Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[CH3:15][C:16]1[N:24]=[CH:23][N:22]=[C:21]2[C:17]=1[NH:18][CH:19]=[N:20]2>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@H:12]([N:20]2[CH:19]=[N:18][C:17]3[C:21]2=[N:22][CH:23]=[N:24][C:16]=3[CH3:15])[CH3:13])[CH2:11][O:10]1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: Cc1ncnc2nc[nH]c12
Product: Cc1ncnc2c1ncn2[C@H](C)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 46 %

Procedure:
Using (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol (587 mg) and 6-methylpurine (353 mg), (2S)-2-(2,4-difluorophenyl)-2-[(1R)-1-[6-methyl-9(9H)-purinyl]ethyl]oxirane (383 mg) was obtained as a white powder by the same way as in Reference Example 2.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH3:14][C:15]([CH3:17])=[O:16].[Cl:18][C:19]1[CH:20]=[C:21]([OH:28])[C:22](=[CH:26][CH:27]=1)[C:23](O)=[O:24]>FC(F)(F)C(O)=O>[Cl:18][C:19]1[CH:27]=[CH:26][C:22]2[C:23](=[O:24])[O:16][C:15]([CH3:17])([CH3:14])[O:28][C:21]=2[CH:20]=1
Reactant: O=C(O)c1ccc(Cl)cc1O
Reactant: CC(C)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)OC(=O)c2ccc(Cl)cc2O1
Temperature: 25 °C
Reaction time: 25 h

Procedure:
10 mL of trifluoroacetic anhydride and 2 mL of acetone were added to a 0° C. slurry of 4-chlorosalicylic acid (2.23 g, 13 mmol) in 16 mL of trifluoroacetic acid. The mixture was allowed to slowly warm to room temperature and stirred for 25 hours under a nitrogen atmosphere. The tan solution was concentrated under vacuum, dissolved and re-concentrated from toluene twice, and dried under vacuum. The crude solid was dissolved in ethyl acetate and washed twice with saturated sodium bicarbonate solution and once with brine. The organic fraction was dried over sodium sulfate, and concentrated to a tan semi-solid, which was partially dissolved in 10 mL of dichloromethane and filtered to remove solids. The mother liquor was concentrated to give 1.28 g of a tan semi-solid. MS: (+) m/z 215.0/213.0 (M+1, 35/37Cl)
Reaction SMILES: [H-].[Na+].[CH2:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH:4]1[OH:12].[CH2:13]([CH:15]1[O:17][CH2:16]1)Br>CN(C=O)C>[O:17]1[CH2:16][CH:15]1[CH2:13][O:12][CH:4]1[CH2:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:3]1
Reactant: OC1Cc2ccccc2C1
Reactant: BrCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc2c(c1)CC(OCC1CO1)C2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 60% NaH (0.18 g, 4.5 mmol) in DMF (10 ml) cooled to 0 degrees was added 2-indanol (0.5 g, 3,73 mmol) in DMF (2 ml) dropwise. After stirring for 30 minutes epibromohydrin (1.11 g, 8.18 mmol) in DMF (1 ml) was added dropwise. The reaction was allowed to warm to room temperature and stirred for 48 h. The solvent was removed in vacuo and the residue was purified using Prep TLC (30:1, DCM:MeOH) to afford compound 6.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:13]([NH:14][C:15](=[O:30])[CH2:16][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N:25]3[CH:29]=[CH:28][N:27]=[CH:26]3)[CH:20]=2)=O)=[CH:12][C:11]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[F:37])=[C:10]([O:38][CH2:39][C:40]([F:43])([F:42])[F:41])[CH:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[C:11]1[C:10]([O:38][CH2:39][C:40]([F:42])([F:43])[F:41])=[CH:9][C:8]2[N:7]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N:25]4[CH:29]=[CH:28][N:27]=[CH:26]4)[CH:20]=3)[CH2:16][C:15](=[O:30])[NH:14][C:13]=2[CH:12]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(-c2ccccc2F)cc1NC(=O)CC(=O)c1cccc(-n2ccnc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-n3ccnc3)c2)=Nc2cc(OCC(F)(F)F)c(-c3ccccc3F)cc2N1

Procedure:
The title compound was prepared from [2′-fluoro-5-[3-(3-imidazol-1-yl-phenyl)-3-oxo-propionylamino]-2-(2,2,2-trifluoro-ethoxy)-biphenyl-4-yl]-carbamic acid tert.-butyl ester (Example M22) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a brown solid (50 mg).
Reaction SMILES: [CH3:1][S:2]([O:5][C@@H:6]1[C@@H:12]([NH:13][C:14](=[O:26])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22](=[O:24])[CH3:23])[C:16]=2[CH3:25])[CH2:11]OC(C)(C)[O:8][CH2:7]1)(=[O:4])=[O:3].C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:5][C@H:6]([C@@H:12]1[CH2:11][O:26][C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22](=[O:24])[CH3:23])[C:16]=2[CH3:25])=[N:13]1)[CH2:7][OH:8])(=[O:3])=[O:4]
Reactant: CC(=O)Oc1cccc(C(=O)N[C@H]2COC(C)(C)OC[C@@H]2OS(C)(=O)=O)c1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1cccc(C2=N[C@H]([C@H](CO)OS(C)(=O)=O)CO2)c1C
Temperature: 25 °C

Procedure:
(5R, 6S)-N-(5-Methanesulfonyloxy-2,2-dimethyl-1,3-dioxepan-6-yl)-3-acetoxy-2-methylbenzamide (compound [9], 34.2 g, 82.3 mmol) was dissolved in dichloromethane (340 ml) and boron trifluoride-diethyl ether complex (30.4 ml, 247 mmol) was added over 5 minutes with stirring at room temperature. The mixture was stirred for 40 hours at room temperature. Triethylamine (34.5 ml, 247 mmol) was added at not more than 15° C. and the solvent was distilled away under reduced pressure to 1/5 volume. The residue was diluted with ethyl acetate (340 ml) and washed successively with 10% brine (340 ml), 10% brine (340 ml) containing citric acid (17 g), and saturated brine (340 ml). After drying over magnesium sulfate, the solution was concentrated to 36 g to give a crude product of (2R)-2-methanesulfonyloxy-2-((4S)-2-(3-acetoxy-2-methylphenyl)-4,5-dihydrooxazol-4-yl)ethanol (compound [10]).
Reaction SMILES: [CH3:1][N:2]([CH3:30])[C:3]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:8][CH2:7][C:6]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:5][CH2:4]1.[H][H]>[Pd].CO>[CH3:30][N:2]([CH3:1])[C:3]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:8][CH2:7][CH:6]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:5][CH2:4]1
Reactant: [H][H]
Reactant: CN(C)C1(c2ccccc2)CC=C(c2[nH]c3ccccc3c2CCCC(=O)O)CC1
Agent: [Pd]
Solvent: CO
Product: CN(C)C1(c2ccccc2)CCC(c2[nH]c3ccccc3c2CCCC(=O)O)CC1

Procedure:
Palladium as the catalyst (Pd/C, 5%, 200 mg) was added to (±)-4-[2-(-4-dimethylamino-4-phenyl-cyclohex-1-enyl)-1H-indol-3-yl]butanoic acid (500 mg, 1.2 mmol) in abs. methanol (50 ml) and hydrogenation was carried out at RT for 6 h (hydrogen pressure: 3 bar). The catalyst was removed with the aid of a frit provided with a layer of Celite 1 cm high. The residue was rinsed thoroughly with methanol (500 ml). The solvent was distilled off in vacuo. 4-[2-(4-Dimethylamino-4-phenylcyclohexyl)-1H-indol-3-yl]butanoic acid was obtained in a yield of 340 mg (68%) as a white solid (one of the two possible diastereoisomers).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].S(O[CH2:28][CH2:29][CH:30]1[O:35][C:34]2[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=2[O:32][CH2:31]1)(C)(=O)=O>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:28][CH2:29][CH:30]4[O:35][C:34]5[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=5[O:32][CH2:31]4)[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CS(=O)(=O)OCCC1COc2ccccc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1ccc2c(C3CCN(CCC4COc5ccccc5O4)CC3)noc2c1

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (4.7 g, 21 mmol), K2CO3 (3.5 g, 25.4 mmol) and 2-mesyloxyethyl-1,4-benzodioxan (5.5 g, 21.3 mmol) in acetonitrile (250 ml) was heated at reflux for 3.5 hours. At the end of the reaction, insolubles were filtered. The solid was washed with dichloromethane (200 ml). The solutions were combined and evaporated to an oil. This crude oil was purified by flash chromatography on a silica gel column. The material thus obtained was crystallized from ethanol. The 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-1,4-benzodioxan crystals were collected and weighed 3.8 g, 48%, m.p.=112°-113° C.
Reaction SMILES: [NH2:1][CH:2]([CH3:16])[CH:3]([NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:4].[OH:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](O)=[O:21].N1C=CN=C1.C1CCC(N=C=NC2CCCCC2)CC1>CCOC(C)=O>[OH:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([NH:1][CH:2]([CH3:16])[CH:3]([NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:4])=[O:21]
Reactant: CC(N)C(C)NC(=O)OCc1ccccc1
Reactant: O=C(O)c1ccccc1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Product: CC(NC(=O)OCc1ccccc1)C(C)NC(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.3 %

Procedure:
To a mixture of benzyl 3-aminobutan-2-ylcarbamate (5.3 g, 23.8 mmol), 2-hydroxybenzoic acid (3.28 g, 23.8 mmol) and imidazole (1.62 g, 23.8 mmol) in EtOAc (180 mL) at 0° C. was slowly added a solution of DCC (4.90 g, 23.8 mmol) in EtOAc (20 mL). The reaction mixture was stirred (RT, 16 h), filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with PE-EA (5:1) to afford benzyl 3-(2-hydroxybenzamido)butan-2-ylcarbamate (3.2 g, 40%) as a colorless oil. Mass calculated for C19H22N2O4=342.39; found: [M+H]+=343.2.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.[H-].[Na+].[Cl:20][C:21]1[CH:26]=[C:25](F)[C:24]([CH3:28])=[CH:23][C:22]=1[N+:29]([O-:31])=[O:30].O>C1COCC1>[Cl:20][C:21]1[C:22]([N+:29]([O-:31])=[O:30])=[CH:23][C:24]([CH3:28])=[C:25]([CH:26]=1)[O:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1
Reactant: Cc1cc([N+](=O)[O-])c(Cl)cc1F
Reactant: CC(C)(C)OC(=O)N1CCN(CCCO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc([N+](=O)[O-])c(Cl)cc1OCCCN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 65 °C

Procedure:
A flask was charged with tert-butyl 4-(3-hydroxypropyl)piperazine-1-carboxylate (905 mg, 3.7 mmol, commercially available from Alrich), sodium hydride, 95% (24 mg, 4.6 mmol) and THF (10 mL), and the mixture was stirred under N2 for 15 minutes, after which time a solution of 1-chloro-5-fluoro-4-methyl-2-nitrobenzene (700 mg, 3.7 mmol, commercially available from Aldrich) in THF (10 mL) was added to the sodium hydride mixture at 0° C. The reaction mixture was heated to 65° C. for 15 hours. Water was added to the cooled reaction mixture and the mixture was extracted with ethyl acetate. The organic solvent was concentrated under reduced pressure and the resulting solid was purified by silica column chromatography eluting with 5% methanol in dichloromethane, to give 1.2 g (78 5 yield) of tert-butyl 4-(3-(5-chloro-2-methyl-4-nitrophenoxy) propyl)piperazine-1-carboxylate. 1H-NMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 6.92 (s, 1H), 3.92 (t, 2H), 3.06 (m, 4H), 2.62 (m, 4H), 2.36 (m, 2H), 2.34 (s, 3H), 1.84 (m, 2H), 1.42 (s, 9H). MS (EI): 414 (MH+).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[CH3:8][CH:9]([C:11](=[O:13])[CH3:12])[CH3:10]>CCO>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:12][C:11](=[O:13])[CH:9]([CH3:10])[CH3:8]
Reactant: O=Cc1ccco1
Reactant: CC(=O)C(C)C
Solvent: CCO
Product: CC(C)C(=O)C=Cc1ccco1

Procedure:
The titled compound was prepared according to General Method 2 by reacting 2-furaldehyde (117 mmol), 2-methyl-butan-3-one (117 mmol), anhydrous Ba(OH)2 (2.2 g) and EtOH (200 mL) to afford the desire compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:18][CH2:19][CH2:20][CH2:21]Br>CN(C=O)C>[Br:18][CH2:19][CH2:20][CH2:21][O:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=1
Reactant: BrCCCBr
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(OCCCBr)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of N-(4-hydroxyphenyl)acetamide (10 g) and potassium carbonate (11 g) in DMF (200 ml) was stirred for 20 min at room temperature. 1,3-Dibromopropane (35 ml) was then added and stirring was continued for 4 h. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was treated with water and extracted with dichloromethane. The organic phase was washed first with dilute sodium hydroxide, then with water, dried and concentrated to give a solid which was triturated with hexane to give the title compound (14 g), MP: 120°.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:31][C:32]1[CH:37]=[C:36]([F:38])[C:35]([F:39])=[CH:34][C:33]=1[F:40])[CH2:9][C:10]([N:12]1[CH2:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[N:15]([CH2:23][C:24](=[O:29])[NH:25][CH:26]2[CH2:28][CH2:27]2)[C:14](=[O:30])[CH2:13]1)=[O:11])(C)(C)C.[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45]>C(Cl)Cl>[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45].[NH2:7][C@H:8]([CH2:31][C:32]1[CH:37]=[C:36]([F:38])[C:35]([F:39])=[CH:34][C:33]=1[F:40])[CH2:9][C:10]([N:12]1[CH2:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[N:15]([CH2:23][C:24]([NH:25][CH:26]2[CH2:28][CH2:27]2)=[O:29])[C:14](=[O:30])[CH2:13]1)=[O:11]
Reactant: CC(C)(C)OC(=O)NC(CC(=O)N1CC(=O)N(CC(=O)NC2CC2)c2ccccc2C1)Cc1cc(F)c(F)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](CC(=O)N1CC(=O)N(CC(=O)NC2CC2)c2ccccc2C1)Cc1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a solution of [3-(1-cyclopropylcarbamoylmethyl-2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester (40 mg, 0.07 mmol) in DCM (2 mL), was added trifluoroacetic acid (0.2 mL, 3 mL/mmol). The reaction mixture was stirred at r.t. for 1 h. After the completion of the reaction as confirmed by TLC, excess of trifluoroacetic acid and DCM were removed in vacuo to afford a gummy solid which was crystallised from hexane to afford trifluoroacetic acid salt of 2-{4-[(R)-3-amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-2-oxo-2,3,4,5-tetrahydro-benzo[e][1,4]diazepin-1-yl}-N-cyclopropyl-acetamide (32 mg, 78%).
Reaction SMILES: [CH:1]([C:4]1[NH:5][CH2:6][CH2:7][CH2:8][N:9]=1)([CH3:3])[CH3:2].[H][H].[H][H].N#N>N1C=CC=CC=1.[Pt]>[CH:1]([C:4]1[N:9]=[CH:8][CH:7]=[CH:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)C1=NCCCN1
Agent: [Pt]
Agent: N#N
Solvent: c1ccncc1
Product: CC(C)c1ncccn1
Yield: 73 %

Procedure:
A solution of 70 g of 2-isopropyl-1, 4, 5, 6-tetrahydropyrimidine in 100 ml of pyridine was fed at about 1 ml/min to a column 1"×20" containing about 50 g of 0.5 percent platinum on α-alumina at 300° to 325° C. while sweeping out the column with a mixture of nitrogen and hydrogen. The catalyst had been activated by passing a 2:1 H2 /N2 stream over the bed for two hours. The effluent was distilled giving 2-isopropylpyrimidine at 152° to 155° C. The yield was 73 percent.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH:16]([CH3:18])[CH3:17])=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[CH:8][CH:7]([CH3:15])[CH2:6]2.[Br:19]Br>ClCCl>[Br:19][C:8]1[CH:7]([CH3:15])[CH2:6][C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[C:4]=2[CH:16]([CH3:18])[CH3:17])[CH:9]=1
Reactant: BrBr
Reactant: COc1cc2c(c(C(C)C)c1OC)CC(C)C=C2
Solvent: ClCCl
Product: COc1cc2c(c(C(C)C)c1OC)CC(C)C(Br)=C2
Reaction time: 0.25 h
Yield: 91 %

Procedure:
Compound 12 (3.00 g, 12.2 mmol) was dissolved in 20 mL of dichloromethane and bromine (1.95 g, 12.2 mmol) in 5 ml of dichloromethane was added dropwise with stirring over a period of 15 min. The solvent was evaporation and the residue was taken up in 15 ml of DMF. The DMF solution was warmed to 50°-60° C. for 1 h. The reaction mixture was poured onto ice and stirred. The solid product was filtered, dried and recrystallized from a concentrated petroleum ether solution to give 3.60 g (11.1 mmol, 91%) of 13 as nearly colorless microcrystalline plates: mp 71°-72° C.; 1H NMR 1.09 (d, J=6.95, 3 H) , 1.32 (d, J=7.2 Hz, 6 H), 2.4-3.2 (m, 3 H), 3.49 (m, 1 H), 3.80 (s, 3 H), 3.82 (s, 3H), 6.43 (s, 1 H), 6.64 (s, 1H). Anal. (C16H21BrO2) C, H.
Reaction SMILES: Br[CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].[C:15]([O-:18])(=[S:17])[CH3:16].[K+].CN(C=O)C>O>[C:15]([S:17][CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4])(=[O:18])[CH3:16]
Reactant: COC(=O)C(Br)Cc1ccc(C)cc1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(Cc1ccc(C)cc1)SC(C)=O
Temperature: 25 °C
Yield: 99.9 %

Procedure:
A mixture of methyl 2-bromo-3-(4-methylphenyl)propionate (25.7 g), potassium thioacetate (CH3COSK) (13.7 g) and DMF (120 ml) was stirred for an hour at room temperature. The mixture was poured into water and extracted with ether. The ethereal layer was washed with water, dried (MgSO4) and concentrated to give methyl 2-acetylthio-3-(4-methylphenyl)propionate (25.2 g, 100%) as an oil.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]([O:18]C(C)(C)C)=[O:17])[CH2:15][C@@:9]1([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C@H:10]([O:23][CH2:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=1)[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48]>ClCCl>[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48].[CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]([OH:18])=[O:17])[CH2:15][C@@:9]1([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C@H:10]([O:23][CH2:24][C:25]1[CH:26]=[C:27]([C:35]([F:37])([F:38])[F:36])[CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=1)[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1

Procedure:
A mixture of (1R*,2R*,5S*,6R*)-8-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-(tert-butoxycarbonyl)-1-phenyl-8-azabicyclo[3.2.1]octane (Example 24; 3.37 g, 5.43 mmol), trifluoroacetic acid (4 ml) and dichloromethane (6 ml) was stirred at reflux for 4.5 hour then concentrated in vacuo to give crude title compound which crystallised from dichloromethane.
Reaction SMILES: [ClH:1].O1CCOCC1.[Br:8][C:9]1[S:13][C:12]([C:14]([N:16]2[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH:17]2[CH2:29][O:30][C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)=[O:15])=[CH:11][CH:10]=1>CO>[ClH:1].[ClH:1].[Br:8][C:9]1[S:13][C:12]([C:14]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH:17]2[CH2:29][O:30][C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)=[O:15])=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(Br)s2)C(COc2cccnc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C(c1ccc(Br)s1)N1CCNCC1COc1cccnc1
Reaction time: 1 h
Yield: 59 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of tert-butyl 4-(5-bromothiophene-2-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate (192.6 mg, 0.399 mmol) in MeOH (1 mL). After 1 h, the reaction mixture was concentrated under reduced pressure and purified by HPLC (5 to 50% MeCN/0.1% TFA in H2O/0.1% TFA gradient). The desired chromatography fractions were concentrated under reduced pressure, dissolved in MeOH (1 mL), and treated with 4 M HCl in 1,4-dioxane (6 mL). This was concentrated under reduced pressure, yielding 108 mg (59%) of the desired product as a white solid. LC-MS: RT=4.16 min, [M+H]+=382.0.
Reaction SMILES: I[C:2]1[CH:14]=[CH:13][C:5]([C:6]([N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[Li]CCCC.[C:20]([C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=[O:28])([O:22][CH3:23])=[O:21].[NH4+].[Cl-]>C1(C)C=CC=CC=1.C1COCC1>[CH2:9]([N:8]([CH2:11][CH3:12])[C:6]([C:5]1[CH:13]=[CH:14][C:2]([CH:27]([OH:28])[C:26]2[CH:25]=[C:24]([CH:31]=[CH:30][CH:29]=2)[C:20]([O:22][CH3:23])=[O:21])=[CH:3][CH:4]=1)=[O:7])[CH3:10]
Reactant: CCN(CC)C(=O)c1ccc(I)cc1
Reactant: COC(=O)c1cccc(C=O)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCN(CC)C(=O)c1ccc(C(O)c2cccc(C(=O)OC)c2)cc1
Temperature: -78 °C
Yield: 48.8 %

Procedure:
INTERMEDIATE 5 (2.8 g, 9.0 mmol) was dissolved in TBF (100 mL) and cooled to −78° C. under nitrogen atmosphere. Then n-BuLi (8.4 mL, 1.07 M solution in hexane, 9.0 mmol) was added dropwise during 10 min at −65 to −78° C. The solution was canulated into 3-carbomethoxybenzaldehyde (1.49 g, 9.1 mmol) in toluene/THF (approx. 1:1, 50 mL) at −78° C. NH4Cl (aq.) was added after 30 min. After concentration in vacuo, extraction with EtOAc/water, drying (MgSO4) and evaporation of the organic phase, the residue was purified by chromatography on silica (0-75% EtOAc/heptane) to give INTERMEDIATE 6 (1.5 g, 49%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH:13]=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH2:15][N:16]1[CH2:20][CH:19]([CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[O:18][C:17]1=[O:28].Cl>>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][C:11]([CH:13]=[N:15][N:16]3[CH2:20][CH:19]([CH2:21][N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)[O:18][C:17]3=[O:28])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(-c2ccc(Cl)cc2)o1
Reactant: NN1CC(CN2CCCCC2)OC1=O
Agent: Cl
Product: O=C1OC(CN2CCCCC2)CN1N=Cc1ccc(-c2ccc(Cl)cc2)o1

Procedure:
5-(4-Chlorophenyl)-2-furancarboxaldehyde [prepared as described in U.S. Pat. No. 4,882,354, to Huang et al. (assigned to Norwich Eaton Pharmaceuticals, Inc.,) issued Nov. 21, 1984; see cols. 7 & 8, hereby incorporated by reference] (3.92 g, 19.0 mmole) and 3-amino-5-(1-piperidinyl)methyl-2-oxazolidinone (3.78 g, 19.0 mole)[(prepared as described in U.S. Pat. No. 2,802,002 to Gever, (assigned to Norwich Eaton Pharmaceuticals, Inc. issued Aug. 6, 1957, see Example I, Part A, hereby incorporated by reference herein) in 150 ml of alcohol is treated with 3 ml of concentrated hydrochloric acid (pH ca. 3). The reaction mixture is stirred and heated at reflux for 2.5 hours. The mixture is chilled and filtered to give crude 3-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]-5-(1-piperidinylmethyl)-2-oxazolidinone hydrochloride, which is purified by one recrystallization from nitromethane (activated charcoal) yielding 3.2 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([CH:15]=2)[C:13]([CH3:16])=[C:12]([C:17]([OH:19])=O)[S:11]3)=[CH:4][CH:3]=1.[Cl-].[NH4+].[B-](F)(F)(F)F.CCOC(C(C#N)=[N:33]OC(N(C)C)=[N+](C)C)=O.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([CH:15]=2)[C:13]([CH3:16])=[C:12]([C:17]([NH2:33])=[O:19])[S:11]3)=[CH:4][CH:3]=1
Reactant: Cc1c(C(=O)O)sc2nc(-c3ccc(F)cc3)cn12
Reactant: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1c(C(N)=O)sc2nc(-c3ccc(F)cc3)cn12
Yield: 28.3 %

Procedure:
6-(4-Fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acid (example 7, 50 mg, 0.18 mmol), ammonium chloride (19.4 mg, 0.36 mmol), TOTU (63.32 mg, 0.2 mmol) and triethylamine (100.6 μl, 0.72 mmol) in 3 ml DMF were stirred at RT for 8 hours. The mixture was evaporated. Ethyl acetate and water were added, the organic layer was separated, washed with water, dried and evaporated. The crude product was purified by preparative HPLC (RP18, acetonitrile/water 0.1% TFA) to yield 14 mg (28%) of the desired product. MS: M+H+=276.03.