Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH:7]2[CH:8]3[CH2:22][CH2:21][CH:20]=[CH:19][C:9]3=[C:10]3[C:18]([CH2:17][C:16]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]3=4)=[C:6]2[C:5](C)([CH3:23])[C:4]([CH3:26])([CH3:25])[C:3]1([CH3:28])[CH3:27].[CH3:30]CCCCC.C([Li])CCC.[F:41][C:42]([F:66])([F:65])[C:43]1[CH:44]=[C:45]([C:49]([C:55]2[CH:60]=[CH:59][CH:58]=[C:57]([C:61]([F:64])([F:63])[F:62])[CH:56]=2)=[C:50]2[CH:54]=[CH:53][CH:52]=[CH:51]2)[CH:46]=[CH:47][CH:48]=1>O1CCCC1>[F:41][C:42]([F:65])([F:66])[C:43]1[CH:44]=[C:45]([C:49]([C:55]2[CH:60]=[CH:59][CH:58]=[C:57]([C:61]([F:64])([F:62])[F:63])[CH:56]=2)([CH:50]2[CH:51]=[CH:52][CH:53]=[CH:54]2)[C:7]2([CH3:30])[C:6]3[C:5]([CH3:23])([CH:12]4[CH2:13][CH2:14][CH:15]=[CH:16][C:11]4=[C:10]4[C:18]=3[CH2:17][C:19]3[CH:20]=[CH:21][CH:22]=[CH:8][C:9]4=3)[C:4]([CH3:26])([CH3:25])[C:3]([CH3:28])([CH3:27])[C:2]2([CH3:1])[CH3:29])[CH:46]=[CH:47][CH:48]=1
Reactant: CCCCCC
Reactant: CC1(C)C2=C3Cc4ccccc4C3=C3C=CCCC3C2C(C)(C)C(C)(C)C1(C)C
Reactant: FC(F)(F)c1cccc(C(=C2C=CC=C2)c2cccc(C(F)(F)F)c2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC12C(=C3Cc4ccccc4C3=C3C=CCCC31)C(C)(C(c1cccc(C(F)(F)F)c1)(c1cccc(C(F)(F)F)c1)C1C=CC=C1)C(C)(C)C(C)(C)C2(C)C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A reaction vessel equipped with a dropping funnel was charged with 30 m of dehydrated tetrahydrofuran and 0.82 g (2.11 mmol) of octamethyloctahydrodibenzofluorene under a nitrogen atmosphere. Then, 1.50 ml (2.32 mmol) of a 1.56 mol/L hexane solution of n-butyllithium was slowly added dropwise while cooling this solution to 0° C. Thereafter, the mixture was stirred overnight at room temperature. Subsequently, the dropping funnel was charged with a solution prepared by dissolving 1.00 g (2.32 mmol) of 6,6-di{m-(trifluoromethyl)phenyl}fulvene in 20 ml of dehydrated tetrahydrofuran. The solution was slowly added dropwise while cooling to −78° C. Thereafter, the mixture was stirred for one day while returning the temperature thereof slowly to room temperature. This reaction solution was subjected to extraction with diethyl ether. The organic layer was washed with 1 N hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and saturated brine. The organic phase collected by separation was dried over anhydrous magnesium sulfate, and magnesium sulfate was separated by filtration. The filtrate was subjected to distillation under reduced pressure with use of a rotary evaporator to remove the solvent. The residue was purified by using a silica gel column to obtain a target product (yield 0.74 g (47%)). The target product was identified by 1H-NMR and FD-MS spectroscopy.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([C:6](=[C:14]2[S:19][CH2:18][S:17][CH2:16][S:15]2)[C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:30])C=1>ClCCl>[F:13][C:10]1[CH:9]=[CH:8][C:7]([C:6](=[C:14]2[S:15][CH2:16][S:17](=[O:30])[CH2:18][S:19]2)[C:5]2[CH:20]=[CH:21][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:12][CH:11]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Fc1ccc(C(=C2SCSCS2)c2ccc(F)cc2)cc1
Solvent: ClCCl
Product: O=S1CSC(=C(c2ccc(F)cc2)c2ccc(F)cc2)SC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 76.4 %

Procedure:
To a 30 ml of dichloromethane of 1.5 g of 2-(4,4'-difluorobenzhydrylidene)-1,3,5-trithiane was added 0.77 g of m-chloroperbenzoic acid in small portions at 0° C., and the resulting mixture was stirred overnight. After completion of the reaction, the reaction mixture was poured into ice-water and extracted with dichloromethane. Usual work up gave crude solid, which was purified by a silica gel column chromatography (chloroform:hexane=3:1) to obtain 1.2 g of white crystals.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH:11]1([C:17]2[C:18]3[CH:19]=[CH:20][C:21]([C:40]([O:42][CH3:43])=[O:41])=[CH:22][C:23]=3[N:24]3[C:30]=2[C:29]2[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=2[N:27]([CH3:35])[CH:26]([C:36](OC)=[O:37])[CH2:25]3)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.CCN(CC)CC>C(Cl)Cl>[CH:11]1([C:17]2[C:18]3[CH:19]=[CH:20][C:21]([C:40]([O:42][CH3:43])=[O:41])=[CH:22][C:23]=3[N:24]3[C:30]=2[C:29]2[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=2[N:27]([CH3:35])[CH:26]([CH:36]=[O:37])[CH2:25]3)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)OC)N(C)c1ccccc1-3
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C=O)N(C)c1ccccc1-3
Temperature: -78 °C
Reaction time: 0.42 h

Procedure:
DMSO (5 eq) was dissolved in DCM and the solution was cooled to −78° C. At this temperature a 2M solution of oxalylchloride in DCM (2.5 eq) was added slowly and the mixture was stirred for 25 min at −78° C. A solution of dimethyl 13-cyclohexyl-5-methyl-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepine-6,10-dicarboxylate (1 eq) in DCM (0.09M) was added slowly at −78° C. and stirring was continued for 25 min at this temperature. Then NEt3 (8 eq) was added and the resulting slurry was placed into an ice bath at 0° C. The mixture was left stirring for 90 min, then diluted with DCM and extracted with sat. aq. NH4Cl, sat. aq. NaHCO3 and brine. After drying over Na2SO4 all volatiles were evaporated in vacuo. The product was obtained as a deep-yellow solid, which was filtered with DCM over a pad of silica. After evaporation of the solvent the product was obtained as a yellowish solid (quant.). (ES+) m/z 417 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]([NH:24][C:25]([C@@H:27]2[CH2:32][CH2:31][CH2:30][N:29]([C:33](=[O:49])[CH2:34][CH2:35][CH:36]3[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]3)[CH2:28]2)=[O:26])[CH2:19][C:20]([O:22]C)=[O:21])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][F:17])=[CH:10][CH:9]=2)[CH:7]=1.[OH-].[Na+]>O1CCCC1.O>[C:45]([O:44][C:42]([N:39]1[CH2:38][CH2:37][CH:36]([CH2:35][CH2:34][C:33]([N:29]2[CH2:30][CH2:31][CH2:32][C@@H:27]([C:25]([NH:24][CH:18]([C:4]3[CH:5]=[C:6]([C:8]4[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][F:17])=[CH:12][CH:13]=4)[CH:7]=[C:2]([F:1])[CH:3]=3)[CH2:19][C:20]([OH:22])=[O:21])=[O:26])[CH2:28]2)=[O:49])[CH2:41][CH2:40]1)=[O:43])([CH3:48])([CH3:47])[CH3:46]
Reactant: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cc(F)cc(-c2ccc(OCCF)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CCC(=O)N2CCC[C@@H](C(=O)NC(CC(=O)O)c3cc(F)cc(-c4ccc(OCCF)cc4)c3)C2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 69.8 %

Procedure:
220 mg (0.32 mmol) tert-butyl 4-{3-[(3R)-3-({1-[5-fluoro-4′-(2-fluoroethoxy)biphenyl-3-yl]-3-methoxy-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate were dissolved in 10.4 ml tetrahydrofurane. 3.85 ml (0.39 mmol) 0.1N sodium hydroxide solution were added. The mixture was stirred at room temperature for 20 hours, diluted with water and a small amount of 1N sodium hydroxide solution and extracted with ethyl acetate. The aqueous layer was brought to pH=4.5 with 10% aqueous citric acid solution and extracted with dichloromethane and dichloromethane/2-propanol 8/2. The organic layer was dried over sodium sulfate and concentrated in vacuum to give 150 mg (70%) 3-({[(3R)-1-{3-[1-(tert-butoxycarbonyl)piperidin-4-yl]propanoyl}piperidin-3-yl]carbonyl}amino)-3-[5-fluoro-4′-(2-fluoroethoxy)biphenyl-3-yl]propanoic acid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][S:8]([CH3:11])(=[O:10])=[O:9])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:16][C:17]1[C:21]2[CH:22]=[C:23]([N:26]3[C:31](=[O:32])[CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[N:28]([CH3:37])[C:27]3=[O:38])[CH:24]=[CH:25][C:20]=2[S:19][N:18]=1.Cl>CS(C)=O.O1CCCC1>[CH3:37][N:28]1[C:29]([C:33]([F:34])([F:35])[F:36])=[CH:30][C:31](=[O:32])[N:26]([C:23]2[CH:24]=[CH:25][C:20]3[S:19][N:18]=[C:17]([CH2:16][N:7]([S:8]([CH3:11])(=[O:10])=[O:9])[C:6](=[O:12])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:21]=3[CH:22]=2)[C:27]1=[O:38]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(CBr)c3c2)c1=O
Reactant: CC(C)(C)OC(=O)NS(C)(=O)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(CN(C(=O)OC(C)(C)C)S(C)(=O)=O)c3c2)c1=O
Yield: 78.6 %

Procedure:
tert-Butyl(methylsulfonyl)carbamate (1.52 g, 0.00780 mol) is added to a mixture of sodium hydride (60%, 0.312 g, 0.00780 mol) and tetrahydrofuran at 0° C. The mixture is allowed to come to room temperature. A solution of 3-[3-(bromomethyl)-1,2-benzisothiazol-5-yl]-1-methyl-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (3.00 g, 0.00714 mol) in dimethyl sulfoxide is added dropwise. The resultant mixture is stirred overnight at room temperature, poured into dilute hydrochloric acid, and extracted with methylene chloride. The combined organic layers are washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The resultant residue is chromatographed on silica gel with ether:methylene chloride to give the title compound as a white solid (3.00 g, 78.7%, mp 109-111° C.) which is identified by NMR spectral analysis.
Reaction SMILES: C[Si](C)(C)[C:3]1[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:5][O:6][C:7]=1[Si:8]([CH3:11])([CH3:10])[CH3:9].[Br:20]Br>C(Cl)(Cl)(Cl)Cl>[Br:20][C:3]1[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:5][O:6][C:7]=1[Si:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: BrBr
Reactant: C[Si](C)(C)c1onc(-c2cccnc2)c1[Si](C)(C)C
Solvent: ClC(Cl)(Cl)Cl
Product: C[Si](C)(C)c1onc(-c2cccnc2)c1Br
Temperature: 40 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
To a solution of anhydrous CCl4 (80 ml) containing compound 62 (4.45 g, 15.4 mmol) was added (1.1 eq, 1.04 ml) Br2. After the addition, the resulting solution was stirred for 18 hours at 40° C. The reaction mixture was cooled and concentrated in vacuo. Ethyl acetate was added and the organic layer was washed with a saturated NaHCO3 solution, dried (Na2SO4), filtered and concentrated in vauo. Purification by flash chromatography (diethyl ether) afforded 3-(4-bromo-5-trimethylsilanyl-isoxazol-3-yl)-pyridine (63) as an oil (4.5 g, ˜100%). 1H-NMR (400 MHz, CDCl3): δ 9.08 (d, J=2 Hz, 1H), 8.73 (dd, J=5 Hz, 2 Hz, 1H), 8.14 (dt, J=8 Hz, 2 Hz, 1H), 7.46-7.41 (m, 1H), 0.40 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7](Br)[CH:6]=[C:5]([F:10])[C:3]=1[NH2:4].[CH2:11]([O:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([O:18][C:19]1[CH:24]=[C:23]([C:7]2[CH:8]=[C:2]([F:1])[C:3]([NH2:4])=[C:5]([F:10])[CH:6]=2)[CH:22]=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OB(O)c1cccc(OCc2ccccc2)c1
Reactant: Nc1c(F)cc(Br)cc1F
Product: Nc1c(F)cc(-c2cccc(OCc3ccccc3)c2)cc1F
Yield: 32.8 %

Procedure:
The title compound (0.143 g) was prepared from 2,6-difluoro-4-bromo aniline (0.3 g, 1.4 mmol) and 3-(benzyloxy)phenylboronic acid (0.426 g, 1.8 mmol) as a colourless liquid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.49-7.44 (m, 2H), 7.39 (t, J 7.2, 2H), 7.35-7.26 (m, 4H), 7.24 (s, 1H), 7.18 (d, J 7.8, 1H), 6.91 (dd, J 1.9, 8.0, 1H), 5.33 (s, 2H), 5.16 (s, 2H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[S:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[C:16]=3[C:24]([C:26]3[CH:31]=[CH:30][C:29](F)=[CH:28][CH:27]=3)=[O:25])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:33][CH2:34][CH2:35][N:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1.[C:41](=[O:44])([O-:43])[O-:42].[K+].[K+].[OH2:47]>CN(C=O)C>[OH2:8].[C:24]([OH:25])(=[O:47])[C:41]([OH:43])=[O:44].[C:41]([OH:42])(=[O:44])[C:7]([OH:8])=[O:47].[C:24]([OH:25])(=[O:47])[C:41]([OH:43])=[O:44].[N:36]1([CH2:35][CH2:34][NH:33][C:29]2[CH:30]=[CH:31][C:26]([C:24]([C:16]3[C:17]4[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=4[S:19][C:15]=3[C:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:10][CH:11]=3)=[O:25])=[CH:27][CH:28]=2)[CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: O=C(c1ccc(F)cc1)c1c(-c2ccc(OCCN3CCCC3)cc2)sc2ccccc12
Reactant: O=C([O-])[O-]
Reactant: NCCN1CCCC1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)C(=O)O
Product: O=C(c1ccc(NCCN2CCCC2)cc1)c1c(-c2ccc(OCCN3CCCC3)cc2)sc2ccccc12
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
4-Fluorophenyl 2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophen-3-yl ketone (Example 145, Part A) (1.1 g; 2.5 mmol) was combined with 1.6 mL (12.3 mmol) of 1-(2-aminoethyl)pyrrolidine and 1.0 g (7.4 mmol) of potassium carbonate in 2 mL of dry DMF. The mixture was heated in an oil bath maintained at 130° C. for 18 h. After cooling to room temperature, the mixture was poured into 150 mL of water and stirred for 0.5 h. The product was isolated by filtration and washed with fresh water. The title compound (0.9 g; 68% yield) was purified by flash chromatography on silica gel, eluting with a gradient of hexanes(75-15%)/Et3N(5%)/THF(20-80%). Conversion to the trioxalate was effected as in Example 137, Part E.
Reaction SMILES: FC1C=CC(CBr)=CC=1.CC1C=CC(S(O[CH2:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)(=O)=O)=CC=1.[CH3:26][C:27]1[CH:31]=[C:30]([N:32]2[C:36](=[O:37])[NH:35][N:34]=[CH:33]2)[S:29][C:28]=1[C:38]([O:40][CH2:41][CH3:42])=[O:39]>>[CH:23]1([CH2:22][CH2:21][N:35]2[C:36](=[O:37])[N:32]([C:30]3[S:29][C:28]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[C:27]([CH3:26])[CH:31]=3)[CH:33]=[N:34]2)[CH2:24][CH2:25]1
Reactant: Cc1ccc(S(=O)(=O)OCCC2CC2)cc1
Reactant: CCOC(=O)c1sc(-n2cn[nH]c2=O)cc1C
Agent: Fc1ccc(CBr)cc1
Product: CCOC(=O)c1sc(-n2cnn(CCC3CC3)c2=O)cc1C
Yield: 80 %

Procedure:
Following the procedure as described in Example 29, making variations as required to replace 4-fluorobenzyl bromide with 2-cyclopropylethyl 4-methylbenzenesulfonate to react with ethyl 3-methyl-5-(5-oxo-1H-1,2,4-triazol-4(5H)-yl)thiophene-2-carboxylate, the title compound was obtained as a yellowish solid in 80% yield: 1H NMR (300 MHz, CDCl3) δ 7.74 (s, 1H), 6.94 (s, 1H), 4.32 (q, J=7.1 Hz, 2H), 2.54 (s, 3H), 3.94 (t, J=7.1 Hz, 2H), 1.72-1.63 (m, 2H), 1.36 (t, J=7.1 Hz, 3H), 0.77-0.63 (m, 1H), 0.49-0.41 (m, 2H), 0.08-0.01 (m, 2H); MS (ES+) m/z 322.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH:10]=1)[C:5]([OH:7])=O.C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.[CH2:41]([NH:44][CH:45]1[CH2:49][CH2:48][CH2:47][CH2:46]1)[CH:42]=[CH2:43]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([N:44]([CH:45]2[CH2:49][CH2:48][CH2:47][CH2:46]2)[CH2:41][CH:42]=[CH2:43])=[O:7])[CH:8]=[C:9]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH:10]=1
Reactant: C=CCNC1CCCC1
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(Cl)cc(C(=O)O)c1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCN(C(=O)c1cc(Cl)cc(O[Si](C)(C)C(C)(C)C)c1)C1CCCC1
Reaction time: 0.08 h
Yield: 99.4 %

Procedure:
To a solution of 3-chloro-5-(tert-butyldimethylsilyloxy)benzoic acid (17.5 g, 60 mmol), as prepared in the preceding step, and CH2Cl2 (250 mL) were added triethylamine (33.8 mL, 0.24 mol) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (17.0 g, 66 mmol). The resulting mixture was stirred for 5 min, then N-allylcyclopentylamine (9.8 mL, 66 mmol) was added. After 1 h, the solution was filtered. The filtrate was washed with 10% aqueous HCl (100 mL), saturated aqueous NaHCO3 (100 mL), and brine (100 mL). The organic layer was dried over anhydrous MgSO4, concentrated in vacuo, and flash chromatographed to provide the title compound as a colorless oil (23.5 g, 97%). 1H NMR (CDCl3) δ 6.95 (s, 1H), 6.84 (s, 1H), 6.71 (s, 1H), 5.93 (br s, 1H), 5.16 (d, 2H), 3.95 (br s, 3H), 1.4-1.9 (m, 8H), 0.97 (s, 9H), 0.20 (s, 6H). Mass spectrum (CI) calcd. for C21H32NO2SiCl: 394 (M+H). Found: 394.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8](=O)[O:9][CH:10]([CH2:11][CH3:12])[C:4]=2[C:3]=1[Cl:14].[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][C:16]1=[O:24]>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8](=[C:17]3[C:18]4[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=4)[NH:15][C:16]3=[O:24])[O:9][CH:10]([CH2:11][CH3:12])[C:4]=2[C:3]=1[Cl:14]
Reactant: CCC1OC(=O)c2cnc(Cl)c(Cl)c21
Reactant: O=C1Cc2ccccc2N1
Product: CCC1OC(=C2C(=O)Nc3ccccc32)c2cnc(Cl)c(Cl)c21

Procedure:
In a manner similar to Example 46, 6,7-dichloro-1-ethyl-1H-furo[3,4-c]pyridine-3-one and 1,3-dihydroindol-2-one are converted to the title compound.
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].[CH:5]([Mg]Br)=[CH2:6].C1COCC1.[CH3:14][C@H:15]1[C:19](=[O:20])[CH2:18][CH2:17][N:16]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>>[OH:20][C@@:19]1([CH:5]=[CH2:6])[CH2:18][CH2:17][N:16]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:15]1[CH3:14]
Reactant: C[C@H]1C(=O)CCN1C(=O)OC(C)(C)C
Reactant: C=C[Mg]Br
Agent: [Ce+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: C=C[C@]1(O)CCN(C(=O)OC(C)(C)C)[C@H]1C

Procedure:
By an operation in the same manner as in Reference Example 3 and using cerium chloride (3.95 g), 1 mol/L vinylmagnesium bromide—THF solution (12.5 mL) and tert-butyl (2S)-2-methyl-3-oxopyrrolidine-1-carboxylate (1.0 g), the title compound was obtained as colorless oil (yield: 0.648 g, yield: 57%).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C:6]2[CH:8]=[C:9]3[O:14][CH2:13][O:12][C:10]3=[CH:11][C:5]=2[CH:4]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[O:3]1.CS(C)=[O:26].[OH-].[Na+].Cl>CN(C)C=O>[CH3:1][C@H:2]1[CH2:7][C:6]2[CH:8]=[C:9]3[O:14][CH2:13][O:12][C:10]3=[CH:11][C:5]=2[C:4]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)([OH:26])[O:3]1
Reactant: C[C@H]1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)O1)OCO3
Reactant: CS(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: C[C@H]1Cc2cc3c(cc2C(O)(c2ccc([N+](=O)[O-])cc2)O1)OCO3
Temperature: 10 °C
Reaction time: 4.5 h

Procedure:
350 grams of the isomeric intermediate from Example 4 was added to a solution of 731 mL of dimethylsulfoxide and 2923 mL of dimethylformamide. The mixture was cooled to 8-12° C. and compressed air was passed through the mixture. 117.5 mL of 50% aqueous sodium hydroxide was added in one portion and the resulting mixture was stirred for 4.5 h. The reaction mixture was added by cannula over 30-60 min to 8.25 L of a stirred 1N hydrochloric acid solution at 10-15° C. The resulting precipitate was filtered and washed with 3 L of water then air dried to a constant weight (384 g). The wet cake was carried into Example 6 without further drying. P chem: Data recorded from a 3:1 isomeric mixture. TLC Rf =0.19 (75:25 hexane:ethyl acetate); IR (CHCl3) 3605, 3590, 3015, 3000, 2960, 2910, 1608, 1522, 1484, 1352, 1240, 1042cm-1 -; 1H NMR (CDCl3, 300 MHz) δ(major isomer) 8.16 (d, 2H, j=6.9 Hz), 7.73 (d, 2H, J=6.9 Hz), 6.55 (s, 1H), 6.38 (s, 1H), 5.86 (s, 1H), 5.83 (s, 1H), 4.38 (M, 1H), 2.70 (m, 2H), 1.39 (d, 3H, J=6.3 Hz); d (minor isomer) 8.27 (d, 2H, J=8.9 Hz), 7.90 (d, 2H, J=8.6 Hz), 6.87 (s, 1H), 6.73 (s, 1H), 6.03 (s, 1H), 6.02 (s, 1H), 3.95 (m, 1H), 2.7 (obscured, m, 2H), 1.24 (d, 3H, J=6.1 Hz); mass spectrum, m/z (FD, M+) 329; Anal. Calcd. for C17H15NO6 : C, 62.01; H, 4.59; N, 4.25. found C, 62.22, H, 4.79; N, 4.29.
Reaction SMILES: C(OC([C:6]1[C:7]([CH3:31])=[C:8]2[C:13]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)=[C:12]([C:28]#[N:29])[CH:11]=[N:10][N:9]2[CH:30]=1)=O)C.[CH3:32][Mg+].[Br-].CC[O:37][CH2:38][CH3:39]>C1COCC1>[OH:37][C:38]([C:6]1[C:7]([CH3:31])=[C:8]2[C:13]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:19][CH:20]=3)=[C:12]([C:28]#[N:29])[CH:11]=[N:10][N:9]2[CH:30]=1)([CH3:39])[CH3:32]
Reactant: CCOCC
Reactant: C[Mg+]
Reactant: CCOC(=O)c1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c2c1C
Agent: [Br-]
Solvent: C1CCOC1
Product: Cc1c(C(C)(C)O)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Temperature: 25 °C

Procedure:
To a solution of 396A (1.85 g, 4.50 mmol) in THF (25 ml) was added a solution of 3M MeMgBr in Et2O (15 ml, 45 mmol) slowly at 0° C. The reaction mixture was warmed to rt, then heated at 50° C. for 30 min. After cooled to 0° C., the reaction was quenched with aqueous NH4Cl, extracted with EtOAc, dried and concentrated to give 1.8 g of crude 396 as a yellow solid. It has a retention time 6.49 min. (Column: HTS, 5 u, 4.6×50 mm; Gradient: 5-100% B in 8.0 min; A=0.1% TFA/H2O; B=0.1% TFA/CH3CN; Run time 10 min; Det: 215 nM; FR: 1.2 ml/min); MS Found: (M−H)+=397.4
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[N:9]2[C:10](=[O:24])[CH:11]([NH:16]C(OC(C)(C)C)=O)[CH2:12][CH:13]=[CH:14][CH2:15][CH:8]2[CH2:7][CH2:6]1)=[O:4]>FC(F)(F)C(O)=O.C(Cl)Cl>[CH3:1][O:2][C:3]([C@H:5]1[N:9]2[C:10](=[O:24])[C@@H:11]([NH2:16])[CH2:12][CH:13]=[CH:14][CH2:15][C@@H:8]2[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1CCC2CC=CCC(NC(=O)OC(C)(C)C)C(=O)N21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1CC[C@H]2CC=CC[C@H](N)C(=O)N21
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
6-tert-butoxycarbonylamino-5-oxo-1,2,3,5,6,7,10,10a-octahydro-pyrrolo[1,2-a]azocine-3-carboxylic acid methyl ester, 7, (3.46 g, 10.2 mmol) is treated with a solution of 1:1 trifluoroacetic acid/CH2Cl2 (50 mL) and allowed to stir for 2 hours at room temperature after which the solution is concentrated in vacuo and the resulting residue purified over silica (5% methanol/methylene chloride) to afford 2.43 g (100% yield) of the desired product as dark orange crystals. 1H NMR (CDCl3): δ 8.11 (bs, 2H), 5.76 (m, 2H), 4.66 (dd, J=9.3, 6.0 Hz, 1H), 4.50 (dd, J=8.7, 3.6, 1H), 4.21 (m, 1H), 3.68 (s, 3H), 2.95 (m, 1H), 2.73 (dt, J=15.3, 6.0, 1H), 2.43 (m, 2H), 2.15 (m, 2H), 1.94 (m, 2H). 13C NMR (CDCl3): δ 172.3, 168.5, 127.1, 60.7, 58.7, 52.3, 51.9, 32.7, 32.6, 31.2, 27.3. ESI MS 239.12 (M+H).
Reaction SMILES: Cl[CH:2]([C:8](=O)[CH2:9][CH3:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:12]([O-:14])=O.[NH4+:15].[OH-].[Na+]>C(O)=O.O.C(OCC)C>[CH2:9]([C:8]1[N:15]=[CH:12][O:14][C:2]=1[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:10]
Reactant: O=C[O-]
Reactant: [NH4+]
Reactant: CCOC(=O)C(Cl)C(=O)CC
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)c1ocnc1CC
Yield: 40.4 %

Procedure:
Ethyl 2-chloro-3-oxopentanoate (29.2 g, 0.164 mol) prepared by the method of E. A. Falco, P. B. Russell and G. H. Hitchings, J. Am. Chem. Soc 1951, 73, 3753, and ammonium formate (60 g, 0.95 mol ) were heated in 100% formic acid (180 ml ) under reflux for 5 h. The cooled mixture was diluted with water (300 ml) and diethyl ether (200 ml), then neutralised with aqueous sodium hydroxide (5M). The layers were separated and the aqueous layer extracted with more ether (4×200 ml). The combined ether layers were dried over magnesium sulphate and the solvent removed by distillation at atmospheric pressure. Vacuum distillation of the residue yielded the desired oxazole (11.2 g, 40%) b.p. 100°-106° (7 mm). This was contaminated with starting material. An analytical sample, obtained by extracting into 5M sulphuric acid, had b.p. 97°-98° (7 mm) . (Found C, 56.64; H, 6.63; N, 8.24; C8H11NO3 requires: C, 56.80; H, 6.55; N, 6.28%); m/e 169 (M+); δ (360 MHz, CDCl3) 1.27 (3H, J=7.5 Hz, ArCH2CH3); 1.40 (3H, t, J=7 Hz, CO2CH2CH3); 2.91 (2H, q, J=7.5 Hz, arCH2CH3); 4.40 (2H, q, J=7 Hz, CO2CH2CH3); 7.89 (1H, s, ArH).