Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8](Cl)=[N:7][CH:6]=1)[CH3:2].[CH:13]1([NH2:16])[CH2:15][CH2:14]1>CCOC(C)=O>[CH:13]1([NH:16][C:8]2[CH:9]=[CH:10][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:12])=[CH:6][N:7]=2)[CH2:15][CH2:14]1
Reactant: NC1CC1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(NC2CC2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.9 %

Procedure:
A microwave vial is charged with ethyl-6-chloronicotinate (1 g, 5.39 mmol) and cyclopropylamine (1 mL, 14.43 mmol), sealed and stirred at 80° overnight. After cooling to RT, the yellow solid was stirred with EtOAc and filtered. The filtrate was preadsorbed on SiO2 and applied to the top of a SiO2 column and eluted with an EtOAc/hexane gradient (0 to 30% EtOAc) to afford 0.71 g of ethyl 6-cyclopropylamino-nicotinoate (332) as an off white solid (17).
Reaction SMILES: C(OC(=O)[N:7]([C:14]1[C:15]2[N:16]([C:20](Br)=[CH:21][N:22]=2)[CH:17]=[CH:18][N:19]=1)[CH2:8][CH2:9][S:10]([CH3:13])(=[O:12])=[O:11])(C)(C)C.CS[C:27]1[N:32]=[C:31]([Sn](CCCC)(CCCC)CCCC)[CH:30]=[CH:29][N:28]=1.[NH2:46][C@H:47]1[CH2:52][CH2:51][C@H:50]([OH:53])[CH2:49][CH2:48]1>>[CH3:13][S:10]([CH2:9][CH2:8][NH:7][C:14]1[C:15]2[N:16]([C:20]([C:31]3[CH:30]=[CH:29][N:28]=[C:27]([NH:46][CH:47]4[CH2:52][CH2:51][CH:50]([OH:53])[CH2:49][CH2:48]4)[N:32]=3)=[CH:21][N:22]=2)[CH:17]=[CH:18][N:19]=1)(=[O:11])=[O:12]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(SC)n1
Reactant: CC(C)(C)OC(=O)N(CCS(C)(=O)=O)c1nccn2c(Br)cnc12
Reactant: N[C@H]1CC[C@H](O)CC1
Product: CS(=O)(=O)CCNc1nccn2c(-c3ccnc(NC4CCC(O)CC4)n3)cnc12

Procedure:
4-{4-[8-(2-Methanesulfonyl-ethylamino)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-ylamino}-cyclohexanol was prepared by a process analogous to that described in Example 12 starting from (3-bromo-imidazo[1,2-a]pyrazin-8-yl)-(2-methanesulfonyl-ethyl)-carbamic acid tert-butyl ester (from Example 5 supra), 2-methylsulfanyl-4-tributylstannanyl-pyrimidine, and trans-4-amino-cyclohexanol. LC-MS: [M+H]+ 432.1.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH2:10]([O:17][C:18]1[CH:30]=[CH:29][C:21]([C:22]([NH:24][CH2:25][C:26]([OH:28])=O)=[O:23])=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[N:54]1([C:60]([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][C:63]=2[C:68]([F:71])([F:70])[F:69])=[O:61])[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]1>CN(C=O)C.O>[CH2:10]([O:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([NH:24][CH2:25][C:26](=[O:28])[N:57]2[CH2:58][CH2:59][N:54]([C:60](=[O:61])[C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][C:63]=3[C:68]([F:71])([F:69])[F:70])[CH2:55][CH2:56]2)=[O:23])=[CH:29][CH:30]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(O)CNC(=O)c1ccc(OCc2ccccc2)cc1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 104.1 %

Procedure:
DIPEA (98 mg, 0.76 mmol) was added to a stirred solution of (4-benzyloxy-benzoylamino]-acetic acid (50 mg, 0.17 mmol) in DMF (3 mL). HOBT (25.8 mg, 0.19 mmol) and EDCI.HCl (83 mg, 0.43 mmol) were added at room temperature. After 2 minutes, piperazine-1-yl-(2-trifluoromethyl-phenyl)-methanone hydrochloride (61.5 mg, 0.21 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was diluted with cold water and the resulting precipitate was filtered, washed with hexane and dried to afford 93 mg (99% yield) of 4-benzyloxy-N-{2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-benzamide. LC-MS purity: 87%, 1H NMR (DMSO): δ 8.5 (s, 1H,), 7.8 (m, 5H), 7.5 (s, 1H), 7.4 (m, 4H), 7.1 (d, 2H), 5.2 (s, 2H), 4.2 (d, 2H), 3.7 (m, 4H), 3.5 (s, 2H), 3.4 (s, 2H), 3.3 (s, 2H).
Reaction SMILES: [CH:1]1([C@H:7]2[N:12]3[CH:13]=[C:14]([C:19]([Cl:21])=[O:20])[C:15]4[CH:16]=[CH:17][CH:18]=[C:10]([C:11]=43)[O:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[CH2:31]([N:38]1[CH2:43][C@H:42]([CH3:44])[NH:41][C@H:40]([CH3:45])[CH2:39]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>ClCCl>[ClH:21].[CH:1]1([C@H:7]2[N:12]3[CH:13]=[C:14]([C:19]([N:41]4[C@H:42]([CH3:44])[CH2:43][N:38]([CH2:31][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[CH2:39][C@@H:40]4[CH3:45])=[O:20])[C:15]4[CH:16]=[CH:17][CH:18]=[C:10]([C:11]=43)[O:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[C@@H]1CN(Cc2ccccc2)C[C@H](C)N1
Reactant: O=C(Cl)c1cn2c3c(cccc13)OC[C@H]2C1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2ccccc2)C[C@H](C)N1C(=O)c1cn2c3c(cccc13)OC[C@H]2C1CCCCC1
Product: Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 42.5 %

Procedure:
To a solution of (R)-3-cyclohexyl-2,3-dihydropyrrolo[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid chloride (380 mg, 1.23 mmol) and N,N diisopropyl ethylamine (0.2 ml, 1.3 mmol) in dichloromethane (20 ml) was added 1-N-benzyl-(cis)3,5-dimethylpiperazine (250 mg, 1.2 mmol) in dichloromethane (5 ml) and the mixture was stirred for 16 h at room temperature. The mixture was partitioned between sodium bicarbonate solution and dichloromethane. The organic layer was separated and the solvent removed in vacuo. The residue was purified by flash chromatography eluting with 0-5% (v/v) methanol in dichloromethane. Hydrochloride salt formation was achieved by the addition of hydrogen chloride (2 M solution in diethyl ether; 2 ml) to the free base in dichloromethane (1 ml). The precipitate was filtered and dried to afford (R)-3-cyclohexyl-2,3-dihydro-6-[(cis)-4-benzyl-2,6-dimethylpiperazin-1-yl-carbonyl]pyrrolo[1,2,3-de]-1,4-benzoxazine hydrochloride salt as a light blue powder (240 mg, 0.51 mmol).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]([C:21]([OH:23])=[O:22])=[C:19]([C:24]([OH:27])([CH3:26])[CH3:25])[N:18]=[C:17]2[CH2:28][CH2:29][CH3:30])=[CH:11][CH:10]=1)#[N:2].[N-:31]=[N+:32]=[N-:33].[Na+].Cl.C(N(CC)CC)C.[OH-].[Na+]>O.C1(C)C=CC=CC=1>[OH:27][C:24]([C:19]1[N:18]=[C:17]([CH2:28][CH2:29][CH3:30])[N:16]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]3[NH:33][N:32]=[N:31][N:2]=3)=[CH:14][CH:13]=2)[C:20]=1[C:21]([OH:23])=[O:22])([CH3:25])[CH3:26]
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: CCCc1nc(C(C)(C)O)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.4 %

Procedure:
Into a 500-ml flask equipped with a reflux condenser, thermometer and stirrer were placed 43.5 g (0.10 mole) of ethyl ester of 1-(2'-cyanobiphenyl-4-yl)methyl-4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylic acid, 19.5 g (0.30 mole) of sodium azide, 41.3 g (0.30 mole) of triethylamine hydrochloride and 206 ml of toluene. The mixture was heated with stirring to a temperature of 95° to 100° C. to undergo a reaction for 24 hours. After completion of the reaction, the reaction mixture was cooled to room temperature. Then, 35.0 g (0.42 mole) of a 48 wt % aqueous solution of NaOH and 335 ml of water were added. The mixture was fractionated after 2 hours' stirring at room temperature. The aqueous layer was washed and fractionated with the addition of 103 ml of toluene. The aqueous layer was adjusted to a pH of 2 to 3.5 with 36 wt % hydrochloric acid to separate out crystals, which were collected by filtration and dried. The crystals were heated, washed with methanol with stirring, cooled, filtered for collection and dried, giving 32.6 g (0.07 mole) of 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(tetrazole-5-yl)phenyl]phenyl}methylimidazole-5-carboxylic acid (yield 72.4% based on ethyl ester of 1-(2'-cyanobiphenyl-4-yl)methyl-4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylic acid). The reaction is illustrated below with chemical formulas. ##STR29##
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[N:7][C:6]2[N:9]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:10]=[CH:11][C:5]=2[C:4]=1[NH:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:23][CH2:22]1.[C:34](N1C=CN=C1)(N1C=CN=C1)=[O:35]>ClCCl>[CH2:27]([N:24]1[CH2:23][CH2:22][CH:21]([N:20]2[C:4]3[C:5]4[CH:11]=[CH:10][N:9]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:17])([CH3:18])[CH3:19])[C:6]=4[N:7]=[CH:8][C:3]=3[CH2:2][NH:1][C:34]2=[O:35])[CH2:26][CH2:25]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C[Si](C)(C)CCOCn1ccc2c(NC3CCN(Cc4ccccc4)CC3)c(CN)cnc21
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1ccc2c3c(cnc21)CNC(=O)N3C1CCN(Cc2ccccc2)CC1
Yield: 77.6 %

Procedure:
5-(Aminomethyl)-N-(1-benzylpiperidin-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-amine (38 mg, 0.081 mmol) in dichloromethane was stirred with 1,1′-carbonyldiimidazole (20.0 mg, 0.123 mmol) at 80° C. for 1 hour. The reaction mixture was concentrated under reduced pressure and, after addition of water, extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=10/1 (v/v)) to give the title compound (30.9 mg, yield 77%).
Reaction SMILES: [CH2:1]([C@H:8]([CH2:12][CH:13]=[CH2:14])[C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[I:15]I>C1COCC1.O.CCOCC>[CH2:1]([C@@H:8]1[CH2:12][C@H:13]([CH2:14][I:15])[O:10][C:9]1=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: II
Reactant: C=CC[C@@H](CCCCCCC)C(=O)O
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCC[C@@H]1C[C@H](CI)OC1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.1 %

Procedure:
To a solution of 7.14 g (0.036 mol) of the product of Example 5 in 750 mL of THF/H2O (2:1), cooled to 0 degrees, was added 7.22 g (0.072 mol) of KHCO3 followed by 11.97 g (0.072 mol) of KI and then 18.30 g (0.072 mol) of iodine. The reaction was allowed to warm to room temperature and stirred for 18 h. The resulting mixture was diluted with ether and the organic layer was washed with aqueous sodium bisulfite solution, H2O and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (1:10) to provide 8.30 g (71%) of the title compound and 3.36 g (29%) of the corresponding iodo-trans lactone as white solids. CI Mass Spec: 325.3 (M+H).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH2:13][Si:14]([CH2:17][CH2:18][CH2:19][CH3:20])([CH3:16])[CH3:15])(=O)=O)=CC=1.[C:22]1([CH:29]=[CH:28][C:26]([OH:27])=[CH:25][CH:24]=1)[OH:23].[OH-].[K+].Cl>O.C(O)C.CO>[CH2:17]([Si:14]([CH3:16])([CH3:15])[CH2:13][CH2:12][CH2:11][O:23][C:22]1[CH:29]=[CH:28][C:26]([OH:27])=[CH:25][CH:24]=1)[CH2:18][CH2:19][CH3:20]
Reactant: Oc1ccc(O)cc1
Reactant: CCCC[Si](C)(C)CCCOS(=O)(=O)c1ccc(C)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CCO
Product: CCCC[Si](C)(C)CCCOc1ccc(O)cc1
Temperature: 65 °C
Yield: 50.6 %

Procedure:
The above-obtained 3-(butyldimethylsilyl)propyl p-toluenesulfonate was added dropwise in 45 min. to a mixture of 2.32 g (21.1 mM) of hydroquinone, 1.13 g (17.1 mM) of 85 %-potassium hydroxide, 6 ml of methanol and 30 ml of ethanol under stirring at 65° C., followed by stirring for 0.5 hour and further stirring for 6 hour at 80° C. After the reaction, the reaction mixture was poured into cold water, acidified with hydrochloric acid (pH≈2) and extracted with ethyl acetate, followed by washing with water and drying with anhydrous magnesium sulfate. The magnesium sulfate in the resultant mixture was filtered off and the filtrate was condensed into a solid, followed by purification by silica gel column chromatography (eluent: toluene) to obtain 2.05 g of 4-[3-(butyldimethylsilyl)propoxy]phenol (Yield: 50.6 %).
Reaction SMILES: ClC(O[O:5][CH2:6][CH:7]([C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]2[O:18][CH2:19][O:20][C:11]=2[CH:10]=1)[CH3:8])=O.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C1C[O:30][CH2:29]C1>>[CH2:19]1[O:18][C:12]2[CH:13]=[C:14]([N+:15]([O-:17])=[O:16])[C:9]([CH:7]([CH3:8])[CH2:6][O:5][C:29]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[O:30])=[CH:10][C:11]=2[O:20]1
Reactant: C1CCOC1
Reactant: CC(COOC(=O)Cl)c1cc2c(cc1[N+](=O)[O-])OCO2
Reactant: C1CCNCC1
Product: CC(COC(=O)N1CCCCC1)c1cc2c(cc1[N+](=O)[O-])OCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
To 2-(3,4-methylenedioxy-6-nitrophenyl)propoxyl chloroformate (650 mg, 2.3 mmol) in dry THF (30 mL) was dropwisely added piperidine (800 μL, 8.1 mmol) in dry THF (20 mL). The reaction mixture was refluxed for 3 h and then stirred at r.t. overnight. The solvent was evaporated and the residue was dissolved in water and washed with ether four times. The organic extracts were combined and dried over anhydrous Na2SO4. The solvent was removed in vacuo and the residue was purified by silica gel chromatography (eluant: AcOEt/Hex, 1/4, v/v). The collected fraction provided 2-(3,4-methylenedioxy-6-nitrophenyl)propoxycarbonyl piperidine (0.61 g, yield 79%). 1H-NMR (600 MHz, CDCl3): δ 7.21 (s, 1H, Ar—H), 6.79 (s, 1H, Ar—H), 6.01 (s, 2H, CH2), 4.12 (m, 2H, CH2), 3.71 (m, 1H, CH), 3.23 (s, 4H, CH2), 1.47 (m, 2H, CH2), 1.38 (s, 4H, CH2), 1.22 (d, 3H, J=6.6 Hz, CH3). 13C-NMR (150 MHz, CDCl3): δ 154.86 (OCOR), 151.50 (C ipso to NO2), 146.13 (C para to NO2), 143.89 (C para to CH(CH3)CH2OCOR), 134.59 (C ipso to CH(CH3)CH2OCOR), 106.75 (C ortho to CH(CH3)CH2OCOR), 105.02 (C ortho to NO2), 102.75 (OCH2O), 68.96 (CH2OCOR), 44.63 (Cα to ring N), 33.45 (CH), 25.47 (Cβ to ring N), 24.21 (Cγ to ring N), 17.78 (CH3). TLC: 33% ethyl acetate in hexanes, Rf=0.5.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([OH:13])[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11].Cl[C:15]1[CH:20]=[CH:19][N:18]=[C:17]([S:21][CH3:22])[N:16]=1>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[O:13][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([S:21][CH3:22])[N:16]=1
Reactant: CSc1nccc(Cl)n1
Reactant: O=[N+]([O-])c1ccc(O)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nccc(Oc2ccc([N+](=O)[O-])c(Cl)c2)n1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 64.1 %

Procedure:
160 mg (6.34 mmol) 95% sodium hydride was given to a solution of 1.00 g (5.76 mmol) 3-chloro-4-nitrophenol in 15 ml DMF. Stirring was continued for 30 min. at room temperature. 925 mg (5.76 mmol) 4-chloro-2-methylsulfanyl-pyrimidine was added and the mixture heated to 80° C. for 16 h. The reaction mixture was evaporated, taken up with water and extracted with ethyl acetate. The organic phase was extracted with water, dried (sodium sulphate) and evaporated. The obtained material was dissolved in ethyl acetate and purified by chromatography over silica (ethyl acetate/n-heptane) to give 1.10 g (64%) 4-(3-chloro-4-nitro-phenoxy)-2-methylsulfanyl-pyrimidine.
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[CH:10][CH:11]=1)[C:8]#[N:9])([O-])=O.[C:14]([C:18]1[CH:19]=[C:20]([OH:25])[C:21](=[CH:23][CH:24]=1)[OH:22])([CH3:17])([CH3:16])[CH3:15]>>[C:8]([C:7]1[CH:10]=[C:11]([CH:4]=[CH:5][C:6]=1[C:12]#[N:13])[O:22][C:21]1[CH:23]=[CH:24][C:18]([C:14]([CH3:17])([CH3:15])[CH3:16])=[CH:19][C:20]=1[O:25][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([C:12]#[N:13])[CH:5]=1)#[N:9]
Reactant: CC(C)(C)c1ccc(O)c(O)c1
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Product: CC(C)(C)c1ccc(Oc2ccc(C#N)c(C#N)c2)c(Oc2ccc(C#N)c(C#N)c2)c1

Procedure:
The experimental procedure and reaction conditions were the same as described for Examples 5 and 6. Reagents used were 3.60 g (0.02 moles plus 0.14 g excess) of 4-nitrophthalonitrile and 1.66 g (0.01 moles) of 4-tert-butylcatechol (Aldrich). After workup and recrystallization 3.2 g (76.55% theoretical yield) of off-white crystals of the title compound were obtained. The product had the formula: ##STR14## The melting point was 161°-162° C. The elemental analysis for C26H18N4O2 was calc.: C, 74.64%; H, 4.30%; N, 13.39%; found: C, 74.55%; H, 4.25%; N, 13.39%.
Reaction SMILES: [H-].[Na+].I[CH2:4][CH3:5].[Br:6][C:7]1[CH:8]=[C:9]2[C:13](=[C:14]([CH3:16])[CH:15]=1)[NH:12][N:11]=[CH:10]2.O>CN(C=O)C>[Br:6][C:7]1[CH:8]=[C:9]2[C:13](=[C:14]([CH3:16])[CH:15]=1)[N:12]([CH2:4][CH3:5])[N:11]=[CH:10]2.[Br:6][C:7]1[CH:15]=[C:14]([CH3:16])[C:13]2[C:9](=[CH:10][N:11]([CH2:4][CH3:5])[N:12]=2)[CH:8]=1
Reactant: Cc1cc(Br)cc2cn[nH]c12
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1cc2cc(Br)cc(C)c2n1
Product: CCn1ncc2cc(Br)cc(C)c21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Sodium hydride (60% in oil, 240 mg) and iodoethane (0.64 mL) were added to a solution of 5-bromo-7-methyl-1H-indazole (844 mg) in DMF (10 mL), and the reaction solution was stirred at room temperature for 15 minutes. Water was added to the reaction solution, and then the reaction solution was extracted with ethyl acetate. The organic layer was washed successively with water and a saturated saline solution. After drying over anhydrous sodium sulfate, the solvent was evaporated under vacuum. The resultant residue was purified by column chromatography on silica gel (developing solvent:hexane/ethyl acetate) to obtain 5-bromo-1-ethyl-7-methyl-1H-indazole and 5-bromo-2-ethyl-7-methyl-2H-indazole.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].[Al+3].[Cl-].[Cl-].[Cl-].[Cl:16][C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=1[O:24][CH3:25].Cl>ClCCCl>[Cl:23][C:22]1[C:17]([Cl:16])=[C:18]([O:24][CH3:25])[CH:19]=[CH:20][C:21]=1[C:4]([C:3]1[C:2]([F:1])=[CH:10][CH:9]=[CH:8][C:7]=1[F:11])=[O:5]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: COc1cccc(Cl)c1Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1ccc(C(=O)c2c(F)cccc2F)c(Cl)c1Cl
Reaction time: 1 h

Procedure:
To a solution of 24.6 g of 2,6-difluoro benzoylchloride in 100 ml of 1,2-dichloroethane, 18.5 g of AlCl3 is added in portions over a 30 minute period. A solution of 22.5 g of 2,3-dichloroanisole in 100 ml of 1,2-dichloroethane is added thereto. The mixture is stirred for one hour and poured over 100 ml concentrated HCl and ice. The organic layer is separated and the aqueous layer extracted with CHCl3. The organic extract is washed with water, dried (Na2SO4) and evaporated to give an oil which crystallizes from hexane to yield solid 2,3-dichloro-4-methoxy-2',6'-difluorobenzophenone which upon recrystallization from ether has an mp 94°-96° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:10](=[O:12])[C:9]([O:13][CH3:14])=[CH:8][C:7](=[O:15])[C:6]=2[C:5]([OH:16])=[C:4]2[C:17](=[O:37])[C@:18]3([C:32]4[C:31]([OH:33])=[C:30]5[C:25]([CH:26]=[C:27]([CH:35]=O)[NH:28][C:29]5=[O:34])=[CH:24][C:23]=4[CH2:22][CH2:21]3)[C:19](=[O:20])[C:3]=12.Br.[NH:39]([C:41]1[NH:42][CH2:43][CH2:44][N:45]=1)[NH2:40].C1C=CC(CNC(CN2C3C(=CC=CC=3)C(C=O)=C2)=O)=CC=1>CN(C=O)C.FC(F)(F)C(O)=O>[NH:45]1[CH2:44][CH2:43][N:42]=[C:41]1[NH:39][N:40]=[CH:35][C:27]1[NH:28][C:29](=[O:34])[C:30]2[C:25]([CH:26]=1)=[CH:24][C:23]1[CH2:22][CH2:21][C:18]3([C:17](=[O:37])[C:4]4=[C:5]([OH:16])[C:6]5[C:7](=[O:15])[CH:8]=[C:9]([O:13][CH3:14])[C:10](=[O:12])[C:11]=5[C:2]([OH:1])=[C:3]4[C:19]3=[O:20])[C:32]=1[C:31]=2[OH:33]
Reactant: COC1=CC(=O)c2c(O)c3c(c(O)c2C1=O)C(=O)[C@]1(CCc2cc4cc(C=O)[nH]c(=O)c4c(O)c21)C3=O
Reactant: NNC1=NCCN1
Agent: Br
Agent: O=Cc1cn(CC(=O)NCc2ccccc2)c2ccccc12
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COC1=CC(=O)c2c(O)c3c(c(O)c2C1=O)C(=O)C1(CCc2cc4cc(C=NNC5=NCCN5)[nH]c(=O)c4c(O)c21)C3=O
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
Five (5.00) mg (9.42 μmol) fredericamycin aldehyde (4) are dissolved in 500 μl DMF and 25 μl trifluoracetic acid. At room temperature, 2.05 mg (11.3 μmol) 2-hydrazino-2-imidazolin hydrobromide is added. After stirring for 4.5 h at room temperature, 1 equivalent each of Wang aldehyde resin and sulfonohydrazide resin are added and stirred for 2 h. Separation of the resin by filtration and concentration of the reaction solution at high vacuum.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][C:8]#[N:9].O.[OH-].[Na+]>CCOCC>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][NH2:9]
Reactant: N#CCCc1cccs1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: NCCCc1cccs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 555.6 %

Procedure:
The product of Example 41 (8.3 g, 10.5 mmol) dissolved in 25 ml of Et2O was added dropwise (15 min.) to a stirred slurry of lithium aluminium hydride(LAH) in 125 ml of dry Et2O under an Ar atmosphere at room temperature. After the addition was complete the reaction was stirred at room temperature an additional 18 h. With great care, 8.0 ml of water were added dropwise to the vigorously stirred reaction mixture. Following this, 8.0 ml of 4N NaOH were then carefully added. Finally 22 ml of H2O were added and the aluminum salts were filtered from the Et2O solution. The filtrate was concentrated to give 8.24 g of the title products which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C@H:13]([C:22]([O:24][CH3:25])=[O:23])[CH2:14][O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]O)=[C:29]([N+:35]([O-:37])=[O:36])[CH:28]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[O:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH:16]1[O:15][CH2:14][CH:13]([N:12]([S:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)(=[O:10])=[O:11])[CH2:31][C:30]1[CH:33]=[CH:34][C:27]([Cl:26])=[CH:28][C:29]=1[N+:35]([O-:37])=[O:36])[C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)[C@H](COC1CCCCO1)NS(=O)(=O)c1ccc(OC)cc1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(COC1CCCCO1)N(Cc1ccc(Cl)cc1[N+](=O)[O-])S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 1.67 g (4.4 mmol) of (D,L) N-(4-methoxybenzenesulfonyl)-O-(2-tetrahydropyranyl) serine, methyl ester, 0.825 g, (4.4 mol) of 4-chloro-2-nitrobenzyl alcohol and 1.16 g (4.4 mmol) of triphenylphosphine in 4.5 ml of tetrahydrofuran was added dropwise a solution of 0.766 g (4.4 mmol) of diethyl azodicarboxylate in 1 ml of tetrahydrofuran. The mixture was stirred at room temperature overnight and the solvent removed under vacuum. The residue was triturated with diethyl ether, filtered and the filtrate passed through a thin pad of hydrous magnesium silicate. The pad was washed with ethyl acetate and the total filtrate concentrated to dryness under vacuum to give 4.54 g of solid. The solid was chromatographed on silica gel with hexane-ethyl acetate (55:45) as solvent. The fractions containing product were combined and the solvent removed to give 0.55 g of oily solid; Mass spectrum (ES) 543.1 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([CH3:20])([CH3:19])[CH:13]=[C:12]2[CH2:21]SC1C=CC(OC)=CC=1.BrCC1[C:42]2[C:37](=[CH:38][CH:39]=[C:40](C3C=CC=CC=3OC)[CH:41]=2)[NH:36]C(C)(C)C=1.C(=O)([O-])[O-].[K+].[K+]>COC1C=CC(S)=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([CH3:20])([CH3:19])[CH:13]=[C:12]2[CH2:21][NH:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: COc1ccc(SCC2=CC(C)(C)Nc3ccc(-c4ccccc4OC)cc32)cc1
Reactant: COc1ccccc1-c1ccc2c(c1)C(CBr)=CC(C)(C)N2
Agent: COc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccccc1-c1ccc2c(c1)C(CNc1ccccc1)=CC(C)(C)N2

Procedure:
6-(2-Methoxyphenyl)-4-(4-methoxyphenylsulfanylmethyl)-2,2-dimethyl-1,2-dihydroquinoline 100 mg of 4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline, 80 mg of potassium carbonate, and 70 μL of 4-methoxy benzenethiol reacted to give 9 mg of the title compound as an oil.