Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[O:13][CH3:14])#[N:2].[NH2:15][OH:16]>CCO>[NH2:2][C:1](=[N:15][OH:16])[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[O:13][CH3:14]
Reactant: COC(=O)c1ccc(C#N)c(OC)c1
Reactant: NO
Solvent: CCO
Product: COC(=O)c1ccc(C(N)=NO)c(OC)c1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a suspension of methyl 4-cyano-3-methoxybenzoate, obtained in step 1 (135 mg; 0.71 mmol; 1 eq.) in EtOH (1.35 mL) was added hydroxylamine (50% in water) (0.21 mL; 3.53 mmol; 5 eq.). The reaction mixture was stirred at 60° C. for 3 h. Solvent were removed to dryness, to afford the title compound as a white powder (191 mg; quantitative). 1H NMR (DMSO-d6, 300 MHz) δ 9.58 (br s, 1H), 7.56-7.51 (m, 3H), 5.71 (br s, 2H), 3.87-3.85 (m, 6H). HPLC (Method A), Rt 1.17 min (purity: 95.0%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C@H:12]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH3:28])[CH:19]=1)[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:7]2.[CH:29]1([C:32](Cl)=[O:33])[CH2:31][CH2:30]1>O1CCCC1>[CH:29]1([C:32]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:10]=2[C:9](=[O:11])[N:8]([C@H:12]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH3:28])[CH:19]=2)[CH2:13][S:14]([CH3:17])(=[O:15])=[O:16])[CH2:7]3)=[O:33])[CH2:31][CH2:30]1
Reactant: O=C(Cl)C1CC1
Reactant: CCOc1cc([C@H](CS(C)(=O)=O)N2Cc3cccc(N)c3C2=O)ccc1OC
Solvent: C1CCOC1
Product: CCOc1cc([C@H](CS(C)(=O)=O)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Yield: 58.7 %

Procedure:
A stirred mixture of 7-amino-2-[(1R)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]isoindolin-1-one (0.91 g, 2.2 mmol) and cyclopropane carbonyl chloride (0.25 mL, 2.8 mmol) in tetrahydrofuran (10 mL) was heated to reflux for 15 min. The solvent was removed in vacuo to give a solid. The solid was recrystallized from ethanol (10 mL) to give cyclopropyl-N-{2-[(1R)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-3-oxoisoindolin-4-yl}carboxamide as an off-white solid (0.61 g, 56% yield); mp, 173-175° C.; 1H NMR (CDCl3) δ 0.86-0.93 (m, 2H, 2CHH), 1.07-1.14 (m, 2H, 2CHH), 1.46 (t, J=6.9 Hz, 3H, CH3), 1.63-1.73 (m, 1H, CH), 2.95 (s, 3H, CH3), 3.68 (dd, J=4.4, 14.3 Hz, 1H, CHH), 3.86 (s, 3H, CH3), 4.07 (q, J=7.1 Hz, 2H, CH2), 4.20 (d, J=16.7 Hz, 1H, CHH), 4.21 (dd, J=9.9, 14.3 Hz, 1H, CHH), 4.44 (d, J=16.7 Hz, 1H, CHH), 5.73 (dd, J=4.3, 9.9 Hz, 1H, NCH), 6.84-7.02 (m, 4H, Ar), 7.44 (t, J=7.8 Hz, 1H, Ar), 8.43 (d, J=8.3 Hz, 1H, Ar), 10.46 (s, 1H, NH); 13C NMR (CDCl3) δ 8.24, 14.61, 16.10, 41.43, 47.81, 51.55, 55.75, 55.88, 64.56, 111.46, 112.09, 116.69, 116.99, 117.76, 119.17, 129.27, 133.54, 138.06, 141.22, 148.84, 149.67, 169.96, 172.59; Anal Calcd for C24H28N2O6S: C, 61.00; H, 5.97; N, 5.93. Found: C, 60.73; H, 5.91; N, 5.69.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12]([O:14][CH3:15])=[O:13])[CH2:10][CH2:9][C:8]([C:16]([O:18][CH3:19])=[O:17])=[CH:7][C:6]=2[CH:20]=1.B([O-])([O-])O[C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>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.C1(C)C=CC=CC=1>[CH3:15][O:14][C:12]([N:11]1[C:5]2[CH:4]=[CH:3][C:2]([C:23]3[CH:24]=[CH:25][C:26]([N:29]4[CH2:30][CH2:31][O:32][CH2:33][CH2:34]4)=[CH:27][CH:28]=3)=[CH:20][C:6]=2[CH:7]=[C:8]([C:16]([O:18][CH3:19])=[O:17])[CH2:9][CH2:10]1)=[O:13]
Reactant: [O-]B([O-])Oc1ccc(N2CCOCC2)cc1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2N(C(=O)OC)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)C1=Cc2cc(-c3ccc(N4CCOCC4)cc3)ccc2N(C(=O)OC)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.2 %

Procedure:
A mixture of methyl 7-bromo-1-methoxycarbonyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.3 g), 4-morpholinophenyl borate (0.22 g), 1M potassium carbonate solution (2.5 ml), ethanol (2.5 ml) and toluene (25 ml) was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakis(triphenylphosphine)palladium (0.04 g), and the mixture was refluxed overnight under argon atmosphere and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 1-methoxycarbonyl-7-(4-morpholinophenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.31 g) as pale yellow crystals.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:18]1[O:21][CH:19]1[CH3:20]>>[OH:21][CH:19]([CH3:20])[CH2:18][N:4]1[CH2:5][CH2:6][N:1]([CH2:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)c1ccc(CN2CCNCC2)cc1
Reactant: CC1CO1
Product: COC(=O)c1ccc(CN2CCN(CC(C)O)CC2)cc1
Yield: 63 %

Procedure:
This is prepared analogously to Example 11 from methyl 4-(piperazin-1-ylmethyl)-benzoate and propylene oxide. Yield 63% of theory; m.p. 63°-64° C.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1.[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>C1(C)C=CC=CC=1>[N:14]1([CH2:2][CH2:3][O:4][C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C1CCNCC1
Reactant: O=[N+]([O-])c1ccc(OCCCl)cc1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(OCCN2CCCCC2)cc1
Yield: 118.7 %

Procedure:
A solution of 1-(2-chloroethoxy)-4-nitrobenzene (2.01 g, 0.01 mol), piperidine (2.55 g, 0.03 mol), and toluene (10 mL) was refluxed overnight. The reaction mixture was filtered and the filtrate evaporated to give 2.97 g of 1-[2-(1-piperidinyl)ethoxy]4-nitrobenzene as an orange oil, MS M+ (m/e) 251.18. This material (1.25 g, 0.004 mol) was hydrogenated in ethanol (25 mL) in the presence of 10% Pd—C catalyst at 40 psig and 25° C. overnight. Filtration and evaporation of the reaction mixture gave 0.95 g of 4-[2-(1-piperidinyl)ethoxy]aniline as a light brown oil, MS M+ (m/e) 221.24. A solution of this oil (0.220 g, 1.0 mmol), 3-methyl-5,8-dimethoxy-2-tetralone (6, 0.206, 0.94 mmol), and 1,2-dichloroethane (3.5 mL) was treated with sodium triacetoxyborohydride (0.300 g, 1.4 mmol) and acetic acid (0.060 g, 1.0 mmol) and the resulting mixture was stirred overnight at 25° C. The reaction was treated with 3N sodium hydroxide solution with vigorous stirring. The organic layer was separated, washed with saturated sodium chloride solution, dried over potassium carbonate, filtered and evaporated to a red oil. This material was purified by C-18 reverse phase high pressure liquid chromatography affording compound 60 as a pink solid. 1H NMR (300 MHz, CDCl3): δ 7.10-7.22 (m, 2H), 6.52-6.82 (m, 4H), 4.25-4.33 (m, 2H), 3.60-3.80 (m, 3H), 3.75 (s, 3H), 3.71 (s, 3H), 3.48-3.38 (m, 2H), 2.80-3.05 (m, 4H), 1.80-2.10 (m, 4H), 1.10-1.50 (m, 3H), 1.00 (d, 3H). MS M+ (m/e) 425.38.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][NH:4]1.[S:13](=O)(=[O:16])([OH:15])[OH:14]>O>[OH:16][S:13]([O:1][CH2:2][C@H:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][NH:4]1)(=[O:15])=[O:14]
Reactant: O=S(=O)(O)O
Reactant: OC[C@H]1Cc2ccccc2CN1
Solvent: O
Product: O=S(=O)(O)OC[C@H]1Cc2ccccc2CN1
Reaction time: 1 h

Procedure:
A solution of (R)-3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline (22.8 g.) in a mixture of sulphuric acid (d = 1.83; 7.9 cc.) and water (50 cc.) is concentrated for 1 hour at 100° C., under reduced pressure (20 mm.Hg) and then for 1 hour at 160° C. The residue crystallises on cooling. (R)-3-Hydroxysulphonyloxymethyl-1,2,3,4-tetrahydroisoquinoline (33.9 g.) is thus obtained in the form of a white crystalline mass melting at 318° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:14])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][N:9]=2)[CH:7]=1.[B:15]1(B2OCC(C)(C)CO2)[O:20]CC(C)(C)C[O:16]1>>[F:14][C:5]1[CH:4]=[CH:3][C:2]([B:15]([OH:20])[OH:16])=[CH:7][C:6]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][N:9]=1
Reactant: Fc1ccc(Br)cc1-c1ccncn1
Reactant: CC1(C)COB(B2OCC(C)(C)CO2)OC1
Product: OB(O)c1ccc(F)c(-c2ccncn2)c1

Procedure:
4-(5-Bromo-2-fluorophenyl)pyrimidine (503 mg, 2.0 mmol) was reacted with bis(neopentyl glycolato)diboron (494 mg, 2.2 mmol) using the method of Example 20 to give 4-fluoro-3-(pyrimidin-4-yl)phenylboronic acid as a tan solid: MS (ES+) m/z 219 [M+H]+.
Reaction SMILES: C12CC(CC1)CC2N[C:9]1[CH:14]=[C:13]([N:15]2[CH2:19][CH2:18][C@@H:17]([NH:20][CH3:21])[CH2:16]2)[CH:12]=[CH:11][N:10]=1.CCOCC.C(Cl)[Cl:28].Cl>CCOCC>[Cl:28][C:9]1[CH:14]=[C:13]([N:15]2[CH2:19][CH2:18][C@@H:17]([NH:20][CH3:21])[CH2:16]2)[CH:12]=[CH:11][N:10]=1
Reactant: CN[C@@H]1CCN(c2ccnc(NC3CC4CCC3C4)c2)C1
Reactant: ClCCl
Agent: Cl
Solvent: CCOCC
Product: CN[C@@H]1CCN(c2ccnc(Cl)c2)C1
Yield: 100 %

Procedure:
To a stirring solution of 2-chloro-4-bromopyridine (4.3 g, 22.1 mmol) in toluene (100 mL) was added (R)-methyl-pyrrolidin-3-yl-amine (1.7 g, 17.0 mmol) and sodium tert-butoxide (2.5 g, 26.0 mmol). The flask was evacuated and flushed with N2(g) twice. A mixture of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos; 590 mg, 1.0 mmol) and tris(dibenzylideneacetone)-dipalladium(0) (Pd2(dba)3; 310 mg, 0.34 mmol) was added in one portion and the mixture was heated at 85° C. for 20 h. The mixture was cooled to room temperature (rt), diluted with H2O (75 mL), and extracted with ethyl acetate (EtOAc; 3×). The combined organic layers were dried and concentrated to give a clear brown oil. The oil was purified by FCC (0 to 5% 2 M NH3 in MeOH/CH2Cl2) to give the title compound as a brown solid (1.1 g, 30%). MS (ESI): mass calcd. for C10H14ClN3, 211.09 m/z found, 212.1 [M+H]. 1H NMR (DMSO-d6): 7.86 (d, J=5.9, 1H), 6.47-6.38 (m, 2H), 3.45-3.17 (m, 4H), 3.11-3.01 (m, 1H), 2.29 (s, 3H), 2.15-2.00 (m, 1H), 1.82 (br s, 1H), 1.79-1.65 (m, 1H). Bicyclo[2.2.1]hept-2-yl-[(3R)-4-(3-methylamino-pyrrolidin-1-yl)-pyridin-2-yl]-amine. To a stirring mixture of [(3R)-1-(2-chloro-pyridin-4-yl)-pyrrolidin-3-yl]-methyl-amine (97 mg, 0.46 mmol), exo-2-aminonorbornane (164 μL, 1.4 mmol) in ethylene glycol dimethyl ether (DME; 4 mL) in a scintillation vial was added sodium tert-butoxide (245 mg, 2.6 mmol). To the stirring mixture was added in one portion Pd(OAc)2 (16 mg, 0.024 mmol) and racemic 2,2′-bis(diphenylphosphino)-1,1′-bihaphthyl (BINAP; 19 mg, 0.031 mmol). The mixture was heated at 65° C. for 20 h, then was cooled to rt and filtered through a plug of diatomaceous earth. The plug was washed with MeOH (2 mL) and the filtrate was purified directly by FCC (5% 2 M NH3 in MeOH/CH2Cl2) to give a clear light golden oil (70 mg, 54%). Bicyclo[2.2.1]hept-2-yl-[(3R)-4-(3-methylamino-pyrrolidin-1-yl)-pyridin-2-yl]-amine. To a stirring solution of bicyclo[2.2.1]hept-2-yl-[(3R)-4-(3-methylamino-pyrrolidin-1-yl)-pyridin-2-yl]-amine in 1:1 Et2O/CH2Cl2 (8 mL) was added 1 N HCl in Et2O (1 mL). The organic layers was separated and concentrated to give the desired product (89 mg, 100%) as a beige solid. MS (ESI): mass calcd. for C17H26N4, 286.2; m/z found, 287.3 [M+H]+. 1H NMR (DMSO-d6): 12.07 (s, 1H), 9.57 (br s, 1H), 9.46 (br s, 1H), 7.81 (d, J=5.1, 1H), 7.66 (d, J=4.6, 1H), 6.28 (d, J=7.4, 1H), 5.64 (s, 1H), 3.89 (br s, 1H), 3.85-3.61 (m, 3H), 3.49 (br s, 2H), 2.60 (s, 3H), 2.35-2.20 (m, 3H), 2.18 (s, 1H), 1.95-1.85 (m, 1H), 1.55-1.46 (m, 3H), 1.37-1.25 (m, 2H), 1.21-1.09 (m, 2H). The compounds in Example 2 through Example 15 were prepared using methods analogous to those described for Example 1.
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)=[O:6].[CH3:19][NH:20][C:21]([NH2:23])=[S:22].O>C(O)C>[CH3:19][NH:20][C:21]1[S:22][CH:2]=[C:3]([CH2:4][C:5](=[O:6])[NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:23]=1
Reactant: CNC(N)=S
Reactant: O=C(CBr)CC(=O)Nc1cccc(C(F)(F)F)c1
Solvent: O
Solvent: CCO
Product: CNc1nc(CC(=O)Nc2cccc(C(F)(F)F)c2)cs1
Yield: 80.9 %

Procedure:
A solution containing 32.4 g (0.10 mole) of 4-bromo-3'-trifluoromethylacetoacetanilide and 11.3 g (0.13 mole) of N-methylthiourea in 250 ml of ethanol was refluxed for four hours. The reaction mixture was poured into 700 ml of water and ethanol was added. A small quantity of insoluble material was removed by filtration and the filtrate was made strongly alkaline by the addition of ammonium hydroxide. The solution was cooled and an additional 400 ml of water was added. The precipitated solid was collected and dried in an oven. There was obtained 25.5 g (81%) of product, m.p. 153°-55°, N.M.R. (dimethyl-d6 sulfoxide) ∂ 2.8-2.9 (CH3, doublet), 3.5 (CH2), 6.3 (hetero-aromatic), 7.3-8.1 (aromatic, NH), 10.4 (HNC=O).
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].I[C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1.C(N(CC)CC)C>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu](I)I>[CH:12]1[C:13]2[C:8](=[CH:7][CH:6]=[CH:15][CH:14]=2)[CH:9]=[CH:10][C:11]=1[C:3]#[C:2][CH2:1][OH:4]
Reactant: C#CCO
Reactant: Ic1ccc2ccccc2c1
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: OCC#Cc1ccc2ccccc2c1
Temperature: 35 °C
Reaction time: 12 h
Yield: 11 %

Procedure:
Bis(triphenylphosphine)palladium (II) chloride (0.18 g, 0.26 mmol, 0.18 mol %) was added to a stirred solution of propargyl alcohol (8.43 mL, 144.8 mmol, 1 eq.), 2-iodonapthalene (36 g, 142 mmol), triethylamine (39.6 mL, 284 mmol, 2 eq.) and copper iodide (0.09 g, 0.49 mmol, 0.3 mol %) in tetrahydrofuran (750 ml). The mixture was stirred at 35° C. for 12 h under nitrogen atmosphere. The mixture was then filtered through a bed of celite and the filtrate was washed with ethyl acetate (200 ml). The filtrate was then concentrated in vacuo. Purification by silica gel chromatography using 1:6 ethyl acetate/petrol as the eluting solvent afforded the desired compound (2.85 g, 11%) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 4.54 (2H, s, CH2), 7.45-7.49 (3H, m, ArH), 7.75-7.81 (3H, m, ArH), 7.95 (1H, s, ArH).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:29]=[CH:28][C:12]([O:13][CH2:14][CH2:15][CH2:16][N:17]2C(=O)C3=CC=CC=C3C2=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>C(O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][CH2:15][CH2:16][NH2:17])=[CH:28][CH:29]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCOc1ccc(OCc2ccccc2)cc1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCCOc1ccc(OCc2ccccc2)cc1
Yield: 58.4 %

Procedure:
A mixture of N-[3-(4-benzyloxyphenoxy)propyl]phthalimide (3.87 g) and hydrazine hydrate (0.55 g) in ethanol (40 ml) was heated at reflux for 3 hours. The reaction mixture was allowed to cool, filtered and the filtrate evaporated. Sodium hydroxide solution (2M, 20 ml) was added to the residue, the aqueous mixture extracted with ethyl acetate and the ethyl acetate extract dried. The solid collected by filtration of the cooled reaction mixture was suspended in sodium hydroxide solution (2M, 20 ml) and extracted with ethyl acetate. The ethyl acetate extract was dried, combined with the dried ethyl acetate derived from the filtrate and the combined extract evaporated to give 3-(4-benzyloxyphenoxy)propylamine as a solid (1.5 g), m.p. 115° C.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[NH:12](C)[CH3:13]>C1(C)C=CC=CC=1>[CH3:1][CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:13][NH2:12]
Reactant: C=CCCCCCCCCC
Reactant: CNC
Solvent: Cc1ccccc1
Product: CCCCCCCCCC(C)CN
Reaction time: 20 h

Procedure:
20g of 1-undecene and 10g of (CH3)2NH are reacted in accordance with the method of example 3 with Zr (Me2N4) (1g) in 50ml of toluene. After 20 hours at 200° C., (N-methyl, N-2 methylundecylamine) is obtained, and is separated by chromatography on an Al2O3 column.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-])=O)[CH:15]=3)[N:10]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[H][H]>O1CCCC1.[Pd]>[C:23]([O:22][C:20]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[N:9]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)n1nc(-c2cccc(F)c2)c2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1nc(-c2cccc(F)c2)c2cc(N)ccc21
Yield: 111.6 %

Procedure:
To a solution of 180 mg of tert-butyl 3-(3-fluorophenyl)-5-nitro-1H-1-indazolecarboxylate in 10 ml tetrahydrofuran was added 100 mg of palladium (5%)-carbon, and the mixture was stirred at room temperature in an atmosphere of hydrogen gas at normal pressure for 3 hours. The reaction mixture was filtrated through Celite and the solvent was evaporated, to give 184 mg of the title compound as a light brown oil.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([C@@H:14]3[CH2:18][C@H:17]([O:19][C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[CH2:16][NH:15]3)=[O:13])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.CCN(CC)CC.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C1COCC1>[CH3:34][S:35]([N:15]1[CH2:16][C@@H:17]([O:19][C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[CH2:18][C@H:14]1[C:12]([N:8]1[CH2:9][CH2:10][CH2:11][N:5]([CH:1]2[CH2:2][CH2:3][CH2:4]2)[CH2:6][CH2:7]1)=[O:13])(=[O:37])=[O:36]
Reactant: O=C([C@@H]1C[C@H](Oc2ccc(F)cc2)CN1)N1CCCN(C2CCC2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1C[C@@H](Oc2ccc(F)cc2)C[C@H]1C(=O)N1CCCN(C2CCC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.2 %

Procedure:
To an ice-cooled solution of (2S,4S)-2-(4-cyclobutyl-[1,4]diazepane-1-carbonyl)-4-(4-fluoro-phenoxy)-pyrrolidine (29 mg, 0.08 mmol) in THF (0.8 mL) with Et3N (60 μL, 0.4 mmol) was added methanesulfonyl chloride (19 μL, 0.24 mmol). The reaction mixture was allowed to warm to rt and was stirred for 18 h. The mixture was diluted with satd. aq. NaHCO3 and extracted with CH2Cl2 (3×). The combined organic layers were dried and concentrated. Purification by FCC provided the desired product (31 mg, 87%). MS (ESI): mass calcd. for C21H30FN3O4S, 439.19; m/z found, 440.5 [M+H]+. 1H NMR (CDCl3): 7.00-6.94 (m, 2H), 6.83-6.78 (m, 2H), 4.94-4.89 (m, 1H), 4.86 (ddd, J=8.8, 4.4, 4.4 Hz, 1H), 4.10-4.03 (m, 1H), 3.78-3.40 (m, 5H), 3.08 (d, J=4.0 Hz, 3H), 2.84 (dd, J=16.2, 7.8 Hz, 1H), 2.75-2.66 (m, 1H), 2.57-2.26 (m, 4H), 2.25-2.14 (m, 1H), 2.07-1.97 (m, 2H), 1.97-1.71 (m, 4H), 1.69-1.55 (m, 2H).
Reaction SMILES: C([O:3][C:4]([C:6]1([S:23]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+].O1CCCC1>CO>[CH3:33][O:32][C:29]1[CH:28]=[CH:27][C:26]([S:23]([C:6]2([C:4]([OH:5])=[O:3])[CH2:7][CH2:8][N:9]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[CH2:10][CH2:11]2)(=[O:25])=[O:24])=[CH:31][CH:30]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(Cc2cccc3ccccc23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3cccc4ccccc34)CC2)cc1

Procedure:
4-(4-Methoxy-benzenesulfonyl)-1-napthalene-ylmethyl-piperidine-4-carboxylic acid was prepared starting from 4-(4-methoxy-benzenesuIfonyl)-napthalene-ylmethyl-piperidine-4-carboxylic acid ethyl ester (6.3g, 13 mmol) dissolved in methanol (30 mL), 10 N sodium hydroxide (30 mL) and tetrahydrofuran (30 mL). The resulting reaction miixture was worked up as outlined in example 83. Yield 2.3 g (36%). yellow solid mp 226-228° C., MS: 440.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10]O)=[CH:4][CH:3]=1.P(Br)(Br)[Br:13].[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][Br:13])=[CH:4][CH:3]=1
Reactant: OCCCc1ccc(Cl)cc1
Reactant: BrP(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Clc1ccc(CCCBr)cc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 83.2 %

Procedure:
66.0 g (387 mmol) of 3-(p-chlorophenyl)-1-propanol was dissolved in 350 ml of toluene, and a solution having 105 g (387 mmol) of phosphorus tribromide dissolved in 50 ml of toluene, was dropwise added thereto. After the dropwise addition, the internal temperature of the reaction solution was raised to 90° C. and returned to room temperature 3 hours later. 250 ml of a 1N sodium hydroxide aqueous solution was added thereto, followed by shaking. Then, the solution was left to stand still for liquid separation, and the water layer was extracted again with 150 ml of toluene. The toluene layers were put together and washed with 150 ml of a saturated sodium chloride aqueous solution, followed by Celite filtration, and then the solvent was distilled off. The residue was Idistilled to obtain 75.2 g (y 83%) of the desired 3-(p-chlorophenyl)-1-propyl bromide {compound (2)) as a colorless oily substance (85-89° C./0.3 mmHg)
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][SH:7])=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([NH:27][CH:28]([CH2:33][CH:34]3[O:36][CH2:35]3)[C:29]([O:31]C)=[O:30])(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1>>[CH3:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:19]=[CH:20][C:21]([S:24]([NH:27][CH:28]([CH2:33][CH:34]([OH:36])[CH2:35][S:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[C:29]([OH:31])=[O:30])(=[O:25])=[O:26])=[CH:22][CH:23]=2)=[CH:16][CH:17]=1
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Reactant: Fc1ccc(CS)cc1
Product: COc1ccc(-c2ccc(S(=O)(=O)NC(CC(O)CSCc3ccc(F)cc3)C(=O)O)cc2)cc1

Procedure:
Example 51 is prepared from 4-fluorobenzylmercaptan and 1d using the procedure described for compound 20.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:20]=[C:21]([C:25](O)=[O:26])[O:22][C:23]=2[CH3:24])=[CH:13][CH:12]=1.[C:28]1([S:34]([NH2:37])(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl.CN(C)CCCN=C=NCC>CN(C1C=CN=CC=1)C.O1CCCC1.C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][C:19]2[CH:20]=[C:21]([C:25]([NH:37][S:34]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:36])=[O:35])=[O:26])[O:22][C:23]=2[CH3:24])=[CH:15][CH:16]=1
Reactant: COc1ccc(-c2ccc(OCc3cc(C(=O)O)oc3C)cc2)c(OC)c1
Reactant: NS(=O)(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CC#N
Product: COc1ccc(-c2ccc(OCc3cc(C(=O)NS(=O)(=O)c4ccccc4)oc3C)cc2)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 34.8 %

Procedure:
A stirred solution of 4-(2′,4′-dimethoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (140) (50 mg, 0.136 mmoles), benzenesulphonamide (32 mg, 0.204 mmoles) and 4-(N,N-dimethylamino)-pyridine (5 mg) in a mixture of tetrahydrofuran (8 ml) and acetonitrile (2 ml) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (32 mg, 0.163 mmoles). The mixture was stirred at room temperature for 16 hours under an argon atmosphere. The reaction mixture was concentrated in vacuo and the residue was purified by HPLC to afford compound 141 (24 mg) as a white solid. LC/MS System C; Rt=8.99 mins, m/z (ES−)=506 (M−H for C27H25NO7S).