Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)=O.[CH3:18][CH:19]([CH3:23])[CH2:20][CH2:21][NH2:22].C([O-])([O-])OC.[BH4-].[Na+]>CO>[CH3:18][CH:19]([CH3:23])[CH2:20][CH2:21][NH:22][CH2:1][C:3]1[S:7][C:6]([O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: CC(C)CCN
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)s2)cc1
Agent: COC([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)CCNCc1ccc(Oc2ccc(C(N)=O)cc2)s1
Reaction time: 3 h

Procedure:
Combine 4-(5-formyl-thiophen-2-yloxy)-benzamide (99 mg, 0.40 mmol) from Example 1 part B, method B, with 3-methyl-butylamine (0.056 mL, 0.48 mmol), methyl orthoformate (0.53 mL) and methanol (0.8 mL). Stir the resulting mixture for 3 hours and then add sodium borohydride in portions. Let stir for few hours. Then, concentrate to remove the methanol. Partition the resulting residue between H2O (4 mL) and CH2Cl2 (6 ml). Dry the organic layer over sodium sulfate, filter and concentrate. Purify through flash chromatography [CH2Cl2/Ammonia (2.0 M in methanol) 20/1] to provide the title compound.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[N:14](S(C4C=CC=CC=4)(=O)=O)[C:15]([C:17]4[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH:22]=4)=[CH:16][C:9]=23)[C:5]([C:39]2[CH:44]=[CH:43][C:42]([NH:45][C:46]([NH:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)=[O:47])=[CH:41][CH:40]=2)=[N:4]1)[CH3:2].[OH-].[Na+]>CO>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH:22]=4)=[CH:16][C:9]=23)[C:5]([C:39]2[CH:40]=[CH:41][C:42]([NH:45][C:46]([NH:48][C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=3)=[O:47])=[CH:43][CH:44]=2)=[N:4]1)[CH3:2]
Reactant: CCn1cc(-c2ccnc3c2cc(C2=CCN(C(=O)OC(C)(C)C)CC2)n3S(=O)(=O)c2ccccc2)c(-c2ccc(NC(=O)Nc3ccccc3)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCn1cc(-c2ccnc3[nH]c(C4=CCN(C(=O)OC(C)(C)C)CC4)cc23)c(-c2ccc(NC(=O)Nc3ccccc3)cc2)n1
Temperature: 25 °C

Procedure:
To a solution of 1,1-dimethylethyl 4-[4-[1-ethyl-3-(4-{[(phenylamino)carbonyl]amino}phenyl)-1H-pyrazol-4-yl]-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-3,6-dihydro-1 (2H)-pyridinecarboxylate (0.38 mmol) in methanol (3.8 mL) was added 6N sodium hydroxide (1.14 mmol). The reaction mixture was refluxed for 5 h, cooled to room temperature and concentrated under reduced pressure. The solid residue was suspended in water, stirred vigorously and collected by filtration to give the title compound as an orange solid which was used without further purification (95%). Alternatively, the solid residue was purified by Gilson reverse phase HPLC to afford the title compound. ESMS [M+H]+: 604.4
Reaction SMILES: [N+]([O-])([O-])=O.[Na+].[BrH:6].N[C:8]1[C:9]([CH3:16])=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][OH:12]>O.[Cu]Br>[Br:6][C:8]1[C:9]([CH3:16])=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][OH:12]
Reactant: Cc1c(N)cccc1CO
Reactant: Br
Agent: [Cu]Br
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1c(Br)cccc1CO
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 40.7 g of sodium nitrate in 300 ml of water is added dropwise to a mixture cooled to 0° C. and consisting of 888 ml of water, 162 ml of 47% strength hydrobromic acid and 81.2 g of 3-amino-2-methylbenzyl alcohol. Stirring is carried out for 30 minutes at 0° C., after which a suspension of 168.7 g of copper(I) bromide in 750 ml of water is added a little at a time at this temperature. The reaction mixture is stirred in succession for 1 hour at 10° C, for 1 hour at room temperature and for 2 hours at 100° C. After cooling, the reaction mixture is extracted several times with ether. The combined organic phases are washed with water, dried and evaporated down. After purification by column chromatography over silica gel using toluene as the mobile phase, 64.2 g of 3-bromo-2-methylbenzyl alcohol of melting point 97°-100 ° C. are obtained.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7](O)=[O:8])=[CH:4][C:3]=1[C:10]1[CH:11]=[N:12][N:13]2[CH:18]=[C:17]([C:19]([O:24][CH3:25])([O:22][CH3:23])[O:20][CH3:21])[CH:16]=[N:15][C:14]=12.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:53][C@H:54]1[C:59]([F:61])([F:60])[CH2:58][CH2:57][CH2:56][C@H:55]1[NH:62][C:63](=[O:69])[O:64][C:65]([CH3:68])([CH3:67])[CH3:66].C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:65]([O:64][C:63](=[O:69])[NH:62][C@@H:55]1[CH2:56][CH2:57][CH2:58][C:59]([F:61])([F:60])[C@@H:54]1[NH:53][C:7]([C:5]1[S:6][C:2]([CH3:1])=[C:3]([C:10]2[CH:11]=[N:12][N:13]3[CH:18]=[C:17]([C:19]([O:24][CH3:25])([O:20][CH3:21])[O:22][CH3:23])[CH:16]=[N:15][C:14]=23)[CH:4]=1)=[O:8])([CH3:66])([CH3:68])[CH3:67]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC(F)(F)[C@@H]1N
Reactant: COC(OC)(OC)c1cnc2c(-c3cc(C(=O)O)sc3C)cnn2c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(OC)(OC)c1cnc2c(-c3cc(C(=O)N[C@@H]4[C@H](NC(=O)OC(C)(C)C)CCCC4(F)F)sc3C)cnn2c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
5-Methyl-4-[6-(trimethoxymethyl)pyrazolo [1,5-a]pyrimidin-3-yl]thiophene-2-carboxylic acid (41.0 mg, 0.113 mmol) and BOP (59.9 mg, 0.135 mmol) were dissolved in DMF (752 μL) and stirred at room temperature for 5 min. To the reaction solution was added tert-butyl [(1R,2R)-2-amino-3,3-difluorocyclohexyl]carbamate (31.1 mg, 0.124 mmol) and diisopropylethyl amine (59.1 μL, 0.338 mmol) and the reaction stirred at room temperature for 2 h. The reaction was then concentrated under reduced pressure and purified by column chromatography (0-60% EtOAc/DCM) to afford the title compound (quantitative yield). LRMS (APCI) calc'd for (C27H35F2N5O6S) [M+H]+, 596.2; found 596.1.
Reaction SMILES: [CH2:1]([C:13]1[CH:52]=[CH:51][C:16]([C:17]([C:19]2[CH:27]=[C:26]([C:28]([OH:30])=[O:29])[C:25]([C:31](=O)[C:32]3[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[CH:34][CH:33]=3)=[CH:24][C:20]=2[C:21]([OH:23])=[O:22])=O)=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[H][H]>[Pd].O1CCCC1>[CH2:38]([C:35]1[CH:36]=[CH:37][C:32]([CH2:31][C:25]2[CH:24]=[C:20]([C:21]([OH:23])=[O:22])[C:19]([CH2:17][C:16]3[CH:15]=[CH:14][C:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:52][CH:51]=3)=[CH:27][C:26]=2[C:28]([OH:30])=[O:29])=[CH:33][CH:34]=1)[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49]
Reactant: [H][H]
Reactant: CCCCCCCCCCCCc1ccc(C(=O)c2cc(C(=O)O)c(C(=O)c3ccc(CCCCCCCCCCCC)cc3)cc2C(=O)O)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCc1ccc(Cc2cc(C(=O)O)c(Cc3ccc(CCCCCCCCCCCC)cc3)cc2C(=O)O)cc1

Procedure:
A solution of 133 grams of 2,5-bis(4-dodecylbenzoyl)terephthalic acid and 1 L of tetrahydrofuran was treated with 8 grams of 10% palladium on carbon (as a catalyst) and heated to 65° C. for 17 hours in an atmosphere of hydrogen at 270 kPa. The reaction mixture was filtered through Celite™ diatomaceous earth filter agent to remove the catalyst. The filtrate was concentrated in vacuo to give a white solid. The solid was triturated with ethyl acetate, and the residue was dried to give 2,5-bis(4-dodecylbenzyl)terephthalic acid.
Reaction SMILES: [O:1]([CH2:8][CH2:9][O:10][C:11]1[C:12]([C:27]([O:29][CH3:30])=[O:28])=[N:13][C:14]([C:17]2[CH:26]=[C:25]3[C:20]([CH2:21][CH2:22][CH2:23][NH:24]3)=[CH:19][CH:18]=2)=[CH:15][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=[C:32]1[NH:40][C:41](=O)[O:42]C1C=CC([N+]([O-])=O)=CC=1>C(#N)C>[S:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=[C:32]1[NH:40][C:41]([N:24]1[C:25]2[C:20](=[CH:19][CH:18]=[C:17]([C:14]3[N:13]=[C:12]([C:27]([O:29][CH3:30])=[O:28])[C:11]([O:10][CH2:9][CH2:8][O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:16][CH:15]=3)[CH:26]=2)[CH2:21][CH2:22][CH2:23]1)=[O:42]
Reactant: COC(=O)c1nc(-c2ccc3c(c2)NCCC3)ccc1OCCOc1ccccc1
Reactant: O=C(Nc1nc2ccccc2s1)Oc1ccc([N+](=O)[O-])cc1
Solvent: CC#N
Product: COC(=O)c1nc(-c2ccc3c(c2)N(C(=O)Nc2nc4ccccc4s2)CCC3)ccc1OCCOc1ccccc1
Yield: 98.2 %

Procedure:
Methyl 3-(2-phenoxyethoxy)-6-(1,2,3,4-tetrahydroquinolin-7-yl)picolinate (27C) (81 mg, 0.2 mmol) and 4-nitrophenyl benzo[d]thiazol-2-ylcarbamate (19) (127 mg, 0.4 mmol) were heated to reflux in acetonitrile (5 mL) for 24 hours. After cooling, the mixture was concentrated under reduced pressure and purified by column chromatography on silica gel eluting with a gradient of PE (100%) to PE/EtOAc (4:6), to provide 114 mg (97%) of the desired product methyl 6-(1-(benzo[d]thiazol-2-ylcarbamoyl)-1,2,3,4-tetrahydroquinolin-7-yl)-3-(2-phenoxyethoxy)picolinate (27D). 1H NMR (300 MHz, CDCl3) δ8.12 (1H, s), 7.85 (1H, d), 7.73 (1H, m), 7.44 (3H, m), 7.29 (4H, m), 7.09 (1H, m), 6.94 (3H, m), 4.44 (2H, m), 4.37 (2H, m), 3.88 (2H, m), 3.78 (3H, m), 2.74 (2H, m), 2.00 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:15]([CH3:17])=O)[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8].[N:18]1([NH:24][C:25]([C:27]2[S:28][C:29]([C:32]([NH:34][NH2:35])=[O:33])=[CH:30][CH:31]=2)=[O:26])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.O>CS(C)=O>[N:18]1([NH:24][C:25]([C:27]2[S:28][C:29]([C:32]([NH:34][N:35]=[C:15]([C:12]3[C:13]([OH:14])=[C:9]([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)[S:10][CH:11]=3)[CH3:17])=[O:33])=[CH:30][CH:31]=2)=[O:26])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CC(=O)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Reactant: NNC(=O)c1ccc(C(=O)NN2CCCCC2)s1
Solvent: CS(C)=O
Solvent: O
Product: CC(=NNC(=O)c1ccc(C(=O)NN2CCCCC2)s1)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Temperature: 25 °C
Yield: 87.4 %

Procedure:
2-(3,4-Dichlorophenyl)-3-hydroxy-4-methylcarbonylthiophene (29 mg, 0.1 mmol) in dimethyl sulfoxide (4.0 mL) was heated with 5-(hydrazinocarbonyl)thiophene-2-carboxylic acid piperidin-1-ylamide (27 mg, 0.1 mmol) prepared in Reference Synthetic Example 9 at 100° C. for 20 hours and allowed to cool to room temperature. 2 mL of water was added, and the precipitated solid was collected by filtration, washed with 1 mL of chloroform and dried to give 47 mg of the desired product (yield 87%).
Reaction SMILES: C([C:4]1[C:5]([C:26]([O-:28])=[O:27])=[C:6](C(C)C)[C:7]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[C:8]([CH:12]=1)[C:9]([O-:11])=[O:10])(C)C.C(C1C(C([O-])=O)=C(C(C)C)C(SCC2C=CC=CC=2)=C(C=1)C([O-])=O)(C)C.[OH-].[K+]>CO.O>[CH3:22][O:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[CH2:14][S:13][C:7]1[CH:6]=[C:5]([C:26]([OH:28])=[O:27])[CH:4]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10]
Reactant: COc1cccc(CSc2c(C(=O)[O-])cc(C(C)C)c(C(=O)[O-])c2C(C)C)c1
Agent: CC(C)c1cc(C(=O)[O-])c(SCc2ccccc2)c(C(C)C)c1C(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cccc(CSc2cc(C(=O)O)ccc2C(=O)O)c1
Yield: 100 %

Procedure:
Following the procedure of Preparation 3(a), but substituting 32 g. of diisopropyl-(m-methoxybenzylthio)-terephthalate for diisopropyl-(benzylthio)-terephthalate, using 350 ml. of methanol, 35 ml. of water and 18 g. of potassium hydroxide, and refluxing for three hours, there is obtained 25.2 g. (yield 100%) of (m-methoxybenzylthio)-terephthalic acid having a melting point of 255°-256° C. after recrystallization from methanol.
Reaction SMILES: Cl.[F:2][C:3]([F:28])([F:27])[C:4]1[CH:26]=[CH:25][CH:24]=[CH:23][C:5]=1[CH:6]([O:18][CH:19]1[CH2:22][NH:21][CH2:20]1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=1.[N-:29]=[C:30]=[O:31]>>[F:28][C:3]([F:27])([F:2])[C:4]1[CH:26]=[CH:25][CH:24]=[CH:23][C:5]=1[CH:6]([O:18][CH:19]1[CH2:22][N:21]([C:30]([NH:29][CH:4]([CH2:5][CH3:6])[CH3:3])=[O:31])[CH2:20]1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=1
Reactant: [N-]=C=O
Reactant: FC(F)(F)Oc1ccc(C(OC2CNC2)c2ccccc2C(F)(F)F)cc1
Agent: Cl
Product: CCC(C)NC(=O)N1CC(OC(c2ccc(OC(F)(F)F)cc2)c2ccccc2C(F)(F)F)C1

Procedure:
This material was prepared from 3-[2-(trifluoromethyl)-4′-(trifluoro-methoxy)benzyloxy]azetidine hydrochloride (141) and the corresponding isocyanate using the procedure described for compound (10).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[C:21]([Cl:31])(=[O:30])[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[ClH:31].[C:21]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(=[O:30])[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCCCSc1ccncc1
Reactant: O=C(Cl)C=Cc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C=Cc1ccccc1)NCCCSc1ccncc1
Yield: 79.2 %

Procedure:
To a solution of 1.00 g (4.15 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 2.78 ml (19.9 mmol) of triethylamine in 40 ml of methylene chloride was added 830 mg (4.98 mmol) of cinnamoyl chloride under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: methanol/ethyl acetate=1:10) to obtain the powder which was washed with ether and dried to obtain 1.10 g of the desired compound (free base) (88.8%, colorless powder), mp: 116.0°-11.7.0° C.
Reaction SMILES: C(O)(=O)C.[NH2:5][CH:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH2:18][CH3:19])[CH:10]=1)[C:7]#[N:8].[C:20]([NH:23][C:24]1[CH:34]=[CH:33][CH:32]=[C:26]2[C:27]([O:29][C:30](=O)[C:25]=12)=[O:28])(=[O:22])[CH3:21]>C(O)(=O)C.CCOC(C)=O>[C:7]([CH:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH2:18][CH3:19])[CH:10]=1)[N:5]1[C:30](=[O:29])[C:25]2[C:26](=[CH:32][CH:33]=[CH:34][C:24]=2[NH:23][C:20](=[O:22])[CH3:21])[C:27]1=[O:28])#[N:8]
Reactant: CC(=O)Nc1cccc2c1C(=O)OC2=O
Reactant: CCOc1cc(C(N)C#N)ccc1OC
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOc1cc(C(C#N)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC
Yield: 85.3 %

Procedure:
To a mixture of 2-amino-2-(3-ethoxy-4-methoxyphenyl)ethanenitrile acetate (4.1 g, 14.6 mmol) and 3-acetamidophthalic anhydride (3.0 g, 14.6 mmol) in glacial acetic acid (60 mL), was heated to reflux for 17 hours. The mixture was concentrated in vacuo to provide an oil. The oil was dissolved in EtOAc and washed with water, brine and dried over MgSO4. Solvent was removed, and the residue was purified by chromatography (SiO2, Hexane:EtOAc 6:4) to give 4.9 g (83%) of N-{2-[cyano(3-ethoxy-4-methoxyphenyl)methyl]-1,3-dioxoisoindolin-4-yl}acetamide as a white solid; mp 118-120° C.; 1H NMR(CDCl3) δ 9.43 (s, 1H), 8.76 (d, J=8.4 Hz, 1H), 7.67 (t, J=7.7 Hz, 1H), 7.51 (d, J=7.2 Hz, 1H), 7.05-6.82 (m, 3H), 5.60-5.54 (dd, J=6.63 and 10.0 Hz, 1H), 4.10 (q, J=6.8 Hz, 2H), 3.81 (s, 3H), 3.81-3.74 (m, 1H), 3.29-3.20 (dd, J=6.2 and 16.8 Hz, 1H), 2.27 (s, 3H), 1.46 (t, J=7 Hz, 3H); 13C NMR (CDCl3) δ 169:56, 169.12, 167.19, 149.92, 148.64, 137.73, 136.30, 130.87, 128.70, 125.11, 119.92, 118.29, 116.76, 114.94, 112.14, 111.98, 64.56, 55.94, 51.08, 24.92, 21.04, 14.68. Aanly. Calculated for C22H21N3O5: C, 64.86; H, 5.20; N, 10.31. Found: C, 65.01; H, 5.10; N, 10.19.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8]C)=O)#[N:2].[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].[Li]>>[C:17]([O:16][C:13](=[O:15])[CH2:14][C:6]([C:5]1[CH:10]=[CH:11][CH:12]=[C:3]([C:1]#[N:2])[CH:4]=1)=[O:8])([CH3:20])([CH3:19])[CH3:18]
Reactant: COC(=O)c1cccc(C#N)c1
Reactant: CC(=O)OC(C)(C)C
Agent: [Li]
Product: CC(C)(C)OC(=O)CC(=O)c1cccc(C#N)c1

Procedure:
The title compound was prepared from methyl 3-cyanobenzoate [CAS-No. 13531-48-1] by treatment with lithium tert.-butyl acetate according to general procedure K (method b). Obtained as a light brown oily semisolid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[CH2:19][C:20]([NH2:22])=[O:21].[C:23](OCC)(=[O:29])[C:24](OCC)=[O:25].CC(C)([O-])C.[K+].Cl>CN(C)C=O.O>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[C:19]1[C:20](=[O:21])[NH:22][C:24](=[O:25])[C:23]=1[OH:29]
Reactant: CC1(C2CCCC2)Cc2cc(CC(N)=O)c(Cl)c(Cl)c2C1=O
Reactant: CCOC(=O)C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C2CCCC2)Cc2cc(C3=C(O)C(=O)NC3=O)c(Cl)c(Cl)c2C1=O

Procedure:
In a nitrogen atmosphere, (+)-(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)acetamide (19.8 g., 0.0582 mole) and diethyl oxalate (9.14 g., 0.626 mole) are dissolved in dimethylformamide (100 ml.) and stirred in an ice bath. Potassium tert. butoxide (15.2 g, 0.136 mole) is added in two portions at a 10 minute interval. The reaction mixture is stirred at 25° C. for 18 hours, poured into water (600 ml) acidified with hydrochloric acid, extracted with ether, washed with water and brine and dried over MgSO4. Evaporation of the ether at reduced pressure gives (+)3-(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-dione as the hemietherate in the form of a foam. Upon drying at reduced pressure, the analysis of the hemietherate is as follows:
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[O:7][C@@H:6]([N:8]2[CH:15]=[C:14]([CH2:16][CH3:17])[C:12](=[O:13])[NH:11][C:9]2=[O:10])[CH2:5][C@@H:4]1[OH:18].C([BH3-])#N.[Na+].[Cl:23][C:24]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:25]=1[O:26][CH:27]([CH3:30])[CH:28]=O>CO.O>[CH2:16]([C:14]1[C:12](=[O:13])[NH:11][C:9](=[O:10])[N:8]([CH:15]=1)[C@@H:6]1[O:7][C@H:3]([CH2:2][NH:1][CH2:30][CH:27]([O:26][C:25]2[CH:31]=[CH:32][C:33]([Cl:35])=[CH:34][C:24]=2[Cl:23])[CH3:28])[C@@H:4]([OH:18])[CH2:5]1)[CH3:17]
Reactant: CCc1cn([C@H]2C[C@H](O)[C@@H](CN)O2)c(=O)[nH]c1=O
Reactant: CC(C=O)Oc1ccc(Cl)cc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCc1cn([C@H]2C[C@H](O)[C@@H](CNCC(C)Oc3ccc(Cl)cc3Cl)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 32.2 %

Procedure:
To a solution, cooled in ice, of 0.45 g of 5'-amino-2',5'-dideoxy-5-ethyluridine in 28 ml of methanol and 9 ml of water were added 0.17 g of sodium cyanoborohydride followed by 0.5 g of 2-(2,4-dichlorophenoxy)propionaldehyde. The mixture was allowed to warm to room temperature and was then stirred at room temperature for 3 days. The solution was concentrated in order to remove methanol, diluted with 20 ml of water and extracted three times with 15 ml of methylene chloride. The combined extracts were dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using methanol/methylene chloride (1:12) for the elution. There was obtained 0.26 g of 2',5'-dideoxy-5-ethyl-5'-[2(RS)-(2,4-dichlorophenoxy)propylamino]uridine, mp 51°-61° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@H:11]([CH2:13][N:14]3[CH:18]=[C:17]([CH3:19])[N:16]=[N:15]3)[O:10][C:9]2=[O:20])[CH:5]=[CH:6][CH:7]=1.[I:21]I>ClCCl.FC(F)(F)C([O-])=O.[Ag+]>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@H:11]([CH2:13][N:14]3[CH:18]=[C:17]([CH3:19])[N:16]=[N:15]3)[O:10][C:9]2=[O:20])[CH:5]=[CH:6][C:7]=1[I:21]
Reactant: Cc1cn(C[C@H]2CN(c3cccc(F)c3)C(=O)O2)nn1
Reactant: II
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Product: Cc1cn(C[C@H]2CN(c3ccc(I)c(F)c3)C(=O)O2)nn1
Reaction time: 8 h
Yield: 42.6 %

Procedure:
Silver trifluoroacetate (0.52 g, 2.35 mM) was added to a solution of (5R)-3-(3-fluorophenyl)-5-[(4-methyl-1H-1,2,3-triazol-1-yl)methyl]-1,3-oxazolidin-2-one (0.50 g, 1.81 mM) in dichloromethane (15 mL). Iodine (0.55 g, 2.17 mM) was added over 1.5 h, and reaction mixture was stirred overnight. After 16 h, the solids were removed by filtration and additional silver trifluoroacetate (0.38 g, 1.72 mM) and iodine (0.27 g, 1.06 mM) were added. After an additional 24 h, the reaction mixture was filtered. The filter cake was washed with methanol. The methanol filtrate was concentrated under vacuum to give 0.31 g of the title product.
Reaction SMILES: [OH-].[CH3:2][N:3]([CH3:16])[C@@H:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[C@H:6]([OH:15])[CH2:5]1.Cl[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25]>CS(C)=O>[CH3:2][N:3]([CH3:16])[C@@H:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[C@H:6]([O:15][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N+:24]([O-:26])=[O:25])[CH2:5]1
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: CN(C)[C@@H]1CCc2ccccc2[C@H](O)C1
Agent: [OH-]
Solvent: CS(C)=O
Product: CN(C)[C@@H]1CCc2ccccc2[C@H](Oc2ccccc2[N+](=O)[O-])C1
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 196.4 %

Procedure:
A mixture of 11 ml of dimethylsulfoxide and 1.1 g of hydroxide as a 50% oil dispersion was heated in a bath at 70° C. for 30 minutes and after cooling the mixture to 20° C., 4.1 g of cis 7-dimethylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol were added thereto. The mixture was stirred for 10 minutes at room temperature and then 6.32 g of o-chloronitrobenzene were added thereto while cooling in an ice bath. The mixture was stirred for 30 minutes at 20° C. and was extracted with methylene chloride. The organic phase was washed with water, dried over magnesium sulfate and was filtered. The filtrate was evaporated to dryness under reduced pressure to obtain 12.8 g of cis N,N-dimethyl-5-[2-nitrophenoxy]-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-amine in the form of a brown oil.
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:15]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:18][CH:19]=2)=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[CH:24]1([C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([C:30]2[CH:31]=[CH:32][C:33]([O:36][CH:2]([C:7]3[CH:12]=[CH:11][C:10]([O:13][C:14]4[CH:15]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:18][CH:19]=4)=[CH:9][CH:8]=3)[C:3]([O:5][CH3:6])=[O:4])=[CH:34][CH:35]=2)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: Oc1ccc(C2CCCCC2)cc1
Reactant: COC(=O)C(Br)c1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Product: COC(=O)C(Oc1ccc(C2CCCCC2)cc1)c1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Yield: 68.5 %

Procedure:
In a manner similar to Example 16, 7.62 g of methyl α-bromo-α-[p-(α,α,α-trifluoro-m-tolyloxy)phenyl]acetate was reacted with 4.4 g of p-cyclohexylphenol to give 6.5 g of product as an amber oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].S(OCC)(O[CH2:16][CH3:17])(=O)=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH2:16]([O:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([F:1])[CH:3]=1)[CH3:17]
Reactant: CCOS(=O)(=O)OCC
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc([N+](=O)[O-])c(F)c1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 98.6 %

Procedure:
To a solution of 3-fluoro-4-nitrophenol (9.9 g, 0.063 mol) and diethyl sulfate (12.17 g, 0.079 mol) in DMF (100 mL) was added K2CO3 (17.39 g, 0.126 mol). The resulting mixture was stirred at 80° C. for 90 min and then cooled to rt. The reaction mixture was diluted with H2O (200 mL) and extracted with 25% EtOAc in hexanes (2×100 mL). The combined organic phases were washed with brine (100 mL), filtered through phase separation filter paper, and concentrated in vacuo to give 11.5 g (98%) of 53 as an orange-yellow solid. 1H NMR (60 MHz, CDCl3): δ 8.8-7.7 (m, 1H), 6.6-6.2 (m, 2H), 4.0 (q, 2H), 1.4 (t, 3H) ppm.