Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:6]2[C:7]([O:11][Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1.[Br:23]N1C(=O)CCC1=O.C(Cl)(Cl)(Cl)Cl>C1COCC1>[Br:23][C:10]1[C:5]2[O:4][CH2:3][C:2]([CH3:1])([CH3:22])[C:6]=2[C:7]([O:11][Si:12]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[CH:19]([CH3:21])[CH3:20])=[CH:8][CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)[Si](Oc1cccc2c1C(C)(C)CO2)(C(C)C)C(C)C
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)[Si](Oc1ccc(Br)c2c1C(C)(C)CO2)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.8 %

Procedure:
[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy][tris(1-methylethyl)]silane (Intermediate 181, 7.4 g, 23.19 mmol) was dissolved in THF (70.0 mL). N-Bromosuccinimide (4.2 g, 23.88 mmol) was added dissolving in few minutes. This mixture was stirred at room temperature for 3 hrs. More NBS (0.64 g, 3.48 mmol) was added and the reaction mixture was stirred at room temperature for a further hour. CCl4 (50 mL) was added to the reaction mixture and the solution was evaporated to dryness. The residue was re-suspended in CCl4 and stirred at room temperature for 15 min. The white solid was removed by filtration and the wet cake was washed with more CCl4. The CCl4 was swapped with ethyl acetate and the organic solution was washed three times with 2.5% w/w aqueous NaHCO3 and finally with water. The organic solution was dried on anhydrous Na2SO4 and evaporated to dryness to give the title compound (8.6 g) as a brown oil.
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[C:19]([CH3:21])[C:18]([OH:22])=[C:17]([CH2:23][CH3:24])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:25])[N:5]=1)[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH2:47]1[O:49][C@@H:48]1[CH2:50]O.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH2:26]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[C:19]([CH3:21])[C:18]([O:22][CH2:50][C@@H:48]4[CH2:47][O:49]4)=[C:17]([CH2:23][CH3:24])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:25])[N:5]=1)[CH3:27]
Reactant: OC[C@@H]1CO1
Reactant: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)c3)n2)cc(C)c1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)c3)n2)cc(C)c1OC[C@@H]1CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
To a solution of 4-[5-(2-diethylamino-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenol (110 mg, 0.30 mmol) in THF (9 mL), PPh3 (150 mg, 0.57 mmol) and (R)-glycidol (42 mg, 0.57 mmol) are added. The mixture is cooled to 0° C. before DEAD (248 mg, 0.57 mmol) is added. The mixture stirred for 1 h and is warmed to rt. The solvent is evaporated and the crude product is purified by CC on silica gel eluting with heptane:EA 7:3 to give diethyl-{4-[3-((S)-3-ethyl-5-methyl-4-oxiranylmethoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-6-methyl-pyridin-2-yl}-amine (119 mg) as a yellow oil; LC-MS: tR=0.95 min; [M+1]+=423.21.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[C:6]2=[CH:16][S:17][C:18]([CH3:19])=[C:5]12)=[O:3].[CH3:20][N:21]([CH3:34])[CH2:22][CH2:23][CH2:24][CH:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][NH2:33])[CH2:27][CH2:26]1>C(OC)(C)(C)C>[CH3:34][N:21]([CH3:20])[CH2:22][CH2:23][CH2:24][CH:25]1[CH2:26][CH2:27][N:28]([CH2:31][CH2:32][NH:33][C:2]([N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7](=[O:15])[C:6]3=[CH:16][S:17][C:18]([CH3:19])=[C:5]23)=[O:3])[CH2:29][CH2:30]1
Reactant: CN(C)CCCC1CCN(CCN)CC1
Reactant: Cc1scc2c1N(C(=O)Cl)c1ccccc1NC2=O
Solvent: COC(C)(C)C
Product: Cc1scc2c1N(C(=O)NCCN1CCC(CCCN(C)C)CC1)c1ccccc1NC2=O
Yield: 17 %

Procedure:
Prepared analogously to Example 1 from 4-(chlorocarbonyl)-4,9-dihydro-3-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 2-[4-[3-(dimethylamino)propyl]-piperidin-l-yl]ethanamine in a yield of 17% of theory. Colourless crystals, m.p. >300° C. (t-butylmethyl ether).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[CH:7]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1)[N:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:35](I)[CH3:36].C(=O)(O)[O-].[Na+]>CN(C)C=O.C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:32])[CH:7]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([O:31][CH2:35][CH3:36])=[CH:29][CH:30]=1)[N:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)CN(Cc1ccccc1)C(Cc1ccc(O)cc1)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCOc1ccc(CC(C(=O)OC(C)(C)C)N(CC(=O)OC(C)(C)C)Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
13.2 g (30 mmol) of N-benzyl-2-(4-hydroxybenzyl)-3-azaglutaric acid-di-tert-butyl ester (Example j) is dissolved in 50 ml of anhydrous N,N-dimethylformamide and mixed at 0° C. under argon with 1.31 g (33 mmol) of sodium hydride dispersion (60% in mineral oil). The batch is allowed to stir for 15 minutes, then 8.05 g (51.7 mmol) of ethyl iodide is added, the reaction temperature is allowed to increase to room temperature and it is stirred for another three hours. For working-up, the batch is taken up in toluene and shaken out several times against aqueous sodium bicarbonate solution. The organic phase is separated, dried on magnesium sulfate, filtered and concentrated by evaporation. The oily residue is chromatographed for purification on silica gel with hexane/diethyl ether/triethylamine. The product fractions are concentrated by evaporation in a vacuum and dried.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:20])[CH2:7][CH:8]([CH3:19])[N:9]3[C:14]=2[C:13]=1[C:12](=[O:15])[C:11]([C:16]([OH:18])=[O:17])=[CH:10]3.[C:21](OC(=O)C)(=[O:23])[CH3:22]>>[C:21]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:20])[CH2:7][CH:8]([CH3:19])[N:9]3[C:14]=2[C:13]=1[C:12](=[O:15])[C:11]([C:16]([OH:18])=[O:17])=[CH:10]3)(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: CC1CC(=O)c2ccc(N)c3c(=O)c(C(=O)O)cn1c23
Product: CC(=O)Nc1ccc2c3c1c(=O)c(C(=O)O)cn3C(C)CC2=O

Procedure:
10-amino-6,7-dihydro-5-methyl-1,7-dioxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid (0.02 mole) and acetic anhydride (50 ml.) are stirred and heated on a steam bath for 3 hours. After cooling, the solid precipitate is separated by filtration to give 10-acetamido-6,7-dihydro-5-methyl-1,7-dioxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid. This product is reduced using sodium borohydride to provide 10-acetamido-6,7-dihydro-7-hydroxy-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([NH2:11])[CH:3]=1.[CH3:12][C:13]1[S:17][C:16](B(O)O)=[CH:15][CH:14]=1>>[CH3:12][C:13]1[S:17][C:16]([C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[C:4]([NH2:11])[CH:3]=2)=[CH:15][CH:14]=1
Reactant: Cc1ccc(B(O)O)s1
Reactant: Nc1cc(Cl)n2nccc2n1
Product: Cc1ccc(-c2cc(N)nc3ccnn23)s1

Procedure:
The titled compound was prepared using a procedure analogous to that described in connection with Example 15 except that 7-chloropyrazolo[1,5-a]pyrimidin-5-amine (1E) and 5-methylthiophen-2-ylboronic acid were used as starting materials. 1H NMR (400 MHz, CHLOROFORM-d) δ 2.59 (s, 3H), 4.76 (s, 2H), 6.21 (d, J=1.8 Hz, 1H), 6.44 (s, 1H), 6.89 (d, J=3.5 Hz, 1H), 7.99-8.04 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7](C(OCC)=O)[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19]C(=O)CC)[CH:14]=2)[CH2:5][C:4](=[O:24])[C:3]=1[C:25](=[O:28])[CH2:26][CH3:27].CO.C(Cl)(Cl)Cl>[OH-].[Na+]>[C:25]([C:3]1[C:4](=[O:24])[CH2:5][CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=2)[CH2:7][C:2]=1[OH:1])(=[O:28])[CH2:26][CH3:27]
Reactant: CCOC(=O)C1C(O)=C(C(=O)CC)C(=O)CC1c1cccc(OC(=O)CC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCC(=O)C1=C(O)CC(c2cccc(O)c2)CC1=O
Temperature: 25 °C

Procedure:
A solution of 36.0 g (0.0926 mol) of 3-hydroxy-5-(3-propionyloxyphenyl)-2-propionyl-4-(carboethoxy)cyclohex-2-en-1-one in 520 mL of 1N NaOH was heated at 75° C. for 4 hours and cooled to room temperature. The reaction mixture was filtered and the filtrate was diluted with 100 mL of water and acidified with 50 mL of concentrated HCl with the product precipitating as an oil. The oil was dissolved in a mixture of 300 mL of methylene chloride and 200 mL of ethyl ether. The organic layer was separated, washed twice with 200 mL portions of water and dried over Na2SO4. The solvent was removed in vacuo leaving 20.4 g of a partially crystalline product which was purified by column chromatography using a 20:80 acetone-chloroform mixture as eluent. The fractions containing the product were combined and the solvent removed in vacuo leaving 13.1 g (54.4 percent of theoretical) of the above named product which melted at 124°-131° C.; Rf -0.38 (silica gel, 10:90 methanol:chloroform), 1H NMR (CDCl3 +D6 --DMSO): δ 1.10 (t, 3H, --CH2CH3), 2.5-3.5 (m, 7H, ring protons and --CH2CH3), 6.55-7.25 (m, 3H, ArH), 8.85 (s, H, ArOH), 18.1 (s, 1H, OH).
Reaction SMILES: [CH3:1][O:2][CH:3]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1)[C:4](OC)=[O:5].O.[NH2:19][NH2:20]>>[CH3:1][O:2][CH:3]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1)[C:4]([NH:19][NH2:20])=[O:5]
Reactant: NN
Reactant: COC(=O)C(OC)c1ccc2ccccc2c1
Solvent: O
Product: COC(C(=O)NN)c1ccc2ccccc2c1
Yield: 47 %

Procedure:
A stirred solution of methyl 2-methoxy-2-(naphthalen-2-yl)acetate (0.358 g, 1 eq) and hydrazine hydrate (4 mL) was heated to reflux for 1 hour. The reaction mixture was then cooled and the solvents removed under reduced pressure. The crude oil was diluted with EtOAc and washed with H2O and the organic phase dried over Na2SO4, filtered, and the solvents removed under reduced pressure to yield a yellow oil (0.17 g, 47%) that was used without further purification.
Reaction SMILES: [OH-].[Na+].[C:3]([C:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][C:12]=1[C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:27]([CH:29]1[O:31][CH2:30]1)Cl>>[C:3]([C:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][C:12]=1[C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH:29]2[O:31][CH2:30]2)=[CH:24][CH:25]=1)(=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: ClCC1CO1
Reactant: O=C(c1ccccc1)c1c(-c2ccc(O)cc2)oc2ccccc12
Agent: [Na+]
Agent: [OH-]
Product: O=C(c1ccccc1)c1c(-c2ccc(OCC3CO3)cc2)oc2ccccc12

Procedure:
To a mixture of 1.6 g. (0.04 mol.) of sodium hydroxide and 3.7 g. (0.012 mol.) of 3-benzoyl-2-p-hydroxyphenylbenzofuran was added with stirring 10.2 g. (0.11 mol.) of epichlorohydrin. The reaction mixture was refluxed for 1.5 hours, then it was cooled and extracted with methylene chloride. The extract was dried (MgSO4) and concentrated to give a residue which, after chromatography, gave 3-benzoyl-2-[4'-(2,3-epoxypropoxy)phenyl]benzofuran.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][C@H:27]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH2:26]2)[C:21]([Cl:36])=[CH:20][N:19]=1>>[Cl:36][C:21]1[C:22]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][C@H:27]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH2:26]2)=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Reactant: CS(=O)(=O)N[C@H]1CCC[C@@H](Nc2nc(Cl)ncc2Cl)C1
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(N[C@@H]4CCC[C@H](NS(C)(=O)=O)C4)n3)cc2CC1

Procedure:
rel-N-((1S,3R)-3-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-cyclohexyl)-methanesulfonamide was prepared from 3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and rel-N-[(1S,3R)-3-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide in an analogous manner to Example 308c. Product isolated as a white foam (76 mg, 42%). LCMS (m/e) 523 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 7.91 (s, 1H), 7.42 (d, 1H, J=8.1 Hz), 7.20 (s, 1H), 7.07 (d, 1H, J=8.1 Hz), 6.82 (s, 1H), 5.07 (d, 1H, J=7.6 Hz), 4.18 (d, 1H, J=7.8 Hz), 4.14-4.02 (m, 1H), 3.56 (t, 2H, J=5.7 Hz), 3.53-3.42 (m, 1H), 3.39 (s, 3H), 2.99-2.88 (m, 4H), 2.95 (s, 3H), 2.81-2.67 (m, 6H), 2.58-2.48 (m, 1H), 2.21-2.11 (m, 2H), 2.00-1.89 (m, 1H), 1.56-1.43 (m, 1H), 1.31-1.11 (m, 3H).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:21](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:22][CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:40][S:41]([C:44]1[CH:49]=[CH:48][C:47](B(O)O)=[CH:46][CH:45]=1)(=[O:43])=[O:42].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:21]([C:47]2[CH:48]=[CH:49][C:44]([S:41]([CH3:40])(=[O:43])=[O:42])=[CH:45][CH:46]=2)=[CH:22][CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cnc2c(c1)cc(C(=CC1CCOCC1)OS(=O)(=O)c1ccc(C)cc1)n2S(=O)(=O)c1ccccc1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1cnc2c(c1)cc(C(=CC1CCOCC1)c1ccc(S(C)(=O)=O)cc1)n2S(=O)(=O)c1ccccc1
Yield: 50.4 %

Procedure:
To a mixture of toluene-4-sulfonic acid-1-(1-benzenesulfonyl-5-methoxy-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(tetrahydro-pyran-4-yl)-vinyl ester (1.1 g, 1.94 mmol), 4-(methanesulfonyl)phenylboronic acid (775 mg, 3.88 mmol), dichlorobis(triphenylphosphine)palladium (II) (136 mg, 0.194 mmol) in dioxane (5 mL) was added an aqueous sodium carbonate solution (2 M, 2.5 mL, 5 mmol). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The resulting mixture was diluted with ethyl acetate (250 mL), washed with a saturated aqueous sodium bicarbonate solution (2×50 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 50% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-2-[1-(4-methanesulfonyl-phenyl)-2-(tetrahydro-pyran-4-yl)-vinyl]-5-methoxy-1H-pyrrolo[2,3-b]pyridine (540 mg, 54%) as a light yellow solid: LC/MS m/e calcd for C28H28N2O6S2 [M+H]+ 553.67, observed 553.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([OH:21])[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2.C[O:23][C:24](=[O:47])[C@H:25]([C@@H:44]([CH3:46])O)[NH:26]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([O:21][C@H:44]([CH3:46])[C@@H:25]([C:24]([OH:47])=[O:23])[NH2:26])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=2[C:15]2[C:20]1=[CH:19][CH:18]=[CH:17][CH:16]=2
Reactant: COC(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)[C@@H](C)O
Reactant: OC1(c2ccccc2F)c2ccccc2-c2ccccc21
Product: C[C@@H](OC1(c2ccccc2F)c2ccccc2-c2ccccc21)[C@H](N)C(=O)O

Procedure:
from 9-(2-fluorophenyl)-9H-fluoren-9-ol (Example 3c) and Nα -(9-fluorenylmethoxycarbonyl)-L-threonine methyl ester;
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[S:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:10](O)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].S(Cl)([Cl:28])=O>>[C:1]([N:4]1[CH2:9][CH2:8][C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[S:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:10]([Cl:28])=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)N1CCC(C(=O)O)(c2ccccc2Sc2ccccc2)CC1
Product: CC(=O)N1CCC(C(=O)Cl)(c2ccccc2Sc2ccccc2)CC1

Procedure:
A suspension of 3.4 g of 1-acetyl-4-(2-phenylthiophenyl)piperidine-4-carboxylic acid in 5 ml of freshly distilled thionyl chloride is warmed on a steam bath for 5 minutes to effect a clear solution. Any excess thionyl chloride is removed at 50° C. under reduced pressure. The residue is recrystallized from a benzene-cyclohexane mixture to provide 1-acetyl-4-(2-phenylthiophenyl)piperidine-4-carbonyl chloride.
Reaction SMILES: FC(F)(F)C(O[I:6](OC(=O)C(F)(F)F)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.[C:22]([N:26]1[C:32](=[O:33])C2C=CC=CC=2[NH:29][C:28](=[O:38])[CH2:27]1)([CH3:25])([CH3:24])[CH3:23].II>C(Cl)Cl.C(OCC)(=O)C>[C:22]([N:26]1[C:32](=[O:33])[C:11]2[CH:12]=[C:7]([I:6])[CH:8]=[CH:9][C:10]=2[NH:29][C:28](=[O:38])[CH2:27]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Reactant: CC(C)(C)N1CC(=O)Nc2ccccc2C1=O
Agent: II
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)N1CC(=O)Nc2ccc(I)cc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.4 %

Procedure:
Bis(trifluoroacetoxy)phenyl iodine (2.05 g, 4.7 mmol) is added to a solution of 4-tert-butyl-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione (1.0 g, 4.3 mmol) and iodine (1.1 g, 4.3 mmol) in methylene chloride. The reaction mixture is stirred overnight at room temperature, diluted with ethyl acetate, washed sequentially with saturated sodium hydrogen carbonate solution, 1N sodium thiosulfate solution and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a residue. Chromatography of the residue using silica gel and 20% to 25% ethyl acetate in hexanes solutions gives the title product as a beige solid (0.9 g, mp 230°-232° C.).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[N:3][C:2]([Cl:1])=[N:7][C:6]=3[CH:8]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1

Procedure:
Prepared using the standard reductive amination conditions with 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde and tert-butyl-1-piperazinecarboxylate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4](=[CH:9][NH:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([NH:21][C:22](=[O:28])[CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[CH:19]=2)[N:14]=[CH:13][N:12]=1)[C:5](OC)=[O:6].C1(OC2C=CC=CC=2)C=CC=CC=1>CCCCCC>[O:6]=[C:5]1[N:12]2[CH:13]=[N:14][C:15]3[CH:16]=[CH:17][C:18]([NH:21][C:22](=[O:28])[CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[CH:19][C:20]=3[C:11]2=[N:10][CH:9]=[C:4]1[C:3]([O:2][CH3:1])=[O:29]
Reactant: CCC(CC)C(=O)Nc1ccc2ncnc(NC=C(C(=O)OC)C(=O)OC)c2c1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Product: CCC(CC)C(=O)Nc1ccc2ncn3c(=O)c(C(=O)OC)cnc3c2c1
Temperature: 255 °C
Yield: 78.1 %

Procedure:
A mixture of dimethyl[[6-(2-ethylbutyramido)-4-quinazolinylamino]methylene]propanedioate (5.3 g) and diphenyl ether (32 ml) was heated at 255° C. for 15 minutes and cooled to ambient temperature. Hexane was added to the reaction mixture. The resulting crystals were filtered off, washed with hexane and dried. The crude crystals were dissolved in a mixture of chloroform and methanol (10:1) under heating. Insoluble materials were removed by filtration. The filtrate was concentrated under reduced pressure to give crystals, which were recrystallized from a mixture of chloroform and hexane to give methyl 4-oxo-10-(2-ethylbutyramido)-4H-pyrimido[1,2-C]quinazoline-3-carboxylate (3.81 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]3[CH2:22][CH2:23][NH:24][CH2:25][CH:26]=3)[CH:19]=2)[NH:14][CH:13]=1)[CH3:11].[S:27](N)([NH2:30])(=[O:29])=[O:28]>O1CCOCC1>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]3[CH2:22][CH2:23][N:24]([S:27]([NH2:30])(=[O:29])=[O:28])[CH2:25][CH:26]=3)[CH:19]=2)[NH:14][CH:13]=1)[CH3:11]
Reactant: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(C3=CCNCC3)cc12
Reactant: NS(N)(=O)=O
Solvent: C1COCCO1
Product: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(C3=CCN(S(N)(=O)=O)CC3)cc12
Temperature: 90 °C

Procedure:
A mixture of 3-[1-(2,6-dichloro-3-fluorophenyl)ethyl]-5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine (10.0 mg, 0.0256 mmol), sulfamide (4.92 mg, 0.0512 mmol) and dioxane (2 mL) was heated to 90° C. for 16 h in a sealed tube. The solution was concentrated in vacuo, redissolved in MeOH and purified via HPLC. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.87 (d, J=7.1 Hz, 3 H), 2.40-2.60 (m, 2 H), 3.32-3.35 (m, 2 H), 3.77 (q, J=2.6 Hz, 2 H), 5.26 (q, J=7.1 Hz, 1 H), 5.90-5.96 (m, 1 H), 7.19 (t, J=8.6 Hz, 1 H), 7.29 (s, 1 H), 7.37 (d, J=1.5 Hz, 1 H), 7.42 (br. s., 1 H), 8.28 (br. s., 1 H). MS (ES+): m/z 469.00 (100) [MH+]. HPLC: tR=3.42 min (ZQ3, polar—5 min).
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]([NH2:12])[S:10][CH:11]=2)=[CH:3][CH:2]=1.[CH3:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1.C(N(CC)CC)C>O1CCOCC1>[CH3:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:12][C:9]2[S:10][CH:11]=[C:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:13])=[CH:6][CH:5]=3)[N:8]=2)=[O:20])=[CH:17][CH:16]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: Cc1ccc(-c2csc(N)n2)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)Nc2nc(-c3ccc(C)cc3)cs2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-p-Tolyl-thiazol-2-ylamine (38.1 mg, 0.200 mmol) and 4-methyl-benzoyl chloride (30.9 mg, 0.200 mmol) were dissolved in 1,4-dioxane (2 mL) containing triethylamine (84.1 μL, 0.600 mmol). The reaction mixture was stirred overnight at room temperature. The crude product was filtered, evaporated to dryness, dissolved in 1 mL of dimethylsulfoxide and purified by reverse-phase preparative liquid chromatography (13.5 mg, 0.0438, 21.9%). ESI-MS m/z calc. 308.1, found 309.0 (M+1)+ Retention time 3.72 minutes.
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][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][CH3:18].O.C([O-])(=O)C.[Cu+2:26].C([O-])(=O)C>C(O)C>[C:1]([O-:20])(=[O:19])[CH2:2][CH2:3][CH2:4][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][CH3:18].[Cu+2:26].[C:1]([O-:20])(=[O:19])[CH2:2][CH2:3][CH2:4][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][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCC(=O)[O-]
Reaction time: 3 h

Procedure:
14.2 g of stearic acid was added to 200 ml of an ethanol solution and sufficiently stirred at 60° C. until the stearic acid was completely dissolved. 5.0 g of copper acetate-monohydrate was dissolved in 200 ml of ethanol solution. Then, the two solutions were mixed and stirred for 3 hours. White powder on the surface of the result was collected and washed three times each with distilled water and with methanol to obtain copper stearate. An anode active material was prepared as in Example 1, except that copper stearate was used, the molar ratio of copper to silicon was 0.2:1, the weight ratio of silicon to graphite was 0.5:1, and the carbon layer was 6.3 wt % of the anode active material.