclotetradecin-6,12-dione and 121 mg of triphenyl-phosphine in 2 ml of tetrahydrofuran were added at 0° C. 80 mg of diethyl azodicarboxylate and 127 mg of diphenylphosphoryl azide. The mixture was stirred at 0° C. for 35 min and then evaporated in vacuo. The residue was chromatographed on silica gel using ethyl acetate/hexane (1:1, v/v) as eluent, to yield (4R,9R)-9-azidomethyl-16-[dimethyl-(1,1,2-trimethyl-propyl)silanyloxy]-14-methoxy-13-methyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)-1,3,4,5,6,7,8,9,10,12-decahydro-11,2,5-benzoxathiaazacyclotetradecin-6,12-dione as a foam
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[Br:16][C:17]1[C:22]([NH2:23])=[CH:21][C:20]([Cl:24])=[CH:19][N:18]=1>N1C=CC=CC=1>[Br:16][C:17]1[C:22]([NH:23][S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:12]([F:15])([F:14])[F:13])[CH:4]=2)(=[O:10])=[O:9])=[CH:21][C:20]([Cl:24])=[CH:19][N:18]=1
Reactant: Nc1cc(Cl)cnc1Br
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(C(F)(F)F)c1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(Cl)cnc1Br)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 60 °C

Procedure:
A mixture of 4-chloro-3-trifluoromethyl-benzenesulfonyl chloride (1.5 g, 5.3 mmol) and 2-bromo-5-chloro-pyridin-3-ylamine (500 mg, 2.4 mmol) dissolved in pyridine (20 mL) was heated at 60° C. for 16 h. The solvent was evaporated and the residue suspended in a 1:1 mixture of 2 M NaOH and methanol (20 mL) and heated at 70° C. for 30 min. The methanol was evaporated under reduced pressure and the residue diluted with 15 mL water. The solution was cooled on ice bath and the pH was adjusted to 3 by drop wise addition of concentrated HCl. The solid formed was collected by filtration and the product was purified by flash chromatography on silica gel column to afford the desired product. MS m/z: 450.8 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N:23]([S:27]([C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=3[F:37])(=[O:29])=[O:28])[CH2:24][O:25][CH3:26])[C:18]=2[F:38])=O)[CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].C1C=C[NH+]=CC=1.Br[Br-]Br.[CH:49]1([N:52]2[CH2:57][CH2:56][CH:55]([C:58](=[S:60])[NH2:59])[CH2:54][CH2:53]2)[CH2:51][CH2:50]1>CN(C=O)C>[CH:49]1([N:52]2[CH2:57][CH2:56][CH:55]([C:58]3[S:60][C:14]([C:12]4[CH:11]=[CH:10][N:9]=[C:8]([NH:7][C:6](=[O:39])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[CH:13]=4)=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([N:23]([S:27]([C:30]5[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=5[F:37])(=[O:29])=[O:28])[CH2:24][O:25][CH3:26])[C:18]=4[F:38])[N:59]=3)[CH2:54][CH2:53]2)[CH2:50][CH2:51]1
Reactant: NC(=S)C1CCN(C2CC2)CC1
Reactant: COCN(c1cccc(C(=O)Cc2ccnc(NC(=O)OC(C)(C)C)c2)c1F)S(=O)(=O)c1cc(F)ccc1F
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: COCN(c1cccc(-c2nc(C3CCN(C4CC4)CC3)sc2-c2ccnc(NC(=O)OC(C)(C)C)c2)c1F)S(=O)(=O)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 60 %

Procedure:
Tert-butyl-{4-[2-(3-{[(2,5-difluorophenyl)sulfonyl](methoxymethyl)amino}-2-fluorophenyl)-2-oxoethyl]pyridin-2-yl}carbamate (prepared as described in Example 9, 374 mg, 0.662 mmol) was dissolved in dry DMF (5 mL) under argon atmosphere. Pyridinium bromide perbromide (190 mg, 0.596 mmol, 0.9 eq) was added and the reaction mixture was stirred at r.t. for 50 min. 1-Cyclopropylpiperidine-4-carbothioamide (146 mg, 0.794 mmol, 1.2 eq) was then added and the mixture was heated to 70° C. After 1 h the reaction was allowed to cool to r.t. overnight. The solvent was concentrated under reduced pressure. The residue was taken up with ethyl acetate and washed with saturated aqueous NaHCO3 and brine. The organic phase was dried over Na2SO4 and evaporated to dryness. The crude product was purified by flash chromatography on silica gel (DCM/MeOH 98:2) to give 290 mg (60%) of tert-butyl {4-[2-(1-cyclopropylpiperidin-4-yl)-4-(3-{[(2,5-difluorophenyl)sulfonyl](methoxymethyl)amino}-2-fluorophenyl)-1,3-thiazol-5-yl]pyridin-2-yl}carbamate as amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:9]4[C:14]=2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:11](=[O:22])[C:10]=4[CH:23]=[CH:24][CH:25]=3)[CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.[CH3:29][OH:30]>C1(C)C=CC=CC=1>[CH3:21][N:19]([CH3:20])[CH2:18][CH2:17][N:12]1[C:11](=[O:22])[C:10]2[CH:23]=[CH:24][CH:25]=[C:8]3[C:9]=2[C:14](=[C:15]2[C:2]([NH:1][C:13](=[O:16])[CH2:14][C:29](=[O:30])[CH2:8][CH2:7][C:6]4[CH:15]=[CH:2][CH:3]=[CH:4][CH:5]=4)=[CH:3][CH:4]=[CH:5][C:6]2=[CH:7]3)[C:13]1=[O:16]
Reactant: CO
Reactant: CN(C)CCN1C(=O)c2cccc3cc4cccc(N)c4c(c23)C1=O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CN(C)CCN1C(=O)c2cccc3cc4cccc(NC(=O)CC(=O)CCc5ccccc5)c4c(c23)C1=O
Temperature: 20 °C
Yield: 53 %

Procedure:
To a solution of 100 mg (0.30 mmole) of 11-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 3) in 8 mL of toluene, magnetically stirred at 20° C., 95 mg of the compound of example 21 were added. The mixture was refluxed during 4.5 hours and then allowed to cool to 20° C. The solvent was then evaporated under reduced pressure and the residue was submitted to a flash chromatography on silica (eluent: CH2Cl2/methanol in a 97:3 volume ratio) to provide 81 mg (yield: 53%) of the desired product (formula below) as a red powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][CH2:12][C:13]2[O:14][CH:15]=[C:16]([OH:20])[C:17](=[O:19])[CH:18]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[OH:21][C:22]1C(=O)C=C(CNS(C2C=CC=CC=2)(=O)=O)OC=1CO>>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][CH2:12][C:13]2[O:14][C:15]([CH2:22][OH:21])=[C:16]([OH:20])[C:17](=[O:19])[CH:18]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=c1cc(CNS(=O)(=O)c2cccc(Cl)c2)occ1O
Reactant: O=c1cc(CNS(=O)(=O)c2ccccc2)oc(CO)c1O
Product: O=c1cc(CNS(=O)(=O)c2cccc(Cl)c2)oc(CO)c1O
Yield: 47.5 %

Procedure:
3-Chloro-N-(5-hydroxy-6-hydroxymethyl-4-oxo-4H-pyran-2-ylmethyl)-benzenesulfonamide (9-05) (7.3 g, 47.50%) was synthesized as a white solid from 3-chloro-N-(5-hydroxy-4-oxo-4H-pyran-2-ylmethyl)-benzenesulfonamide (8-05) (14.0 g, 44.44 mmol) following the procedure described for N-(5-hydroxy-6-hydroxymethyl-4-oxo-4H-pyran-2-ylmethyl)-benzenesulfonamide (9-01).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:15][CH2:16][CH2:17][O:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[CH2:13][NH:12][C:11](=[O:14])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([O:38][CH3:39])[C:35]=1[O:36][CH3:37])[C:30](Cl)=[O:31]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:15][CH2:16][CH2:17][O:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[CH2:13][N:12]([C:30](=[O:31])[C:29]3[CH:28]=[C:27]([O:26][CH3:25])[C:35]([O:36][CH3:37])=[C:34]([O:38][CH3:39])[CH:33]=3)[C:11](=[O:14])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: O=C1CC(CCCOC2CCCCO2)(c2ccc(Cl)c(Cl)c2)CN1
Product: COc1cc(C(=O)N2CC(CCCOC3CCCCO3)(c3ccc(Cl)c(Cl)c3)CC2=O)cc(OC)c1OC

Procedure:
Prepare according to the procedure of example 59.1 using 4-(3,4-dichloro-phenyl)-4-[3-(tetrahydro-pyran-2-yloxy)-propyl]-pyrrolidin-2-one (5.0 mmol) and 3,4,5-trimethoxy-benzoyl chloride (5.0 mmol). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][C@H:9]1[C:20]([O:22]C)=[O:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:10][C@H:9]1[C:20]([OH:22])=[O:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H]1C[C@H](Oc2ccccc2)CN1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](Oc2ccccc2)C[C@H]1C(=O)O
Yield: 58.4 %

Procedure:
To a stirred solution of methyl (2S,4S)-1-tert-butoxycarbonyl-4-phenoxy-2-pyrrolidinylcarboxylate (5.31 g, 16.5 mmol) in THF (132 ml) was added 0.25 N NaOH (132 ml, 33.0 mmol) at room temperature. The resulting mixture was stirred over night. After removal of the solvent, the mixture was acidified by the addition of 1 N HCl and extracted with CHCl3. The combined extracts were washed with brine, dried over Na2SO4 and evaporated. The residue was recrystallized from n-hexane-CHCl3, to give (2S, 4S)-1-tert-butoxycarbonyl-4-phenoxy-2-pyrrolidinylcarboxylic acid (2.96 g, 58%) as a white powder. 1H-NMR (DMSO-d6) δ 1.36 (s, 9H), 2.16 (d, J=13.2 Hz, 1H), 2.56 (m, 1H ), 3.46 (m, 1H), 3.71 (dt, J=12.0, 5.4 Hz, 1H), 4.26 (dt, J=9.5, 7.1 Hz, 1H), 4.99 (m, 1H), 6.85 (m, 2H), 6.94 (t, J=7.3 Hz, 1H), 7.28 (t, J=7.3 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[C:4]([F:10])[CH:3]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:4]([F:10])[CH:3]=1
Reactant: Fc1cc(Br)ccc1CBr
Reactant: C1COCCN1
Solvent: CN(C)C=O
Product: Fc1cc(Br)ccc1CN1CCOCC1
Temperature: 60 °C
Reaction time: 13 h
Yield: 45.1 %

Procedure:
4-bromo-1-(bromomethyl)-2-fluorobenzene (600 mg, 2.24 mmol) was dissolved in DMF (8 mL), and KI (400 mg, 2.46 mmol) was added and morpholine (0.78 mL, 8.96 mmol) was added, followed by stirring at 60° C. for 13 hours. When the reaction was completed, the reaction mixture was concentrated under reduced pressure to remove DMF, and extracted two times or more with ethyl acetate and brine. The organic layer was treated with sodium sulfate to remove extra water, and then concentrated under reduced pressure, followed by column chromatography using 30% ethyl acetate/hexane, to give 4-(4-bromo-2-fluorobenzyl)morpholine (278 mg, 1.01 mmol) with a yield of 45%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[CH:6]=[C:5]2O.P(Cl)(Cl)([Cl:22])=O>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[CH:6]=[C:5]2[Cl:22]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1cc(-c2cccc(F)c2)nc2ccc(Br)cc12
Solvent: O
Product: Fc1cccc(-c2cc(Cl)c3cc(Br)ccc3n2)c1
Temperature: 110 °C
Yield: 83.8 %

Procedure:
Into a 500 mL three-neck round-bottom flask equipped with a condenser, magnetic stirrer and nitrogen inlet was placed 5.2 g (16.3 mmoles) of 6-bromo-2-(3-fluorophenyl)-quinolin-4-ol. To this was added 15.2 mL (25.0 g, 163 mmoles, 10 equiv.) of phosphorus oxychloride with stirring. The mixture was then heated to 110° C. for 4 hr. At the end of this time the reaction was cooled to room temperature and water cautiously added dropwise until all of the POCl3 was consumed. The product crystallised from the water and the solids were collected by filtration. The solids were washed with water and placed in a 250 mL Erlenmeyer where they were then triturated with water. After collection by filtration, washing with water, and drying in a vacuum oven, 4.6 g (84%) of the pure product was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14](=[O:26])[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)([O-])=O.[OH:27][CH2:28][CH2:29][NH:30][C:31]([C:33]1[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=1)=[O:32]>>[OH:27][CH2:28][CH2:29][NH:30][C:31](=[O:32])[C:33]1[CH:40]=[CH:39][C:36]([C:37]2[NH:10][C:9]3[CH:8]=[CH:7][C:6]([NH:13][C:14](=[O:26])[C:15]4[CH:20]=[CH:19][C:18]([N:21]5[CH2:25][CH2:24][CH2:23][CH2:22]5)=[CH:17][CH:16]=4)=[CH:5][C:4]=3[N:1]=2)=[CH:35][CH:34]=1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1ccc(N2CCCC2)cc1
Reactant: O=Cc1ccc(C(=O)NCCO)cc1
Product: O=C(NCCO)c1ccc(-c2nc3cc(NC(=O)c4ccc(N5CCCC5)cc4)ccc3[nH]2)cc1

Procedure:
Compound 227 was prepared according to the procedure similar to that described in Scheme III from N-(3,4-dinitrophenyl)-4-pyrrolidinylbenzamide and 4-(2-hydroxyethyl)aminocarbonylbenzaldehyde. [M+H]+ calcd for C27H27N5O3: 470.22; found: 469.58.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=O)=[CH:3]1.[CH3:14][O:15][C:16]1[C:29]2[CH2:28][CH2:27][C@H:26]3[C@H:21]([CH2:22][CH2:23][CH2:24][NH:25]3)[C:20]=2[CH:19]=[CH:18][CH:17]=1>>[CH3:14][O:15][C:16]1[C:29]2[CH2:28][CH2:27][C@H:26]3[C@H:21]([CH2:22][CH2:23][CH2:24][N:25]3[C:11]([C:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:2]([CH3:1])[CH:3]=3)=[O:13])[C:20]=2[CH:19]=[CH:18][CH:17]=1
Reactant: Cn1cc(C(=O)O)c2ccccc21
Reactant: COc1cccc2c1CC[C@@H]1NCCC[C@H]21
Product: COc1cccc2c1CC[C@H]1[C@@H]2CCCN1C(=O)c1cn(C)c2ccccc12
Yield: 82 %

Procedure:
The title compound is prepared from 1-methyl-1H-indole-3-carboxylic acid and cis-7-methoxy-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1. Yield: 82% of theory; LC (method 1): tR=4.39 min; Mass spectrum (ESI+): m/z=375 [M+H]+.
Reaction SMILES: [CH3:1][NH2:2].Br[CH:4]([CH3:21])[C:5]([NH:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:10][C:9]=1[CH3:20])=[O:6]>C1C=CC=CC=1>[CH3:1][NH:2][CH:4]([CH3:21])[C:5]([NH:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:10][C:9]=1[CH3:20])=[O:6]
Reactant: CCCCOc1cc(C)c(NC(=O)C(C)Br)c(C)c1
Reactant: CN
Solvent: c1ccccc1
Product: CCCCOc1cc(C)c(NC(=O)C(C)NC)c(C)c1

Procedure:
To a cold stirred solution of 14.8 g. of monomethyl amine in 250 ml dry benzene was added (portionwise, keeping temperature below 10°) 19.5 g (0.0594 mole) of 2-bromo-4'-butoxy-2',6'-dimethyl propionanilide (made according to the procedure in the first part of this example); this dissolved readily, forming a clear solution. The mixture was heated to 70° for ca 1 hr. with stirring, at which point a white precipitate had separated and reflux became so vigorous that the reaction had to be controlled by external cooling.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[CH2:3][CH2:4][CH2:5][CH:6]1[C:12]2[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:16][C:11]=2[CH2:10][CH2:9][C:8]2[CH:24]=[CH:25][CH:26]=[CH:27][C:7]1=2.O[N:30]1[C:34](=[O:35])[CH2:33][CH2:32][C:31]1=[O:36].Cl.C(N=C=NCCCN(C)C)C>ClCCl>[O:36]=[C:31]1[CH2:32][CH2:33][C:34](=[O:35])[N:30]1[O:22][C:21](=[O:23])[CH2:20][CH2:19][CH2:18][O:17][C:15]1[CH:14]=[CH:13][C:12]2[CH:6]([CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:28])[C:7]3[CH:27]=[CH:26][CH:25]=[CH:24][C:8]=3[CH2:9][CH2:10][C:11]=2[CH:16]=1
Reactant: CN(C)CCCC1c2ccccc2CCc2cc(OCCCC(=O)O)ccc21
Reactant: O=C1CCC(=O)N1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CN(C)CCCC1c2ccccc2CCc2cc(OCCCC(=O)ON3C(=O)CCC3=O)ccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 98.1 %

Procedure:
To a solution of 200 mg (0.52 mmol) of 8 in 40 ml of dichloromethane (distilled over calcium hydride) was added 92 mg (0.8 mmol) of N-hydroxysuccinimide and 152 mg (0.8 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC). The reaction mixture was allowed to stir at room temperature for 48 hours. The reaction mixture was diluted with 50 ml of dichloromethane and washed with 50 ml of brine, 2×50 ml of saturated sodium bicarbonate followed by 2×50 ml of brine. The resulting solution was dried (Na2SO4) and concentrated to give 245 mg (0.51 mmol, 98%) of 9 as a white solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[S:15][C:14]([CH2:16][NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:29])[F:28])(=[O:20])=[O:19])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].I[CH2:32][CH3:33].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[CH2:32]([N:17]([CH2:16][C:14]1[S:15][C:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=2)=[CH:12][CH:13]=1)[S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]([F:30])([F:28])[F:29])(=[O:20])=[O:19])[CH3:33]
Reactant: CS(=O)(=O)c1cccc(-c2ccc(CNS(=O)(=O)c3ccccc3C(F)(F)F)s2)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CCN(Cc1ccc(-c2cccc(S(C)(=O)=O)c2)s1)S(=O)(=O)c1ccccc1C(F)(F)F

Procedure:
In analogy to example 10, step 3, N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-2-trifluoromethyl-benzenesulfonamide (example 27, step 1) was reacted with iodoethane and cesium carbonate in N,N-dimethylacetamide to give N-ethyl-N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-2-trifluoromethyl-benzenesulfonamide as a light yellow oil. MS: 520.9 ([M+NH4]+)
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(OCC)=O)C.[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]2[CH2:28]O2)[N:21]=1>C1(C)C=CC=CC=1.CCOC(C)=O>[C:15]([O:14][C:12]([C@@H:11]1[CH2:28][C@H:26]1[C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([F:19])[N:21]=1)=[O:13])([CH3:16])([CH3:17])[CH3:18]
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Reactant: Fc1cccc(C2CO2)n1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[C@@H]1C[C@H]1c1cccc(F)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 18.3 %

Procedure:
To a suspension of NaH (60% oil dispersion, 320 mg, 8 mmol) in toluene (10 mL) was added dropwise t-butyl diethylphosphonoacetate (1.92 g, 7.6 mmol). The resulting mixture was stirred at rt for 10 min., then a solution of 2-fluoro-6-oxiranyl-pyridine (530 mg, 3.8 mmol) in toluene (5 mL) was added dropwise to the reaction mixture. The resulting mixture was then heated at reflux for 12 h. The mixture was cooled to rt and diluted with EtOAc and washed with NH4Cl (saturated) and water. The EtOAc layer was dried (Na2SO4). The solvent was removed and the residue was subjected to ISCO (40 g column, hexane 3 min. then 0-60% EtOAc in hexane over 60 min.) to give the desired product (165 mg). MS (MH+ 238).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[NH:13][C:14]4[C:19]([C:20]=3[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:18][CH:17]=[CH:16][CH:15]=4)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:26][CH2:27][C:28]#[N:29].[F:30][C:31]([F:41])([F:40])[C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34]Br>>[CH2:21]([C:20]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:34][C:33]2[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=2[C:31]([F:30])([F:40])[F:41])[C:12]=1[C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([Br:1])=[C:3]([O:26][CH2:27][C:28]#[N:29])[CH:4]=[CH:5]2)[CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: CCCCCc1c(-c2ccc3c(Br)c(OCC#N)ccc3c2)[nH]c2ccccc12
Product: CCCCCc1c(-c2ccc3c(Br)c(OCC#N)ccc3c2)n(Cc2ccccc2C(F)(F)F)c2ccccc12

Procedure:
The title compound was prepared as a solid (0.053 g, 14%) from {[1-bromo-6-(3-pentyl-1H-indol-2-yl)-2-naphthyl]oxy}acetonitrile using 2-trifluoromethyl benzyl bromide and the procedure from step 4 of Example 2; 1H NMR (DMSO-d6) δ 0.72 (t, J=7.0 Hz, 3H), 1.11-1.22 (m, 4H), 1.54-1.62 (m, 2H), 2.71 (t, J=7.4 Hz, 2H), 5.42 (s, 2H), 5.48 (s, 2H), 6.34 (d, J=7.9 Hz, 1H), 7.11-7.20 (m, 2H), 7.28 (d, J=7.8 Hz, 1H), 7.37 (t, J=7.8 Hz, 1H), 7.45 (t, J=7.8 Hz, 1H), 7.57 (dd, J=1.7, 8.9 Hz, 1H), 7.63-7.68 (m, 2H), 7.69 (d, J=7.2 Hz, 1H), 7.95 (d, J=1.2 Hz, 1H), 8.03 (d, J=9.2 Hz, 1H), 8.12 (d, J=8.7 Hz, 1H).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][N:20]([C:29](SC)=[N:30][C:31](=[O:39])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[N:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1CCCCC1>[CH3:19][N:20]([C:29]([NH:15][CH2:14][CH2:13][CH2:12][O:11][C:10]1[CH:16]=[CH:17][CH:18]=[C:8]([CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:9]=1)=[N:30][C:31](=[O:39])[CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[N:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: CSC(=NC(=O)Cc1ccccc1)N(C)N=Cc1ccccc1
Solvent: C1CCCCC1
Product: CN(N=Cc1ccccc1)C(=NC(=O)Cc1ccccc1)NCCCOc1cccc(CN2CCCCC2)c1
Yield: 80.8 %

Procedure:
A mixture of 3-[3-(1-piperidinylmethyl)phenoxy]propanamine (0.38 g) and methyl 1-methyl-N-phenylacetyl-2-(phenylmethylene)hydrazinecarboximidothioate (0.5 g) was heated at 50° under water pump vacuum during 4 h. The residue was dissolved in cyclohexane (20 ml) and light petroleum (b.p. 60°-80°) was added. The precipitate was removed by filtration and the filtrate was evaporated to give the title compound (0.65 g) as a colourless oil. tlc. System A Rf 0.7.