Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:2]([C:4]([OH:6])=O)[CH3:3].CC1C=CC(S(O)(=O)=O)=CC=1.[CH:25]1[CH:30]=[CH:29][C:28]([CH2:31][O:32][C:33]([CH2:35][NH2:36])=[O:34])=[CH:27][CH:26]=1>C(Cl)Cl>[NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:2]([C:4]([NH:36][CH2:35][C:33]([O:32][CH2:31][C:28]1[CH:29]=[CH:30][CH:25]=[CH:26][CH:27]=1)=[O:34])=[O:6])[CH3:3]
Reactant: NCC(=O)OCc1ccccc1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: C[C@@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 90.8 %

Procedure:
Boc-D-Ala-OH (5.68 g, 30 mmole) and H-Gly-OBzl.TosOH (10.6 g, 1.05 eq) were suspended in CH2Cl2. WSCI (6 ml, 1.1 eq) was added dropwise while cooling, and the solution was stirred overnight. The CH2Cl2 was distilled off. The residue was dissolved in AcOEt (500 ml); washed with 1N HCl, water, 5% NaHCO3, and water in order; and dried over Na2SO4. AcOEt was distilled off, and the residue was recrystalized twice with AcOEt/n-hexane to give the desired product (9.16 g, 90.7%).
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[O:13]=[C:14]1[NH:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[C:17](=[O:25])[N:16]([CH2:26][C@H:27]2[CH2:32][CH2:31][C@H:30]([C:33](O)=[O:34])[CH2:29][CH2:28]2)[CH2:15]1.[N:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>C(Cl)Cl>[N:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[N:42]1[CH2:43][CH2:44][N:45]([C:33]([C@H:30]2[CH2:29][CH2:28][C@H:27]([CH2:26][N:16]3[C:17](=[O:25])[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[NH:20][C:14](=[O:13])[CH2:15]3)[CH2:32][CH2:31]2)=[O:34])[CH2:46][CH2:47]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: O=C1CN(C[C@H]2CC[C@H](C(=O)O)CC2)C(=O)c2ccccc2N1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=C1CN(C[C@H]2CC[C@H](C(=O)N3CCN(c4ccccn4)CC3)CC2)C(=O)c2ccccc2N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
CDI (0.18 mmol, 0.03 g) was added to a solution of trans-4-(2,5-Dioxo-1,2,3,5 tetrahydrobenzo[e][1,4]diazepin-4-ylmethyl)-cyclohexanecarboxylic acid (0.16 mmol, 0.05 g) in dry DCM (1 mL) under argon. After 1 h at room temperature, 1-Pyridin-2-yl-piperazine (0.24 mmol, 35 μL) was added and the reaction mixture was left stirring at room temperature under argon overnight. The DCM solution was washed with water, the solvent was removed under reduced pressure and the crude purified by column chromatography on silica gel using DCM/MeOH 95/5 as eluent to give 45 mg (yield 59%) of the titled compound.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[N+:12]([C:15]1[CH:16]=[C:17]([CH:25]([OH:27])[CH3:26])[CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)([O-:14])=[O:13].C(N(CC)CC)C>ClCCl>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([S:7]([O:27][CH:25]([C:17]2[CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=[C:15]([N+:12]([O-:14])=[O:13])[CH:16]=2)[CH3:26])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: CC(O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC(C)c2cc([N+](=O)[O-])cc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 80.6 %

Procedure:
Add p-toluenesulfonyl chloride (1.7 g, 8.9 mmol) dropwise at 0° C. to the mixture of 1-(3-nitro-5-(trifluoromethyl)phenyl)ethanol (520 mg, 2.23 mmol) and triethylamine (1.4 g, 13.4 mmol) in dichloromethane (20 mL), stir the resulting mixture for 12 hrs at ambient temperature. Concentrate the mixture under reduced pressure to get a residue, purify the residue by chromatography (silica gel, EtOAc:PE=1:10) to afford the title compound (700 mg, 80.6%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[NH:13][C:12]([O:16][CH3:17])=[N:11][C:10]=1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:28][C:29]([O:31][CH3:32])=[O:30]>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[N:11][C:12]([O:16][CH3:17])=[N:13][C:14]=1[O:15][CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CBr
Reactant: COc1nc(C(=O)OC(C)(C)C)c(OCc2ccccc2)c(=O)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1nc(OC)nc(C(=O)OC(C)(C)C)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 29.9 %

Procedure:
tert-Butyl 5-(benzyloxy)-2-methoxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate (300 mg, 0.903 mmol) and sodium hydride (36.1 mg, 0.903 mmol) were stirred in anhydrous DMF (903 μl) at 0° C. under argon for 30 min. Methyl 2-bromoacetate (83 μl 0.90 mmol) was added and the mixture was stirred at rt for 3 h. The reaction was carefully quenched with water at 0° C. The reaction mixture was extracted with EtOAc (3×). The combined organic layers were washed with water, brine, dried over Na2SO4, concentrated and purified by flash chromatography (hexanes/EtOAc, eluted at ca. 30% EtOAc) to give tert-butyl 5-(benzyloxy)-2-methoxy-6-(2-methoxy-2-oxoethoxy)pyrimidine-4-carboxylate (109 mg, 0.270 mmol, 29.9% yield) as a colorless oil and Example 267A (117 mg, 0.289 mmol, 32.1% yield) as a colorless oil. 1H NMR (500 MHz, chloroform-d) δ 7.49-7.44 (m, 2H), 7.37-7.32 (m, 2H), 7.32-7.27 (m, 1H), 5.12 (s, 2H), 4.74 (s, 2H), 4.00 (s, 3H), 3.75 (s, 3H), 1.51 (s, 9H). LC-MS (ESI) 349.0 (M+H-t-Bu), retention time=2.07 min (Method B).
Reaction SMILES: [CH:1]1([C:11]([OH:13])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:14]([C:16]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[CH:26][CH:25]=2)=[CH:18][CH:17]=1)[CH3:15]>>[CH2:14]([C:16]1[CH:21]=[CH:20][C:19]([N:22]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)=[CH:26][CH:25]=2)[C:11]([CH:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)=[O:13])=[CH:18][CH:17]=1)[CH3:15]
Reactant: CCc1ccc(NCc2ccc(N3CCOCC3)cc2)cc1
Reactant: O=C(O)C1CCCc2ccccc21
Product: CCc1ccc(N(Cc2ccc(N3CCOCC3)cc2)C(=O)C2CCCc3ccccc32)cc1
Yield: 68.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.34 g) and (4-ethylphenyl)[(4-morpholinophenyl)methyl]amine (0.59 g) as starting materials, N-(4-ethylphenyl)-N-[(4-morpholinophenyl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.60 g) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:21][C@@H:22]1[C@@H:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][N:24]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O:40]C)=[O:39])[CH2:23]1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.C1COCC1>[C:1]([O:5][C:6]([N:8]([CH2:21][C@@H:22]1[C@@H:26]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:25][N:24]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])[CH2:23]1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)CCCCCN1C[C@H](CN(C(=O)OC(C)(C)C)[C@H](C)c2cccc3ccccc23)[C@@H](c2ccccc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](c1cccc2ccccc12)N(C[C@H]1CN(CCCCCC(=O)O)C[C@@H]1c1ccccc1)C(=O)OC(C)(C)C

Procedure:
A 262 mg portion of methyl 6-[(3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]hexanoate was dissolved in 3 ml of methanol and 3 ml of THF, mixed with 2 ml of 1 M sodium hydroxide aqueous solution at room temperature and stirred for 7Hours. The reaction solution was washed with diethyl ether, and 1 M hydrochloric acid was added to the water layer until it became pH 3. After its extraction with diethyl ether, the organic layer was dried with anhydrous sodium sulfate and concentrated under a reduced pressure to obtain 6-[(3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]hexanoic acid as a crude product. The thus obtained crude product was dissolved in 3.0 ml of 4 M hydrogen chloride/1,4-dioxane solution at room temperature, and the reaction solution was concentrated under a reduced pressure. THF and diethyl ether were added to the thus obtained residue, and the resulting precipitate was collected by filtration and dried under a reduced pressure to obtain 123 mg of 6-[(3S,4S)-3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]hexanoic acid dihydrochloride as a white solid.
Reaction SMILES: [NH2:1][C:2]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)=[S:3].Br[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=O.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:21]1([C:19]2[N:1]=[C:2]([CH:4]3[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]3)[S:3][CH:18]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=S)CC1
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccccc3)cs2)CC1
Temperature: 110 °C
Reaction time: 1.5 h
Yield: 55.3 %

Procedure:
A mixture of tert-butyl 4-(aminocarbonothioyl)piperidine-1-carboxylate (1.00 g, 7.24 mmol), 2-bromoacetophenone (1.58 g, 7.96 mmol), potassium carbonate (1.00 g, 7.24 mmol) and N,N-dimethylformamide (30 ml) was stirred at 110° C. for 1.5 hours. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate=1:1) to obtain the desired product (1.38 g, 55.2%) as an oil.
Reaction SMILES: CC(C[AlH]CC(C)C)C.C[O:11][C:12](=O)[CH2:13][CH2:14][C:15]1[CH:26]=[CH:25][C:24]2[CH2:23][CH:22]3[CH:27]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:19]([CH2:20][CH2:21]3)[CH2:18][C:17]=2[CH:16]=1>C1(C)C=CC=CC=1>[C:32]([O:31][C:29](=[O:30])[NH:28][CH:27]1[CH:22]2[CH2:21][CH2:20][CH:19]1[CH2:18][C:17]1[CH:16]=[C:15]([CH2:14][CH2:13][CH:12]=[O:11])[CH:26]=[CH:25][C:24]=1[CH2:23]2)([CH3:35])([CH3:33])[CH3:34]
Reactant: COC(=O)CCc1ccc2c(c1)CC1CCC(C2)C1NC(=O)OC(C)(C)C
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC1C2CCC1Cc1cc(CCC=O)ccc1C2
Temperature: -78 °C
Reaction time: 2 h
Yield: 55.8 %

Procedure:
DIBAL-H (1M in toluene, 855 μl, 0.855 mmol) was added dropwise to a stirred solution of the product of Step 1 (290 mg, 0.777 mmol) in toluene (8 ml) maintaining the reaction temperature below −70° C. After stirring at −78° C. for 2 hours, more DIBAL-H (77 μl) was added and stirring was continued for 2 additional hours at −78° C. The mixture was quenched with methanol at −78° C., allowed to warm to room temperature and dispersed between ethyl acetate and 1N HCl. The organic phase was washed with sodium bicarbonate solution (sat), brine, dried and concentrated to give a colourless oil. Analysis by NMR showed ˜15% starting ester present, so the product was subjected to a further treatment with DIBAL-H (122 μl) for 2 hours at −78° C. as described above. The crude product was purified by column chromatography on silica gel eluting with 5:1 isohexane-ethyl acetate to give a colourless oil 149 mg (56%).1 NMR (CDCl3, 360 MHz) δ 9.81 (1H, s), 7.00 (1H, m), 6.90 (2H, m), 4.97 (1H, m), 4.04 (1H, m), 2.86–3.03 (4H, m), 2.75 (2H, m), 2.45–2.63 (4H, m), 1.71 (2H, m), 1.47 (9H, s), 1.19 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].C([O:13][C:14]1[C:15](=[O:25])[C:16](=O)[C:17]=1[NH:18][C:19]([CH3:23])([CH3:22])[CH2:20][CH3:21])C>C(#N)C>[Cl:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:16]1[C:15](=[O:25])[C:14](=[O:13])[C:17]=1[NH:18][C:19]([CH3:22])([CH3:23])[CH2:20][CH3:21]
Reactant: CCOc1c(NC(C)(C)CC)c(=O)c1=O
Reactant: NCc1ccc(F)cc1Cl
Solvent: CC#N
Product: CCC(C)(C)Nc1c(NCc2ccc(F)cc2Cl)c(=O)c1=O

Procedure:
This compound was prepared according to the procedure for Example 59. From 2-chloro-4-fluorobenzylamine and 3-ethoxy-4-(1,1-dimethyl-propylamino)-cyclobut-3-ene-1,2-dione in acetonitrile. The title compound was obtained, after recrystallization from petroleum ether, as a white solid (60%); mp 201°-203° C.; 1H NMR (DMSO-d6) δ0.81 (t, 3H), 1.30 (s, 6H), 1.68 (q, 2H), 4.76 (d, 2H), 7.25 (m, 1H), 7.50 (m, 3H), 7.78 (m, 1H) ppm; IR (KBr) 3250, 3040, 1790, 1660, 1580, 1530, 1490 cm-1 ; MS (m/z) 325 ([M+H]+).
Reaction SMILES: [CH2:1]([N:4]1[C:8](=[O:9])[CH2:7][NH:6][C:5]1=[S:10])[CH:2]=[CH2:3].[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.Cl>O>[CH2:1]([N:4]1[C:8](=[O:9])[C:7](=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:6][C:5]1=[S:10])[CH:2]=[CH2:3]
Reactant: O=Cc1ccccc1
Reactant: C=CCN1C(=O)CNC1=S
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Product: C=CCN1C(=O)C(=Cc2ccccc2)NC1=S
Reaction time: 18 h

Procedure:
A flask equipped with a magnetic stirrer, condenser, and nitrogen pressure was charged with 3-allylthiohydantoin (15 g, 0.096 mol), water (90 mL), and benzaldehyde (10.2 g, 0.096 mol). As the mixture was stirred, triethylamine (19.4 g, 0.192 mol) was added slowly. After 18 hr, HPLC analysis indicated the absence of starting material, and the mixture was transferred to an Erlenmeyer flask. The mixture was stirred vigorously as 3 M hydrochloric acid was added dropwise until the pH reached 3 (65 mL). The mixture was stirred for an additional 90 min, and then the solid that had formed was collected by filtration. The still wet solid was resuspended in 100 mL of water, stirred for 30 min, and collected. After air drying, the orange solid weighed 18.4 g (79%). HPLC analysis indicated a purity of 95% at 215 nm. NMR (CDCl3) δ 9.3 (bs, 1H), 7.4 (s, 5H), 6.8 (s, 1H), 5.1-6.3 (m, 3H), 4.6 (d, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=O)[CH2:7][O:8][C:4]=2[CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[NH4+].C(OCC)(=O)C>O1CCCC1>[O:8]1[C:4]2[CH:3]=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=2[CH2:6][CH2:7]1
Reactant: O=C1COc2cc(O)ccc21
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Oc1ccc2c(c1)OCC2
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
6-Hydroxy-2H-benzofuran-3-one (3 g) was suspended in anhydrous tetrahydrofuran under an argon atmosphere and cooled to 0° C. Lithium aluminium hydride (20 ml of a 1M solution in tetrahydrofuran) was added dropwise over 10 min and the reaction allowed to reach room temperature over 2 hours. The reaction was cooled to 0° C. and treated dropwise with saturated ammonium chloride solution. Ethyl acetate (200 ml) was added and the mixture filtered through Celite. The ethyl acetate layer was separated, dried (MgSO4) and evaporated to dryness under reduced pressure. The resulting mixture of 2,3-dihydro-benzofuran-3,6-diol and benzofuran-6-ol (approximately 1:1 by 250 MHz 1H NMR) was dissolved in a mixture of hydrochloric acid (200 ml, 5M aqueous solution) and methanol (300 ml) and palladium hydroxide (0.5 g) added. The mixture was stirred under a hydrogen atmosphere for 3 hours then filtered through Celite. The organics were removed by evaporation under reduced pressure and the resulting solution neutralised with concentrated anmmonia solution. The product was extracted into dichloromethane. The dichloromethane solution was dried (MgSO4) and evaporated to dryness under reduced pressure to yield the title compound (2.5 g, 92%). 1H NMR (250 MHz, CDCl3) δ: 3.11 (2H, t, J=8.4 Hz), 4.57 (2H, t, J=8.4 Hz), 6.27-6.34 (2H, m), 6.92-7.02 (1H, m); m/z (API+): 139.1 (M+3H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:15])=[C:6]([CH:14]=1)[C:7]([NH:9][CH2:10][CH:11]=[N:12][OH:13])=[O:8].CN(C1C=CC(N=NC2C=CC(S(O)(=O)=O)=CC=2)=CC=1)C.[CH3:37][OH:38].Cl.C([BH3-])#N.[Na+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:15])=[C:6]([CH:14]=1)[C:7]([NH:9][CH2:10][CH2:11][N:12]([CH:37]=[O:38])[OH:13])=[O:8]
Reactant: O=C(NCC=NO)c1cc(Br)ccc1Cl
Reactant: CO
Agent: CN(C)c1ccc(N=Nc2ccc(S(=O)(=O)O)cc2)cc1
Agent: Cl
Agent: [BH3-]C#N
Product: O=CN(O)CCNC(=O)c1cc(Br)ccc1Cl
Reaction time: 2 h
Yield: 35 %

Procedure:
To a solution of 5-bromo-2-chloro-N-(2-hydroxyimino-ethyl)-benzamide (2 g, 6.9 mmol) in MeOH (75 mL) under an argon atmosphere at 0° C. was added methyl orange (trace) followed by a saturated solution of MeOH/HCl until a persistent red color was observed. Sodium cyanoborohydride (0.52 g, 8.2 mmol) was dissolved in MeOH (10 mL) and was added sequentially with saturated MeOH/HCl over 0.5 h. The reaction mixture was stirred an additional 2 h and the MeOH was removed in vacuo. The residue was basidified with saturated Na2CO3 and extracted (7×25 mL) with dichloromethane/MeOH (9:1). The combined organic extracts were washed with brine, were dried (Na2SO4) and were concentrated to provide the title compound (0.7 g, 35%) as a white solid. ESMS: M+H=293.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:8][C@H:7]([N:9]([C:14]([C:16]2[N:20]([CH2:21][CH2:22][CH2:23][CH2:24][O:25][CH3:26])[C:19]3[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=3[N:17]=2)=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])[CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1.[C:38](OCC)(=[O:40])[CH3:39].[ClH:44]>C(OCC)(=O)C>[ClH:44].[ClH:44].[C:38]([O:1][CH2:2][C@@H:3]1[CH2:8][C@H:7]([N:9]([C:14]([C:16]2[N:20]([CH2:21][CH2:22][CH2:23][CH2:24][O:25][CH3:26])[C:19]3[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=3[N:17]=2)=[O:15])[CH2:10][CH:11]([CH3:12])[CH3:13])[CH2:6][NH:5][CH2:4]1)(=[O:40])[CH3:39]
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](CO)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Reactant: CCOC(C)=O
Agent: Cl
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@@H]2CNC[C@H](COC(C)=O)C2)nc2ccccc21
Reaction time: 1 h

Procedure:
tert-Butyl (3R,5S)-3-(hydroxymethyl)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate (200 mg) was dissolved in ethyl acetate (2 ml), 4N hydrogen chloride-ethyl acetate (5 ml) was added, and the mixture was stirred for 1 hr. The solvent was evaporated under reduced pressure to give the object product (200 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[NH:12][C@H:11]([C:13](OCC)=[O:14])[CH2:10][CH2:9]2)[CH:5]=[N:6][CH:7]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[NH:12][C@H:11]([CH2:13][OH:14])[CH2:10][CH2:9]2)[CH:5]=[N:6][CH:7]=1
Reactant: CCOC(=O)[C@@H]1CC[C@H](c2cncc(F)c2)N1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OC[C@@H]1CC[C@H](c2cncc(F)c2)N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 104.8 %

Procedure:
To a solution of (2S,5R)-ethyl 5-(5-fluoropyridin-3-yl)pyrrolidine-2-carboxylate (1.10 g, 4.62 mmol) in dry THF (20 mL) was added 2M LiAlH4 in THF (3.00 mL, 6.00 mmol). The reaction was stirred at ambient temperature for 30 minutes and Na2SO4 10H2O (3.00 g, 9.31 mmol) was added in small portions. The mixture was stirred for 3 hours at ambient temperature and was filtered. The collected solid was washed with EtOAc and the washes combined with the filtrate. The solution was concentrated to provide crude ((2S,5R)-5-(5-fluoropyridin-3-yl)pyrrolidin-2-yl)methanol (0.95 g, 105% yield) that was used directly in the next step. MS (apci) m/z=197.1 (M+H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:23][C:24]1[CH:33]=[CH:32][C:31]2[C:30](B(O)O)=[CH:29][CH:28]=[CH:27][C:26]=2[N:25]=1>>[F:18][C:17]1[C:12]2[N:13]([C:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([C:30]4[CH:29]=[CH:28][CH:27]=[C:26]5[C:31]=4[CH:32]=[CH:33][C:24]([CH3:23])=[N:25]5)[CH:3]=3)=[CH:10][N:11]=2)[CH:14]=[CH:15][C:16]=1[C:19]([OH:22])([CH3:21])[CH3:20]
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Reactant: Cc1ccc2c(B(O)O)cccc2n1
Product: Cc1ccc2c(-c3cc(-c4cnc5c(F)c(C(C)(C)O)ccn45)ccc3F)cccc2n1
Yield: 4 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and 2-methylquinoline-5-boronic acid were coupled in the same way as in Example 30 to give 2-{8-fluoro-3-[4-fluoro-3-(2-methylquinolin-5-yl)phenyl]imidazo[1,2-α]pyridin-7-yl}propan-2-ol as an off-white solid (5 mg, 4%): m/z (ES+) 430 [MH+].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[O:10]2)[CH:5]=[CH:6][C:7]=1[F:8].C(N(CC)CC)C.[Cl:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:25]=1[C:26](Cl)=[O:27]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[N:12]([C:26](=[O:27])[C:25]3[C:24]([Cl:23])=[CH:32][CH:31]=[CH:30][C:29]=3[Cl:33])[C:11](=[O:15])[O:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=c1[nH]c(=O)n(-c2ccc(F)c(F)c2)o1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(c1c(Cl)cccc1Cl)n1c(=O)on(-c2ccc(F)c(F)c2)c1=O
Reaction time: 24 h

Procedure:
2-(3,4-Difluorophenyl)-1,2,4-oxadiazolidin-3,5-dione (0.03 mole), toluene (100 ml) and triethylamine (5 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2,6-Dichlorobenzoyl chloride (0.03 mole) dissolved in toluene (20 ml) is then added to the reaction flask and the resulting mixture is heated at reflux with stirring for a period of about 24 hours. After this time the reaction mixture is filtered and the filtrate is washed with water, dilute hydrochloric acid and with aqueous sodium bicarbonate. The washed solution is then dried over anhydrous magnesium sulfate. The dried solution is stripped of solvent under reduced pressure leaving a solid residue. The residue is recrystallized to yield the desired product 2-(3,4-difluorophenyl)-4-(2,6-dichlorobenzoyl)-1,2,4-oxadiazolidin-3,5-dione.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([I:19])[CH:17]=[CH:18][C:13]=2[N:12]([CH3:20])[C:11](=[O:21])[CH2:10][N:9]=1.C(O[CH:25](OCC)[N:26]([CH3:28])[CH3:27])C>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([I:19])[CH:17]=[CH:18][C:13]=2[N:12]([CH3:20])[C:11](=[O:21])[C:10](=[CH:25][N:26]([CH3:28])[CH3:27])[N:9]=1
Reactant: CCOC(OCC)N(C)C
Reactant: CN1C(=O)CN=C(c2ccccc2Cl)c2cc(I)ccc21
Product: CN(C)C=C1N=C(c2ccccc2Cl)c2cc(I)ccc2N(C)C1=O
Temperature: 130 °C

Procedure:
A mixture consisting of 8 gm of 5-(2'-chloro-phenyl)-1,3-dihydro-7-iodo-1-methyl-2H-1,4-benzodiazepin-2-one and 16 ml of N,N-dimethyl-formamide-diethylacetal was heated for 90 minutes at 130°C. Thereafter, the reaction mixture was allowed to cool, and the crystalline substance which separated out was collected by vacuum filtration and washed with benzene and petroleum ether, yielding the compound named in the heading, which had a melting point of 182°-184°C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([CH:26]([CH3:28])[CH3:27])=[C:11]([CH2:13][CH2:14]OS(C2C=CC(C)=CC=2)(=O)=O)[N:12]=1.[I-:29].[Na+].O>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([CH:26]([CH3:28])[CH3:27])=[C:11]([CH2:13][CH2:14][I:29])[N:12]=1
Reactant: [I-]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3Cl)oc2C(C)C)cc1
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)c1oc(-c2ccccc2Cl)nc1CCI
Yield: 95.4 %

Procedure:
In acetone (2 mL) was dissolved 2-(2-chlorophenyl)-5-isopropyl-4-[2-(p-toluenesulfonyloxy)ethyl]oxazole (123 mg, 0.293 mmol). To the solution was added sodium iodide (176 mg, 1.17 mmol). The mixture was heated overnight under reflux. The reaction mixture was allowed to reach room temperature, poured into water, and extracted with ethyl acetate. The organic layer was successively washed with water and saturated brine, dried over sodium sulfate, filtered, and concentrated, to obtain the desired compound (105 mg, 96%).