Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.Cl.[Cl:9][CH2:10][CH2:11][CH2:12][NH2:13].[CH2:14]([N:20]=[C:21]=[O:22])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>C(Cl)Cl>[Cl:9][CH2:10][CH2:11][CH2:12][NH:13][C:21]([NH:20][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:22]
Reactant: NCCCCl
Reactant: CCCCCCN=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCNC(=O)NCCCCl
Reaction time: 1 h
Yield: 86.1 %

Procedure:
Triethylamine (35 g; 35 mmole) was slowly added to a mixture of chloropropylamine hydrochloride (39 g; 0.3 mol), n-hexyl isocyanate (38.2 g; 0.3 mole) and methylene chloride (500 ml). The resulting solution was stirred for one hour, and then the solvent was removed in vacuo. The residue was treated with ether, and the colorless solid was filtered off. The ether solution was then washed with water, dried (magnesium sulfate) and concentrated to give pure 1-(3-chloropropyl)-3-n-hexylurea (57.0 g; 86% yield) as colorless crystals, m.p. 48°-50° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([NH:11][C@H:12]([C:20]([NH:22][C@H:23]2[C@H:26](OC(=O)C)[NH:25][C:24]2=[O:31])=[O:21])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:32][CH2:33][CH:34]([OH:37])[CH2:35][Br:36].O>C1C=CC=CC=1.C1(C)C=CC=CC=1.O.O.C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[C:1]1([CH2:7][CH2:8][C:9]([NH:11][C@H:12]([C:20]([NH:22][C@H:23]2[C@H:26]([O:37][CH:34]([CH2:35][Br:36])[CH2:33][Br:32])[NH:25][C:24]2=[O:31])=[O:21])[CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)O[C@@H]1NC(=O)[C@H]1NC(=O)[C@H](Cc1ccccc1)NC(=O)CCc1ccccc1
Reactant: OC(CBr)CBr
Agent: CC(=O)[O-]
Agent: [Zn+2]
Solvent: O
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: O=C(CCc1ccccc1)N[C@@H](Cc1ccccc1)C(=O)N[C@@H]1C(=O)N[C@H]1OC(CBr)CBr
Yield: 7 %

Procedure:
A mixture of (3S,4S)-3-{N-(3-phenylpropionoyl)-L-phenylalanyl}amino-4-acetoxy-azetidin-2-one (1.67 g, 3.95 mmole), 1,3-dibromo-2-propanol (689 mg, 3.16 mmole), and zinc acetate dihydrate (435 mg, 1.98 mmole) in a mixture of benzene (25 ml) and toluene (25 ml) was refluxed overnight using Dean-Stark water separator. After cooling, the reaction mixture was partitioned between ethyl acetate (200 ml), acetone (40 ml) and water (150 ml). The organic layer was washed with water, brine and dried over sodium sulfate. After removal of the solvent, the residue was purified by silica gel column chromatography using ethyl acetate-hexane (4:3) as eluent and (3S,4S)-3-{N-(3-phenylpropionoyl)-L-phenylalanyl}amino-4-(1,3-dibromoprop-2-yl)oxy-azetidin-2-one was obtained (170 mg, 7% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH3:12])[C:9]=1[OH:10])[CH:5]=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[O:6])[CH:7]=[C:8]([O:11][CH3:12])[C:9]=1[O:10][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)CBr
Reactant: COc1cc(C=O)cc(F)c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1c(F)cc(C=O)cc1OC
Reaction time: 1 h
Yield: 79.2 %

Procedure:
To a solution of 3-fluoro-4-hydroxy-5-methoxybenzaldehyde (302 mg, 1.78 mmol) in acetone (20 mL) was added cesium carbonate (765 mg, 2.35 mmol), followed by ethyl bromoacetate (0.30 mL, 2.7 mmol). The mixture was refluxed in acetone under stirring for 1 hour. After evaporation of acetone under reduced pressure, 100 mL of water were added and the mixture was extracted with dichloromethane (200 mL). The organic phase was washed with brine (100 mL), dried over magnesium sulfate and concentrated under vacuum. The residue was purified by column chromatography over silica gel (eluent: dichloromethane) to give 361 mg of an oil (79% yield). 1H NMR (500 MHz, CD3COCD3): δ 1.25 (t, J=7.2 Hz, 3H), 3.98 (s, 3H), 4.20 (q, J=7.2 Hz, 2H), 4.89 (t, J=1.6 Hz 2H), 7.34 (dd, J=10.3 Hz, 1.6 Hz, 1H), 7.41 (s, 1H), 9.88 (d, J=1.5 Hz, 1H). 13C NMR (126 MHz, CD3COCD3): δ 15.0, 57.6, 62.1, 70.3 (d, J=1.9 Hz), 110.0, 111.8 (d, J=20.6 Hz), 133.1 (d, J=7.2 Hz), 141.8, (d, J=12.7 Hz), 154.8 (d, J=4.5 Hz), 155.0 d, J=46.1 Hz) 169.7, 191.3.
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[OH:13].[C:14]([C:16]1[CH:17]=[C:18]([S:23]([N:26]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:34]=2[O:41][CH3:42])[C:27]2[S:31][N:30]=[CH:29][N:28]=2)(=[O:25])=[O:24])[CH:19]=[CH:20][C:21]=1F)#[N:15]>>[C:14]([C:16]1[CH:17]=[C:18]([S:23]([N:26]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:34]=2[O:41][CH3:42])[C:27]2[S:31][N:30]=[CH:29][N:28]=2)(=[O:25])=[O:24])[CH:19]=[CH:20][C:21]=1[O:13][C:3]1[CH:4]=[CH:5][C:6]([O:8][C:9]([F:11])([F:12])[F:10])=[CH:7][C:2]=1[I:1])#[N:15]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(F)c(C#N)c2)c(OC)c1
Reactant: Oc1ccc(OC(F)(F)F)cc1I
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(Oc3ccc(OC(F)(F)F)cc3I)c(C#N)c2)c(OC)c1

Procedure:
The title compound was prepared according to Preparation 255 using 2-iodo-4-(trifluoromethoxy)phenol (Preparation 226) and 3-cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-1,2,4-thiadiazol-5-ylbenzene sulfonamide (Preparation 68).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][N:5]2[C:11]=1[CH3:12].[CH2:13]([C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:16]=1[CH2:17]Cl)[CH3:14].[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[CH3:1][C:2]1[N:3]=[C:4]2[C:9]([O:10][CH2:17][C:16]3[C:19]([CH3:23])=[CH:20][CH:21]=[CH:22][C:15]=3[CH2:13][CH3:14])=[CH:8][CH:7]=[CH:6][N:5]2[C:11]=1[CH3:12]
Reactant: Cc1nc2c(O)cccn2c1C
Reactant: CCc1cccc(C)c1CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCc1cccc(C)c1COc1cccn2c(C)c(C)nc12

Procedure:
2,3-Dimethyl-8-hydroxyimidazo[1,2-a]pyridine (0.8 g, 5 mmol), 2-ethyl-6-methylbenzyl chloride, sodium iodide (0.25 g, 1.7 mmol) and sodium carbonate (1.2 g, 11 mmol) were added to acetone (40 ml) and the mixture was refluxed for 5 h. The acetone was evaporated and the residue was solved in methylene chloride and washed with water. The organic solvent was dried and was evaporated under reduced pressure. The residue was purified twice by column chromatography on silica gel using (a) methylene chloride: ethylacetate(1:2), (b) methylene chloride:ethylacetate(2:1), as eluent to give the title compound. (0.02 g, 1.4%)
Reaction SMILES: [CH3:1][N:2]([S:21]([C:24]1[S:25][CH:26]=[CH:27][N:28]=1)(=[O:23])=[O:22])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18](O)=[O:19])[CH2:15][N:16]=1)=[CH:8]2.Cl.C[N:31](C)CCCN=C=NCC.CN(C)C=O>C(OCC)(=O)C.O>[CH3:1][N:2]([S:21]([C:24]1[S:25][CH:26]=[CH:27][N:28]=1)(=[O:23])=[O:22])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([NH2:31])=[O:19])[CH2:15][N:16]=1)=[CH:8]2
Reactant: CN(c1cccc2cc(C3=NCC(CC(=O)O)S3)[nH]c12)S(=O)(=O)c1nccs1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CN(c1cccc2cc(C3=NCC(CC(N)=O)S3)[nH]c12)S(=O)(=O)c1nccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.6 %

Procedure:
A mixture of (2-{7-[methyl(1,3-thiazol-2-ylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetic acid (250 mg), 1H-1,2,3-benzotriazol-1-ol-ammonia complex (114 mg), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (144 mg) and N,N-dimethylformamide (10 mL) was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate (100 mL) and water (100 mL), and the organic layer was washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained solid was washed with ethyl acetate to give the title compound (166 mg, yield 67%) as a white solid. melting point 216-218° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[C:3]=1[C:4](O)=[O:5].S(Cl)(Cl)=O>O1CCCC1>[Cl:1][C:2]1[C:3]([CH2:4][OH:5])=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH:8]=[CH:9][N:10]=1
Reactant: O=C(O)c1c(-c2ccc(Cl)cc2)ccnc1Cl
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: OCc1c(-c2ccc(Cl)cc2)ccnc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.5 %

Procedure:
To a solution of 2-chloro-4-(4-chlorophenyl)nicotinic acid (2.4 g) in tetrahydrofuran (60 ml) was added thionyl chloride (3.2 g), and the mixture was heated under reflux for 3 hrs. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (60 ml). Sodium borohydride (1.5 g) was added by small portions at 0° C., and the mixture was allowed to warm gradually and stirred at room temperature for 2 hrs. Water was added to quench the reaction and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (1.9 g) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:20]([C:30]([O:32]C)=[O:31])[CH:19]=1)[C:14](O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:42][O:43][CH2:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[CH:47][CH:46]=1>>[C:48]1([C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH:49]=[CH:50][C:45]([CH2:44][O:43][NH:42][C:14](=[O:15])[C@@H:13]([NH:12][C:10](=[O:11])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH:19]=2)[C:30]([OH:32])=[O:31])=[CH:46][CH:47]=1
Reactant: NOCc1ccc(-c2ccccc2)cc1
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Agent: Cl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccc(OCC(=O)O)c(C(=O)O)c1)C(=O)NOCc1ccc(-c2ccccc2)cc1
Yield: 41.3 %

Procedure:
Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)4-(2-methoxy-2-oxoethoxy)phenyl]propanoic acid (91 mg, 0.16 mmol) and 4-[(aminooxy)methyl]-1,1′-biphenyl hydrochloride (46 mg, 0.20 mmol) according to Method C with HPLC purification to give the title compound (47 mg). 1H-NMR (400 MHz, CD3OD-Me2SO-d6) d 7.74-7.16 (17H), 4.84 (1H), 4.76 (1H), 4.64 (s, 2H), 4.32 (m, 1H), 3.03 (m, 3H), 1.41 (s, 9H); IR (KBr) 3272, 2978, 1681, 1652 cm−1; HRMS m/z 711.2831 (calc. of monoisotopic mass for C39H41N3O10 gives 711.2792).
Reaction SMILES: [NH:1]([C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[C@H:2]([C:10]([O:12]CC1C=CC=CC=1)=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.[NH2:31][CH2:32][C:33]([NH2:35])=[O:34].CCN(CC)CC>CN(C=O)C.O.CCOC(C)=O>[NH:1]([C:20]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:21])[C@H:2]([C:10]([NH:31][CH2:32][C:33]([NH2:35])=[O:34])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Reactant: NCC(N)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
To a solution of Z-L-Phe-OBn (25, 19.2 mg, 0.05 mmol) in DMF (0.25 mL) and water (0.144 mL), glycinamide hydrochloride (31, 17 mg, 0.15 mmol) and Et3N (0.15 mmol, 0.0625 mL) were added, followed by the addition of S166C—S-inden-oxaz(S,R) (ME-n, 0.106 mL, 0.5 mg of active enzyme in 10 mM MES buffer (pH 5.8) including 1 mM CaCl2). The reaction was stirred for one hour at room temperature. The mixture was diluted with AcOEt and washed with 1 M KHSO4 (1 mL×1) and brine (1 mL×1), and the organic layer was dried over MgSO4. After evaporation, the residue was purified by preparative TLC (CH2Cl2/MeOH=90/10) to afford Z-L-Phe-Gly-NH2 (33, 17.8 mg, quantitative).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:14]1([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>[N+](C1C=CC=CC=1)([O-])=O>[C:5]([C:17]1[CH:18]=[CH:19][C:14]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:5](=[O:12])[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:25][CH:26]=2)=[CH:15][CH:16]=1)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: c1ccc(Cc2ccccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C(c1ccccc1)c1ccc(Cc2ccc(C(=O)c3ccccc3)cc2)cc1
Temperature: 70 °C
Yield: 67.3 %

Procedure:
In a 5-liter four-necked flask equipped with a stirring device, a thermometer, a condenser and a nitrogen substituting device, 317.0 g of aluminum chloride and 1.5 liters of nitrobenzene were mixed and then 209.0 g of benzoyl chloride was introduced with ice cooling to be dissolved, and then a solution of 100.0 g of diphenylmethane in 100 milliliters of nitrobenzene was added dropwise for 30 minutes. 30 minutes after the end of the dropwise adding, the temperature was increased to 70° C. by removing an ice bath, and stirring was carried out with maintaining the temperature for 5 hours. After the end of the reaction was confirmed by a gas chromatography, the reaction solution was poured on 1.0 liter of ice, and then extracted with 2.5 liters of chloroform. Thereafter, the solution was washed with a 6N-HCl aqueous solution, an aqueous solution of sodium hydrogencarbonate, brine and water, removed off chloroform and nitrobenzene by a rotary evaporator, and then 150.7 g of 1,1-bis(4-benzoylphenyl)methane was obtained as crystals after recrystallizing from ethyl acetate.
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[O:12][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])=[N:10][CH:9]=1.C1COCC1.[OH-].[Na+]>CCO>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:11]1[O:12][C:8]([CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:21])=[O:2])=[CH:9][N:10]=1
Reactant: COC(=O)CCCCc1cnc(-c2ccccc2OC)o1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccccc1-c1ncc(CCCCC(=O)O)o1
Yield: 89.6 %

Procedure:
Combine 5-[2-(2-methoxy-phenyl)-oxazol-5-yl]-pentanoic acid methyl ester (2.1 g, 7.3 mmol) with THF (4 mL), EtOH (4 mL) and 2N NaOH (15 mL) and stir until hydrolysis is complete. Concentrate the mixture, dilute the residue with water and adjust the pH to 3.0-4.0 using aq HCl. Extract the mixture with CH2Cl2 and concentrate the extracts in vacuo. Drying gives 5-[2-(2-methoxy-phenyl)-oxazol-5-yl]-pentanoic acid (1.8 g, 91%). MS (ES): (M+1)+ 274.1, 275.1 m/z.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(O[CH2:19][CH:20]1[CH2:24][CH2:23][CH:22]([CH2:25]OS(C2C=CC(C)=CC=2)(=O)=O)[O:21]1)(C1C=CC(C)=CC=1)(=O)=O.COCCOCCOCCOC>[OH-].[Na+]>[C:2]1([N:1]2[CH2:25][CH:22]3[O:21][CH:20]([CH2:24][CH2:23]3)[CH2:19]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCC(COS(=O)(=O)c3ccc(C)cc3)O2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOCCOCCOC
Product: c1ccc(N2CC3CCC(C2)O3)cc1
Temperature: 185 °C

Procedure:
Aniline (1.2 mole, 111.8 grams) was added to a mixture of 2,5-bis(tosyloxymethyl)tetrahydrofuran, represented by formula (II), (0.4 mole, 176.2 grams) and 300 ml of Ansul 161 (triethylene glycol dimethyl ether) and the reaction mixture heated for 4 hours at 185° C. The reaction mixture was cooled to room temperature and neutralized with a methanolic sodium hydroxide solution (32 grams NaOH in 300 ml CH3OH). Sodium tosylate was filtered and Ansul 161 and excess aniline stripped from the filtrate under aspirator pressure. 3-Phenyl-8-oxa-3-azabicyclo(3.2.1)octane, represented by formula (XX), was distilled at 113° C./0.15 mm Hg. The product solidified on standing and after recrystallization from methanol had a melting point of 84°-85° C.
Reaction SMILES: CO.C[O-].[Na+].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.Br[CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)[C:16]([O:18][CH3:19])=[O:17]>C1C=CC=CC=1.O>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:15]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)[C:16]([O:18][CH3:19])=[O:17])=[CH:9][CH:8]=1
Reactant: COC(=O)C(Br)c1ccc(Oc2ccc(C#N)cc2)cc1
Reactant: Oc1ccc(Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: c1ccccc1
Product: COC(=O)C(Oc1ccc(Cl)cc1)c1ccc(Oc2ccc(C#N)cc2)cc1

Procedure:
To a solution of 40 ml of methanol, 1.19 g of sodium methoxide and 3.21 g of p-chlorophenol is added 7.4 g of methyl α-bromo-α-[p-(p-cyanophenoxy)phenyl]acetate in 15 ml of benzene. The mixture is refluxed for 20 hours, poured into ice and water, and extracted with ether. The ether extracts are washed with 10% potassium carbonate and with water. Drying over magnesium sulfate and removal of the solvent under vacuum gives a tan oil. Filtration once through silica gel with chloroform as solvent gives an oil in the first fractions. The oil is filtered through silica gel with benzene as the solvent to give, in the first fractions, a pale yellow oil.
Reaction SMILES: [OH:1][C@@H:2]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3]([N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].[OH-].[Li+]>>[CH:12]1([CH2:11][C@H:2]([OH:1])[C:3]([N:5]2[CH2:6][CH2:7][O:8][CH2:9][CH2:10]2)=[O:4])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C([C@@H](O)Cc1ccccc1)N1CCOCC1
Agent: [Li+]
Agent: [OH-]
Product: O=C([C@@H](O)CC1CCCCC1)N1CCOCC1
Yield: 46 %

Procedure:
This reaction is performed as previously described by Deechongkit, S.; You, S.-L.; Kelly, J. W. Org. Lett. 2004, 6, 497, using (R)-3-benzylsulfanyl-2-hydroxy-propionic acid methyl ester 2 and lithium hydroxide. (R)-3-Benzylsulfanyl-2-hydroxy-propionic acid 3 (3.08 g, 14.51 mmol, 46%) is isolated as a viscous oil: MS calculated for C10H12O3S (M+Na+) 235.1, found 235.3.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br.BrC[CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.CN(C=O)C.[C:23]1([C:29]2[S:34][C:33]3[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=3[O:31][C:30]=2[C:39]2[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(OCC)(=O)C>[C:23]1([C:29]2[S:34][C:33]3[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=3[O:31][C:30]=2[C:39]2[CH:40]=[CH:41][C:42]([O:45][CH2:15][CH2:16][CH2:17][N:12]3[CH2:11][CH2:10][CH2:14][CH2:13]3)=[CH:43][CH:44]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Oc1ccc(C2=C(c3ccccc3)Sc3ccccc3O2)cc1
Reactant: BrCCCN1CCCCC1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: c1ccc(C2=C(c3ccc(OCCCN4CCCC4)cc3)Oc3ccccc3S2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 53.5 %

Procedure:
Potassium carbonate (83 mg) and 1-(3-bromopropyl)piperidine hydrobromide (54.6 mg) were added to a DMF (3 mL) solution of 4-(3-phenyl-1,4-benzoxathiin-2-yl)phenol (63.7 mg, 0.2 mmol) obtained in Reference Example 1-1, and stirred at 80° C. for 8 hours. The reaction liquid was restored to room temperature, diluted with ethyl acetate, and extracted with distilled water. The organic layer was dried with magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by preparative thin-layer silica gel column chromatography (chloroform:methanol=9:1) to obtain the entitled compound (43.7 mg, 51%) as a yellow oil.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][C@H:7]2[C@H:5]([CH2:6]2)[N:4]1[C:9]([C:11]1[N:12]=[C:13]([CH3:23])[S:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)=[O:10].[S:24]1[CH:28]=[CH:27][N:26]2[C:29]([C:32](O)=[O:33])=[CH:30][N:31]=[C:25]12>>[F:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:4]2[C@H:3]([CH2:2][NH:1][C:32]([C:29]3[N:26]4[C:25]([S:24][CH:28]=[CH:27]4)=[N:31][CH:30]=3)=[O:33])[CH2:8][C@H:7]3[C@@H:5]2[CH2:6]3)=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)c1cnc2sccn12
Reactant: Cc1nc(C(=O)N2[C@H](CN)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1
Product: Cc1nc(C(=O)N2[C@H](CNC(=O)c3cnc4sccn34)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [(1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl]-[5-(3-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone with imidazo[2,1-b]thiazole-5-carboxylic acid. LC-MS (basic): tR=0.80 min; [M+H]+=482.1.
Reaction SMILES: [CH2:1]([O:3]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:2].Br[C:20]1[CH:45]=[CH:44][C:23]2[O:24][C:25]3[CH:43]=[CH:42][CH:41]=[CH:40][C:26]=3[C@@H:27]3[C@H:32]([NH:33][C:34](=[O:39])[C:35]([F:38])([F:37])[F:36])[CH2:31][CH2:30][CH2:29][N:28]3[C:22]=2[CH:21]=1.Cl>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([C:20]1[CH:45]=[CH:44][C:23]2[O:24][C:25]3[CH:43]=[CH:42][CH:41]=[CH:40][C:26]=3[C@@H:27]3[C@H:32]([NH:33][C:34](=[O:39])[C:35]([F:36])([F:38])[F:37])[CH2:31][CH2:30][CH2:29][N:28]3[C:22]=2[CH:21]=1)(=[O:3])[CH3:2]
Reactant: O=C(N[C@@H]1CCCN2c3cc(Br)ccc3Oc3ccccc3[C@H]12)C(F)(F)F
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc2c(c1)N1CCC[C@@H](NC(=O)C(F)(F)F)[C@H]1c1ccccc1O2
Temperature: 140 °C
Reaction time: 3 h
Yield: 46.2 %

Procedure:
(1-Ethoxyvinyl)tributyl tin (90 μl, 0.23 mmol) was added to a solution of trans-N-(7-bromo-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide (100 mg, 0.23 mmol) and PdCl2(PPh3)2 (3 mg, 4.3 μmol) in toluene (6 mL) under N2. The reaction mixture was heated to 140° C. and stirred for 3 h. After cooling to room temperature, 2N (aq) HCl (450 ul) was added and the reaction mixture was stirred for 1 h. The reaction was quenched with sat NaHCO3 (aq) and extracted with ethyl acetate. The organic layer was washed with brine, dried (Na2SO4) and evaporated. The crude compound was chromatographed with heptane/ethyl acetate 1:1. Purifcation by HPLC gave the title compound (43 mg, 47%). Data: 1H-NMR (400 MHz, DMSO) 1.60-2.09 (m, 4H), 3.21 (t, J=11.2, 1H), 3.90 (d, J=14.0, 1H), 4.16 (d, J=10.4, 1H), 4.44 (m, 1H), 7.04-7.54 (m, 10H), 9.20 (d, J=10.0, 1H). (m/z)=405 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]([CH3:12])[C:9]([NH2:11])=[S:10])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:15][C:16](=O)[CH3:17]>C(O)C>[C:1]([O:5][C:6](=[O:13])[NH:7][C@@H:8]([C:9]1[S:10][CH:15]=[C:16]([CH3:17])[N:11]=1)[CH3:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)CCl
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(N)=S
Solvent: CCO
Product: Cc1csc([C@@H](C)NC(=O)OC(C)(C)C)n1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of tert-butyl[(1R)-2-amino-1-methyl-2-thioxoethyl]carbamate (100 mg, 0.49 mmol) with 3 equivalents of chloroacetone (0.135 g) in ethanol (1 mL) was heated at 80° C. for 2 h. After cooling, the solution was concentrated. The residue was dissolved in DCM (1 ml). To the solution was added TFA (1 mL). The mixture was stirred at RT for 30 min. The volatiles were removed under reduced pressure to yield desired product.
Reaction SMILES: Br[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][C@@H:7]([NH:12][C:13](=[O:15])[CH3:14])[C:6]=2[CH:5]=[N:4][CH:3]=1.[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][C:21]([C:2]2[C:11]3[CH2:10][CH2:9][CH2:8][C@@H:7]([NH:12][C:13](=[O:15])[CH3:14])[C:6]=3[CH:5]=[N:4][CH:3]=2)=[CH:20][CH:19]=1
Reactant: CC(=O)N[C@@H]1CCCc2c(Br)cncc21
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: CC(=O)N[C@@H]1CCCc2c(-c3ccc(C(F)(F)F)cc3)cncc21
Yield: 87 %

Procedure:
In analogy to the procedure described for the preparation of example 1, (+)-(R)—N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)acetamide (intermediate A-12) was reacted with 4-(trifluoromethyl)phenylboronic acid to give the title compound as white solid in 87% yield. MS: 335.1 (M+H+).