Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([N:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[CH2:9][NH:10]C(=O)C1C(OC)=CC=C([Cl:20])C=1OC)[CH3:3].[Br:24][C:25]1[C:26]([O:37][CH3:38])=[C:27]([C:31]([O:35][CH3:36])=[C:32]([Br:34])[CH:33]=1)[C:28]([OH:30])=O.NCC1CCCN1CC>S(Cl)(Cl)=O>[ClH:20].[CH2:2]([N:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[CH2:9][NH:10][C:28](=[O:30])[C:27]1[C:31]([O:35][CH3:36])=[C:32]([Br:34])[CH:33]=[C:25]([Br:24])[C:26]=1[O:37][CH3:38])[CH3:3]
Reactant: CCN1CCCC1CNC(=O)c1c(OC)ccc(Cl)c1OC
Reactant: COc1c(Br)cc(Br)c(OC)c1C(=O)O
Agent: CCN1CCCC1CN
Agent: Cl
Solvent: O=S(Cl)Cl
Product: CCN1CCCC1CNC(=O)c1c(OC)c(Br)cc(Br)c1OC

Procedure:
Using the same method as for compound of Example 8 this compound is prepared from 20.4 g (0.06 mol) of 3,5-dibromo-2,6-dimethoxybenzoic acid, 50 ml of thionyl chloride and 7.7 g (0.06 mol) of 2-(aminomethyl)-1-ethylpyrrolidine. The obtained product is recrystallized from ethanol-ethyl ether. Yield: 20.2 g, m.p. 164°-65° C. The free base is precipitated from the water solution of the hydrochloric salt by the addition of sodium hydroxide, m.p. 133°-134° C.
Reaction SMILES: COC1C=CC(C([NH:24][C:25]2[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:34])([CH3:33])[C@:27]([C:36]3[CH:41]=[C:40](Br)[CH:39]=[CH:38][C:37]=3[F:43])([CH3:35])[N:26]=2)(C2C=CC(OC)=CC=2)C2C=CC=CC=2)=CC=1.[NH2:44][C:45]1[CH:46]=[C:47]([CH:50]=[CH:51][CH:52]=1)[C:48]#[N:49]>>[NH2:24][C:25]1[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:34])([CH3:33])[C@:27]([C:36]2[CH:41]=[C:40]([NH:44][C:45]3[CH:46]=[C:47]([CH:50]=[CH:51][CH:52]=3)[C:48]#[N:49])[CH:39]=[CH:38][C:37]=2[F:43])([CH3:35])[N:26]=1
Reactant: N#Cc1cccc(N)c1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)C(C)(C)C(=O)N2C)(c2ccccc2)c2ccc(OC)cc2)cc1
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Nc3cccc(C#N)c3)ccc2F)N=C1N

Procedure:
The coupling of (S)-2-{[bis-(4-methoxy-phenyl)-phenyl-methyl]-amino}-6-(5-bromo-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate K) and 3-amino-benzonitrile according to procedure B followed by deprotection yielded the title compound as a pale yellow foam. MS (ESI): m/z=380.3 [M+H]+.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[C:13]2[C:8](=[C:9]([C:18](=[O:20])[CH3:19])[C:10]([O:14][CH2:15][CH:16]=[CH2:17])=[CH:11][CH:12]=2)[O:7][C:6](=[O:21])[CH:5]=1.[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)C.O>[CH3:3][C:4]1[C:13]2[C:8](=[C:9]([C:18](=[O:20])[CH:19]=[CH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:10]([O:14][CH2:15][CH:16]=[CH2:17])=[CH:11][CH:12]=2)[O:7][C:6](=[O:21])[CH:5]=1
Reactant: O=Cc1ccccc1
Reactant: C=CCOc1ccc2c(C)cc(=O)oc2c1C(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=CCOc1ccc2c(C)cc(=O)oc2c1C(=O)C=Cc1ccccc1
Temperature: 25 °C
Yield: 42.3 %

Procedure:
A solution of KOH 50% (3 ml) is added to an equimolar solution of 4-methyl-7-allyloxy-8-acetylcoumarin (1.93 g, 0.0075 mol) and benzaldehyde (0.8 g, 0.0075 mol) in ethanol 95%; the addition is performed under energetic stirring at room temperature. The reaction is left under stirring for one night and then diluted with water and acidified. The precipitate is separated by filtration and dried under vacuum. The compound is crystallized by methanol to give 1.1 g of product m.p. 136-139° C., 1H-NMR (CDCl3) δ: 2.43 (s, 3H); 4.65 (d, 2H, J=5.1 Hz); 4.25-4.55 (m, 2H); 5.15-5.35 (m, 1H); 6,16 (s, 1H); 6.93 (d, 1H, J=8.9 Hz); 7.03 (d, 1H) J=16 Hz); 7.04-7.15 (m, 3H); 7.15-7.26 (m, 2H); 7.33 (d, 1H, J=16 Hz); 7.64 (d, 1H, J=8.9 Hz).
Reaction SMILES: [CH3:1][C:2](=[CH2:17])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:8][CH:7]=1.ClC1C=CC=C(C(OO)=[O:26])C=1>>[CH3:17][C:2]1([CH2:3][O:4][CH2:5][C:6]2[CH:11]=[CH:10][C:9]([O:12][C:13]([F:14])([F:15])[F:16])=[CH:8][CH:7]=2)[CH2:1][O:26]1
Reactant: C=C(C)COCc1ccc(OC(F)(F)F)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CC1(COCc2ccc(OC(F)(F)F)cc2)CO1
Yield: 93 %

Procedure:
Epoxidation of alkene 121 with 3-chloroperbenzoic acid as in Example 2G, followed by chromatography of the product on silica gel, eluting with 0-15% CH2Cl2/petroleum ether (foreruns) and then with 15-75% CH2Cl2/petroleum ether and CH2Cl2, gave 2-methyl-2-({[4-(trifluoromethoxy)benzyl]oxy}methyl)oxirane (123) (93%) as an oil; 1H NMR (CDCl3) δ 7.37 (dt, J=8.7, 2.4 Hz, 2H), 7.19 (br d, J=7.9 Hz, 2H), 4.59 (d, J=12.1 Hz, 1H), 4.54 (d, J=12.1 Hz, 1H), 3.61 (d, J=11.1 Hz, 1H), 3.44 (d, J=11.1 Hz, 1H), 2.75 (d, J=4.9 Hz, 1H), 2.64 (d, J=4.9 Hz, 1H), 1.40 (s, 3H); HRCIMS (NH3) calcd for C12H17F3O3N m/z [M+H+NH3]+ 280.1161. found 280.1144.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([CH:18]=1)[CH2:7][C:8]1[CH:9]=[CH:10][C:11]2[O:16][CH2:15][CH2:14][NH:13][C:12]=2[CH:17]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C>[CH2:26]([N:13]1[C:12]2[CH:17]=[C:8]([CH2:7][C:6]3[CH:18]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=3[Cl:19])[CH:9]=[CH:10][C:11]=2[O:16][CH2:15][CH2:14]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCc1ccccc1
Reactant: Clc1ccc(Br)cc1Cc1ccc2c(c1)NCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ccc(Br)cc1Cc1ccc2c(c1)N(Cc1ccccc1)CCO2
Temperature: 50 °C
Yield: 69 %

Procedure:
To a stirred solution of 6-(5-bromo-2-chloro-benzyl)-3,4-dihydro-2H-benzo[1,4]oxazine (8.0 g, 23.66 mmol) in DMF (35 mL) was added potassium carbonate (6.53 g, 36.0 mmol), benzyl bromide (4.33 mL, 35.50 mmol) and heated to 50° C. for 8 h. Reaction mixture was cooled to room temperature, quenched by the addition of water (50 mL), extracted with ethyl acetate (3×20 mL). The organic layer was washed with water (50 mL), brine (50 mL), dried over sodium sulfate, concentrated and purified by silica gel column chromatography to furnish 4-benzyl-6-(5-bromo-2-chloro-benzyl)-3,4-dihydro-2H-benzo[1,4]oxazine (7.0 g).
Reaction SMILES: C[O:2][C:3](=[O:28])[C@@H:4]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:8][CH:7]=1.Cl>CO.[OH-].[Na+].CCOCC>[CH3:26][C:24]([CH3:27])([O:23][C:21]([NH:20][C@@H:4]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:8][CH:7]=1)[C:3]([OH:28])=[O:2])=[O:22])[CH3:25]
Reactant: COC(=O)[C@H](Cc1ccc(CC(=O)OC(C)(C)C)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Product: CC(C)(C)OC(=O)Cc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Yield: 77.9 %

Procedure:
A solution of 1.471 g of (S)-alpha-[[(1,1-dimethylethoxy)carbonyl]amino]-4-[2-(1,1-dimethylethoxy)-2-oxoethyl]-benzenepropanoic acid methyl ester in 25 mL of methanol and 5 mL of 1N sodium hydroxide solution was stirred at room temperature for 2 hours. The mixture was acidified with a slight excess of hydrochloric acid, was diluted with 100 mL of ether, and was washed with water and saturated sodium chloride solution. The residue obtained after filtration and evaporation was chromatographed over 100 g of silica gel, eluting with 40:59:0.5 ethyl acetate-hexane-acetic acid. The product containing fractions were combined, evaporated, diluted with toluene and evaporated finally under high vacuum to give 1.105 g of (S)-alpha-[[(1,1-dimethylethoxy)carbonyl]amino]-4-[2-(1,1-dimethylethoxy)-2-oxoethyl]-benzenepropanoic acid [α]D +21.41 (ethanol).
Reaction SMILES: NC1C=CC=CC=1.[OH:8][CH2:9][CH2:10][S:11]([C:14]1[CH:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[CH:16][C:15]=1Cl)(=[O:13])=[O:12].[CH2:24]([CH2:26][NH2:27])[OH:25]>CO>[OH:8][CH2:9][CH2:10][S:11]([C:14]1[CH:19]=[C:18]([CH:17]=[CH:16][C:15]=1[NH:27][CH2:26][CH2:24][OH:25])[NH2:20])(=[O:13])=[O:12]
Reactant: NCCO
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)CCO)c1
Solvent: CO
Solvent: Nc1ccccc1
Product: Nc1ccc(NCCO)c(S(=O)(=O)CCO)c1
Reaction time: 6 h

Procedure:
The aniline compound employed under (a) with the β-sulfatoethylsulfonyl group can be prepared, for example, as follows: 132.8 parts of 2-(β-hydroxyethylsulfonyl)-4-nitrochlorobenzene are added slowly to a solution of 76.5 parts of ethanolamine in 500 parts by volume of methanol at a temperature of 65° C., and the reaction batch is stirred for a further 6 hours at this temperature. 400 parts by volume of methanol are subsequently distilled off from the reaction batch while simultaneously and continuously adding water. 2-(β-hydroxyethylsulfonyl)-4-nitro-1-(β-hydroxyethyl)aminobenzene crystallizes on cooling from the now aqueous medium in high purity. This compound can be employed for the conversion of the nitro group to the amino group during catalytic hydrogenation. For this, 58 parts of this nitro compound are dissolved in 400 parts by volume of methanol and hydrogenated in an autoclave in the presence of a nickel catalyst at a temperature of 100° C. and pressure of 50 bar of hydrogen. The catalyst is subsequently filtered off and the filtrate allowed to crystallize out by cooling of the methanolic solution. 3-(β-hydroxyethylsulfonyl)-4-(β-hydroxyethylamino)aniline is obtained in good yield and high purity.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][CH2:14][CH2:15][CH2:16][CH:17]([C:19]([O:21]C)=[O:20])[CH2:18][C:11]=3[O:10][N:9]=2)=[CH:4][CH:3]=1.[OH-].[K+].O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH2:13][CH2:14][CH2:15][CH2:16][CH:17]([C:19]([OH:21])=[O:20])[CH2:18][C:11]=3[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)C1CCCCc2c(-c3ccc(Cl)cc3)noc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C1CCCCc2c(-c3ccc(Cl)cc3)noc2C1
Yield: 15.9 %

Procedure:
2.4 g (0.039 mol) of methyl 3-(4-chlorophenyl)-4,5,6,7,8,9-hexahydrocyclooct[d]isoxazole-8-carboxylate were stirred for 18 hours in 10 ml of methanol, 0.5 g of potassium hydroxide and 2 ml of water. The methanol was removed by evaporation and the residual gum was dissolved in water. Acidification with a few drops of concentrated hydrochloric acid gave a white granular precipitate which was filtered off, washed with water and dried. After crystallization from glacial acetic acid, there were obtained 1.9 g of 3-(4-chlorophenyl)-4,5,6,7,8,9-hexahydrocyclooct[d]isoxazole-8-carboxylic acid of melting point 215° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][NH:5][C:4]2=[N:8][CH:9]=[CH:10][C:3]=12.O(C(C)(C)C)[K].C1COCC1.[C:22]1([CH2:28][SH:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)(C)C>[CH2:28]([S:29][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: SCc1ccccc1
Reactant: Clc1nc[nH]c2nccc1-2
Agent: CC(C)(C)O[K]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: c1ccc(CSc2ncnc3[nH]ccc23)cc1
Temperature: 85 °C
Reaction time: 48 h
Yield: 79 %

Procedure:
To a round bottomed flask with a stir bar was added 4-chloro-1H-pyrrolo-[2,3-d]pyrimidine (5.07 g, 33.0 mmol), 1.00 M of KO-t-Bu in THF (49.5 mL, 49.5 mmol), and benzenemethanethiol (5.81 mL, 49.5 mmol) in isopropyl alcohol (350 mL). The reaction mixture was heated to reflux at 85° C. under an atmosphere of nitrogen. After 48 h, the reaction mixture was cooled and solvent was removed in vacuo. To the residue was added water (300 mL) and the solution was filtered to collect the resulting white solid. The solid was washed with diethyl ether and MeOH and dried under vacuum to afford the product as a white solid (6.29 g, 79% yield). LC/MS: Rt=1.68 min, ES+ 242 (FA standard). Reference: Pathak, A. K., Pathak, V., Seitz, L. E., Suling, W. J., Reynolds, R. C. J. Med. Chem., 2004, 47, 273-276.
Reaction SMILES: O=O.[CH3:3][C:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[C:6]([CH3:11])[C:5]=1[OH:12].S(=O)(=O)(O)[OH:14]>C(O)(=O)C>[CH3:10][C:9]1[C:8](=[O:14])[CH:7]=[C:6]([CH3:11])[C:5](=[O:12])[C:4]=1[CH3:3]
Reactant: Cc1ccc(C)c(O)c1C
Reactant: O=S(=O)(O)O
Agent: O=O
Solvent: CC(=O)O
Product: CC1=CC(=O)C(C)=C(C)C1=O
Temperature: 40 °C
Yield: 1567.4 %

Procedure:
Oxygen was passed into a solution of 0.68 g (2 mmol) of iron 5,14-dihydrodibenzo[b,i][5,9,14,18]tetraaza[14]annulene in 150 ml of 85% by weight aqueous acetic acid and, during this, a solution of 13.6 g (100 mmol) of 2,3,6-trimethylphenol and 0.5 g of concentrated sulfuric acid in 75 ml of 85% by weight acetic acid was added dropwise while stirring vigorously at 40° C. After oxygen uptake ceased, the mixture was subjected to a steam distillation. The distillate was extracted with tert-butyl methyl ether. The organic phase was shaken with aqueous sodium bicarbonate solution and then with water, separated from the aqueous phase, dried over magnesium sulfate, filtered and evaporated to dryness to yield 12.0 g (80%) of 2,3,5-trimethylbenzoquinone in the form of yellow oily crystals.
Reaction SMILES: Br[CH2:2][C:3]1([CH3:29])[CH:7]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[N:6]2[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:5]2[S:4]1.[N-:30]=[N+:31]=[N-:32].[Na+].CC(C)=O>O>[N:30]([C:3]1([CH3:2])[CH:7]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:13])[Cl:14])=[O:9])[N:6]2[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C@H:5]2[S:4][CH2:29]1)=[N+:31]=[N-:32]
Reactant: CC1(CBr)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC1(N=[N+]=[N-])CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 16.9 %

Procedure:
A mixture of 2,2,2-trichloroethyl 2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (1.08 g), sodium azide (0.26 g), acetone (20 ml) and water (4 ml) was stirred for 4 hours at room temperature. After acetone was distilled off under reduced pressure, the residue was extracted with ethyl acetate. The ethyl acetate layer was washed with water, with saturated sodium bicarbonate aqueous solution and further with water and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure and a small quantity of ether was added to the residue to give colorless crystals of 2,2,2-trichloroethyl 3-azido-3-methyl-7-(2-phenylacetamido)cepham-4-carboxylate (170 mg). This substance was recrystallized from carbon tetrachloride to give crystals melting at 136° to 140° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:8]([CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:12]=2)[CH:9]=1)([O-])=O.[F:18][C:19]([F:36])([F:35])[C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32](O)=[O:33])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1>>[F:18][C:19]([F:35])([F:36])[C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([NH:1][C:4]3[CH:5]=[CH:6][C:7]4[N:8]([CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:12]=4)[CH:9]=3)=[O:33])=[CH:28][CH:27]=2)=[CH:24][CH:25]=1
Reactant: O=C(O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: CCOC(=O)c1cn2cc([N+](=O)[O-])ccc2n1
Product: CCOC(=O)c1cn2cc(NC(=O)c3ccc(-c4ccc(C(F)(F)F)cc4)cc3)ccc2n1
Yield: 31.1 %

Procedure:
Operations similar to Example 1 were conducted using ethyl 6-nitroimidazo[1,2-a]pyridine-2-carboxylate (600 mg) and 4′-(trifluoromethyl)[1,1′-biphenyl]-4-carboxylic acid (700 mg), to provide ethyl 6-({[4′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]carbonyl}-amino)imidazo[1,2-a]pyridine-2-carboxylate (360 mg) as white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:8](=[O:17])[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:3][CH:2]=1.Cl.[H][H]>[Pd].C(O)C>[NH:1]1[CH2:2][CH2:3][CH:4]([C:7]2[C:8](=[O:17])[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:5][CH2:6]1
Reactant: [H][H]
Reactant: O=c1[nH]c2ccccc2cc1-c1ccncc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: O=c1[nH]c2ccccc2cc1C1CCNCC1

Procedure:
A mixture of 8.6 g (0.0387 mol) of 3-(4-pyridinyl)-2(1H)-quinolone, 1.2 1 of ethanol, 39 ml (0.039 mol) of 1N hydrochloric acid and 8.0 g of 10% palladium/charcoal was hydrogenated at a temperature of 40° C. until about 0.08 mol of hydrogen had been taken up. The mixture was freed from catalyst, the filtrate was evaporated down in vacuo, the residue was taken up in 200 ml of water and made ammoniacal. Common salt was added up to saturation point and the mixture was continuously extracted with dichloromethane using a perforator. The dichloromethane phase was evaporated down, the residue remaining was separated from by-products by chromatography over silica gel using FM1 as eluant. The appropriate fractions were combined, freed from solvent, dissolved in a little isopropanol and converted with ethanolic hydrogen chloride solution into the hydrochloride. Colourless crystals. Yield: 2.68 g (26.2% of theory).
Reaction SMILES: [C:1]1([C@H:7]([NH:10][C:11]([C:13]2[CH:14]=[CH:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][C:17]=23)=[O:12])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:22]N1C(=O)CCC1=O.[OH-].[Na+].O>ClCCl>[C:1]1([C@H:7]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([Br:22])[N:16]3[CH2:21][CH2:20][O:19][CH2:18][C:17]=23)=[O:12])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC[C@@H](NC(=O)c1ccn2c1COCC2)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC[C@@H](NC(=O)c1cc(Br)n2c1COCC2)c1ccccc1
Temperature: -78 °C
Reaction time: 1.83 h
Yield: 93.3 %

Procedure:
To a solution of 3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid ((R)-1-phenyl-propyl)-amide (9a) (2.50 g, 8.79 mmol) in dry dichloromethane (245 ml) at −78° C. was added N-bromo-succinimide (1.565 g, 8.79 mmol) in several portions (over 2 min) and the mixture was stirred for 110 min at −78° C., then aqueous 0.1 M sodium hydroxide was added, water was added, and the mixture was extracted 3 times with dichloromethane, the combined organic layers were dried over sodium sulfate, and evaporated to give 2.98 g (93%) of 6-bromo-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid ((R)-1-phenyl-propyl)-amide. LC/MS (method 4): Rt=1.27 min; m/z=363.07 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:65]1[C:69]([C:70]2[CH:71]=[C:72]([NH2:76])[CH:73]=[CH:74][CH:75]=2)=[N:68][N:67]=[N:66]1>C(Cl)Cl>[NH:68]1[C:69]([C:70]2[CH:71]=[C:72]([NH:76][C:28]([CH:9]3[CH:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=4[F:31])[C:12]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]3)=[O:29])[CH:73]=[CH:74][CH:75]=2)=[N:65][N:66]=[N:67]1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)Nc2cccc(-c3nnn[nH]3)c2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.172 mmol) in methylene chloride (10 mL), HATU (Aldrich, 130 mg, 0.344 mmol) was added followed by the addition of DIPEA (90 uL, 0.52 mmol) and 3-(1H-tetrazol-5-yl)-phenylamine (Alfa, 55 mg, 0.344 mmol). The mixture was stirred at rt for 2 hrs. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on a reverse phase HPLC (24 g column, eluent, 30% EtOAc/methylene chloride) to give a yellow solid. 21 mg.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O>C(Cl)Cl.FC(F)(F)C(OC(=O)C(F)(F)F)=O>[Br:19][C:16]1[CH:17]=[CH:18][C:13]2[O:12][CH2:11][C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:10][C:6]=3[C:7](=[O:9])[C:14]=2[CH:15]=1
Reactant: O=C(O)c1cc(Br)ccc1COc1ccc(Br)cc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: O=C1c2cc(Br)ccc2COc2ccc(Br)cc21
Temperature: 0 °C
Yield: 47 %

Procedure:
A solution of 5-bromo-2-(4-bromophenoxymethyl)benzoic acid (100 g, 0.26 mole), and trifluoroacetic anhydride (160 mL) in one liter of methylene chloride containing 20 drops of boron trifluoride-ether complex was refluxed for three hours. The mixture was poured into ice water and then extracted with diethyl ether. Concentration of ether solution under reduced pressure and chromatography of the residue on a silica gel column (Waters Associates, Prep 500) with hexane/ethyl acetate (9:1) gave the ketone (45 g) mp 193°-194° C. pmr (DMSO-d6) δ: 8.12 (d, J=2.7 Hz, 1H, H4) , 7.27-7.91 (m, 4H, aromatic H) , 7.10 (d, J=8.8 Hz, 1H, H4), 5.32 (s, 2H, ArCH2O).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:22][CH2:21][C:18]3([O:20][CH2:19]3)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:23]1([NH2:26])[CH2:25][CH2:24]1>CO.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:16][CH2:17][C:18]([CH2:19][NH:26][CH:23]3[CH2:25][CH2:24]3)([OH:20])[CH2:21][CH2:22]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CC1
Reactant: c1ccc(COc2ccc(N3CCC4(CC3)CO4)cc2)cc1
Solvent: CO
Solvent: CCOC(C)=O
Product: OC1(CNC2CC2)CCN(c2ccc(OCc3ccccc3)cc2)CC1
Yield: 85.8 %

Procedure:
6-[4-(benzyloxy)phenyl]-1-oxa-6-azaspiro[2,5]octane (500 mg, 1.69 mmol) and cyclopropylamine (195 mg, 3.38 mmol) were mixed in methanol, and heated overnight under reflux. The reaction solution was diluted with ethyl acetate, washed with water and saturated saline in that order, and the organic layer was dried with sodium sulfate. The solvent was evaporated off under reduced pressure to obtain a crude product. The resulting crude product was purified through silica gel column chromatography (eluate: methanol/chloroform=1/99 to 6/94) to obtain the entitled compound (511 mg, 85%) as a yellow solid.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:5][C@H:4]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:3]1.C(N(CC)CC)C.[CH2:31]([O:38][CH2:39][C:40](Cl)=[O:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[CH2:31]([O:38][CH2:39][C:40]([N:16]1[CH2:15][CH2:14][CH:13]([C:10]2[CH:11]=[CH:12][C:7]([N:6]3[CH2:5][C@H:4]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:3][C:2]3=[O:1])=[CH:8][CH:9]=2)[CH2:18][CH2:17]1)=[O:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3CCNCC3)cc2)C(=O)O1
Reactant: O=C(Cl)COCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC[C@H]1CN(c2ccc(C3CCN(C(=O)COCc4ccccc4)CC3)cc2)C(=O)O1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of (S)-(-)-N-[[2-oxo-3-[4-(4-piperidinyl)phenyl]-5-oxazolidinyl]methyl]acetamide (EXAMPLE 17, 300 mg) and triethylamine (0.20 mL) in dry methylene chloride (19 mL) at 0° C. under N2 is treated with benzyloxyacetyl chloride (0.18 mL), and the resulting solution is stirred at 0° C. for one hour and at ambient temperature for one hour. The reaction mixture is then washed with water (2×10 mL), saturated aqueous sodium bicarbonate (10 mL) and saline (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product which is chromatographed on silica gel (230-400 mesh, 45 g), eluting with a gradient of methanol/methylene chloride (1/99-2/98). Pooling and concentration of those fractions with an Rf =0.28 by TLC (methanol/chloroform, 5/95) gives the title compound, NMR (CDCl3, 400 MHz) 7.45, 7.35, 7.18, 6.26, 4.75, 4.63, 4.22, 4.04, 3.78, 3.70, 3.60, 3.09, 2.70, 2.02, 1.85, 1.60 δ.