Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [P:1]([O:13][CH2:14][CH2:15][NH:16][S:17]([C:20]1[CH:37]=[CH:36][C:23]2[C:24]3[CH:25]([CH2:34][Cl:35])[CH2:26][NH:27][C:28]=3[CH:29]=[C:30]([N+:31]([O-:33])=[O:32])[C:22]=2[CH:21]=1)(=[O:19])=[O:18])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[CH3:39][N:40]([CH3:56])[CH2:41][CH2:42][O:43][C:44]1[CH:45]=[C:46]2[C:50](=[CH:51][CH:52]=1)[NH:49][C:48]([C:53](O)=[O:54])=[CH:47]2.CCN=C=NCCCN(C)C.CC1C=CC(S(O)(=O)=O)=CC=1>CC(N(C)C)=O>[P:1]([O:13][CH2:14][CH2:15][NH:16][S:17]([C:20]1[CH:37]=[CH:36][C:23]2[C:24]3[CH:25]([CH2:34][Cl:35])[CH2:26][N:27]([C:53]([C:48]4[NH:49][C:50]5[C:46]([CH:47]=4)=[CH:45][C:44]([O:43][CH2:42][CH2:41][N:40]([CH3:56])[CH3:39])=[CH:52][CH:51]=5)=[O:54])[C:28]=3[CH:29]=[C:30]([N+:31]([O-:33])=[O:32])[C:22]=2[CH:21]=1)(=[O:19])=[O:18])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OP(=O)(OCCNS(=O)(=O)c1ccc2c3c(cc([N+](=O)[O-])c2c1)NCC3CCl)OC(C)(C)C
Reactant: CN(C)CCOc1ccc2[nH]c(C(=O)O)cc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CC(=O)N(C)C
Product: CN(C)CCOc1ccc2[nH]c(C(=O)N3CC(CCl)c4c3cc([N+](=O)[O-])c3cc(S(=O)(=O)NCCOP(=O)(OC(C)(C)C)OC(C)(C)C)ccc43)cc2c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 87.8 %

Procedure:
A mixture of 227 (351 mg, 0.61 mmol), 5-[2-(dimethylamino)ethoxy]indole-2-carboxylic acid hydrochloride (225 mg, 0.79 mmol), EDCI (466 mg, 2.4 mmol) and TsOH (21 mg, 0.12 mmol) in DMA (3 mL) was stirred at room temperature for 3.5 h and then cooled to 0° C. Ice-cold aqueous NaHCO3 was added, and the resulting precipitate was filtered off, washed with aqueous NaHCO3 and water, and dried. Trituration with acetone gave di(tert-butyl) 2-({[1-(chloromethyl)-3-{5-[2-(dimethylamino)ethoxy]indol-2-carbonyl}-5-nitro-1,2-dihydro-3H-benzo[e]indol-7-yl]sulfonyl}amino)ethyl phosphate (229) (433 mg, 88%) as a yellow solid: mp 220-225° C. (dec.); 1H NMR [(CD3)2SO] δ 11.73 (s, 1H), 9.30 (s, 1H), 8.87 (d, J=1.7 Hz, 1H), 8.45 (d, J=8.9 Hz, 1H), 8.16 (br s, 1H), 8.02 (dd, J=8.9, 1.7 Hz, 1H), 7.42 (d, J=8.9 Hz, 1H), 7.22 (d, J=1.6 Hz, 1H), 7.18 (d, J=2.4 Hz, 1H), 6.96 (dd, J=−8.9, 2.4 Hz, 1H), 5.00-4.94 (m, 1H), 4.73 (dd, J=11.0, 2.4 Hz, 1H), 4.68-4.62 (m, 1H), 4.19-4.11 (m, 2H), 4.07 (t, J=5.9 Hz, 2H), 3.87-3.80 (m, 2H), 3.08-3.03 (m, 2H), 2.66 (t, J=5.9 Hz, 2H), 2.24 (s, 6H), 1.36 (s, 18H. Anal. (C36H47ClN5O10PS.½H2O) C, H, N.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][CH2:5]1.[Cl:11][C:12]1[CH:31]=[CH:30][C:15]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23](O)=[C:24]([O:27][CH3:28])[CH:25]=3)[N:20]=[CH:19][N:18]=2)=[C:14]([F:32])[CH:13]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C(Cl)Cl>[Cl:11][C:12]1[CH:31]=[CH:30][C:15]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:1][CH2:2][CH2:3][N:4]4[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][CH2:5]4)=[C:24]([O:27][CH3:28])[CH:25]=3)[N:20]=[CH:19][N:18]=2)=[C:14]([F:32])[CH:13]=1
Reactant: CN1CCN(CCO)CC1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCN1CCN(C)CC1
Reaction time: 3.5 h
Yield: 25.3 %

Procedure:
A solution of 1-(2-hydroxyethyl)4-methylpiperazine (112 mg, 0.78 mmol) in methylene chloride (1 ml) was added to a stirred suspension of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxy-quinazoline (225 mg, 0.7 mmol), (prepared as described for the starting material in Example 4), and tributylphosphine (420 mg, 2.1 mmol) in methylene chloride (10 ml). 1,1′-(Azodicarbonyl)dipiperidine (525 mg, 2.1 mmol) was then added in portions to the mixture. The resulting clear, pale yellow solution was stirred for 3.5 hours, then allowed to stand overnight. The reaction mixture was quenched with ether (8 ml) and the precipitate was removed by filtration. The solvent was removed from the filtrate by evaporation and the residue dissolved in acetone and treated with 1M ethereal hydrogen chloride until the hydrochloride salt precipitated. The precipitate was collected by filtration, dissolved in methanol and then basified with excess triethylamine. The volatiles were removed by evaporation and the residue purified by column chromatography eluting with methylene chloride/methanol/0.88 aqueous ammonia (100/8/1). The resulting purified oil was triturated with ether, collected by filtration and dried to give 4-(4-chloro-2-fluoroanilino)-6-methoxy 7-(2-(4-methylpiperazin-1-yl)ethoxy)quinazoline (79 mg, 25%) as a white solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[N+:7]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[C:13]([OH:15])=O)([O-])=O.CN(C)C=O.[Cl:26][C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][C:33]=1[Cl:34])[NH2:30]>>[NH2:7][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[C:13]([NH:30][C:29]1[CH:31]=[CH:32][C:33]([Cl:34])=[C:27]([Cl:26])[CH:28]=1)=[O:15]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: COc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2ccc(Cl)c(Cl)c2)cc1N
Yield: 68.5 %

Procedure:
Prepared according to the procedure described for Example 1 using oxalyl chloride (5.0 mL, 57.31 mmol), 3-nitro-4-methoxybenzoic acid (5.04 g, 25.56 mmol), dimethylformamide (0.5 mL, 6.46 mmol), and 3,4-dichloroaniline (8.3 g, 51 mmol) to afford the product (5.45 g); m.p. 179-182° C.
Reaction SMILES: C[C@@H]1O[C@@H](OC(C[C@H](CC(O[C@H](CC([O:36][C@@H:37]2[C@@H:44]([C:45]([OH:47])=[O:46])[N:43]([CH3:48])[C:41](=[O:42])[C@H:40]([C@H:49]([O:65][C@@H:66]3[O:70][C@H:69]([CH2:71][NH2:72])[C@@H:68]([OH:73])[C@H:67]3[OH:74])[C@H:50]3[O:54][C@@H:53]([N:55]4[C:61](=[O:62])[NH:60][C:58](=[O:59])[CH:57]=[CH:56]4)[C@H:52]([OH:63])[C@@H:51]3[OH:64])[N:39]([CH3:75])[CH2:38]2)=O)CCCCCCCCCCCC(C)C)=O)C)=O)[C@H](OC)[C@H](OC)[C@H]1OC.N>CN(C)C=O>[CH3:75][N:39]1[C@@H:40]([C@H:49]([O:65][C@@H:66]2[O:70][C@H:69]([CH2:71][NH2:72])[C@@H:68]([OH:73])[C@H:67]2[OH:74])[C@H:50]2[O:54][C@@H:53]([N:55]3[C:61](=[O:62])[NH:60][C:58](=[O:59])[CH:57]=[CH:56]3)[C@H:52]([OH:63])[C@@H:51]2[OH:64])[C:41](=[O:42])[N:43]([CH3:48])[C@H:44]([C:45]([OH:47])=[O:46])[C@@H:37]([OH:36])[CH2:38]1
Reactant: CO[C@@H]1[C@@H](OC)[C@H](C)O[C@@H](OC(=O)C[C@@H](C)CC(=O)O[C@@H](CCCCCCCCCCCC(C)C)CC(=O)O[C@H]2CN(C)[C@@H]([C@H](O[C@@H]3O[C@H](CN)[C@@H](O)[C@H]3O)[C@H]3O[C@@H](n4ccc(=O)[nH]c4=O)[C@H](O)[C@@H]3O)C(=O)N(C)[C@@H]2C(=O)O)[C@@H]1OC
Agent: N
Solvent: CN(C)C=O
Product: CN1C[C@H](O)[C@@H](C(=O)O)N(C)C(=O)[C@@H]1[C@H](O[C@@H]1O[C@H](CN)[C@@H](O)[C@H]1O)[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 96 h
Yield: 100.4 %

Procedure:
The reaction of Step (1) is as shown below. Specifically, 150 mg of caprazamycin B were dissolved in 1.5 mL of N,N-dimethylformamide. To this solution, 1.5 mL of 28% aqueous ammonia were added and the resulting mixture was stirred at room temperature for 4 days for hydrolysis. The insoluble material developed in the reaction mixture was removed by filtration and the filtrate was concentrated. The resulting residue was washed with acetone and dried to afford 74.7 mg of caprazol as a colorless solid (99% yield).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:4](=[O:21])[C:3]=1[C:22](=O)[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1.O.[NH2:33][NH2:34]>C(O)C>[N+:18]([C:14]1[CH:13]=[C:12]([N:5]2[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]3[NH:33][N:34]=[C:22]([CH2:23][CH2:24][C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)[C:3]=3[C:4]2=[O:21])[CH:17]=[CH:16][CH:15]=1)([O-:20])=[O:19]
Reactant: NN
Reactant: O=C(CCc1ccncc1)c1c(O)c2cccnc2n(-c2cccc([N+](=O)[O-])c2)c1=O
Solvent: CCO
Solvent: O
Product: O=c1c2c(CCc3ccncc3)n[nH]c2c2cccnc2n1-c1cccc([N+](=O)[O-])c1
Yield: 95.5 %

Procedure:
To a suspension of 4-hydroxy-1-(3-nitrophenyl)-3-[1-oxo-3-(pyridin-4-yl)propyl]-1,8-naphthyridin-2 (1H)-one (416 mg, 1.0 mmol, prepared in Synthetic Example 4) in ethanol (15 ml) was added hydrazine monohydrate (80%, 180 μl, 4.5 mmol, 4.5 eq.), and the resultant mixture was treated in the same manner as in Example 1 to give 5-(3-nitrophenyl)-3-[2-(pyridin-4-yl)ethyl]-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (394 mg, 96%).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]([F:23])([F:22])[F:21])[CH:18]=3)[CH2:13][CH2:12]2)[N:3]=1.[NH2:24][C@H:25]1[CH2:30][CH2:29][C@H:28]([NH2:31])[CH2:27][CH2:26]1>>[F:21][C:20]([F:23])([F:22])[C:17]1[CH:18]=[C:19]2[C:14]([CH2:13][CH2:12][N:11]2[C:4]2[N:3]=[C:2]([NH:24][C@H:25]3[CH2:30][CH2:29][C@H:28]([NH2:31])[CH2:27][CH2:26]3)[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][NH:8]3)=[CH:15][CH:16]=1
Reactant: FC(F)(F)c1ccc2c(c1)N(c1nc(Cl)nc3[nH]cnc13)CC2
Reactant: N[C@H]1CC[C@H](N)CC1
Product: N[C@H]1CC[C@H](Nc2nc(N3CCc4ccc(C(F)(F)F)cc43)c3nc[nH]c3n2)CC1
Temperature: 140 °C

Procedure:
340 mg of product obtained in stage 1 above are mixed with 800 mg of trans-1,4-diaminocyclohexane, and the mixture is then heated at 140° C. for approximately 8 hours. The mixture is allowed. to return to ambient temperature. Purification is carried out by chromatography on silica with a CH2Cl2-MeOH—NH4OH: 85-15-1.5 mixture for eluent. 275 mg of product are obtained and a paste is formed in HCl/ethanol: 50-50. Partial drying and drying under vacuum at 50° C. are carried out. 244 mg of expected product are obtained.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=O)([CH3:5])[CH2:3][CH3:4].[CH2:15]([O:17][C:18]([C:20]1([NH2:29])[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21]1)=[O:19])[CH3:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH2:15]([O:17][C:18]([C:20]1([NH:29][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[C:2]([CH3:1])([CH3:5])[CH2:3][CH3:4])[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21]1)=[O:19])[CH3:16]
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Reactant: CCC(C)(C)c1ccccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1(NC(=O)c2ccccc2C(C)(C)CC)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.4 %

Procedure:
To a solution of 2-(1,1-dimethyl-propyl)-benzoic acid (140 mg, 0.73 mmol), 2-amino-indan-2-carboxylic acid ethyl ester (150 mg, 0.73 mmol), HATU (333 mg, 0.87 mmol) in anhydrous DMF (1 mL) is added DIPEA (1904, 1.1 mmol). The resulting solution is stirred at RT overnight. Water (10 mL) is then poured into the reaction mixture, and then the reaction mixture is extracted with EtOAc (3×5 mL). The combined organic layers are concentrated in vacuo. The residue is purified by flash column chromatography (12 g silica gel, gradient elution: 0-30% EtOAc in heptane) to give product (247) as yellow oil (220 mg, 89%).
Reaction SMILES: [CH:1]1([S:7][CH2:8][CH2:9][N:10]([N:16]=[O:17])[C@H:11]([C:13]([OH:15])=O)[CH3:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N(N[C@H](C(O)=O)C)=O.C(OC(=O)C)(=O)C>O>[CH:1]1([S:7][CH2:8][CH2:9][N+:10]2[N-:16][O:17][C:13](=[O:15])[C:11]=2[CH3:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[C@@H](C(=O)O)N(CCSC1CCCCC1)N=O
Agent: C[C@H](NN=O)C(=O)O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: Cc1c(=O)o[n-][n+]1CCSC1CCCCC1
Reaction time: 96 h

Procedure:
The oil obtained in Example 3, N-[2-cyclohexylthio)ethyl]-N-nitrosoalanine, is treated with 54 parts of acetic anhydride and allowed to stand for 4 days at room temperature. After that time, the reaction mixture is added to 500 parts of water and extracted with methylene chloride. The organic extracts are washed with water and aqueous sodium bicarbonate, dried over anhydrous sodium sulfate and evaporated to dryness. The oil remaining is crystallized from ether by seeding and cooling. The crystalline material is recovered by filtration and dried to afford pure 3-[2-(cyclohexylthio)ethyl] -4-methylsydnone, melting at about 82°-83°. That compound is represented structurally by the following formula ##STR7##
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:24][C:25]4[CH:26]=[N:27][C:28]([O:32][CH3:33])=[C:29]([F:31])[CH:30]=4)=[N:18][CH:19]=[C:20]([CH:23]=3)[CH:21]=[O:22])[N:10]=2)=CC=1.C(O)(C(F)(F)F)=O.S(O)(C(F)(F)F)(=O)=O>C(Cl)Cl>[NH2:8][C:9]1[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]2[C:17]([NH:24][C:25]3[CH:26]=[N:27][C:28]([O:32][CH3:33])=[C:29]([F:31])[CH:30]=3)=[N:18][CH:19]=[C:20]([CH:23]=2)[CH:21]=[O:22])[N:10]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C=O)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ncc(Nc2ncc(C=O)cc2-c2nc(C)nc(N)n2)cc1F
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
A solution of 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)nicotinaldehyde (380 mg, 0.638 mmol) in DCM (5 mL) was treated with TFA (6.0 mL, 78 mmol) and then TfOH (0.050 mL, 0.563 mmol). The solution was heated at 80° C. under a condenser. After 2.5 h, more TfOH (0.050 mL, 0.563 mmol) was added. After 24 h, the mixture was concentrated. The residue was azeotroped with toluene (10 mL) once. The mixture was suspended in 1:1 DMSO-water (5 mL each) and filtered. The resulting solid was then suspended in saturated NaHCO3 for several hours and filtered. The mother liquor was discarded. The resulting sludge was dissolved in hot DMSO and filtered. The filtrate was diluted with MeOH (2× v/v) and allowed to settle. The resulting suspension was filtered. The resulting solid was again dissolved in hot DMSO and diluted with MeOH. After 3 repetitions, the solid was about 95% pure product (50 mg). LCMS (ES, pos.): calcd for C16H14FN7O2: 355.1. found: 356.2 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 12.47 (br. s., 1H); 9.92 (s, 1H); 9.17 (br. s., 1H); 8.81 (br. s., 1H); 8.42 (br. s., 1H); 8.32 (d, J=13.11 Hz, 1H); 8.01 (br. s., 1H); 7.85 (d, J=0.78 Hz, 1H); 3.96 (s, 3H); 2.46 (br. s., 3H). 19F NMR (377 MHz, d6-DMSO) δ −139.31 (d, J=11.44 Hz, 1F).
Reaction SMILES: Cl[CH2:2][O:3][CH3:4].CC#N.[Cl:8][C:9]1[CH:10]=[C:11]([OH:19])[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(OCC)C>[Cl:8][C:9]1[CH:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[CH:12]=[C:11]([O:19][CH2:2][O:3][CH3:4])[CH:10]=1
Reactant: COCCl
Reactant: Oc1cc(Cl)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CC#N
Product: COCOc1cc(Cl)cc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
Neat chloro(methoxy)methane (1.8 mL, 23.8 mmol) was added to a MeCN solution (20 mL) of 3-chloro-5-(trifluoromethyl)phenol (3.6 g, 18.3 mmol) and Cs2CO3 and the resulting mixture was stirred at room temperature. After 5 h the resulting mixture was diluted with diethyl ether, filtered and concentrated. The resulting material was filtered through a short pad of silica gel, followed by concentration to yield 1-chloro-3-(methoxymethoxy)-5-(trifluoromethyl)benzene.
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][CH2:8][CH:9]([C:13]([OH:15])=O)[CH2:10][C:11](=[O:12])[C:5]=2[CH:4]=[CH:3][CH:2]=1.O=S(Cl)Cl.[C:20]1([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>C(Cl)Cl>[C:20]1([CH:26]2[CH2:27][CH2:28][N:29]([C:13]([CH:9]3[CH2:8][CH2:7][C:6]4[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=4[C:11](=[O:12])[CH2:10]3)=[O:15])[CH2:30][CH2:31]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1CC(C(=O)O)CCc2ccccc21
Reactant: c1ccc(C2CCNCC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: O=C1CC(C(=O)N2CCC(c3ccccc3)CC2)CCc2ccccc21
Reaction time: 8 h
Yield: 95.9 %

Procedure:
To a solution of 0.3 g (1.47 mmol) of (±)-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one-7-carboxylic acid in 5 mL of CH2Cl2 were added, at 0° C., 0.27 mL (3.69 mmol) of SOCl2 and the solution was warmed at 50° C. for 20 min. The solvent and the excess SOCl2 were removed in vacuo and the resulting residue was redissolved in 5 mL of CH2Cl2. 0.24 g (1.47 mmol) of 4-phenylpiperidine and 0.2 mL (1.47 mmol) of triethylamine dissolved in 5 mL of CH2Cl2 were added at room temperature to this solution; the stirring was continued overnight, then the solvent was removed in vacuo and the residue was taken up in AcOEt; the organic phase was washed successively with 10% NaOH, 10% HCl and water, the solvent was removed in vacuo yielding 0.49 g of the title compound as an oil which was used without further purification.
Reaction SMILES: [OH-].[Na+].[C:3]1([N:13]2[C:17](S)=[N:16][N:15]=[N:14]2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.C([OH:21])C.C1OC1C>O>[C:3]1([N:13]2[C:17]([OH:21])=[N:16][N:15]=[N:14]2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: CCO
Reactant: Sc1nnnn1-c1cccc2ccccc12
Agent: CC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Oc1nnnn1-c1cccc2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a mixture of sodium hydroxide (114 mg, 2.9 mmol) in water (0.5 mL) was added 1-(naphthalen-1-yl)-1H-tetrazole-5-thiol (490 mg, 2.2 mmol) and ethanol (5 mL). The reaction mixture was then cooled to 0° C., propylene oxide (168 mg, 2.9 mmol) added dropwise and the mixture stirred at 0° C. for 30 minutes and then room temperature for 5 hours. The mixture was taken up and washed with ethyl acetate. The aqueous layer was acidified with aqueous HCl solution (1N) and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to give pure 1-(naphthalen-1-yl)-1H-tetrazol-5-ol (420 mg, 90%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([CH3:8])=[N:6][CH:7]=1.C1C(=O)N([Br:16])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>ClC(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][C:5]([CH2:8][Br:16])=[N:6][CH:7]=1
Reactant: Cc1ncc(Br)cn1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ncc(Br)cn1
Yield: 47.9 %

Procedure:
A mixture of 5-bromo-2-methylpyrimidine (100 mg, 0.58 mmol), NBS (103 mg, 0.58 mmol), dibenzoyl peroxide (10 mg, 0.04 mmol) in tetrachloromethane (10 mL) was refluxed for 36 h. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel (ethyl acetate in petroleum ether, 1% v/v) to give 5-Bromo-2-(bromomethyl)pyrimidine (70 mg, 48%) as a white solid. 1HNMR (400 MHz, CDCl3) δ 4.49 (s, 2H), 8.72 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:15](=O)[CH3:16])[C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[F:8].S(O)(O)(=O)=O.[CH3:23][O:24][C:25](=[NH:27])[NH2:26].C([O-])(O)=O.[Na+]>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[NH:27][C:25]([O:24][CH3:23])=[N:26][C:15]([CH3:16])=[C:10]2[C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC(=O)C(=Cc1ccc(F)c(F)c1)C(C)=O
Reactant: COC(=N)N
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C1=C(C)N=C(OC)NC1c1ccc(F)c(F)c1
Temperature: 70 °C
Yield: 35.2 %

Procedure:
A mixture of methyl 2-{(3,4-difluorophenyl)methylene}-3-oxobutyrate (8.8 g, 36.6 mmol), O-methylisourea hydrogen sulfate (9.4 g, 55 mmol), and NaHCO3 (12.3 g, 0.146 mol) in DMF (30 mL) was stirred and heated at 70° C. for 16 hours. The mixture was cooled, diluted with EtOAc (300 mL) and washed with water (5×300 mL), brine (300 mL), and dried (MgSO4). Solvent was evaporated and the crude product was purified by flash column chromatography on silica gel using 10% through 20% EtOAc in hexane as the gradient eluent, to leave the product as an oil (3.82 g, 30.2%); 1H-NMR (CDC13): δ 2.32,2.39 (2 s, 3 H), 3.58, 3.64 (2 s, 3 H), 3.72, 3.85 (2 s, 3 H), 5.55 ( s, 1H), 6.13-7.8 (m, 4 H).
Reaction SMILES: [ClH:1].[CH3:2][C:3]([CH3:15])([CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[C:4]([OH:6])=[O:5].[CH3:16][C:17]1([CH3:40])[C:22]2[CH2:23][S:24][CH2:25][C:21]=2[C:20]2[C:26](O)=[CH:27][C:28]([CH:30]([CH:32]([CH3:38])[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH3:31])=[CH:29][C:19]=2[O:18]1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[ClH:1].[CH3:40][C:17]1([CH3:16])[C:22]2[CH2:23][S:24][CH2:25][C:21]=2[C:20]2[C:26]([O:5][C:4](=[O:6])[C:3]([CH3:15])([CH3:2])[CH2:7][CH2:8][N:9]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]3)=[CH:27][C:28]([CH:30]([CH:32]([CH3:38])[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH3:31])=[CH:29][C:19]=2[O:18]1
Reactant: CC(C)(CCN1CCCCC1)C(=O)O
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CSC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: CCCCCC(C)C(C)c1cc(OC(=O)C(C)(C)CCN2CCCCC2)c2c(c1)OC(C)(C)C1=C2CSC1

Procedure:
2,2-Dimethyl-4-piperidinobutyric acid hydrochloride is reacted with 1,3-dihydro-4,4-dimethyl-7-(3-methyl-2-octyl)-9-hydroxy-4H-thieno[3,4-c][1]benzopyran in methylene chloride in the presence of dicyclohexylcarbodiimide to produce 1,3-dihydro-4,4-dimethyl-7-(3-methyl-2-octyl)-9[2,2-dimethyl-4-(piperidino)butyryloxy]-4H-thieno[3,4-c][1] benzopyran hydrochloride.
Reaction SMILES: [C:1]([C:4]1[C:5]([OH:25])=[C:6]([CH2:22][CH:23]=[CH2:24])[CH:7]=[C:8]([C:10]2[C:11]([OH:21])=[C:12]([CH2:18][CH:19]=[CH2:20])[CH:13]=[C:14]([CH2:16][CH3:17])[CH:15]=2)[CH:9]=1)(=O)[CH3:2].[CH3:26][NH2:27].B.[Na].Cl.C(=O)([O-])O.[Na+]>O.CO>[CH2:18]([C:12]1[CH:13]=[C:14]([CH2:16][CH3:17])[CH:15]=[C:10]([C:8]2[CH:9]=[C:4]([CH:1]([NH:27][CH3:26])[CH3:2])[C:5]([OH:25])=[C:6]([CH2:22][CH:23]=[CH2:24])[CH:7]=2)[C:11]=1[OH:21])[CH:19]=[CH2:20]
Reactant: CN
Reactant: C=CCc1cc(-c2cc(CC)cc(CC=C)c2O)cc(C(C)=O)c1O
Agent: B
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CO
Product: C=CCc1cc(CC)cc(-c2cc(CC=C)c(O)c(C(C)NC)c2)c1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution was prepared by dissolving 0.10 g of 5'-acetyl-3,3'-diallyl-5-ethyl-2,4'-biphenyldiol into 2 ml of 40% metanol solution of methylamine. The solution was reflexed by heating for 3 hours, cooled, 0.2 g of sodium boron hydride was added thereinto, was reflexed by heating. The solution was added 0.2 g of sodium boron hydride and stirred from 1 hour at room temperature. The reaction mixture, wherein an excess of reagent was decomposed with hydrochloric acid, was neutralized with water solution of sodium hydrogencarbonate and extracted with diethylether. The extract was washed with an aqueous solution saturated with NaCl, dried with sodium sulfate and concentrated. The concentrate was purified by silica gel column-chromatography (dichloroethane:methanol=50:1) to yield 80 mg of 3,3'-diallyl-5-ethyl-5'-(1-methylaminoethyl)-2,4'-biphenyldiol.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.Cl[C:10]1[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:14]([CH3:21])[N:13]=[C:12]2[N:22]([CH2:25][CH3:26])[N:23]=[CH:24][C:11]=12.C(N(CC)C(C)C)(C)C>C(#N)C>[CH2:25]([N:22]1[C:12]2=[N:13][C:14]([CH3:21])=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:10]([NH:2][CH:3]3[CH2:8][CH2:7][O:6][CH2:5][CH2:4]3)=[C:11]2[CH:24]=[N:23]1)[CH3:26]
Reactant: NC1CCOCC1
Reactant: CCOC(=O)c1c(C)nc2c(cnn2CC)c1Cl
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1c(C)nc2c(cnn2CC)c1NC1CCOCC1
Temperature: 85 °C

Procedure:
4-Aminotetrahydropyran hydrochloride (Intermediate 21, 0.413 g, 3.0 mmol) was added to a mixture of Intermediate 58 (0.268 g, 1.0 mmol) and N,N-diisopropylethylamine (0.87 ml, 5.0 mmol) in acetonitrile (3 ml). The resulting mixture was heated at 85° C. for 24 hours. Volatiles were removed in vacuo and the residue was dissolved in chloroform (1.5 ml) and applied to a SPE cartridge (silica, 5 g). The cartridge was eluted successively with Et2O, EtOAc and EtOAc-MeOH (9/1). Fractions containing the desired product were combined and concentrated in vacuo to give the desired product contaminated with starting material (Intermediate 51). Further purification using a SPE cartridge (silica, 5 g) eluting with ethyl acetate-cyclohexane (1:3) afforded Intermediate 59 (0.248 g). LCMS showed MH+=333; TRET=2.75 min.