Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1.[Cl:17][C:18]1([Cl:25])[CH2:20][C:19]1([CH3:24])[C:21](O)=[O:22].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[Cl:17][C:18]1([Cl:25])[CH2:20][C:19]1([C:21]([N:12]1[CH2:11][CH2:10][N:9]([C:4]2[C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:14][CH2:13]1)=[O:22])[CH3:24]
Reactant: CC1(C(=O)O)CC1(Cl)Cl
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC1(C(=O)N2CCN(c3ncccc3C(F)(F)F)CC2)CC1(Cl)Cl
Yield: 56 %

Procedure:
Coupling of 1-(3-(trifluoromethyl)pyridin-2-yl)piperazine (271 mg, 1.17 mmol) with 2,2-dichloro-1-methylcyclopropanecarboxylic acid (100 mg, 0.59 mmol) was carried out according to a similar procedure described for example 19A using N,N-dimethylformamide (1 mL) as solvent and benzotriazole-1 yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (700 mg, 1.56 mmol) as coupling agent. 1-[(2,2-dichloro-1-methylcyclopropyl)carbonyl]-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine was obtained in 56% yield (127 mg) as colorless oil.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].Cl[S:7]([C:10]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[C:11]=1[C:12]([O:14][CH3:15])=[O:13])(=[O:9])=[O:8].Cl>ClCCl>[C:1]([NH:5][S:7]([C:10]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[C:11]=1[C:12]([O:14][CH3:15])=[O:13])(=[O:8])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: COC(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At 0° C., 1.4 ml (13.3 mmol) of tert-butylamine are added dropwise to a solution of 1.00 g (3.58 mmol) of methyl 2-(chlorosulfonyl)-6-nitrobenzoate in 8 ml of dichloromethane, and the reaction mixture is then allowed to warm to room temperature. After 2 h, the reaction mixture is poured into ice-water, adjusted to pH 3 using 2 N aqueous hydrochloric acid and extracted with dichloromethane. The organic phase is then dried over sodium sulfate, filtered off and concentrated to dryness under reduced pressure. The residue that remains is digested with diethyl ether and filtered off with suction. This gives 1.06 g (91% of theory) of methyl 2-[(tert-butylamino)sulfonyl]-6-nitrobenzoate of m.p. 89-91° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]2[N:7]([C:10]3[CH:19]=[CH:18][C:17]4[C:12](=[C:13]([C:20]5[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=5)[CH:14]=[CH:15][CH:16]=4)[N:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1.CN.C(O)(=O)C.[C:36]([BH3-])#[N:37].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]2[N:7]([C:10]3[CH:19]=[CH:18][C:17]4[C:12](=[C:13]([C:20]5[CH:27]=[CH:26][C:23]([CH2:24][NH:37][CH3:36])=[CH:22][CH:21]=5)[CH:14]=[CH:15][CH:16]=4)[N:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)ncn2-c1ccc2cccc(-c3ccc(C=O)cc3)c2n1
Reactant: [BH3-]C#N
Agent: CN
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CNCc1ccc(-c2cccc3ccc(-n4cnc5cc(OC)ccc54)nc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 174.3 %

Procedure:
4-[2-(5-Methoxy-benzoimidazol-1-yl)-quinolin-8-yl]-benzaldehyde 5A (120 mg, 0.32 mMol) was dissolved in 2 mL of methanol under an atmosphere of dry N2. To this solution was added 800 μL of a solution of 2.0 M methylamine in methanol and then acetic acid (AcOH) was added dropwise until the pH of the solution was ˜5. To this solution was added (42 mg, 0.64 mMol) sodium cyanoborohydride (NaCNBH3) and the reaction mixture was stirred at ambient temperature overnight. The reaction mixture was then concentrated under vacuum and subsequently partitioned between DCM and 0.1 N aqueous NaOH. The DCM layer was washed again with 0.1 N aqueous NaOH, then dried over MgSO4, filtered and concentrated under vacuum to give 220 mg of a green residue. The residue was chromatographed on flash silica gel eluting with a gradient DCM/MeOH (595) to DCM/MeOH (15/85) to DCM/MeOH/NH4OH (1584.50.5) to give 50 mg of a white solid of the title compound 5.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[NH:19][C:18](=[O:20])[CH2:17][C:16](=[O:21])[N:15]([CH3:22])[C:14]=2[CH:23]=1.[CH2:24](I)[CH3:25]>O>[CH2:24]([N:19]1[C:18](=[O:20])[CH2:17][C:16](=[O:21])[N:15]([CH3:22])[C:14]2[CH:23]=[C:10]([O:9][CH3:8])[CH:11]=[CH:12][C:13]1=2)[CH3:25]
Reactant: CCI
Reactant: COc1ccc2c(c1)N(C)C(=O)CC(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN1C(=O)CC(=O)N(C)c2cc(OC)ccc21
Temperature: 0 °C
Yield: 76.7 %

Procedure:
Sodium hydride (60% in oil, 44 mg) was suspended in of DMF (8 ml), and was cooled to 0° C. in an ice water bath. 8-Methoxy-1-methyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (220 mg) was added thereto at the same temperature, and the mixture was stirred at 0° C. for an hour. Ethyl iodide (187 mg) was added thereto, and the mixture was stirred at room temperature overnight. Water was added to the reaction liquid, followed by extraction by ethyl acetate. The organic layer was dried over sodium sulfate, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate=4:1→1:1). The purified product was condensed to dryness to give the title compound (190.2 mg) as a yellow solid.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[OH:26][CH2:27][C:28]([NH:32][S:33]([C:36]1[S:37][C:38]([Cl:42])=[C:39]([NH2:41])[CH:40]=1)(=[O:35])=[O:34])([CH2:30][OH:31])[CH3:29]>>[Cl:42][C:38]1[S:37][C:36]([S:33](=[O:35])(=[O:34])[NH:32][C:28]([CH2:27][OH:26])([CH3:29])[CH2:30][OH:31])=[CH:40][C:39]=1[NH:41][C:12]([C:11]1[CH:10]=[N:9][N:8]2[C:3]([CH:2]([F:25])[F:1])=[CH:4][C:5]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=3)=[N:6][C:7]=12)=[O:14]
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CC(CO)(CO)NS(=O)(=O)c1cc(N)c(Cl)s1
Product: CC(CO)(CO)NS(=O)(=O)c1cc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c(Cl)s1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 4-amino-5-chloro-thiophene-2-sulfonic acid (2-hydroxy-1-hydroxymethyl-1-methyl-ethyl)-amide (example B.7) according to general procedure II. Light yellow solid. MS (ISP) 638.0 [(M−H)−]; mp 237° C.
Reaction SMILES: [C:1]1([CH:7]([CH3:12])[CH2:8][C:9](=[O:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13](Cl)(=[O:17])[CH:14]([CH3:16])[CH3:15]>>[C:13]([C:4]1[CH:5]=[CH:6][C:1]([CH:7]([CH3:12])[CH2:8][C:9](=[O:11])[CH3:10])=[CH:2][CH:3]=1)(=[O:17])[CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)C(=O)Cl
Reactant: CC(=O)CC(C)c1ccccc1
Product: CC(=O)CC(C)c1ccc(C(=O)C(C)C)cc1

Procedure:
As in Example 1 except using 4-phenyl-2-pentanone instead of benzyl acetone, and iso butyryl chloride instead of benzoyl chloride b.p. 130-134 (0.4 mm).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[OH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(N(C(C)C)C(C)C)C>CN(C1C=CN=CC=1)C>[CH3:9][NH:8][C:6]([C:5]1[CH:10]=[CH:11][C:2]([N:16]2[CH2:17][CH2:18][CH:13]([OH:12])[CH2:14][CH2:15]2)=[N:3][CH:4]=1)=[O:7]
Reactant: CNC(=O)c1ccc(Cl)nc1
Reactant: OC1CCNCC1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc(N2CCC(O)CC2)nc1
Yield: 86 %

Procedure:
A mixture of 8.51 g (49.9 mmol) 6-chloro-N-methyl-nicotinamide, 5.66 g (54.9 mmol) 4-hydroxypiperidine, 26.1 ml (150 mmol) N-ethyldiisopropylamine and 0.31 g (2.5 mmol) 4-(N,N-dimethylamino)-pyridine was heated at reflux over night. After cooling to room temperature the crude mixture was transferred to a flash chromatography column. Elution afforded 10.1 g (86.1%) of the title compound as a light yellow solid.
Reaction SMILES: [CH:1]([C:4]1[S:5][CH:6]=[C:7]([C:9]([N:11]2[CH2:16][C:15]3([CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)[O:14][CH2:13][CH2:12]2)=[O:10])[N:8]=1)([CH3:3])[CH3:2].[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32]>C(Cl)Cl>[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32].[CH:1]([C:4]1[S:5][CH:6]=[C:7]([C:9]([N:11]2[CH2:16][C:15]3([CH2:17][CH2:18][NH:19][CH2:20][CH2:21]3)[O:14][CH2:13][CH2:12]2)=[O:10])[N:8]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(C(=O)OC(C)(C)C)CC3)C2)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Reaction time: 16 h
Yield: 91 %

Procedure:
To a solution of tert-butyl 4-(2-isopropylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (limiting reagent) (step a) in DCM (5 volumes) was added trifluoroacetic acid (13.4 molar equivalents) in portions at 10-15° C. The solution was allowed to warm to ambient and stirred for 16 hr. Solvent was evaporated and the residue was dissolved in diethyl ether (10 volumes). The solution was cooled in ice and scratched to give precipitation; the slurry was stirred at 0°-10° C. for 0.5 hr then filtered cold. The cake was washed with diethyl ether (5 volumes) and dried in vacuo at 35° C. to give a beige coloured powder. Yield: 91% of theoretical.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([C:19](O)=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1>C(OCC)C>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2([CH2:19][OH:20])[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:12][CH:13]=1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCC1(c2ccc(Cl)cc2)CCCC1

Procedure:
This compound is prepared in a manner analogous to that of Step A of Example 4, using 2.4 grams (0.06.3 mole) of lithium aluminum hydride, 21.8 grams (0.097 mole) of 1-(4-chlorophenyl)-1-cyclopentanecarboxylic acid (commercially available) in about 300 mL of diethyl ether, yielding [1-(4-chlorophenyl)-1-cyclopentyl]methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=O)[NH:30][C:29]=2[CH3:36])=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1>C(O)C.N1CCCCC1>[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=[C:10]3[C:9]4[C:13](=[CH:14][CH:15]=[CH:16][C:8]=4[C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[NH:12][C:11]3=[O:17])[NH:30][C:29]=2[CH3:36])=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCn1ccnn1
Reactant: O=C1Cc2c(cccc2-c2cccc(Cl)c2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(Cl)c4)c32)c(C)c1C(=O)NCCn1ccnn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 44.4 %

Procedure:
To a solution of 4-(3-chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (67.9 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(3-chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)amide as a yellow solid (54 mg, 44%).
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH3:31])[S:9][CH2:8][CH2:7][N:6]2[C:10]([C:13]3([C:16]4[CH:21]=[CH:20][C:19]([C:22]5[CH:30]=[CH:29][C:25]([C:26](N)=[O:27])=[CH:24][N:23]=5)=[CH:18][CH:17]=4)[CH2:15][CH2:14]3)=[N:11][N:12]=[C:5]2[CH2:4]1.[OH-:32].[K+].Cl>C(O)C.O>[OH:1][CH2:2][C:3]1([CH3:31])[S:9][CH2:8][CH2:7][N:6]2[C:10]([C:13]3([C:16]4[CH:21]=[CH:20][C:19]([C:22]5[CH:30]=[CH:29][C:25]([C:26]([OH:27])=[O:32])=[CH:24][N:23]=5)=[CH:18][CH:17]=4)[CH2:15][CH2:14]3)=[N:11][N:12]=[C:5]2[CH2:4]1
Reactant: [OH-]
Reactant: CC1(CO)Cc2nnc(C3(c4ccc(-c5ccc(C(N)=O)cn5)cc4)CC3)n2CCS1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC1(CO)Cc2nnc(C3(c4ccc(-c5ccc(C(=O)O)cn5)cc4)CC3)n2CCS1
Temperature: 25 °C
Yield: 83 %

Procedure:
A mixed solution of the compound (200 mg, 0.458 mmol) obtained in Example 65 and potassium hydroxide (129 mg) in ethanol (5.00 mL) and water (1.50 mL) was stirred at 100° C. for 9 h. The reaction mixture was cooled to room temperature, poured into 0.05 N hydrochloric acid (50.0 mL) with ice cooling, extracted with dichloromethane/2-propanol (4/1), and dried with anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. Diisopropyl ether was added to the residue, and the white precipitate was collected by filtration and dried under reduced pressure to obtain the title compound (166 mg, 83%) as a white solid.
Reaction SMILES: Br[C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=2)=[N:5][NH:4][C:3]=1[NH2:14].[C:15]([N:23]=[C:24]=[S:25])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCOCC1>[Cl:13][C:9]1[CH:8]=[C:7]([C:6]2[C:2]3[S:25][C:24]([NH:23][C:15](=[O:22])[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)=[N:14][C:3]=3[NH:4][N:5]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: Nc1[nH]nc(-c2cccc(Cl)c2)c1Br
Reactant: O=C(N=C=S)c1ccccc1
Solvent: C1COCCO1
Product: O=C(Nc1nc2[nH]nc(-c3cccc(Cl)c3)c2s1)c1ccccc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 16.6 %

Procedure:
To a stirring solution of 4-bromo-5-(3-chloro-phenyl)-2H-pyrazol-3-ylamine (50 mg, 0.183 mmol) in dioxane (1 mL) was added benzoyl isothiocyanate (27 μL, 0.202 mmol). The reaction mixture was stirred overnight at 90° C., cooled at room temperature, and partitioned between ethyl acetate and sodium bicarbonate. The organic layer was isolated and absorbed on silica gel. Purification on silica gel with 0-10% MeOH in CH2Cl2 as eluent provided 10.8 mg (17%) of N-[3-(3-chloro-phenyl)-1H-pyrazolo[3,4-d]thiazol-5-yl]-benzamide as a white solid. 1H NMR (d6-DMSO) δ: 13.70 and 13.72 (2 broad s, 1H, NH+tautomer), 12.9 (broad s, 1H, NH), 8.12 (d, 2H), 7.81 and 7.85 (2 broad s, 1H, tautomers), 7.65-7.74 (m, 2H), 7.54-7.62 (m, 3H), 7.45 (m, 1H); HPLC/MS m/z: 355 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([S:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[O:11][C:12]=2[CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:4][CH:3]=1.I[CH2:26][CH3:27]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([S:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[O:11][C:12]=2[CH2:13][CH2:14][C:15]([O:17][CH2:26][CH3:27])=[O:16])=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1oc(Sc2ccccn2)nc1-c1ccc(Cl)cc1
Reactant: CCI
Solvent: O
Product: CCOC(=O)CCc1oc(Sc2ccccn2)nc1-c1ccc(Cl)cc1
Yield: 96 %

Procedure:
Water was added to a mixture which was obtained by reacting 4-(4-chlorophenyl)-2-(2-pyridylthio)-5-oxazolepropionic acid with iodoethane in the same manner as Example 52. This was extracted with ethyl acetate. The ethyl acetate layer was washed with water, and dried (MgSO4). The residue obtained by evaporated the solvent was subjected to silica gel column chromatography. From the fraction eluted with ethyl acetate-hexane (1:4, v/v), obtained was ethyl 4-(4-chlorophenyl)-2-(2-pyridylthio)-5-oxazolepropionate(yield: 96%) as an oily substance.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([Mg]Br)=[CH:10][CH:9]=1.[O:16]1[CH:20]=[CH:19][N:18]=[C:17]1[CH:21]=[O:22]>C1COCC1>[O:16]1[CH:20]=[CH:19][N:18]=[C:17]1[CH:21]([C:11]1[CH:12]=[CH:13][C:8]([O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)=[CH:9][CH:10]=1)[OH:22]
Reactant: Br[Mg]c1ccc(OC2CCCCO2)cc1
Reactant: O=Cc1ncco1
Solvent: C1CCOC1
Product: OC(c1ccc(OC2CCCCO2)cc1)c1ncco1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
4-(2-Tetrahydro-3-H-pyranoxy)phenylmagnesium bromide (6.7 mmol) in THF (0.5 M) was added dropwise to a solution of oxazole-2-carbaldehyde (5.15 mmol) in THF (8 mL). After it was stirred at room temperature for 2.5 hours, the reaction was quenched with water and extracted with EtOAc (200 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was column chromatographed (silica gel, 1:2 EtOAc/hexane). Compound M11.1 was obtained. MS ESI (pos.) m/e:276 (M+H). 1H NMR (400 MHz) (DMSO-d6) δ 8.02 (s, 1H); 7.31 (d, J=8.7 Hz, 2H); 7.14 (s, 1H); 6.97-7.01 (m, 2H); 6.27 (d, J=5 Hz, 1H); 5.74 (d, J=5 Hz, 1H); 5.44 (s, 1H); 3.74 (m, 1H); 3.52 (M, 1H); 1.72-1.81 (m, 3H); 1.52-1.60(m, 4H).
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[O:18][CH3:19])[C:7](=[O:20])[C@H:6]1[NH:21][C:22](=[O:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[N+]=[N-].[CH2:31]([OH:33])[CH3:32]>[Pd]>[C:31]([NH:1][CH2:4][C@H:5]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[O:18][CH3:19])[C:7](=[O:20])[C@H:6]1[NH:21][C:22](=[O:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:33])[CH3:32]
Reactant: COc1ccc(CN2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2CN=[N+]=[N-])c(OC)c1
Reactant: CCO
Agent: [Pd]
Product: COc1ccc(CN2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2CNC(C)=O)c(OC)c1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 449 mg of cis-4-azidomethyl-1-(2,4-dimethoxybenzyl)-3-phenylacetamido-2-oxoazetidine in 80 ml of ethanol is added 200 mg of 10% palladium on charcoal, and the mixture is subjected to hydrogenation for 1.5 hours at room temperature and atmospheric pressure. The reaction mixture is filtered to remove the catalyst and the filtrate is concentrated to dryness in vacuo. The residue is taken up in 30 ml of methylene chloride. Under stirring at 0° C., 0.20 ml of triethylamine is added to the resulting methylene chloride solution, and a solution of 0.10 ml of acetyl chloride in methylene chloride is added dropwise over 10 minutes thereto. The reaction mixture is stirred for 40 minutes and then washed with dilute hydrochloric acid, water, an aqueous sodium hydrogen carbonate solution and an aqueous sodium chloride solution in this order, and dried over magnesium sulfate, and the solvent is distilled off in vacuo. Ethyl acetate is added to the residue and the resulting crystals are collected by filtration to give cis- 4-acetamidomethyl-1-(2,4-dimethoxybenzyl)-3-phenylacetamido-2-oxoazetidine, m.p. 205°-207° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH:10]1[CH2:25][C:26]([O:28]CC)=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)C.[OH-].[Na+].Cl>O1CCCC1>[CH2:18]([O:17][C:15]([N:11]1[CH2:12][CH2:13][CH2:14][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH:10]1[CH2:25][C:26]([OH:28])=[O:27])=[O:16])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)CC1C(NC(=O)OC(C)(C)C)CCCN1C(=O)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CCCN(C(=O)OCc2ccccc2)C1CC(=O)O
Yield: 104.4 %

Procedure:
Benzyl (2RS,3SR)-3-[(tert-butoxycarbonyl)amino]-2-(2-ethoxy-2-oxoethyl)piperidine-1-carboxylate (3.08 g), ethanol (30 mL), tetrahydrofuran (8 mL) and aqueous 2N sodium hydroxide solution (4.4 mL) were stirred at room temperature for 4 hours. The reaction solution was neutralized with aqueous 2N hydrochloric acid solution and then concentrated. The residue was added water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, concentrated and obtained the title compound (3.00 g) having the following physical properties.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([C:23]([CH3:25])=[CH2:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([CH2:37][CH:38]=O)[CH:34]=2)[CH2:29]1)=[O:27])C1C=CC=CC=1.[CH:40]1([O:45][C:46](=[O:53])[C:47]2([CH2:52][CH2:51][CH2:50][CH2:49]2)[NH2:48])[CH2:44][CH2:43][CH2:42][CH2:41]1>>[OH:8][C:9]1[CH:14]=[C:13]([OH:15])[C:12]([CH:23]([CH3:24])[CH3:25])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([CH2:37][CH2:38][NH:48][C:47]3([C:46]([O:45][CH:40]4[CH2:41][CH2:42][CH2:43][CH2:44]4)=[O:53])[CH2:49][CH2:50][CH2:51][CH2:52]3)[CH:34]=2)[CH2:29]1)=[O:27]
Reactant: NC1(C(=O)OC2CCCC2)CCCC1
Reactant: C=C(C)c1cc(C(=O)N2Cc3ccc(CC=O)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Product: CC(C)c1cc(C(=O)N2Cc3ccc(CCNC4(C(=O)OC5CCCC5)CCCC4)cc3C2)c(O)cc1O

Procedure:
Prepared from Intermediate F and cycloleucine cyclopentyl ester. 1H NMR (300 MHz, d3-MeOD) 6.99-7.20 (4H, m), 6.26 (1H, s) 5.01 (1H, t, J=5.7 Hz), 3.38-3.67 (3H, m), 3.09 (1H, sep, J=6.8 Hz), 2.57-2.75 (4H, m), 1.37-2.15 (16H, m), 1.10 (6H, d, J=6.9 Hz) LC/MS: purity >98%, m/z 521.25 [M+H]+
Reaction SMILES: Br[C:2]1[C:10]2[NH:9][C:8](=[O:11])[NH:7][C:6]=2[CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[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:13][C:12]([F:15])([F:14])[C:4]1[CH:3]=[C:2]([C:21]2[CH:22]=[CH:23][C:18]([C:17]([F:28])([F:27])[F:16])=[CH:19][CH:20]=2)[C:10]2[NH:9][C:8](=[O:11])[NH:7][C:6]=2[CH:5]=1
Reactant: O=c1[nH]c2cc(C(F)(F)F)cc(Br)c2[nH]1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: O=c1[nH]c2cc(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)c2[nH]1

Procedure:
4-Bromo-6-trifluoromethyl-1,3-dihydro-benzoimidazol-2-one 562 mg, 2.0 mmol, Example 6a) reacted with 4-trifluoromethylphenylboronic acid (760 mg, 4.0 mmol, Aldrich) under the conditions of Example 10 to give the title compound as a white solid. MS (ESI, neg. ion) m/z: 345 (M−1).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@H:13]([C:14]2([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:16][CH2:15]2)[CH2:12][N:11]([C@H:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH3:23])[C:10]1=S)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(O)C.[Ni]>[Si:1]([O:8][C@H:9]1[C@H:13]([C:14]2([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:15][CH2:16]2)[CH2:12][N:11]([C@H:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH3:23])[CH2:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1([C@H]2CN([C@@H](C)c3ccccc3)C(=S)[C@@H]2O[Si](C)(C)C(C)(C)C)CC1
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)C1([C@@H]2CN([C@@H](C)c3ccccc3)C[C@H]2O[Si](C)(C)C(C)(C)C)CC1
Yield: 73.8 %

Procedure:
3-(R)-Tert-butyldimethylsilyloxy-4-(S)-(1-ethoxycarbonylcyclopropyl)-1-[1-(S)-phenylethyl]-2-pyrrolidinethione (7.96 g, 17.-74 mmol) was dissolved in anhydrous ethanol (490 ml), and the solution was mixed with Raney nickel (25 ml) and heated under reflux for 40 minutes. After removing the catalyst by celite filtration (ethanol washing), the resulting filtrate was concentrated under reduced pressure. The thus obtained residue was dissolved in chloroform (400 ml), washed with 10% ammonia water (300 ml), water (300 ml) and saturated brine (300 ml) in that order and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the resulting residue was subjected to flash silica gel chromatography and eluted with an eluant of n-hexane:ethyl acetate=6:1, to thereby obtain 5.48 g (74%) of the title compound as a colorless oil.