Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:17])[C@@H:15]([NH2:16])[C@H:12]2[S:11][CH2:10][C:9]=1[CH:18]([S:26][C:27]1[NH:31][N:30]=[N:29][N:28]=1)[CH2:19][CH2:20][NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(C1C=C(C=C(C(C)(C)C)C=1O)[CH:39]=[O:40])(C)(C)C.[Pb](=O)=O>C1C=CC=CC=1.ClCCCl>[C:1]([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:17])[C@:15]([NH2:16])([O:40][CH3:39])[C@H:12]2[S:11][CH2:10][C:9]=1[CH:18]([S:26][C:27]1[NH:31][N:30]=[N:29][N:28]=1)[CH2:19][CH2:20][NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C1=C(C(CCNS(C)(=O)=O)Sc2nnn[nH]2)CS[C@@H]2[C@H](N)C(=O)N12
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Agent: O=[Pb]=O
Solvent: ClCCCl
Solvent: c1ccccc1
Product: CO[C@@]1(N)C(=O)N2C(C(=O)OC(C)(C)C)=C(C(CCNS(C)(=O)=O)Sc3nnn[nH]3)CS[C@@H]21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1.18 g (2.4 mmol) of 7β-amino-3-[1-(2-methanesulfonamidoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid t-butyl ester and 0.56 g (2.4 mmol) of 3,5-di-t-butyl-4-hydroxybenzaldehyde in 100 ml of dry benzene is refluxed for 4 hours under a Dean-Stark trap. The solution is evaporated under reduced pressure to leave a residue which is dissolved in 100 ml of 1,2-dichloroethane and cooled to ca. 5° in an ice bath. Three grams of freshly prepared lead dioxide is added in portions over 20 minutes until the starting material is completely consumed. The mixture is filtered through Celite and the filter cake is washed with two 20 ml portions of cold 1,2-dichloroethane. The filtrate is treated with 25 ml of methanol (distilled from magnesium) and the reaction mixture is allowed to stand at room temperature until complete consumption of the oxidized intermediate and formation of a new slower-moving product is shown by thin layer chromatography. The mixture is evaporated and the residue is dissolved in 30 ml of methanol and treated with 2.5 g of Girard reagent T (trimethylaminoacetohydrazide chloride). The reaction mixture is stirred at room temperature for 3 hours, then evaporated to give a residue which is partitioned between ethyl acetate and 20% sodium chloride solution. The organic phase is washed with 10% sodium chloride solution water and a saturated sodium chloride solution. The organic phase is dried (MgSO4), filtered and evaporated to dryness to give 7β-amino-7α-methoxy-3-[1-(2-methanesulfonamidoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid t-butyl ester.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.[Li]CCCC.[O:14]=[C:15]1[C:20]2([CH2:22][CH2:21]2)[CH2:19][N:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:17][CH2:16]1>C1COCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]2([OH:14])[C:20]3([CH2:22][CH2:21]3)[CH2:19][N:18]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH2:17][CH2:16]2)=[CH:3][CH:4]=1
Reactant: Clc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C2(CC2)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)cc2)C2(CC2)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 64.2 %

Procedure:
In a flame-dried 100 mL three necked flask, a solution of 1-bromo-4-chlorobenzene (3.51 g, 18.36 mmol) in THF (20 mL) was cooled to −78° C. and treated with the dropwise addition of 1.6 M BuLi in hexanes (12.00 mL, 19.19 mmol) at a rate which did not allow the temperature to exceed −60° C. The mixture was stirred at −78° C. for 1 h, during which time a white precipitate was observed. The mixture was treated with the dropwise addition of a solution of tert-butyl 8-oxo-5-azaspiro[2.5]octane-5-carboxylate (1.88 g, 8.35 mmol) in THF (5 mL), at a rate which did not allow the temperature to exceed −60° C. The mixture was stirred for 3 h, then allowed to warm to −20° C. and quenched with saturated ammonium chloride solution. The mixture was extracted 3× with ethyl acetate, the combined organic phases were washed with water followed by brine, then dried over sodium sulfate and concentrated in-vacuo. The residue was purified over a 5×15 cm silica gel column, eluting with ethyl acetate/hexanes (5%-10%-15%-20% ethyl acetate, to yield the title compound (1.81 g, 5.36 mmol, 64.2% yield) as a colorless powder. MS (ESI+)=264.27, (M-tBuO)+, 220 (M−H2O-Boc)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][S:6][C:7]1[N:12]=[C:11]([Cl:13])[CH:10]=[C:9](Cl)[N:8]=1)[CH3:2].[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][S:6][C:7]1[N:8]=[C:9]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:21][CH:22]=2)[CH:10]=[C:11]([Cl:13])[N:12]=1)[CH3:2]
Reactant: CCOC(=O)CSc1nc(Cl)cc(Cl)n1
Reactant: Nc1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CSc1nc(Cl)cc(Nc2ccc(-c3ccccc3)cc2)n1
Yield: 39.1 %

Procedure:
A stirred mixture of 5.3 g of (4,6-dichloro-2-pyrimidinylthio)acetic acid ethyl ester, 3.4 g of 4-aminobiphenyl and 2.1 g of sodium carbonate in 100 ml. of ethanol was heated under reflux for 5 hr. The reaction mixture was filtered and water was added to the filtrate to initiate precipitation. The precipitate was recrystallized from ethanol to give 3.1 g of product, mp. 110°-112°C..
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([F:9])=[CH:4][C:3]=1[CH3:10].[C:11](O)(=[O:15])[C:12](O)=[O:13]>Cl.O>[F:9][C:5]1[CH:6]=[C:7]2[C:2]([NH:1][C:11](=[O:15])[C:12](=[O:13])[NH:8]2)=[C:3]([CH3:10])[CH:4]=1
Reactant: Cc1cc(F)cc(N)c1N
Reactant: O=C(O)C(=O)O
Agent: Cl
Solvent: O
Product: Cc1cc(F)cc2[nH]c(=O)c(=O)[nH]c12

Procedure:
20 g (0.118 mol) of 2,3-diamino-5-fluorotoluene and 15.8 g (0.176 mol) of oxalic acid are stirred at reflux for 16 hours in 4N hydrochloric acid. The reaction mixture is cooled, diluted with water, filtered off on a suction filter and washed with water. The title compound is obtained as beige crystals of m.p.>300° C.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1([C:6]([N:8]2[CH2:13][C@@H:12]3[CH2:14][C@H:9]2[C:10](=[O:15])[O:11]3)=[O:7])[CH2:5][CH2:4]1.Cl.[NH2:19][C:20]1([C:23]#[N:24])[CH2:22][CH2:21]1.C(C(CCCC)C([O-])=O)C.[Na+].Cl.[Cl-].[Na+]>O.O1CCCC1>[C:23]([C:20]1([NH:19][C:10]([C@@H:9]2[CH2:14][C@H:12]([OH:11])[CH2:13][N:8]2[C:6]([C:3]2([C:2]([F:17])([F:16])[F:1])[CH2:5][CH2:4]2)=[O:7])=[O:15])[CH2:22][CH2:21]1)#[N:24]
Reactant: O=C1O[C@H]2C[C@@H]1N(C(=O)C1(C(F)(F)F)CC1)C2
Reactant: N#CC1(N)CC1
Agent: CCCCC(CC)C(=O)[O-]
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: N#CC1(NC(=O)[C@@H]2C[C@H](O)CN2C(=O)C2(C(F)(F)F)CC2)CC1
Temperature: 53 °C
Reaction time: 20 h
Yield: 87.2 %

Procedure:
(1S,4S)-5-(1-Trifluoromethyl-cyclopropanecarbonyl)-2-oxa-5-aza-bicyclo[2.2.1]heptan-3-one (220 g, 883 mmol), 1-amino-cyclopropanecarbonitrile hydrochloride (140 g, 1.18 mol) and sodium 2-ethylhexanoate (97%, 230 g, 1.34 mol) were dissolved in water (1.32 L). The mixture was stirred for 20 h at 53° C. After cooling to room temperature, tetrahydrofuran (880 mL) was added and the mixture was acidified by addition of concentrated hydrochloric acid (37% m/m, 47 mL), followed by the addition of sodium chloride (440 g). After extraction with ethyl acetate (1×1.4 L, 3×550 mL), the combined organic extracts were dried over sodium sulfate and concentrated in vacuo. At a volume of ca. 1.5 L, the product started to crystallize upon addition of seed crystals. The volume of the suspension was further reduced to ca. 500 mL and cooled to 2° C. (ice bath). After stirring for 60 min, the crystals were filtered off, washed with ethyl acetate/heptane 1:1 (v/v, 600 mL) and heptane (300 mL), and dried in vacuo to provide the title compound as off-white crystals (255.0 g, 87%). 1H NMR (CDCl3, 400 MHz): δ 1.18-1.29 (m, 4H), 1.30-1.42 (m, 2H), 1.50-1.59 (m, 2H), 2.17-2.26 (m, 1H), 2.29 (d, J=14.5 Hz, 1H), 3.73 and 3.96 (ABX, JAB=11.8 Hz, JAX=4.3 Hz, JBX=0 Hz, each 1H), 4.43-4.53 (m, 2H), 4.81 (br d, J=8.3 Hz, 1H), 7.73 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:4]=2[S:5][C:6]=1[C:7]#[N:8].Cl>C(O)(=O)C>[NH2:13][C:10]1[CH:11]=[CH:12][C:3]2[C:2]([Cl:1])=[C:6]([C:7]#[N:8])[S:5][C:4]=2[CH:9]=1
Reactant: N#Cc1sc2cc([N+](=O)[O-])ccc2c1Cl
Agent: Cl
Solvent: CC(=O)O
Product: N#Cc1sc2cc(N)ccc2c1Cl
Temperature: 25 °C

Procedure:
A stirred suspension of 0.1 mole of the nitrile in a mixture of 200 ml. of concentrated hydrochloric acid and 200 ml. of glacial acetic acid containing 72.0 g. of stannous chloride was heated to a temperature of 90° C. At this temperature heating was stopped and the reaction mixture was allowed to cool to room temperature. The product which separated was dissolved in 5% hydrochloric acid solution and filtered to remove any insoluble material. The filtrate was made basic with concentrated ammonium hydroxide solution and the precipitated solid was taken up in methylene chloride. After drying over potassium carbonate, the methylene chloride was removed in vacuo to give a solid residue. Recrystallization of this residue from nitromethane gave 6-amino-3-chlorobenzo-[b]thiophene-2-carbonitrile, m.p. 158°-160° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:13])[CH2:9][C:10]([CH3:12])=[O:11])([CH3:6])([CH3:5])[CH3:4].Cl>C(OCC)(=O)C.C([Li])CCC.C(OC(=O)CC)C>[C:3]([O:7][C:8](=[O:13])[CH2:9][C:10](=[O:11])[CH2:12][C:8](=[O:7])[CH2:9][CH3:10])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Agent: Cl
Agent: [H-]
Agent: [Li]CCCC
Solvent: CCOC(=O)CC
Solvent: CCOC(C)=O
Product: CCC(=O)CC(=O)CC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 121071.6 %

Procedure:
The following is based on the procedure disclosed in B. Lygo, Tetrahedron, 51, pp. 12859-12868 (1995). To an oven dried 5 liter flask was added sodium hydride (60% dispersion in mineral oil, 1.21 mmoles, 48.55 g) under nitrogen gas. The hydride was washed with hexanes (4×250 mL). The hydride was then suspended in dry tetrahydrofuran (THF) (2000 mL) and the mixture cooled to 0° C. in an ice bath. To this solution was added t-butylacetoacetate (160 g, 1.01 mmol) via an addition funnel dropwise over 2 hours at 0° C. with a constant flow of nitrogen gas. After the addition was complete the reaction was allowed to stir at 0° C. under nitrogen for an additional 30 minutes. To this mixture was added n-butyllithium (2 M in cyclohexane, 556 mL, 1.11 mmol) via addition funnel dropwise over 3 hours. After the addition was complete the reaction mixture was allowed to stir at 0° C. for an additional 30 minutes. Ethylpropionate (85.94 mL, 1.01 mmol) was loaded into an addition funnel and added to reaction slowly over 1.5 hours. At this point the reaction was allowed to warm up to room temperature while stirring overnight. The reaction was once again cooled to 0° C. in an ice bath and 2 N HCl (1.15 liters, cooled to 0° C. before addition) was added dropwise via an addition funnel over 2 hours. The reaction pH was checked to ensure neutralization. If needed, more 2 N HCl was added by pipette to adjust the solution to pH 7. At this point the major portion of THF/cyclohexane was decanted away from the aqueous layer and the organic solvent was reduced by ˜75% using rotary evaporation. The aqueous layer was extracted with ethyl acetate (3×200 mL). The residue obtained from volume reduction was diluted with ethyl acetate (500 mL) and combined with the organic pool from aqueous extraction. This organic pool was washed with saturated sodium chloride (3×250 mL), dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation. The residue was then subjected to high vacuum distillation (140 microns, short path distillation head) to yield 131 g of crude compound U as a clear oil. 1H NMR CDCl3 δ: 15.16 (bs, 1H), 5.59 (s, 1H), 3.24 (s, 2H), 3.22 (q, 2H, J=8.0 Hz), 1.46 (s, 9H), 1.14 (t, 3H, J=8.0 Hz). ESMS m/z: 237 [M+Na+], 159 [M-t-butyl]+.
Reaction SMILES: C([O:5][C:6]([C:8]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([OH:22])[N:11]=[C:10]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=2[Cl:31])[N:9]=1)=[O:7])(C)(C)C.O.[OH-].[Li+]>O1CCCC1.O>[CH2:15]([O:14][C:13]1[C:8]([C:6]([OH:7])=[O:5])=[N:9][C:10]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=2[Cl:31])=[N:11][C:12]=1[OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)c1nc(Cc2cccc(Cl)c2Cl)nc(O)c1OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1nc(Cc2cccc(Cl)c2Cl)nc(O)c1OCc1ccccc1
Yield: 85.3 %

Procedure:
To a stirred solution of 5-benzyloxy-2-(2,3-dichlorobenzyl)-6-hydroxypyrimidine-4-carboxylic acid tert-butyl ester (130) (10 g, 21.69 mmol) in a mixture of tetrahydrofuran-water (2:1, 90 mL) was added lithium hydroxide, monohydrate (4.55 g, 108.42 mmol). The mixture was refluxed for 18 h. After completion of the reaction, the volume was reduced by evaporation as much as possible, water was added, and the residue was washed with ethyl acetate to remove non-acidic impurities. The separated aqueous part was acidified with 2(N)HCl to bring the pH to approx. 5 to 6. The acidified aqueous part was extracted with dichloromethane, the separated organic part was dried over sodium sulfate and concentrated under reduced pressure to get 5-benzyloxy-2-(2,3-dichlorobenzyl)-6-hydroxypyrimidine-4-carboxylic acid (131) (7.5 g, 85.32%) as a white solid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[C:18]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:16])[CH2:10][CH2:9]1)C1C=CC=CC=1.C1CCCCC=1>C(O)C.CO.[OH-].[Pd+2].[OH-]>[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[C:18]([C:23]3[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:27][CH:28]=3)=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:16])[CH2:10][CH2:9]1
Reactant: O=C(NC1CCN(Cc2ccccc2)CC1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Solvent: C1=CCCCC1
Product: O=C(NC1CCNCC1)c1ccccc1-c1ccc(C(F)(F)F)cc1

Procedure:
31.6 g (0.072 mol) of 4′-trifluoromethyl-biphenyl-2-carboxylic acid-(1-benzyl-piperidin-4-yl)-amide are dissolved in 180 ml ethanol and 180 ml methanol, mixed with 84 ml (0.83 mol) of cyclohexene and 6.53 g of palladium hydroxide (20% on charcoal) and refluxed for four hours. The hot reaction mixture is filtered through kieselguhr and the reaction mixture is concentrated by rotary evaporation.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([CH3:32])=[CH:26]2>>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:22][C:23]3[CH:24]=[C:25]4[C:29](=[CH:30][CH:31]=3)[NH:28][C:27]([CH3:32])=[CH:26]4)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Reactant: Cc1cc2cc(O)ccc2[nH]1
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCc1ccccc1
Yield: 91.2 %

Procedure:
Using an analogous procedure to that described in Example 32, 7-benzyloxy-4-chloro-6-methoxyquinazoline (1 g, 3.33 mmol), (prepared as described for the starting material in Example 1), was reacted with 5-hydroxy-2-methylindole (0.59 g, 4 mmol) to give 7-benzyloxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (1.25 g, 91%).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[O:3]1.[N+:14]([O-])([OH:16])=[O:15].O>S(=O)(=O)(O)O>[N+:14]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[O:3][C:2]([CH3:13])([CH3:1])[CH2:11][C:10]2=[O:12])([O-:16])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: CC1(C)CC(=O)c2ccccc2O1
Agent: O=S(=O)(O)O
Solvent: O
Product: CC1(C)CC(=O)c2cc([N+](=O)[O-])ccc2O1
Temperature: 0 °C

Procedure:
2,2-Dimethylchroman-4-one (4 g, 23.2 mmol) was added portionwise over 10 minutes to 7 ml of concentrated sulfuric acid at 0°-5° C., then cooled in an acetone-ice bath as concentrated nitric acid (s.g. 1.5, 90%, 1.4 ml) in 3 ml concentrated sulfuric acid was added dropwise over 20 minutes. The resulting mixture was poured into 100 ml ice and water and extracted 2×50 ml ethyl acetate. The organic layers were combined, washed 4×50 ml water and then brine, dried over magnesium sulfate, stripped to solids (5.3 g) and chromatographed on 500 g silica gel, gradiently eluting with 20:1, 15:1, 10:1 and finally 5:1 hexane:diethyl ether to yield title product as a white solid, 2.1 g (39%); tlc Rf 0.3 (1:1 diethyl ether:hexane); m/e 221(P+), 206, 166, 120.
Reaction SMILES: Br[CH:2]([CH:12]([CH3:14])[CH3:13])[C:3](=O)[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5].[NH2:15][C:16]([NH2:18])=[S:17]>C(O)C>[NH2:18][C:16]1[S:17][C:2]([CH:12]([CH3:14])[CH3:13])=[C:3]([C:4]([N:6]2[CH2:10][CH2:9][CH2:8][CH2:7]2)=[O:5])[N:15]=1
Reactant: NC(N)=S
Reactant: CC(C)C(Br)C(=O)C(=O)N1CCCC1
Solvent: CCO
Product: CC(C)c1sc(N)nc1C(=O)N1CCCC1
Yield: 1467.2 %

Procedure:
Add 3-bromo-4-methyl-1-pyrrolidin-1-yl-pentane-1,2-dione (3.0 g, 11.44 mmol, 1.0 eq.) to the solution of thiourea (1.31 mmol, 1.5 eq.) in ethanol (40 mL). Stir the reaction mixture at reflux for overnight. Concentrate in vacuo. Add dichloromethane (200 mL). Wash the organic layer with sodium bicarbonate (sat. 2×30 mL), aqueous saturated sodium chloride (2×20 mL) and water (2×30 mL). Dry the organic phase over MgSO4 and filter the drying reagent off. Concentrate in vacuo. Purify by column chromatography (0%→5% ethyl acetae in dichloromethane) to afford product (4.60 g, 66%). MS(ES), m/z 240 (M+1).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[N:17][O:18][CH2:19][CH2:20][OH:21])[CH3:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.O[C:25]1[CH:57]=[CH:56][C:28]([CH2:29][CH:30]2[S:34][C:33](=[O:35])[N:32]([C:36]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:31]2=[O:55])=[CH:27][CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[F:1][C:2]([F:22])([F:23])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[N:17][O:18][CH2:19][CH2:20][O:21][C:25]3[CH:57]=[CH:56][C:28]([CH2:29][CH:30]4[S:34][C:33](=[O:35])[N:32]([C:36]([C:49]5[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=5)([C:43]5[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=5)[C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)[C:31]4=[O:55])=[CH:27][CH:26]=3)[CH3:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=NOCCO)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(=NOCCOc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Yield: 87.6 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 647 mg of 2-[1-(4'-trifluoromethylbiphenyl-4-yl)ethylideneaminooxy]ethanol (prepared as described in Preparation 28), 931 mg of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 577 mg of triphenylphosphine and 366 mg of diethyl azodicarboxylate, 1.35 g of the title compound were obtained as a foam-like solid.
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](OP(O)(O)=O)[C@@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.[CH2:61]([N:68]1[CH2:72][CH2:71][C:70](=[O:73])[CH2:69]1)[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1.Cl.[OH-].[Na+]>>[CH2:61]([N:68]1[CH2:72][CH2:71][CH:70]([OH:73])[CH2:69]1)[C:62]1[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=1
Reactant: O=C1CCN(Cc2ccccc2)C1
Agent: Cl
Agent: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: OC1CCN(Cc2ccccc2)C1
Temperature: 30 °C
Reaction time: 16 h
Yield: 93 %

Procedure:
To 25 ml of the culture fluid of the recombinant E.coli HB101 (pTSBH, pSTVG) obtained in Example 9 were added 2.5 g of glucose, 3.0 mg of NADP and 0.25 g of N-benzyl-3-pyrrolidinone. While this reaction mixture was stirred at 30° C. with pH adjusted to 6.5 using 5 M hydrochloric acid or sodium hydroxide, N-benzyl-3-pyrrolidinone was added thereto at an interval of 0.25 g/hour. After addition of a total of 2.0 g of N-benzyl-3-pyrrolidinone, stirring was further continued for 16 hours. After completion of the reaction, 2.5 ml of a 5 M aqueous solution of sodium hydroxide was added, the mixture was extracted with toluene, and the solvent was removed. Analysis of the resulting extract revealed that N-benzyl-3-pyrrolidinol was obtained in 93% yield. The N-benzyl-3-pyrrolidinol produced on that occasion was the S form with an optical purity of not less than 99% ee.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:27][C:28]([C:30]2[C:31](=[O:43])[N:32]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:33]([CH3:36])[C:34]=2[CH3:35])=[O:29])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH2:20][CH2:21][CH2:22][C:23]3([OH:26])[CH2:25][CH2:24]3)=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1.[C:44]([NH:51][CH2:52][C:53](O)=[O:54])([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.ClCCl>[C:47]([O:46][C:44]([NH:51][CH2:52][C:53]([O:26][C:23]1([CH2:22][CH2:21][CH2:20][O:19][C:15]2[CH:14]=[C:13]3[C:18]([C:9]([O:8][C:7]4[CH:6]=[CH:5][C:4]([NH:27][C:28]([C:30]5[C:31](=[O:43])[N:32]([C:37]6[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=6)[N:33]([CH3:36])[C:34]=5[CH3:35])=[O:29])=[CH:3][C:2]=4[F:1])=[CH:10][CH:11]=[N:12]3)=[CH:17][CH:16]=2)[CH2:25][CH2:24]1)=[O:54])=[O:45])([CH3:50])([CH3:49])[CH3:48]
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(OCCCC5(O)CC5)ccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(OCCCC5(OC(=O)CNC(=O)OC(C)(C)C)CC5)ccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.8 %

Procedure:
To a mixture of N-(3-fluoro-4-(7-(3-(1-hydroxycyclopropyl)propoxy)-quinolin-4-yl-oxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (218 mg, 0.374 mmol), N-Boc-glycine (133.4 mg, 0.768 mmol, Alfa), and DMAP (7.03 mg, 0.058 mmol, Aladdin) in 10 mL of dichloromethane was added DCC solid (323.4 mg, 1.54 mmol, Aldrich) slowly at 0° C. The reaction was then warmed up to rt and continued to stir at rt overnight. The mixture was filtered and the solid was washed with CH2Cl2 (10 mL×2). The combined organic phases were washed with 15 mL of saturated NaHCO3 solution followed by 15 mL of brine, dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed on a silica gel column (PE:EtOAc=1:6) to give the desired compound as a yellow solid (160 mg, 60%).