Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:20][CH2:21][CH3:22])[CH2:5][O:6][C@H:7]([CH2:17][CH:18]=[CH2:19])[CH2:8][O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2].[C:23]([O:27][CH3:28])(=[O:26])C=C>ClCCl.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1>[CH2:10]([O:9][CH2:8][C@H:7]([O:6][CH2:5][CH:4]([O:3][CH2:1][CH3:2])[O:20][CH2:21][CH3:22])[CH2:17]/[CH:18]=[CH:19]/[C:23]([O:27][CH3:28])=[O:26])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C=CC(=O)OC
Reactant: C=CC[C@H](COCc1ccccc1)OCC(OCC)OCC
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2)c(C)c1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: ClCCl
Product: CCOC(CO[C@H](C/C=C/C(=O)OC)COCc1ccccc1)OCC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
This reaction was carried out in 10 batches. To a solution of C2 (10 g, 32 mmol) in dichloromethane (400 mL) was added [1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro(phenylmethylene)(tricyclohexylphosphine)ruthenium (Grubbs 2nd-generation catalyst, 1.38 g, 1.62 mmol) and methyl prop-2-enoate (69.7 g, 0.81 mol), and the reaction mixture was stirred at room temperature for 18 hours. Solvent was removed in vacuo, and the residue was purified via silica gel chromatography (Eluent: 3:1 petroleum ether/ethyl acetate) to provide the product as a yellow oil. Combined yield: 70 g, 0.19 mol, 59%. 1H NMR (400 MHz, CDCl3) δ 7.27-7.38 (m, 5H), 6.94-7.04 (m, 1H), 5.89 (br d, J=15.6 Hz, 1H), 4.58 (dd, J=5.3, 5.0 Hz, 1H), 4.54 (s, 2H), 3.73 (s, 3H), 3.44-3.7 (m, 9H), 2.41-2.55 (m, 2H), 1.21 (t, J=7.0 Hz, 3H), 1.20 (t, J=7.0 Hz, 3H).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[Cl:11])=[N+:2]=[N-:3].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]#[N:22])=[CH:16][CH:15]=1.C[O-].[Na+]>C(O)C.C(OCC)(=O)C>[Cl:11][C:5]1[CH:6]=[C:7]([F:10])[CH:8]=[CH:9][C:4]=1[N:1]1[C:21]([NH2:22])=[C:20]([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)[N:3]=[N:2]1
Reactant: [N-]=[N+]=Nc1ccc(F)cc1Cl
Reactant: COc1ccc(CC#N)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(-c2nnn(-c3ccc(F)cc3Cl)c2N)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 34.1 %

Procedure:
To an ice-cooled and stirred mixture of 1-azido-2-chloro-4-fluoro-benzene (0.300 g, 1 eq) and commercial (4-methoxy-phenyl)-acetonitrile (0.309 g, 1.2 eq) in ethanol (5 ml) kept under nitrogen, a solution of sodium methoxide (0.142 g, 1.5 eq) in ethanol (5 ml) is added drop-wise (15 min). After the addition, the reaction mixture is allowed to reach room temperature spontaneously and stirring is then continued overnight at room temperature. The resulting reaction mixture is diluted with ethyl acetate (20 ml), washed with water (2×25 ml), dried over MgSO4 and evaporated to dryness. The yellow semisolid residue (˜0.500 g) is purified by flash chromatography using 60-120 mesh silica gel and eluting with 20% ethylacetate in hexane, to afford the title compound as a white solid (0.190 g, 34% yield). M.p. 136.3-141.2° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]=[C:10]([C:19](=O)[CH3:20])[C:11]([O:13][CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:12].[NH2:22][C:23]([CH2:29][F:30])=[CH:24][C:25]([O:27][CH3:28])=[O:26]>C(O)(C)(C)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:10]([C:11]([O:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:12])=[C:19]([CH3:20])[NH:22][C:23]([CH2:29][F:30])=[C:24]1[C:25]([O:27][CH3:28])=[O:26]
Reactant: CC(=O)C(=Cc1cccc(Cl)c1Cl)C(=O)OC1CCCC1
Reactant: COC(=O)C=C(N)CF
Solvent: CC(C)(C)O
Product: COC(=O)C1=C(CF)NC(C)=C(C(=O)OC2CCCC2)C1c1cccc(Cl)c1Cl
Temperature: 25 °C

Procedure:
A solution of the product of step (a) (5.1 g, 14.3 mmoles) and methyl 3-amino-4-fluoro-2-butenoate (1.9 g, 14.3 mmoles) in dry tert-butanol (25 ml) was heated to 60° (oil bath temperature) for 108 hours. The solution was allowed to cool to room temperature and the solvent removed in vacuo. Chromatography on silica eluting with dichloromethane afforded the title compound as a yellow oil which crystallises on addition of petroleum ether (60°-80° ) to afford the title compound 1.5 g mp 148°-9°. (Identical with the product of Example 3).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[C:24]1([CH3:34])[C:25]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][S:30]([C:25]3[C:24]([CH3:34])=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:32])=[O:31])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: Cc1ccccc1S(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(NS(=O)(=O)c3ccccc3C)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
Sulfonylation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) with -toluenesulfonyl chloride (12 mg) and N,N-diisopropylethylamine (22 l) in tetrahydrofuran (25 ml) was performed according to the acylation method described in example 6.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22](O)=[O:23])=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].O=C1[N:44](P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C.C(=O)([O-])[O-].[NH4+].[NH4+]>O1CCCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22](=[O:23])[NH2:44])=[C:15]2[CH2:14]1)=[O:12])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Reactant: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: O=C([O-])[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(N)=O)c2C1)Cc1cc(F)c(F)cc1F
Yield: 109.2 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (0.15 g, 0.27 mmol), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.206 g, 1.08 mmol) and triethylamine (0.25 mL, 1.62 mmol) were dissolved in 10 mL of tetrahydrofuran under stirring. After stirring for 10 minutes, ammonium carbonate (78 mg, 0.81 mmol) was added. The reaction mixture was reacted at room temperature over-night and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-(1-carbamoyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl)-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 24a (0.162 g) as a white solid.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][C:15](=[NH:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.Cl[P:29]([CH:33]([CH3:35])[CH3:34])[CH:30]([CH3:32])[CH3:31]>>[CH:30]([P:29]([CH:33]([CH3:35])[CH3:34])[N:22]=[C:15]([NH:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[S:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([CH3:32])[CH3:31]
Reactant: N=C(Nc1ccccc1Sc1ccccc1)c1ccccc1
Reactant: CC(C)P(Cl)C(C)C
Agent: [Li]CCCC
Product: CC(C)P(N=C(Nc1ccccc1Sc1ccccc1)c1ccccc1)C(C)C

Procedure:
Procedure as described for NP Amidine I using the following amounts and modifications: 1.52 g of N1-(2-(phenylthio)phenyl)benzamidine (Amidine XIV, 5.0 mmol), 2.50 mL of 2.0 M butyllithium (5.0 mmol), 0.80 mL chlorodiisopropylphosphine (5.0 mmol). After filtration to remove lithium chloride and removal of solvent, a yellow oil was isolated (2.07 g, 98%).
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.F[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=1[N+:18]([O-:20])=[O:19].CCOC(C)=O>CN(C=O)C>[F:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([O:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:12]=1[N+:18]([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1c(F)cccc1F
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1c(F)cccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.9 %

Procedure:
252 mg of sodium hydride as a 60% suspension in oil (6.29 mmol) are placed in a 50 mL three-necked flask containing 10 mL of DMF and 0.592 g of phenol. The mixture is stirred at room temperature for 1 hour and a solution of 2,6-difluoronitrobenzene 47 (1.0 g, 6.29 mmol) in 10 mL of DMF is added. The reaction medium is left at room temperature for 24 hours. 50 mL of EtOAc are added and the mixture is washed twice with 20 mL of distilled water. The organic phase is dried over MgSO4, filtered and finally evaporated to dryness. The crude product is chromatographed on a silica cartridge (120 g) eluting with heptane/EtOAc (as an EtOAc gradient: 0 to 50%). 1.07 g of expected product 57 are obtained (yellow oil).
Reaction SMILES: [Na].[O-]CC.[Na+].[C:6]([O:14][CH2:15][CH3:16])(=[O:13])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH2:17]([O:19][C:20](=[O:43])/[CH:21]=[CH:22]/[C@@H:23]1[CH2:27][C@@H:26]([O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[CH2:25][N:24]1[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH3:18].C(O)(=O)C>C(O)C>[C:39]([O:38][C:36]([N:24]1[CH2:25][C@H:26]([O:28][Si:29]([C:32]([CH3:33])([CH3:34])[CH3:35])([CH3:30])[CH3:31])[CH2:27][C@H:23]1[CH:22]([CH2:21][C:20]([O:19][CH2:17][CH3:18])=[O:43])[CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:6]([O:14][CH2:15][CH3:16])=[O:13])=[O:37])([CH3:42])([CH3:40])[CH3:41]
Reactant: CCOC(=O)/C=C/[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)CC(C(C(=O)OCC)C(=O)OCC)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
To sodium metal (6.90 g, 0.30 mol), absolute ethanol (300 ml) was gradually added to prepare sodium ethoxide, and a solution of diethyl malonate (151.9 ml, 1.0 mol) in ethanol (500 ml) was dropwise added thereto at room temperature. A solution of (E)-3-[(2S,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxypyrrolidin-2-yl]-acrylic acid ethyl ester (400 g, 1.0 mol, compound of Reference Example 1-4) in ethanol (1500 ml) was further added thereto at the same temperature, and stirred overnight. After acetic acid (17.2 ml, 0.30 mol) was added thereto under cooling with ice, the reaction solution was concentrated under reduced pressure to obtain triethyl 2-[(2S,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxypyrrolidin-2-yl]-1,1,3-propanetricarboxylate (558.3 g) as a crude oil.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:11])[CH2:6][C:7]([O:9][CH3:10])=[O:8].[Cl:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[C:15]([N+:22]([O-:24])=[O:23])[C:14]=1Cl>CN(C=O)C>[Cl:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[C:15]([N+:22]([O-:24])=[O:23])[C:14]=1[CH:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]([O:4][CH3:3])=[O:11]
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)c([N+](=O)[O-])c1
Reactant: COC(=O)CC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C(=O)OC)c1c(Cl)cc([N+](=O)[O-])cc1[N+](=O)[O-]

Procedure:
Sodium hydride was added under ice-cooling to a DMF solution of malonic acid dimethyl ester, and then 1,2-dichloro-3,5-dinitrobenzene was added thereto and allowed to undergo the reaction at room temperature overnight. By post-treating the reaction liquid, dimethyl (2-chloro-4,6-dinitrophenyl)malonate (Dat, FN: 332) was obtained. This was dissolved in DMSO, lithium chloride and water were added, followed by stirring at 100° C. for 2 hours. By post-treating the reaction liquid, methyl (2-chloro-4,6-dinitrophenyl)acetate was obtained.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[NH2:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][CH:26]=1)[CH2:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16](=[O:23])[NH:15][N:14]=1.C(N(CC)CC)C>O1CCOCC1>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([NH:8][C:9]1[CH:26]=[CH:25][CH:24]=[C:11]([CH2:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:23])[NH:15][N:14]=2)[CH:10]=1)=[O:6]
Reactant: O=C(Cl)CCCCl
Reactant: Nc1cccc(Cc2n[nH]c(=O)c3ccccc23)c1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C(CCCCl)Nc1cccc(Cc2n[nH]c(=O)c3ccccc23)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Chlorobutyryl chloride (5.42 g, 38.4 mmol) was added dropwise at ambient temperature to a stirred mixture of 4-(3-aminobenzyl)-2H-phthalazin-1-one (8 g, 32 mmol; prepared in a manner similar to that described above), triethylamine (5.35 ml, 38.4 mmol) and 1,4-dioxane (40 ml), the mixture was stirred at ambient temperature for 1 hour, then it was poured into ice-water (100 ml). The resulting solid was collected by filtration, washed with water (30 ml) and dried in vacuo to give 4-chloro-N-[3-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)phenyl]butyramide (12.34 g) as an off-white solid, m.pt. 180–184° C.
Reaction SMILES: [C:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11](=[O:23])[C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=2[Cl:22])[CH2:6][CH2:5]1)(=O)[CH3:2].[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CN(C=O)C.Cl[SiH](Cl)Cl>C(Cl)Cl>[Cl:22][C:13]1[CH:14]=[CH:15][C:16]([C:18]([F:21])([F:20])[F:19])=[CH:17][C:12]=1[C:11]([NH:10][C@H:7]1[CH2:8][CH2:9][C@H:4]([CH:1]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH3:2])[CH2:5][CH2:6]1)=[O:23]
Reactant: Nc1ccccc1
Reactant: CC(=O)[C@H]1CC[C@H](NC(=O)c2cc(C(F)(F)F)ccc2Cl)CC1
Agent: Cl[SiH](Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(Nc1ccccc1)[C@H]1CC[C@H](NC(=O)c2cc(C(F)(F)F)ccc2Cl)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of Trans-N-(4-acetylcyclohexyl)-2-chloro-5-(trifluoromethyl)-benzamide (200 mg, 0.57 mmol) and aniline (54 mg, 0.57 mmol) in DCM (10 mL) is added DMF (0.1 mL) followed by trichlorosilane (78 mg, 0.57 mmol). After stirring at room temperature for 1 hour, further trichlorosilane (5×78 mg, 5×0.57 mmol) is added at 1 hour intervals for the next 5 hours. Further DMF (0.1 mL) was then added and the mixture is stirred at room temperature overnight. The colourless solid that is formed is recovered by filtration, washed successively with water and then EtOAc and dried. [MH+ 425.38]. The racemic mixture was separated by supercritical fluid chromatography on chiral stationary phase analogously to that reported for Example 1.37.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[N:4]=1)#[N:2].C[O-].[Na+].[Cl-].[NH4+:24].C(O)(=O)C>CO>[F:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][N:5]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:11]2[C:3]([C:1](=[NH:24])[NH2:2])=[N:4]1
Reactant: [NH4+]
Reactant: N#Cc1nn(Cc2ccccc2F)c2ncccc12
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: N=C(N)c1nn(Cc2ccccc2F)c2ncccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
108.00 g (0.43 mol) of 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (example I, step 4) are dissolved in one liter of methanol and added dropwise to a solution of 94.73 g (1.67 mol; purity: 95%) of sodium methoxide in 3 l of methanol. After stirring at RT for 2 hours, 28.83 g (0.54 mol) of ammonium chloride are added, and subsequently 100.03 g (1.67 mol) of glacial acetic acid are added dropwise. This solution is stirred under reflux overnight. The solvent is removed in vacuo, the residue is twice suspended in acetone and the insoluble solid is filtered off with suction. The latter is dissolved in 1.5 l of ethyl acetate, and 590 ml of an aqueous 20% strength sodium carbonate solution are added. Stirring for 20 minutes is followed by dilution with 200 ml of 1N sodium hydroxide solution. The organic phase is washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and filtered. The solvent is removed in vacuo. 99.10 g (86% of theory) of the product are obtained.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:11][CH:10]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=2)[CH2:9]1)=[O:7])(C)(C)C.F[C:22](F)(F)[C:23](O)=O.C(Cl)(=O)CC.C(N(CC)CC)C>C(Cl)Cl>[N+:18]([C:15]1[CH:16]=[CH:17][C:12]([CH:10]2[CH2:9][N:8]([C:6](=[O:7])[CH2:22][CH3:23])[CH2:11]2)=[N:13][CH:14]=1)([O-:20])=[O:19]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC(c2ccc([N+](=O)[O-])cn2)C1
Agent: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)N1CC(c2ccc([N+](=O)[O-])cn2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
A solution of 3-(5-nitro-pyridin-2-yl)-azetidine-1-carboxylic acid tert-butyl ester (1.22 g, 4.36 mmol) in CH2Cl2 (100 ml) was treated with trifluoroacetic acid (TFA) (15 ml) and then stirred at room temperature for 2 h. After concentration, the raw mixture was digested in CH2Cl2 and washed with saturated aqueous NaHCO3. The aqueous phase was extracted with CH2Cl2 (×3), the combined organic layers dried over Na2SO4 and evaporated. The raw material was next dissolved in THF (80 ml) and the solution cooled to 0° C. Propionyl chloride (4604 5.26 mmol) and triethylamine (7354 5.28 mmol) were next added, the mixture allowed to reach 20° C. and stirred for a further 12 h. It was then diluted with CH2Cl2 and washed successively with 1N aqueous HCl, saturated aqueous NaHCO3 and water. The organic layer was dried (Na2SO4) and evaporated. The residue was chromatographied on silica gel (CH2Cl2:methanol, 49:1) to afford the title compound (880 mg, 85% for two steps) as a brown oil.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].C[O-].[Na+].F[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1>CO>[CH2:1]([C:5]1[N:6]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)[C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCCCc1nc(Cl)c(C=O)[nH]1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCc1nc(Cl)c(C=O)n1-c1ccc([N+](=O)[O-])cc1
Temperature: 100 °C
Yield: 29.8 %

Procedure:
2-n-Butyl-4-chloroimidazole-5-carboxaldehyde (10.00 g, 53.6 mmol, 1 eq.) was dissolved in a freshly prepared solution of sodium methoxide (1.23 g Na, 53.6 mmol, 1 eq.) in methanol (175 mL). The methanol was removed in vacuo and replaced with DMF (100 mL). 4-Fluoro-1-nitrobenzene (11.37 mL, 107.0 mmol, 2 eq.) was then added. The mixture was heated at 100° C. for 36 h. Two more equivalents of 4-fluoro-1-nitrobenzene were then added and the mixture heated at 100° C. for an additional 48 hours. The DMF was removed in vacuo and the residue partitioned between ethyl acetate and water. The aqueous phase was extracted twice more with ethyl acetate, the organic layers combined, dried (MgSO4) and the solvent removed in vacuo. Flash chromatography of the residue over silica gel in 9:1 toluene/ethyl acetate yielded 4.92 g (30%) of an amber oil. NMR (CDCl3): δ9.74 (s, 1H); 8.42 (d, 2H, J=9 Hz); 7.46 (d, 2H, J=9 Hz); 2.51 (t, 2H, J=7 Hz); 1.67 (t of t, 2H, J=7,7 Hz); 1.30 (t of q, 2H, J=7,7 Hz); 0.84 (t, 3H, J=7 Hz). Anal. calcd. for C14H14ClN3O3 : C, 54.64; H, 4.59; Cl, 11.52, N, 13.65. Found: C, 54.91; H, 4.67; Cl, 11.20; N, 13.62.
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[N:41]([CH2:45][CH3:46])[CH:42]=[CH:43][N:44]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:47]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:56])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[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[N:41]([CH2:45][CH3:46])[CH:42]=[CH:43][N:44]=5)=[O:56])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:47]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nccn4CC)cc2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nccn4CC)cc2)CCN3CC(C)C)cc1
Reaction time: 0.5 h
Yield: 53.4 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[(1-ethylimidazol-2-yl)methyl]sulfanyl]phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (150 mg) in dichloromethane (10 ml) was added dropwise 70% solution of 3-chloroperbenzoic acid (55.3 mg) in dichloromethane (10 ml) at −78° C. After finishing the dropping, an aqueous solution of sodium thiosulfate was added to the mixture, and the mixture was allowed to be at room temperature, stirred for 30 minutes, and extracted with ethyl acetate. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate, and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (hexane:ethyl acetate=1:1), and was recrystallized from hexane-ethyl acetate, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[(1-ethylimidazol-2-yl)methyl]sulfinyl]phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (82 mg) (Compound 333) as yellow crystals.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH2:10][CH2:9][C:8]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)(=O)C.O.[Pd]>[C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C1=C(c2ccccc2)C=CCC1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1ccccc1-c1ccccc1
Yield: 79.4 %

Procedure:
A mixture of ethyl 2-phenylcyclohexa-1,3-dienecarboxylate(90 mg, 0.395 mmol) and 5%Pd/C(50 mg) in acetic acid(1.5 ml) and water(1.5 ml) was refluxed for 2 hr. The reaction mixture was filtrated and the solvent was evaporated under reduced pressure. Toluene was added to the residue and it was dried over MgSO4. After removal of the solvent, the residue was purified by column chromatography on silica gel with n-hexane-AcOEt to afford 71 mg of ethyl 2-phenylbenzoate(y=80.0%) as a pale yellow oil. 1H-NMR(ppm, 300 MHz, CDCl3) δ 7.82(1H, dd, J=1.4 and 7.7 Hz), 7.10-7.60(8H), 4.08(2H, d, J=7.0 Hz), 0.98(3H, t, J=7.0 Hz)
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH:13]([CH3:15])[CH3:14])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:19])[CH:5]=[C:6]([S:16]([CH3:18])=O)[O:7]2.[OH:20][C:21]1[CH:26]=[CH:25]C(S)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O>[OH:1][C:2]1[CH:11]=[C:10]([O:12][CH:13]([CH3:15])[CH3:14])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:19])[CH:5]=[C:6]([S:16][C:18]1[CH:25]=[CH:26][C:21]([OH:20])=[CH:22][CH:23]=1)[O:7]2
Reactant: CC(C)Oc1cc(O)c2c(=O)cc(S(C)=O)oc2c1
Reactant: Oc1ccc(S)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)Oc1cc(O)c2c(=O)cc(Sc3ccc(O)cc3)oc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
A mixture consisting of 7.01 g (24.59 mmol) 5-hydroxy-7-isopropoxy-2-methylsulfinylchromone, 3.72 g (29.51 mmol) 4-hydroxybenzenethiol, 4.07 g (29.51 mmol) potassium carbonate, and 170 ml acetone was stirred over 1 hour at room temperature. The solution thus reacted was neutralized by addition of dilute hydrochloric acid. Subsequently, the product was extracted twice with chloroform. The organic layer was washed with saturated salt water and dried over sodium sulfate anhydride. The solvent was distilled out under reduced pressure. The resulting crude product was subjected to recrystallization from ethanol-methanol, whereby 6.64 g of 5-hydroxy2-(4-hydroxyphenylthio)-7-isopropoxychromone was obtained (yield: 78%).