Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO.C(=O)([O-])[O-].[Na+].[Na+].Br[C:10]1[CH:11]=[CH:12][C:13]([C:16]#[C:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])=[N:14][CH:15]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29](OB(O)O)=[CH:28][CH:27]=1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Si:18]([C:17]#[C:16][C:13]1[CH:12]=[CH:11][C:10]([C:29]2[CH:30]=[CH:31][C:26]([Cl:25])=[CH:27][CH:28]=2)=[CH:15][N:14]=1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: OB(O)Oc1ccc(Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)C#Cc1ccc(Br)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)(C)[Si](C)(C)C#Cc1ccc(-c2ccc(Cl)cc2)cn1

Procedure:
250 mL of MeOH, 220 mL of 2N sodium carbonate (Na2CO3) solution, and 1.80 g (2.46 mmol) of PdCl2(dppf) are added to a solution of 59.5 g (201.0 mmol) of 5-bromo-2-[(tert-butyldimethylsilanyl)ethynyl]pyridine and 36.5 g (233.4 mmol) of 4-chlorophenylboric acid in 600 mL of 1,4-dioxane and the mixture is refluxed for 1 hour. The reaction mixture is evaporated down in vacuo and diluted with EtOAc. The organic phase is washed with water and semisaturated sodium bicarbonate (NaHCO3) solution, dried over sodium sulfate, and evaporated down in vacuo. The residue is purified by column chromatography (silica gel, Cyc/EtOAc 9:1). Yield: 38.5 g (58% of theoretical); C19H22ClNSi (M=327.923); calc.: molpeak (M+H)+: 328/330 (Cl); found: molpeak (M+H)+: 328/330 (Cl); Rf value: 0.60 (silica gel, Cyc/EtOAc 8:1).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH2:10])[CH:5]=1>C1COCC1>[NH2:10][C:6]1[CH:5]=[C:4]([CH2:3][OH:2])[CH:9]=[CH:8][N:7]=1
Reactant: COC(=O)c1ccnc(N)c1
Solvent: C1CCOC1
Product: Nc1cc(CO)ccn1
Temperature: -45 °C

Procedure:
2-Amino-isonicotinic acid methyl ester (6.0 g, 39.4 mmol) was dissolved in 80 mL anhydrous THF in a flame dried round bottom flask under nitrogen gas. The solution was cooled to −45° C. and LAH (39.4 mL, 1M in THF) was added slowly. The reaction was allowed to warm to 0° C. and was quenched by the addition of 15 mL of 1M NaOH (aq). The solution was filtered and the solid was washed with THF. The filtrate was concentrated to afford the pure product.
Reaction SMILES: C[C@@H]1[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@@]2(O)O[C@H]([C@H](C(O)=O)[C@@H](O)C2)C[C@@H](O[C@H]2O[C@@H](C)[C@H](O)[C@@H:58]([NH2:64])[C@H]2O)C=CC=CC=CC=CCCC=CC=C1.[CH2:66](O)[C@H:67]1[O:72][C@H:71]([O:73][C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H:70]([OH:85])[C@@H:69]([OH:86])[C@@H:68]1[OH:87]>CN(C)C=O>[CH3:58][NH:64][CH2:66][C@@H:67]([C@H:68]([C@@H:69]([C@@H:70]([CH2:71][OH:73])[OH:85])[OH:86])[OH:87])[OH:72]
Reactant: C[C@@H]1[C@H](O)[C@@H](C)C=CC=CCCC=CC=CC=CC=C[C@H](O[C@H]2O[C@@H](C)[C@H](O)[C@@H](N)[C@H]2O)C[C@@H]2O[C@](O)(C[C@@H](O)[C@H](O)CC[C@@H](O)C[C@@H](O)C[C@@H](O)CC(=O)O[C@H]1C)C[C@H](O)[C@H]2C(=O)O
Reactant: OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Agent: C[C@@H]1[C@H](O)[C@@H](C)/C=C/C=C/CC/C=C/C=C/C=C/C=C/[C@H](O[C@H]2O[C@@H](C)[C@H](O)[C@@H](N)[C@H]2O)C[C@@H]2O[C@](O)(C[C@@H](O)[C@H](O)CC[C@@H](O)C[C@@H](O)C[C@@H](O)CC(=O)O[C@H]1C)C[C@H](O)[C@H]2C(=O)O
Solvent: CN(C)C=O
Product: CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Yield: 427 %

Procedure:
5 g of nystatin and 3.0 g of maltose were suspended in 50 ml of dimethyl formamide and next the procedure was carried out as in Example IV. 4.5 g of N-methylglucamine salt of N-glycosyl nystatin of E1 cm1% =580 at 304 nm and IC50 =0.45 mcg/ml were obtained. Original antibiotic exhibited: E1 cm1% =790 at 304 nm and IC50 =0.18 mcg/ml.
Reaction SMILES: Cl[C:2]1[N:11]2[CH:12]=[N:13][N:14]=[C:10]2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[CH:15]1([C:18]2[O:22][N:21]=[C:20]([CH2:23][N+:24]#[C-:25])[N:19]=2)[CH2:17][CH2:16]1.CC(C)([O-])C.[K+]>CN(C=O)C>[CH:15]1([C:18]2[O:22][N:21]=[C:20]([C:23]3[N:24]=[CH:25][N:3]4[C:4]5[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=5[C:10]5=[N:14][N:13]=[CH:12][N:11]5[C:2]=34)[N:19]=2)[CH2:17][CH2:16]1
Reactant: [C-]#[N+]Cc1noc(C2CC2)n1
Reactant: Clc1nc2ccccc2c2nncn12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc2c(c1)c1nncn1c1c(-c3noc(C4CC4)n3)ncn21

Procedure:
To a stirred slurry of 5-chloro-1,2,4-triazolo[4,3-c]quinazoline (3.5 g, 17 mmol) in 40 ml of dry DMF at 10° C. was first added 5-cyclopropyl-3-isocyanomethyl-1,2,4-oxadiazole (purity 80%, 3.4 g, 18 mmol) and then a solution of potassium tert-butoxide (2.55 g, 23 mmol) in 40 ml of DMF, allowing the temperature to rise to room temperature. After 1/2 h the mixture was filtered and the filter cake washed with water and finally with ether and dried, giving the title compound as colorless crystals, m.p. 308°-314° C.
Reaction SMILES: [Mg].Br[C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.Br[C:9]1[S:10][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:12][CH:13]=1.Cl>C1COCC1>[CH2:14]([C:11]1[S:10][C:9]([C:3]2[S:4][CH:5]=[CH:6][CH:7]=2)=[CH:13][CH:12]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCCc1ccc(Br)s1
Reactant: Brc1cccs1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCCCCCCCc1ccc(-c2cccs2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65934.5 %

Procedure:
Magnesium (8.90 g, 0.365 mmol) and THF (100 ml) were placed in a 300-ml flask equipped with a reflux tube. A solution of 2-bromothiophene (54.0 g, 0.332 mmol) in THF (100 ml) was slowly added drowpwise thereto, and the mixture was heated under reflux for about 2 hr to prepare a Grignard reagent. This Grignard reagent was added dropwise to a mixed solution composed of [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (1:1) (1.80 g, 2.21 mmol), 2-bromo-5-decylthiophene (67.0 g, 221 mmol) prepared above, and THF (100 ml) at about 0° C. After the completion of the dropwise addition, the mixture was stirred at room temperature overnight. After the completion of the reaction, 1 N HCl (200 ml) was added to the reaction solution, and the organic layer was extracted with chloroform, was dried over sodium sulfate, and was applied to column chromatography (n-hexane) to give an objective compound 5-decyl-2,2′-bithiophene as a light yellow solid (67.1 g, yield 99.1%). An NMR spectrum of the compound thus obtained was measured at room temperature with an NMR spectrometer (model JNM-LA400W, manufactured by Japan Electric Optical Laboratory). 1H-NMR (CDCl3, TMS/ppm): 0.88 (t, 3H, J=6.83 Hz), 1.31 (m, 14H), 1.67 (m, 2H), 2.78 (t, 2H, J=7.32 Hz), 6.67 (d, 1H, J=3.90 Hz), 6.98 (m, 2H), 7.09 (d, 1H, J=3.90 Hz), 7.15 (d, 1H, J=4.88 Hz)
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.[NH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CN(C)C=O.C(O)(=O)C>[Br:1][C:2]1[S:6][C:5]([CH2:7][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)s1
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Brc1ccc(CN2CCCC2)s1
Temperature: 0 °C
Reaction time: 2 h
Yield: 141.8 %

Procedure:
5-Bromo-2-thiophenecarbaldehyde (191 mg, 1.0 mmol) was diluted in a mixture of dichloromethane (6 mL) and N,N-dimethylformamide (2 mL), and cooled to 0° C. Pyrrolidine (107 mg, 1.5 mmol)) was added, followed by sodium triacetoxyborohydride (1.04 g, 4.9 mmol, 4.9 eq) and glacial acetic acid (2 drops). The reaction mixture was stirred at 23° C. for 2 h, then carefully quenched with saturated aq sodium bicarbonate (fizzing!). The reaction mixture was extracted with dichloromethane (2×10 mL), then the combined organic layers were filtered through a SCX cartridge (5 grams), eluting with methanol (10 mL). The first fraction was discarded if no product was present by tlc, and the desired product was eluted from the resin with methanol in ammonia (2M, Aldrich, 25 mL). The latter fraction was concentrated to afford 349 mg (>100%) of the title compound.
Reaction SMILES: [NH:1]([C:8]1[N:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:10]2[CH:11]=[C:12]([CH3:22])[N:13]=[C:14]([C:19]([OH:21])=O)[C:15]=2[C:16](=[O:18])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:30][NH:31][O:32][CH3:33].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[NH:1]([C:8]1[N:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:10]2[CH:11]=[C:12]([CH3:22])[N:13]=[C:14]([C:19]([N:31]([O:32][CH3:33])[CH3:30])=[O:21])[C:15]=2[C:16](=[O:18])[CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNOC
Reactant: Cc1cc2c(c(C(=O)O)n1)c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CON(C)C(=O)c1nc(C)cc2c1c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Reaction time: 1 h
Yield: 54.8 %

Procedure:
2-anilino-7-methyl-4-oxo-1-phenyl-1,4-dihydro-1,6-naphthyridine-5-carboxylic acid (80 mg, 0.22 mmol), N,O-dimethylhydroxylamine hydrochloride (64 mg, 0.66 mmol), HOBT (89 mg, 0.66 mmol) and EDCI (126 mg, 0.66 mmol) were dissolved in CH2Cl2 (9 mL). To this solution was added TEA (120 uL, 0.88 mmol). The reaction was stirred for 1 h and was diluted with CH2Cl2, washed with 0.5N HCl, saturated NaHCO3, and brine. The organic layer was collected, dried over Na2SO4, and concentrated in vacuo. The solid obtained was triturated with Et2O and dried to give 2-anilino-N-methoxy-N,7-dimethyl-4-oxo-1-phenyl-1,4-dihydro-1,6 naphthyridine-5-carboxamide as a light yellow solid (50 mg, 55%): LCMS RT: 2.08 min, MH+: 414.9. This transformation can also be accomplished by coupling the appropriate amine with the corresponding acid chloride.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3[CH:14]=[CH:15][C:16]4[O:17][CH2:18][CH2:19][O:20][C:21]=4[C:12]=3[O:11][CH2:10]2)[C:2]1=[O:22].[NH:23]1[C:31]2[C:26](=CC=C[CH:30]=2)[C:25]2([C:43]3[C:34](=CC4OCCOC=4C=3)OC2)C1=O.Br.BrCC1C=CC=CN=1.BrCC1N=CC=CC=1C(OCC)=O>>[N:23]1[CH:34]=[CH:43][CH:25]=[CH:26][C:31]=1[CH2:30][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3[CH:14]=[CH:15][C:16]4[O:17][CH2:18][CH2:19][O:20][C:21]=4[C:12]=3[O:11][CH2:10]2)[C:2]1=[O:22]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: O=C1Nc2ccccc2C12COc1c2ccc2c1OCCO2
Agent: Br
Agent: BrCc1ccccn1
Agent: CCOC(=O)c1cccnc1CBr
Product: O=C1N(Cc2ccccn2)c2ccccc2C12COc1c2ccc2c1OCCO2

Procedure:
Following the procedure as described in EXAMPLE 5.30 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-f][1,4]-benzodioxine-7,3′-indol]-2′(1′H)-one to replace 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one, and 2-(bromomethyl)pyridine hydrobromide to replace ethyl 2-(bromomethyl)nicotinate, (pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-f][1,4]benzodioxine-7,3′-indol]-2′(1′H)-one was obtained (57%) as a colorless solid: mp 205-206° C.; 1H NMR (300 MHz, DMSO-d6) δ8.52 (d, 1H, J=4.7 Hz), 7.79 (ddd, J=7.7, 7.7, 1.7 Hz, 1H), 7.35-7.20 (m, 4H), 7.02 (dd, J=7.5, 7.5 Hz, 1H), 6.93 (d, J=7.7 Hz, 1H), 6.29 (ABq, 2H), 5.04 (ABq, 2H), 4.84 (ABq, 2H), 4.27 (s, 4H); 13C NMR (75 MHz, DMSO-d6) δ176.7, 155.2, 149.2, 148.8, 144.6, 142.5, 137.0, 131.6, 129.2, 128.6, 123.6, 122.9, 122.6, 122.4, 121.4, 114.4, 109.8, 109.2, 80.2, 64.1, 63.9, 57.3, 44.8; MS (ES+) m/z 387.7 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[CH:13]=O.[CH3:15][N:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[NH2:17]>Cl.C(O)C>[CH3:15][N:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[N:17]=[CH:13][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc2ccccc2c1C=O
Reactant: CN(N)c1ccccc1
Agent: Cl
Solvent: CCO
Product: COc1ccc2ccccc2c1C=NN(C)c1ccccc1

Procedure:
3.7 g of 2-methoxy-1-naphthaldehyde and 4.9 g of 1-methyl-1-phenylhydrazine were added to 50 ml of ethanol. To the mixture, two or three drops of 1 N hydrochloric acid were added. The mixture was heated and refluxed for about one hour. The reaction mixture was cooled and the crystals then separated, which were then collected on a suction funnel. The thus obtained crude 2-methoxy-1-naphthaldehyde 1-methyl-1-phenylhydrazone was recrystallized from ethanol. The yield was 3.7 g (63.8%) of light yellow scalelike crystals which melt at 90.5°-91.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)=[CH:16][CH:17]=1)=[O:12].Br[C:29]([CH3:38])([CH3:37])[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]>>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11](=[O:12])[C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:20][CH:19]=2)=[CH:16][CH:17]=1)[O:8][C:29]([CH3:38])([CH3:37])[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Reactant: O=C(CCc1ccc(O)cc1Cl)c1ccc(-c2ccc(C(F)(F)F)cc2)s1
Product: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)c(Cl)c1

Procedure:
Tert-butyl 2-(3-chloro-4-(3-oxo-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)-2-methylpropanoate is prepared from 3-(2-chloro-4-hydroxyphenyl)-1-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propan-1-one and tert-butyl bromoisobutyrate according to general procedure D.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]#[N:12])=[CH:8][CH:9]=2)[N:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:3]=1[C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[C:26](OCC)(=[O:28])[CH3:27]>>[C:26]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]#[N:12])=[CH:8][CH:9]=2)[N:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:3]=1[C:18](=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)(=[O:28])[CH3:27]
Reactant: CCOC(=O)n1c(C(=O)c2ccccc2)c(N)c2ccc(C#N)cc21
Reactant: CCOC(C)=O
Product: CCOC(=O)n1c(C(=O)c2ccccc2)c(NC(C)=O)c2ccc(C#N)cc21

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 2 (Method A) from 3-amino-2-benzoyl-6-cyano-1-(ethoxycarbonyl)indole (step 2). tlc: Rf=0.1 (33% ethyl acetate in hexanes)
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:14](=[O:15])[CH2:13][CH2:12][C@@H:11]1/[CH:16]=[CH:17]/[C:18](=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=1.P([O-])([O-])([O-])=O>C(#N)C>[Cl:26][C:22]1[CH:21]=[C:20]([CH2:19][C:18](=[O:27])/[CH:17]=[CH:16]/[C@H:11]2[CH2:12][CH2:13][C:14](=[O:15])[N:10]2[CH2:9][CH2:8][CH2:7][CH2:6][O:5][CH2:4][C:3]([OH:28])=[O:2])[CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)COCCCCN1C(=O)CC[C@@H]1/C=C/C(=O)Cc1cccc(Cl)c1
Agent: O=P([O-])([O-])[O-]
Solvent: CC#N
Product: O=C(O)COCCCCN1C(=O)CC[C@@H]1/C=C/C(=O)Cc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.5 %

Procedure:
A mixture of (4-{(R)-2-[(E)-4-(3-chlorophenyl)-3-oxo-but-1-enyl]-5-oxo-pyrrolidin-1-yl}-butoxy)-acetic acid methyl ester (2.4 mg, 0.006 mmol), rabbit liver esterase (1 mg, 134 units/mg), pH 7.2 phosphate buffer (2.5 mL) and acetonitrile (0.1 mL) was stirred together at rt for 18 h. Acetonitrile (5 mL) was then added and the mixture was concentrated in vacuo to dryness. The residue was purified by flash column chromatography (0%→10% MeOH/CH2Cl2) to afford 1.1 mg (47%) of (4-{(R)-2-[(E)-4-(3-chlorophenyl)-3-oxo-but-1-enyl]-5-oxo-pyrrolidin-1-yl}-butoxy)-acetic acid.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[C:12]([N:19]1[CH2:22][CH:21]([OH:23])[CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[H-].[Na+].O>CN(C=O)C.CC(=O)OCC.O.C1(C)C=CC=CC=1>[C:15]([O:14][C:12]([N:19]1[CH2:22][CH:21]([O:23][C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:7])[CH:8]=2)[CH2:20]1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: Nc1cc(F)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(Oc2ccc([N+](=O)[O-])c(N)c2)C1
Temperature: 100 °C
Yield: 84 %

Procedure:
A flask was charged with 5-fluoro-2-nitroaniline (329 mg), 1-Boc-3-hydroxyazetidine (346 mg) and NaH (65% in oil, 62.4 mg) in DMF (6 mL). The mixture was heated at 100° C. for 7 h, cooled down, and diluted water. The solvent was coevaporated with toluene. The residue was taken up in EA/water and the org. layer was evaporated in vacuo. The residue was purified by CC (Biotage, SNAP 25 g cartridge, solvent A: Hept; solvent B: EA; gradient in % B: 8 for 4CV, 8 to 66 over 10CV, 66 for 2CV) to afford 519 mg of orange foam. LC-MS (B): tR=0.88 min. 1H-NMR (CDCl3): 8.11 (d, 1H, 9.5 Hz); 6.22 (s, NH2); 6.19 (dd, 1H, 2.6 Hz and 9.5 Hz); 5.97 (d, 1H, 2.5 Hz); 4.90 (m, 1H); 4.33 (m, 2H); 4.02 (m, 2H); 1.47 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[C:5]([NH:7][C@@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:9])=O.B>>[Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[CH2:5][NH:7][C@@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:9]
Reactant: C[C@@H](NC(=O)c1ccc(Cl)c(Br)c1)c1ccccc1
Agent: B
Product: C[C@@H](NCc1ccc(Cl)c(Br)c1)c1ccccc1
Yield: 60.7 %

Procedure:
To (R)-3-bromo-4-chloro-N-(1-phenylethyl)benzamide 72 (8.15 g, 24.1 mmol) was added borane (130 mL, 129 mmol) (1 M in THF). The reaction mixture was heated to reflux for 3 d, quenched with saturated NaHCO3, and diluted with EtOAc and water. The aqueous phase was extracted with EtOAc (1×) and the combined organic extracts were washed with brine (1×), dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash column chromatography on silica gel (eluted with 10% to 40% EtOAc in hexanes) gave (R)—N-(3-bromo-4-chlorobenzyl)-1-phenylethanamine 73 (4.75 g, 60.8% yield) as a colorless oil. Mass spectrum: calculated for C15H15BrClN 323.0. found 324.1 (M++1).
Reaction SMILES: [OH-].[Na+:2].[Cl:3][C:4]1[C:8]([Cl:9])=[C:7]([CH3:10])[NH:6][C:5]=1[C:11]([NH:13][C@@H:14]1[CH2:19][CH2:18][N:17]([C:20]2[S:21][C:22]([C:32]([OH:34])=[O:33])=[C:23]([C:25]([NH:27][CH2:28][CH2:29][O:30][CH3:31])=[O:26])[N:24]=2)[CH2:16][C@@H:15]1[O:35][CH3:36])=[O:12]>CO>[Cl:3][C:4]1[C:8]([Cl:9])=[C:7]([CH3:10])[NH:6][C:5]=1[C:11]([NH:13][C@@H:14]1[CH2:19][CH2:18][N:17]([C:20]2[S:21][C:22]([C:32]([O-:34])=[O:33])=[C:23]([C:25]([NH:27][CH2:28][CH2:29][O:30][CH3:31])=[O:26])[N:24]=2)[CH2:16][C@@H:15]1[O:35][CH3:36])=[O:12].[Na+:2]
Reactant: COCCNC(=O)c1nc(N2CC[C@@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@@H](OC)C2)sc1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCCNC(=O)c1nc(N2CC[C@@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@@H](OC)C2)sc1C(=O)[O-]
Reaction time: 0.08 h

Procedure:
Sodium hydroxide (0.056 mL, 0.056 mmol, Acros 1N) was added to a suspension of 2-((3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-{[(2-methoxyethyl)amino]carbonyl}-1,3-thiazole-5-carboxylic acid (0.03 g, 0.056 mmol, Example 387) in methanol (5 mL). After stirring five minutes the reaction was homogeneous. The reaction mixture was concentrated and the resulting white solid was dried overnight (0.030 g). MS (ES) MH+: 534 for C20H24C2N5O6SNa; NMR: 1.73 (s, 2 H) 2.19 (s, 3 H) 3.24 (s, 3 H) 3.32 (s, 2 H) 3.36 (s, 3 H) 3.51 (s, 1 H) 3.84 (s, 1 H) 4.22 (d, 2 H) 7.17 (d, 1 H) 12.17 (s, 1 H) 13.26 (s, 1 H).
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)[CH:9]=2)[O:6][C:5](=[O:7])[NH:4][CH2:3]1.[H-].[Na+].[CH:23](Br)([CH3:25])[CH3:24]>CN(C)C=O>[CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)[CH:9]=2)[O:6][C:5](=[O:7])[N:4]([CH:23]([CH3:25])[CH3:24])[CH2:3]1
Reactant: CC(C)Br
Reactant: COc1ccc(C2(C)CNC(=O)O2)cc1OCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C2(C)CN(C(C)C)C(=O)O2)cc1OCC1CC1
Reaction time: 17 h
Yield: 29.4 %

Procedure:
500 mg (1.8 mmol) of 5-methyl-5-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-oxazolidinone was first stirred with 75 mg (3.1 mmol) of sodium hydride in 17 ml of dimethylformamide for 30 minutes and, after adding 0.25 ml (2.7 mmol) of isopropyl bromide, for 17 hours at room temperature. The process was continued analogously to Example 1, thus obtaining 169 mg of 5-methyl-5-(3-cyclopropylmethoxy-4-methoxyphenyl)-3-isopropyl-2-oxazolidinone as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.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.[I-].[CH2:46]([N+:50]1[N:54]=[C:53]([CH3:55])[S:52][C:51]=1[CH3:56])[CH2:47][CH2:48][CH3:49]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([C:7](=[O:9])/[CH:56]=[C:51]2\[S:52][C:53]([CH3:55])=[N:54][N:50]\2[CH2:46][CH2:47][CH2:48][CH3:49])[CH:10]=1
Reactant: O=C(O)c1cc(Br)ccc1Cl
Reactant: CCCC[n+]1nc(C)sc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1N=C(C)S/C1=C\C(=O)c1cc(Br)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 5-bromo-2-chlorobenzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.89 (t, 3 H) 1.25-1.36 (m, 2 H) 1.68-1.76 (m, 2 H) 2.51 (s, 3 H) 4.16 (t, 2 H) 6.26 (s, 1 H) 7.42-7.46 (m, 1 H) 7.58-7.63 (m, 1 H) 7.65-7.68 (m, 1 H); MS (ESI) m/z 387 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:19])[C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:28]=1.[CH2:29]([N:31]1[CH2:36][CH2:35][CH2:34][CH:33](O)[CH2:32]1)[CH3:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCOC(/N=N/C(OCC)=O)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:19])[C:12]3[CH:13]=[CH:14][C:15]([O:18][CH:33]4[CH2:34][CH2:35][CH2:36][N:31]([CH2:29][CH3:30])[CH2:32]4)=[CH:16][CH:17]=3)=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:28]=1
Reactant: CCN1CCCC(O)C1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(O)cc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCN1CCCC(Oc2ccc(C(=O)c3c(-c4ccc(OC)cc4)sc4cc(OC)ccc34)cc2)C1
Yield: 17 %

Procedure:
6-Methoxy-2-(4-methoxyphenyl)-3-(4-hydroxybenzoyl)benzo[b]thiophene (1.17 g, 3.00 mmol), 1-ethyl-3-hydroxypiperidine (775 mg, 6.00 mmol), triphenylphosphine (1.57 g, 6.00 mmol), and DEAD (6.0 nmol) were converted to product by the procedure of Example 11 to give 256 mg of the title compound. Yield: 17%. MS(FD) 501(M+). EA calculated for C30H31NO4S: C, 71.83; H, 6.23; N, 2.79. Found: C, 72.10; H, 6.47; N, 3.07.