Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[S:16]([CH3:18])=[O:17])[N:9]3[CH2:19][CH2:20][CH2:21][CH:22]([CH2:23][C:24]([O:26]CC)=[O:25])[C:8]=23)=[CH:4][CH:3]=1.C1COCC1.CO.[Li+].[OH-]>CC(O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[S:16]([CH3:18])=[O:17])[N:9]3[CH2:19][CH2:20][CH2:21][CH:22]([CH2:23][C:24]([OH:26])=[O:25])[C:8]=23)=[CH:29][CH:30]=1
Reactant: CCOC(=O)CC1CCCn2c1c(Cc1ccc(Cl)cc1)c1c(S(C)=O)cccc12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CS(=O)c1cccc2c1c(Cc1ccc(Cl)cc1)c1n2CCCC1CC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.4 %

Procedure:
To a solution of the ester of Step 13 (70 mg) in a THF/MeOH (3:1) mixture at r.t. was added 1N LiOH (aqueous solution). The reaction mixture was stirred at r.t. for 2 h and AcOH was added. The aqueous layer was extracted with EtOAc and the combined organic layers were dried over Na2SO4 and concentrated. The residue was swished in EtOAc/MeOH to give 35 mg of the desired acid as a white solid.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([OH:5])[CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[C:12](Cl)(=[O:21])[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1.O>[OH:5][CH:3]1[CH2:4][N:1]([C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:21])[CH2:2]1
Reactant: OC1CNC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(OCc1ccccc1)N1CC(O)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.8 %

Procedure:
A solution of azetidin-3-ol (14.7 g) dissolved in THF (170 mL) and water (85 mL) was treated with potassium carbonate (37.1 g) under nitrogen. The mixture was stirred at RT for 30 minutes before cooling to 0° C. and adding benzyl carbonochloridate (20.0 mL) dropwise over 30 minutes at 0° C. The resulting mixture was stirred at 20° C. for 60 hours. The reaction mixture was diluted with water (150 mL), and extracted with ethyl acetate (200 mL). The organic was dried over magnesium sulfate, filtered and evaporated to afford crude product as a colourless oil. The crude product was purified by flash silica chromatography, elution 50% ethyl acetate in isohexane to 100% ethyl acetate. Pure fractions were evaporated to dryness to afford the sub-title product (19.40 g, 69.8%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=1)[N:7]=[C:6]2[CH2:25][C:26](O)=[O:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:48][C:49]1[C:50]([CH3:61])=[C:51]([N:55]2[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]2)[CH:52]=[CH:53][CH:54]=1>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=1)[N:7]=[C:6]2[CH2:25][C:26]([N:58]1[CH2:59][CH2:60][N:55]([C:51]2[CH:52]=[CH:53][CH:54]=[C:49]([Cl:48])[C:50]=2[CH3:61])[CH2:56][CH2:57]1)=[O:27]
Reactant: Cc1c(Cl)cccc1N1CCNCC1
Reactant: COc1ccc(Cn2nc(CC(=O)O)c3cc(OC)c(OC)cc32)cc1OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(Cn2nc(CC(=O)N3CCN(c4cccc(Cl)c4C)CC3)c3cc(OC)c(OC)cc32)cc1OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 100.1 %

Procedure:
5,6-dimethoxy-1-(3,4-dimethoxybenzyl)-1H-indazole-3-acetic acid (41.0 g) was suspended in dichloromethane (500 ml). Then 2,2-dipyridyl disulfide (24.5 g) and triphenylphosphine (30.0 g) were added thereto and the mixture was stirred at room temperature. Next, (3-chloro-2-methyl-phenyl)piperazine (23.5 g) dissolved in dichloromethane (200 ml) was dropped thereinto within 5 minutes and the mixture was stirred at room temperature for 30 minutes. Then dichloromethane (1000 ml) was added to the reaction mixture. After washing with water, the organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue thus obtained was purified by using a silica gel column (ethyl acetate/hexane=2/1, silica gel 2 kg) to give 61.5 g of a colorless solid. This solid product was used in the subsequent reaction without purification. A small amount of this product was taken and recrystallized from ethanol. Thus colorless prism crystals (m.p.: 165°-169° C.) were obtained.
Reaction SMILES: CN(C)C1C=CC(CN[C:9](=[O:18])[NH:10][CH2:11][CH2:12][CH2:13][C:14]([NH:16][OH:17])=[O:15])=CC=1.[NH2:22][CH2:23][CH:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[OH:25]>>[OH:17][NH:16][C:14](=[O:15])[CH2:13][CH2:12][CH2:11][NH:10][C:9]([NH:22][CH2:23][CH:24]([OH:25])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:18]
Reactant: CN(C)c1ccc(CNC(=O)NCCCC(=O)NO)cc1
Reactant: NCC(O)c1ccccc1
Product: O=C(CCCNC(=O)NCC(O)c1ccccc1)NO

Procedure:
Compound 15 was prepared using the methodology described for the preparation of compound 2, by substituting 4-dimethylaminobenzylamine dihydrochloride with 2-amino-1-phenyl-ethanol. 1H NMR (CD3OD) δ 7.42-7.24 (m, 5H), 4.73 (dd, J=7.8, 4.2 Hz, 1H), 3.43 (dd, J=13.8, 4.2 Hz, 1H), 3.26 (dd, J=13.8, 7.8 Hz, 1H), 3.14 (t, J=6.9 Hz, 2H), 2.12 (t, J=7.2 Hz, 2H), 1.76 (m, 2H). 13C NMR (CD3OD) δ 172.7, 161.5, 144.2, 129.5, 128.7, 127.3, 74.6, 48.1, 39.4, 30.6, 27.0.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:13](=[O:15])[N:12]([CH3:16])[C:11](=[O:17])[N:10]([CH:18]([CH3:20])[CH3:19])[C:9]=2[S:8][CH:7]=1)=[O:5])[CH3:2].[CH3:21][C:22]1[C:26]([CH:27]=[O:28])=[C:25]([CH3:29])[S:24][N:23]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:13](=[O:15])[N:12]([CH3:16])[C:11](=[O:17])[N:10]([CH:18]([CH3:19])[CH3:20])[C:9]=2[S:8][C:7]=1[CH:27]([C:26]1[C:22]([CH3:21])=[N:23][S:24][C:25]=1[CH3:29])[OH:28])=[O:5])[CH3:2]
Reactant: Cc1nsc(C)c1C=O
Reactant: CCOC(=O)c1csc2c1c(=O)n(C)c(=O)n2C(C)C
Product: CCOC(=O)c1c(C(O)c2c(C)nsc2C)sc2c1c(=O)n(C)c(=O)n2C(C)C

Procedure:
Prepared by the method of example 15 part a) using 1,2,3,4-tetrahydro-3-methyl-1-(1-methylethyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylic acid ethyl ester, and 3,5-dimethyl-4-isothiazolecarboxaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH:11]3[CH2:16][CH2:15][N:14](C(OCC)=O)[CH2:13][CH2:12]3)[C:7](=[O:10])[N:8]([CH3:9])[C:4]=2[CH:3]=1.[OH-].[K+].CC(O)C>O>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]3)[C:7](=[O:10])[N:8]([CH3:9])[C:4]=2[CH:3]=1
Reactant: CCOC(=O)N1CCC(n2c(=O)n(C)c3cc(Cl)ccc32)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: Cn1c(=O)n(C2CCNCC2)c2ccc(Cl)cc21

Procedure:
A mixture of 12.8 parts of ethyl 4-(5-chloro-1,3-dihydro-3-methyl-2-oxo-2H-benzimidazol-1-yl)-1-piperidinecarboxylate, 20 parts of potassium hydroxide, 128 parts of 2-propanol and 2.5 parts of water is stirred and refluxed overnight. The reaction mixture is cooled and evaporated. Water is added to the residue and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is triturated in 2,2'-oxybispropane. The product is filtered off and dried, yielding 5-chloro-1,3-dihydro-3-methyl-1-(4-piperidinyl)-2H-benzimidazol-2-one; mp. 200.9° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH3:22])[C:7]([CH:19]([CH3:21])[CH3:20])=[C:8]([N+:16]([O-:18])=[O:17])[C:9]=1[NH:10]C(CC)CC)([O-:3])=[O:2].S(=O)(=O)(O)O>O>[N+:1]([C:4]1[CH:5]=[C:6]([CH3:22])[C:7]([CH:19]([CH3:20])[CH3:21])=[C:8]([N+:16]([O-:18])=[O:17])[C:9]=1[NH2:10])([O-:3])=[O:2]
Reactant: CCC(CC)Nc1c([N+](=O)[O-])cc(C)c(C(C)C)c1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1cc([N+](=O)[O-])c(N)c([N+](=O)[O-])c1C(C)C

Procedure:
A mixture of 4,6-dinitro-N-(1-ethylpropyl)-o-cymen-5-amine (55 g, 0.18 mole) aqueous sulfuric acid (from conc. sulfuric acid (680 ml.) and water (680 ml.) are stirred and heated at 70°-75° C. for several hrs. The mixture is then diluted with ice and water and extracted with chloroform to give 37.7 g. of crude 4,6-dinitro-o-cymen-5-amine, a liquid which crystallized, and which was determined to be 83 area % pure by glc analysis.
Reaction SMILES: [CH3:1][C:2]#[N:3].[Li]CCCC.[O:9]1[CH2:14][CH2:13][CH:12]([CH2:15][O:16][C:17]2[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=2)[C:20](OC)=[O:21])[CH2:11][CH2:10]1>C1COCC1>[O:21]=[C:20]([C:19]1[CH:24]=[CH:25][CH:26]=[C:17]([O:16][CH2:15][CH:12]2[CH2:11][CH2:10][O:9][CH2:14][CH2:13]2)[CH:18]=1)[CH2:1][C:2]#[N:3]
Reactant: COC(=O)c1cccc(OCC2CCOCC2)c1
Reactant: CC#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#CCC(=O)c1cccc(OCC2CCOCC2)c1
Reaction time: 0.5 h

Procedure:
The solution of CH3CN (0.37 g, 8.9 mmol) in THF (40 mL) was added to n-BuLi (1.6 M in hexanes, 0.58 g, 8.9 mmol) at −78° C. and the reaction mixture was stirred for 30 min. Solution of ester (12) (1.5 g, 5.9 mmol) in THF (10 mL) was added to the reaction mixture and the resulting solution was further stirred for 30 min. The reaction mixture was quenched by addition of aq.NH4Cl (200 mL) and extracted with EtOAc (100 mL). Drying over anhydrous Na2SO4 and concentration under reduced pressure gave 3-oxo-3-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)propanenitrile (13). Yield (1.5 g, 96%); 1H NMR (400 MHz, DMSO-d6) δ 7.43-7.37 (m, 3H), 7.26-7.21 (m, 1H), 4.75 (bs, 2H), 3.89-3.83 (m, 4H), 3.32 (t, J=11.6 Hz, 2H), 2.03-1.98 (m, 1H), 1.69-1.66 (m, 2H), 1.38-1.28 (m, 2H).
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([CH2:9][C:10]([OH:12])=O)[N:8]=1)=[O:2].N1C(C)=CC=CC=1C.C(Cl)(=O)C(C)(C)C.[NH2:28][CH:29]1[C:64](=[O:65])[N:31]2[C:32]([C:48]([O:50][CH:51]([C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)[C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)=[O:49])=[C:33]([CH2:37][O:38][C:39]([N:41]3[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]3)=[O:40])[CH2:34][S:35](=[O:36])[C@H:30]12>C(Cl)Cl.C(N(CC)CC)C>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([CH2:9][C:10]([NH:28][CH:29]2[C:64](=[O:65])[N:31]3[C:32]([C:48]([O:50][CH:51]([C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=4)[C:52]4[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=4)=[O:49])=[C:33]([CH2:37][O:38][C:39]([N:41]4[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]4)=[O:40])[CH2:34][S:35](=[O:36])[C@H:30]23)=[O:12])[N:8]=1)=[O:2]
Reactant: CN1CCN(C(=O)OCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N)[C@H]3S(=O)C2)CC1
Reactant: O=CNc1nc(CC(=O)O)cs1
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CN1CCN(C(=O)OCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)Cc4csc(NC=O)n4)[C@H]3S(=O)C2)CC1
Temperature: 22 °C
Reaction time: 0.67 h
Yield: 78.4 %

Procedure:
A mixture of 2-(2-formamidothiazol-4-yl)acetic acid (0.70 g), 2,6-lutidine (0.44 ml), triethylamine (0.05 ml) and pivaloyl chloride (457 mg) in dry methylene chloride (10 ml) was stirred at -15° C. for 20 minutes, at 12° C. for 20 minutes and at 22° C. for a further 40 minutes. A mixture of benzhydryl 7-amino-3-(4-methyl-1-piperazinyl)carbonyloxymethyl-3-cephem-4-carboxylate-1-oxide (1.7 g) in methylene chloride (20 ml) was cooled to -30° C. and thereto was added the acid anhydride solution obtained above followed by stirring at -20° to -10° C. for an hour and at -10° C. to ambient temperature for a further one hour. The reaction mixture was evaporated and to the residue was added ethyl acetate (20 ml) and water (10 ml) followed by stirring. Insoluble substances were collected by filtration, washed with water and ethyl acetate and then dried under reduced pressure to give benzhydryl 7-[2-(2-formamidothiazol-4-yl)acetamido]-3-(4-methyl-1-piperazinyl)carbonyloxymethyl-3-cephem-4-carboxylate-1-oxide (1.75 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][C@@H:6]([C:25]1[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=1)[CH:7]=[CH:8][CH2:9][N:10]1[C@H:14]([CH3:15])[CH2:13][C@H:12]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:11]1=[O:24])[CH3:2]>CO.C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:33])[CH2:5][C@@H:6]([C:25]1[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=1)[CH2:7][CH2:8][CH2:9][N:10]1[C@H:14]([CH3:15])[CH2:13][C@H:12]([NH:16][C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[C:11]1=[O:24])[CH3:2]
Reactant: CCOC(=O)C[C@H](C=CCN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C[C@H]1C)c1ccc(OC)nc1
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: CCOC(=O)C[C@H](CCCN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C[C@H]1C)c1ccc(OC)nc1
Reaction time: 1.5 h

Procedure:
To stirred solution of 4-6 (250 mg) in methanol (15 mL) was added a suspension of 10% Pd on carbon (90 mg) in ethanol (2 mL). The resulting suspension was stirred under an atmosphere of hydrogen for 1.5 hours. The mixture was filtered through Celite. The solvent was evaporated to give 4-7 as a colorless oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:4])=[O:3].C([Li])CCC.CN1CCCN(C)C1=O.[C:25](OC)(=[O:29])/[CH:26]=[CH:27]/[CH3:28].[H-].C([Al+]CC(C)C)C(C)C.ClCCl>O1CCCC1.C(=O)([O-])[O-].[NH4+].[NH4+]>[C:5]1([S:2]([CH2:1][CH:27]([CH3:28])[CH2:26][CH2:25][OH:29])(=[O:4])=[O:3])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CS(=O)(=O)c1ccccc1
Reactant: C/C=C/C(=O)OC
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])[O-]
Agent: [H-]
Solvent: CN1CCCN(C)C1=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(CCO)CS(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A solution of methanesulphonylbenzene (2.17 g, 13.9 mmol) in tetrahydrofuran (10 ml) was cooled to −78° C. and treated with butyllithium (1.6M in hexanes, 8.7 ml, 13.9 mmol) followed by 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1.68 ml, 13.9 mmol). The reaction was stirred at −78° C. for 15 minutes then methyl crotonate (7.36 ml, 69.5 mmol) added. The reaction was allowed to warm to room temperature and quenched with water. The mixture was extracted with ethyl acetate and the combined organic layers dried (MgSO4)and concentrated in vacuo. The residue was dissolved in dichloromethane (10 ml) and cooled to −5° C. A solution of diisobutylaluminium hydride in dichloromethane (1M, 27.8 ml, 27.8 mmol) was added and the reaction allowed to warm to room temperature. The mixture was diluted with aqueous ammonium carbonate solution and extracted with ethyl acetate. The combined organic layers were dried (MgSO4) and concentrated in vacuo. A portion of the residue was purified by preparative thin layer chromatography, eluting with 5% methanol/dichloromethane, to give the title compound.
Reaction SMILES: [Li].[CH3:2][C:3]1([CH3:18])[CH:8]=[C:7]([CH3:9])[CH2:6][C:5]([CH3:11])([CH3:10])[CH:4]1[C:12]([CH3:17])=[CH:13][C:14](=[O:16])[CH3:15].N.[Cl-].[NH4+]>C(O)C.CCOCC>[CH3:15][CH:14]([OH:16])[CH2:13][CH:12]([CH3:17])[CH:4]1[C:5]([CH3:11])([CH3:10])[CH2:6][C:7]([CH3:9])=[CH:8][C:3]1([CH3:18])[CH3:2]
Reactant: CC(=O)C=C(C)C1C(C)(C)C=C(C)CC1(C)C
Agent: N
Agent: [Cl-]
Agent: [Li]
Solvent: CCO
Solvent: CCOCC
Product: CC1=CC(C)(C)C(C(C)CC(C)O)C(C)(C)C1
Yield: 77.5 %

Procedure:
Lithium shot (0.5 g, 0.071 mol) was added portionwise over a 40 min. period to a cold (-30° to -40° C.) mixture of 4-(2,2,4,6,6-pentamethyl-3-cyclohexen-1-yl)-3-penten-2-one (1.08 g, 0.0046 mol), ether (20 mL), ethanol (20 mL) and ammonia (80 mL). Ammonium chloride (8.0 g) was added to the blue colored reaction mixture. The ammonia was allowed to evaporate. Ether (100 mL) and water (200 mL) were added to the residue. The aqueous layer was extracted with ether (100 mL). The combined organic extracts were washed with 0.5N HCl (2×100 mL), saturated sodium bicarbonate solution (100 mL) and dried. Evaporation of solvents, chromatography of the residue and kugelrohr distillation provided 0.850 g (78% yield) of α,γ,2,2,4,6,6-heptamethyl-3-cyclohexene-1-propanol. GLC analysis shows 4 isomers of 4.1%, 12.8% and 82.3% (two peaks incompletely resolved). 1H-NMR (60 MHz, CDCl3) δ0.98 and 1.05 (12H, 2s), 1.12 (3H, d, J=6 Hz), 1.25 (3H, d, J=4 Hz), 1.60 (3H, s), 1.0-2.5 (7H, m), 3.6-4.1 (1H, m), 5.00 (1H, broad s). IR (film) vmax 3320, 2950, 1640, 1470, 1450, 1380, 1360 cm-1 ; Ms m/e 238, 223, 180, 151, 109, 96.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:23][CH2:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1>C(O)CCC>[NH2:29][C:28]1[CH:30]=[CH:31][C:25]([CH2:24][NH:23][C:2]2[C:3]3[C:10]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[C:9]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[O:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:26][CH:27]=1
Reactant: Clc1ncnc2oc(-c3ccccc3)c(-c3ccccc3)c12
Reactant: NCc1ccc(N)cc1
Solvent: CCCCO
Product: Nc1ccc(CNc2ncnc3oc(-c4ccccc4)c(-c4ccccc4)c23)cc1
Yield: 70.3 %

Procedure:
4-Chloro-5,6-diphenylfuro[2,3-d]pyrimidine (0.10 g) and 4-(aminomethyl)aniline (0.05 g) in n-butanol (5 mL) were heated at 80° C. for 16 h. The reaction mixture was concentrated and the residue was partitioned between water and ethyl acetate. The organic layer was concentrated and the residue was purified by silica gel column chromatography using a mixture of dichloromethane:methanol (40:1), to give N-(4-aminobenzyl)-5,6-diphenylfuro[2,3-d]pyrimidin-4-amine (0.09 g, 70%). 1H NMR (300 MHz, CDCl3): δ 8.44 (s, 1H), 7.54-7.44 (m, 8H), 7.27-7.25 (m, 2H), 6.93 (d, 2H), 6.10 (d, 2H), 4.87 (t, 1H), 4.51 (d, 2H), 3.65 (brs, 2H). LC-MS (ESI) m/z 393.7 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[N:5]([CH3:13])[C:3]1=[O:4].C(=O)([O-])[O-].[K+].[K+].[Cl:20][C:21]1[CH:36]=[CH:35][C:24]([C:25]([C:27]2[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=2)=[O:26])=[CH:23][N:22]=1>CN(C=O)C.O>[Cl:20][C:21]1[CH:36]=[CH:35][C:24]([C:25]([C:27]2[CH:34]=[CH:33][C:30]([CH2:31][N:9]3[C:10]4[C:11](=[O:12])[N:2]([CH3:1])[C:3](=[O:4])[N:5]([CH3:13])[C:6]=4[N:7]=[CH:8]3)=[CH:29][CH:28]=2)=[O:26])=[CH:23][N:22]=1
Reactant: O=C(c1ccc(CBr)cc1)c1ccc(Cl)nc1
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)c2c(ncn2Cc2ccc(C(=O)c3ccc(Cl)nc3)cc2)n(C)c1=O
Yield: 96.4 %

Procedure:
A solution of 1,3-dimethylxanthine (712 mg), potassium carbonate (578 mg) and 4-(6-chloronicotinoyl)benzyl bromide (1515 mg) in DMF (10 ml) was stirred at 60° C. for 5 hours. This reaction mixture was poured in water and extracted with ethyl acetate. The extract was washed with water, dried, and. concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate =1:3) and recrystallized from chloroform-isopropyl ether to provide the title compound as colorless solid (1562 mg).
Reaction SMILES: [CH2:1]([Si:3]([C:8]#[CH:9])([CH2:6]C)[CH2:4]C)C.[Li]CCCC.CCCCCC.CON(C)[C:24]([CH:26]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:25]>C1COCC1>[CH:26]1([C:24](=[O:25])[C:9]#[C:8][Si:3]([CH3:1])([CH3:4])[CH3:6])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: C#C[Si](CC)(CC)CC
Reactant: CON(C)C(=O)C1CCCCCC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#CC(=O)C1CCCCCC1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a solution of triethylsilylacetylene (4.78 ml, 14 mmol) in THF (10 ml) at −78° C. was added dropwise a solution of BuLi in hexane (8 ml, 13 mmol). After 30 minutes, the mixture was warmed to −10° C. and a solution of N-methoxy-N-methylcycloheptanecarboxamide (2 g, 10.8 mmol) in THF (10 ml) was added. The mixture was stirred for 30 minutes at −10° C., quenched by addition of aqueous saturated ammonium chloride, allowed to warm up to room temperature and diluted with ether. The layers were separated and the aqueous phase was extracted with ether. Combined organic layers were washed with brine, dried over Na2SO4 and concentrated. After purification by chromatography on silica gel (hexane/CH2Cl2 90/10), the 1-cycloheptyl-3-(trimethylsilyl)-2-propyn-1-one 28 was obtained as a colorless liquid (1.74 g, 72%).
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[Cl:16][C:17]1[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=1[F:24].[C:25]([O:44][CH2:45][C@@H:46]1[C@@H:53]2[C:49](=[N:50][O:51][CH2:52]2)[CH2:48][O:47]1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[Cl:16][C:17]1[C:22]([F:23])=[C:21]([C@:49]23[CH2:48][O:47][C@H:46]([CH2:45][O:44][C:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C@H:53]2[CH2:52][O:51][NH:50]3)[CH:20]=[CH:19][C:18]=1[F:24]
Reactant: c1ccc(C(OC[C@H]2OCC3=NOC[C@@H]32)(c2ccccc2)c2ccccc2)cc1
Reactant: Fc1cccc(F)c1Cl
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Fc1ccc([C@]23CO[C@H](COC(c4ccccc4)(c4ccccc4)c4ccccc4)[C@H]2CON3)c(F)c1Cl
Temperature: -78 °C
Reaction time: 1 h
Yield: 34.3 %

Procedure:
A stirred solution of 2,2,6,6-tetramethylpiperidine (1.31 mL, 7.78 mmol) in dry THF (20 mL) under nitrogen was cooled in an acetone/dry ice cooling bath. n-Butyl lithium (2.5 M in hexanes, 3.11 mL, 7.78 mmol) was added to this solution such that the internal temperature remained below −75° C. The pale yellow solution was stirred at this temperature for 15 minutes before the addition of a solution of 2-chloro-1,3-difluoro-benzene (0.86 mL, 7.78 mmol) in dry THF (2 mL). The solution was stirred for an additional 30 minutes at −78° C. before the addition of a solution of (3aR,4S)-4-((trityloxy)methyl)-3,3a,4,6-tetrahydrofuro[3,4-c]isoxazole (1.5 g, 3.89 mmol) in dry THF (12 mL). The reaction was stirred at −78° C. After 60 min, the reaction was quenched with saturated aqueous ammonium chloride and then removed from the cooling bath. The mixture was partitioned between EtOAc and water and the layers were separated. The aqueous layer was extracted with EtOAc (3×). The combined organic extracts were washed with brine (1×), then dried over (Na2SO4), filtered and evaporated. The residue was purified by column chromatography (normal phase, 50 g, Biotage SNAP cartridge KP-Sil, 50 mL per min, gradient 5% to 20% to 30% EtOAc in n-hexane) to give the title compound (712 mg). 1H NMR (400 MHz, CDCl3) δ ppm: 3.23-3.35 (m, 2 H) 3.47 (dd, J=9.84, 6.42 Hz, 1 H) 3.86 (dd, J=8.31, 3.79 Hz, 1 H) 3.91 (dd, J=10.33, 1.90 Hz, 1 H) 4.08-4.20 (m, 2 H) 4.22-4.33 (m, 1 H) 6.92-7.00 (m, 1 H) 7.20-7.36 (m, 9 H) 7.41-7.48 (m, 6 H) 7.57-7.67 (m, 1 H).
Reaction SMILES: [NH2:1][CH:2]([C:6]([NH2:8])=[O:7])[C:3]([NH2:5])=[O:4].[C:9](OCC)(OCC)(OCC)[CH2:10][CH3:11].S(=O)(=O)(O)O>C(O)C>[CH2:10]([C:11]1[NH:8][C:6]([OH:7])=[C:2]([C:3]([NH2:5])=[O:4])[N:1]=1)[CH3:9]
Reactant: CCOC(CC)(OCC)OCC
Reactant: NC(=O)C(N)C(N)=O
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CCc1nc(C(N)=O)c(O)[nH]1
Yield: 63.7 %

Procedure:
To a suspension of aminomalonamide (7.13 g) in anhydrous ethanol (240 ml) were added triethyl orthopropionate (42.93 g) and concentrated sulfuric acid (1.6 g). The reaction mixture was refluxed for 2 hours and then ice-cooled. The precipitate product was filtered and washed with ethanol, isopropylether to give 2-ethyl-5-hydroxy-1H-imidazole-4-carboxamide (6.02 g).