Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@@H:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])/[CH:6]=[CH:7]/[C@@H:8]1[C@@H:12]([CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C:11](=O)[CH:10]2[O:23][CH:9]12)(=[O:3])[CH3:2].O.NN.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.C(O)(=O)C>[C:1]([O:4][C@@H:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])/[CH:6]=[CH:7]/[C@@H:8]1[C@@H:12]([CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH:11]=[CH:10][CH:9]1[OH:23])(=[O:3])[CH3:2]
Reactant: CCCCC[C@@H](/C=C/[C@H]1C2OC2C(=O)[C@@H]1C/C=C\CCCC(=O)O)OC(C)=O
Agent: NN
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CCCCC[C@@H](/C=C/[C@H]1C(O)C=C[C@@H]1C/C=C\CCCC(=O)O)OC(C)=O

Procedure:
to a solution of 30 parts of (5Z,13E,15S)-15-acetyloxy-10ξ,11ξ-epoxy-9-oxoprosta-5,13-dien-1-oic acid in 1200 parts of methanol at 5° is added a solution of 12 parts of 100% hydrazine hydrate in 96 parts of methanol followed by a solution of 1 part of acetic acid in 5 parts of methanol. The resultant mixture is stirred at 5° for 30 minutes, then acidified with aqueous 2% citric acid. The mixture thus obtained is extracted with dichloromethane. The extract is washed with water, dried over anhydrous sodium sulfate, and stripped of solvent by vacuum distillation. The residual red oil is taken up in benzene; and the benzene solution is chromatographed on silica gel, using benzene and mixtures thereof with increasing amounts of ethyl acetate as developing solvents. From an eluate comprising 20% ethyl acetate in benzene, on evaporation of solvent, (5Z,13E,15S)-15-acetyloxy-11ξ-hydroxyprosta-5,9,13-trien-1-oic acid is obtained as a colorless oil which gradually darkens upon standing.
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[C:9]([N+:16]([O-])=O)[CH:8]=1)[CH3:2].[O:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][C:30]([NH:33][C:34]([C:36]3[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=3)=[O:35])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1>>[CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]2[N:13]=[C:40]([C:39]3[CH:38]=[CH:37][C:36]([C:34]([NH:33][C:30]4[CH:29]=[CH:28][C:27]([N:24]5[CH2:23][CH2:22][O:21][CH2:26][CH2:25]5)=[CH:32][CH:31]=4)=[O:35])=[CH:43][CH:42]=3)[NH:16][C:9]=2[CH:8]=1)[CH3:2]
Reactant: O=Cc1ccc(C(=O)Nc2ccc(N3CCOCC3)cc2)cc1
Reactant: CCN(CC)CCOc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Product: CCN(CC)CCOc1ccc2nc(-c3ccc(C(=O)Nc4ccc(N5CCOCC5)cc4)cc3)[nH]c2c1

Procedure:
Compound 643 was prepared according to the procedure similar to that described in Scheme III from 1-(2-diethylaminoethyloxy)-3,4-dinitrobenzene and 4-(4-(4-morpholinophenyl)aminocarbonylbenzaldehyde. [M+H]+ calcd for C30H35N5O3: 514.27; found: 514.13.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([F:8])[N:3]=1.[CH2:9]([O:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([C:21]2[CH:22]=[CH:23][C:18]([O:17][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:19][CH:20]=2)[N:3]=1
Reactant: Fc1cncc(Cl)n1
Reactant: CCCCCCCCOc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: c1ccccc1
Product: CCCCCCCCOc1ccc(-c2cncc(F)n2)cc1
Yield: 94.7 %

Procedure:
7.99 g (60.0 mmol) of 2-chloro-6-fluoropyrazine, 15.08 g (60.0 mmol) of 4-octyloxyphenylboronic acid, 12.78 g (120.0 mmol) of sodium carbonate and 0.72 g (0.6 mmol) of tetrakis(triphenylphosphine)palladium(0) are heated at 80° C. for 2 hours in 400 ml of benzene, 300 ml of ethanol and 150 ml of water. The reaction mixture is partitioned between aqueous sodium chloride solution and ether, the organic phase is washed with aqueous sodium chloride solution, dried over sodium sulfate, filtered and freed from the solvents, and the residue is purified by chromatography (silica gel/hexane: ethyl acetate = 8:2). 17.18 g of 2-fluoro-6-(4-octyloxyphenyl)pyrazine are obtained. ##STR15## 1c
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH:11]3[O:23][CH2:24][C:25]3[CH:34]=[CH:33][C:32]4[C:27](=CC=CC=4)[CH:26]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.BrCC1C=CC=CC=1[C:39]#[N:40]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17])[CH2:12][CH:11]3[O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:32]=[CH:33][C:34]=3[C:39]#[N:40])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc3c(c2)OCO3)C(OCc2ccc3ccccc3c2)C1
Reactant: N#Cc1ccccc1CBr
Product: CC(C)(C)OC(=O)N1CCC(c2ccc3c(c2)OCO3)C(OCc2ccccc2C#N)C1

Procedure:
In an analogous manner to that described in Example 1(g), by alkylating tert-butyl (3RS,4RS)-4-benzo[1,3]dioxol-5-yl-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate [Example 8(f)] with 2-bromomethyl-benzonitrile there was obtained tert-butyl (3RS,4RS)-4-benzo[1,3]dioxol-5-yl-3-(2-cyano-benzyloxy)-piperidine-1-carboxylate as colourless crystals; MS: 455 (M+H)+.
Reaction SMILES: [OH-].[K+].[C:3]([O:7][C:8]([N:10]1[CH2:16][CH2:15][C:14]2[C:17]([S:22]C(=O)N(C)C)=[C:18]([Cl:21])[CH:19]=[CH:20][C:13]=2[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[CH2:29][CH2:30][CH2:31][N:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34](C(C)=C)[C:33]1=[O:44]>CO>[C:3]([O:7][C:8]([N:10]1[CH2:16][CH2:15][C:14]2[C:17]([S:22][CH2:29][CH2:30][CH2:31][N:32]3[C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=4[NH:34][C:33]3=[O:44])=[C:18]([Cl:21])[CH:19]=[CH:20][C:13]=2[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Reactant: C=C(C)n1c(=O)n(CCCBr)c2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCCCn3c(=O)[nH]c4ccccc43)c2CC1
Temperature: 25 °C
Yield: 82.4 %

Procedure:
Add potassium hydroxide (933 mg, 16.6 mmol) in one portion to a solution of 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine (200 mg, 0.52 mmol) in methanol (10 mL). Heat the reaction at reflux under nitrogen 4 h. Then cool to room temperature and add 1-(3-bromo-propyl)-3-isopropenyl-1,3-dihydro-benzoimidazol-2-one (142 mg, 0.52 mmol). Stir the reaction at room temperature overnight. Remove solvents in vacuo, extract into diethyl ether (2×50 mL), wash with water (2×50 mL) and brine (50 mL). Dry over MgSO4, filtrate and concentrate in vacuo to give 3-tert-butoxycarbonyl-7-chloro-6-[3-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-propylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine as an oil (209 mg, 76%). MS (ES+) m/z: 550 (M+Na)+.
Reaction SMILES: C(SC1C=C(O)C(=O)NC=1)C1C=CC=CC=1.[CH3:17][C:18]1[C:22]([CH2:23][S:24][C:25]2[CH:26]=[C:27]([O:35]COC)[C:28](=[O:34])[N:29](COC)[CH:30]=2)=[C:21]([CH3:39])[O:20][N:19]=1>>[CH3:17][C:18]1[C:22]([CH2:23][S:24][C:25]2[CH:26]=[C:27]([OH:35])[C:28](=[O:34])[NH:29][CH:30]=2)=[C:21]([CH3:39])[O:20][N:19]=1
Reactant: COCOc1cc(SCc2c(C)noc2C)cn(COC)c1=O
Agent: O=c1[nH]cc(SCc2ccccc2)cc1O
Product: Cc1noc(C)c1CSc1c[nH]c(=O)c(O)c1

Procedure:
Prepared as described for 5-(benzylsulfanyl)-3-hydroxypyridin-2(1H)-one (Example 12) from 5-{[(3,5-dimethyl-1,2-oxazol-4-yl)methyl]sulfanyl}-3-(methoxymethoxy)-1-(methoxymethyl)pyridin-2(1H)-one (Intermediate 20).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:13]([N:15]1[CH2:20][CH2:19][CH:18]([C:21]#[N:22])[CH2:17][CH2:16]1)=[O:14])[C:9]([CH3:12])([CH3:11])[CH3:10])(C)(C)C.[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27]>C(Cl)Cl>[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27].[NH2:7][C@H:8]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:13]([N:15]1[CH2:16][CH2:17][CH:18]([C:21]#[N:22])[CH2:19][CH2:20]1)=[O:14]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCC(C#N)CC1)C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[C@@H](N)C(=O)N1CCC(C#N)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of [(R)-1-(4-cyano-piperidine-1-carbonyl)-2,2-dimethyl-propyl]-carbamic acid tert-butyl ester (3.4 g, 10.5 mmol) in CH2Cl2 (60 mL) was added trifluoroacetic acid (20 mL). The reaction mixture was stirred at room temperature overnight then concentrated to afford 1-((R)-2-amino-3,3-dimethyl-butyryl)-piperidine-4-carbonitrile trifluoroacetate as a light brown oil which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:15])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:7]=1[CH3:8].[CH2:16]([O:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28](Cl)=[CH:29][CH:30]=[N:31]2)=[CH:26][C:25]=1[O:35][CH3:36])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH2:16]([O:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([O:15][C:4]3[C:5]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)=[N:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=3)=[CH:29][CH:30]=[N:31]2)=[CH:26][C:25]=1[O:35][CH3:36])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cc1cc(O)c(-c2ccccc2)nc1C
Reactant: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccccc3)ccnc2cc1OCc1ccccc1
Temperature: 140 °C
Reaction time: 4 h
Yield: 103.9 %

Procedure:
5,6-Dimethyl-2-phenyl-pyridin-3-ol (400 mg), 7-benzyloxy-4-chloro-6-methoxyquinoline (1.81 g), and 4-dimethylaminopyridine (736 mg) were suspended in o-dichlorobenzene (10 ml), and the suspension was stirred at 140° C. for 4 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform-methanol to give the title compound (965 mg, yield 100%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:17][C:16](=O)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:21])=O>CN(C)C=O>[Cl:21][C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[N:17]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(-c2nc3ccccc3c(=O)[nH]2)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2nc(Cl)c3ccccc3n2)cc1
Temperature: 0 °C

Procedure:
To a mixture of 7 g of 2-(4-methylphenyl)quinazolin-4(3H)-one and 50 ml of thionyl chloride was slowly added 2.16 g of dimethylformamide and the mixture was heated under reflux for 75 minutes. The mixture was poured into 250 ml of ice and the ice allowed to melt. The precipitate was collected to give 6.7 g of 4-chloro-2-(4-methylphenyl)quinazoline which melted at 113°-115° after recrystallization from petroleum ether (30°-60° fraction); ir and nmr spectra were consistent with the assigned structure. Calcd. for C15H11ClN2 : C, 70.73; H, 4.35; N, 11.00. Found: C, 70.92; H, 4.39; N, 11.09.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[Ru:21](Cl)([Cl:23])[Cl:22]>CO>[Ru:21]([Cl:23])[Cl:22].[C:14]1([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1.[C:14]1([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1.[C:14]1([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cl[Ru](Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: O
Product: Cl[Ru]Cl
Temperature: 75 °C

Procedure:
To a 100 cc glass flask is added 50 mls. of methanol, 5.0 grams of triphenylphosphine and 1.0 gram of ruthenium trichloride hydrate. The resulting mixture is stirred and heated by means of an oil bath under an atmosphere of nitrogen to a temperature of 75° C. and maintained at that temperature for 6 hours. Tris(triphenylphosphine) ruthenium dichloride is formed as a brown insoluble powder, which is recovered by filtration (3.9 gram).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12]([OH:14])[CH3:13])[CH2:11][O:10]1.[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[N:23]1[CH:27]=[CH:26][NH:25][C:24]1=O.FC1C=C(F)C=CC=1[C@]1(OC1)[C@H](N1C=CN(C2C=CC(F)=CC=2F)C1=O)C>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@H:12]([O:14][C:24]2[N:23]([C:17]3[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=3[F:15])[CH:27]=[CH:26][N:25]=2)[CH3:13])[CH2:11][O:10]1
Reactant: O=c1[nH]ccn1-c1ccc(F)cc1F
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Agent: C[C@@H](n1ccn(-c2ccc(F)cc2F)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Product: C[C@@H](Oc1nccn1-c1ccc(F)cc1F)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 27.4 %

Procedure:
In the same manner as in Reference Example 5, starting from 1.36 g of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 1.06 g of 1-(2,4-difluorophenyl)-2(1H,3H)-imidazolone, 0.53 g of 1-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-3-(2,4-difluorophenyl)-2(1H,3H)-imidazolone and 0.56 g of (2R)-2-(2,4-difluorophenyl)- 2-[(1R)-1-[1-(2,4-difluorophenyl)-2-imidazolyloxy]ethyl]oxirane were obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[O:68][C:67]([C:69]([O:71][CH3:72])=[O:70])=[CH:66][CH:65]=1>>[CH3:72][O:71][C:69]([C:67]1[O:68][C:64]([NH:63][C:30]([C@@H:20]2[NH:19][C@@H:18]([CH2:33][C:34]([CH3:36])([CH3:37])[CH3:35])[C@:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[C@H:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[CH:65][CH:66]=1)=[O:70]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: COC(=O)c1ccc(N)o1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Cl)c2F)o1
Yield: 1.6 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.3 g, 0.52 mmol), was reacted with diisopropylethylamine (0.34 g, 2.6 mmol), diphenylphosphinic chloride (0.25 g, 1 mmol), then reacted with methyl 5-aminofuran-2-carboxylate (Lancaster) (0.11 g, 0.78 mmol) to give rac-5-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-furan-2-carboxylic acid methyl ester as a yellow solid (Yield 5 mg, 2%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1.[H-].[Na+].Br[CH2:10][CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1>[CH2:13]([O:12][CH2:11][CH2:10][O:6][CH:3]1[CH2:4][CH2:5][O:1][CH2:2]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCCOCc1ccccc1
Reactant: OC1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: c1ccc(COCCOC2CCOC2)cc1
Reaction time: 0.17 h

Procedure:
Tetrahydrofuran-3-ol (0.881 g) in tetrahydrofuran (15 mL) was treated with 60% sodium hydride (0.8 g). After 10 minutes, ((2-bromoethoxy)methyl)benzene (3.23 g) was added. The solution was stirred for 16 hours. The reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was separated, and was extracted with additional ethyl acetate twice. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 1:1 ethyl acetate:hexane to provide the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[I-].[CH3:16][S+](C)(C)=O.CC(C)([O-])C.[Na+]>C1COCC1.COCCOC>[O:1]1[C:2]2([CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)[CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C[S+](C)(C)=O
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [Na+]
Solvent: COCCOC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (0.50 g, 2.51 mmol) in THF/DME (2:1, 6 mL) at 60° C. was added trimethylsulfoxonium iodide (0.58 g, 2.63 mmol) and sodium t-butoxide (0.25 g, 2.63 mmol). The reaction mixture was stirred at 60° C. for 30 min, cooled to rt and concentrated. Water was added and the mixture was extract with EtOAc twice. The combined organics were dried over Na2SO4, filtered and concentrated. Purification on silica gel (3:1, hexanes:EtOAc) gave tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate as a clear oil that solidified upon standing.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:25])[CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[CH:13]=[CH:14][C:15]([C:18](=[O:25])[CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:16][CH:17]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: COC(=O)CCC(=O)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)CCC(=O)c1ccc(-c2ccc(C)cc2)cc1
Yield: 69.4 %

Procedure:
To a stirred mixture of (4-methylphenyl)boronic acid (0.818 g, 0.00602 mol) and 4-(4-bromo-phenyl)-4-oxo-butyric acid, methyl ester (1.3556 g, 0.00500 mol) in toluene (10 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.173 g, 0.000150 mol) and 2.0 M aqueous sodium carbonate (5.0 mL, 0.010 mol), and the mixture was heated at reflux under nitrogen for 12 hours and allowed to cool. The mixture was diluted with toluene and dichloromethane (10 mL/10 mL), and filtered through a pad of Celite. The Celite was washed with additional toluene and dichloromethane. Filtrate and washings were combined and washed with 2.0 M aqueous sodium carbonate, brine, 3% aqueous ammonium hydroxide, water, and brine. The organics were dried (Na2SO4) and rotary evaporated. The residue was dissolved in chloroform and purified by column chromatography on silica gel (144 g, 230-400 mesh), eluting with hexanes-acetone (6:1, 17×125 mL) to give 0.98 g of 4-(4′-methyl-biphenyl-4-yl)-4-oxo-butyric acid, methyl ester as a white solid; mp 121-122° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][C:13]=1[F:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[Cl-].C([O-])([O-])=O.[Na+].[Na+].[C:30]([Si:34]([CH3:51])([CH3:50])[O:35][CH:36]1[CH2:41][CH2:40][C:39](OS(C(F)(F)F)(=O)=O)=[CH:38][CH2:37]1)([CH3:33])([CH3:32])[CH3:31]>C1(C)C=CC=CC=1.CCOCC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCO>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:39]2[CH2:40][CH2:41][CH:36]([O:35][Si:34]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:50])[CH3:51])[CH2:37][CH:38]=2)=[CH:14][C:13]=1[F:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OC1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: O=C(Nc1ccc(B(O)O)cc1F)OCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)OC1CC=C(c2ccc(NC(=O)OCc3ccccc3)c(F)c2)CC1
Temperature: 100 °C
Yield: 76.8 %

Procedure:
4-Benzyloxycarbonylamino-3-fluoro-benzene boronic acid (2.53 g, 8.75 mmol, 1.25 equiv.) and LiCl (840 mg, 21 mmol, 3.0 equiv.) was placed in a 125 mL round bottom flask equipped with a condenser. To this was added aq. Na2CO3 (2 M, 14 mL) and EtOH (14 mL) to form a nice suspension. To this was transferred a solution of trifluoromethanesulfonic acid 4-(tert-butyl-dimethyl-silanyloxy)-cyclohex-1-enyl ester (2.52 g, 7 mmol, 1 equiv.) in toluene (36 mL). This suspension was subjected to a vacuum/nitrogen exchange three times. Pd(PPh3)4 (CAS 14221-01-3) (406 mg, 0.10 mmol, 7.5 mol %) was then added. The brown mixture was heated in an oil bath at 100° C. for 40 min when the suspension became dark. TLC showed the reaction was complete. The reaction was diluted with ether (20 mL) and water (20 mL). The two layers were separated, and the aqueous layer was extracted with Et2O (2×10 mL). The combined Et2O extracts were washed with sodium bicarbonate (5 mL), brine (5 mL) and dried (anhydrous potassium carbonate). The solution was passed through a short Celite/silica gel pad, eluted with EtOAc. The filtrate was concentrated in vacuo to obtain a crude product. This was purified on silica gel column to get a solid. The solid was crystallized in 10% EtOAc in heptane to get 2.45 g (77%) of the title compound as a white crystalline solid. mp 116.1-119° C.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[O:4][C@@H:3]([C:11]2[CH:24]=[CH:23][C:14]([CH2:15][N:16]3[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]3)=[CH:13][CH:12]=2)[CH2:2]1.[O:25]1[CH2:30][CH2:29][CH:28]([C:31](O)=[O:32])[CH2:27][CH2:26]1>>[O:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[O:4][C@@H:3]([C:11]2[CH:12]=[CH:13][C:14]([CH2:15][N:16]3[CH2:17][CH2:18][CH:19]([NH:22][C:31]([CH:28]4[CH2:29][CH2:30][O:25][CH2:26][CH2:27]4)=[O:32])[CH2:20][CH2:21]3)=[CH:23][CH:24]=2)[CH2:2]1
Reactant: O=C(O)C1CCOCC1
Reactant: NC1CCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1
Product: O=C(NC1CCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1)C1CCOCC1

Procedure:
Compound 290 is synthesized from Intermediate M and Tetrahydro-pyran-4-carboxylic acid according to the procedure used to synthesize Example 261. (LC/MS method 16: ES+m/z 438.4 [M+H]+, Rt=1.44 mM)