Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[NH:11][C:12]1[C:13]2[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][NH:18][C:14]=2[N:15]=[CH:16][CH:17]=1.[H][H]>C(O)C.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[NH:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]2[NH:18][CH:19]=[C:20]([C:21]([F:24])([F:22])[F:23])[C:13]=12
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(Nc2ccnc3[nH]cc(C(F)(F)F)c23)c(F)c1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(Nc2ccnc3[nH]cc(C(F)(F)F)c23)c(F)c1

Procedure:
10 mg of 10% palladium-on-carbon are added to a solution of 129 mg (0.38 mmol) of N-(2-fluoro-4-nitrophenyl)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-4-amine in 5 ml of ethanol, and the suspension is stirred in a hydrogen atmosphere at atmospheric pressure overnight. The suspension is filtered through kieselguhr and the kieselguhr is washed with ethanol. The filtrate is concentrated. The product is purified by preparative HPLC.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:11]=[CH:12][C:13]2[C:14](=O)[NH:15][N:16]=[CH:17][C:18]=2[N:19]=1.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:14]1[C:13]2[CH:12]=[CH:11][C:10]([NH:9][C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[N:19][C:18]=2[CH:17]=[N:16][N:15]=1
Reactant: O=c1[nH]ncc2nc(Nc3ccc(F)cc3F)ccc12
Reactant: O=P(Cl)(Cl)Cl
Product: Fc1ccc(Nc2ccc3c(Cl)nncc3n2)c(F)c1
Temperature: 100 °C

Procedure:
A heterogeneous mixture of 2-(2,4-difluorophenylamino)pyrido[3,2-d]pyridazin-5(6H)-one (1.08 g, 3.9 mmol) and phosphorus oxychloride (10.00 mL, 39 mmol) was heated at 100° C. for 1.5 h. The excess POCl3 was removed on the rotovap and the crude residue was treated with ice cold 1N NaOH. The precipitated solid was filtered, rinsed with 2×5 mL of water followed by 2×5 mL of ether, and dried in a vacuum oven at 45° C. for 18 h to provide 5-chloro-N-(2,4-difluorophenyl)pyrido[3,2-d]pyridazin-2-amine as a tan solid. MS (ESI, pos.ion) m/z: M+1=293.0
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[O:15]1[C:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]1[C:17]([O:19][CH3:20])=[O:18].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[OH:15][CH:16]([C:21]([O:1][CH2:2][CH2:3][NH:4][C:5]([O:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:14])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:17]([O:19][CH3:20])=[O:18]
Reactant: O=C(NCCO)OCc1ccccc1
Reactant: COC(=O)C1OC1(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: COC(=O)C(O)C(OCCNC(=O)OCc1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
9.8 g (50 mmol) of benzyl (2-hydroxyethyl)carbamate and 12.7 g (50 mmol) of methyl 2,3-epoxy-3,3-diphenylpropionate were dissolved in 80 ml of methylene chloride and, with ice-cooling, 0.95 g (5 mmol) of p-toluenesulfonic acid was added. The reaction mixture was stirred at room temperature for 24 hours and then diluted with methylene chloride and extracted with 2M aqueous sodium hydroxide solution, the organic phase was separated off and dried over sodium sulfate and the solvent was distilled off. The residue (22.2 g of an oil) was directly reacted further.
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([CH:9]=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(=O)([O-])[O-].[K+].[K+]>COCCOC>[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][C:21]([C:2]2[C:3]3[C:8]([CH:9]=[C:10]4[C:15]=2[CH:14]=[CH:13][CH:12]=[CH:11]4)=[CH:7][CH:6]=[CH:5][CH:4]=3)=[CH:20][CH:19]=1
Reactant: Brc1c2ccccc2cc2ccccc12
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: FC(F)(F)c1ccc(-c2c3ccccc3cc3ccccc23)cc1
Temperature: 25 °C

Procedure:
5.1 g (20 mmol) of 9-bromoanthracene, 3.8 g (20 mmol) of 4-trifluoromethylphenylboronic acid, and 244 mg (0.8 mmol) of tri(o-tolyl)phosphine were put into a 100-mL three-neck flask, and nitrogen substitution in the system was carried out. 20 mL of ethylene glycol dimethyl ether (DME) was added to this mixture, and the mixture was stirred under reduced pressure and degassed. After that, 45 mg (0.20 mmol) of palladium acetate(II) and 10 mL (2.0 mol/L) of a potassium carbonate solution were added. This reaction mixture was stirred at 80° C. for 3 hours under nitrogen gas stream. Then, the reaction mixture was cooled to the room temperature, and a solid that was precipitated was collected by suction filtration. The collected solid was dissolved in toluene, and the solution was subjected to suction filtration through Florisil, celite, and then alumina. The filtrate was condensed to obtain a solid, and the solid was recrystallized with ethanol, whereby 5.7 g of a white powdery solid, which was a target matter, was obtained with the yield of 88%.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([C:20]3[O:21][C:22]([CH3:25])=[N:23][N:24]=3)[CH:17]=[CH:16][C:15]=2[CH3:26])=[CH:10][CH:9]=1)=[O:7].I[CH2:32][CH3:33]>>[Cl:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]([CH2:32][CH3:33])[C:6]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[C:18]([C:20]3[O:21][C:22]([CH3:25])=[N:23][N:24]=3)[CH:17]=[CH:16][C:15]=2[CH3:26])=[CH:12][CH:13]=1)=[O:7]
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCc4ccccc4Cl)cc3)c2)o1
Reactant: CCI
Product: CCN(Cc1ccccc1Cl)C(=O)c1ccc(-c2cc(-c3nnc(C)o3)ccc2C)cc1

Procedure:
N-(2-Chlorobenzyl)-N-ethyl-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from N-(2-chlorobenzyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide and iodoethane using method L. NMR; δH [2H6]—DMSO 7.89,(1H, d), 7.77,(1H, b), 7.58-7.32,(9H, m), 4.76-4.60,(2H, m), 3.42-3.27,(2H, b), 2.56,(3H, s), 2.32-2.28,(3H, m), 1.08,(3H, b). LCMS; retention time 3.66 min, MH+ 446/448.
Reaction SMILES: [CH3:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[CH2:3][CH2:4][CH:5]=[CH2:6].C([Li])CCC.[C:18]1(=O)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19]1.Cl>O1CCCC1>[CH2:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18]([C:2]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)([CH3:1])[CH2:3][CH2:4][CH:5]=[CH2:6])=[CH:19]1
Reactant: C=CCCC(C)c1ccccn1
Reactant: O=C1CCc2ccccc21
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CCCC(C)(C1=CCc2ccccc21)c1ccccn1

Procedure:
A solution of 8.95 g (0.0556 mol) of 2-(1-methyl4-pentenyl)pyridine in 50 ml of tetrahydrofuran was cooled to −20° C. and 35 ml of n-butyllithium (15 w.-% in hexane, 0.0556 mol) were subsequently added while stirring. The mixture was allowed to come to room temperature and was stirred for a further one hour. A solution of 7.33 g of 1-indanone in 8 ml of tetrahydrofuran was then added at such a rate that the temperature remained at 25° C. The mixture was stirred for a further 3 hours and hydrolyzed with 150 ml of dilute hydrochloric acid. The organic phase was separated off, the aqueous phase was extracted once with ethyl acetate, the aqueous phase was subsequently neutralized with aqueous ammonia solution and was extracted three times with 80 ml each time of dichloromethane. The organic phases were combined, dried over magnesium sulfate, the magnesium sulfate was filtered off and the solvent was distilled off. The crude product (about 10 g) was purified by column chromatography using a mixture of hexane:CH2Cl2=1:1 for the separation from starting 2-(1-methyl4-pentenyl)pyridine. Then, a mixture of hexane:CH2Cl2=1:2 was used. This gave 4.81 g (31%) of 2-[1-(1H-inden-3-yl)-1-methyl-4-pentenyl]pyridine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([CH:23]=[CH2:24])=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:32]1[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[C:34]([C:42]([F:45])([F:44])[F:43])[CH:33]=1>>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12](/[CH:23]=[CH:24]/[C:37]2[CH:32]=[CH:33][C:34]([C:42]([F:43])([F:45])[F:44])=[C:35]([C:38]([F:39])([F:41])[F:40])[CH:36]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Reactant: FC(F)(F)c1ccc(Cl)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: FC(F)(F)c1ccc(/C=C/c2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc1C(F)(F)F
Temperature: 140 °C

Procedure:
3,4-bis(Benzyloxy)-6-ethenylpyridazine (Intermediate 78: 0.578 g, 1.816 mmol), cesium carbonate (0.887 g, 2.72 mmol), dichloropalladiumtricyclohexylphosphane (1:2) (0.067 g, 0.091 mmol) and 4-chloro-1,2-bis(trifluoromethyl)benzene (0.542 g, 2.179 mmol) were combined. The reaction vessel was evacuated and purged with nitrogen before toluene (6.05 ml) was added under vacuum and the whole was stirred under nitrogen and heated to 140° C. for 11 hours. Upon quenching with saturated aqueous ammonium chloride, the resulting mixture was diluted with dichloromethane, passed through a phase separator and concentrated in vacuo. The residue was purified by column chromatography eluting (silica, 0-50% ethyl acetate in petrol) to yield crude 3,4-bis(benzyloxy)-6-[(E)-2-[3,4-bis(trifluoromethyl)phenyl]-ethenyl]-pyridazine which was used directly in the next step without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:21]=[CH:20][C:7]([O:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([O:15]S(C)(=O)=O)[CH2:10]2)=[C:6]([CH2:22][CH2:23][CH3:24])[C:5]=1[OH:25])(=[O:3])[CH3:2].O[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:29][C:28]=1[Br:38].[H-].[Na+].C1OCCOCCOCCOCCOC1>C1(C)C=CC=CC=1.C1COCC1>[C:1]([C:4]1[CH:21]=[CH:20][C:7]([O:8][C@H:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([O:15][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:29][C:28]=3[Br:38])[CH2:10]2)=[C:6]([CH2:22][CH2:23][CH3:24])[C:5]=1[OH:25])(=[O:3])[CH3:2]
Reactant: COC(=O)Cc1ccc(O)c(Br)c1
Reactant: CCCc1c(O[C@@H]2CCC[C@H](OS(C)(=O)=O)C2)ccc(C(C)=O)c1O
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCCc1c(O[C@H]2CCC[C@H](Oc3ccc(CC(=O)OC)cc3Br)C2)ccc(C(C)=O)c1O

Procedure:
To a solution of the title compound of Step C of this example (500 mg; 1.35 mmole) in toluene (30 ml) and THF (1.5 ml) was added successively 4-hydroxy-3-bromophenylacetic acid, methyl ester (1 g, 4 mmoles), sodium hydride (169 mg; 7 mmoles) and 15-crown-5 (10 mg). The reaction mixture was refluxed for 10 hours under nitrogen. It was then worked-up as in Step B of Example 8 to yield the title compound of this step.
Reaction SMILES: C([SnH](CCCC)CCCC)CCC.N(C(C)(C)C#N)=NC(C)(C)C#N.[CH2:26]([O:29][C:30]([N:32]1[C@H:36]([CH:37]([C:43]2[S:47][C:46]3=[CH:48][N:49]=[C:50]([Cl:51])[N:45]3[CH:44]=2)OC(SC)=S)[CH2:35][C@@H:34]([O:52][Si:53]([C:56]([CH3:59])([CH3:58])[CH3:57])([CH3:55])[CH3:54])[CH2:33]1)=[O:31])[CH:27]=[CH2:28]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:26]([O:29][C:30]([N:32]1[C@H:36]([CH2:37][C:43]2[S:47][C:46]3=[CH:48][N:49]=[C:50]([Cl:51])[N:45]3[CH:44]=2)[CH2:35][C@@H:34]([O:52][Si:53]([C:56]([CH3:59])([CH3:58])[CH3:57])([CH3:54])[CH3:55])[CH2:33]1)=[O:31])[CH:27]=[CH2:28]
Reactant: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(OC(=S)SC)c1cn2c(Cl)ncc2s1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1Cc1cn2c(Cl)ncc2s1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 71.8 %

Procedure:
Tri-n-butyltin hydride (1.8 ml) and 147 mg of 2,2′-azobisisobutyronitrile are added to a solution of 2.520 g of (3R,5S)-1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5-[1-(5-chloroimidazo[5,1-b]thiazol-2-yl)-1-(methylthiothiocarbonyloxy)methyl]pyrrolidine (a diastereomer mixture) in 22.5 ml of dry toluene, and the mixture is stirred in an argon atmosphere at an external temperature of 80° C. for 90 min. The reaction solution is diluted with 200 ml of ethyl acetate, washed with semi-saturated saline and dried over anhydrous magnesium sulfate. The solvent is removed by evaporation under reduced pressure to give a crude product which is then purified by column chromatography on silica gel (hexane:ethyl acetate=2:1) to give 1.467 g of (3R,5s)-1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5-(5-chloroimidazo[5,1-b]thiazol-2-yl)methylpyrrolidine as a slightly yellow oil.
Reaction SMILES: CC1C=C(C)N([C:8]([CH:10]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:17][C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])N=1.[CH3:24][O:25][CH2:26][C:27]1[O:31][C:30]([NH2:32])=[N:29][N:28]=1>>[CH3:24][O:25][CH2:26][C:27]1[O:31][C:30]([NH:32][C:8]([CH:10]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[O:17][C:18]3[C:23]2=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:9])=[N:29][N:28]=1
Reactant: COCc1nnc(N)o1
Reactant: Cc1cc(C)n(C(=O)C2c3ccccc3Oc3ccccc32)n1
Product: COCc1nnc(NC(=O)C2c3ccccc3Oc3ccccc32)o1

Procedure:
The title compound, white solid, m.p. 233-234° C. and MS: m/e=337.1 (M+H+) was prepared in accordance with the general method of example 48a from (3,5-dimethylpyrazol-1-yl)-(9H-xanthen-9-yl)-methanone and 5-methoxymethyl-[1,3,4]oxadiazol-2-ylamine.
Reaction SMILES: [N:1]1[C:6]2[CH2:7][CH2:8][NH:9][CH2:10][C:5]=2[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[N:3][CH:2]=1.[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>C1COCC1.CC([O-])=O.CC([O-])=O.[Cu+2]>[F:21][C:18]([F:20])([F:19])[C:15]1[CH:14]=[CH:13][C:12]([NH:11][C:4]2[C:5]3[CH2:10][N:9]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:8][CH2:7][C:6]=3[N:1]=[CH:2][N:3]=2)=[CH:17][CH:16]=1
Reactant: FC(F)(F)c1ccc(Nc2ncnc3c2CNCC3)cc1
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(Nc2ncnc3c2CN(c2ccccc2)CC3)cc1
Reaction time: 6 h
Yield: 6.4 %

Procedure:
The (5,6,7,8-Tetrahydro-pyrido[4,3-d]pyrimidin-4-yl)-(4-trifluoromethylphenyl)amine (100 mg, 0.34 mmol) was dissolved in anhydrous THF (2 mL). To the mixture was added phenylboronic acid (83 mg, 0.68 mmol), Cu(OAc)2 (124 mg, 0.68 mmol) and triethylamine (0.68 g, 0.095 mL). The mixture was agitated for 6 h and the solvent was removed under the vacuum. The residue was purified using a gradient of ethyl acetate:hexane (0-100%) to give the desired compound as reddish powder (8.0 mg, 6.0%).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:17]2[C:25]3[C:24]([NH2:26])=[N:23][CH:22]=[N:21][C:20]=3[N:19]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH2:34][CH2:35][N:36]4[CH:40]=[CH:39][N:38]=[CH:37]4)[CH:28]=3)[CH:18]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])C1C=CC=CC=1.[H][H].C(O)C>C1COCC1.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([C:17]2[C:25]3[C:24]([NH2:26])=[N:23][CH:22]=[N:21][C:20]=3[N:19]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH2:34][CH2:35][N:36]4[CH:40]=[CH:39][N:38]=[CH:37]4)[CH:28]=3)[CH:18]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: [H][H]
Reactant: COc1ccc(-c2cn(-c3cccc(OCCn4ccnc4)c3)c3ncnc(N)c23)cc1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(-c2cn(-c3cccc(OCCn4ccnc4)c3)c3ncnc(N)c23)cc1O

Procedure:
0.75 g of 5-(3-benzyloxy-4-methoxyphenyl)-7-[3-(2-(1-imidazolyl)ethoxy)phenyl]-4-amino-pyrrolo[2,3-d]pyrimidine is hydrogenated in a hydrogen atmosphere at normal pressure and about 50° C. for 12 h in 20 ml of THF and 10 ml of ethanol in the presence of 0.2 g of 5% palladium/carbon. After filtration through Celite and crystallization of the residue from methylene chloride, 5-(3-hydroxy-4-methoxyphenyl)-7-[3-(2-(1-imidazolyl)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine having an m.p. of 205°-207° C. is obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][CH2:7][OH:8].C[Si](Cl)(C)C.[C:14]1([C:20]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[S:21]Cl)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>N1C=CC=CC=1.C(Cl)Cl>[OH:1][CH2:2][CH2:3][N:4]([S:21][C:20]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:5][CH2:6][CH2:7][OH:8]
Reactant: ClSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCCCNCCO
Agent: C[Si](C)(C)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: OCCCN(CCO)SC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(2-hydroxyethyl)-3-amino-1-propanol (5.0 g, 41.9 mmol) is coevaporated several times with pyridine (20 mL) and then dissolved in pyridine (100 mL). The reaction flask is flushed with Argon and trimethylsilylchloride (2.47 g, 209.5 mmol) is added dropwise. The reaction mixture is stirred for 1 hour. Triphenyl methanesulfenyl chloride (14.32 g, 46.09 mmol) is dissolved in CH2Cl2 and added via dropping funnel to the cooled reaction mixture. The reaction mixture is warmed to room temperature and stirred for 18 hours. The reaction mixture is concentrated in vacuo and the resultant residue is partitioned between H2O and EtOAc (100 ml, 1:1). The H2O layer is separated and extracted with EtOAc (3×50 ml). The EtOAc extracts are pooled, dried (MgSO4) and filtered. The filtrate is concentrated in vacuo and the residue is purified by silica gel flash column chromatography with EtOAc/hexanes as the eluent. The appropriate fractions are pooled and concentrated in vacuo to give the title compound.
Reaction SMILES: Cl[CH2:2][C@@H:3]1[C:12]([CH3:14])([CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:15])[CH:10]=2)[C:5]([CH3:17])([CH3:16])[CH2:4]1.O.O.O.C([O-])(=O)C.[Na+]>[C].[Pd].C(O)(C)C>[CH3:16][C:5]1([CH3:17])[C:6]2[C:11](=[CH:10][C:9]([CH3:15])=[CH:8][CH:7]=2)[C:12]([CH3:14])([CH3:13])[C@@H:3]([CH3:2])[CH2:4]1
Reactant: Cc1ccc2c(c1)C(C)(C)[C@@H](CCl)CC2(C)C
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: Cc1ccc2c(c1)C(C)(C)[C@@H](C)CC2(C)C
Yield: 99.8 %

Procedure:
Into an autoclave, (S)-3-(chloromethyl)-1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphthalene 200 mg; 0.798 mmol), isopropanol (10 ml), sodium acetate trihydrate (120 mg; 0.882 mmol) and 10 % palladium carbon (160 mg) were charged, and the resultant mixture was stirred at 50° C. under a hydrogen pressure of 80 kg/cm2 for 12 hours. After cooling, the reaction mixture was filtered to separate palladium carbon, admixed with water and extracted with n-hexane. The extract was washed with saturated sodium hydrogen carbonate solution, dried and concentrated to give (S)-1,1,3,4,4,6-hexamethyl-1,2,3,4-tetrahydronaphthalene (172 mg; 0.796 mmol).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([C:23](=[O:26])[CH2:24]Br)[CH:12]=[C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][NH:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>CN(C=O)C>[C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:23]([CH2:24][N:46]([CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][O:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=3)[OH:26])[CH:12]=[C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CBr)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Reactant: c1ccc(CNCCCCCCOCCCCCCc2ccccn2)cc1
Solvent: CN(C)C=O
Product: OC(CN(CCCCCCOCCCCCCc1ccccn1)Cc1ccccc1)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 66.7 %

Procedure:
A solution of 1-[3,5-bis(phenylmethoxy)phenyl]-2-bromoethanone (1.76 g) in dry DMF (15 ml) was added dropwise to a solution of N-[6-[[6-(2-pyridinyl)hexyl]oxy]hexyl]benzenemethanamine (1.58 g) and DEA (0.56 g) in dry DMF (15 ml) under nitrogen. The mixture was stirred at room temperature for 4.5 h, and the solvent was evaporated. Sodium borohydride (1.75 g) was added portionwise to the ice-cooled solution of the residue in ethanol (40 ml) under nitrogen and the reaction mixture was stirred at room temperature for 16 h and concentrated. The residue was partitioned between ethyl acetate (70 ml) and water (70 ml), the organic layer was washed with brine (70 ml), dried and concentrated to give an oil which was purified by FCC eluting with ethyl acetatehexane-triethylamine (25:75:1) to give the title compound as a colourless oil (2.00 g), t.l.c. (ethyl acetate-hexane (1:2)+ few drops triethylamine) Rf 0.19.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].O>C(O)(=O)C>[N+:1]([C:27]1[CH:28]=[C:23]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:24]=[CH:25][C:26]=1[OH:29])([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: CCCCCCCCCCCCCCCCCCc1ccc(O)cc1
Solvent: CC(=O)O
Solvent: O
Product: CCCCCCCCCCCCCCCCCCc1ccc(O)c([N+](=O)[O-])c1
Reaction time: 1 h

Procedure:
40 ml of nitric acid (d=1.18) was added dropwise to a solution of 10 g of p-octadecylphenol dissolved in 300 ml of acetic acid at 10° to 40° C. After one hour, the reaction mixture was poured into water, extracted with ethyl acetate, washed with water, then with aqueous sodium bicarbonate solution, followed by drying. After the solvent was evaporated, the residued crystals were recrystallized from n-hexane. 2-Nitro-4-octadecylphenol of m.p. 71° C. was obtained in an amount of 8.4 g.
Reaction SMILES: [N+](C1C=CC(COC([N:12]=[C:13]([N:15]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([C@@H:24]3[CH2:28][C@H:27]([S:29][C:30]4[C@H:31]([CH3:54])[C@@H:32]5[C@@H:49]([C@H:50]([OH:52])[CH3:51])[C:48](=[O:53])[N:33]5[C:34]=4[C:35]([O:37]CC4C=CC([N+]([O-])=O)=CC=4)=[O:36])[CH2:26][N:25]3C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)=[O:23])[CH2:17][CH2:16]2)[CH3:14])=O)=CC=1)([O-])=O>O1CCCC1.O>[C:13]([N:15]1[CH2:21][CH2:20][CH2:19][N:18]([C:22]([C@@H:24]2[CH2:28][C@H:27]([S:29][C:30]3[C@H:31]([CH3:54])[C@@H:32]4[C@@H:49]([C@H:50]([OH:52])[CH3:51])[C:48](=[O:53])[N:33]4[C:34]=3[C:35]([OH:37])=[O:36])[CH2:26][NH:25]2)=[O:23])[CH2:17][CH2:16]1)(=[NH:12])[CH3:14]
Reactant: CC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)N1CCCN(C(=O)[C@@H]2C[C@H](SC3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Solvent: O
Solvent: C1CCOC1
Product: CC(=N)N1CCCN(C(=O)[C@@H]2C[C@H](SC3=C(C(=O)O)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)CN2)CC1
Yield: 33.8 %

Procedure:
144 mg of 4-nitrobenzyl (1R,5S,6S)-2-[(2S,4S)-2-(4-(N-4-nitrobenzyloxycarbonylacetimidoyl)homopiperazin-1-ylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate [prepared as described in step (a) above] were dissolved in 7.5 ml of a 2:1 by volume mixture of tetrahydrofuran and water, and were hydrogenated by bubbling hydrogen through the solution at room temperature for 1.5 hours in the presence of 375 mg of 10% w/w palladium-on-charcoal. At the end of this time, the reaction mixture was worked up and purified by the same procedure as described in Example 1(b), to give 24 mg of the title compound as a powder.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][N:5]=1)([CH3:3])[CH3:2]>CO.[Ni]>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc([N+](=O)[O-])cn1
Agent: [Ni]
Solvent: CO
Product: CC(C)c1ccc(N)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.6 %

Procedure:
2-Isopropyl-5-nitro-pyridine (1.30 g, 7.82 mmol) was dissolved in methyl alcohol (20 mL), and Raney Ni (0.25 g) was added. The mixture was stirred under H2 (1 atm) at room temperature for 2 h. The catalyst was filtered off, and the filtrate was concentrated under vacuum to give 2-isopropyl-5-amino-pyridine (E-9) (0.55 g, 52%). 1H NMR (CDCl3) δ 8.05 (s, 1 H), 6.93-6.99 (m, 2 H), 3.47 (br s, 2 H), 2.92-3.02 (m, 1 H), 1.24-1.26 (m, 6 H). ESI-MS 137.2 m/z (MH+).