Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:30][CH3:31])[CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][S:24]3(=[O:29])=[O:28])[C:11](=[O:32])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C([Li])(CC)C.I[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([O:46][CH3:47])[N:41]=1.C(=O)(O)[O-].[Na+]>C1COCC1.C1CCCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([C@@H:21]([CH2:30][CH3:31])[CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][S:24]3(=[O:29])=[O:28])[C:11](=[O:32])[C@H:10]([CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[C:42]([O:46][CH3:47])[N:41]=3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](CN1CCCS1(=O)=O)N1C(=O)CC[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: COc1cccc(CI)n1
Agent: O=C([O-])O
Agent: [Li]C(C)CC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CC[C@@H](CN1CCCS1(=O)=O)N1C(=O)[C@H](Cc2cccc(OC)n2)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: -10 °C
Reaction time: 0.08 h

Procedure:
To a solution of (5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxidoisothiazolidin-2-yl)butan-2-yl)piperidin-2-one (Example 420, Step A, 0.7 g, 1.413 mmol) in THF (5.65 ml) at −78° C. was added dropwise sec-butyllithium, (1.4 M in cyclohexane, 1.06 ml, 1.483 mmol). The reaction was warmed to −10° C. After about 5 minutes, the reaction was returned to a −78° C. bath. A solution of 2-(iodomethyl)-6-methoxypyridine (Example 420, Step B, 0.387 g, 1.554 mmol) in THF (1 mL) was added dropwise to the cooled reaction mixture. The reaction was allowed to warm to room temperature and stirred for 1 h. The reaction contents were poured into saturated sodium bicarbonate and the aqueous layer was extracted with dichloromethane (3×50 mL). The combined organics were dried with sodium sulfate and concentrated in vacuo. Silica gel chromatography (step gradient elution 5 to 50% diethyl ether in dichloromethane) afforded the title compound as the more polar diastereomer.
Reaction SMILES: O(P(O[C:18]1[CH2:19][C@@H:20]2[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:21]2[C:22]=1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[SH:42][C@@H:43]1[CH2:47][N:46]([C:48]([O:50][CH2:51][C:52]2[CH:57]=[CH:56][C:55]([N+:58]([O-:60])=[O:59])=[CH:54][CH:53]=2)=[O:49])[C@@H:45]([CH:61]2[CH2:65][NH:64][C:63](=[O:66])[CH2:62]2)[CH2:44]1>>[OH:40][C@@H:38]([C@H:37]1[C:36](=[O:41])[N:21]2[C:22]([C:23]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=3)=[O:24])=[C:18]([S:42][C@@H:43]3[CH2:47][N:46]([C:48]([O:50][CH2:51][C:52]4[CH:57]=[CH:56][C:55]([N+:58]([O-:60])=[O:59])=[CH:54][CH:53]=4)=[O:49])[C@@H:45]([CH:61]4[CH2:65][NH:64][C:63](=[O:66])[CH2:62]4)[CH2:44]3)[CH2:19][C@H:20]12)[CH3:39]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(Oc3ccccc3)Oc3ccccc3)C[C@H]12
Reactant: O=C1CC([C@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CN1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@H](C4CNC(=O)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)C[C@H]12
Yield: 33.2 %

Procedure:
The same procedure as in Example 1-1 was carried out by using p-nitrobenzyl (5R,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-carbapen-2-em-3-carboxylate (300 mg, 0.55 mmol) and (2R,4S)-4-mercapto-N-(p-nitrobenzyloxycarbonyl)-2-(2-pyrrolidon-4-yl)pyrrolidine (200 mg, 0.55 mmol, compound of Reference Example 2) to obtain p-nitrobenzyl (5R,6S)-6-[(R)-1-hydroxyethyl]-2-[(2R,4S)-N-(p-nitrobenzyloxycarbonyl)-2-(2-pyrrolidon-4-yl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylate (127 mg, yield: 35%).
Reaction SMILES: O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[C:27](=[O:28])[C:26](I)=[C:25]([O:30][CH3:31])[C:24](=[O:32])[NH:23][C:22]=2[CH:33]=1.C([Sn](CCCC)(CCCC)[C:39]1[S:40][CH:41]=[CH:42][CH:43]=1)CCC>C1(C)C=CC=CC=1>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[C:27](=[O:28])[C:26]([C:39]3[S:40][CH:41]=[CH:42][CH:43]=3)=[C:25]([O:30][CH3:31])[C:24](=[O:32])[NH:23][C:22]=2[CH:33]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: COc1c(I)c(=O)c2ccc(Cl)cc2[nH]c1=O
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: Cc1ccccc1
Product: COc1c(-c2cccs2)c(=O)c2ccc(Cl)cc2[nH]c1=O
Reaction time: 0.17 h

Procedure:
A solution of tri(2-furyl)phosphine (0.026 g) and tris(dibenzylideneacetonedipalladium (O) (0.26 g) in toluene (50 mL) was allowed to stir for 10 minutes. To this solution was added 8-chloro-4-iodo-3-methoxy-2,5-dioxo-2,5-dihydro-1H-benz[b]azepine (1.0 g), followed by 2-tributylstannylthiophene (1.24 g). The reaction was heated to reflux for 1.5 hours, was allowed to cool, and the toluene was evaporated. The residue was triturated with hot hexanes (75 mL). The title compound was afforded upon filtration (0.76 g); mp >240; NMR: 11.47 (bs, 1), 7.73 (dd, 1, J=5.1, 0.8), 7.60 (d, 1, J=7.9), 7.51 (dd, 1, J=4.0), 7.33 (d, 1, J=7.8), 7.31 (s, 1), 7.14 (dd, 1, J=5.1, 4.1), 3.88 (s, 3). Analysis for C15H1003SClN: Calculated: C, 56.34; H, 3.15; N, 4.38; Found C, 55.96; H, 3.34; N, 4.33.
Reaction SMILES: FC1C(F)=C(OCCCCCCCC)C=CC=1[B:18]([OH:20])[OH:19].Br[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[C:30]([F:43])[C:29]=2[F:44])=[CH:24][CH:23]=1.C([Li])CCC.C(OB(OC(C)C)OC(C)C)(C)C>>[F:44][C:29]1[C:30]([F:43])=[C:31]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH:32]=[CH:33][C:28]=1[C:25]1[CH:26]=[CH:27][C:22]([B:18]([OH:20])[OH:19])=[CH:23][CH:24]=1
Reactant: CCCCCCCCOc1ccc(B(O)O)c(F)c1F
Reactant: CCCCCCCCOc1ccc(-c2ccc(Br)cc2)c(F)c1F
Agent: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Product: CCCCCCCCOc1ccc(-c2ccc(B(O)O)cc2)c(F)c1F

Procedure:
This was prepared using a similar method to that described for compound 5. Quantities: 4'-bromo-2,3-difluoro-4-octoxybiphenyl (8) (3.18g, 8.0 mmol), n-butyllithium (3.2 ml, 2.5M/hexane, 8.0 mmol), tri-isopropylborate (3.01 g, 16.0 mmol).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([C@H:16]3[CH2:18][C@H:17]3[CH2:19][CH2:20][OH:21])[CH2:12][CH2:11]2)=[N:8][CH:9]=1.[Br:22][C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][C:24]=1[Cl:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([O:21][CH2:20][CH2:19][C@@H:17]2[CH2:18][C@@H:16]2[CH:13]2[CH2:14][CH2:15][N:10]([C:7]3[N:8]=[CH:9][C:4]([CH2:3][O:2][CH3:1])=[CH:5][N:6]=3)[CH2:11][CH2:12]2)=[CH:25][C:24]=1[Cl:30]
Reactant: Oc1ccc(Br)c(Cl)c1
Reactant: COCc1cnc(N2CCC([C@H]3C[C@H]3CCO)CC2)nc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COCc1cnc(N2CCC([C@H]3C[C@H]3CCOc3ccc(Br)c(Cl)c3)CC2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-[(1S,2R)-2-{1-[5-(methoxymethyl)pyrimidin-2-yl]piperidin-4-yl}cyclopropyl]ethanol (670 mg, 2.30 mmol) was dissolved in toluene (5 ml) and 4-bromo-3-chlorophenol (525 mg, 2.53 mmol), triphenylphosphine (905 mg, 3.45 mmol), and DIAD (671 μl, 3.45 mmol) added and the mixture stirred at RT overnight. The mixture was concentrated in vacuo and the residue purified by column chromatography on SiO2 using a Biotage 50M cartridge using a gradient eluant of 0-50% EtOAc:hexanes to afford the title compound. LC/MS (m/z): 481 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6](=[O:16])[C:7]3[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl.Cl[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6](=[O:16])[C:7]3[CH:14]=[CH:13][C:12]([O:15][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: O=C1c2ccc(O)cc2CCc2cc(Cl)ccc21
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1c2ccc(Cl)cc2CCc2cc(OCCN3CCOCC3)ccc21

Procedure:
For the synthesis of the title compound, 0.44 g (1.69 mmol) of 2-chloro-8-hydroxy-10,11-dihydrodibenzo[a,d]cyclohepten-5-one, 0.345 g (1.86 mmol) of 4-(2-chloroethyl)morpholine hydrochloride and 0.93 g (6.75 mmol) of K2CO3 in 15 ml of acetonitrile are reacted by method Q. C21H22ClNO3(Mr=371.87)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]#[N:8].S(Cl)([Cl:12])(=O)=O>C1(C)C=CC=CC=1.CN(C)C=O>[Cl:12][C:3]1[C:2]([C:7]#[N:8])=[N:1][CH:6]=[CH:5][N:4]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: N#Cc1cnccn1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: N#Cc1nccnc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.4 %

Procedure:
Pyrazine-2-carbonitrile (26.36 g) is dissolved in toluene (187 ml)/N,N-dimethylformamide (19 ml), and thereto is added dropwise sulfuryl chloride (135 g) under ice-cooling. After completion of addition, the reaction solution is warmed to room temperature gradually and stirred overnight. The toluene layer is separated and the residual red oil is extracted with diethyl ether. The organic layers are combined, cooled with ice, and after pouring thereto ice-water, neutralized by adding saturated aqueous sodium hydrogen carbonate solution. The organic layer is separated, and aqueous layer is extracted with diethyl ether. The organic layers are combined, washed with water, dried over sodium sulfate and evaporated to remove the solvent under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=4/1) to give the title compound (16.58 g).
Reaction SMILES: [NH:1]1[CH2:3][CH2:2]1.C(=O)([O-])O.[Na+].[F:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[C:12]([O:19][CH3:20])[CH:11]=1.[OH-].[Na+]>O.ClC(Cl)Cl>[F:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([N:1]2[CH2:3][CH2:2]2)=[O:15])=[C:12]([O:19][CH3:20])[CH:11]=1
Reactant: C1CN1
Reactant: COc1cc(F)ccc1C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1cc(F)ccc1C(=O)N1CC1
Temperature: 0 °C
Reaction time: 0.62 h

Procedure:
To 231 parts of a aziridine solution 0.95M in water are added 16 parts of sodium hydrogen carbonate while stirring vigorously at 0° C. Then there is added dropwise, during a 45 minutes-period, a solution of 36 parts of 4-fluoro-2-methoxybenzoyl chloride in 150 parts of trichloromethane while still cooling at 0° C. Upon completion, stirring is continued for 30-45 minutes without cooling. The reaction mixture is adjusted to pH 8 with a diluted sodium hydroxide solution and the product is extracted three times with trichloromethane. The combined extracts are washed three times with water, dried, filtered and evaporated, yielding 40.5 parts of 1-(4-fluoro-2-methoxybenzoyl)-aziridine as a residue.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[NH:5][CH:6]=[N:7]2.C(=O)([O-])[O-].[K+].[K+].[Cl:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:20]=1[CH2:21]Cl>CN(C)C(=O)C>[Cl:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:20]=1[CH2:21][N:7]1[CH:6]=[N:5][C:4]2[C:8]1=[N:9][CH:10]=[N:11][C:3]=2[NH:2][CH3:1]
Reactant: CNc1ncnc2nc[nH]c12
Reactant: ClCc1c(Cl)cccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CNc1ncnc2c1ncn2Cc1c(Cl)cccc1Cl
Yield: 61.7 %

Procedure:
In a procedure analogous to that of Example 9, by using 1.49 g of 6-methylaminopurine, 1.38 g of potassium carbonate, 50 ml of N,N-dimethylacetamide and 3.92 g of 2,6-dichlorobenzyl chloride, there was obtained 1.9 g of 9-(2,6-dichlorobenzyl)-6-methylaminopurine as colorless needles (yield: 62%), m.p. 219°-220° C. NMR spectrum of this product is identical with that of the corresponding compound synthesized in Example 2.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[N:17]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH:29]([CH:33]([C:42]([NH2:44])=[O:43])[C:34]2[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=2)[CH2:30][CH2:31][CH3:32])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>CN(C)C=O>[N:17]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH:29]([CH:33]([C:42]([NH2:44])=[O:43])[C:34]2[CH:35]=[CH:36][C:37]([CH:38]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:40][CH:41]=2)[CH2:30][CH2:31][CH3:32])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCCC(c1ccccc1N1CCCCC1)C(C(N)=O)c1ccc(C=O)cc1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCC(c1ccccc1N1CCCCC1)C(C(N)=O)c1ccc(C=CC(=O)OCC)cc1
Reaction time: 0.25 h

Procedure:
A solution of 2.80 gm (12.5 m mol) of ethyl diethylphosphonoacetate in 10 ml of absolute dimethylformamide was added dropwise, at ambient temperature, to 0.60 gm (12.5 m mol) of sodium hydride (50% in oil) in 15 ml of absolute dimethylformamide. The mixture was stirred for 15 minutes (until the development of gas ceased), and then a solution of 2.4 gm (6.34 m mol) of 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzaldehyde in 10 ml of absolute dimethylformamide was added thereto dropwise. The mixture was stirred for two hours at ambient temperature, concentrated by evaporation in vacuo, and distributed between water and ether. The ether phase was dried, filtered, and then evaporated in vacuo. The evaporation residue was purified by column chromatography on silica gel [toluene/acetone (10:1)].
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[CH3:14][CH:15]([C:31](=[O:37])[CH2:32][CH:33]=[C:34]([CH3:36])[CH3:35])[CH2:16][CH2:17][CH2:18][C:19]1([CH3:30])[CH:25]2[O:26][C:22]([CH2:27][CH2:28][OH:29])([CH2:23][CH2:24]2)[CH2:21][O:20]1.CC(C)=O.CC(O)C>O>[CH3:14][CH:15]([C:31](=[O:37])[CH2:32][CH:33]=[C:34]([CH3:36])[CH3:35])[CH2:16][CH2:17][CH2:18][C:19]1([CH3:30])[CH:25]2[O:26][C:22]([CH2:27][C:28]([OH:3])=[O:29])([CH2:23][CH2:24]2)[CH2:21][O:20]1
Reactant: CC(C)=O
Reactant: CC(C)=CCC(=O)C(C)CCCC1(C)OCC2(CCO)CCC1O2
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)O
Product: CC(C)=CCC(=O)C(C)CCCC1(C)OCC2(CC(=O)O)CCC1O2

Procedure:
A slight excess of Jones reagent is added to a mixture of (1RS,4SR,5RS)-4-(4,8-dimethyl-5-oxo-7-nonenyl)-4-methyl-3,8-dioxabicyclo[3.2.1]octane-1-ethanol (13 mg, 0.04 mM) and acetone (3 ml) at 0° C. under nitrogen for thirty minutes. The resulting mixture is treated with 2-propanol (1 ml) and stirred for ten minutes. The mixture is treated with water (10 ml) and extracted with ether (3×20 ml). The combined organic layers are dried (Na2SO4) and evaporated in vacuo to give crude (1RS,4SR,5RS)-4-(4,8-dimethyl-5-oxo-7-nonenyl)-4-methyl-3,8-dioxabicyclo[3.2.1]octane-1-acetic acid (10 mg) as a yellowish oil. This material is dissolved in methanol (2 ml) and treated with sodium borohydride (50 mg) at 0° C. under nitrogen. After stirring for five minutes, the mixture is allowed to warm to room temperature, acetone (0.5 ml) is added and the resulting mixture is stirred for thirty minutes. Most of the solvent is removed in vacuo, 2 N hydrochloric acid (5 ml) is added and the resulting mixture is extracted with ether (3×10 ml). The combined organic layers are dried (Na2SO4), evaporated in vacuo and the residue is purified by column chromatography on silica gel (5 g) with ether to give (1RS,4SR,5RS)-4-(4,8-dimethyl-5-hydroxy-7-nonenyl)-4-methyl-3,8-dioxabicyclo[3.2.1]octane-1-acetic acid (7 mg) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:17])[CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[N:13]1.[H-].[Na+].Cl[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[N:26][CH:27]=1.O>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[N:13]1)[O:17][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:35])[F:36])[CH:29]=2)=[N:26][CH:27]=1
Reactant: Cc1cc(O)ccc1CCCCn1ccnn1
Reactant: FC(F)(F)c1cccc(-c2ccc(CCl)cn2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCc2ccc(-c3cccc(C(F)(F)F)c3)nc2)ccc1CCCCn1ccnn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.8 %

Procedure:
A solution of 100 mg (0.43 mmol) 3-methyl-4-(4-[1,2,3]triazol-1-yl-butyl)phenol in 4.0 ml N,N-dimethylformamide was treated at 0° C. with 18 mg (0.45 mmol) of 60% sodium hydride and stirred at 0° C. for 30 min. Then 117 mg (0.43 mmol) 5-Chloromethyl-2-(3-trifluoromethyl-phenyl)-pyridine were added and stirred continued at r.t. over night. After addition of 8 ml water, the precipitate was isolated, washed thoroughly with water, methanol/water 1:1 and diisopropylether. The residue was dried at 40° C. to give 160 mg (79%) of the title compound as white powder.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[N:10]=[CH:9][NH:8][C:7]=2[C:6](=[O:12])[NH:5][C:4]1=[O:13])[CH3:2].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH2:25](Cl)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O>[CH2:25]([N:8]1[C:7]2[C:6](=[O:12])[NH:5][C:4](=[O:13])[N:3]([CH2:1][CH3:2])[C:11]=2[N:10]=[CH:9]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCn1c(=O)[nH]c(=O)c2[nH]cnc21
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Temperature: 80 °C

Procedure:
180 g (1 mol) of 3-ethylxanthine were initially introduced into 1000 ml of dimethylformamide, the mixture was heated to 80° C. with stirring and, after the introduction of 88 g (0.64 mol) of potassium carbonate, treated dropwise with 133 g (1.05 mol) of benzyl chloride in the course of 1 hour. It was then stirred at 100° C. for 2 hours, treated with 1000 ml of water, and the precipitated product was filtered on a suction filter, washed with water until salt-free and dried in a vacuum drying oven at 100° C. If necessary, a further purification can be carried out by reprecipitating from 1 N sodium hydroxide solution using 4 N hydrochloric acid analogously to Example 1a).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.C1[CH2:16][N:15]([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)[CH2:14]C1.F[P-](F)(F)(F)(F)F.CNC>CN(C=O)C.CCOCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:15]([CH3:16])[CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: O=C(O)Cc1ccc(Br)cc1
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CN(C)C(=O)Cc1ccc(Br)cc1
Reaction time: 8 h
Yield: 51.1 %

Procedure:
To a suspension of 4-bromophenylacetic acid (2.0 g, 9.3 mmol) and PyBOP (4.8 g, 9.3 mmol) in DMF (15 mL) was added dimethylamine (2 M solution in THF, 12 mL, 24 mmol). The solution was stirred overnight, then diluted with ether and washed with 1 M HCl, saturated aqueous NaHCO3 and brine to give 1.15 g 2-(4-bromophenyl)-N,N-dimethylacetamide.
Reaction SMILES: [C:1]([NH:4][C:5]12[CH2:10][CH:9]1[CH2:8][NH:7][CH2:6]2)(=[O:3])[CH3:2].C(N(CC)CC)C.Cl[C:19]1[N:28]=[C:27]2[C:22]([C:23](=[O:35])[C:24]([C:32]([OH:34])=[O:33])=[CH:25][N:26]2[CH:29]2[CH2:31][CH2:30]2)=[CH:21][C:20]=1[F:36]>C(#N)C>[C:1]([NH:4][C:5]12[CH2:10][CH:9]1[CH2:8][N:7]([C:19]1[N:28]=[C:27]3[C:22]([C:23](=[O:35])[C:24]([C:32]([OH:34])=[O:33])=[CH:25][N:26]3[CH:29]3[CH2:31][CH2:30]3)=[CH:21][C:20]=1[F:36])[CH2:6]2)(=[O:3])[CH3:2]
Reactant: CC(=O)NC12CNCC1C2
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)NC12CC1CN(c1nc3c(cc1F)c(=O)c(C(=O)O)cn3C1CC1)C2
Yield: 51 %

Procedure:
A mixture of 1-acetylamino-3-azabicyclo[3.1.0]hexane (150 mg, 0.70 mmol) and triethylamine (0.48 ml, 3.5 mmol) in acetonitrile (7 ml) was treated with 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (192.1 mg, 0.68 mmol) and heated to 80° for 18 hours. Filtration of the reaction mixture provided the title product as a white solid, mp 275° with decomposition (135.8 mg, 0.35 mmol, 51% yield). 1H NMR (CDCl3): 8.55 (s, 1H), 8.49 (s, 1H), 7.96 (d, J=13 Hz, 1H), 4.22 (m, 1H), 3.98 (bs, 2H), 3.81 (m, 1H), 3.68 (m, 1H), 1.82 (bs, 4H), 1.12 (m, 5H), 0.78 (m, 1H).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[CH:12]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:18][OH:19].C([O-])(=O)C.[Na+]>>[C:1]1([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[CH:12]=[N:18][OH:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1cccc(C#Cc2ccccc2)c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: ON=Cc1cccc(C#Cc2ccccc2)c1

Procedure:
The procedure was the same as described in Example 1b, except there were used 16.5 g of 3-(phenylethynyl)-benzaldehyde, 8.3 g of hydroxylamine hydrochloride and 8.2 g of sodium acetate to give 16.8 g (94.8% of the theoretical yield) of the title compound in form of a yellowish powder (mixture of isomers).
Reaction SMILES: O[CH:2]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:14])[CH3:13])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[CH3:15][C:16]1[CH:17]=[C:18](O)[CH:19]=[C:20]([CH3:22])[CH:21]=1>C(OCC)(=O)C.CCCCCC>[CH:12]([C:9]1[CH:10]=[CH:11][C:6]([CH:2]2[C:17]3[C:16]([CH3:15])=[CH:21][C:20]([CH3:22])=[CH:19][C:18]=3[O:5][C:3]2=[O:4])=[CH:7][CH:8]=1)([CH3:14])[CH3:13]
Reactant: CC(C)c1ccc(C(O)C(=O)O)cc1
Reactant: Cc1cc(C)cc(O)c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cc(C)c2c(c1)OC(=O)C2c1ccc(C(C)C)cc1
Yield: 45 %

Procedure:
Using hydroxy(4-isopropylphenyl)acetic acid synthesized in Reference Example 1 and 3,5-dimethylphenol, the title compound was synthesized in the same manner as in Reference Example 2. Yield 45%. Melting point: 76-77° C. (ethyl acetate-hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.[CH3:12][C:13]1(C)[O:18]C(=O)[CH2:16][C:15](=O)[O:14]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](=[O:11])[CH2:12][C:13]([O:14][CH2:15][CH3:16])=[O:18]
Reactant: O=C(O)Cc1ccccc1Cl
Reactant: CC1(C)OC(=O)CC(=O)O1
Product: CCOC(=O)CC(=O)Cc1ccccc1Cl
Yield: 43 %

Procedure:
The title compound was prepared in 43% yield from 2-(2-chlorophenyl)acetic acid and 2,2-dimethyl-1,3-dioxane-4,6-dione according to the procedure for the preparation of Example 162, part A.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].[CH3:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[C:10]=1[CH:17]1[C:22](=[O:23])[CH2:21][CH:20]([CH2:24][CH:25]2[CH2:29][CH2:28][O:27][CH2:26]2)[CH2:19][C:18]1=[O:30].C(N(CC)CC)C>ClCCl>[O:23]=[C:22]1[CH2:21][CH:20]([CH2:24][CH:25]2[CH2:29][CH2:28][O:27][CH2:26]2)[CH2:19][C:18]([O:30][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1])=[C:17]1[C:10]1[C:11]([CH3:16])=[CH:12][C:13]([CH3:15])=[CH:14][C:9]=1[CH3:8]
Reactant: Cc1cc(C)c(C2C(=O)CC(CC3CCOC3)CC2=O)c(C)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(C2=C(OC(=O)C(C)(C)C)CC(CC3CCOC3)CC2=O)c(C)c1
Temperature: 0 °C
Reaction time: 0.03 h

Procedure:
A solution of trimethylacetyl chloride (55 mg, 0.457 mmol) in dichloromethane (2 ml) is added dropwise to a solution of 2-(2,4,6-trimethylphenyl)-5-(tetrahydrofuran-3-ylmethyl)-cyclohexane-1,3-dione (120 mg, 0.38 mmol) in dichloromethane (2 ml) and the mixture is cooled in an ice bath and stirred at 0° C. for 2 minutes. A solution of triethylamine (46 mgs, 0.457 mmol) in dichloromethane (1 ml) is added, and once the addition is complete the cooling bath is removed and the reaction mixture is stirred at room temperature for 2 hours. The mixture is diluted with dichloromethane (20 ml) and washed with saturated aqueous sodium bicarbonate solution (3×20 ml). The organic phase is dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated in vacuo. The residue is purified by column chromatography on silica gel to give 2,2-dimethylpropionic acid 3-oxo-5-(tetrahydrofuran-3-ylmethyl)-2-(2,4,6-trimethylphenyl)cyclohex-1-enyl ester as a white solid, m.p. 108-110° C.