Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[F:13][C:14]([F:41])([F:40])[C:15]1[N:16]=[CH:17][N:18]([C:20]2[CH:39]=[CH:38][C:23]([O:24][CH:25]([C:29]3[CH:37]=[CH:36][C:32]([C:33]([OH:35])=O)=[CH:31][CH:30]=3)[CH2:26][CH2:27][CH3:28])=[CH:22][CH:21]=2)[CH:19]=1.Cl.[NH2:43][CH2:44][CH2:45][C:46]([O:48][CH3:49])=[O:47].ON1C2N=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[F:40][C:14]([F:13])([F:41])[C:15]1[N:16]=[CH:17][N:18]([C:20]2[CH:39]=[CH:38][C:23]([O:24][CH:25]([C:29]3[CH:37]=[CH:36][C:32]([C:33]([NH:43][CH2:44][CH2:45][C:46]([O:48][CH3:49])=[O:47])=[O:35])=[CH:31][CH:30]=3)[CH2:26][CH2:27][CH3:28])=[CH:22][CH:21]=2)[CH:19]=1
Reactant: COC(=O)CCN
Reactant: CCCC(Oc1ccc(-n2cnc(C(F)(F)F)c2)cc1)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(Oc1ccc(-n2cnc(C(F)(F)F)c2)cc1)c1ccc(C(=O)NCCC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (40 mg, 0.21 mmol) was added to a room temperature solution of (+/−)-4-(1-(4-(4-(trifluoromethyl)-1H-imidazol-1-yl)phenoxy)butyl)benzoic acid (80 mg, 0.20 mmol), methyl 3-aminopropanoate hydrochloride (28 mg, 0.20 mmol), 1-hydroxy-7-azabenzotriazole (30 mg, 0.22 mmol), and triethylamine (31 μL, 0.22 mmol) in dichloromethane (2 mL). The solution was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane (20 mL) and washed with water, then brine. The organic layer was dried over magnesium sulfate, filtered and concentrated to give (+/−)-methyl 3-(4-(1-(4-(4-(trifluoromethyl)-1H-imidazol-1-yl)phenoxy)butyl)benzamido)propanoate (89 mg, 90%). 1H NMR (400 MHz, CDCl3, δ): 7.74-7.70 (m, 2H), 7.69-7.66 (s, 1H), 7.44-7.41 (m, 1H), 7.40-7.36 (m, 2H), 7.18-7.13 (m, 2H), 6.91-6.86 (m, 2H), 6.83-6.75 (m, 1H), 5.16-5.12 (m, 1H), 3.72-3.66 (m, 5H), 2.66-2.60 (m, 2H), 2.06-1.93 (m, 1H), 1.86-1.74 (m, 1H), 1.55-1.35 (m, 2H), 0.99-0.91 (m, 3H).
Reaction SMILES: [F:1][C:2]1[C:3]([O:25][CH3:26])=[C:4]([CH:21]=[C:22]([F:24])[CH:23]=1)[CH2:5][C@H:6]1[C@H:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=2)[CH2:9][NH:8][CH2:7]1.C(N(CC)CC)C.[C:34](Cl)(=[O:36])[CH3:35].O>C(Cl)(Cl)Cl>[C:34]([N:8]1[CH2:9][C@@H:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=2)[C@H:6]([CH2:5][C:4]2[CH:21]=[C:22]([F:24])[CH:23]=[C:2]([F:1])[C:3]=2[O:25][CH3:26])[CH2:7]1)(=[O:36])[CH3:35]
Reactant: COc1ccc([C@@H]2CNC[C@H]2Cc2cc(F)cc(F)c2OC)cc1OC
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1ccc([C@@H]2CN(C(C)=O)C[C@H]2Cc2cc(F)cc(F)c2OC)cc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2.17 g (6.17 mmol) of trans-3-(3,5-difluoro-2-methoxybenzyl)-4-(3,4-dimethoxyphenyl)pyrrolidine prepared in step (13) of Example 4 was dissolved in 30 ml of chloroform, and 0.75 g (7.4 mmol) of triethylamine was added thereto. 10 ml of a solution of 0.5 ml (7.0 mmol) of acetyl chloride in chloroform was dropwise added thereto under cooling with ice, and the mixture was stirred at room temperature for 3 hr. 1 ml of water was added thereto to stop the reaction. The reaction mixture was washed with water, a 2N hydrochloric acid solution, and a saturated aqueous sodium hydrogencarbonate solution sequentially, and dried over anhydrous sodium sulfate. The solvent was distilled off in vacuo, and the residue was subjected to silica gel column chromatography (methylene chloride:methanol=97:3) to prepare 2.5 g (quantitative) of the intended product.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][O:10][C@@H:11]2[C@H:15]([OH:16])[C@@H:14]([CH2:17][OH:18])[O:13][C@H:12]2[N:19]2[C:29]3[N:28]=[C:26]([NH2:27])[NH:25][C:23](=[O:24])[C:22]=3[N:21]=[CH:20]2)[CH:5]=[CH:4][N:3]=[CH:2]1.C[Si](Cl)(C)C.[C:35](Cl)(=[O:39])[CH:36]([CH3:38])[CH3:37]>N1C=CC=CC=1>[C:35]([NH:27][C:26]1[NH:25][C:23](=[O:24])[C:22]2[N:21]=[CH:20][N:19]([C:29]=2[N:28]=1)[C@@H:12]1[O:13][C@H:14]([CH2:17][OH:18])[C@@H:15]([OH:16])[C@H:11]1[O:10][CH2:9][CH2:8][CH2:7][CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)(=[O:39])[CH:36]([CH3:38])[CH3:37]
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2OCCCCn2ccnc2)c(=O)[nH]1
Reactant: CC(C)C(=O)Cl
Agent: C[Si](C)(C)Cl
Solvent: c1ccncc1
Product: CC(C)C(=O)Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2OCCCCn2ccnc2)c(=O)[nH]1

Procedure:
2′-O-(imidazol-1-yl)butylguanosine in pyridine will be treated with trimethylsilyl chloride (5 eq) and isobutyryl chloride (5 eq) as per the procedure of Example 4 to yield the product.
Reaction SMILES: CN(C)[C:3]1[CH:4]=[C:5]([CH2:9]O)[CH:6]=[CH:7][CH:8]=1.[NH:12]1[CH:16]=[CH:15][CH:14]=[N:13]1.[CH3:17]C1(C)C(C)(C)OB(C2C=NNC=2)O1>>[CH3:17][C:5]1([CH2:9][N:12]2[CH:16]=[CH:15][CH:14]=[N:13]2)[CH2:4][CH2:3][CH2:8][CH2:7][CH2:6]1
Reactant: c1cn[nH]c1
Reactant: CN(C)c1cccc(CO)c1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: CC1(Cn2cccn2)CCCCC1

Procedure:
The title compound was prepared by substituting EXAMPLE 82A for (3-(dimethylamino)phenyl)methanol and 1H-pyrazole for 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in EXAMPLE 34A.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14]([C@:17]([C@H:21]([C@@H:30]([C@@H:39]([CH2:41][O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[OH:40])[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([OH:20])C=O)(=[O:16])C.[OH-].[Na+]>C1COCC1.CO>[C:8]1([S:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1.[CH2:23]([O:22][C@@H:21]([C@@H:30]([C@@H:39]([CH2:41][O:42][CH2:43][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)[OH:40])[O:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C@@H:17]([OH:20])[CH:14]=[O:16])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(=O)[C@](O)(C=O)[C@@H](OCc1ccccc1)[C@H](OCc1ccccc1)[C@H](O)COCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc(Sc2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CO
Product: O=C[C@H](O)[C@@H](OCc1ccccc1)[C@H](OCc1ccccc1)[C@H](O)COCc1ccccc1
Reaction time: 8 h
Yield: 93 %

Procedure:
To a solution of (CXII) (802 mg, 1.37 mmol) in 10 mL of THF is added MeOH (20 mL) and 12 drops of a saturated methanolic solution of NaOH. The reaction is stirred overnight then diluted with 150 mL of MeOH. Amberlite acidic resin is added and the reaction is stirred for 10 minutes. Litmus paper indicates that the pH is neutral and the resin is filtered off. The filtrate is concentrated in vacuo and the residue is purified by flash chromatography (20% EtOAc/petroleum ether to give 654 mg (93%) of the β sulfide (CXIII), and 49 mg (7%) of the a sulfide as white solids. Rf(β)=0.20 (15% EtOAc/petroleum ether) Rf(α)=0.13 (15% EtOAc/petroleum ether); 1H NMR (β) (CDCl3, 500 MHz) δ 7.25-7.63 (m, 20H), 4.87-4.98 (m, 3H), 4.55-4.68 (m, 4H), 3.85 (dd, J=11.0, 1.5 Hz, 1H), 3.79 (dd, J=10.5, 4.5 Hz, 1H), 3.63-3.68 (m, 2H), 3.54-3.60 (m, 2H), 2.50 (s, 1H, free OH); 13C NMR (β) (CDCl3, 500 MHz) δ 139.2, 139.0, 138.8, 133.6, 132.6, 129.7, 129.3, 129.2, 129.1, 128.8, 128.7, 128.5, 128.4, 128.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([S:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][C:20]4[S:21][C:22]5[CH2:28][CH2:27][CH2:26][C:25](=O)[C:23]=5[N:24]=4)[C:15](=[O:30])[CH2:14]3)(=[O:12])=[O:11])[S:7][C:6]=2[CH:31]=1.Cl.[NH2:33][OH:34].C([O-])(=O)C.[Na+].CCO>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([S:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][C:20]4[S:21][C:22]5[CH2:28][CH2:27][CH2:26][C:25](=[N:33][OH:34])[C:23]=5[N:24]=4)[C:15](=[O:30])[CH2:14]3)(=[O:12])=[O:11])[S:7][C:6]=2[CH:31]=1
Reactant: O=C1CCCc2sc(CN3CCN(S(=O)(=O)c4cc5ccc(Cl)cc5s4)CC3=O)nc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: O=C1CN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CCN1Cc1nc2c(s1)CCCC2=NO
Reaction time: 3.5 h

Procedure:
2-[4-(6-Chloro-benzo[b]thiophene-2-sulfonyl)-2-oxo-piperazin-1-ylmethyl]-6,7-dihydro-5H-benzothiazol-4-one (24 mg, 0.05 mmol), hydroxylamine hydrochloride (20 mg, 0.3 mmol), sodium acetate (20 mg, 0.3 mmol) and EtOH (2 mL) are combined and stirred 3.5 h. The reaction is diluted with CH2Cl2 and washed with NH4Cl, NaHCO3 and concentrated to provide 2-[4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-2-oxo-piperazin-1-ylmethyl]-6,7-dihydro-5H-benzothiazol-4-one oxime. 1H NMR (300 MHz, DMSO-d6) δ 10.92 (s, 1H), 8.34 (d, 1H), 8.20 (s, 1H), 8.07 (d, 1H), 7.59 (dd, 1H), 4.70 (s, 2H), 3.87 (s, 2H), 3.49 (s, 4H), 2.74 (t, 2H), 2.61 (t, 2H), 1.81 (dt, 2H); (Ion Spray) 511 (M+H)+.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[O:9]1[C:13]2([CH2:18][CH2:17][CH:16]([NH:19][C:20]3[N:21]=[CH:22][C:23]4[C:28]([CH:29]=3)=[C:27](F)[CH:26]=[CH:25][C:24]=4[CH3:31])[CH2:15][CH2:14]2)[O:12][CH2:11][CH2:10]1.C1OCCOCCOCCOCCOC1>C1COCC1.CS(C)=O>[CH:1]1([O:6][C:27]2[CH:26]=[CH:25][C:24]([CH3:31])=[C:23]3[C:28]=2[CH:29]=[C:20]([NH:19][CH:16]2[CH2:17][CH2:18][C:13]4([O:12][CH2:11][CH2:10][O:9]4)[CH2:14][CH2:15]2)[N:21]=[CH:22]3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(F)c2cc(NC3CCC4(CC3)OCCO4)ncc12
Reactant: OC1CCCC1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: Cc1ccc(OC2CCCC2)c2cc(NC3CCC4(CC3)OCCO4)ncc12
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
In a dry box, in a microwave test tube cyclopentanol (600.0 mg, 7.0 mmol) was dissolved in 5 ml of THF. To this solution was added the NaH (273.0 mg, 11.4 mmol) at room temperature and the mixture was stirred for 30 min. N-1,4-dioxaspiro[4.5]dec-8-yl-5-fluoro-8-methylisoquinolin-3-amine (1.8 g, 5.7 mmol) mixed with 15-crown-5 ether (0.13 g, 0.57 mmol) in 15 ml of DMSO was added to above solution. The microwave test tube was capped and moved out from the dry box. The tube was placed into Microwave apparatus and heated to 140° C. for 2 hours. The crude product was purified using a silica gel column to give 263.0 mg (yield 53%). 1H NMR (400 MHz, CHLOROFORM-d) ppm 0.89 (m, 1H), 1.17-1.40 (m, 2H), 1.57-2.02 (m, 10H), 2.05-2.29 (m, 2H), 2.47-2.63 (m, 3H), 3.54-3.78 (m, 1H), 3.90-4.06 (m, 4H), 4.64-5.02 (m, 2H), 6.46-6.77 (m, 1H), 6.79-6.98 (m, 2H), 7.20-7.43 (m, 1H), 8.91 (s, 1H). MS m/z, (APCI); 383.2 ([M+H]+).
Reaction SMILES: [C:1](O)(=O)C.C(N)=N.COCCO.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21]1[CH:33]=[CH:32][C:24]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[C:23]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[CH:22]=1.C(OCC)(=O)C>O>[N:20]1([C:21]2[CH:33]=[CH:32][C:24]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[C:23]([NH:34][C:35]3[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=3)[CH:22]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[CH:1]1
Reactant: CC(=O)O
Reactant: CC(C)(C)OC(=O)c1ccc(Nc2ccccc2N)cc1Nc1ccc(F)cc1
Agent: N=CN
Solvent: CCOC(C)=O
Solvent: COCCO
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(-n2cnc3ccccc32)cc1Nc1ccc(F)cc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 104 %

Procedure:
Formamidine acetate 0.10 g was added to ethylene glycol monomethyl ether 3.0 mL solution of tert-butyl 4-((2-aminophenyl)amino)-2-(4-fluoroanilino)benzoate 0.15 g at room temperature, and it was stirred at 80° C. for 6 hours. After the reaction mixture was cooled to room temperature, and ethyl acetate and water were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after sequential washing with saturated sodium hydrogen carbonate aqueous solution and saturated sodium chloride aqueous solution, the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Fuji SILYSIA Chemical Ltd., PSQ100B(spherical type), eluent; hexane:ethyl acetate=2:1] to give tert-butyl 4-(1H-benzimidazol-1-yl)-2-(4-fluoroanilino)benzoate 0.16 g of a pale red solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.C(O)C.C([O-])([O-])=O.[K+].[K+].[C:20]([O:24][C:25](=[O:34])[N:26]([C:28]1[S:32][C:31](Br)=[N:30][CH:29]=1)[CH3:27])([CH3:23])([CH3:22])[CH3:21]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:20]([O:24][C:25](=[O:34])[N:26]([C:28]1[S:32][C:31]([C:5]2[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:30][CH:29]=1)[CH3:27])([CH3:23])([CH3:21])[CH3:22]
Reactant: OB(O)c1ccc(Cl)nc1
Reactant: CN(C(=O)OC(C)(C)C)c1cnc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CN(C(=O)OC(C)(C)C)c1cnc(-c2ccc(Cl)nc2)s1
Temperature: 100 °C
Yield: 82.9 %

Procedure:
To a suspension of 6-chloro-3-pyridine boronic acid (158 mg, 1.0 mmol) in toluene (4 mL) was added absolute ethanol (2 mL) followed by a 2.0 M solution of K2CO3 (1.0 mL). To this mixture was added (2-bromo-thiazol-5-yl)-methyl-carbamic acid tert-butyl ester (322 mg, 1.1 mmol) followed by tetrakis(triphenylphosphine)palladium(0) (58 mg, 0.05 mmol). The reaction mixture was heated to 100° C. for 16 h. The mixture was cooled and diluted with ethyl acetate. The organic layer was washed with saturated aqueous NaHCO3, dried over Na2SO4, filtered and concentrated. The organic layer was purified by silica gel chromatography (0-100% ethyl acetate/hexanes) to afford an off-white solid (270 mg, 83%): mp 167-170° C.; 1H NMR (300 MHz, CDCl3) δ 8.88 (br s, 1H), 8.16 (dd J=3.0, 8.0 Hz, 1H), 7.40 (d, J=7.0 Hz, 1H), 7.39 (s, 1H), 3.45 (s, 3H), 1.61 (s, 9H); ESIMS m/z 326 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])[CH2:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:41][C:42]1[CH:43]=[C:44]([CH:49]=[CH:50][C:51]=1[NH:52][C:53](OC1C=CC([N+]([O-])=O)=CC=1)=[O:54])[C:45]([O:47][CH3:48])=[O:46].C(=O)([O-])O.[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:7]([CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:53]([NH:52][C:51]2[CH:50]=[CH:49][C:44]([C:45]([O:47][CH3:48])=[O:46])=[CH:43][C:42]=2[Cl:41])=[O:54])[CH2:11][CH:10]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])=[O:33])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)c(Cl)c1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCNCC1c1ccccc1)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(NC(=O)N2CCC(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C(c3ccccc3)C2)c(Cl)c1
Reaction time: 8 h
Yield: 131.8 %

Procedure:
To a solution of 181 mg of the crude tert-butyl[(1R)-1-(1-naphthyl)ethyl][(3-phenylpiperidin-4-yl)methyl]carbamate and 0.114 mL of triethylamine in 3.0 mL of THF was added 171 mg of methyl 3-chloro-4-{[(4-nitrophenoxy)carbonyl]amino}benzoate at room temperature, followed by stirring overnight. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 352 mg of methyl 4-({[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]carbonyl}amino)-3-chlorobenzoate as a crude product. ESI+: 656
Reaction SMILES: [C:1]1([C:7]2[N:8]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:9]3[C:14]([N:15]=2)=[C:13]([NH:16][CH2:17][CH2:18][CH:19]=O)[N:12]=[CH:11][N:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[Cl:28][C:29]1[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][C:30]=1[N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>ClCCCl>[Cl:28][C:29]1[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][C:30]=1[N:36]1[CH2:41][CH2:40][N:39]([CH2:19][CH2:18][CH2:17][NH:16][C:13]2[N:12]=[CH:11][N:10]=[C:9]3[C:14]=2[N:15]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]3[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:38][CH2:37]1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Reactant: O=CCCNc1ncnc2c1nc(-c1ccccc1)n2-c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Clc1cccc(N2CCN(CCCNc3ncnc4c3nc(-c3ccccc3)n4-c3ccccc3)CC2)c1Cl
Temperature: 45 °C
Reaction time: 18 h
Yield: 38.7 %

Procedure:
To the solution of 3-(8,9-diphenyl-9H-purin-6-ylamino)propanal obtained in step 2 (0.73 g, 2.13 mmol) and 1-(2,3-dichlorophenyl)piperazine hydrochloride (0.6 g, 2.13 mmol) in 1.2-dichloroethane was added Na(OAc)3BH (0.72 g, 3.40 mmol) and acetic acid (0.24 mL, 4.25 mmol) at room temperature and stirred for 18 hours at 45° C. The resulting reaction mixture was concentrated under reduced pressure. The residue was diluted with CH2Cl2, and washed with water. The organic layer thus separated was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude product thus obtained was purified by preparative HPLC (purification system, Gilson) to provide the title compound (460 mg) as a white solid.
Reaction SMILES: N[C@@H]1C2C(=CC=CC=2)C[C@@H]1O.[C:12]([C:16]1[CH:21]=[CH:20][C:19]([CH:22](F)[C:23]2[C:24]([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)=[C:25]3[C:30](=[CH:31][C:32]=2[CH:33]([CH3:35])[CH3:34])[O:29][C:28]([CH3:37])([CH3:36])[CH2:27][C:26]3=[O:38])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13].CO>O1CCCC1.C(OCC)(=O)C>[C:12]([C:16]1[CH:17]=[CH:18][C:19]([CH2:22][C:23]2[C:24]([C:39]3[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=3)=[C:25]3[C:30](=[CH:31][C:32]=2[CH:33]([CH3:35])[CH3:34])[O:29][C:28]([CH3:36])([CH3:37])[CH2:27][C@@H:26]3[OH:38])=[CH:20][CH:21]=1)([CH3:14])([CH3:15])[CH3:13]
Reactant: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(F)c1ccc(C(C)(C)C)cc1)C(=O)CC(C)(C)O2
Agent: N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1Cc1ccc(C(C)(C)C)cc1)[C@@H](O)CC(C)(C)O2
Reaction time: 0.5 h

Procedure:
150 μl (840 μmol) of borane/N,N-diethylaniline complex are added slowly to a solution of 4.70 mg (30 μmol) of (1R,2S)-1-aminoindan-2-ol in 5 ml of tetrahydrofuran, and the mixture is stirred for 30 min. A solution of 100 mg (210 μmol) of rac-6-[(4-tert-butylphenyl)(fluoro)methyl]-5-(4-fluorophenyl)-7-isopropyl-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one (Example 28A) in 5 ml of tetrahydrofuran is then slowly added dropwise. After 3 h of stirring at room temperature, methanol is added and the solvent is reduced under reduced pressure. The residue is taken up in ethyl acetate and washed in each case twice with 1 M hydrochloric acid and saturated sodium bicarbonate solution and once with saturated sodium chloride solution. The organic phase is dried over sodium sulfate and then concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (mobile phase: gradient cyclohexane→cyclohexane/ethyl acetate 10:1→5:1) gives the target product.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.[C:25](=O)([O:36][CH2:37][CH2:38][N:39]1[CH:43]=[CH:42][CH:41]=[N:40]1)[O:26]C1C=CC([N+]([O-])=O)=CC=1.Cl>N1C=CC=CC=1.O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][N:17]([C:25]([O:36][CH2:37][CH2:38][N:39]5[CH:43]=[CH:42][CH:41]=[N:40]5)=[O:26])[CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Reactant: O=C(OCCn1cccn1)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCN(C(=O)OCCn4cccn4)CC3)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.6 %

Procedure:
A mixture of 3.3 g (0.01 mol) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(piperazin-1-yl)-quinoline-3-carboxylic acid and 2.8 g (0.01 mol) of 4-nitrophenyl 2-(pyrazol-1-yl)-ethyl carbonate in 40 ml of pyridine is stirred for 1 day at room temperature. Thereafter, it is diluted with 30 ml of water and acidified with 2N hydrochloric acid, and the precipitate is filtered off under suction and recrystallised from glycol monomethyl ether. 2.8 g (60% of theory) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-{-4-[(pyrazol-1-yl)-ethoxycarbonyl]-piperazin-1-yl}-quinoline-3-carboxylic acid of melting point 205°-208° C. are obtained.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[CH:15][CH:14]=1)OC1C=CC=CC=1)#[N:2].[Cl:25][C:26]1[CH:31]=[C:30]([NH:32][NH2:33])[N:29]=[CH:28][N:27]=1.C(N(C(C)C)CC)(C)C.ClCCl>CN1CCCC1=O>[Cl:25][C:26]1[N:27]=[CH:28][N:29]=[C:30]([N:32]2[C:1]([NH2:2])=[N:3][C:4]([NH:12][C:13]3[CH:14]=[CH:15][C:16]([N:19]4[CH2:20][CH2:21][O:22][CH2:23][CH2:24]4)=[CH:17][CH:18]=3)=[N:33]2)[CH:31]=1
Reactant: NNc1cc(Cl)ncn1
Reactant: N#CNC(=Nc1ccc(N2CCOCC2)cc1)Oc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Nc1nc(Nc2ccc(N3CCOCC3)cc2)nn1-c1cc(Cl)ncn1
Temperature: 220 °C
Reaction time: 0.5 h
Yield: 39 %

Procedure:
A mixture of N-cyano-N′-(4-morpholinopheny)-O-phenylisourea (8.76 g, 27.2 mmol, 4-chloro-6-hydrazino-pyrimidine (4.12 g, 28.5 mmol) and di-iso-propylethylamine (18.9 mL, 109 mmol) in N-methyl-pyrrolidinone (50 mL) was heated in the microwave apparatus at 220° C. for 5 min, cooled, poured into ice-water, stirred 0.5 h and filtered to obtain crude product (9.30 g). Purification by flash chromatography (SiO2) eluted with 2:98 methanol:dichloromethane provided the title compound (3.91 g, 39% yield) as a yellow powder.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([NH:7][C:8]1[CH:20]=[CH:19][C:11]([CH:12]=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:9]=1)=[O:6].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[O:6]=[C:5]1[CH2:4][CH2:3][CH2:2][N:7]1[C:8]1[CH:20]=[CH:19][C:11]([CH:12]=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:9]=1
Reactant: CCOC(=O)C=Cc1ccc(NC(=O)CCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1ccc(N2CCCC2=O)cc1
Temperature: 50 °C
Yield: 181.5 %

Procedure:
To a stirred solution of ethyl 4-(4-bromobutyramido)cinnamate (420 mg) in N,N-dimethylformamide (5 ml) was added potassium carbonate (552 mg) at ambient temperature and the resulting mixture was warmed at 50° C. for three hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic phase was dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography eluting with chloroform to afford ethyl 4-(2-oxo-1-pyrrolidinyl)cinnamate (581 mg) as a pale yellow solid.