Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([N:4]=[C:5]1[NH:9][CH2:8][CH2:7][NH:6]1)([O-:3])=[O:2].[CH:10](=O)[CH2:11][CH3:12].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O>CN(C)C=O.C(OCC)(=O)C>[CH:10]([N:6]1[CH2:7][CH2:8][NH:9][C:5]1=[N:4][N+:1]([O-:3])=[O:2])=[CH:11][CH3:12]
Reactant: O=[N+]([O-])N=C1NCCN1
Reactant: CCC=O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC=CN1CCNC1=N[N+](=O)[O-]
Temperature: 10 °C
Reaction time: 0.17 h
Yield: 65.8 %

Procedure:
5.0 g of 2-nitroiminoimidazolidine and 4.5 g of propionaldehyde were dissolved in 25 ml of N,N-dimethylformamide, and 4.0 g of phosphorus pentoxide was added thereto with cooling with ice over a period of 20 minutes and thereafter stirred for 10 minutes at 10° C. 20 ml of water and 20 ml of ethyl acetate were added to the reaction mixture, and the crystals thus precipitated out were filtrated and dried to give 4.3 g of 1-(1-propenyl)-2-nitroiminoimidazolidine.
Reaction SMILES: [OH-:1].[Na+].C(O)C.C1(N=[C:13]([OH:59])[C:14]2[C:15](=[C:19]([O:47][C:48]3[CH:53]=[CH:52][C:51]([O:54][CH2:55][CH2:56][CH2:57][CH3:58])=[CH:50][CH:49]=3)[C:20](=[C:24]([C:34]=2[O:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH2:43][CH2:44][CH2:45][CH3:46])=[CH:38][CH:37]=2)[C:25](=NC2C=CC=CC=2)[OH:26])[C:21]([OH:23])=[O:22])[C:16]([OH:18])=[O:17])C=CC=CC=1.Cl.[OH2:61]>>[CH2:43]([O:42][C:39]1[CH:40]=[CH:41][C:36]([O:35][C:34]2[C:24]([C:25]([OH:1])=[O:26])=[C:20]([C:21]([OH:23])=[O:22])[C:19]([O:47][C:48]3[CH:53]=[CH:52][C:51]([O:54][CH2:55][CH2:56][CH2:57][CH3:58])=[CH:50][CH:49]=3)=[C:15]([C:16]([OH:18])=[O:17])[C:14]=2[C:13]([OH:59])=[O:61])=[CH:37][CH:38]=1)[CH2:44][CH2:45][CH3:46]
Reactant: [OH-]
Reactant: O
Reactant: CCCCOc1ccc(Oc2c(C(=O)O)c(C(O)=Nc3ccccc3)c(Oc3ccc(OCCCC)cc3)c(C(O)=Nc3ccccc3)c2C(=O)O)cc1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCCCOc1ccc(Oc2c(C(=O)O)c(C(=O)O)c(Oc3ccc(OCCCC)cc3)c(C(=O)O)c2C(=O)O)cc1
Temperature: 25 °C

Procedure:
Into 150 ml of 10% NaOH solution made from 1:1 (v:v) mixture of ethanol and water were dissolved 2 g of N,N'-diphenyl-3,6-bis[4-(n-butyloxy)phenyloxy]pyromellitic diimide obtained from above. This solution was refluxed for 72 hr under nitrogen atmosphere and then cooled to ambient temperature. When it was neutralized with 5%, aqueous HCl, white precipitates were formed. These precipitates were filtered, air-dried and recrystallized from 1:1 (v:v) mixture of hexane and ethyl acetate to obtain 3,6-bis[4-(n-butyloxy)phenyloxy]pyromellitic acid.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([S:7][CH3:8])[N:3]=1.[Cl:9][C:10]1[CH:11]=[C:12]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[CH2:13][OH:14].[H-].[Na+].[Cl-].[Na+]>CN(C)C=O>[Cl:9][C:10]1[CH:11]=[C:12]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[CH2:13][O:14][C:2]1[S:6][N:5]=[C:4]([S:7][CH3:8])[N:3]=1
Reactant: CSc1nsc(Cl)n1
Reactant: OCc1cc(Cl)cc(Cl)c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nsc(OCc2cc(Cl)cc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.7 %

Procedure:
Into 4 ml of N,N-dimethylformamide were dissolved 334 mg of 5-chloro-3-methylthio-1,2,4-thiadiazole and 389 mg of 3,5-dichlorobenzyl alcohol, 96 mg of sodium hydride (60% in oil) was added thereto under ice-cooling, and the reaction mixture was stirred for 0.5 hour under ice-cooling and for 4 hours at room temperature. The reaction mixture was added to saturated sodium chloride aqueous solution, and extracted with t-butyl methyl ether. The organic layer was concentrated, and the residue obtained was subjected to silica gel column chromatography to give 380 mg of 5-(3,5-dichlorobenzyloxy)-3-methylthio-1,2,4-thiadiazole (hereinafter, referred to as the present compound (28)).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:16]=[CH:15][C:8]([O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=1)=[O:4].[N:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1>C(#N)C>[N:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:24][CH2:25][N:26]([CH2:2][C:3]([C:5]3[CH:16]=[CH:15][C:8]([O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=3)=[O:4])[CH2:27][CH2:28]2)=[CH:19][CH:18]=1
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: COC(=O)COc1ccc(C(=O)CBr)cc1
Solvent: CC#N
Product: COC(=O)COc1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1
Reaction time: 1.5 h

Procedure:
A solution of methyl 4-bromoacetylphenoxyacetate (4.3 g) in acetonitrile (50 ml) was added dropwise over 40 minutes to a stirred solution of 1-(4-pyridyl)piperazine (4.9 g) in acetonitrile (100 ml). Stirring was continued for a further 1.5 hours, then the solution was filtered and the filtrate evaporated in vacuo. The solid residue was triturated with water (50 ml), then dried and suspended in methylene chloride (50 ml). The suspension was then filtered and the filtrate concentrated to a small volume. Purification by flash chromatography on neutral alumina eluting first with dichloromethane, then 0.5% v/v methanol/dichloromethane and finally 1% v/v methanol/dichloromethane gave the title compound, 1.93 g, as a solid: m.p. 150°-152° C.; NMR(d6DMSO) δ8.14(2H,d), 7.98(2H,d), 7.03(2H,d), 6.78(2H,d), 4.90(2H,s), 3.83 (2H,s), 3.72(3H,s), 3.34(4H,bt), 2.65(4H,bt); m/e 370 (M+H)+ ; calculated for C20H23N3O4 : C, 65.0; H, 6.3; N, 11.4. found: C, 65.2; H, 6.4; N, 11.3%.
Reaction SMILES: [CH2:1]([N:8]1[N:12]=[C:11]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22](/[N:25]=[CH:26]/[C:27]4[O:28][C:29]([N+:32]([O-:34])=[O:33])=[CH:30][CH:31]=4)=[CH:21][C:20]=3[F:35])[CH2:15][CH2:14]2)[O:10][C:9]1=[O:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CC(O)=O.CO>[CH2:1]([N:8]1[N:12]=[C:11]([CH:13]2[CH2:14][CH2:15][N:16]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][CH2:26][C:27]4[O:28][C:29]([N+:32]([O-:34])=[O:33])=[CH:30][CH:31]=4)=[CH:21][C:20]=3[F:35])[CH2:17][CH2:18]2)[O:10][C:9]1=[O:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1oc(C2CCN(c3ccc(/N=C/c4ccc([N+](=O)[O-])o4)cc3F)CC2)nn1Cc1ccccc1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=c1oc(C2CCN(c3ccc(NCc4ccc([N+](=O)[O-])o4)cc3F)CC2)nn1Cc1ccccc1
Yield: 83.9 %

Procedure:
3-Benzyl-5-[1-(2-fluoro-4-[(E)-1-(5-nitro-2-furyl)methylidene]aminophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (9 h, 0.49 g, 1 mmol) on reduction with sodiumcyanoborohydride (0.12 g, 2 mmol) in the presence of catalytic amount of CH3COOH (3 drops) in methanol at 0° C. for 12 h. After completion of the reaction as indicated by TLC, the reaction mixture is neutralized with sodium bi carbonate and extracted into chloroform. The crude product thus obtained was purified by column chromatography using ethyl acetate-hexane (8:2) as eluant to obtain product 3-benzyl-5-[1-(2-fluoro-4-[(5-nitro-2-furyl)methyl]aminophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (10 h, 414 mg, 84%).
Reaction SMILES: [I:1]Cl.[Cl:3][S:4]([OH:7])(=[O:6])=[O:5].[F:8][C:9]([F:13])=[C:10]([F:12])[F:11]>>[S:4]([Cl:3])([O:7][C:10]([F:12])([F:11])[C:9]([I:1])([F:13])[F:8])(=[O:6])=[O:5]
Reactant: ClI
Reactant: FC(F)=C(F)F
Reactant: O=S(=O)(O)Cl
Product: O=S(=O)(Cl)OC(F)(F)C(F)(F)I
Reaction time: 2 h
Yield: 74 %

Procedure:
Into a 1-liter pressure reactor was charged a mixture of iodine monochloride (390 g, 2.4 mol) and chlorosulfonic acid (490 g, 4.206 mol). The reactor was cooled and kept at 0-10° C. until 300 g of tetrafluoroethylene (3.0 mol) was added. After the addition of TFE was complete, the reaction mixture was held at 0-10° C. for 6 hr, at 25° C. for 2 hr and at 50° C. for 2 hr. The reaction mixture was then slowly poured into a large amount of ice with stirring, and worked up as described above. The desired product was obtained (610 g, 74% yield), bp. 62-64° C./6.7 kPa. 19F NMR (188.24 MHz, CDCl3): -85.6 (t, J=4.5 Hz, 2F), -65.3 (t, J=4.5 Hz, 2F). Anal. Calcd. for C2F4IClSO3 : C: 7.02, F: 22.19; Found: C: 7.19, F: 22.73.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:31](=[O:32])[N:6]2[C:7]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)=[O:19])=[C:8]([C:10]3[S:14][C:13]4=[CH:15][N:16]=[CH:17][N:12]4[CH:11]=3)[CH2:9][C@H:5]12)[CH3:3].[I:33][CH2:34][C:35]([NH2:37])=[O:36]>CC(C)=O>[I-:33].[C:35]([CH2:34][N:16]1[CH:15]=[C:13]2[S:14][C:10]([C:8]3[CH2:9][C@@H:5]4[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:31](=[O:32])[N:6]4[C:7]=3[C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)=[O:19])=[CH:11][N+:12]2=[CH:17]1)(=[O:36])[NH2:37]
Reactant: NC(=O)CI
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cncc4s3)C[C@H]12
Solvent: CC(C)=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3c[n+]4cn(CC(N)=O)cc4s3)C[C@H]12
Product: [I-]
Temperature: 25 °C
Reaction time: 25 h

Procedure:
To a suspension of 69 mg of 4-nitrobenzyl (5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate in 2 ml of acetone was added 281 mg of iodoacetamide, and the mixture was stirred at room temperature for 25 hours. The reaction mixture was concentrated under reduced pressure to dryness. The residue was triturated with 3 ml of ethyl acetate, and the insolubles were collected by filtration to give 4-nitrobenzyl (5R,6S)-2-(6-carbamoylmethylimidazo[5,1-b]thiazolium-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate iodide.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13].C(N(CC)CC)C.Cl[S:22]([N:25]1[C:28]([CH3:30])([CH3:29])[CH2:27][C:26]1=[O:31])(=[O:24])=[O:23].[CH3:32][OH:33]>>[CH3:32][O:33][S:22]([NH:25][C:28]([CH3:30])([CH3:29])[CH2:27][C:26]([NH:1][C@@H:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13])=[O:31])(=[O:24])=[O:23]
Reactant: CO
Reactant: CC1(C)CC(=O)N1S(=O)(=O)Cl
Reactant: N[C@@H]1CCc2ccccc2NC1=O
Solvent: CCN(CC)CC
Product: COS(=O)(=O)NC(C)(C)CC(=O)N[C@@H]1CCc2ccccc2NC1=O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A suspension of 98.31 g (0.530 mol) of 3(R)-amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one in 1600 mL of methanol at room temperature was treated with 155 mL (1.112 mol) of triethylamine. The resulting suspension was cooled to 0° C. and treated with a solution of 110.01 g (0.557 mol) of N-chlorosulfonyl-4,4-dimethylazetidin-2-one in 960 mL of methanol over 20 minutes maintaining the internal temperature below 10° C. Additional methanol (100 mL) was used to rinse the flask and the rinse was transferred into the reaction vessel. The reaction mixture was warmed to room temperature and stirred for 90 minutes.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:7][CH2:6][C:5]([CH3:9])([CH3:8])[C:4](=O)[C:3]1=O.[CH:13]1([NH2:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[NH2:19].O>C(O)(=O)C>[CH3:1][C:2]1([CH3:12])[C:3]2[C:4](=[N:19][C:14]3[CH2:15][CH2:16][CH2:17][CH2:18][C:13]=3[N:20]=2)[C:5]([CH3:9])([CH3:8])[CH2:6][CH2:7]1
Reactant: NC1CCCCC1N
Reactant: CC1(C)CCC(C)(C)C(=O)C1=O
Solvent: O
Solvent: CC(=O)O
Product: CC1(C)CCC(C)(C)c2nc3c(nc21)CCCC3

Procedure:
20.0 g of 3,3,6,6,-tetramethyl-1,2-cyclohexanedione and 20 ml of 1,2-cyclohexanediamine were dissolved in 20 ml of acetic acid. The obtained solution was heated under reflux for 6 hours, cooled by allowing to stand, and poured into water, followed by the extraction with ethyl acetate. The organic phase was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate, and concentrated in a vacuum. The obtained residue was purified by silica gel chromatography (developer: 5% ethyl acetate/hexane) to give 16.0 g of the title compound as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[NH:23]1[CH2:27][CH2:26][C@@H:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:24]1.CC(O)C.CCN(C(C)C)C(C)C>O>[Br:1][C:2]1[C:3]([N:23]2[CH2:27][CH2:26][C@@H:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[CH2:24]2)=[N:4][CH:5]=[C:6]([C:7](=[O:8])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[CH:21]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
Temperature: 25 °C

Procedure:
A mixture of 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2, 0.5 g, 1.264 mmol), (R)-tert-butyl pyrrolidin-3-ylcarbamate (283 mg, 1.517 mmol), iPrOH (4 mL) and DIPEA (0.442 mL, 0.327 g, 2.53 mmol) were subjected to MW irradiation at 140° C. for 30 min. The vial was cooled to RT and the RM was added to water (100 mL) and the resulting precipitate was collected by filtration. The obtained solid was washed with water (50 mL) and dried to afford the title compound as an off-white powder. LC-MS (Condition 6) tR=1.47 min, m/z=488.9/490.9 [M+H—H2C═C(CH3)2], m/z=545/547.0 [M+H]+.
Reaction SMILES: C(O)(=[S:3])C.[OH-].[K+].Br[CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:17])[CH:14]=2)[C:9]1=[O:18].O>C(O)C>[Cl:17][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:18])[CH:8]([SH:3])[CH2:16]2
Reactant: O=C1c2ccc(Cl)cc2CC1Br
Reactant: CC(O)=S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C1c2ccc(Cl)cc2CC1S
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1.37 g (18 mmoles) of thioacetic acid in 30 ml of ethanol is neutralized exactly, in a nitrogen atmosphere, by the dropwise addition of a 40% strength aqueous KOH solution, and 3.7 g (15 mmoles) of 2-bromo-5-chloro-1-indanone (Example 1 (a)) are added. The reaction mixture is stirred for 1 hour at room temperature and poured into 200 ml of water. The product which crystallizes after some time is filtered off and introduced, under nitrogen, into 35 ml of a 5% strength aqueous NaOH solution. After stirring for 1 hour at room temperature, the pH is adjusted to 1 with 2 N hydrochloric acid and the crystalline precipitate is filtered off. The resulting 5-chloro-2-mercapto-1-indanone decomposes at 173°-175° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[C:11](=[CH:12][N:13]=[C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:15]=2)[CH:10]=[CH:9][N:8]=1)(=O)=O.[CH3:27][N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.CCOC(C)=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>[CH2:18]([O:17][C:14]1[CH:15]=[C:16]2[C:11]([CH:10]=[CH:9][N:8]=[C:7]2[C:31]2[CH:30]=[N:29][N:28]([CH3:27])[CH:32]=2)=[CH:12][N:13]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=S(=O)(Oc1nccc2cnc(OCc3ccccc3)cc12)C(F)(F)F
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1cc(-c2nccc3cnc(OCc4ccccc4)cc23)cn1
Temperature: 100 °C
Yield: 86.4 %

Procedure:
To a suspension of 7-(benzyloxy)-2,6-naphthyridin-1-yl trifluoromethanesulfonate (Preparation 87, 350 mg, 0.911 mmol) in 1,4-dioxane (6 mL) and water (3 mL) was added 1-Methylpyrazole-4-boronic acid pinacol ester (379 mg, 1.821 mmol), cesium carbonate (460 mg, 1.412 mmol) and Pd(PPh3)4 (220 mg, 0.190 mmol). The reaction mixture was heated to 100° C. for 30 minutes under microwave conditions. The reaction mixture was diluted with EtOAc (25 mL) and water (25 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 0-15% MeOH in DCM followed by a second chromatography eluting with 0-10% MeOH in DCM to give the title compound (249 mg, 86%).
Reaction SMILES: [CH3:1][CH2:2][N:3]([CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12](/[C:15](/[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[C:16](/Cl)\[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:13][CH:14]=1)[CH2:4][CH3:5].C([Li])(C)(C)C.[CH2:35]1[O:37][CH2:36]1.O>O1CCCC1>[CH3:1][CH2:2][N:3]([CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12](/[C:15](/[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[C:16](\[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)/[CH2:35][CH2:36][OH:37])=[CH:13][CH:14]=1)[CH2:4][CH3:5]
Reactant: CCN(CC)CCOc1ccc(/C(=C(/Cl)c2ccccc2)c2ccccc2)cc1
Reactant: C1CO1
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: CCN(CC)CCOc1ccc(/C(=C(/CCO)c2ccccc2)c2ccccc2)cc1
Reaction time: 0.08 h

Procedure:
Clomiphene (6.06 q, 14.9 mmol) was dissolved in tetrahydrofuran (100 ml) and cooled to -40° C. t-Butyl lithium (1 M in pentane, 24 mmol) was added slowly. After 5 minutes, ethylene oxide (14.6 ml, 290 mmol) was added, and the reaction mixture was stirred for 6 hours, poured into water and extracted with ether. The ether layer was evaporated and chromatographed on a silica gel column using 1:1:0.1 ether/petroleum ether/triethylamine as eluant to yield trans product (1.96 g, 27.1%, oil): and cis product (1.56 g, 21.5%, oil): Assignment of 1HNMR for aliphatic protons are presented in Table 3.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][C:16](=[O:19])[CH:17]=[CH2:18])[C:5]([C:20]([F:23])([F:22])[F:21])=[CH:4][N:3]=1.[NH2:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[CH3:34])[C:28]([NH2:30])=[O:29].CO.C(Cl)Cl>CC1C=CC(S(O)(=O)=O)=CC=1.O1CCOCC1>[C:16]([NH:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[NH:8][C:6]1[C:5]([C:20]([F:23])([F:22])[F:21])=[CH:4][N:3]=[C:2]([NH:24][C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=2[CH3:34])[C:28]([NH2:30])=[O:29])[N:7]=1)(=[O:19])[CH:17]=[CH2:18]
Reactant: C=CC(=O)Nc1ccccc1Nc1nc(Cl)ncc1C(F)(F)F
Reactant: Cc1ccc(C(N)=O)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: ClCCl
Solvent: C1COCCO1
Product: C=CC(=O)Nc1ccccc1Nc1nc(Nc2cc(C(N)=O)ccc2C)ncc1C(F)(F)F
Temperature: 95 °C
Reaction time: 16 h
Yield: 44.7 %

Procedure:
To a solution of Intermediate 1 (1 g, 2.923 mmol) in 0.04 M PTSA solution in 1,4-Dioxane (20 mL) was added 3-amino-4-methylbenzamide (526 mg, 3.5076 mmol), and the mixture was stirred at 95° C. for 16 h. TLC showed completion of starting material. (TLC system: 10% Methanol/DCM, (Rf): 0.6). The reaction mixture was directly absorbed on silica gel and purified by column chromatography using 4% methanol/DCM as eluents. The resulting off-white solid was stirred in a mixture of DCM:EtOAc:Diethyl Ether (10 mL:10 mL:30 mL) for 10 min, then filtered and dried under vacuum to obtain 596 mg of the desired compound (44%). 1HNMR (400 MHz, DMSO-d6) δ 2.15 (s, 3H), 5.78-5.81 (dd, 1H, J=1.9, 10.0 Hz), 6.26-6.31 (dd, 1H, J=2.0, 17.0 Hz), 6.40-6.46 (dd, 1H, J=10.0, 16.9 Hz), 7.02-7.09 (m, 2H), 7.13-7.15 (d, 1H, J=7.5 Hz), 7.19-7.21 (dd, 1H, J=7.9 Hz), 7.32 (br s, 1H), 7.57-7.59 (dd, 1H, J=1.6, 7.6 Hz), 7.66-7.68 (d, 1H, J=8 Hz), 7.88-7.91 (d, 2H, J=11.4 Hz), 8.21 (s, 1H), 8.27 (s, 1H), 9.12 (br s, 1H) 10.3 (s, 1H). MS: m/z 457.3 (ES+, M+H).
Reaction SMILES: [NH:1]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@H:2]([C:15]([OH:17])=[O:16])[CH2:3][CH2:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH:25]1(O)[CH2:29][CH2:28][CH2:27][CH2:26]1.C(Cl)CCl>ClCCl.CN(C1C=CN=CC=1)C>[CH:25]1([O:16][C:15](=[O:17])[C@@H:2]([NH:1][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:3][CH2:4][C:5]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:14])[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: OC1CCCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OC1CCCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 68.7 %

Procedure:
To a solution of Boc-L-Glu(OBzl)-OH (15 g, 44.5 mmol) in dichloromethane (220 ml) in an ice-bath, was added cyclopentanol (4.8 ml, 53.3 mmol, 1.2 eq), EDC (9.4 g, 48.9 mmol, 1.1 eq) and DMAP (543 mg, 4.4 mmol, 0.1 eq). The reaction mixture was allowed to warm to room temperature and stirred for 12 hours for complete reaction. The reaction mixture was diluted with DCM (200 ml) and washed with 1M HCl, 1M Na2CO3 and brine. The organic layer was then dried over magnesium sulphate and evaporated under reduced pressure. The product was purified by column chromatography using ethyl acetate/heptane (1:4) to give 12.4 g, 69% yield of title compound as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].O.[OH:17][C:18]1[CH:28]=[CH:27][C:21]([CH:22](O)[C:23](O)=[O:24])=[CH:20][CH:19]=1>C(O)(=O)C>[C:11]([C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]2[O:15][C:23](=[O:24])[CH:22]([C:21]3[CH:27]=[CH:28][C:18]([OH:17])=[CH:19][CH:20]=3)[C:7]=2[CH:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Reactant: O=C(O)C(O)c1ccc(O)cc1
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OC(=O)C2c1ccc(O)cc1
Yield: 56.7 %

Procedure:
A mixture of 103.2 g (0.50 mol) of 2,4-di-tert-butylphenol and 102.4 g (0.55 mol) of 4-hydroxymandelic acid monohydrate in 100 ml of acetic acid is refluxed for 24 hours under a nitrogen atmosphere. The reaction mixture is then diluted with 140 ml of 50% aqueous acetic acid, cooled, and the precipitate formed is filtered off. The residue is washed with another 200 ml of 50% aqueous acetic acid and then dried, giving 95.9 g (57%) of 5,7-di-tert-butyl-3-(4-hydroxyphenyl)benzofuran-2-one, melting point 187°-190° C. (compound (101), Table 1).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([C:15](=[O:16])[NH:14][C:13](=[O:17])[CH:12]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=[O:7].[CH3:35]I>>[F:32][C:29]([F:30])([F:31])[C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:28]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([C:15](=[O:16])[N:14]([CH3:35])[C:13](=[O:17])[CH:12]2[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:24][CH2:25]1)=[O:7]
Reactant: CI
Reactant: O=C1NC(=O)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)C1c1ccccc1
Product: CN1C(=O)C(c2ccccc2)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)C1=O

Procedure:
The title compound, MS: m/e=499.2 (M+H+), was prepared in accordance with the general method of example 121 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-4-phenyl-2,8-diaza-spiro[4.5]decane-1,3-dione and methyl iodide.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[C:7]([CH3:12])=[N:8][CH:9]=[CH:10][CH:11]=1)(=[O:4])=[O:3].O.[Se](=O)=[O:15]>O1CCOCC1>[CH3:1][S:2]([NH:5][C:6]1[C:7]([CH:12]=[O:15])=[N:8][CH:9]=[CH:10][CH:11]=1)(=[O:3])=[O:4]
Reactant: Cc1ncccc1NS(C)(=O)=O
Reactant: O=[Se]=O
Solvent: O
Solvent: C1COCCO1
Product: CS(=O)(=O)Nc1cccnc1C=O
Yield: 83.6 %

Procedure:
To a solution of 3-methylsulfonamido-2-methylpyridine (310 mg, 1.66 mmol) in dioxane (8 mL) was added water (0.8 mL) and selenium(IV) oxide (241 mg, 2.17 mmol) and the mixture stirred at reflux overnight. The reaction mixture was concentrated under reduced pressure and purified by column chromatography on silica gel (Hexanes/ethyl acetate, 1:1) to afford the title compound (278 mg, 83%). 1H NMR (CDCl3) □ 3.14 (s, 3H), 7.53 (dd, 1H, J=9, 6 Hz), 8.16 (dd, 1H, J=9, 3 Hz), 8.53 (dd, 1H, J=6, 3 Hz), 10.09 (s, 1H), 10.41 (br s, 1H, NH).