Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]=[C:6]=[O:7])[CH2:2][CH2:3][CH3:4].[CH3:8][N:9]([CH3:14])[CH2:10][CH2:11][CH2:12][NH2:13]>>[N:9]([CH2:10][CH2:11][CH2:12][NH:13][C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:7])([CH3:14])[CH3:8]
Reactant: CN(C)CCCN
Reactant: CCCCN=C=O
Product: CCCCNC(=O)NCCCN(C)C
Reaction time: 1 h

Procedure:
With stirring and cooling to 55°-60° C., 49.5 g of freshly distilled butyl isocyanate are added dropwise to freshly distilled 3-dimethylamino-1-propylamine under nitrogen in the course of 15 minutes. After 1 hour at 60° C., low boiling constituents are removed at a pressure of 0.1 torr and a maximum bath temperature of 140° C. Yield: 98.7 g (98%) of product of the above structure. Titration: 1 equivalent=208.3 g (theory 201.3 g).
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][C:9]2[N:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[N+:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][C:9]2[N:14]=[CH:13][C:12]([CH2:15][O:16][S:27]([CH3:26])(=[O:29])=[O:28])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(CO)cn2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccc(Oc2ccc([N+](=O)[O-])cc2)nc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
[6-(4-nitrophenoxy)pyridin-3-yl]methanol (6.1 g, 24.8 mmol) was dissolved in dichloromethane (150 mL), and to the resulting solution was added triethylamine (4.15 mL, 29.8 mmol) under ice cooling. To the resulting solution was added dropwise methanesulfonic acid chloride (2.11 mL, 27.3 mmol), and then stirred under a nitrogen atmosphere for 30 minutes at 0° C. The reaction solution was washed with a saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate, and evaporated. To the residue was added a mixed solvent (50 mL) of n-hexane ethyl acetate=1:1. The precipitated crystals were removed by suction filtration, to thereby yield 7.9 g of the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])C=C[C:7]=1[Cl:8].[NH:25]1C2C(=CC(S(N)(=O)=O)=CC=2)CC1.ClC1N=C(C(O)=O)C=CC=1>>[Cl:8][C:7]1[N:25]=[C:9]([C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH:4]=[CH:3][CH:2]=1
Reactant: NS(=O)(=O)c1ccc2c(c1)CCN2
Reactant: NS(=O)(=O)c1ccc2c(c1)CCN2C(=O)Cc1ccc(Cl)c(Cl)c1
Agent: O=C(O)c1cccc(Cl)n1
Product: NS(=O)(=O)c1ccc2c(c1)CCN2C(=O)c1cccc(Cl)n1
Yield: 49 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 64, indoline-5-sulfonamide (Intermediate 54A, 300 mg, 1.51 mmol) and 6-chloropicolinic acid (262 mg, 1.66 mmol) were converted to the title compound (250 mg, 49%). 1H NMR (DMSO-d6) δ 8.69 (d, J=2.0 Hz, 1H), 8.15-8.13 (m, 2H), 7.72-7.67 (m, 3H), 7.27 (s, 2H), 4.11 (t, J=8.4 Hz, 2H), 3.17 (t, J=8.4 Hz, 2H); MS(ESI+) m/z 338.1 (M+H)+.
Reaction SMILES: [Si]([O:8][C@@H:9]1[CH2:13][C:12](=[O:14])[N:11]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=2)[C@H:10]1[CH2:27][CH3:28])(C(C)(C)C)(C)C.C(O)C.Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:27]([C@H:10]1[C@H:9]([OH:8])[CH2:13][C:12](=[O:14])[N:11]1[C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([C:23]([F:26])([F:24])[F:25])[CH:16]=1)[CH3:28]
Reactant: CC[C@H]1[C@H](O[Si](C)(C)C(C)(C)C)CC(=O)N1c1ccc(C#N)c(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC[C@H]1[C@H](O)CC(=O)N1c1ccc(C#N)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.2 %

Procedure:
To a solution of 4-[(2S,3R)-3-(tert-butyldimethylsilyloxy)-2-ethyl-5-oxopyrrolidin-1-yl]-2-(trifluoromethyl)benzonitrile (1.32 g) in tetrahydrofuran (30 mL)-ethanol (15 mL) was added 6 mol/L hydrochloric acid (15 mL), and the mixture was stirred at room temperature for 18 hr. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=6/1→1/9) to give the title compound as a colorless solid (yield: 507.3 mg, 53%).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].CCN(C(C)C)C(C)C.[C:19]([O:23][C:24]([N:26]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:36]=[CH:35][C:34]([SH:37])=[CH:33][C:32]=2[O:38][CH3:39])[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].OS([O-])(=O)=O.[K+].[O-]S([O-])(=O)=O.[Na+].[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[C:19]([O:23][C:24]([N:26]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:36]=[CH:35][C:34]([S:37][C:2]3[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=3[C:4]#[N:5])=[CH:33][C:32]=2[O:38][CH3:39])[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: COc1cc(S)ccc1C1CCN(C(=O)OC(C)(C)C)C1
Reactant: N#Cc1ccccc1Br
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Sc2ccccc2C#N)ccc1C1CCN(C(=O)OC(C)(C)C)C1
Yield: 90 %

Procedure:
Pd2(dba)3 (13 mg, 0.01414 mmol), Xantphos (16 mg, 0.02828 mmol), 2-bromobenzonitrile (0.103 mg, 0.5655 mmol) and DIPEA (0.103 mL, 1.131 mmol) were added to a solution of 3-(4-mercapto-2-methoxy-phenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.175 g, 0.5655 mmol) in 1,4-dioxane (10 mL). The reaction mixture was heated at reflux for 16 hours, then cooled and a solution of 10% KHSO4/Na2SO4 was added. The mixture was extracted with EtOAc, and the combined organic extracts were washed with water and brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The resulting crude material was purified via flash chromatography (hexane/EtOAc, 7/3) to give 0.209 g (90% yield) of 3-[4-(2-cyano-phenylsulfanyl)-2-methoxy-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester as a clear oil.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:27]([O:29][CH3:30])=[O:28])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17][C@@H:16]([OH:26])[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.CCOC(C)=O>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:27]([O:29][CH3:30])=[O:28])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17][C:16](=[O:26])[CH2:15]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@H](O)COc1ccccc1-3
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(=O)COc1ccccc1-3
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl (7S)-14-cyclohexyl-7-hydroxy-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (from Step 3) in DCM (0.1 M) was added Dess-Martin periodinane (DMP, 1.2 eq), and the mixture was stirred for 1 h at RT. At this point another 0.6 eq of DMP were added and the reaction left overnight. The reaction mixture was diluted with EtOAc and washed with an aqueous solution of a 1:1 mixture containing sodium thiosulfate and NaHCO3 (both saturated solutions), then with water and brine. Drying over Na2SO4, filtration and concentration in vacuo gave the crude product, which was used without further purification (90%); MS (ES+) m/z 404 (M+H)+.
Reaction SMILES: [N:1]1([C:7]([NH:9][C:10]2[CH:31]=[CH:30][C:13]([O:14][CH2:15][C:16]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:17]=3[O:18][CH:19]([CH3:24])[C:20]([O:22][CH3:23])=[O:21])=[CH:12][C:11]=2[F:32])=[S:8])[CH2:6][CH2:5][CH2:4][CH2:3][NH:2]1.Cl[C:34](OC(Cl)(Cl)Cl)=[O:35].C(N(CC)CC)C>O1CCOCC1>[N:1]12[CH:7]([N:9]=[C:10]3[CH:31]=[CH:30][C:13]([O:14][CH2:15][C:16]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:17]=4[O:18][CH:19]([CH3:24])[C:20]([O:22][CH3:23])=[O:21])=[CH:12][CH:11]3[F:32])[S:8][C:34](=[O:35])[N:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2
Reactant: COC(=O)C(C)Oc1cc(C)ccc1COc1ccc(NC(=S)N2CCCCN2)c(F)c1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)C(C)Oc1cc(C)ccc1COC1=CC(F)C(=NC2SC(=O)N3CCCCN23)C=C1
Yield: 31.4 %

Procedure:
By the method of Example 1, Step D, of U.S. Pat. No. 4,906,281, 1.50 g (0.00325 mole) of methyl 2-[2-[4-(perhydropyridazin-1-ylthiocarbonylamino)-3-fluorophenoxymethyl]-5-methylphenoxy]propionate and 0.36 g (0.09017 mole) of trichloromethyl chloroformate were reacted in the presence of 0.36 g (0.0035 mole) of triethylamine in 35 mL of dioxane, yielding 0.50 g of methyl 2-[2-[4-(8-thia-1,6-diazabicyclo[4.3.0]nonane-7-on-9-ylimino)-3-fluorophenoxymethyl]-5-methylphenoxy]propionate as a syrup. The NMR and IR spectra were consistent with the proposed structure. NMR: 1.60 (d, 3H, JHH =8.0 Hz); 1.78-1.96 (m, 4H); 2.30 (s, 3H); 3.64-3.80 (m, 4H); 3.70 (s, 3H); 4.80 (q, 1H, JHH =8.0 Hz); 5.10 (dd, 2H); 6.58-7.30 (m, 6H).
Reaction SMILES: [ClH:1].[NH:2]1[CH:6]=[C:5]([CH2:7][N:8]2[C:14]3[CH:15]=[CH:16][C:17]([C:19]#[N:20])=[CH:18][C:13]=3[CH2:12][N:11]([S:21]([CH3:24])(=[O:23])=[O:22])[C@H:10]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:9]2)[N:4]=[CH:3]1.[N:32]1[CH:37]=C[CH:35]=[C:34](S([Cl:41])(=O)=O)[CH:33]=1>>[ClH:41].[ClH:1].[ClH:41].[C:19]([C:17]1[CH:16]=[CH:15][C:14]2[N:8]([CH2:7][C:5]3[N:4]=[CH:3][NH:2][CH:6]=3)[CH2:9][C@@H:10]([CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:11]([S:21]([C:24]3[CH:37]=[N:32][CH:33]=[CH:34][CH:35]=3)(=[O:22])=[O:23])[CH2:12][C:13]=2[CH:18]=1)#[N:20]
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: CS(=O)(=O)N1Cc2cc(C#N)ccc2N(Cc2c[nH]cn2)C[C@H]1Cc1ccccc1
Agent: Cl
Product: N#Cc1ccc2c(c1)CN(S(=O)(=O)c1cccnc1)[C@H](Cc1ccccc1)CN2Cc1c[nH]cn1
Yield: 15 %

Procedure:
Example 387 was prepared as a yellow solid in 15% yield from Compound C of Example 248 and 3-pyridinesulfonyl chloride as described for Example 284.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])S(Cl)(=O)=O.[CH2:9]([O:11][C:12]([C:14]1[NH:15][CH:16]=[C:17]([CH3:19])[CH:18]=1)=[O:13])[CH3:10].OP([O-])([O-])=O.[K+].[K+]>C(#N)C.CCOC(C)=O.O>[CH3:19][C:17]1[CH:18]=[C:14]([C:12]([O:11][CH2:9][CH3:10])=[O:13])[NH:15][C:16]=1[C:2]([F:8])([F:7])[F:1]
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: CCOC(=O)c1cc(C)c[nH]1
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)c1cc(C)c(C(F)(F)F)[nH]1
Temperature: 25 °C
Reaction time: 144 h
Yield: 44.4 %

Procedure:
Trifluoromethanesulfonyl chloride (40.7 mL, 381.67 mmol) was added to the argon degassed solution of ethyl-4-methyl-1H-pyrrole-2-carboxylate (40 g, 254.45 mmol), K2HPO4 (132.9 g, 763.35 mmol), dichlorotris(1,10-phenanthroline) ruthenium (II) hydrate (3.6 g, 5.08 mmol) in acetonitrile. The reaction mixture was stirred for 6 d at room temperature adjacent to a fluorescent light bulb (23 W). The reaction mixture was diluted with EtOAc and H2O. The aqueous layer was extracted with EtOAc (2×700 mL). Combined organic layer was dried over anhydrous Na2SO4, concentrated under reduced pressure to yield crude mass which was then purified by column chromatography (100-200 mesh Silica gel; 20% ethyl acetate/hexane; Rff-value 0.7) to afford title compound (25 g, 71.13% yield, white color solid).
Reaction SMILES: [CH2:1]1[C@@H:5]2[CH2:6][NH:7][CH2:8][C@@H:4]2[CH2:3][N:2]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[Br:16][C:17]1[CH:18]=[N:19][CH:20]=[C:21](Br)[CH:22]=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[Br:16][C:17]1[CH:22]=[C:21]([N:7]2[CH2:6][C@@H:5]3[CH2:1][N:2]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3][C@@H:4]3[CH2:8]2)[CH:20]=[N:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CNC[C@H]2C1
Reactant: Brc1cncc(Br)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(Br)c3)C[C@@H]2C1
Temperature: 70 °C
Yield: 54.3 %

Procedure:
The product from example 1C (541 mg, 2.55 mmol) and 3,5-dibromopyridine (724 mg, 3.06 mmol) were combined in a 100 mL flask with toluene (14 mL). The solution was stirred at room temperature as sodium t-butoxide (367 mg, 3.82 mmol) was added as a solid. In a test tube, racemic-2,2′-bis(diphenylphosphino-1,1′-binaphthyl) (31 mg, 0.05 mmol) and tris(dibenzylideneacetone)dipalladium (0) (22 mg, 0.024 mmol) were combined with toluene (2 mL) and the mixture was heated at 70° C. for 5 min, then cooled to room temperature. This mixture was rinsed into the 100 mL flask with toluene (2 mL), and the reaction flask was evacuated and purged with nitrogen (3 cycles). The mixture was heated at 80° C. for 20 h, then cooled to room temperature and loaded onto a column of silica gel (45 g) and eluted with hexanes-EtOAc (1:1) to provide the titled compound as an off-white solid (0.51 g, 54%). 1H NMR (300 MHz, CD3OD) δ ppm 1.45 (s, 9H), 3.00-3.14 (m, 2H), 3.20-3.28 (m, 2H), 3.26-3.31 (m, 2H), 3.50-3.59 (m, 2H), 3.59-3.71 (m, 2H), 7.14-7.19 (m, 1H), 7.79-7.90 (m, 2H).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[C:26]4[CH:27]=[C:28]([Cl:31])[CH:29]=[CH:30][C:25]=4[O:24][N:23]=3)[CH2:18][CH2:17]2)[CH2:10][CH2:9]1)(C)(C)C.Cl.O1CCOCC1>ClCCl.C(OC(C)C)(C)C>[ClH:31].[Cl:31][C:28]1[CH:29]=[CH:30][C:25]2[O:24][N:23]=[C:22]([CH:19]3[CH2:20][CH2:21][N:16]([CH2:15][CH2:14][C@H:11]4[CH2:12][CH2:13][C@H:8]([NH2:7])[CH2:9][CH2:10]4)[CH2:17][CH2:18]3)[C:26]=2[CH:27]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCC(c3noc4ccc(Cl)cc34)CC2)CC1
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: C1COCCO1
Solvent: ClCCl
Product: N[C@H]1CC[C@H](CCN2CCC(c3noc4ccc(Cl)cc34)CC2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Trans-(4-{2-[4-(5-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-carbamic acid tert-butyl ester (1.35 g, 2.92 mmol) was dissolved in 2 ml dichloromethane and 4N HCl in dioxane (8.8 ml, 38.8 mmol) was added. The white suspension was stirred for 4 hours at room temperature, diluted with diisopropylether and filtered. The crystals were washed with diisopropylether and dried for 2 hours at 50° C. and <20 mbar, to get the desired salt as a white solid (1.65 g, quant.) [MS: m/e=362.2 (M+H+)].
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9](/[CH:12]=[CH:13]/[CH2:14][OH:15])[CH2:8][CH2:7]1.Cl[C:17]([O:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)=[O:18].C(N(C(C)C)CC)(C)C>ClCCl.CCOCC>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([O:19][C:17](=[O:18])[N:3]([CH2:4][CH2:5][C@H:6]2[CH2:11][CH2:10][C@H:9](/[CH:12]=[CH:13]/[CH2:14][OH:15])[CH2:8][CH2:7]2)[CH3:2])=[CH:21][CH:22]=1
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Reactant: CNCC[C@H]1CC[C@H](/C=C/CO)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(CC[C@H]1CC[C@H](/C=C/CO)CC1)C(=O)Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 150 mg (0.642 mmol) trans-3-[4-(2-methylamino-ethyl)-cyclohexyl]-(E)-prop-2-en-1-ol HCl-salt and 125 mg (0.654 mmol) 4-chlorophenyl chloroformate in 1.5 ml of dichloromethane was added at room temperature 0.55 ml (3.21 mmol) diisopropyl ethyl amine. The reaction mixture was stirred for 1 hour at room temperature, taken up in ether and washed with 1N hydrogen chloride solution and water. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure and the residue then chromatographed on silica gel with a 2:1 v/v mixture of hexane and ethylacetate as the eluent giving 146 mg (64.7%) trans-{2-[4-(3-hydroxy-(E)-propenyl)-cyclohexyl]-ethyl}-methyl-carbamic acid 4-chloro-phenyl ester, MS: 369 (MNH4+, 1Cl).
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1.[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][CH:9]2[CH2:10][CH2:11][N:12]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]3[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=3)[CH2:13][CH2:14]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: ClCCCCCCCCc1cccnc1
Reactant: C(=C(c1ccccc1)c1ccccc1)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C(=C(c1ccccc1)c1ccccc1)C1CCN(CCCCCCCCc2cccnc2)CC1
Temperature: 75 °C

Procedure:
The title compound was prepared in a manner similar to that employed for the compound of Example 23 above starting with 8.64 g of 4-(2,2-diphenylethenyl)piperidine, 7.4 g of 3-(8-chlorooctyl)pyridine, 4.92 g of sodium iodide, 3.48 g of sodium carbonate, and 50 mL of dimethylformamide. The mixture was stirred an heated at 75° C. for 18 hours and then evaporated to dryness. The residue was partitioned between ethyl acetate and 1N sodium hydroxide and the organic layers were dried over sodium sulfate and evaporated to give 11.0 g (74%) of crude free base. Recrystallization from hexane gave the analytically pure, 3-[8-[4-(2,2-diphenylethenyl)-1-piperidinyl]octyl]pyridine, mp 54°-55° C. Analysis Calculated for C32H40N2 : C, 84.91; H, 8.91; N, 6.19. Found: C, 84.81; H, 8.74; N, 6.14. The fumaric acid salt was crystallized from ethanol/acetone, mp 128° -129° C. Analysis Calculated for C32H40N2.C4H4O4 : C, 76.02; H, 7.80; N, 4.93. Found: C, 76.15, H, 7.79, N, 4.89.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH2:9])[CH3:2].[2H]Cl.[C:12]([O:18][CH3:19])(=[O:17])[CH2:13][C:14]([CH3:16])=O.S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH:9]/[C:14](/[CH3:16])=[CH:13]\[C:12]([O:18][CH3:19])=[O:17])[CH3:2]
Reactant: CCN1CCCC1CN
Reactant: COC(=O)CC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [2H]Cl
Agent: [Mg+2]
Solvent: ClCCl
Product: CCN1CCCC1CN/C(C)=C\C(=O)OC
Yield: 81.1 %

Procedure:
38.4 G (0.3 MOLE) OF N-ethyl-2-aminomethylpyrrolidine and a drop of hydrochloric acid d=1.18 were added into a 250 ml flask provided with a stirrer, a thermometer, a condenser and a dropping funnel; 34.8 g (0.3 mole) of methyl acetoacetate were added drop by drop. The temperature reached 54° C. by the end of the introduction. The mixture was next allowed to return to ambient temperature while stirring, and 150 ml of methylene chloride and 5 g of magnesium sulphate were then added. The mixture was stirred for one hour, filtered, the solvent was vaporated in vacuo, and the residue was distilled. 55 g of methyl N-(1-ethyl-2-pyrrolidylmethyl)-3-aminocrotonate were obtained. (Yield: 81.1%; boiling point--3 mm/Hg: 132°-134° C.).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][N:8]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C@@H:21]([NH2:23])[CH3:22])=[CH:17][CH:16]=1)[CH2:9]2.[C:24](OC(=O)C)(=[O:26])[CH3:25].CO>C(Cl)Cl>[CH3:2][O:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][N:8]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C@@H:21]([NH:23][C:24](=[O:26])[CH3:25])[CH3:22])=[CH:19][CH:20]=1)[CH2:9]2
Reactant: COc1cccc2c1CCN(Cc1ccc([C@H](C)N)cc1)C2
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COc1cccc2c1CCN(Cc1ccc([C@H](C)NC(C)=O)cc1)C2
Temperature: 25 °C

Procedure:
To 80 mg (0.24 mmol) (S)-1-[4-(5-methoxy-3,4-dihydro-1H-isoquinolin-2-ylmethyl)-phenyl]-ethylamine hydrochloride (example XXXIII.2) in 2.0 mL DCM are added 67 μL (0.48 mmol) TEA and 34 μL (0.26 mmol) acetic anhydride and the resulting mixture is stirred at r.t. over night. 200 μL MeOH are added and the reaction mixture is purified by HPLC.
Reaction SMILES: [ClH:1].Cl.[CH2:3]1[N:8]([CH2:9][CH2:10][CH2:11][C:12]([NH:14][C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=2)=O)[CH2:7][CH2:6][N:5]2[CH2:27][CH2:28][CH2:29][CH2:30][CH:4]12.B>O1CCCC1>[ClH:1].[ClH:1].[ClH:1].[ClH:1].[CH2:3]1[N:8]([CH2:9][CH2:10][CH2:11][CH2:12][NH:14][C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=2)[CH2:7][CH2:6][N:5]2[CH2:27][CH2:28][CH2:29][CH2:30][CH:4]12
Reactant: COc1cc(NC(=O)CCCN2CCN3CCCCC3C2)cc(OC)c1OC
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: COc1cc(NCCCCN2CCN3CCCCC3C2)cc(OC)c1OC

Procedure:
1.0 g of the compound obtained in Step C of Example 2 is dissolved in 50 ml of tetra-hydrofuran and, under argon, 5 ml of a 1M solution of borane in tetrahydrofuran are added, and the mixture is then refluxed for 6 hours. After hydrolysis with 1 ml of 4N HCl and evaporation to dryness, the residue is dissolved in 5 ml of ethanol and 1 ml of ethereal hydrogen chloride to yield the expected product.
Reaction SMILES: [Cl:1][C:2]1[N:30]=[CH:29][C:5]2[N:6]=[C:7]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:14][C:13]=3[O:27][CH3:28])[N:8]([CH3:11])[C:9](=[O:10])[C:4]=2[CH:3]=1.S(C1C=CC(C)=CC=1)(OC[CH2:36][F:37])(=O)=O>>[Cl:1][C:2]1[N:30]=[CH:29][C:5]2[N:6]=[C:7]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:23][CH2:24][CH2:25][CH2:26]4)=[CH:14][C:13]=3[O:27][CH2:28][CH2:36][F:37])[N:8]([CH3:11])[C:9](=[O:10])[C:4]=2[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCCF)cc1
Reactant: COc1cc(OCCCN2CCCC2)ccc1-c1nc2cnc(Cl)cc2c(=O)n1C
Product: Cn1c(-c2ccc(OCCCN3CCCC3)cc2OCCF)nc2cnc(Cl)cc2c1=O

Procedure:
The intended compound was produced according to the method of Example 60 but starting from 6-chloro-2-[2-methoxy-4-(3-pyrrolidin-1-ylpropoxy)phenyl]-3-methylpyrido[3,4-d]pyrimidin-4(3H)-one and 2-fluoroethyl tosylate.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:31]=[CH:30][C:16]([CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]([F:29])=[C:23]([CH:28]=3)[C:24]([O:26][CH3:27])=[O:25])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH2:32]([O:34][C:35]([CH:37]1[CH2:39][CH:38]1[CH:40]=O)=[O:36])[CH3:33].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C([O-])(O)=O.[Na+]>ClCCCl>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][N:18]([CH2:40][CH:38]3[CH2:39][CH:37]3[C:35]([O:34][CH2:32][CH3:33])=[O:36])[C:19]3[CH:20]=[CH:21][C:22]([F:29])=[C:23]([CH:28]=3)[C:24]([O:26][CH3:27])=[O:25])=[CH:30][CH:31]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)C1CC1C=O
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc(F)c(C(=O)OC)c3)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CCCCc1ccc(C#Cc2ccc(CN(CC3CC3C(=O)OCC)c3ccc(F)c(C(=O)OC)c3)cc2)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 52.3 %

Procedure:
To solution of methyl 5-({4-[(4-butylphenyl)ethynyl]benzyl}amino)-2-fluorobenzoate (500 mg; 1.20 mmol) in anhydrous DCE (30 mL) were added ethyl-2-formyl-1-cyclopropanecarboxylate (Aldrich, 0.40 mL; 3.01 mmol), triacetoxyborohydride (382 mg; 1.81 mmol).The resulting mixture was stirred at 50° C. under N2 atmosphere for 4 hours. The mixture was poured into a saturated solution of NaHCO3 (50 mL) and extracted with DCM (2×50 mL). The combined organic layers were washed with brine (100 mL), dried over magnesium sulfate, filtrated and the solvents were removed under reduced pressure to give 872 mg. Purification of this crude by flash chromatography on silicagel (c-Hex/EtOAc, gradient 95:5 to 90:10) gave 340 mg (65%) of the title compound as a yellow oil. HPLC, Rt: 6.06 min (purity=96.2%). LC/MS, M+(ESI): 542.3. 1H NMR (CDCl3) δ: 7.43 (t, J=8.5 Hz, 4H), 7.32 (m, 1H), 7.22 (d, J=7.9 Hz, 2H), 7.15 (d, J=7.9 Hz, 2H), 6.93 (m, 2H), 4.54 (s, 2H), 4.08 (m, 2H), 3.89 (s, 3H), 3.35 (m, 2H), 2.61 (t, J=7.5 Hz, 2H), 1.32-1.58 (m, 7H), 1.24 (t, J=7.0 Hz, 3H), 0.92 (t, J=7.3 Hz, 3H), 0.88 (m, 1H).