Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22](Br)=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1.[CH3:32][N:33]1[C:37]([C:38]([C:40]2[N:44]([CH3:45])[C:43]([CH3:46])=[N:42][CH:41]=2)=[O:39])=[CH:36][N:35]=[C:34]1[CH3:47].C(=O)=O.CC(C)=O>C1COCC1>[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22]([C:38]([C:37]3[N:33]([CH3:32])[C:34]([CH3:47])=[N:35][CH:36]=3)([C:40]3[N:44]([CH3:45])[C:43]([CH3:46])=[N:42][CH:41]=3)[OH:39])=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1
Reactant: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Reactant: Cc1ncc(C(=O)c2cnc(C)n2C)n1C
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: COc1nc2ccc(C(O)(c3cnc(C)n3C)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
n-BuLi (1.63 M in hexane, 0.124 mL, 0.203 mmol) was added dropwise under argon at ˜−70° C. to a solution of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-4-chloro-2-methoxyquinoline (81.6 mg, 0.19 mmol, Intermediate 10) in THF (1.9 mL). After 2 additional minutes, an opaque milky suspension of bis(1,2-dimethyl-1H-imidazol-5-yl)methanone (42.4 mg, 0.194 mmol, Intermediate 11) in LaCl3-2LiCl (0.5 M in THF, 0.381 mL, 0.19 mmol) and THF (2.5 mL) was added rapidly dropwise over 1.5 minutes. The resulting yellow slurry was stirred in the dry ice/acetone bath for 10 minutes, and was then transferred to an ice bath and stirred overnight as the bath warmed to room temperature. The reaction was then quenched with 5 M aqueous NH4Cl (0.06 mL) and diluted with DCM (˜5 mL) and MeOH (˜2 mL), and the suspension was partitioned with 0.75 M aqueous tetrasodium EDTA (4 mL) and 9:1 DCM/MeOH (10 mL). The organic layer was dried (Na2SO4), filtered, and concentrated. The residue was purified by C18 HPLC (20% to 100% CH3CN gradient with 0.1% TFA throughout) and the lyophilisate neutralized with 9:1 DCM/MeOH) and 2 M aqueous K2CO3. The organic layer was dried (Na2SO4), filtered, and concentrated to dryness to provide the title compound as a colorless film. 1H NMR (400 MHz, CDCl3) δ 8.23 (s, 1H), 7.86 (d, J=2.53 Hz, 1H), 7.63-7.70 (m, 2H), 7.58 (d, J=8.59 Hz, 2H), 7.38 (d, J=8.59 Hz, 2H), 7.37 (m, 1H), 6.42 (t, J=1.99 Hz, 1H), 6.14 (s, 2H), 5.82 (br. s., 1H), 4.29 (s, 2H), 4.08 (s, 3H), 3.38 (s, 6H), 2.26 (s, 6H); MS m/e 568.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].Cl[C:12]([S:14]Cl)=[O:13]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][C:12](=[O:13])[S:14][N:7]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(Cl)SCl
Reactant: NC(=O)c1cccc(Cl)c1
Product: O=c1oc(-c2cccc(Cl)c2)ns1
Reaction time: 1.5 h
Yield: 65.8 %

Procedure:
m-Chlorobenzamide (75 g, 0.48 mol) and chlorocarbonylsulfenyl chloride (79 g, 0.6 mol, 25% excess) were reacted as described in Example 2 for 1.5 hours. Volatile components were removed under reduced pressure. The dark brown oil was taken up in hot cyclohexane, and the mixture was filtered. Cooling resulted in separation of a dark orange solid. The solid, recrystallized twice from hot ethyl acetate, gave 64.21 g (0.316 mol, 65.8%) of off-white solid, m.p. 83°-84.5°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:32]=[CH:31][C:20]([CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:19][CH:18]=1.C1C(=O)N([Br:40])C(=O)C1>>[Br:40][C:11]1[C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]([C:17]2[CH:32]=[CH:31][C:20]([CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[CH:19][CH:18]=2)=[C:3]([O:2][CH3:1])[CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(CCNC(=O)OC(C)(C)C)cc1
Product: COc1cc(Br)c2[nH]c(=O)c3sccc3c2c1-c1ccc(CCNC(=O)OC(C)(C)C)cc1
Yield: 59.6 %

Procedure:
Following General Procedure I, tert-butyl 4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenethylcarbamate (600 mg, 1.3 mmol) was reacted with NBS (280 mg, 1.5 mmol) to afford the desired product (410 mg, 60%) as a reddish brown solid. ESI MS m/z 529 [C25H25BrN2O4S H]+.
Reaction SMILES: [CH2:1]([CH:3]1[C:7](=O)[CH:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]1)[CH3:2].[CH3:14][CH:15]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:16]([C:18]1C=C(O)[CH:21]=[C:22]([CH:24]=1)[OH:23])[CH3:17]>>[CH2:1]([CH:3]1[C:7]2[C:21]3[C:22]([OH:23])=[CH:24][C:18]([CH:16]([CH:15]([CH3:14])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH3:17])=[CH:13][C:12]=3[O:11][C:9](=[O:10])[C:6]=2[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCOC(=O)C1CCC(CC)C1=O
Reactant: CCCCCC(C)C(C)c1cc(O)cc(O)c1
Product: CCCCCC(C)C(C)c1cc(O)c2c3c(c(=O)oc2c1)CCC3CC

Procedure:
5-Ethyl-2-carboethoxycyclopentanone is reacted with 5-(3-methyl-2-octyl)-resorcinol to produce 1-ethyl-4-oxo-9-hydroxy-7-(3-methyl-2-octyl)-1,2,3,4-tetrahydrocyclopenta[c] [1]benzopyran.
Reaction SMILES: C([N:8](C(OC(C)(C)C)=O)[C@H:9]([C:14]([OH:16])=O)[CH2:10][CH2:11][CH2:12][NH2:13])(OC(C)(C)C)=O.[CH3:24][CH:25]([CH2:27][CH2:28][CH2:29][C@H:30]([C@@H:32]1[C@:50]2([CH3:51])[C@H:35]([C@H:36]3[C@H:47]([CH2:48][CH2:49]2)[C@:45]2([CH3:46])[C:39]([CH2:40][C@H:41]([CH2:43][CH2:44]2)[OH:42])=[CH:38][CH2:37]3)[CH2:34][CH2:33]1)[CH3:31])[CH3:26].C1CCC(N=C=NC2CCCCC2)CC1.CO.[Cl:69]CCl>CN(C1C=CN=CC=1)C>[ClH:69].[ClH:69].[NH2:8][C@H:9]([C:14]([C@@:41]1([OH:42])[CH2:43][CH2:44][C@@:45]2([CH3:46])[C:39](=[CH:38][CH2:37][C@@H:36]3[C@@H:47]2[CH2:48][CH2:49][C@@:50]2([CH3:51])[C@H:35]3[CH2:34][CH2:33][C@@H:32]2[C@H:30]([CH3:31])[CH2:29][CH2:28][CH2:27][CH:25]([CH3:26])[CH3:24])[CH2:40]1)=[O:16])[CH2:10][CH2:11][CH2:12][NH2:13]
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@@H](CCCN)C(=O)O
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CO
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@](O)(C(=O)[C@@H](N)CCCN)CC[C@]4(C)[C@H]3CC[C@]12C
Product: Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 94 %

Procedure:
997 mg (3 mmol) of di-BOC-ornithine was dissolved in 40 ml of dichloromethane. 1.16 g (3 mmol) of cholesterol, 640 mg (3.1 mmol) of DCC, and 50 mg of DMAP were added, and the mixture was stirred at room temperature for 24 h. The dicyclohexylurea precipitate was removed by filtration, the solvent removed in vacuo and the residual solid was recrystallized from 5 ml of hexane yielding 1.62 g (77%) of 3β-BOC-ornithyl-cholesterol as a colorless, crystalline solid. 190 mg (0.27 mmol) of 3β-di-BOC-ornithyl-cholesterol was treated with 6 ml of MeOH (10 mmol HCl) and was stirred at ambient temperature for 1 h. Subsequent removal of the solvent under high vacuum yielded 146 mg (94%) of 3β-ornithyl-cholesterol-dihydrochloride VI as a colorless solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([NH:15][CH2:16][CH2:17][O:18][CH3:19])=[O:14])[CH:11]=2)[NH:6][CH:5]=1.CN1C(N)=N[C:23](=[O:24])[CH2:22]1.S(=O)(=O)(O)O.O.[CH2:34]([OH:36])C>>[CH3:19][O:18][CH2:17][CH2:16][NH:15][C:13]([C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[NH:6][CH:5]=[C:4]2[CH2:3][CH2:2][NH:1][C:34](=[O:36])[O:24][CH2:23][C:22]1[CH:11]=[CH:12][CH:4]=[CH:3][CH:2]=1)=[O:14]
Reactant: CCO
Reactant: CN1CC(=O)N=C1N
Reactant: COCCNC(=O)c1ccc2[nH]cc(CCN)c2c1
Agent: O=S(=O)(O)O
Solvent: O
Product: COCCNC(=O)c1ccc2[nH]cc(CCNC(=O)OCc3ccccc3)c2c1

Procedure:
(ii)f [2-[5-[[(2-Methoxyethyl)amino]carbonyl]-1H-indol-3-yl]ethyl]carbamic acid, phenylmethyl ester (2.0 g) gave 3-(2-aminoethyl)-N-(2-methoxyethyl)-1H-indole-5-carboxamide, compound with creatinine, sulphuric acid and water (1:1:1:2) (0.8 g) as a white crystalline solid m.p. 193°-5° C. (from aqueous ethanol)
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Cl[C:12]1[N:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][N:13]=1.C(N(C(C)C)C(C)C)C>O1CCCC1.ClCCl>[CH2:18]([C:15]1[CH:14]=[N:13][C:12]([N:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)=[N:17][CH:16]=1)[CH3:19]
Reactant: CCc1cnc(Cl)nc1
Reactant: C1CC2(CCN1)OCCO2
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1cnc(N2CCC3(CC2)OCCO3)nc1
Temperature: 25 °C

Procedure:
A mixture of 1,4-dioxa-8-aza-spiro[4.5]decane (11.08 mL), 2-chloro-5-ethylpyrimidine (7.50 mL), and ethyldiisopropylamine (15.50 mL) in tetrahydrofuran (60 mL) is heated under reflux for 30 min. After cooling to room temperature, the reaction mixture is diluted with dichloromethane and washed with 0.1 M citric acid and brine. The aqueous phase is basified with 1 M aqueous NaOH solution and extracted with dichloromethane. The combined organic phases are dried over MgSO4 and the solvent is evaporated in vacuo to give the title compound. LC (method 11): tR=1.10 min; Mass spectrum (ESI+): m/z=250 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:43]=[C:42]([Cl:44])[C:16]([C:17]([NH:19][C@@H:20]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[C:32](=[O:41])[N:33]([CH3:40])[C:34](=[O:39])[N:35]([CH3:38])[C:36]=3[CH3:37])=[CH:27][CH:26]=2)[C:21]([OH:23])=[O:22])=[O:18])=[C:15]([Cl:45])[CH:14]=1.O=C1CCC(=O)N1[O:53][C:54](=O)[CH2:55][CH2:56][O:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][O:66][CH2:67][CH2:68][O:69][CH2:70][CH2:71][O:72][CH2:73][CH2:74][O:75][CH2:76][CH2:77][O:78][CH2:79][CH2:80][NH:81][C:82](=[O:92])[CH2:83][CH2:84][N:85]1[C:89](=[O:90])[CH:88]=[CH:87][C:86]1=[O:91].CCN(C(C)C)C(C)C>>[Cl:45][C:15]1[CH:14]=[C:13]([O:12][CH2:11][CH2:10][CH2:9][NH:8][C:54](=[O:53])[CH2:55][CH2:56][O:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][O:66][CH2:67][CH2:68][O:69][CH2:70][CH2:71][O:72][CH2:73][CH2:74][O:75][CH2:76][CH2:77][O:78][CH2:79][CH2:80][NH:81][C:82](=[O:92])[CH2:83][CH2:84][N:85]2[C:89](=[O:90])[CH:88]=[CH:87][C:86]2=[O:91])[CH:43]=[C:42]([Cl:44])[C:16]=1[C:17]([NH:19][C@@H:20]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[C:32](=[O:41])[N:33]([CH3:40])[C:34](=[O:39])[N:35]([CH3:38])[C:36]=2[CH3:37])=[CH:27][CH:26]=1)[C:21]([OH:23])=[O:22])=[O:18]
Reactant: O=C(CCN1C(=O)C=CC1=O)NCCOCCOCCOCCOCCOCCOCCOCCOCCC(=O)ON1C(=O)CCC1=O
Reactant: Cc1c(-c2ccc(C[C@H](NC(=O)c3c(Cl)cc(OCCCN)cc3Cl)C(=O)O)cc2)c(=O)n(C)c(=O)n1C
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(-c2ccc(C[C@H](NC(=O)c3c(Cl)cc(OCCCNC(=O)CCOCCOCCOCCOCCOCCOCCOCCOCCNC(=O)CCN4C(=O)C=CC4=O)cc3Cl)C(=O)O)cc2)c(=O)n(C)c(=O)n1C

Procedure:
The title compound was prepared using a similar procedure as described in Example 1, Step 11, starting from (S)-2-[4-(3-aminopropoxy)-2,6-dichlorobenzoylamino]-3-[4-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)phenyl]propionic acid trifluoroacetate salt (98 mg, 0.145 mmol), 3-[2-[2-[2-[2-[2-[2-[2-[[3-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)-propionylamino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]propionic acid-2,5-dioxo-pyrrolidin-1-yl ester (100 mg, 0.145 mmol), and DIPEA (187 mg, 252 uL, 1.45 mmol), and after HPLC purification, resulted in a hygroscopic white solid (88 mg, 53%). ES(+)-HRMS m/e calcd. for C52H70Cl2N6O18 (M+H)+ 1137.4197, obsd. 1137.4196.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[OH:12].N1C=CC=CC=1.S(Cl)([Cl:21])=O>O1CCCC1.CN(C)C=O>[Cl:21][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[OH:12]
Reactant: Cc1cccc(CCCO)c1O
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cccc(CCCCl)c1O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(3-hydroxypropyl)-6-methylphenol (3.0 g) in tetrahydrofuran (30 mL) were added pyridine (730 μL), thionyl chloride (2 mL) and one drop of N,N-dimethylformamide. After stirring at 60° C. for 2 hours, the reaction mixture was evaporated, and then diethyl ether was added to the residue. The resulting solution was washed with distilled water and brine, dried over anhydrous magnesium sulfate and evaporated in vacuo to give the title compound in quantitative yield.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[N:6]=[C:7]([NH:10][CH:11]3[C:15]4[C:16]([O:20][CH3:21])=[CH:17][CH:18]=[CH:19][C:14]=4[O:13][CH2:12]3)[O:8][CH2:9][C:4]=2[CH:3]=1.[NH2:24][C:25]1[N:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=1>>[CH3:21][O:20][C:16]1[C:15]2[CH:11]([NH:10][C:7]3[O:8][CH2:9][C:4]4[CH:3]=[C:2]([NH:24][C:25]5[N:30]=[C:29]([C:31]([F:34])([F:32])[F:33])[CH:28]=[CH:27][N:26]=5)[CH:23]=[CH:22][C:5]=4[N:6]=3)[CH2:12][O:13][C:14]=2[CH:19]=[CH:18][CH:17]=1
Reactant: Nc1nccc(C(F)(F)F)n1
Reactant: COc1cccc2c1C(NC1=Nc3ccc(Br)cc3CO1)CO2
Product: COc1cccc2c1C(NC1=Nc3ccc(Nc4nccc(C(F)(F)F)n4)cc3CO1)CO2
Yield: 59 %

Procedure:
The title compound (135 mg, 59%), yellow foam, MS (ISP): m/e=458.2 (M+H+), was prepared in accordance with the general method of Example 35 from rac-(6-bromo-4H-benzo[d][1,3]oxazin-2-yl)-(4-methoxy-2,3-dihydro-benzofuran-3-yl)-amine (example 54) (188 mg, 0.5 mmol) and commercially available 2-amino-4-trifluoromethyl-pyrimidine (163 mg, 1.0 mmol).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]([OH:14])=[O:13])=[CH:11][C:6]=2[N:5]=[C:4]1[CH3:15])[CH3:2].S(Cl)(Cl)=O.[CH3:20]O>>[CH3:20][O:13][C:12]([C:10]1[CH:9]=[CH:8][C:7]2[N:3]([CH2:1][CH3:2])[C:4]([CH3:15])=[N:5][C:6]=2[CH:11]=1)=[O:14]
Reactant: CO
Reactant: CCn1c(C)nc2cc(C(=O)O)ccc21
Solvent: O=S(Cl)Cl
Product: CCn1c(C)nc2cc(C(=O)OC)ccc21
Reaction time: 6 h

Procedure:
To a suspension of 1.1 g (5.4 mmol) of the title C compound, 1-ethyl-2-methyl-1H-benzoimidazole-5-carboxylic acid in 25 mL of MeOH is added dropwise 0.7 g (5.9 mmol) of thionyl chloride and the resulting solution is stirred at 700 for 6 h, then at RT for 18 h. The solvent is removed under reduced pressure and 8% aqueous NaHCO3 solution is added to the residue. The mixture is extracted with EtOAc and the organic phase is dried over anhydrous Na2SO4. The organic solution is concentrated until the product precipitated. The solid is collected by filtration, washed with EtOH and MTBE to give 1-ethyl-2-methyl-1H-benzoimidazole-5-carboxylic acid methyl ester as a beige solid: mp=118-121° C.; IR (KBr) 3430, 1695 cm−1; 1H-NMR (CDCl3) δ 8.39 (s, 1H), 7.98 (dd, 1H), 7.32 (d, J=8.45, 1H), 4.19 (q, 2H), 3.94 (s, 3H), 2.64 (s, 3H), 1.43 (t, 3H); [M+1]+=219.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([OH:20])=[CH:17][CH:18]=3)[C:13]([C:21]#[N:22])=[CH:12]2)=[CH:7][CH:6]=1)[CH3:2].[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[CH2:29]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N=C=NC(C)C)(C)C>O1CCCC1>[CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([O:20][CH2:29][C:25]4[S:24][CH:28]=[CH:27][CH:26]=4)=[CH:17][CH:18]=3)[C:13]([C:21]#[N:22])=[CH:12]2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: OCc1cccs1
Reactant: CCOC(=O)c1ccc(-n2cc(C#N)c3cc(O)ccc32)cc1
Agent: CC(C)N=C=NC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(-n2cc(C#N)c3cc(OCc4cccs4)ccc32)cc1
Reaction time: 3 h

Procedure:
To a solution of 4-(5-hydroxy-3-cyanoindol-1-yl)benzoic acid ethyl ester and tiophene-2-methanol (0.057 g) and triphenylphosphine (0.012 g) in tetrahydrofuran (2.5 mL) was added diisopropylcarbodiimide (40% toluene solution, 0.18 mL) at room temperature, and this mixture was stirred for 3 hours. This reaction mixture was concentrated under reduced pressure. This residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane=1/3) to give the title compound (0.10 g).
Reaction SMILES: [CH3:1][N:2]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-])=O)[CH:15]=1)[C:3](=[O:12])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CCO.O>[Fe].CC(O)=O>[NH2:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[CH2:13][N:2]([CH3:1])[C:3](=[O:12])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CN(Cc1cccc([N+](=O)[O-])c1)C(=O)OCc1ccccc1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CN(Cc1cccc(N)c1)C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 95.7 %

Procedure:
To a refluxing solution of 60A (1.7 g, 5.8 mmol), EtOH (60 mL), water (15 mL) and AcOH (4 mL) was added portion-wise Fe powder (1.63 g, 29.0 mmol) over 30 min. The mixture was heated for 45 min. before cooling to ambient temperature and filtered through celite. Filtrate concentrated in vacuo to afford 60B (1.5 g, 95%) as an oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.25-1.41 (m, J=4.39 Hz, 3 H) 2.27 (s, 3 H) 2.61 (s, 2 H) 2.92 (s, 2 H) 4.22 (s, 2 H) 4.64 (s, 1 H) 6.84-7.56 (m, 12 H)
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:14]([CH:16]1[O:18][CH2:17]1)Cl>CC(C)=O.C1(C)C=CC=CC=1>[O:18]1[CH2:17][CH:16]1[CH2:14][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: c1ccc(OCC2CO2)cc1
Yield: 59.9 %

Procedure:
A mixture of 9.4 gm (0.1 mole) of phenol, 28 gm (0.2 mole) of potassium carbonate and 30 mL (0.4 mole) of epichlorohydrin in 250 mL acetone was heated to reflux for 12 hours. The reaction medium was then filtered and evaporated leaving an oil which was taken up in toluene and successively washed with 100 mL water, 2×100 mL 1.0 N sodium hydroxide and 2×100 mL water. The toluene phase was dried with magnesium sulfate and evaporated to provide a clear oil which was chromatographed on a Prep-500 silica gel column employing hexane: ethyl acetate (9:1) as the mobile phase. Collection of the major peak and evaporation of solvent provided 9 gm (60%) of a clear oil whose NMR and IR spectra were consistent with the assigned structure.
Reaction SMILES: [N:1]1([CH2:6][C:7]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)=[N+:8]([O-:10])[CH3:9])[CH:5]=[N:4][CH:3]=[N:2]1.[C:21]1(/[CH:27]=[CH:28]/[CH:29]=[CH2:30])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(OCC)(=O)C.CCCCC>C1(C)C=CC=CC=1>[CH3:9][N:8]1[C:7]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)([CH2:6][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)[CH2:30][CH:29](/[CH:28]=[CH:27]/[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:10]1
Reactant: C=C/C=C/c1ccccc1
Reactant: C[N+]([O-])=C(Cn1cncn1)c1ccc2ccccc2c1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCCCC
Product: CN1OC(/C=C/c2ccccc2)CC1(Cn1cncn1)c1ccc2ccccc2c1

Procedure:
A mixture of 2-(1H-1,2,4-triazol-1-yl)-N-methyl-1-(2-naphthalenyl)ethanimine N-oxide (15.0 g, 0.056 mol) and trans-1-phenyl-1,3-butadiene (11.0 g, 0.084 mol) in 500 ml toluene is heated to 95°-105° C. for 48 hours, then cooled and evaporated to dryness. The resulting oil is decolorized with carbon and purified by flash chromatography on silica gel (eluent comprised of 90% ethyl acetate and 10% hexane by volume) giving two diastereomers. Isomer A (5.66 g) has a melting point of 80°-84° C. (ethyl acetate-pentane). Isomer B (1.64 g) has a melting point 157°-160° C.
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=O)OCC)C.C[O-].[Na+].[CH2:19]([O:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]=O)[CH:24]=1)[CH3:20].C1(C)C=CC=CC=1>O1CCCC1>[CH2:19]([O:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]=[CH:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:24]=1)[CH3:20]
Reactant: CCOP(=O)(Cc1ccccc1)OCC
Reactant: CCOC(=O)c1cccc(C=O)c1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cccc(C=Cc2ccccc2)c1
Temperature: 0 °C
Yield: 37.7 %

Procedure:
45.6 g (0.2 mol) of benzylphosphonic acid diethyl ester, dissolved in 50 ml of tetrahydrofuran, were added dropwise to a mixture of 300 ml of tetrahydrofuran and 46.4 g (0.22 mol) of a methanolic sodium methylate solution at 0°-5° C., whilst stirring. The mixture was subsequently stirred at 0° C. for 2 hours and 35.6 g (0.2 mol) of 3-formyl-benzoic acid ethyl ester, dissolved in 50 ml of tetrahydrofuran, were then added dropwise, also at 0° C. and whilst stirring. The reaction mixture was then stirred at 20°-25° C. for 12 hours, 300 ml of toluene were subsequently added and the mixture was then extracted by shaking twice with 600 ml of water each time. The organic phase was separated off and dried over magnesium sulphate and the solvent was distilled off under a waterpump vacuum. The oily residue was distilled at 160°-190° C. and under a pressure of 3 mm Hg. The semi-crystalline product thus obtained was dissolved in a little petroleum ether and the solution was cooled to 0° C. The crystals which had precipitated were filtered off and dried. 19 g (37.7% of theory) of 3-(2-phenyl-vinyl)-benzoic acid ethyl ester were obtained as colourless crystals with the melting point 82° C. (isomer mixture, about 90% transconfiguration). ##STR65##
Reaction SMILES: [C:1]([C:5]1[C:6]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:11]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[O:31][N:30]=[C:29](C(O)=O)[CH:28]=4)=[CH:23][CH:22]=3)[C:10](=[O:35])[C:7]=2[NH:8][N:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C[N:44]([CH:46]=[O:47])C.[C:48]([OH:52])([CH3:51])([CH3:50])[CH3:49]>>[C:1]([C:5]1[C:6]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:11]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[O:31][N:30]=[C:29]([O:52][C:48]([CH3:51])([CH3:50])[CH3:49])[C:28]=4[N:44]=[C:46]=[O:47])=[CH:23][CH:22]=3)[C:10](=[O:35])[C:7]=2[NH:8][N:9]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)O
Reactant: CN(C)C=O
Reactant: COc1ccccc1C1c2c(C(C)(C)C)n[nH]c2C(=O)N1c1ccc(-c2cc(C(=O)O)no2)cc1
Solvent: CCN(CC)CC
Product: COc1ccccc1C1c2c(C(C)(C)C)n[nH]c2C(=O)N1c1ccc(-c2onc(OC(C)(C)C)c2N=C=O)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
To a mixture of 3-t-butyl-5-[4-(3-carboxy-5-isoxazolyl)phenyl]-4-(2-methoxyphenyl)-4,5-dihydro-1H-pyrrolo[3,4-c]pyrazol-6-one (0.948 g, 2.0 mmol), triethylamine (0.33 mL, 2.4 mmol) and DMF (15 mL), diphenyl phosphorylazido (0.52 mL, 2.4 mmol) was added, and the mixture was stirred at 60° C. for 2 hr. Then, t-butanol (15 mL) and molecular sieve powder 4 A (2 g) was added and the mixture was stirred at 90° C. for 3 hr. Insoluble matter was removed by filtration, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous ammonium chloride and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was crystallized from dichloromethane to give 3-t-butyl-5-[4-(3-t-butoxy-carbonylamino-5-isoxazolyl)phenyl]-4-(2-methoxyphenyl)-4,5-dihydro-1H-pyrrolo[3,4-c]pyrazol-6-one (0.566 g, 52%) as colorless crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.[NH2:10][C@H:11]([C@@H:19]([OH:31])[C@H:20]([OH:30])[C@@H:21]([NH2:29])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N=[C:33]=[NH:34]>C(Cl)(Cl)Cl>[N:34]1[CH:33]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([NH:10][C@H:11]([C@@H:19]([OH:31])[C@H:20]([OH:30])[C@@H:21]([NH:29][C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[O:9])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:9]
Reactant: O=C(O)c1ccccn1
Reactant: N[C@@H](Cc1ccccc1)[C@@H](O)[C@H](O)[C@@H](N)Cc1ccccc1
Reactant: N=C=N
Solvent: ClC(Cl)Cl
Product: O=C(N[C@@H](Cc1ccccc1)[C@@H](O)[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1ccccn1)c1ccccn1

Procedure:
Picolinic acid was coupled to the resultant compound of Example 171 using the carbodiimide coupling procedure described in Example 55 to provide, after chromatography on silica gel using 5% methanol in chloroform, 58 mg (60%) of the desired compound (Rf 0.6, 10% methanol in chloroform) as a white solid, m.p. 179°-184° C. Mass spectrum: (M+H)+ =511.