Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].Cl[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][C:13]2[N:14]=[C:15]([C:19]3[O:20][CH:21]=[CH:22][CH:23]=3)[O:16][C:17]=2[CH3:18])=[N:9][CH:10]=1.[CH2:24]([O:26][C:27](=[O:40])[CH2:28][C:29]1[C:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[N:31][NH:32][CH:33]=1)[CH3:25].O>CN(C)C=O>[O:20]1[CH:21]=[CH:22][CH:23]=[C:19]1[C:15]1[O:16][C:17]([CH3:18])=[C:13]([CH2:12][O:11][C:8]2[N:9]=[CH:10][C:5]([CH2:4][N:32]3[CH:33]=[C:29]([CH2:28][C:27]([O:26][CH2:24][CH3:25])=[O:40])[C:30]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[N:31]3)=[CH:6][CH:7]=2)[N:14]=1
Reactant: CCOC(=O)Cc1c[nH]nc1-c1ccccc1
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(CCl)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1cn(Cc2ccc(OCc3nc(-c4ccco4)oc3C)nc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.6 %

Procedure:
Sodium hydride (60%, oily, 70.0 mg) was added to a solution of 5-chloromethyl-2-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]pyridine (533 mg) and ethyl(3-phenyl-1H-pyrazol-4-yl)acetate (403 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl [1-[6-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-pyridylmethyl]-3-phenyl-1H-pyrazol-4-yl]acetate (581 mg, yield: 67%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[N:16]=[C:15]([C:26]([NH:28][CH:29]3[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]3)=[O:27])[C:14]=2[CH3:42])=[CH:9][CH:8]=1.C(N(CC)CC)C>O1CCCC1>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[N:16]=[C:15]([C:26]([NH:28][CH:29]3[CH2:34][CH2:33][N:32]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:31][CH2:30]3)=[O:27])[C:14]=2[CH3:42])=[CH:9][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1c(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1c(C(=O)NC2CCN(S(C)(=O)=O)CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reaction time: 16 h
Yield: 87.4 %

Procedure:
Methanesulfonyl chloride (2 eq., 0.01 mL, 0.15 mmol) was added to tert-Butyl 4-[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-amido]piperidine-1-carboxylate (1 eq., 35 mg, 0.076 mmol) and triethyamine (3 eq., 0.03 mL, 0.227 mmol) in tetrahydrofuran (2 mL). The reaction was stirred for 16 h. The reaction was concentrated in vacuo. The crude reaction material was then purified by silica gel column chromatography using 0-100% ethyl acetate/hexane to yield pure 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-N-(1-methanesulfonyl-piperidin-4-yl)-4-methyl-1H-pyrazole-3-carboxamide (36 mg, 87%). 1H NMR (300 MHz, CHLOROFORM-d) d ppm 1.53-1.78 (m, 2H) 2.06-2.22 (m, 2H) 2.37 (s, 3H) 2.67-3.00 (m, 5H) 3.82 (d, J=12.24 Hz, 2H) 4.01-4.17 (m, 1H) 6.88 (d, J=8.01 Hz, 1H) 7.07 (s, 2H) 7.19-7.36 (m, 4H) 7.43 (d, J=1.70 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([O:44][Si](C(C)(C)C)(C)C)[CH2:21][NH:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:33]=[C:34]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH:35]=[CH:36][CH:37]=3)=[CH:27][CH:26]=2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F.F.F.C(N(CC)CC)C>O1CCCC1.[OH-].[Na+]>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([OH:44])[CH2:21][NH:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:33]=[C:34]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:35]=[CH:36][CH:37]=3)=[CH:27][CH:26]=2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CNCCc1ccc(Oc2cccc(-c3ccccc3)c2)cc1)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=c1ccc2c([C@@H](O)CNCCc3ccc(Oc4cccc(-c5ccccc5)c4)cc3)ccc(OCc3ccccc3)c2[nH]1
Yield: 45.7 %

Procedure:
The product of step (d) (275 mg) and triethylamine trihydrofluoride (1.0 mL) in tetrahydrofuran (10 mL) was stirred at room temperature for 16 h. The solution was diluted with sodium hydroxide (0.5M, 10 mL), extracted with dichloromethane (2×10 mL) and the combined organics dried over sodium sulfate and evaporated to afford the title intermediate (105 mg), which was used directly in the next step without further purification.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:19])=[C:11]([F:18])[C:12]=3[O:14]C(C)C)[C:7](=[O:20])[C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1.[N+:26]([O-])([O-:28])=[O:27].[K+]>OS(O)(=O)=O>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([N+:26]([O-:28])=[O:27])[C:10]([F:19])=[C:11]([F:18])[C:12]=3[OH:14])[C:7](=[O:20])[C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(OC(C)C)c(F)c(F)cc2c1=O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCOC(=O)c1cn(C2CC2)c2c(O)c(F)c(F)c([N+](=O)[O-])c2c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 64.9 %

Procedure:
A solution of ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-isopropoxy-4-oxoquinoline-3-carboxylate (600 mg, 1.71 mmol) in concentrated H2SO4 (5 mL) was treated portion wise with solid KNO3 (242 mg, 2.39 mmol) at 0° C. After stirred at 0° C. for 30 min and at room temperature for 1 h, the reaction mixture was poured into ice-water and the resulting precipitate was collected by filtration, washed with water and dried to yield ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-hydroxy-5-nitro-4-oxoquinoline-3-carboxylate (393 mg, 65%) as a pale brown solid.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:28](=[O:29])[N:7]2[CH:8]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=3)[C:9]3[NH:10][C:11]4[C:16]([C:17]=3[CH2:18][C:6]2([CH3:30])[C:5]1=[O:31])=[CH:15][C:14]([O:19][CH3:20])=[CH:13][CH:12]=4.[CH3:32][NH:33][CH3:34]>>[CH3:32][N:33]([CH3:34])[CH2:2][CH2:3][N:4]1[C:28](=[O:29])[N:7]2[CH:8]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=3)[C:9]3[NH:10][C:11]4[C:16]([C:17]=3[CH2:18][C:6]2([CH3:30])[C:5]1=[O:31])=[CH:15][C:14]([O:19][CH3:20])=[CH:13][CH:12]=4
Reactant: CNC
Reactant: COc1ccc2[nH]c3c(c2c1)CC1(C)C(=O)N(CCBr)C(=O)N1C3c1cccc(O)c1
Product: COc1ccc2[nH]c3c(c2c1)CC1(C)C(=O)N(CCN(C)C)C(=O)N1C3c1cccc(O)c1

Procedure:
The title compound is prepared similarly as described for example 30 using (+)-2-(2-Bromo-ethyl)-10-(3-hydroxy-phenyl)-6-methoxy-3a-methyl-3a,4,9,10-tetrahydro-2,9,10a-triaza-cyclopenta[b]fluorene-1,3-dione (example 24a) and dimethylamine as starting materials.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][C:8]([NH:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.Br[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[F:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][O:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]([NH:10][CH3:11])=[O:9])=[CH:12][CH:13]=1
Reactant: CNC(=O)COc1ccc(O)cc1
Reactant: Fc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CNC(=O)COc1ccc(OCc2ccccc2F)cc1

Procedure:
In analogy to the procedure described in Example 3b), the alkylation of 2-(4-hydroxy-phenoxy)-N-methyl-acetamide [Example 3a)] with 1-bromomethyl-2-fluoro-benzene in 2-butanone using potassium carbonate as the base yielded the 2-[4-(2-fluoro-benzyloxy)-phenoxy]-N-methyl-acetamide as white crystals; MS: m/e=290 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][S:4][C:5]1[N:6]=[CH:7][N:8]2[CH:12]=[C:11]([C:13]3[C@H:14]([CH3:37])[C@@H:15]4[C@@H:32]([C@H:33]([OH:35])[CH3:34])[C:31](=[O:36])[N:16]4[C:17]=3[C:18]([O:20]CC3C=CC([N+]([O-])=O)=CC=3)=[O:19])[S:10][C:9]=12.[NH2:38][C:39]([NH2:41])=[S:40]>C(#N)C.CN(C=O)C>[OH:35][C@@H:33]([C@H:32]1[C:31](=[O:36])[N:16]2[C:17]([C:18]([OH:20])=[O:19])=[C:13]([C:11]3[S:10][C:9]4=[C:5]([S:4][CH2:3][CH2:2][NH:41][C:39](=[NH:38])[SH:40])[N:6]=[CH:7][N:8]4[CH:12]=3)[C@H:14]([CH3:37])[C@H:15]12)[CH3:34]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(SCCBr)c4s3)[C@H](C)[C@H]12
Reactant: NC(N)=S
Solvent: CN(C)C=O
Solvent: CC#N
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(c3cn4cnc(SCCNC(=N)S)c4s3)[C@H](C)[C@H]12
Temperature: 50 °C
Reaction time: 18 h
Yield: 14.7 %

Procedure:
4-Nitrobenzyl (1S,5R,6S)-2-[7-(2-bromoethyl)thioimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (128 mg) was dissolved in 3 ml of acetonitrile and 0.5 ml of DMF. Thiourea (222 mg) was added to the solution. The mixture was stirred at 50° C. for 18 hr. The reaction solution was concentrated under the reduced pressure. The residue was purified by column chromatography on Sephadex LH-20 (dichloromethane:methanol=1:1), followed by a reaction and purification in the same manner as in Example 1c). Thus, 14.5 mg of the title compound was prepared.
Reaction SMILES: B(Br)(Br)Br.[CH3:5][CH:6]([CH3:32])[CH2:7][C:8]([C:10]1[CH:29]=[CH:28][C:13]2[O:14][C:15]3[C:24]([O:25][CH3:26])=[CH:23][C:22]([CH3:27])=[CH:21][C:16]=3[CH2:17][O:18][C:19](=[O:20])[C:12]=2[C:11]=1[O:30]C)=[O:9].CO>ClCCl>[OH:30][C:11]1[C:12]2[C:19](=[O:20])[O:18][CH2:17][C:16]3[CH:21]=[C:22]([CH3:27])[CH:23]=[C:24]([O:25][CH3:26])[C:15]=3[O:14][C:13]=2[CH:28]=[CH:29][C:10]=1[C:8](=[O:9])[CH2:7][CH:6]([CH3:5])[CH3:32]
Reactant: COc1cc(C)cc2c1Oc1ccc(C(=O)CC(C)C)c(OC)c1C(=O)OC2
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: COc1cc(C)cc2c1Oc1ccc(C(=O)CC(C)C)c(O)c1C(=O)OC2
Reaction time: 1.5 h

Procedure:
10.8 ml of a 1M boron tribromide solution in dichloromethane are added dropwise at -70° C. under argon to a solution of 6.2 g (16.1 mmol) of 3-(3-methyl-1-butanonyl)-4,11-dimethoxy-9-methyl-7H-dibenzo[b,g][1,5]-dioxocin-5-one in 160 ml of dichloromethane. After 1.5 h, 6 ml of methanol are added and the solution is brought to room temperature after a further 40 minutes. It is washed with sodium hydrogen carbonate solution and water, dried over magnesium sulphate and concentrated in vacuo. The residue is purified on a silica gel column using petroleum ether/ethyl acetate 6:1.
Reaction SMILES: C1(O[C:8](=[O:49])[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38](=[O:47])[NH:39][C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)[CH2:37][CH2:36]4)=[O:34])=[CH:28][C:27]=3[F:48])[CH:22]=[CH:21][N:20]=2)C(OC2C=CC=CC=2)=O)C=CC=CC=1.[CH3:50][N:51]1[CH2:56][CH2:55][CH:54]([N:57]2[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]2)[CH2:53][CH2:52]1>CN(C)C=O>[F:48][C:27]1[CH:28]=[C:29]([NH:32][C:33]([C:35]2([C:38]([NH:39][C:40]3[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=3)=[O:47])[CH2:36][CH2:37]2)=[O:34])[CH:30]=[CH:31][C:26]=1[O:25][C:23]1[CH:22]=[CH:21][N:20]=[C:19]([NH:9][C:8]([N:60]2[CH2:59][CH2:58][N:57]([CH:54]3[CH2:55][CH2:56][N:51]([CH3:50])[CH2:52][CH2:53]3)[CH2:62][CH2:61]2)=[O:49])[CH:24]=1
Reactant: CN1CCC(N2CCNCC2)CC1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Solvent: CN(C)C=O
Product: CN1CCC(N2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)C5(C(=O)Nc6ccc(F)cc6)CC5)cc4F)ccn3)CC2)CC1
Reaction time: 8 h
Yield: 89.6 %

Procedure:
To a solution of [4-(2-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (66 mg) in N,N-dimethylformamide (1.0 ml) was added 1-(1-methylpiperidin-4-yl)piperazine (73.3 mg) at room temperature, followed by stirring overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5). Fractions containing the target compound were concentrated under reduced pressure. A solid was precipitated by addition of diethyl ether:heptane=1:3 to the resultant residue. The solid was collected by filtration and dried under aeration to provide the titled compound as white powder (56.4 mg, 89%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])=[CH:4][CH:3]=1.[C:14](Cl)([N:16]=[C:17]=[O:18])=[O:15]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:9]3[O:13][C:17](=[O:18])[NH:16][C:14](=[O:15])[C:10]=3[CH2:11][CH2:12]2)=[CH:6][CH:7]=1
Reactant: O=C1CCCC1c1ccc(Cl)cc1
Reactant: O=C=NC(=O)Cl
Solvent: CCOC(C)=O
Product: O=c1[nH]c(=O)c2c(o1)C(c1ccc(Cl)cc1)CC2
Temperature: 130 °C
Reaction time: 2 h
Yield: 51.1 %

Procedure:
A solution of 2-(4-chlorophenyl)cyclopentanone (7.80 g, 40.1 mmol) and carbonisocyanatidic chloride (7.61 g, 72.1 mmol) was stirred at 58° C. in a high-pressure vessel for 1 h. The temperature was raised to 130° C. and the reaction mixture was stirred for an additional 2 h. After cooling to rt, the reaction mixture solidified. The solid residue was dissolved in ethyl acetate and washed with saturated aqueous solution of sodium bicarbonate. The organic layer was separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuum and the oily residue was purified by column chromatography on silica gel to provide 7-(4-chlorophenyl)-6,7-dihydrocyclopenta[e][1,3]oxazine-2,4(3H,5H)-dione (5.4 g, 20.48 mmol, 51.1% yield). LC-MS (M+H)+=264.2. 1H NMR (500 MHz, CDCl3) δ ppm 7.32 (2H, d, J=8.5 Hz), 7.12 (2H, d, J=8.5 Hz), 4.15-4.25 (1H, m), 2.56-2.93 (4H, m).
Reaction SMILES: C(O[C:4](=O)[CH2:5][C:6]([CH:8]=[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH2:10]1)=O)C.[C:20]([CH:25]=[C:26]1[NH:30][CH2:29][CH2:28][NH:27]1)([O:22][CH2:23][CH3:24])=[O:21]>C(O)C>[CH2:23]([O:22][C:20]([C:6]1[CH:8]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)[C:25]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:26]2[NH:27][CH2:28][CH2:29][N:30]2[C:5]=1[CH3:4])=[O:21])[CH3:24]
Reactant: CCOC(=O)C=C1NCCN1
Reactant: CCOC(=O)CC(=O)C=C1CC=Cc2ccccc21
Solvent: CCO
Product: CCOC(=O)C1=C(C)N2CCNC2=C(C(=O)OCC)C1c1cccc2ccccc12
Yield: 52 %

Procedure:
Heating a solution of 9.0 g of (naphth-1-ylidene)-acetoacetic acid ethyl ester and 5.2 g of 2-carbethoxymethylideneimidazolidine in 60 ml of ethanol for 6 hours yields 5-methyl-7-(naphth-1-yl)-1,2,3,7-tetrahydroimidazolo[ 1,2-a]pyridine6,8-dicarboxylic acid diethyl ester of melting point 169° - 170°C (ethanol).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:11](=[O:20])[CH:10]2[CH2:21][CH2:22][CH:23]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[OH:24])=[CH:5][CH:4]=1.[OH:32][CH:33]([CH:47]([OH:54])[CH:48]([OH:53])[CH:49]([OH:52])[CH2:50][OH:51])[C:34]([NH:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][C:44](O)=[O:45])=[O:35].C(N=C=NC(C)C)(C)C.OC1C2N=NNC=2C=CC=1>CN(C)C=O.C(#N)C>[F:19][C:16]1[CH:15]=[CH:14][C:13]([N:12]2[C:11](=[O:20])[CH:10]([CH2:21][CH2:22][CH:23]([C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[OH:24])[CH:9]2[C:6]2[CH:7]=[CH:8][C:3]([CH2:2][NH:1][C:44]([CH2:43][O:42][CH2:41][CH2:40][O:39][CH2:38][CH2:37][NH:36][C:34](=[O:35])[CH:33]([OH:32])[CH:47]([OH:54])[CH:48]([OH:53])[CH:49]([OH:52])[CH2:50][OH:51])=[O:45])=[CH:4][CH:5]=2)=[CH:18][CH:17]=1
Reactant: NCc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Reactant: O=C(O)COCCOCCNC(=O)C(O)C(O)C(O)C(O)CO
Agent: CC(C)N=C=NC(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CC#N
Solvent: CN(C)C=O
Product: O=C(COCCOCCNC(=O)C(O)C(O)C(O)C(O)CO)NCc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1

Procedure:
22 is prepared similarly to 18 starting from 100 mg of 4-(4-aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one, 122 mg of {2-[2-(2,3,4,5,6-pentahydroxyhexanoylamino)ethoxy]ethoxy}acetic acid 20, 93 μl of diisopropylcarbodiimide and 65 mg of hydroxybenzotriazole in 2 ml of dimethylformamide and 1 ml of acetonitrile. This gives 22:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH:10]=[C:11]([C:13]([OH:15])=[O:14])[N:12]=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[F:42][C:43]1[C:48](O)=[C:47]([F:50])[C:46]([F:51])=[C:45]([F:52])[C:44]=1[F:53]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:16]2[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=2)[CH:10]=[C:11]([C:13]([O:15][C:48]2[C:47]([F:50])=[C:46]([F:51])[C:45]([F:52])=[C:44]([F:53])[C:43]=2[F:42])=[O:14])[N:12]=1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: O=C(O)c1cn(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1cn(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.5 %

Procedure:
Step 1, 2-(2-Chlorophenyl)-1-(4-chlorophenyl)-1H-imidazole-4-carboxylic acid (1.5 g, 4.5 mmol) was dissolved in dichloromethane (40 mL). 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 946 mg, 4.95 mmol) and triethylamine (500 mg, 4.95 mmol) were added followed by pentafluorophenol (815 mg, 4.37 mmol). The mixture was stirred at rt under argon for one hour before it was washed with 5% HCl, sodium bicarbonate solution, and then brine. The organic layer was dried (MgSO4), filtered, and concentrated to give the crude product (1.26 g) which was chromatographed over silica gel (20% EtOAc in hexanes) to afford pentafluorophenyl 2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazole-4-carboxylate (0.73 g, 32% yield): LC-MS m/z 499.0 (MH+), retention time 3.93 min (method 1).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:14]=[CH:13][C:6]2[O:7][C:8]3([C:11](=[O:12])[C:5]=2[CH:4]=1)[CH2:10][CH2:9]3.ClC1C=CC=C(C(OO)=[O:23])C=1>>[CH3:1][S:2]([C:3]1[CH:14]=[CH:13][C:6]2[O:7][C:8]3([C:11](=[O:12])[C:5]=2[CH:4]=1)[CH2:10][CH2:9]3)=[O:23]
Reactant: CSc1ccc2c(c1)C(=O)C1(CC1)O2
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CS(=O)c1ccc2c(c1)C(=O)C1(CC1)O2
Yield: 76.3 %

Procedure:
5-Methylthiospiro[benzo[b]furan-2(3H), 1'-cyclopropane]-3-one (600 mg.) and m-chloroperbenzoic acid (627 mg.) were allowed to react in the same manner as Example 65. The product was recrystallized from ethyl acetate-hexane to give colorless prisms of 5-methylsulfinylspiro[benzo[b]furan-2(3H), 1'-cyclopropane]-3-one (493 mg.). m.p. 87°-90° C.
Reaction SMILES: CO[CH2:3][N:4]([CH2:12][Si](C)(C)C)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH:17]1([O:22][C:23]2[CH:24]=[C:25]([C:31](=[CH2:36])[C:32]([O:34][CH3:35])=[O:33])[CH:26]=[CH:27][C:28]=2[O:29][CH3:30])[CH2:21][CH2:20][CH2:19][CH2:18]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:17]1([O:22][C:23]2[CH:24]=[C:25]([C:31]3([C:32]([O:34][CH3:35])=[O:33])[CH2:36][CH2:3][N:4]([CH2:5][C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=4)[CH2:12]3)[CH:26]=[CH:27][C:28]=2[O:29][CH3:30])[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: C=C(C(=O)OC)c1ccc(OC)c(OC2CCCC2)c1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1(c2ccc(OC)c(OC3CCCC3)c2)CCN(Cc2ccccc2)C1
Reaction time: 12 h
Yield: 97.7 %

Procedure:
To a solution of N-methoxymethyl-N-(phenylmethyl)trimethylsilylmethylamine (1.42 g, 6.0 mmol) and methyl 2-(3-cyclopentoxy-4-methoxyphenyl)prop-2-enoate (1.38 g, 5.0 mmol) in 10 mL of CH2Cl2 cooled to 0° C. was added a 0.7 mL of a 1M solution of trifluoroacetic acid. Stirring was continued for 12 hr, and the solution was partitioned between ether and sat. NaHCO3. The layers were separated and the aqueous layer was extracted ethyl acetate (2×). The combined organic layers were dried (K2CO3), filtered, and concentrated under reduced pressure to a pale yellow oil. Chromatography on silica gel (3:1, hexanes:ethyl acetate) provided 3-(3-cyclopentoxy-4-methoxyphenyl)-3-methoxycarbonyl-1-(phenylmethyl)pyrrolidine (2.0 g, 99%) as a colorless oil. 1H-NMR (300 MHz): δ 2.75 (d, 1, J=9), 3.54 (d, 1, J=9), 3.67 (s, 3), 3.69 (s, 2), 3.81 (s, 3). Anal. Calcd for C25H31NO4 : C, 73.32; H, 7.63; N, 3.42. Found: C, 73.25; H, 7.65; N, 3.40.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH:3]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:4](=[O:15])[N:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][CH:7]=[CH:8]1.[H][H]>[Pd].CCOC(C)=O>[CH3:1][C:2]1([CH3:24])[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:4](=[O:15])[CH:3]1[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)NC1C(=O)N(c2ccccc2)CC=CC1(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1C(=O)N(c2ccccc2)CCCC1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a 2-neck round bottom flask was added (Z)-tert-butyl 4,4-dimethyl-2-oxo-1-phenyl-2,3,4,7-tetrahydro-1H-azepin-3-ylcarbamate (7 mg, 0.02 mmol), 10% Pd/C (2.3 mg, 0.021 mmol) and EtOAc (1 mL). The reaction was then charged with hydrogen with a balloon and then stirred at rt for 2 hr. The reaction was filtered through CELITE® and the filtrate was concentrated to give tert-butyl 4,4-dimethyl-2-oxo-1-phenylazepan-3-ylcarbamate (6.5 mg, 0.020 mmol, 92% yield) as a clear film. Anal. Calcd. for C19H28N2O3 m/z 332.2. found: 333.2 (M+H)+.
Reaction SMILES: [Si:1]([N:8]1[C:16]2[C:11](=[C:12]([C:17]3[N:26]=[CH:25][C:24]4[NH:23][CH2:22][CH:21]5[CH2:27][O:28][CH2:29][CH2:30][N:20]5[C:19]=4[N:18]=3)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][C:40](Cl)=[O:41])=[CH:35][CH:34]=1.C(N(CC)CC)C>C(Cl)Cl>[Si:1]([N:8]1[C:16]2[C:11](=[C:12]([C:17]3[N:26]=[CH:25][C:24]4[N:23]([C:40](=[O:41])[CH2:39][C:36]5[CH:37]=[CH:38][C:33]([O:32][CH3:31])=[CH:34][CH:35]=5)[CH2:22][CH:21]5[CH2:27][O:28][CH2:29][CH2:30][N:20]5[C:19]=4[N:18]=3)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)n1ccc2c(-c3ncc4c(n3)N3CCOCC3CN4)cccc21
Reactant: COc1ccc(CC(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CC(=O)N2CC3COCCN3c3nc(-c4cccc5c4ccn5[Si](C)(C)C(C)(C)C)ncc32)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 73.7 %

Procedure:
2-(1-(tert-Butyldimethylsilyl)-1H-indol-4-yl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x12, 42 mg, 0.100 mmol) in CH2Cl2 (1 mL) was cooled to 0° C. 2-(4-Methoxyphenyl)acetyl chloride (0.018 mL, 0.120 mmol) was added, followed by triethylamine (0.028 mL, 0.199 mmol) to give a yellow solution. The reaction mixture was stirred for 2 hours at 0° C. The solvent was subsequently removed in vacuo and the resulting concentrate was loaded onto an ISCO® silica gel cartridge (4 g) and eluted using an ethyl acetate/hexane gradient. The product was collected and concentrated in vacuo to afford the title compound as a yellow oil (42 mg, 74%). 1H NMR (400 MHz, DMSO-d6) δ 0.64 (s, 6H), 0.89 (s, 9H), 3.02-3.22 (m, 4H), 3.42-3.61 (m, 2H), 3.66-3.78 (m, 3H), 3.87-3.92 (m, 2H), 3.91-3.98 (m, 1H), 4.30-4.47 (m, 1H), 4.64-4.75 (m, 1H), 6.79-6.93 (m, 2H), 7.00-7.30 (m, 3H), 7.42-7.51 (m, 2H), 7.61-7.68 (m, 1H), 8.02-8.07 (m, 1H), 8.32-9.02 (m, 1H). ESI-MS m/z [M+H]+ calc'd for C32H39N5O3Si, 570.28. found 570.6.