Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=C1)([N:3]1[CH:7]=[CH:6]N=[CH:4]1)=[O:2].[CH2:13](N)/[CH:14]=C/C.C(O)(=O)C(O)=O.[F:24][C:25]([F:38])([F:37])[C:26]1[CH:36]=[CH:35][C:29]([O:30]C2CNC2)=[CH:28][CH:27]=1>C(N(CC)CC)C>[CH2:12]([NH:8][C:1]([N:3]1[CH2:4][CH:6]([O:30][C:29]2[CH:35]=[CH:36][C:26]([C:25]([F:24])([F:37])[F:38])=[CH:27][CH:28]=2)[CH2:7]1)=[O:2])/[CH:11]=[CH:13]/[CH3:14]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: FC(F)(F)c1ccc(OC2CNC2)cc1
Reactant: C/C=C/CN
Agent: O=C(O)C(=O)O
Solvent: CCN(CC)CC
Product: C/C=C/CNC(=O)N1CC(Oc2ccc(C(F)(F)F)cc2)C1
Reaction time: 1 h
Yield: 85.1 %

Procedure:
A mixture of 3.6 g (0.022 mole) of 1,1'-carbonyldiimidazole and 1.6 g (0.022 mole) of trans-crotylamine was stirred for 1 hr, then treated with 6.2 g (0.02 mole) of 3-[4-(trifluoromethyl)phenoxy]azetidine oxalate and followed in 0.5 hr with 5 ml of triethylamine with stirring continued for 16 hr. The partially crystalline mixture was washed with 2×50 ml of water, dried over magnesium sulfate and concentrated on a rotary evaporator to a solid residue, 14.2 g. Recrystallization from methanol-water yielded 5.35 g (85.1%) of fine white crystals, m.p. 157°-158° C.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:11][CH2:10][CH:9]2[O:12][CH:8]2[CH2:7][CH2:6]1)(=[O:4])=[O:3].[CH3:13][C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=1[OH:21].[OH-].[Na+]>C(#N)C>[OH:12][C@H:8]1[C@H:9]([O:21][C:15]2[CH:16]=[CH:17][CH:18]=[C:19]([CH3:20])[C:14]=2[CH3:13])[CH2:10][CH2:11][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH2:7]1
Reactant: CS(=O)(=O)N1CCC2OC2CC1
Reactant: Cc1cccc(O)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: Cc1cccc(O[C@@H]2CCN(S(C)(=O)=O)CC[C@H]2O)c1C
Temperature: 25 °C

Procedure:
7.0 g (0.036 mol) of 1-methanesulphonyl-hexahydro-4,5-epoxy-1H-azepine are dissolved, together with 8.9 g (0.073 mol) of 2,3-dimethyl-phenol, with 36.6 ml of 2 N sodium hydroxide solution (0.013 mol) in 200 ml of acetonitrile. The reaction mixture is heated under reflux for 5 days, then cooled to room temperature and concentrated under a water pump vacuum. The residue is then dissolved in 200 ml of methylene chloride and the organic phase is washed with three times 100 ml of 2 N sodium hydroxide solution and then with water, dried over sodium sulphate and evaporated under a water pump vacuum. The resulting crude product is purified by preparative thick layer chromatography (100×20 cm silica gel plates, layer thickness 1.5 mm). Crystalline trans-4-hydroxy-5-(2,3-dimethylphenoxy)-1-methanesulphonyl-hexahydro-1H-azepine with a melting point of 112°-115° is obtained by elution with a 3:1 mixture of toluene/ethyl acetate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@@H:9]1[C:21](O)=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].B.C1COCC1.CO>C1COCC1>[OH:22][CH2:21][C@H:9]1[CH2:10][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH2:12][CH2:13][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](C(=O)O)C1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](CO)C1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 99.4 %

Procedure:
A 250-mL round bottom flask was charged with (2R)-1,4-bis(tert-butoxycarbonyl)-2-piperazinecarboxylic acid (10.5 g, 31.8 mmol, ASW Medchem, New Brunswick, N.J.) under nitrogen. THF (20 mL) was added and the mixture was cooled in an ice bath. A solution of BH3.THF (1M in THF, 65 mL, 65.0 mmol, Sigma-Aldrich) was added over 10 min. The ice bath was removed and after 15 min, the flask was equipped with a reflux condenser and was the reaction was heated at 60° C. After 1.5 h, the mixture was cooled in an ice bath and was then quenched with MeOH (10 mL, 247 mmol) over 20 min. The mixture was concentrated, treated with MeOH (20 mL), and concentrated a second time to give di-tert-butyl (2R)-2-(hydroxymethyl)-1,4-piperazinedicarboxylate as a white solid (10 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH:10]([C:12]([OH:14])=O)[CH3:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.[CH3:16][O:17][C:18](=[O:24])[C@H:19]([CH2:21][CH2:22][CH3:23])[NH2:20]>>[CH3:16][O:17][C:18](=[O:24])[C@@H:19]([NH:20][C:12](=[O:14])[C@H:10]([CH3:11])[NH:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCC[C@H](N)C(=O)OC
Reactant: CC(Nc1cc(Cl)cc(Cl)c1)C(=O)O
Agent: Cl
Product: CCC[C@H](NC(=O)[C@H](C)Nc1cc(Cl)cc(Cl)c1)C(=O)OC

Procedure:
Following General Procedure D and using N-(3,5-dichlorophenyl)-D,L-alanine (from Example B above) and L-norvaline methyl ester hydrochloride (Sennchem), the title compound was prepared. The reaction product was purified by silica gel chromatography using 50% ethyl acetate/hexane.
Reaction SMILES: N[C:2]1[CH:7]=[C:6](OC)[CH:5]=[CH:4][C:3]=1[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([O:20][CH3:21])[C:14]([O:22][CH3:23])=[CH:13]2.Cl.[N:25]([O-:27])=[O:26].[Na+].O>C(O)(=O)C>[N+:25]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([O:20][CH3:21])[C:14]([O:22][CH3:23])=[CH:13]2)([O-:27])=[O:26]
Reactant: O=N[O-]
Reactant: COc1ccc(-c2ccc3cc(OC)c(OC)cc3c2)c(N)c1
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc2ccc(-c3ccccc3[N+](=O)[O-])cc2cc1OC
Reaction time: 8 h
Yield: 41.4 %

Procedure:
6-(2-Amino-4-methoxyphenyl)-2,3-dimethoxynaphthalene (32) (12 mg, 0.039 mmol) was dissolved in acetic acid (0.6 mL) and concentrated hydrochloric acid (0.06 mL). The solution was cooled in an ice bath and diazotized by the dropwise addition of a solution of sodium nitrite (0.026 g in 0.5 mL water). The resulting diazonium solution was allowed to rise to room temperature slowly and left overnight. To the resulting red solution which contained some precipitate was added 30 mL water and the mixture was extracted with ethyl acetate (30 mL×3). The organic layers were combined and washed with diluted sodium hydroxide solution first, then with water and brine. The ethyl acetate extracts were dried with anhydrous sodium sulfate and evaporated in vacuo. The crude product was purified by column chromatography on silica gel using 40:60 hexanes:ethyl acetate to give the pure 4 (5 mg) in 40% yield; mp 244-246° C.; IR (KBr) 2919, 1619, 1507, 1388, 1292, 1277, 1204 cm−1; UV (MeOH) 292, 266, 216 nm; 1H NMR (CDCl3) δ4.10 (6H, s), 4.22 (3H, s), 7.32 (1H, s), 7.54 (1H, dd, J1=9.1, J2=2.6), 8.04-8.08 (2H, m), 8.28 (1H, d, J=8.9), 8.49 (1H, d, J=9.1), 9.16 (1H, s); 13C NMR δ56.33, 56.52, 56.92, 104.36, 107.93, 108.92, 116.88, 117.08, 119.48, 123.51, 124.54, 127.14, 128.42, 132.46, 141.77, 148.52, 151.12, 151.40, 160.45; HRMS (EI) calcd for C19H16N2O3 m/z: 320.1161; found: 320.0384.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][CH:12]([C:14]1[O:19][C:18](=[O:20])[C:17]([C:21](=[O:24])[CH2:22][CH3:23])=[C:16](O)[CH:15]=1)[CH3:13])(C(C)(C)C)(C)C.C([O-])(O)=[O:27].[Na+]>CC(O)=O.C1COCC1.O>[OH:27][C:15]1[CH:16]=[C:17]([C:21](=[O:24])[CH2:22][CH3:23])[C:18](=[O:20])[O:19][C:14]=1[CH:12]([CH3:13])[CH2:11][CH2:10][CH2:9][OH:8]
Reactant: O=C([O-])O
Reactant: CCC(=O)c1c(O)cc(C(C)CCCO[Si](C)(C)C(C)(C)C)oc1=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CCC(=O)c1cc(O)c(C(C)CCCO)oc1=O

Procedure:
6-(5-(t-Butyldimethylsilyloxy)pentan-2-yl)-4-hydroxy-3-propionyl-2-H-pyran-2-one (IV; 3 g; 8.15 mmol) in 100 ml AcOH/THF/water (3/1/1, v/v/v) was stirred for 18 h at 25° C. The reaction mixture was neutralized with saturated NaHCO3, extracted with 3×50 ml EtOAc, dried with anhydrous Na2SO4, and evaporated to an oil. The product was purified via silica chromatography (40% EtOAc in hexanes).
Reaction SMILES: ClC(Cl)C.[Br:5][C:6]1[CH:15]=[N:14][C:13]2[NH:12][C:11](=O)[C:10]([CH3:18])([CH3:17])[O:9][C:8]=2[CH:7]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:25][NH2:26]>C(Cl)Cl>[Br:5][C:6]1[CH:15]=[N:14][C:13]2[NH:12]/[C:11](=[N:26]/[CH3:25])/[C:10]([CH3:18])([CH3:17])[O:9][C:8]=2[CH:7]=1
Reactant: CC1(C)Oc2cc(Br)cnc2NC1=O
Reactant: CN
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: C/N=C1/Nc2ncc(Br)cc2OC1(C)C
Temperature: -78 °C
Yield: 89 %

Procedure:
A dichloroethane (5 mL) solution of 7-bromo-2,2-dimethyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (520 mg, 2 mmol) and phosphorus pentachloride (840 mg, 4 mmol) was irradiated in a microwave oven for 10 min at 160° C. The solution was cooled to −78° C. and methylamine (2M in THF) was added it slowly until it became permanently basic. The mixture was diluted with CH2Cl2, washed with dilute solution of NaOH, dried and evaporated. Crystallization from CH2Cl2/hexane afforded 480 mg (89%) of the title compound. 1H NMR (300 MHz, CDCl3, 8) 8.07 (d, J=2.1 Hz, 1H), 7.21 (d, J=2.1 Hz, 1H), 4.9 (s, br, 1H), 3.06 (d, J=4.5 Hz, 3H), 1.46 (s, 6H). MS (ESI) m/e 270 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](N3C=CN=C3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:27]1([OH:33])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:33][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2c(Cl)cccc2-n2cnc(C(=O)n3ccnc3)c2[C@@H]2CCCN12
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Oc1ccccc1)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Temperature: 25 °C
Reaction time: 26 h

Procedure:
A mixture of 1.84 g (5 mmol) of (S)-1-[(8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-1-yl)carbonyl]imidazole, 0.56 g (6 mmol) of phenol, 0.83 g (6 mmol) of powdered potassium carbonate and 20 ml of dry dimethylformamide is stirred at room temperature for 26 hours, then poured into 100 ml of water and extracted three times with chloroform. The chloroform solution is washed twice with water and three times with saturated sodium chloride solution, dried over magnesium sulphate and evaporated. The crude product is purified by chromatography on silica gel while eluting with ethyl acetate and recrystallization from ethyl acetate. There is obtained phenyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 211°-212°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12](Cl)[CH:11]=[CH:10][C:9]=2OCC)[N:5]=[C:4]([NH2:18])[N:3]=1.[Br:19]C1C=C(B(O)O)C=CC=1.NC1N=C(Cl)C=C(Cl)N=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([Br:19])[CH:13]=2)[N:5]=[C:4]([NH2:18])[N:3]=1
Reactant: CCOc1ccc(Cl)cc1-c1cc(Cl)nc(N)n1
Reactant: OB(O)c1cccc(Br)c1
Agent: Nc1nc(Cl)cc(Cl)n1
Product: Nc1nc(Cl)cc(-c2cccc(Br)c2)n1

Procedure:
4-Chloro-6-(3-bromo-phenyl)-pyrimidin-2-ylamine was prepared according to the method described for 4-chloro-6-(5-chloro-2-ethoxy-phenyl)-pyrimidin-2-ylamine (Example 53) using 3-bromophenyl boronic acid and 2-amino-4,6-dichloropyrimidine.
Reaction SMILES: [NH2:1][C:2]([C:4]12[N:10]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[CH:7]([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)=O.CCN(CC)CC.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[C:2]([C:4]12[N:10]([C:11]([O:13][CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[O:12])[CH:7]([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)#[N:1]
Reactant: NC(=O)C12CCC(CC1)N2C(=O)OCc1ccccc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#CC12CCC(CC1)N2C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Benzyl 1-(aminocarbonyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate (C-36) in dichloromethane was treated at 0° C. with Et3N (2.1 eq.) and trifluoroacetic anhydride (1.1 eq.) was added dropwise. The reaction mixture was stirred at 0° C. for 30 minutes. Then, it was diluted with dichloromethane, washed with saturated NaHCO3 solution, H2O, brine and dried over Na2SO4. Filtration and evaporation afforded the titled compound (C-37).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.[Cl:8][C:9]1[CH:34]=[CH:33][C:12]([CH2:13][O:14][C@@H:15]2[O:20][C@@H:19]([CH2:21]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1>CN(C)C=O>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][O:14][C@@H:15]2[O:20][C@@H:19]([CH2:21][N:3]3[CH:7]=[CH:6][N:5]=[CH:4]3)[CH2:18][CH2:17][CH2:16]2)=[CH:33][CH:34]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCC[C@H](OCc3ccc(Cl)cc3)O2)cc1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(CO[C@H]2CCC[C@H](Cn3ccnc3)O2)cc1
Temperature: 25 °C
Yield: 89.7 %

Procedure:
A mixture of 0.28 g (12 mmoles) of 50% sodium hydride (i.e. 50% w/w sodium hydride in mineral oil) and 0.817 g (12 mmoles) of imidazole was stirred in 25 ml of dimethylformamide at 80° C. for 30 minutes. The mixture was then left to cool at room temperature, after which there was added a solution of 3.30 g of trans-6-(4-chlorobenzyloxy)-2-tosyloxymethyltetrahydropyran in 5 ml of dimethylformamide, at room temperature, and then the mixture was heated at 80°-85° C. for 2 hours. After cooling the mixture, it was poured into ice-water and then extracted with diethyl ether. The ethereal extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulphate, after which the solvent was evaporated off. The residue was purified by column chromatography through 50 g of silica gel eluted with a 30:1:1 by volume mixture of ethyl acetate, ethanol and triethylamine, to give 2.21 g of the title compound as a colourless oil.
Reaction SMILES: C([O:3][C:4](=[O:29])[C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3([O:22][CH2:23][CH3:24])[CH2:21][CH2:20]3)=[C:15]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:14]=2)=[CH:7][CH:6]=1)C.[OH-].[Na+]>C(O)C.O1CCCC1>[CH2:23]([O:22][C:19]1([C:16]2[CH:17]=[CH:18][C:13]([CH2:12][CH2:11][C:8]3[CH:7]=[CH:6][C:5]([C:4]([OH:29])=[O:3])=[CH:10][CH:9]=3)=[CH:14][C:15]=2[C:25]([CH3:26])([CH3:28])[CH3:27])[CH2:21][CH2:20]1)[CH3:24]
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(C3(OCC)CC3)c(C(C)(C)C)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC1(c2ccc(CCc3ccc(C(=O)O)cc3)cc2C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.6 %

Procedure:
Using General Procedure I; a solution of ethyl4-[4-(1-ethoxycyclopropyl)-3-tert-butyl-phenylethynyl]-benzoate (Compound 103, 70.0 mg, 0.18 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (240.0 mg, 6.0 mmols, 3.0 mL of a 2N aqueous solution) and stirred overnight at room temperature. Work-up afforded 40 mg (62%) the title compound as a pale-yellow solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[CH:34]1([NH2:37])[CH2:36][CH2:35]1>C1COCC1.CCOC(C)=O>[CH:34]1([NH:37][S:20]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C:10]3[N:9]=[C:8]([C:6]4[CH:5]=[C:4]([C:24]5[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:28][CH:29]=5)[CH:3]=[C:2]([CH3:1])[N:7]=4)[CH:13]=[CH:12][CH:11]=3)[CH:15]=2)(=[O:21])=[O:22])[CH2:36][CH2:35]1
Reactant: NC1CC1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)NC4CC4)c3)n2)n1
Yield: 43.2 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example I.2) (0.200 g, 0.409 mmol) by treatment with commercially available cyclopropylamine (0.14 ml, 2.05 mmol) in THF (5 mL) at 23° C. for 16 h. Diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with EtOAc followed by trituration with diethyl ether/heptane to give the title compound (0.090 g, 43%) as a white solid. MS (ISP) 510.2 [(M+H)+]; mp 150° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH2:11]([N:13]([CH2:16]C)[CH2:14]C)[CH3:12].C1C[O:21]CC1>C(O)C>[C:8]([C:4]1[CH:3]=[C:2]([NH:1][C:12](=[O:21])[CH2:11][N:13]([CH3:16])[CH3:14])[CH:7]=[CH:6][CH:5]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1cccc(N)c1
Reactant: C1CCOC1
Reactant: CCN(CC)CC
Solvent: CCO
Product: CC(=O)c1cccc(NC(=O)CN(C)C)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
A solution of 3′-amino-acetophenone (25 mmol) in THF (100 mL) was added chloroacyl chloride (30 mmol). The mixture was stirred for 30 min, poured into ice cold 2M NaOH (aq) and extracted with Et2O. The organic phase was dried and the solvent was removed under reduced pressure giving the pure product. A solution of the product (10 mmol) and triethyl amine (30 mmol) in ethanol was added amine (20 mmol) and the mixture was refluxed for 4 hours. Ethanol was removed under reduced pressure and the product was dissolved in EtOAc and washed with 2M NaOH (aq). EtOAc was removed under reduced pressure giving the product as pure brown oil in 85% yield. 1H-NMR (CDCl3) 5 9.31 (s, 1H), 8.05 (m, 2H), 7.72 (dt,1H), 7.46 (t, 1H), 3.11 (s, 2H), 2.62 (s, 3H), 2.41 (s,.6H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)OCC1.[CH2:11]([O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH:17]=O)[CH3:12].C([BH3-])#N.[Na+].Cl>C(O)C.O.C(O)(=O)C>[CH2:11]([O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:17][N:8]1[CH2:7][CH2:6][C:5](=[O:1])[CH2:10][CH2:9]1)[CH3:12]
Reactant: C1CC2(CCN1)OCCO2
Reactant: CCOc1cc(C=O)ccc1OC
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CCOc1cc(CN2CCC(=O)CC2)ccc1OC
Temperature: 50 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
A mixture of 1,4-dioxa-8-aza-spiro[4.5]decane (9.33 g, 65.16 mmol, 1.0 equiv; commercially available) and 3-ethoxy-4-methoxy-benzaldehyde (14.09 g, 78.19 mmol, 1.2 equiv; commercially available) in ethanol (50 mL) and acetic acid (5 mL) was heated to 50° C. for 1 h. Sodium cyanoborohydride (4.91 g, 78.19 mmol, 1.2 equiv), dissolved in ethanol (20 mL), was added and the reaction mixture heated to 50° C. After 2 h, a solution of 37% HCl in water (100 mL) was added and the reaction mixture heated to 100° C. for 3 h. The solvent was removed under reduced pressure and the crude reaction product extracted from a solution of 1 M NaOH (100 mL) with ethyl acetate (3×100 mL). The combined organic phases were dried over Mg504, concentrated by evaporation under reduced pressure and the crude material purified with column chromatography on silica eluting with a gradient of heptane/ethyl acetate (1:3)→ethyl acetate to provide 11.23 g (59%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.46 (t, J=6.9 Hz, 3H), 2.41-2.44 (m, 4H), 2.69-2.73 (m, 4H), 3.53 (s, 2H), 3.87 (s, 3H), 4.11 (q, J=6.9 Hz, 2H), 6.80-6.86 (m, 2H), 6.94 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 14.49, 41.16, 52.71, 55.90, 61.00, 64.50, 111.43, 113.71, 121.04, 130.77, 148.17, 148.68, 208.71. MS (ISP): 263.9 [M+H]+.
Reaction SMILES: [CH2:1]([N:3](CC)CC)[CH3:2].[Cl:8][C:9]1[C:18]([C:19](Cl)=[O:20])=[C:17]([S:22]([CH3:25])(=[O:24])=[O:23])[CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:8][C:9]1[C:18]([C:19]2[O:20][CH2:2][CH2:1][N:3]=2)=[C:17]([S:22]([CH3:25])(=[O:24])=[O:23])[CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: CCN(CC)CC
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C(=O)Cl)c1Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(S(C)(=O)=O)c(C2=NCCO2)c1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 45.6 %

Procedure:
At room temperature, 41.8 g (0.41 mol) of triethylamine and then 31.1 g (0.10 mol) of methyl 2-chloro-3-chlorocarbonyl-4-methylsulfonylbenzoate in 150 ml of toluene were added dropwise to 26.6 g (0.13 mol) of I-amino-2-bromoethane hydrobromide in 500 ml of toluene. The mixture was heated under reflux for 5 hours and then stirred at room temperature for 12 hours, another 5.0 g (0.02 mol) of I-amino-2-bromoethane hydrobromide were added and the mixture was heated under reflux for 7.5 hours. The reaction mixture was allowed to cool, diluted with ethyl acetate, washed with water, dried and concentrated. The residue was then recrystallized from methyl tert-butyl ether/ethyl acetate. 14.5 g (46% of theory) of methyl 2-chloro-4-methylsulfonyl-3-(4,5-dihydrooxazol-2-yl)benzoate were obtained.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([OH:13])[CH:10]([N:14]2[CH2:19][CH2:18][N:17]([C:20](=[O:28])[C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[CH2:16][CH2:15]2)[CH2:9]1)=O)(C)(C)C.O1CCOCC1>C(Cl)Cl.CCOCC>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C:20]([N:17]2[CH2:18][CH2:19][N:14]([CH:10]3[CH:11]([OH:13])[CH2:12][NH:8][CH2:9]3)[CH2:15][CH2:16]2)=[O:28])=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CC(O)C(N2CCN(C(=O)c3ccc(Cl)cc3)CC2)C1
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=C(c1ccc(Cl)cc1)N1CCN(C2CNCC2O)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
3-[4-(4-Chloro-benzoyl)-piperazin-1-yl]4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (26 g) was dissolved in CH2Cl2 (150 mL). 4M HCL/Dioxane (150 mL) was added. The mixture was stirred at RT for 4 h. White precipitate was formed. The mixture was diluted with ether, filtered. The white solid was washed with ether and dried to give the desired product (99% yield). 1H-NMR (300 MHz, DMSO, HCl salt): δ 3.04.0 (m, 12 H), 4.85 (m, 2 H), 7.25 (d, 2 H), 7.54 (d, 2 H). Retention Time (LC, method: Formic acid polar): 1.01 min. MS (M+H+): 310