Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([SH:21])=[CH:17][CH:16]=1)([O-:14])=[O:13].C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.[Cu]>[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([S:21][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=2)=[CH:17][CH:16]=1)([O-:14])=[O:13]
Reactant: Brc1ccc2ccccc2c1
Reactant: O=[N+]([O-])c1ccc(S)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(Sc2ccc3ccccc3c2)cc1
Yield: 11.6 %

Procedure:
2-Bromonaphthalene (0.08 moles, 16.6 g), 4-nitrothiophenol (0.08 moles, 12,4 g), potassium carbonate (0.1 moles, 13.4 g), copper bronze (6.0 g) and cuprous chloride (0.02 moles, 2.0 g) were heated under reflux for 4 days in 300 ml pyridine. The solution was filtered hot, concentrated, dissolved in ethyl acetate and washed thoroughly with 2N HCl and water. The solution was dried over sodium sulfate, concentrated and purified by HPLC over silica gel eluted with 5% ethyl acetate in hexane. The product was recrystallized from ethyl acetate and hexane to yield 2-(4-nitrophenylthio)naphthalene 2.6 g, 12% in the first crop. Mass spec. (FD) 281.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][N:3]=1.[F:17][C:18]([F:30])([F:29])[O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[CH2:15]([O:14][C:12]([C:5]1[C:6]([C:8]([F:11])([F:10])[F:9])=[N:7][C:2]([C:23]2[CH:22]=[CH:21][C:20]([O:19][C:18]([F:17])([F:29])[F:30])=[CH:25][CH:24]=2)=[N:3][CH:4]=1)=[O:13])[CH3:16]
Reactant: CCOC(=O)c1cnc(Cl)nc1C(F)(F)F
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Product: CCOC(=O)c1cnc(-c2ccc(OC(F)(F)F)cc2)nc1C(F)(F)F

Procedure:
In analogy to the procedures described in examples 108B], ethyl 2-chloro-4-(trifluoromethyl)pyrimidine-5-carboxylate and 4-(trifluoromethoxy)phenylboronic acid gave the title compound as an off-white powder.
Reaction SMILES: [Cl:1][C:2]([Cl:22])([Cl:21])[C:3](=[O:20])[C:4](=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:23][C:24]([CH3:31])=[CH:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>C(O)(C)(C)C>[OH:20][C:3]1([C:2]([Cl:21])([Cl:22])[Cl:1])[CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:24]([CH3:31])[NH:23]1
Reactant: CCOC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)C(Cl)(Cl)Cl
Reactant: CCOC(=O)C=C(C)N
Solvent: CC(C)(C)O
Product: CCOC(=O)C1=C(C)NC(O)(C(Cl)(Cl)Cl)C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Yield: 40747.3 %

Procedure:
Ethyl 4,4,4-trichloro-2-(3-nitrophenylmethylene)-3-oxobutanoate (7.19 g, 0.02 mmoles) and ethyl 3-amino-2-butenoate (2.53 g) were heated at 60° for 24 hours in tert-butanol (60 ml). The solvent was evaporated and the residue chromatographed on silica eluting with ether/petroleum ether (60°-80°) mixtures to give the title compound (4.04 g). Recrystallised from 2-propanol. mp 125°-6.5°.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]([NH2:8])=[O:7])=[N:2]1.[C@@H:9]1(N2C3N=CN=C(O)C=3N=C2)[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].P([O-])(O)(O)=O.[K+]>>[CH:5]1[N:1]([C@@H:9]2[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]2[OH:11])[N:2]=[C:3]([C:6]([NH2:8])=[O:7])[N:4]=1
Reactant: NC(=O)c1nc[nH]n1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)[C@H](O)[C@@H]1O
Agent: O=P([O-])(O)O
Agent: [K+]
Product: NC(=O)c1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)n1
Reaction time: 24 h
Yield: 72.55 %

Procedure:
The above cell suspension was added to 800 ml of an aqueous solution containing 50 mM 1,2,4-triazole-3-carboxamide, 75 mM inosine and 50 mM monopotassium dihydrogen phosphate, and the reaction was carried out at 60° C. for 24 hours to give a ribavirin yield of 72.55%.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](Cl)[N:22]=3)[CH:16]=2)[CH:10]([CH2:28][CH3:29])[CH2:9]1)=O)(C)(C)C.[NH2:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1>>[CH2:28]([CH:10]1[CH2:9][NH:8][CH2:13][CH2:12][N:11]1[CH2:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([NH:30][CH2:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=3)[N:22]=2)[CH:18]=[CH:19][CH:20]=1)[CH3:29]
Reactant: CCC1CN(C(=O)OC(C)(C)C)CCN1Cc1cccc(-c2ccnc(Cl)n2)c1
Reactant: NCCc1ccc(O)cc1
Product: CCC1CNCCN1Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 130 was coupled with tyramine following procedure F. The product was deprotected following procedure G2. LC-MS showed the product had the expected M+H+ of 418. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.35 (s, 1H) 8.29 (d, 2H) 8. 7.81 (d, 1H) 7.68 (t, 1H) 7.49 (d, 1H) 7.2-7.2 (m, 3H) 6.68 (d, 2H) 4.8 (d, 1H) 4.17 (d, 1H) 3.85 (br s, 2H) 3.68 (d, 1H) 3.1-3.6 (m, 6H) 2.9 (t, 2H) 2.2 (m, 1H) 1.9 (m, 1H) 1.1 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[C:23]([O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[CH:22]=[CH:21][C:4]=1[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:9][CH:8]=1.C(N(CC)CC)C.[CH:39]1([C:45](Cl)=[O:46])[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:24]=[C:23]([O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[CH:22]=[CH:21][C:4]=1[CH2:5][N:6]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:9][CH:8]=1)[C:45]([CH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1)=[O:46]
Reactant: O=C(Cl)C1CCCCC1
Reactant: COc1cc(OC2CCCCO2)ccc1CNc1ccc(OCCN2CCCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(OC2CCCCO2)ccc1CN(C(=O)C1CCCCC1)c1ccc(OCCN2CCCC2)cc1
Reaction time: 1 h

Procedure:
To a solution of [2-methoxy-4-(tetrahydro-pyran-2-yloxy)-benzyl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine (0.100 g, 0.23 mmol) and triethylamine (0.10 mL, 0.70 mmol) in 2 mL methylene chloride was added cyclohexanecarbonyl chloride (0.078 mL, 0.58 mmol), dropwise. The reaction mixture was stirred for 1 hr. at room temperature. Saturated aqueous sodium bicarbonate was added and the layers were separated. The aqueous layer was washed with an additional 2 mL of methylene chloride. The combined organic layers were concentrated in vacuo to give the title compound of Step A. MS 537.2 (M+1)+
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:16][C:17]([S:20][C:21]2[CH:26]=[C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:24]([OH:31])=[C:23]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:22]=2)([CH3:19])[CH3:18])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].[CH2:36]([O:38][CH:39]1[O:43][CH:42]([CH2:44][CH2:45]O)[CH:41]([CH2:47][CH2:48][OH:49])[O:40]1)[CH3:37].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:12]([C:9]1[CH:8]=[C:7]([S:16][C:17]([S:20][C:21]2[CH:22]=[C:23]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:24]([O:31][CH2:45][CH2:44][CH:42]3[CH:41]([CH2:47][CH2:48][OH:49])[O:40][CH:39]([O:38][CH2:36][CH3:37])[O:43]3)=[C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:26]=2)([CH3:18])[CH3:19])[CH:6]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:13])([CH3:14])[CH3:15]
Reactant: CCOC1OC(CCO)C(CCO)O1
Reactant: CC(C)(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC1OC(CCO)C(CCOc2c(C(C)(C)C)cc(SC(C)(C)Sc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)cc2C(C)(C)C)O1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 28.4 %

Procedure:
To a solution of probucol (19.0 g, 37 mmol) and 2-[2-ethoxy-5-(2-hydroxy-ethyl)-[1,3]dioxolan-4-yl]-ethanol (Ex-14C, 7.6 g, 37 mmol) in tetrahydrofuran (160 mL) was added triphenylphosphine (10.6 g, 41 mmol) and the resulting mixture was cooled to 0° C. Diethyl azodicarboxylate (7.1 g, 41 mmol) was then added dropwise, stirred at 0° C. for 30 min, and allowed to warm to rt. The solution was ultimately heated to 65° C. and stirred for an additional 18 h for the reaction to complete. The reaction mixture was concentrated under reduced pressure to an orange viscous oil and titurated with hexanes and the resulting slurry was stirred at rt for 30 min. The solution was filtered to remove the triphenylphosphine oxide and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel chromatography (10% ethyl acetate/hexanes with a gradual increase to 30% ethyl acetate/hexanes) to afford 7.4 g (30%) of 2,6-di-tert-butyl-4-[1-(3,5-di-tert-butyl-4-{2-[2-ethoxy-5-(2-hydroxy-ethyl)-[1,3]dioxolan-4-yl]-ethoxy}-phenylsulfanyl)-1-methyl-ethylsulfanyl]-phenol as a white solid. 1H-NMR (300 MHz, CDCl3) δ7.53 (s, 2H), 7.45 (s, 2H), 5.81 (s. 1H), 5.36 (s, 1H), 4.09–4.19 (m, 2H), 3.84–3.92 (m, 4H), 3.59 (q, 2H, J=6.8 Hz), 2.17–2.19 (m, 2H), 2.02–2.05 (m, 1H), 1.86–1.96 (m, 2H), 1.42–1.44 (m, 42H), 1.19–1.24 (m, 3H). HRMS (ESI) calcd for C40H64O6S2 (M+K), 727.4042; found, 727.4050. Anal. calcd. for C40H64O6S2: C, 66.62, H, 9.55, S, 8.68; found: C, 66.65, H, 9.35, S, 9.01.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:30]=[CH:29][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[C:14]([CH2:26][CH2:27][CH3:28])=[C:15]([CH:23]=[CH:24][CH:25]=2)[O:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:6]([CH2:31][CH:32]2[CH2:34][CH2:33]2)[C:5]=1[OH:35])=[O:3].[C:36](OCC)(=O)C.CCCCCC>>[NH2:1][C:2]([C:4]1[CH:30]=[CH:29][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[C:14]([CH2:26][CH2:27][CH3:28])=[C:15]([CH:23]=[CH:24][CH:25]=2)[O:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:6]([CH2:31][CH:32]2[CH2:33][CH2:34]2)[C:5]=1[O:35][CH3:36])=[O:3]
Reactant: CCCc1c(OCCCOc2ccc(C(N)=O)c(O)c2CC2CC2)cccc1OCC(=O)OCC
Reactant: CCOC(C)=O
Solvent: CCCCCC
Product: CCCc1c(OCCCOc2ccc(C(N)=O)c(OC)c2CC2CC2)cccc1OCC(=O)OCC

Procedure:
The compound of Example 70 is exposed to the conditions described in Example 25. Chromatography of the crude product on silica gel using ethyl acetate/hexane, (3:7) as eluant affords the product.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]2[NH:9][C:10](=[O:20])[N:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])[CH2:12][C:6]2=[CH:5][N:4]=1.ClN1C(=O)CCC1=O.[NH2:29][C@H:30]1[CH2:35][CH2:34][C@H:33]([OH:36])[CH2:32][CH2:31]1>CN1CCCC1=O.O>[OH:36][C@H:33]1[CH2:34][CH2:35][C@H:30]([NH:29][C:3]2[N:8]=[C:7]3[NH:9][C:10](=[O:20])[N:11]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[CH3:19])[CH2:12][C:6]3=[CH:5][N:4]=2)[CH2:31][CH2:32]1
Reactant: CSc1ncc2c(n1)NC(=O)N(c1ccccc1C)C2
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1ccccc1N1Cc2cnc(N[C@H]3CC[C@H](O)CC3)nc2NC1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of sulfide 10.2 (2 g) in 4 mL 1-methyl-2-pyrrolidinone was combined with N-chlorosuccinimide (1.03 g) in 4 mL 1-methyl-2-pyrrolidinone and 0.125 g water, and the mixture was stirred for 1.5 hours at 25° C. To this solution was added trans-4-aminocyclohexanol (2.65 g). The mixture was heated to 60° C. for 48 hours, cooled to 20-25° C. and treated with 10 mL water. This mixture was cooled to 5° C. and stirred for 2 hours. The solid was collected by filtration, washed with water, hexanes and dried in vacuo. The solid was purified by flash column chromatography using 95/5-90/10 dichloromethane/methanol as eluant to give 614 mg of 7-(trans-4-hydroxycyclohexylamino)-3-ortho-tolyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one. The resulting solid was converted to the hydrochloride salt by the action of ethereal hydrochloric acid/ethyl acetate on the free base.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)=[O:4].[CH2:13]([OH:17])[CH2:14]CC.CC1C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>C(O)CO>[Br:1][CH2:2][C:3]1([C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=2)[O:17][CH2:13][CH2:14][O:4]1
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Reactant: CCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: OCCO
Solvent: c1ccccc1
Product: N#Cc1ccc(C2(CBr)OCCO2)cc1
Reaction time: 4 h

Procedure:
To a stirred solution of 112 parts of 4-(2-bromoacetyl)-benzonitrile in 320 parts of butanol are added 5 parts of 4-methylbenzenesulfonic acid and 360 parts of benzene. Then there are added dropwise 46.5 parts of 1,2-ethanediol. Upon completion, sitrring is continued for 4 hours at reflux. The reaction mixture is evaporated. The oily residue is crystallized from 2,2'-oxybispropane. The product is filtered off and recrystallized from methanol, yielding 95.12 parts of 4-[2-(bromomethyl)-1,3-dioxolan-2-yl] benzonitrile; mp. 92.4° C.
Reaction SMILES: [N:1]([CH:4]([CH2:10][CH2:11]I)[C:5](OCC)=[O:6])=[N+:2]=[N-:3].[C:13]([O:17][C:18](=[O:22])[C@H:19]([CH3:21])[NH2:20])([CH3:16])([CH3:15])[CH3:14]>>[N:1]([CH:4]1[CH2:10][CH2:11][N:20]([C@@H:19]([CH3:21])[C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:22])[C:5]1=[O:6])=[N+:2]=[N-:3]
Reactant: CCOC(=O)C(CCI)N=[N+]=[N-]
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Product: C[C@@H](C(=O)OC(C)(C)C)N1CCC(N=[N+]=[N-])C1=O

Procedure:
Using ethyl 2-azido-4-iodobutanoate and L-alanine tert-butyl ester, and the procedure described for Intermediate 33, the title compound was prepared as a mixture of two diastereoisomers.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[C:6]([CH:9]([CH3:26])[C:10]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[F:25])([OH:17])[CH2:11][N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)[N:5]=[CH:4][N:3]=1.C([O-])(=O)C.[Na+]>C(O)C.[Pd]>[Cl:8][C:7]1[C:6]([CH:9]([CH3:26])[C:10]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[F:25])([OH:17])[CH2:11][N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)=[N:5][CH:4]=[N:3][CH:2]=1
Reactant: CC(c1ncnc(Cl)c1Cl)C(O)(Cn1cncn1)c1ccc(F)cc1F
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(c1ncncc1Cl)C(O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
A solution of 3-(4,5-dichloropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol, enantiomeric pair B (see Preparation 6(iii)) (0.58 g, 1.46 mmol) in ethanol (20 ml) was hydrogenated at atmospheric pressure and at room temperature in the presence of 10% palladium-on-charcoal (45 mg) and sodium acetate (122 mg, 1.5 mmol) for 7 hours. The catalyst was then removed by filtration and the filtrate was concentrated under reduced pressure. "Flash " chromatography of the residue on silica using ethyl acetate as the eluant provided, after combination and evaporation of the appropriate fractions, the title compound (0.35 g, 72%), m.p. 128° C. Found: C,51.68; H,3.89; N,18.58; C16H14ClF2N5O.0.3 H2O requires: C,51.76; H,3.94; N,18.87%.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[N:3]1.CN(C)CCN(C)C.C([Li])CCC.[O:20]1[CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:21]12>C1COCC1>[CH3:1][N:2]1[C:6]([C@H:22]2[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C@@H:21]2[OH:20])=[CH:5][CH:4]=[N:3]1
Reactant: C1CCC2OC2CC1
Reactant: Cn1cccn1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1nccc1[C@H]1CCCCC[C@@H]1O
Yield: 13 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 4a by using 1-methylpyrazole (3.66 g, 44.6 mmol), N,N,N′,N′-tetramethylethylenediamine (6.68 mL, 44.6 mmol), n-butyl lithium (1.63 M solution in hexane; 32 mL, 52.2 mmol), 1,2-epoxycycloheptane (5.0 g, 44.6 mmol) and THF (60 mL), to yield the title compound (1.13 g, 13%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=O)[C:6](=[O:19])[N:5]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:4]=2[N:3]=1.O[NH:26][C:27]([C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)=[NH:28]>CN(C=O)C>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]3[O:18][N:28]=[C:27]([C:29]4[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=4)[N:26]=3)[C:6](=[O:19])[N:5]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:4]=2[N:3]=1
Reactant: N=C(NO)c1ccc(O)cc1
Reactant: CCCCCn1c(=O)n(CCCCC(=O)O)c(=O)c2[nH]c(Cl)nc21
Solvent: CN(C)C=O
Product: CCCCCn1c(=O)n(CCCCc2nc(-c3ccc(O)cc3)no2)c(=O)c2[nH]c(Cl)nc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 5-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoic acid (50 mg, 0.14 mmol) in DMF (2 ml) was treated with CDl (23 mg, 0.14 mmol) and stirred at rt for 30 min. N,4-dihydroxybenzenecarboximidamide (26 mg, 0.17 mmol) was added and the mixture heated in the microwave at 120° C. for 15 min. After cooling the reaction was partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated, concentrated and purified by the MDAP. The title compound was obtained as an off-white solid (17 mg, 26%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1([CH2:22][CH2:23][CH2:24][CH2:25]Br)[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:8].[N:27]1([C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]=2)[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1([CH2:22][CH2:23][CH2:24][CH2:25][N:30]2[CH2:31][CH2:32][N:27]([C:33]3[CH:42]=[CH:41][C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:34]=3)[CH2:28][CH2:29]2)[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:8]
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Reactant: COCCCNC(=O)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: COCCCNC(=O)C1(CCCCN2CCN(c3ccc4ccccc4n3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(3-methoxy-propyl)-amide and 2-piperazin-1-yl-quinoline.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]2[CH:8]=[C:9]([C:11]([OH:13])=O)[O:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].Cl.Cl.[NH2:18][C@@H:19]1[CH:24]2[CH2:25][CH2:26][N:21]([CH2:22][CH2:23]2)[CH2:20]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[N:21]12[CH2:26][CH2:25][CH:24]([CH2:23][CH2:22]1)[C@@H:19]([NH:18][C:11]([C:9]1[O:10][C:6]3[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:15]=[CH:14][C:7]=3[CH:8]=1)=[O:13])[CH2:20]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: O=C(O)c1cc2ccc([N+](=O)[O-])cc2o1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2ccc([N+](=O)[O-])cc2o1
Reaction time: 0.67 h

Procedure:
1040 mg (5.02 mmol) of 6-nitrobenzofuran-2-carboxylic acid, 1000 mg (5.02 mmol) of (R)-3-aminoquinuclidine dihydrochloride, 2290 mg (6.03 mmol) of HATU, 2250 mg (18.08 mmol) of N,N-diisopropylethylamine and 15 ml of DMF are reacted according to the general procedure (variant B). DMF is removed under reduced pressure. The product is taken up in 100 ml of 1N aqueous sodium hydroxide solution and extracted three times with in each case 50 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate and the solvent is removed under reduced pressure using a rotary evaporator. The reaction mixture is taken up in methanol and, together with acidic ion exchange resin (Dowex WX2-200), stirred for about 40 min. The loaded ion exchange is washed six times with in each case 100 ml of methanol. The product is then eluted with methanol/triethylamine 99:1 to 90:10. The solvent is removed under reduced pressure. The product is dried over magnesium sulfate. 1.75 g (99% of theory) of the title compound are isolated.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:55])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=5)=[O:55])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cccnc4)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cccnc4)cc2)CCN3CC(C)C)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 29.9 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(3-pyridinylmethyl)sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.32 g) was dissolved in methylene chloride (9.6 ml), m-chloroperbenzoic acid (87 mg) was added to the mixture at 0° C., and the mixture was stirred for 20 minutes at 0° C. The reaction mixture was added to an aqueous solution of saturated sodium thiosulfate, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(3-pyridinylmethyl)sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 210) (98 mg).
Reaction SMILES: [CH:1]([C:3]([C@H:5]1[N:8]([CH:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[C:7](=[O:28])[C@@H:6]1[C@H:29]([O:31][C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[CH3:30])=[CH2:4])=[O:2].CC(=CC)C.Cl([O-])=[O:48].[Na+].P([O-])([O-])(O)=O.[Na+].[Na+]>C(O)(C)(C)C>[C:1]([C:3]([C@H:5]1[N:8]([CH:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C:7](=[O:28])[C@@H:6]1[C@H:29]([O:31][C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[CH3:30])=[CH2:4])([OH:48])=[O:2]
Reactant: [O-][Cl+][O-]
Reactant: C=C(C=O)[C@@H]1[C@@H]([C@@H](C)OC(=O)OCc2ccccc2)C(=O)N1C(Cc1ccc(OC)cc1)Cc1ccc(OC)cc1
Agent: CC=C(C)C
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: CC(C)(C)O
Product: C=C(C(=O)O)[C@@H]1[C@@H]([C@@H](C)OC(=O)OCc2ccccc2)C(=O)N1C(Cc1ccc(OC)cc1)Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(3S,4S)-4-(1-Formylethenyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-1-di(p-anisyl)methyl-2-azetidinone (4.5 g) was dissolved in t-butanol (380 ml). After addition of 2-methyl-2-butene (42.5 ml) thereto, there was dropwise added an aqueous solution (72.3 ml) of sodium chlorite (7.15 g) and disodium hydrogenphosphate (7.15 g). The resulting mixture was stirred at room temperature for 1 hour and concentrated in vacuo at 40° C. or lower. The concentrate was diluted with ethyl acetate (150 ml) and water (75 ml), and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (80 ml), and the combined ethyl acetate layer was washed with brine (150 ml) and extracted with a saturated sodium bicarbonate solution (150 ml). The alkaline layer was acidified with conc. hydrochloric acid under ice-cooling and extracted with ethyl acetate. The extracts were washed with brine and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate in vacuo gave (3S,4S)-4-(1-carboxyethenyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-1-di(p-anisyl)methyl-2-azetidinone.