Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10](=[O:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[OH-].[Na+]>P([O-])([O-])([O-])=O>[CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCN(Cc2ccccc2)C1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: O[C@H]1CCN(Cc2ccccc2)C1
Reaction time: 24 h
Yield: 59.3 %

Procedure:
A liquid medium having the composition given in Example 2 was prepared and distributed in 100-ml portions into twenty-five 500-ml Sakaguchi flasks and steam-sterilized at 120° C. for 20 minutes. The contents of each flask was aseptically inoculated with 2 ml of a fluid culture obtained by cultivating Micrococcus luteus IFO 13867 in the same manner as in Example 2, and shake-culture was carried out at 30° C. for 24 hours. Cells were harvested from the resultant culture fluids by centrifugation and suspended in 500 ml of 100 mM phosphate buffer (pH 6.5). To this suspension was added 5 g of N-benzyl-3-pyrrolidinone, and 10 g of glucose. The reaction was allowed to proceed at 30° C. with stirring for 24 hours, while the reaction mixture wag maintained at pH 6.5 with 6N aqueous sodium hydroxide solution. Thereafter, the reaction mixture was extracted with 2.5 L of ethyl acetate, and the aqueous layer was further extracted with 1 L of ethyl acetate. The organic layers were combined and dehydrated over anhydrous sodium sulfate, and the solvent was then distilled off under reduced pressure. The residue was distilled to give 3 g of (S)-N-benzyl-3-pyrrolidinol. The yield was 60%, the optical purity was 99.8% ee, the boiling point was 132 to 137° C./3 mm Hg, and the optical rotation [α]D20 was −3.77° (CH3OH, c=5). 1H-NMR δ (CDCl3): 1.63-1.76 (1H, m), 2.09-2.21 (1H, m), 2.26-2.37 (1H, m), 2.51-2.64 (2H, m), 2.75-2.85 (1H, m), 3.38 (1H, brs), 3.61 (2H, s), 4.24-4.33 (1H, m), 7.19-7.37 (5H, m).
Reaction SMILES: C([O:3][C:4]([C@:6]1([CH3:22])[C@H:10]([CH2:11][F:12])[CH2:9][N:8]([C@@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[C:7]1=[O:21])=[O:5])C.[OH-].[Na+].O>C(O)C>[F:12][CH2:11][C@@H:10]1[CH2:9][N:8]([C@@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[C:7](=[O:21])[C@:6]1([CH3:22])[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)[C@@]1(C)C(=O)N([C@H](C)c2ccccc2)C[C@H]1CF
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C[C@H](c1ccccc1)N1C[C@@H](CF)[C@@](C)(C(=O)O)C1=O
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
To a solution of (3R,4S)-3-ethoxycarbonyl-4-fluoromethyl-3-methyl-1-[(1R)-1-phenylethyl]-2-pyrrolidone (1.05 g, 3.42 mmol) in ethanol (20 mL), 10 mol/l aqueous solution of sodium hydroxide (3.42 mL, 34.2 mmol) was added dropwise in an ice bath, and the mixture was stirred for 30 minutes. Water (20 mL) was added to the reaction mixture in an ice bath, and the aqueous solution was washed with diethylether (50 mL). To the aqueous layer was added concentrated hydrochloric acid to pH 2 to 3 in an ice bath, and the solution was extracted with chloroform (50 mL×3). The organic layer was washed with saturated aqueous solution of sodium chloride (50 mL), and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The concentrate was azeotropically distilled by adding toluene (20 mL), and dried under reduced pressure to obtain 950 mg (99%) of the title compound as a colorless oily substance.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][O:20][CH2:21][CH2:22][CH2:23][NH:24][C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][N:26]=1>>[CH3:19][O:20][CH2:21][CH2:22][CH2:23][NH:24][C:25]1[N:26]=[CH:27][C:28]([NH:31][C:12]([C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][C:9]=2[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:29][CH:30]=1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: COCCCNc1ccc(N)cn1
Product: COCCCNc1ccc(NC(=O)c2nc(-c3ccccc3)oc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 16 above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(3-methoxy-propylamino)-pyridin-3-yl]-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and N2-(3-methoxy-propyl)-pyridine-2,5-diamine. LCMS calcd for C20H19F3N4O3 (m/e) 420, obsd 421 (M+H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][CH3:12])[CH:4]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>S(=O)(=O)(O)O>[C:13]([NH:1][CH2:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][CH3:12])[CH:4]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(CN)nc(OC)n1
Agent: O=S(=O)(O)O
Product: COc1cc(CNC(C)=O)nc(OC)n1

Procedure:
A sample of 6-aminomethyl-2,4-dimethoxypyrimidine (from Example 11) was stirred at 20° C. with excess acetic anhydride and a few drops of sulfuric acid for about 20 hours. Evaporation, extraction into chloroform and reisolation provided 6-acetylaminomethyl-2,4-dimethoxypyrimidine.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[S:16])[NH2:15])[CH2:10][CH2:9]1)=O)(C)(C)C.Br[CH2:18][C:19]([C:21]1[CH2:25][CH:24]([C:26]2[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=2[F:33])[O:23][N:22]=1)=O>CC(C)=O>[F:33][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:26]=1[CH:24]1[O:23][N:22]=[C:21]([C:19]2[N:15]=[C:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[S:16][CH:18]=2)[CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=S)CC1
Reactant: O=C(CBr)C1=NOC(c2c(F)cccc2F)C1
Solvent: CC(C)=O
Product: Fc1cccc(F)c1C1CC(c2csc(C3CCNCC3)n2)=NO1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
A mixture of 1-tert-butoxycarbonylpiperidine-4-carbothioamide (7.33 g, 30 mmol) and 2-bromo-1-(4,5-dihydro-5-(2,6-difluorophenyl)-3-isoxazolyl)ethanone (i.e. the product of Step C) (9.12 g, 30 mmol) in acetone (100 mL) was heated at 45° C. for 3 h, and then stirred at room temperature overnight. The reaction mixture was concentrated, and the resulting residue was dissolved in dichloromethane (100 mL) and trifluoroacetic acid (40 mL), stirred at room temperature for 3 h and then concentrated under reduced pressure. The resulting oil was dissolved in aqueous hydrochloric acid solution (0.5 N, 200 mL) and extracted with ethyl acetate. The organic layer was basified by adding aqueous sodium hydroxide solution (10% in water), then washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure to provide the title compound as a thick amber-colored oil (8.62 g, weight included residual ethyl acetate).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[S:30][C:11]3=[N:12][C:13]([N:17]4[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]4)=[CH:14][C:15](=[O:16])[N:10]3[N:9]=2)[CH:5]=[CH:4][N:3]=1.CC(OC([NH:38][CH2:39][C:40]([NH2:42])=[O:41])=O)(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:38][CH2:39][C:40]([NH:42][C:2]1[CH:7]=[C:6]([C:8]2[S:30][C:11]3=[N:12][C:13]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)=[CH:14][C:15](=[O:16])[N:10]3[N:9]=2)[CH:5]=[CH:4][N:3]=1)=[O:41]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(=O)n3nc(-c4ccnc(Cl)c4)sc3n2)CC1
Reactant: CC(C)(C)OC(=O)NCC(N)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1CCOC1
Product: NCC(=O)Nc1cc(-c2nn3c(=O)cc(N4CCNCC4)nc3s2)ccn1
Temperature: 25 °C
Yield: 135.1 %

Procedure:
To a solution of tert-butyl 4-(2-(2-chloropyridin-4-yl)-5-oxo-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-7-yl)piperazine-1-carboxylate (160 mg, 0.36 mmol) in THF (5 ml) are added Boc-gly-NH2 (124 mg, 0.72 mmol), XantPhos (124 mg, 0.14 mmol), Pd(OAc)2 (24 mg, 0.07 mmol) and K2CO3 (197 mg, 1.44 mmol). The microwave tube is purged with nitrogen for 1 min then sealed. The mixture is microwaved at 90° C. for 2 h. After cooling to room temperature, EtOAc (30 ml) and water (30 ml) are added. The organic layer is separated, washed with brine and dried over sodium sulfate. After the removal of organic solvent in vacuo, the residue is purified through Biotage column chromatography (MeOH/DCM=1/100 to 5/20) to give the desired product (188 mg, 90%).
Reaction SMILES: CC(C)([O-])C.[K+].S([CH2:17][N+:18]#[C-])(C1C=CC(C)=CC=1)(=O)=O.CO.[C:22]([Si:26]([CH3:38])([CH3:37])[O:27][CH:28]1[CH2:35][CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30][CH2:29]1)([CH3:25])([CH3:24])[CH3:23]>COCCOC>[C:22]([Si:26]([CH3:38])([CH3:37])[O:27][CH:28]1[CH2:35][CH2:34][CH2:33][CH:32]([C:17]#[N:18])[CH2:31][CH2:30][CH2:29]1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)OC1CCCC(=O)CCC1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OC1CCCC(C#N)CCC1
Temperature: 25 °C

Procedure:
Potassium tert-butoxide (30.4 mL, 1 M in tetrahydrofuran, 30.4 mmol) was added drop wise to a stirred and cooled (0° C.) solution of tosylmethyl isocyanide (4.74 g, 24.27 mmol) in dry DME (40 mL). After ten minutes, dry methanol (0.98 mL, 24.28 mmol) was added and followed by a solution of the product of Example 5B (3.11 g, 12.14 mmol) in DME (10 mL). The resulting solution was allowed to warm to room temperature and then heated (45° C.) for thirty minutes. After cooling, the reaction mixture was partitioned with diethyl ether and water. The organic phase was washed with brine, dried (MgSO4), filtered, and evaporated. The residue was purified over silica gel using 2-10% diethyl ether in hexanes to give the title compound as an oil.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[S:27][C:28]2[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][CH2:36][CH3:37])[C:29]=2[N:30]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[S:27][C:28]5[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][CH2:36][CH3:37])[C:29]=5[N:30]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CCCc1cccc2sc(Cl)nc12
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1cccc2sc(Sc3ccc4c(c3)CC[C@H]3N(C)C(=O)CC[C@]43C)nc12
Yield: 69.9 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloro-4-propylbenzothiazole (97 mg, 0.46 mmol) and 1 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (6×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (80% ethyl acetate/hexanes eluent) to give 116 mg (70%) of the title compound as an amorphous solid. mp 109°-111°. FDMS: m/e=436. α[D]589 =+45.00 (c=0.80, chloroform).
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[C:15]([F:23])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[C:24]1([CH2:30][CH2:31][C:32](Cl)=[O:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:32](=[O:33])[CH2:31][CH2:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[C:15]([F:23])[CH:14]=2)=[CH:6][CH:7]=1
Reactant: NC(Cc1ccc(C(F)(F)F)c(F)c1)C(O)c1ccc(F)cc1
Reactant: O=C(Cl)CCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(CCc1ccccc1)NC(Cc1ccc(C(F)(F)F)c(F)c1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.7 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(3-fluoro-4-(trifluoromethyl)phenyl)-1-propanol (400 mg, 1.21 mmol) in ethyl acetate (20 ml) were added 3-phenylpropionyl chloride (269 ml, 1.81 mmol) and saturated aqueous sodium hydrogen carbonate (20 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (486 mg, 87%).
Reaction SMILES: [CH:1]1([C@H:7]([NH:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][C:26](OCC)=[O:27])=[N:22][CH:23]=2)[C:8]([O:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:32][OH:33].[OH-].[K+]>C(O)C.O>[CH:1]1([C@H:7]([NH:16][CH2:17][C:18]2[CH:23]=[N:22][C:21]([CH2:24][CH2:25][C:26]([NH:32][OH:33])=[O:27])=[CH:20][CH:19]=2)[C:8]([O:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NO
Reactant: CCOC(=O)CCc1ccc(CN[C@H](C(=O)OC2CCCC2)C2CCCCC2)cn1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(CCc1ccc(CN[C@H](C(=O)OC2CCCC2)C2CCCCC2)cn1)NO
Reaction time: 0.33 h
Yield: 16.9 %

Procedure:
Ethyl 3-[5-({[(1S)-1-cyclohexyl-2-(cyclopentyloxy)-2-oxoethyl]amino}methyl)pyridin-2-yl]propanoate (0.9 g, 2.16 mmol) and hydroxylamine hydrochloride (0.6 g, 8.64 mmol) were dissolved in ethanol (10 mL) then cooled to <5° C. Potassium hydroxide (0.97 g, 17.28 mmol) was dissolved in water (2.07 mL) and then charged to the reaction which was stirred at <5° C. for 20 min. The reaction was quenched to pH ˜7 and extracted with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4) and concentrated under reduced pressure. The residue was dissolved in hot EtOH (2 mL) and water (3 mL) added. On cooling some of the resulting solid (235 mg) was collected by filtration and dried to give cyclopentyl (2S)-cyclohexyl[({6-[3-(hydroxyamino)-3-oxopropyl]pyridin-3-yl}methyl)amino]ethanoate (147 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Cl:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:22](Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Cl:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: ClCc1ccccc1
Reactant: CCOC(=O)c1cc2cc(Cl)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(Cl)ccc2n1Cc1ccccc1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
5-Chloroindole-2-carboxylic acid ethyl ester (1.4 g) was dissolved in N,N-dimethylformamide (30 mL), and to the solution were added potassium carbonate (2.9 g) and benzyl chloride (2.4 mL), followed by stirring in a bath at a temperature of 100° C. for 1.5 hours. The reaction mixture was concentrated, and the residue was poured into ice water. The thus-obtained mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and was dried over sodium sulfate anhydrate. The solvent was distilled away, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:19). The thus-obtained compound was crystallized from diethyl ether-hexane, to thereby give the title compound (1.6 g).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH:5]1OCCO1.Cl.[C:11]1([O:17][NH2:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[C:11]1([O:17][N:18]=[CH:5][CH2:4][CH2:3][CH2:2][Cl:1])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: ClCCCC1OCCO1
Reactant: NOc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: ClCCCC=NOc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 2-(3-chloro-propyl)-[1,3]-dioxolane (5.7 g; 0.038 mol), THF (50 ml) and aqueous acid chloride (1/1) was stirred at room temperature for 24 hours. O-phenyl-hydroxylamine hydrochloride (5 g; 0.034 mol) was then added and the resulting mixture was stirred at room temperature for 48 hours. The reaction mixture was concentrated under vacuum. Then the product was extracted with methylene chloride. The organic extract was dried (Mg SO4) and evaporated under vacuum. After purification by Flash Chromatography on silica gel using as eluent hexane/ethyl acetate (95/5), the desired compound was obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([F:38])=[C:13]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:17][CH:16]2[C:35](O)=[O:36])[CH:14]=1.CC1(C)[O:44][C@@H:43]([CH2:45][CH2:46][NH2:47])[CH2:42][O:41]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.Cl>C(Cl)Cl.O1CCCC1>[OH:44][C@H:43]([CH2:42][OH:41])[CH2:45][CH2:46][NH:47][C:35]([CH:16]1[CH:15]([C:13]2[CH:14]=[C:9]([Cl:8])[CH:10]=[CH:11][C:12]=2[F:38])[C:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:17]1)=[O:36]
Reactant: CC1(C)OC[C@H](CCN)O1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cc(Cl)ccc2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)NCC[C@H](O)CO)C(c2cc(Cl)ccc2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 95.5 %

Procedure:
In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3S,4R,5S)-3-(5-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 98c (0.4 g, 0.68 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.3 g, 2.06 mmol), HATU (0.47 g, 1.24 mmol) and iPr2NEt (0.6 mL, 3.44 mmol) in CH2Cl2 at room temperature for 20 h, then reacted with aqueous HCl solution in tetrahydrofuran at room temperature to give rac-(2R,3S,4R,5S)-3-(5-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.36 g, 80%).
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[F:15])[C:8]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:23]([N:25]=[C:26]=[O:27])[CH3:24]>O1CCOCC1>[CH2:23]([NH:25][C:26](=[O:27])[O:22][C:19]1[CH:18]=[CH:17][C:16]([C:8]2[C:9]3[C:14](=[C:13]([F:15])[CH:12]=[CH:11][CH:10]=3)[N:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[N:7]=2)=[CH:21][CH:20]=1)[CH3:24]
Reactant: CCN=C=O
Reactant: Oc1ccc(-c2nn(C3CCCC3)c3c(F)cccc23)cc1
Solvent: C1COCCO1
Product: CCNC(=O)Oc1ccc(-c2nn(C3CCCC3)c3c(F)cccc23)cc1
Yield: 74.8 %

Procedure:
A solution of 4-(1-cyclopentyl-7-fluoro-1H-indazol-3-yl)phenol (0.30 g, 1.0 mmol) and ethyl isocyanate (0.080 mL, 1.0 mmol) in 10 mL of dioxane was heated at 80° C. for 48 hours. The reaction mixture was concentrated in vacuo. The residue was crystallized from EtOAc/hexane to give 0.275 g of the title compound as a white solid.
Reaction SMILES: C(Cl)Cl.[CH3:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1.[NH2:15][C:16]1[CH:28]=[C:27]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:26]=[CH:25][C:17]=1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(=O)([O-])O.[Na+]>C(N(CC)CC)C>[CH3:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH:15][C:16]2[CH:28]=[C:27]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:26]=[CH:25][C:17]=2[C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])=[O:11])=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1N
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2cc(Oc3ccccc3)ccc2C(=O)OC(C)(C)C)cc1
Reaction time: 1 h

Procedure:
5.0 mL of methylene chloride, 0.056 mL of triethylamine and 51 mg of 4-methoxybenzoyl chloride were added sequentially to 57 mg of tert-butyl 2-amino-4-phenoxybenzoate at room temperature, and stirred at the same temperature for 1 hour. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the organic layer was separated, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufacture by Trikonex Company, eluent; hexane:ethyl acetate=4:1]to obtain tert-butyl 2-(4-methoxybenzamido)-4-phenoxybenzoate.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[CH2:22]([O:29][CH2:30][CH:31]1[CH2:33][O:32]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([O:29][CH2:30][CH:31]([OH:32])[CH2:33][N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: c1ccc(COCC2CO2)cc1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(CC(O)COCc3ccccc3)CC1)O2

Procedure:
Compound 171 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 2-[(benzyloxy)methyl]oxirane and conditions outlined in procedure X. LCMS: 466 [M+H]; Rt=1.01 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=O)=O)=[CH:5][CH:4]=1.S(O)(=O)(=O)C.S(O)(=O)(=O)C.[NH2:31][NH:32][C:33]([NH2:35])=[NH:34]>>[NH2:35][C:33]1[N:32]=[N:31][C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:34]=1
Reactant: COc1ccc(C(=O)C(=O)c2ccc(OC)cc2)cc1
Reactant: N=C(N)NN
Agent: CS(=O)(=O)O
Product: COc1ccc(-c2nnc(N)nc2-c2ccc(OC)cc2)cc1

Procedure:
Prepared by reacting 4,4′-dimethoxybenzil with aminoguanidine bismesylate using the above procedure. The title compound was obtained as pale yellow plates in 92.5%, mpt=179-181°
Reaction SMILES: CO[C:3]1[CH:8]=CC(C2C=CC(=O)NN=2)=C[C:4]=1OCCC.C(OC1C=C(C2C=CC(=O)NN=2)C=CC=1OC)C=C.[CH2:39]([O:41][C:42]1[CH:43]=[C:44]([C:50]2[CH:51]=[CH:52][C:53](=[O:56])[NH:54][N:55]=2)[CH:45]=[CH:46][C:47]=1[O:48][CH3:49])[CH3:40].C(OC1C=CC(C2C=CC(=O)NN=2)=CC=1OC)(C)C>>[CH3:49][O:48][C:47]1[CH:46]=[CH:45][C:44]([C:50]2[CH:51]=[CH:52][C:53](=[O:56])[NH:54][N:55]=2)=[CH:43][C:42]=1[O:41][CH2:39][CH2:40][CH:3]([CH3:8])[CH3:4]
Reactant: CCOc1cc(-c2ccc(=O)[nH]n2)ccc1OC
Reactant: CCCOc1cc(-c2ccc(=O)[nH]n2)ccc1OC
Agent: C=CCOc1cc(-c2ccc(=O)[nH]n2)ccc1OC
Agent: COc1cc(-c2ccc(=O)[nH]n2)ccc1OC(C)C
Product: COc1ccc(-c2ccc(=O)[nH]n2)cc1OCCC(C)C

Procedure:
The following are obtained analogously: 6-(4-methoxy-3-n-propoxyphenyl)-3[2H]pyridazinone, m.p. 196°, 17.5% of theory, 6-(3-allyloxy-4-methoxyphenyl)-3[2H]pyridazinone, m.p. 175°, 16.3% of theory, 6-(3-ethoxy-4-methoxyphenyl)-3[2H]pyridazinone, m.p. 171°, 15.1% of theory and 6-(4-isopropoxy-3-methoxyphenyl)-3[2H]pyridazinone, m.p. 200°, 26.4% of theory.