Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[C@@H:14]([OH:15])[CH2:13][CH2:12][N:11]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].[F:25][C:26]1[CH:27]=[C:28]([N+:33]([O-:35])=[O:34])[CH:29]=[C:30](F)[CH:31]=1>CN(C=O)C>[Si:1]([O:8][CH2:9][C@@H:10]1[C@@H:14]([O:15][C:30]2[CH:29]=[C:28]([N+:33]([O-:35])=[O:34])[CH:27]=[C:26]([F:25])[CH:31]=2)[CH2:13][CH2:12][N:11]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1cc(F)cc(F)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)[C@H]1CO[Si](C)(C)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2cc(F)cc([N+](=O)[O-])c2)[C@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 82 %

Procedure:
To a 0° C. solution of (2R,3S)-tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)-3-hydroxypyrrolidine-1-carboxylate (1equiv) in DMF (0.5 M) was added NaH (1.3 equiv) as a solid. After stirring for 15 min at 0° C., 3,5-difluoronitrobenzene (1.2 equiv) was added by syringe. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction was quenched by the addition of water, and the mixture was diluted with EtOAc. The organic layer was washed four times with water and once with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification by flash chromatography (0-20% EtOAc/Hexanes) provided the title compound in 82% yield.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].O[C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[CH:16]2>>[C:6]1([NH:5][C:3]([CH2:2][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH:17]=[CH:16]3)=[O:4])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(CCl)Nc1ccccc1
Reactant: Oc1ccc2[nH]ccc2c1
Product: O=C(Cc1ccc2[nH]ccc2c1)Nc1ccccc1

Procedure:
The title compound was prepared by a method analogous to that described in Example 1 from chloroacetanilide and 5-hydroxyindole. MS CI (MH+)=267.
Reaction SMILES: [OH:1][C@H:2]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C@@H:3]([CH2:18][CH2:19][C:20]#[CH:21])[C:4](N1C(C2C=CC=CC=2)COC1=O)=[O:5].[O:28]1CCCC1.OO.[OH-].[Li+]>O>[OH:1][C@H:2]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C@@H:3]([CH2:18][CH2:19][C:20]#[CH:21])[C:4]([OH:5])=[O:28]
Reactant: C1CCOC1
Reactant: C#CCC[C@@H](C(=O)N1C(=O)OCC1c1ccccc1)[C@H](O)c1ccccc1
Agent: OO
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: C#CCC[C@@H](C(=O)O)[C@H](O)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
To a stirred solution of 65.0 g (179 mmol) of 4S)-3-{(2R)-2-[(S)-hydroxy(phenyl)methyl]hex-5-ynoyl}-4-phenyl-1,3-oxazolidin-2-one from Step B above in 1050 mL of a 20 to 1 mixture of anhydrous tetrahydrofuran to water at 0° C. under an atmosphere of nitrogen was added 77.0 mL (894 mmol) of a 35% aqueous hydrogen peroxide solution at a rate slow enough to keep the internal temperature below 3° C. Next, 395 mL (395 mmol) of a 1.0 M aqueous lithium hydroxide solution was added at a rate slow enough to keep the internal temperature of the reaction below 5° C. and the resulting mixture was stirred for 3 h at 0° C. The reaction was quenched with 755 mL (984 mmol) of a 1.3 M aqueous sodium sulfite solution at a rate slow enough to keep the internal temperature of the mixture below 5° C. All volatiles were removed in vacuo and the remaining aqueous phase was extracted with ethyl acetate (3×200 mL). The aqueous phase was then cooled to 0° C. and acidified with a 6 M aqueous hydrogen chloride solution until a pH of 3 was achieved. The aqueous phase was then extracted with ethyl acetate (3×300 mL) and the combined organics were washed with brine (100 ml), dried over magnesium sulfate, filtered and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with a 5-10% ethyl acetate and 3% acetic acid in hexanes gradient to afford the title compound as a colorless gum (32.0 g, 82.0%). 1H NMR (500 MHz, CDCl3): δ 7.39-7.28 (m, 5H), 4.85 (d, J=8.2, 1H), 3.03-2.97 (m, 1H), 2.29-2.15 (m, 2H), 1.97 (t, J=2.5 Hz, 1H), 1.93-1.82 (m, 1H), 1.62-1.55 (m, 1H). LC-MS: m/z (ES) 201.0 (MH—H2O)+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][C:10]=1[N:11]1[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12]1)[NH2:7].[N:17]#[C:18][NH2:19].Cl>C(O)C.O>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([NH:7][C:18]([NH2:19])=[NH:17])[CH:8]=[CH:9][C:10]=1[N:11]1[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12]1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: N#CN
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1

Procedure:
3-Methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline hydrochloride (3 g, 12.52 mmol), cyanamide (0.684 g, 16.27 mmol) and hydrochloric acid (1.564 mL, 18.77 mmol) in ethanol (20 mL) were heated to reflux o.n. The reaction mixture was concentrated under reduced pressure before the residue was poured on potassium carbonate (1.730 g, 12.52 mmol) in water (60 mL) and then put in refrigerator o.n. The formed carbonate-salt was filtered off, and dried in vacuum oven o.n. The solid was washed with several portions of DCM, dried and used as such in next step (52.3%). MS (ES+) m/z 246.2 (M+H)+
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.Br[CH2:11][CH2:12][CH2:13][O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1>CN(C=O)C.O>[O:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH:15]1[O:14][CH2:13][CH2:12][CH2:11][N:7]1[CH:8]=[CH:9][C:4](=[O:3])[CH:5]=[CH:6]1
Reactant: BrCCCOC1CCCCO1
Reactant: Oc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1ccn(CCCOC2CCCCO2)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 35.3 %

Procedure:
Sodium hydride (946 mg of a 50% suspension in mineral oil, 19.7 mmol) was added to a solution of 4-hydroxypyridine (1.88 g, 19.7 mmol) in DMF (50 ml) and the mixture stirred for 30 minutes. 2-(3-Bromopropoxy)tetrahydropyran (4.0 g, 17.9 mmol), (J. Chem. Soc. 1963, 3440), was added and the mixture heated at 100° C. for 3 hours. The reaction mixture was allowed to cool, diluted with water and extracted with ethyl acetate. The extract was washed with water, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol mixtures (100/0 increasing to 95/5) to give 1-[3-(tetrahydropyran-2-yloxy)propyl]1-,4-dihydro-4-pyridone (1.5 g, 35%).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:12]([CH2:15]Cl)=[CH:11][C:8]=2[C:9]#[N:10])=[CH:4][C:3]=1[C:19]([F:22])([F:21])[F:20].[CH3:23][O:24][C:25]1[N:30]=[CH:29][C:28]([CH2:31][C:32]2[C:33](=[O:39])[NH:34][C:35](=[S:38])[NH:36][CH:37]=2)=[CH:27][N:26]=1.CCN(C(C)C)C(C)C>ClCCCl>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:12]([CH2:15][S:38][C:35]3[NH:36][CH:37]=[C:32]([CH2:31][C:28]4[CH:29]=[N:30][C:25]([O:24][CH3:23])=[N:26][CH:27]=4)[C:33](=[O:39])[N:34]=3)=[CH:11][C:8]=2[C:9]#[N:10])=[CH:4][C:3]=1[C:19]([F:22])([F:21])[F:20]
Reactant: COc1ncc(Cc2c[nH]c(=S)[nH]c2=O)cn1
Reactant: N#Cc1cc(CCl)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ncc(Cc2c[nH]c(SCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)c(C#N)c3)nc2=O)cn1
Yield: 21.6 %

Procedure:
The same procedure as E63 from 2-(4-chloro-3-(trifluoromethyl)phenoxy)-5-(chloromethyl)benzonitrile (200 mg, 0.578 mmol), 5-{[2-(methyloxy)-5-pyrimidinyl]methyl}-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone (174 mg, 0.693 mmol) and DIPEA (0.303 mL, 1.733 mmol) in DCE (3.0 mL), except that the reaction time was prolonged to 1.5 h, to afford the title compound (70 mg, 21.64% yield). LCMS: rt=3.44 min, [M+H+]=560
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:51])[C@@H:15]([NH:21][C:22]([C:24]2[CH:28]=[C:27]([O:29][CH2:30][C:31]([N:33]3[CH2:37][CH2:36][CH2:35][C@H:34]3[C:38](=[O:44])[NH:39][CH:40]3[CH2:43][CH2:42][CH2:41]3)=[O:32])[N:26]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[N:25]=2)=[O:23])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].[CH2:52](Cl)CCl.CO>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:51])[C@@H:15]([NH:21][C:22]([C:24]2[CH:28]=[C:27]([O:29][CH2:30][C:31]([N:33]3[CH2:37][CH2:36][CH2:35][C@H:34]3[C:38](=[O:44])[NH:39][CH:40]3[CH2:43][CH2:42][CH2:41]3)=[O:32])[N:26]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[N:25]=2)=[O:23])[CH2:16][CH2:17][C:18]([O:20][CH3:52])=[O:19])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: ClCCCl
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: CN(C)C=O
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1

Procedure:
To a solution of 120 mg 4-[(S)-4-Carboxy-2-({5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid butyl ester in 3 ml DMF were added 39 mg EDC, 25 mg DMAP and 34 μl methanol. After 3 h the reaction mixture was concentrated and the residue purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were lyophilized to yield the pure product. Yield: 47 mg MS (ES+): m/e=724.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([C:18]([OH:20])=O)[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.[NH2:31][C:32]1[C:33](=[O:44])[N:34]([CH3:43])[C:35]2[C:40]([C:41]=1[NH2:42])=[CH:39][CH:38]=[CH:37][N:36]=2.CCN=C=NCCCN(C)C>CN(C=O)C.O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([C:18](=[O:20])[NH:31][C:32]2[C:33](=[O:44])[N:34]([CH3:43])[C:35]3[C:40]([C:41]=2[NH2:42])=[CH:39][CH:38]=[CH:37][N:36]=3)[CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c(=O)c(N)c(N)c2cccnc21
Reactant: O=C(NC1CCCC(C(=O)O)C1)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)c(NC(=O)C2CCCC(NC(=O)OCc3ccccc3)C2)c(N)c2cccnc21
Temperature: 0 °C
Yield: 12.2 %

Procedure:
3-Benzyloxycarbonylamino-cyclohexanecarboxylic acid (0.277 g, 1.0 mmol), TEA (0.10 g, 1.0 mmol), and HOBt (0.135 g, 1.0 mmol) were added sequentially to a stirred solution of 3,4-diamino-1-methyl-1H-[1,8]naphthyridin-2-one (0.19 g, 1.0 mmol) in DMF (8 mL) at room temperature. The solution was cooled to 0° C. and EDCI (0.19 g, 1.0 mmol) was added. The resulting solution was allowed to stir, with warming to room temperature, for 17 h. The mixture was diluted with water (5 mL) and extracted with CH2Cl2, dried with MgSO4, and concentrated. The residue was purified by flash chromatography eluting with 5% MeOH in CH2Cl2 to give [3-(4-amino-1-methyl-2-oxo-1,2-dihydro-[1,8]naphthyridin-3-ylcarbamoyl)-cyclohexyl]carbamic acid benzyl ester (55 mg, 12% yield), and 60 mg (32%) of unreacted diamine. 1H-NMR (CDCl3): δ 8.59 (m, 1H), 8.21 (m, 1H), 7.91 (m, 1H), 7.33 (m, 6H), 7.20 (dd, 1H, J=8.0, 4.8), 5.51 (m, 2H), 5.12 (m, 2H), 4.76 (m, 1H), 4.10 (m, 1H), 3.81 (s, 3H), 2.60 (m, 1H), 2.33 (m, 1H), 1.93–2.05 (m, 3H), 1.73 (m, 2H), 1.45 (m, 2H). MS: calculated for C24H27N5O4+H 450.2; found: 450.5.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].S(Cl)(Cl)=O.C([O-])(O)=O.[Na+].[CH2:23](O)[CH3:24]>>[CH2:23]([O:12][C:11](=[O:13])[CH2:10][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Br:1])[CH:3]=1)[CH3:24]
Reactant: COc1ccc(CC(=O)O)cc1Br
Reactant: CCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: CCOC(=O)Cc1ccc(OC)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 3-bromo-4-methoxyphenylacetic acid (24 g, 97.9 mmol) in ethanol (240 mL) was added thionyl chloride (7.8 mL, 107.7 mmol), and the reaction was stirred at room temperature for 1 hour. Once no starting material was seen by analytical LCMS, the mixture was basified with saturated aqueous NaHCO3 and extracted with dichloromethane. The combined organic layers were dried over MgSO4, filtered, and concentrated to give the desired product.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]I)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:14].[O:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[C:24]1[CH:34]=[CH:33][C:27]([CH2:28][O:29][CH2:30][CH2:31][NH2:32])=[CH:26][CH:25]=1.[H-].[Na+].Cl.CCO>C1COCC1>[ClH:14].[O:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[C:24]1[CH:34]=[CH:33][C:27]([CH2:28][O:29][CH2:30][CH2:31][NH:32][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:26][CH:25]=1
Reactant: NCCOCc1ccc(-c2nc3ccccc3o2)cc1
Reactant: ICCCCCCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: c1ccc(CCCCCCNCCOCc2ccc(-c3nc4ccccc4o3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-phenyl-1-hexyl iodide (0.63 g; 2.2 mmol) in THF (12 ml) is added 2-[4-(benzoxazol-2-yl)benzyloxy]ethylamine hydrochloride (0.6 g; 2 mmol) followed by NaH (60% suspension; 0.11 g). The reaction mixture is stirred for 1 hour at room temperature and then heated for 11/2 hours at reflux. The mixture is next cooled, acidified with HCl/EtOH, concentrated and purified by column chromatography using 10% MeOH/CH2Cl2 as eluant. The resultant product is treated with HCl/EtOH and recrystallized from EtOH to give pure N-[2-(4-(benzoxazol-2-yl)benzyloxy)ethyl]-6-phenyl-1-hexanamine hydrochloride. (m.p. 163°-165° C.).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:11]([NH:13][CH2:14][C:15]([CH2:21][NH:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][N:27]2[C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)([OH:20])[C:16]([F:19])([F:18])[F:17])[CH3:12]>>[CH2:11]([N:13]([CH2:14][C:15]([CH2:21][NH:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][N:27]2[C:32]1[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=1)([OH:20])[C:16]([F:18])([F:19])[F:17])[C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[CH3:1])[CH3:12]
Reactant: CCNCC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F
Reactant: Cc1ccccc1C(=O)O
Product: CCN(CC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F)C(=O)c1ccccc1C

Procedure:
Prepared similarly to Example 1 from 2-methylbenzoic acid and 3-(ethylamino)-1,1,1-trifluoro-2-({[1-(4-fluorophenyl)-1H-indazol-4-yl]amino}methyl)-2-propanol.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([NH:15][CH2:16]C(O)=O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([O-:23])(=[O:22])[CH3:21].[Na+]>C(O)(=O)C.[Pt]>[C:20]([O:23][CH2:16][NH:15][C:13](=[O:14])[CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])(=[O:22])[CH3:21]
Reactant: O=C(O)CNC(=O)CNC(=O)OCc1ccccc1
Reactant: CC(=O)[O-]
Agent: [Pt]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)OCNC(=O)CNC(=O)OCc1ccccc1
Yield: 60 %

Procedure:
Benzyloxycarbonylglycylglycine (3.99 g, 15 mmole) was suspended in a solution of anhydrous sodium acetate (0.9 g, 11 mmole) in glacial acetic acid (75 ml). The mixture was stirred and ice-cooled while being electrolysed (two 5 sq.cm. platinum foil electrodes placed 2 mm apart) using a current of 200-250 mA for 5 hours. The acetic acid was evaporated under reduced pressure and the residue was dissolved in ethyl acetate (150 ml). The solution was washed with saturated sodium bicarbonate solution (5) ml portions, until the wash remained alkaline) and then with water (50 ml). The solution was dried (magnesium sulphate) and the solvent was evaporated under reduced pressure to yield the title compound as colourless crystals (1.85 g, 6.6 mmole).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH:9]1[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[S:29](Cl)(=[O:31])=[O:30]>>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([S:29]([C:20]2[CH:21]=[CH:22][C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:19]=2)(=[O:31])=[O:30])[CH2:10][CH:9]1[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: CCOC(=O)C1CNCCN1Cc1ccccc1
Product: CCOC(=O)C1CN(S(=O)(=O)c2ccc3ccccc3c2)CCN1Cc1ccccc1
Yield: 93 %

Procedure:
Using an analogous procedure to that described in Example 2, ethyl 1-benzylpiperazine-2-carboxylate was reacted with 2-naphthylsulphonyl chloride to give ethyl 1-benzyl-4-(2-naphthylsulphonyl)piperazine-2-carboxylate in 93% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[O:12])[NH:8]2)=[CH:4][C:3]=1[O:19][CH:20]1[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([S:30]([CH3:29])(=[O:32])=[O:31])[CH2:15][CH2:14]3)=[O:12])[NH:8]2)=[CH:4][C:3]=1[O:19][CH:20]1[CH2:21][CH2:22][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:24][CH2:25]1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCNCC4)[nH]c3cc2Cl)CC1
Product: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCN(S(C)(=O)=O)CC4)[nH]c3cc2Cl)CC1
Yield: 72 %

Procedure:
The title compound was synthesized in analogy to example 37, from [6-chloro-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-piperazin-1-yl-methanone (example 36), and methanesulfonyl chloride, to afford the title compound as an off-white solid (72%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([OH:13])=O)=[CH:5][CH:4]=1)#[N:2].[CH3:14][C:15]([CH3:19])([CH3:18])[CH2:16][NH2:17].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:14][C:15]([CH3:19])([CH3:18])[CH2:16][NH:17][C:11]([CH2:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=1)=[O:13]
Reactant: N#Cc1ccc(CCC(=O)O)cc1
Reactant: CC(C)(C)CN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)CNC(=O)CCc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.8 %

Procedure:
Combine 3-(4-cyanophenyl)-propionic acid (870 mg, 4.9 mmol), 2,2-dimethylpropylamine (0.6 mL, 5.4 mmol), EDCI (1.0 g, 5.4 mmol), HOBT (804 mg, 5.9 mmol), triethylamine (2 mL, 14.8 mmol) and DMAP (60.5 mg, 0.5 mmol) in anhydrous DCM (50 mL). Stir at room temperature for 1 day under nitrogen. Concentrate the mixture in vacuo and purify by chromatography on silica gel eluting with hexane/EtOAc (1:1) to obtain the desired intermediate as a white solid (740 mg, 61%). MS (ES+) m/z: 245 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:13]([CH2:26][CH3:27])[C@H:14]2[CH2:19][CH2:18][C@H:17]([N:20]([CH2:22][CH2:23][O:24][CH3:25])[CH3:21])[CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH2:28]([N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)[C:29]#[CH:30].C(N(CC)CC)C>CN(C=O)C.[Cu]I.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>[CH2:26]([N:13]([C@H:14]1[CH2:19][CH2:18][C@H:17]([N:20]([CH2:22][CH2:23][O:24][CH3:25])[CH3:21])[CH2:16][CH2:15]1)[C:4]1[C:5]([CH3:12])=[C:6]([CH:11]=[C:2]([C:30]#[C:29][CH2:28][N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[CH:3]=1)[C:7]([O:9][CH3:10])=[O:8])[CH3:27]
Reactant: C#CCN1CCOCC1
Reactant: CCN(c1cc(Br)cc(C(=O)OC)c1C)[C@H]1CC[C@H](N(C)CCOC)CC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(c1cc(C#CCN2CCOCC2)cc(C(=O)OC)c1C)[C@H]1CC[C@H](N(C)CCOC)CC1
Temperature: 105 °C

Procedure:
To a solution of methyl 5-bromo-3-(ethyl((trans)-4-((2-methoxyethyl)(methyl)amino)cyclohexyl)amino)-2-methylbenzoate (30 g, 68.02 mmol), 4-(prop-2-yn-1-yl) morpholine (25.51 g, 204 mmol) and triethylamine (20.61 g, 204 mmol) in DMF (300 mL) was bubbled Argon for 20 min. Then CuI (3.87 g, 20.36 mmol) and Pd (PPh3)4 (7.85 g, 6.79 mmol) were added and Argon was bubbled through for further 20 min. The reaction mixture was heated at 105° C. for 4 h and then cooled to room temperature. The reaction was quenched with water (100 mL) and the aqueous phase was extracted with 10% MeOH/DCM (400 mL×3). The combined organic extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography to afford the title compound (21 g, 63.7% yield).
Reaction SMILES: [C:1](=[N:4][O:5][CH:6]([CH3:12])[C:7]([O:9]CC)=[O:8])([CH3:3])[CH3:2].[OH-].[Na+].Cl>>[C:1](=[N:4][O:5][CH:6]([CH3:12])[C:7]([OH:9])=[O:8])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(C)ON=C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)=NOC(C)C(=O)O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
The ethyl α-(isopropylideneaminooxy)propionate was added to 5% NaOH solution (1.2 L) at 70° C. After 20 min, the solution was cooled to rt and acidified to pH 2.0 with 5N HCl solution. Then to the solution was added (NH4)2SO4 (500 g) and the mixture was extracted with 1:1 benzene:Et2O (2×300 mL). The combined organic extracts were dried over Na2SO4 and concentrated to approximately 200 mL. Petroleum ether (500 mL) was added and the solution was cooled to −20° C. overnight. The recrystallized product was recovered by filtration. 80 g of product 2 was recovered as a white solid (37%). 1H NMR (CDCl3): δ 4.64 (q, 1H, J=6.9 Hz, CH), 1.93 (s, 3 H, CH3), 1.90 (s, 3 H, CH3), 1.50 (d, 3H, J=6.9 Hz, CH3); M.p. 59-61° C.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][CH:17]([NH:20]C(OCC4C=CC=CC=4)=O)[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[N:2]1.[H][H]>CO.C1COCC1.[C].[Pd]>[N:1]1([CH2:6][CH2:7][C:8]2[CH:9]=[CH:10][C:11]([N:14]3[CH2:15][CH2:16][CH:17]([NH2:20])[CH2:18][CH2:19]3)=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: [H][H]
Reactant: O=C(NC1CCN(c2ccc(CCn3ccnn3)cc2)CC1)OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: NC1CCN(c2ccc(CCn3ccnn3)cc2)CC1

Procedure:
The N-(4-(2-(1,2,3-triazol-1-yl)-ethyl)-phenyl)-4-benzyloxycarbonylaminopiperidine (1.3 g, 50 mmol) obtained in Example 7 (6) was dissolved in methanol (13 ml) and THF (13 ml), and 10% palladium-carbon (hereinafter referred to as Pd—C) (130 mg) was added, followed by stirring at room temperature in an atmosphere of hydrogen gas for 24 hours. After the insoluble material was filtered with Celite, the solvent was evaporated from the filtrate under reduced pressure, thereby obtaining N-(4-(2-(1,2,3-triazol-1-yl)-ethyl)-phenyl)-4-aminopiperidine (870 mg, 99%) as a white solid.