Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:63])[C@@H:24]([NH:25][C:26](=[O:62])/[C:27](/[C:49]4[N:50]=[C:51]([NH:54]C(OC(C)(C)C)=O)[S:52][CH:53]=4)=[N:28]\[O:29]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C@H:21]3[S:20][CH2:19][C:18]=2[S:64][CH2:65][S:66][C:67]2[N:68]=[N:69][N:70]([CH3:72])[N:71]=2)=[O:16])C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C1(OC)C=CC=CC=1.[N+](C)([O-])=O.O>[NH2:54][C:51]1[S:52][CH:53]=[C:49](/[C:27](=[N:28]/[OH:29])/[C:26]([NH:25][C@@H:24]2[C:23](=[O:63])[N:22]3[C:17]([C:15]([OH:16])=[O:14])=[C:18]([S:64][CH2:65][S:66][C:67]4[N:68]=[N:69][N:70]([CH3:72])[N:71]=4)[CH2:19][S:20][C@H:21]23)=[O:62])[N:50]=1
Reactant: Cn1nnc(SCSC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)/C(=N\OC(c4ccccc4)(c4ccccc4)c4ccccc4)c4csc(NC(=O)OC(C)(C)C)n4)[C@H]3SC2)n1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: COc1ccccc1
Solvent: C[N+](=O)[O-]
Product: Cn1nnc(SCSC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)/C(=N\O)c4csc(N)n4)[C@H]3SC2)n1
Reaction time: 1 h
Yield: 78.6 %

Procedure:
To a solution of 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetylamino]-3-(2-methyltetrazol-5-ylthiomethylthio)-3-cephem-4-carboxylic acid diphenylmethyl ester (1.16 g: 1.12 mMol.) in a mixture of anisole (4 ml) and nitromethane (16 ml) at -40° C. is added a solution of aluminum chloride (1.19 g: 8.95 mMol.) in anisole (4 ml), and the mixture is stirred at -30° to -40° C. for 1 hour. The reaction mixture is mixed with 1N-hydrochloric acid (9 ml), diluted with water, washed with ethyl acetate, concentrated to remove the remaining organic solvents, and passed through a column of styrene-divinylbenzene copolymer adsorbent. The adsorbed material is eluted with water-methanol (1:4) and concentrated to give powder which is washed with ethyl acetate to give 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-(2-methyltetrazol-5-ylthiomethylthio)-3-cephem-4-carboxylic acid (466 mg) as yellow powder. Yield: 79%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][C:10]2[CH:33]=[CH:32][C:13]([C:14]([NH:16][CH2:17][C@H:18]([NH:22][S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:19]([OH:21])=[O:20])=[O:15])=[CH:12][CH:11]=2)[N:3]=1.[OH-].[Na+]>O.[Pd]>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][C:10]2[CH:33]=[CH:32][C:13]([C:14]([NH:16][CH2:17][C@H:18]([NH:22][S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:19]([OH:21])=[O:20])=[O:15])=[CH:12][CH:11]=2)[N:3]=1
Reactant: Nc1cccc(C#Cc2ccc(C(=O)NC[C@H](NS(=O)(=O)c3ccccc3)C(=O)O)cc2)n1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1cccc(CCc2ccc(C(=O)NC[C@H](NS(=O)(=O)c3ccccc3)C(=O)O)cc2)n1

Procedure:
Alkyne 29-6 (60 mg, 0.13 mmol), was suspended in 1.3 mL H2O, 1 N NaOH was added until the mixture was homogeneous, 10% Pd/C (12 mg) was added, and an H2 balloon was applied. After 16 h the reaction was filtered, concentrated, and purified by flash chromatography (silica, 12:10:1:1 EtOAc/EtOH/NH4OH/H2O) providing 29-7 as a white solid.
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[N+:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20](Cl)(=[O:22])=[O:21])([O-:13])=[O:12]>C([O-])(O)=O.[Na+].C(OCC)C.O>[CH3:8][C:7]1[CH:9]=[C:2]([O:10][S:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N+:11]([O-:13])=[O:12])(=[O:21])=[O:22])[CH:3]=[C:4]([OH:5])[CH:6]=1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: Cc1cc(O)cc(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: Cc1cc(O)cc(OS(=O)(=O)c2ccccc2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
Orcinol monohydrate (4.27 g, 30.0 mmol) and 2-nitrobenzenesulfonyl chloride (6.65 g, 30.0 mmol) were mixed in saturated aqueous NaHCO3 (100 mL) and diethyl ether (100 mL). The biphasic mixture was stirred vigorously at ambient temperature overnight. The reaction mixture was diluted with water (150 mL) and extracted into ethyl acetate (3×100 mL). The organic phase was washed with brine (2×100 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane to 5% ethyl acetate in dichloromethane) to give the title compound as a pale yellow solid (6.10 g, 73%). 1H-NMR (300 MHz, CDCl3) δ 8.09 (d, J=7.8 Hz, 1H), 7.85 (m, 2H), 7.71 (m, 1H), 6.62 (s, 1H), 6.59 (s, 1H), 6.51 (s, 1H), 5.06 (s, 1H), 2.26 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:6]([N+:18]([O-])=O)[CH:5]=1>C(OCC)(=O)C.CO.[Pd]>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2)=[C:6]([NH2:18])[CH:5]=1
Reactant: COC(=O)c1ccc(NCC2CCCCC2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccc(NCC2CCCCC2)c(N)c1
Reaction time: 4 h

Procedure:
12.00 g 4-(Cyclohexylmethyl-amino)-3-nitro-benzoic acid methyl ester were dissolved in 75 ml ethyl acetate and 75 ml methanol, 0.45 g of palladium on carbon (10%) were added and the mixture was hydrogenated at 5 bar for 4 h. The catalyst was removed by filtration over celite, the filtrate was concentrated and after precipitation with cyclohexane 12.00 g (93%) of 3-Amino-4-(cyclohexylmethyl-amino)-benzoic acid methyl ester were obtained.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[CH3:28][S:29]([CH2:32][C:33](O)=[O:34])(=[O:31])=[O:30]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:33](=[O:34])[CH2:32][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: CS(=O)(=O)CC(=O)O
Agent: Cl
Product: CS(=O)(=O)CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, off-white solid (106 mg, 78%), MS (ISP) m/z=451.3 [(M+H)+], mp 260.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (132 mg, 0.3 mmol) and 2-methylsulfonyl-acetic acid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH2:15][C@@H:16]([C@@H:22]([O:26][Si:27]([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:30])[CH3:29])[C@@H:23]([OH:25])[CH3:24])[CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1C=CC=C([N+]([O-])=O)C=1C(OC(C1C([N+]([O-])=O)=CC=CC=1C)=O)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[CH2:13][CH2:14][CH2:15][C@H:16]([CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[C@@H:22]([O:26][Si:27]([CH:34]([CH3:36])[CH3:35])([CH:28]([CH3:29])[CH3:30])[CH:31]([CH3:32])[CH3:33])[C@H:23]([CH3:24])[O:25][C:10]1=[O:11])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)CC[C@@H](CCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)[C@@H](O[Si](C(C)C)(C(C)C)C(C)C)[C@H](C)O
Agent: CN(C)c1ccncc1
Agent: Cc1cccc([N+](=O)[O-])c1C(=O)OC(=O)c1c(C)cccc1[N+](=O)[O-]
Solvent: ClCCl
Product: CC(C)CC[C@H]1CCC[C@H](NC(=O)OC(C)(C)C)C(=O)O[C@@H](C)[C@@H]1O[Si](C(C)C)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 59.1 %

Procedure:
A solution of (2S,6R)-2-((tert-butoxycarbonyl)amino)-6-((1R,2S)-2-hydroxy-1-((triisopropylsilyl)oxy)propyl)-9-methyldecanoic acid (7.76 g, 13.1 mmol) in anhydrous CH2Cl2 (500 mL) was added to a solution of MNBA (9.04 g, 26.3 mmol) and DMAP (12.8 g, 105.0 mmol) in anhydrous CH2Cl2 (2.5 L) at room temperature over the course of 4 h. After the addition was complete, the reaction was stirred for 12 h at room temperature, concentrated and purified by column chromatography on SiO2 (gradient, hexanes/ethyl acetate) to furnish the title product as a sticky pale yellow solid (3.98 g, 59%): 1H NMR (400 MHz, CDCl3) δ 5.14 (d, J=8.2 Hz, 1H), 4.90-4.78 (m, 1H), 4.20-4.09 (m, 1H), 3.61 (t, J=7.6 Hz, 1H), 2.26-2.10 (m, 1H), 1.79-1.65 (m, 1H), 1.65-1.40 (m, 3H), 1.44 (s, 9H), 1.37 (d, J=6.5 Hz, 3H), 1.32-0.97 (m, 28H), 0.884 (d, J=6.7 Hz, 3H), 0.878 (d, J=6.7 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 173.12, 154.92, 79.62, 78.59, 75.82, 60.33, 53.07, 45.68, 36.92, 34.17, 28.64, 28.58, 28.31, 27.27, 22.82, 22.49, 18.95, 18.86, 18.38, 18.33, 13.75; ESIMS m/z 536.5 ([M+Na]+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]=2[CH:17]=1.[C:18]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][C:26]=1[F:27])(=[O:20])[CH3:19]>>[C:18]([C:21]1[CH:22]=[C:23]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]=3[CH:17]=2)[CH:24]=[CH:25][C:26]=1[F:27])(=[O:20])[CH3:19]
Reactant: CCC1(CC)OC(=O)N(C)c2ccc(N)cc21
Reactant: CC(=O)c1cc(B(O)O)ccc1F
Product: CCC1(CC)OC(=O)N(C)c2ccc(Nc3ccc(F)c(C(C)=O)c3)cc21

Procedure:
Prepared from 6-amino-4,4-diethyl-1-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one and 3-acetyl-4-fluorophenylboronic acid according to the coupling procedure described in example 1. MS (ESI) m/z 371 ([M+H]+); MS (ESI) m/z 369 ([M−H]−); High Resolution Mass Spectrometry (HRMS): calcd for C21H23FN2O3, 370.1693; found (ESI+), 371.17619; Anal. calcd for C21H23FN2O3: C, 68.09; H, 6.26; N, 7.56. Found: C, 67.36; H, 6.45; N, 7.65.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH:7](O)[CH2:8][CH2:9][N:10]2[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:17]3[C:12]([N:13]([CH3:28])[C:14](=[O:27])[N:15]([CH3:26])[C:16]3=[O:25])=[CH:11]2)[S:5][CH:6]=1.C(N(CC)CC)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([CH:7]2[C:11]3[N:10]([C:18]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[C:17]4[C:16](=[O:25])[N:15]([CH3:26])[C:14](=[O:27])[N:13]([CH3:28])[C:12]4=3)[CH2:9][CH2:8]2)[S:5][CH:6]=1
Reactant: Cn1c(=O)c2c(-c3ccccc3)n(CCC(O)c3nc(Cl)cs3)cc2n(C)c1=O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1c(=O)c2c(-c3ccccc3)n3c(c2n(C)c1=O)C(c1nc(Cl)cs1)CC3

Procedure:
Trifluromethanesulfonic anhydride (0.576 mL, 3.41 mmol) in DCM (3 mL) was added slowly to a solution of 6-(3-(4-chlorothiazol-2-yl)-3-hydroxypropyl)-1,3-dimethyl-5-phenyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (490 mg, 1.137 mmol) and triethylamine (0.792 mL, 5.69 mmol) in DCM (40 mL) at 0° C. Further portions of triethylamine (0.792 mL, 5.69 mmol) and trifluoromethanesulfonic anhydride (0.576 mL, 3.41 mmol) were added to allow the reaction to run to completion. The reaction was quenched with saturated NaHCO3(aq) and extracted with DCM. The organic phase was passed through a hydrophobic frit and evaporated under vacuum. Purification by mass-directed HPLC under the following conditions afforded the title compound.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][C:8]([CH3:15])=[C:7]2[CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:20][CH2:19]1.[Sn].Cl.[OH-].[Na+]>C(OCC)(=O)C.C(O)C>[ClH:1].[ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][C@@H:8]([CH3:15])[C@H:7]2[CH2:16][CH2:17][N:18]1[CH2:19][CH2:20][CH:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:22][CH2:23]1
Reactant: COc1cc2[nH]c(C)c(CCN3CCC(c4ccccc4)CC3)c2cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc2c(cc1OC)[C@H](CCN1CCC(c3ccccc3)CC1)[C@H](C)N2

Procedure:
A stirred mixture of 1.7 g. of the product of Example 3, 14.0 g. of mossy tin 35 ml. of ethanol and 28.0 ml. of concentrated hydrochloric acid is heated under reflux for 48 hours. The reaction mixture is poured into dilute aqueous sodium hydroxide. This mixture is filtered and the filter cake is extracted with ethyl acetate. The extract is dried over magnesium sulfate and the solvent is evaporated to give 1.12 g. of a brown tar. The tar is dissolved in ethyl acetate, then the solution is treated with anhydrous hydrogen chloride to make it just acidic. A solid is formed and is collected. The material is dissolved in isopropyl alcohol, then hexane is added to precipitate a solid. The mixture is dissolved in water, made basic with aqueous sodium hydroxide solution and extracted with chloroform. The chloroform is dried over magnesium sulfate and concentrated to give a viscous liquid. The liquid is dissolved in ethyl acetate. The solution is made just acidic with anhydrous hydrogen chloride to provide a precipitate. The precipitate is collected to give cis-5,6,-dimethoxy-2-methyl-3-[2-(4-phenylpiperidino)ethyl]indoline dihydrochloride as cream-colored crystals, mp. 125°-132° C.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].IC.[C:21]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:21])[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(C(=O)OC(C)(C)C)oc2cccc(O)c12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cccc2oc(C(=O)OC(C)(C)C)c(C)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.3 %

Procedure:
To 4-hydroxy-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester (300 mg, 1.21 mmol) was added iodomethane (0.75 mL, 10 eq), K2CO3 (332 mg, 2.4 mmol) and 2 mL of DMF. The mixture was stirred at room temperature overnight. The mixture was washed with brine and extracted with ethyl acetate. The combined ethyl acetate solution was washed with brine. Removal of the solvent gave 312 mg (98% yield) of 4-methoxy-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester as an amber colored oil.
Reaction SMILES: C([O:5][C:6]([C:8]1([O:11][C:12]2[C:17]([NH:18][CH:19]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)=[CH:16][C:15]([Cl:32])=[CH:14][N:13]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36]>>[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36].[Cl:32][C:15]1[CH:14]=[N:13][C:12]2[O:11][C:8]3([CH2:10][CH2:9]3)[C:6](=[O:5])[N:18]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[C:17]=2[CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(Cl)cnc2OC2(C(=O)OC(C)(C)C)CC2)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C1N(C2CCNCC2)c2cc(Cl)cnc2OC12CC2
Reaction time: 2 h

Procedure:
A trifluoroacetic acid solution (70 ml) of tert-butyl 4-[(2-{[1-(tert-butoxycarbonyl)cyclopropyl]oxy}-5-chloropyridin-3-yl)amino]piperidine-1-carboxylate (7.09 g) was stirred at 70° C. for 28 hours. The temperature was brought back to room temperature, followed by concentration under reduced pressure, and toluene was further added and concentrated under reduced pressure. After ether was added to the residue, the suspension was stirred for 2 hours, and then the insolubles were collected by filtration to afford 7′-chloro-1′-piperidin-4-ylspiro[cyclopropane-1,3′-pyrido[2,3-b][1,4]oxazine]-2′(1′H)-one trifluoroacetate (5.37 g).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)=[O:4].[ClH:15].[F:16][C:17]1[CH:30]=[CH:29][C:20]([C:21]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:22])=[CH:19][CH:18]=1.[I-].[K+].C(=O)([O-])O.[Na+].Cl>C(O)C>[ClH:15].[F:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([CH:23]2[CH2:28][CH2:27][N:26]([CH2:2][C:3]([C:5]3[CH:14]=[CH:13][C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[CH:6]=3)=[O:4])[CH2:25][CH2:24]2)=[O:22])=[CH:29][CH:30]=1
Reactant: O=C(CBr)c1ccc2ccccc2c1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CCO
Product: O=C(CN1CCC(C(=O)c2ccc(F)cc2)CC1)c1ccc2ccccc2c1

Procedure:
49.7 g of 2-bromo-2'-acetonaphthone, 49.9 g of 4-(p-fluorobenzoyl)piperidine hydrochloride, 0.5 g of potassium iodide and 50.4 g of sodium hydrogencarbonate were added to 500 ml of ethanol and the mixture was refluxed for 2 h. The solvent was distilled off and chloroform was added to the residue. The mixture was washed with water and dried. Chloroform was distilled off and the residue was purified according to silica gel column chromatography to obtain 58.9 g of the crystalline intended product, which was converted into its hydrochloride and recrystallized by an ordinary process to obtain the intended hydrochloride.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.Cl.[CH2:12]([O:14][C:15](=[O:19])[CH2:16][CH2:17][NH2:18])[CH3:13].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[O:53]=[C:54]1[C:59]([C:60](O)=[O:61])=[CH:58][C:57]([C:63]2[CH:68]=[CH:67][N:66]=[CH:65][CH:64]=2)=[N:56][NH:55]1>CN(C)C=O>[O:53]=[C:54]1[C:59]([C:60]([NH:18][CH2:17][CH2:16][C:15]([O:14][CH2:12][CH3:13])=[O:19])=[O:61])=[CH:58][C:57]([C:63]2[CH:68]=[CH:67][N:66]=[CH:65][CH:64]=2)=[N:56][NH:55]1
Reactant: O=C(O)c1cc(-c2ccncc2)n[nH]c1=O
Reactant: CCOC(=O)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CCNC(=O)c1cc(-c2ccncc2)n[nH]c1=O
Temperature: 19 °C
Reaction time: 12 h
Yield: 32.9 %

Procedure:
0.733 g of 1-hydroxybenzotriazole, 0.833 g of β-alanine ethyl ester hydrochloride, 0.96 cm3 of N,N-diisopropylethylamine and 2.06 g of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate were successively added to 0.94 g of 3-oxo-6-pyridin-4-yl-2,3-dihydropyridazine-4-carboxylic acid dissolved in 100 cm3 of N,N-dimethylformamide. The reaction medium was stirred for 12 hours at 19° C. The solvent was evaporated off under reduced pressure (2 kPa; 55° C.). The solid residue was triturated in 20 cm3 of dichloromethane, suction-filtered and oven-dried under reduced pressure (10 kPa; 20° C.). After purification by chromatography on silica gel (particle size 40-63 μm, under an argon pressure of 150 kPa) eluting with dichloromethane, 0.45 g of ethyl 3-[(3-oxo-6-pyridin-4-yl-2,3-dihydropyridazine-4-carbonyl)amino]propionate was obtained in the form of a white solid melting at 180° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[C:24]([C:26]1([C:32]2[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=2)[C:35](O)=[O:36])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)#[N:25].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[C:24]([C:26]1([C:32]2[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=2)[C:35]([NH:1][C:2]2[CH:23]=[CH:22][CH:21]=[C:4]([O:5][C:6]3[CH:7]=[CH:8][C:9]4[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]5[CH2:20][CH2:19]5)=[O:17])[N:14]=4)[N:11]=3)[CH:3]=2)=[O:36])[CH2:27][CH2:28][O:29][CH2:30][CH2:31]1)#[N:25]
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: N#CC1(c2cccc(C(=O)O)c2)CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(NC(=O)C6CC6)cn5n4)c3)c2)CCOCC1
Yield: 58.6 %

Procedure:
Using N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.49 mmol), 3-(4-cyanotetrahydro-2H-pyran-4-yl)benzoic acid (120 mg, 0.51 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (95 mg, 0.50 mmol), 1-hydroxybenzotriazole (67 mg, 0.50 mmol), triethylamine (130 μL, 0.97 mmol) and N,N-dimethylformamide (8.0 mL) as starting materials and in the same manner as in Example 318, the title compound (150 mg, 58%) was obtained as a white powder.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:11])[C:7](=[CH:9][CH:10]=1)[OH:8])([O-:3])=[O:2].[C:12](Cl)(=[O:26])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>>[O:26]=[C:12]([O:11][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=[CH:9][C:7]=1[O:8][C:12](=[O:26])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: O=[N+]([O-])c1ccc(O)c(O)c1
Reactant: CCCCCCCCCCCCCC(=O)Cl
Product: CCCCCCCCCCCCCC(=O)Oc1ccc([N+](=O)[O-])cc1OC(=O)CCCCCCCCCCCCC

Procedure:
Using this procedure, the reaction of 4-nitrocatechol with tetradecanoyl chloride gave 3,4-bis [(1-oxotetradecyl)oxy]nitrobenzene (mp 58°-60°, Anal. Calcd for C34H57NO6 : C, 70.72; H, 9.98; N, 2.43. Found: C, 70.91; H, 9.61; N, 2.41.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:17]=[C:16]3[C:12]([N:13]=[CH:14][NH:15]3)=[C:11]([N:18]3[CH2:24][CH2:23][C:22]4[N:25]=[CH:26][NH:27][C:21]=4[CH2:20][CH2:19]3)[N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:28][CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.ClC1N=C2C(N=CN2)=C(N2CCC3N=CNC=3C2)N=1.NC1C=CC(NC2CCN(C(OC(C)(C)C)=O)CC2)=C(F)C=1.[F:76][C:77]([F:88])([F:87])[CH2:78]OS(C(F)(F)F)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:17]=[C:16]3[C:12]([N:13]=[CH:14][NH:15]3)=[C:11]([N:18]3[CH2:19][CH2:20][C:21]4[N:27]=[CH:26][NH:25][C:22]=4[CH2:23][CH2:24]3)[N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:28][CH:29]1[CH2:34][CH2:33][N:32]([CH2:78][C:77]([F:88])([F:87])[F:76])[CH2:31][CH2:30]1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: Fc1cc(Nc2nc(N3CCc4nc[nH]c4CC3)c3nc[nH]c3n2)ccc1NC1CCNCC1
Agent: CC(C)(C)OC(=O)N1CCC(Nc2ccc(N)cc2F)CC1
Agent: Clc1nc(N2CCc3nc[nH]c3C2)c2nc[nH]c2n1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Fc1cc(Nc2nc(N3CCc4nc[nH]c4CC3)c3nc[nH]c3n2)ccc1NC1CCN(CC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
40 mg of 2-fluoro-N1-piperidin-4-yl-N4-[6-(4,5,7,8-tetrahydro-1H-imidazo[4,5-d]azepin-6-yl)-9H-purin-2-yl]-benzene-1,4-diamine (prepared analogously to Example 1 from 2-chloro-6-(3,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)-9H-purine and tert-butyl 4-(4-amino-2-fluoro-phenylamino)-piperidine-1-carboxylate), 12.86 μL of 2,2,2-trifluoroethyl-trifluoromethylsulphonate and 61.63 mg potassium carbonate are suspended in N,N-dimethylformamide and stirred for 2 h at 25° C. The reaction mixture is filtered to remove the insoluble constituents and the filtrate is purified by column chromatography. The carrier material used is C18-RP silica gel and the product is passed through a gradient that consists of 85% water and 15% acetonitrile at the starting point and 5% water and 95% acetonitrile at the finishing point. 0.2% NH3KHCO3 is added to both eluants. The suitable fractions are freeze-dried.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1N)=[O:4].N([O-])=O.[Na+].[BrH:15]>O.[Cu]Br>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[Br:15])=[O:4]
Reactant: Br
Reactant: COC(=O)c1sccc1N
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1sccc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-Amino-2-thiophenecarboxylic acid methyl ester (9.4 g) was suspended in hydrobromic acid (20 ml), and the mixture was stirred at room temperature for 30 minutes. The mixture was cooled to 0° C., and sodium nitrite (4.2 g) in water (10 ml) was added dropwise below 10° C. The mixture was stirred for 1 hour, and then poured into copper (I) bromide (9.06 g) in hydrobromic acid (25 ml). The resulting mixture was stirred at 60° C. for 1 hour and extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure and distilled under reduced pressure to give 3-bromo-2-thiophenecarboxylic acid methyl ester (7.99 g) as crystals.