Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:9]([O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Brc1ccccc1OCc1ccccc1
Yield: 100 %

Procedure:
To a stirring solution of 2-bromophenol (10.0 g, 57.8 mmol), and benzyl bromide (9.9 g, 57.8 mmol) in acetone (150 mL) was added K2CO3 (12.0 g, 86.7 mmol). After stirring at reflux for 4 h, the mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by column chromatography (silica gel, ethyl acetate/hexane) to yield the title compound as a colorless oil (15.2 g, 57.8 mmol). 1HNMR (400 MHz, CDCl3) δ 7.62 (m, 1H), 7.54 (m, 2H), 7.45 (m, 2H), 7.37 (m, 1H), 7.28 (m, 1H), 6.98 (m, 1H), 6.91 (m, 1H), 5.17 (s, 2H).
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([O:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])[CH2:18][CH2:17]3)[CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[CH3:34][CH:35]([S:37]([Cl:40])(=[O:39])=[O:38])[CH3:36]>C(Cl)Cl>[ClH:40].[ClH:40].[CH2:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([O:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26][S:37]([CH:35]([CH3:36])[CH3:34])(=[O:39])=[O:38])[CH2:18][CH2:17]3)[CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc(OC2CCN(CCCCN)CC2)c2ncccc2c1
Reactant: CC(C)S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCc1cc(OC2CCN(CCCCNS(=O)(=O)C(C)C)CC2)c2ncccc2c1
Product: Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
(4-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)amine (for example, as prepared for Intermediate 37) (87 mg, 0.24 mmol) was dissolved in DCM (2 ml), and treated with triethylamine (167 μl, 1.2 mmol), and 2-propanesulfonyl chloride (commercially available, for example, from Aldrich) (54 μl, 0.48 mmol). The mixture was stirred at room temperature for 1.5 h. LCMS analysis indicated that reaction was not complete. Further triethylamine (167 μl, 1.2 mmol), and 2-propanesulfonyl chloride (54 μl, 0.48 mmol) were added and the mixture stirred at room temperature for 1 h. The reaction was quenched by the addition of methanol then concentrated under a stream of nitrogen. The residue was re-dissolved in methanol and applied to an SCX-2 cartridge (20 g) eluting with methanol, followed by 10% aqueous 0.88 s.g. ammonia in methanol. The relevant fractions were concentrated, and the residue was purified by MDAP. The appropriate fractions were combined and concentrated, but the product was found to contain impurities, thought to be (3-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}propyl)sulfamic acid. The material was dissolved in methanol and applied to an aminopropyl cartridge (5 g) eluting with methanol. The relevant fractions were combined and concentrated to give the title compound as the free base (43 mg, 39%): LCMS RT=2.63 min, ES+ve m/z 462 (M+H)+. Approximately half the material was dissolved in methanol and treated with 1.25 M hydrogen chloride in methanol (1 ml, excess). The volatiles were removed under a stream of nitrogen to give the title compound (26 mg): LCMS RT=2.70 min, ES+ve m/z 462 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:21][CH2:22][CH2:23][O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[C:5]([O:7][CH3:8])=[O:6].[C:31]([C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1)([CH3:34])([CH3:33])[CH3:32]>N1C=CC=CC=1.C1(C)C=CC=CC=1>[C:31]([C:35]1[CH:40]=[CH:39][C:38]([S:41]([NH:1][C:2]2[CH:3]=[C:4]([CH:9]=[C:10]([O:21][CH2:22][CH2:23][O:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][O:26]3)[C:11]=2[O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[C:5]([O:7][CH3:8])=[O:6])(=[O:43])=[O:42])=[CH:37][CH:36]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1cc(N)c(Oc2cccc(OC)c2)c(OCCOC2CCCCO2)c1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COC(=O)c1cc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c(Oc2cccc(OC)c2)c(OCCOC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.35 9 of methyl 3-amino-4-(3-methoxy-phenoxy)-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoate was dissolved in pyridine (10 ml), treated dropwise while cooling with ice with a solution of 0.312 g of 4-tert.butyl-benzenesulphonyl chloride in toluene (3 ml) and subsequently stirred at RT for 24 hours. The reaction mixture was poured on to ice/3M HCl, the product was extracted with ethyl acetate, the organic phase was washed with 2M KHCO3 solution and dried over magnesium sulphate. After removing the solvent there was obtained the desired methyl 3-(4-tert-butyl-benzenesulphonylamino)-4-(3-methoxy-phenoxy)-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoate as a solid.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].[C:12]([O:18][CH3:19])(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15].C(O)(=O)C.N1CCCCC1>>[CH3:19][O:18][C:12](=[O:17])[CH2:13][C:14]([CH:16]=[CH:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])=[O:15]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: COC(=O)CC(C)=O
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: COC(=O)CC(=O)C=Cc1ccccc1[N+](=O)[O-]
Yield: 97 %

Procedure:
In the first step of the synthesis 2-nitro-benzaldehyde is reacted with methyl acetoacetate in the presence of a catalytic amount (0.01-0.7 mole, related to 1 mole of methyl acetoacetate) of piperidine acetate to give methyl-2-nitro-benzylidene-acetoacetate with a high yield of about 97%. This product is reacted after or without isolation with methyl-3-amino-crotonate. The yield of the second step is 87%, the total yield of both steps amounts to 84.4%. According to the disclosure of the cited Hungarian patent the thin layer chromatogram of the nifedipine thus obtained shows no by-products (Merck-type plate coated with kieselgel; developped with a 3:2:5 mixture of chloroform, acetone and petrolether).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:13]2[S:12][C:11]([NH:14][C:15](=[O:17])[OH:16])=[N:10][C:9]=2[C:8]([O:18][CH3:19])=[CH:7][CH:6]=1)=O.[C:20]([O:24][C:25]([NH:27][C:28]([NH2:30])=[NH:29])=[O:26])([CH3:23])([CH3:22])[CH3:21]>C(#N)C>[C:20]([O:24][C:25]([NH:27][C:28]1[NH:29][CH:2]=[C:3]([C:5]2[C:13]3[S:12][C:11]([NH:14][C:15](=[O:17])[OH:16])=[N:10][C:9]=3[C:8]([O:18][CH3:19])=[CH:7][CH:6]=2)[N:30]=1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)NC(=N)N
Reactant: COc1ccc(C(=O)CBr)c2sc(NC(=O)O)nc12
Solvent: CC#N
Product: COc1ccc(-c2c[nH]c(NC(=O)OC(C)(C)C)n2)c2sc(NC(=O)O)nc12
Yield: 17 %

Procedure:
0.25 g of (7-bromoacetyl-4-methoxy-benzothiazol-2-yl)-carbamic acid methyll ester (0.0007 Mol) and 0.33 g of tert-butoxycarbonylguanidine (0.0021 Mol) were heated to reflux in acetonitril (3 ml) for 3 hrs. After evaporation of the solvent the residue was triturated with water (10 ml) and filtered. The filtrate was evaporated and the residue subjected to column chromatography (silicagel, ethyl-acetate/hexanes 1:1) to yield the title compound as a white solid (17%); F.p.: 255-265° C.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[C:13]([F:14])=[C:12]([F:15])[C:11](F)=[C:10]([F:17])[C:9]=2[F:18])=[C:6]([F:19])[C:5]([F:20])=[C:4]([F:21])[C:3]=1[F:22].[CH2:23]([O:30][C:31]([C:33]1[CH:39]=[CH:38][C:36]([O-:37])=[CH:35][CH:34]=1)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[K+].[K]>CN(C)C=O>[CH2:23]([O:30][C:31]([C:33]1[CH:34]=[CH:35][C:36]([O:37][C:11]2[C:10]([F:17])=[C:9]([F:18])[C:8]([C:7]3[C:2]([F:1])=[C:3]([F:22])[C:4]([F:21])=[C:5]([F:20])[C:6]=3[F:19])=[C:13]([F:14])[C:12]=2[F:15])=[CH:38][CH:39]=1)=[O:32])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Fc1c(F)c(F)c(-c2c(F)c(F)c(F)c(F)c2F)c(F)c1F
Reactant: O=C(OCc1ccccc1)c1ccc([O-])cc1
Agent: [K+]
Agent: [K]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1ccc(Oc2c(F)c(F)c(-c3c(F)c(F)c(F)c(F)c3F)c(F)c2F)cc1
Temperature: -10 °C
Reaction time: 48 h

Procedure:
37.6 g of decafluorobiphenyl (0.112 mol) are dissolved in 700 ml of dimethylformamide, and the solution is cooled to -10° C. by means of a cryostat, and a solution of 15 g of potassium 4-benzyloxycarbonylphenoxide (0.056 mol) in 300 ml of dimethylformamide is then added drop wise over the course of 2 hours. After 48 hours at -10° C., the potassium salt has reacted. The dimethylformamide is then removed in a rotary evaporator, and the residue is taken up in a little tetrahydrofuran and filtered via a silica-gel column. The clear solution obtained is evaporated in a rotary evaporator until the reaction product precipitates out. The reaction product is then stirred in n-hexane, filtered off via a fluted filter and then dried for 48 hours under nitrogen at 40° C./10 mbar in a vacuum drying cabinet.
Reaction SMILES: [C:1]([CH2:9][C:10]([C:12]([F:15])([F:14])[F:13])=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:17][OH:18].[OH-:19].[Na+]>>[C:2]1([C:1]2[CH2:9][C:10]([OH:19])([C:12]([F:13])([F:14])[F:15])[O:18][N:17]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: NO
Reactant: O=C(CC(=O)C(F)(F)F)c1ccccc1
Agent: Cl
Agent: [Na+]
Product: OC1(C(F)(F)F)CC(c2ccccc2)=NO1
Temperature: 25 °C
Yield: 91.5 %

Procedure:
Prepared according to J. Org. Chem., 1995, 60, 3907. A solution of benzoyltrifluoroacetone (21 g, 97 mmol) was added dropwise over 1 h, at 20-30° C., to a solution of hydroxylamine HCl (6.82 g, 98 mmol) containing sodium hydroxide (2 N, 51 mL, 102 mmol) and the resulting mixture heated under reflux for 45 min. After cooling to room temperature, the mixture was poured into ice-water (500 mL), the precipitate was filtered off, washed with water and dried under vacuum to afford the title compound (20.51 g, 91%) which was obtained as a white solid. MS: m/e=230.2 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][CH:12]=C)[C:6]=2[CH:14]=1.I([O-])(=O)(=O)=[O:16].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][CH:12]=[O:16])[C:6]=2[CH:14]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCn1c(=O)sc2ccc(Cl)cc21
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=CCn1c(=O)sc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5-chloro-3-(2-propen-1-yl)-1,3-benzothiazol-2(3H)-one (0.43 g, 1.9 mmol) (0.43 g, 1.9 mmole) was dissolved in 1,4-dioxane (20 ml) and water (22 ml) was added. Sodium periodate (0.94 g, 4.4 mmol) was added followed by 4% osmium tetroxide in water (2.1 ml) and stirred at rt for 30 mins after which time a heavy precipitate had formed. Water (20 ml) was added followed by more sodium periodate (1.9 g, 8.9 mmol) and the mixture stirred at rt for 18 h. The mixture was concentrated in-vacuo to a small volume and partitioned between water (50 ml) and DCM (2×50 ml). The organics were separated and dried. Chromatography on silica gel eluting with a gradient of 25-100% ethyl acetate/40-60 petroleum ether gave 0.21 g, 48%) of the title compound.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([C:15]2[CH:19]=[CH:18][N:17]([Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])[CH:16]=2)[CH:12]=[CH:11][C:10]=1[N:30]1[S:34](=[O:36])(=[O:35])[NH:33][C:32](=[O:37])[CH2:31]1)C1C=CC=CC=1>CCO.CCOC(C)=O.CCO.[Pd]>[OH:8][C:9]1[CH:14]=[C:13]([C:15]2[CH:19]=[CH:18][N:17]([Si:20]([CH:21]([CH3:22])[CH3:23])([CH:24]([CH3:25])[CH3:26])[CH:27]([CH3:29])[CH3:28])[CH:16]=2)[CH:12]=[CH:11][C:10]=1[N:30]1[S:34](=[O:36])(=[O:35])[NH:33][C:32](=[O:37])[CH2:31]1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc(-c2ccc(N3CC(=O)NS3(=O)=O)c(OCc3ccccc3)c2)c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc(-c2ccc(N3CC(=O)NS3(=O)=O)c(O)c2)c1
Reaction time: 18 h

Procedure:
To a slurry of Pd/C (10 mg) in 10 mL of EtOH/EtOAc (1:1) is added a solution of 5-[2-benzyloxy-4-(1-triisopropylsilanyl-1H-pyrrol-3-yl)-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one in EtOH. The mixture is stirred under an atmosphere of H2 for 18 h then the catalyst is removed by filtration through a pad of Celite. The filtrate is concentrated under reduced pressure to afford the title compound which is used directly in the next step: (M−1)−=448.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:22])[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[C:7]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=1)[CH3:2].[Sn](Cl)Cl>C(OCC)(=O)C.CO>[CH2:1]([NH:3][C:4](=[O:22])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:6]=1)[CH3:2]
Reactant: CCNC(=O)c1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CCNC(=O)c1ccc(N)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 21 h
Yield: 87.8 %

Procedure:
N-Ethyl-3-benzyloxy-4-nitrobenzamide (5.40 g, 18.0 mmol) obtained in Example 312b) was dissolved in ethyl acetate (60 ml) and methanol (40 ml), anhydrous tin(II) chloride (17.6 g, 89.9 mmol, 5.0 eq.) was added, and the mixture was stirred at room temperature for 21 hr. The reaction mixture was concentrated, and methanol was evaporated. The residue was diluted with ethyl acetate (200 ml) and mixed with 1.44N sodium hydroxide (150 ml). The obtained suspension was filtered through celite (diameter 60 mm) and washed with ethyl acetate (100 ml). The filtrate and washing were combined, washed sequentially with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was subjected to column chromatography (elution solvent, ethyl acetate-hexane=1:1-2:1) on silica gel (manufactured by E. Merck, Art.7734, 50 g). The fraction obtained by elution with ethyl acetate-hexane (3:2) was concentrated, and diethyl ether was added. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (4.27 g, 15.8 mmol, 87.8%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH:16][C@:17]23[CH2:51][CH2:50][C@@H:49]([C:52]([CH3:54])=[CH2:53])[C@@H:18]2[C@@H:19]2[C@@:32]([CH3:35])([CH2:33][CH2:34]3)[C@@:31]3([CH3:36])[C@@H:22]([C@:23]4([CH3:48])[C@@H:28]([CH2:29][CH2:30]3)[C:27]([CH3:38])([CH3:37])[C:26]([C:39]3[CH:47]=[CH:46][C:42]([C:43]([OH:45])=[O:44])=[CH:41][CH:40]=3)=[CH:25][CH2:24]4)[CH2:21][CH2:20]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:55](N1CCNCC1)([CH3:58])([CH3:57])[CH3:56]>>[C:55]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][NH:16][C@:17]23[CH2:51][CH2:50][C@@H:49]([C:52]([CH3:54])=[CH2:53])[C@@H:18]2[C@@H:19]2[C@@:32]([CH3:35])([CH2:33][CH2:34]3)[C@@:31]3([CH3:36])[C@@H:22]([C@:23]4([CH3:48])[C@@H:28]([CH2:29][CH2:30]3)[C:27]([CH3:38])([CH3:37])[C:26]([C:39]3[CH:47]=[CH:46][C:42]([C:43]([OH:45])=[O:44])=[CH:41][CH:40]=3)=[CH:25][CH2:24]4)[CH2:21][CH2:20]2)[CH2:12][CH2:13]1)([CH3:58])([CH3:57])[CH3:56]
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCN(C(=O)OC(C)(C)C)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CC(C)(C)N1CCNCC1
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCN(C(C)(C)C)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid using 1-(tert-butyl)piperazine as the alkylating reagent in Step 3. The product was isolated as a white solid (9 mg, 40%). LCMS: m/e 698.67 (M+H)+, 2.27 min (method 11). 1H NMR (500 MHz, Acetic) δ 8.04 (d, J=8.0 Hz, 2H), 7.30 (d, J=8.0 Hz, 2H), 5.38 (d, J=5.2 Hz, 1H), 4.84 (s, 1H), 4.74 (s, 1H), 3.77 (br. s., 2H), 3.51-2.82 (m, 11H), 2.41-1.16 (m, 22H), 1.77 (s, 3H), 1.49 (s, 9H), 1.30 (s, 3H), 1.15 (s, 3H), 1.10 (s, 3H), 1.02 (s, 3H), 1.01 (s, 3H).
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[O:15])[NH:8][C:7]1=[S:16])[CH2:2][CH2:3][CH2:4][CH3:5].S(OC)(O[CH3:21])(=O)=O.C(O)(=O)C>[OH-].[Na+].O>[CH3:21][S:16][C:7]1[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[O:15])[N:8]=1
Reactant: COS(=O)(=O)OC
Reactant: CCCCCn1c(=S)[nH]c(=O)c2[nH]cnc21
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CCCCCn1c(SC)nc(=O)c2[nH]cnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.9 %

Procedure:
To a solution of 3-pentyl-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one (13.0 g, 54.6 mmol) in 2 M of sodium hydroxide in water (250 mL) was added dimethyl sulfate (6.2 mL, 66 mmol), and the reaction mixture was stirred at room temperature for 1 hour, then neutralized with acetic acid. The precipitate was collected by filtration and recrystallized from ethyl acetate-MeOH (1:1) to give the desired product (5.50 g, 40%). LCMS calculated for C11H17N4OS (M+H): 253.1. Found: 253.1.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=2)[C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:4][CH:3]=[CH:2]1.Cl.[CH3:17][NH:18][CH3:19].[CH2:20]=O>C(O)C>[CH3:17][N:18]([CH2:20][C:5]1[N:1]([C:6]2[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=2)[C:9]([O:11][CH3:12])=[O:10])[CH:2]=[CH:3][CH:4]=1)[CH3:19]
Reactant: COC(=O)c1cccc(-n2cccc2)c1
Reactant: CNC
Reactant: C=O
Agent: Cl
Solvent: CCO
Product: COC(=O)c1cccc(-n2cccc2CN(C)C)c1
Yield: 59.6 %

Procedure:
The mixture of methyl 3-(pyrrol-1-yl)benzoate (20.0 g), dimethylamine hydrochloride (12.2 g) and paraformaldehyde (13.4 g) in ethanol (60 ml) was heated under reflux for 3 hours under stirring. The solvent was removed by concentration and the residue was added to the mixture of ethyl acetate and water. The mixture was adjusted to pH 12 with 5N-sodium hydroxide solution. The separated organic layer was washed with brine, dried over magnesium sulfate, and evaporated. The residue was purified by column chromatography on silica gel eluting with a mixture of chloroform and methanol (9:1, V/V). The eluted fractions containing the desired product were collected and evaporated in vacuo to give methyl 3-(2-dimethylaminomethylpyrrol-1-yl)benzoate (15.3 g) as an oil.
Reaction SMILES: [C:1]([OH:13])(=O)[CH2:2][NH:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH2:14]([O:21][C:22](=[O:37])[C@H:23]([CH2:25][CH2:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[NH2:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.O>[CH2:14]([O:21][C:22](=[O:37])[C@H:23]([CH2:25][CH2:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[NH:24][C:1](=[O:13])[CH2:2][NH:3][C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:5])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(O)CNC(=O)c1ccccc1
Reactant: N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CNC(=O)c1ccccc1)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The starting material compound 3 was prepared as follow. To a solution of hippuric acid (0.90 g, 5×10-3 moles) and L-glutamic acid dibenzyl ester (2.50 g, 5×10-3 moles) in DMF (35 ml) was added 1-hydroxybenzotriazole (0.73 g, 5.5×10-3 moles), triethylamine (1.4 ml. 9.7×10-3 moles) and 1(3-dimethyl-aminopropyl)-3-ethylcarbodiimide. HCl salt (1.05 g, 5.5×10-3 moles). The mixture was stirred overnight at room temperature, poured into water (400 ml) and extracted twice with ethyl acetate (100 ml). The combined extracts were washed with saturated sodium bicarbonate solution, water, 2N HCl and water. The organic phase was dried over MgSO4 and evaporated to obtain the desired starting material as a yellow oil. 2.06 g (84%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]#[N:10])[C:4]=1[CH3:11])#[N:2].Cl.[NH2:13][OH:14].C(N(CC)CC)C.Cl>C(Cl)(Cl)Cl.C1COCC1>[C:1]([C:3]1[C:4]([CH3:11])=[C:5]([C:9](=[NH:10])[NH:13][OH:14])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: Cc1c(C#N)cccc1C#N
Reactant: NO
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1c(C#N)cccc1C(=N)NO
Temperature: 50 °C
Reaction time: 7 h
Yield: 14.6 %

Procedure:
A suspension of 2,6-dicyanotoluene (25.0 g, 176 mmol), hydroxylamine hydrochloride (73.0 g, 1.06 mol) and triethylamine (142 g, 1.41 mol) in chloroform (500 ml) was stirred at 50° C. for 7 h, then allowed to stand at room temperature overnight. The reaction mixture was cooled in ice, treated with 5M HCl to pH1 and extracted three times with chloroform. The aqueous was extracted with THF (×7), cooled in ice, raised to pH4 with 40% NaOH and extracted with THF (×3). The latter THF extracts were combined and evaporated to dryness to give a buff solid consisting of the product and approximately a third of an equivalent of triethylamine (11.0 g). 1H NMR (400 MHz, d4-MeOH) δ (inter alia) 7.70-7.76 (1H, m), 7.57-7.63 (1H, m), 7.35-7.62 (1H, m), 2.58 (3H, s); MS (ES) C9H9N3O requires 175; found 176 [M+H]+. The former seven extracts of THF were combined, evaporated to dryness and dissolved in water. The aqueous solution was extracted twice with chloroform, adjusted to pH4 and extracted with THF (×3). Evaporation of the combined THF extracts gave a further 4.5 g of product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2=[O:13].C([O-])([O-])=O.[K+].[K+].Br[CH2:21][C:22]([O:24][CH3:25])=[O:23]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:7](=[O:12])[C:6]2=[O:13]
Reactant: COC(=O)CBr
Reactant: COc1ccc2c(c1)C(=O)C(=O)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)C(=O)c2cc(OC)ccc21

Procedure:
To a solution of 5-methoxyindoline-2,3-dione (1 g, 5.64 mmol) in DMF (15 ml), K2CO3 (0.936 g, 6.77 mmol) and methyl 2-bromoacetate (0.628 ml, 6.77 mmol) were added, and the mixture was reacted under microwave irradiation for 1 hour at 100° C. Then the insoluble inorganic salts were filtered off, and the resulting crude title compound was obtained (1.6 g) and used in the next step without further purification. MS/ESI+ 250.1 [MH]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[C:5]#[N:6].[CH2:11]([C:13]1[CH:14]=[C:15]([OH:22])[C:16]([O:20]C)=[CH:17][C:18]=1[F:19])[CH3:12].[OH-].[K+].O.[C:26](#N)C>>[CH2:11]([C:13]1[C:18]([F:19])=[CH:17][C:16]([O:20][C:9]2[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=2[F:1])=[C:15]([O:22][CH3:26])[CH:14]=1)[CH3:12]
Reactant: N#Cc1ccc(F)c(F)c1
Reactant: CC#N
Reactant: CCc1cc(O)c(OC)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCc1cc(OC)c(Oc2ccc(C#N)cc2F)cc1F

Procedure:
To 3,4-difluorobenzonitrile (12.26 g) dissolved in acetonitrile (10 volumes) was added 4-ethyl-5-fluoroguaiacol (15 g; which may be prepared as hereinbefore described for D2). Then, potassium hydroxide (0.33 parts) was added and the reaction mixture was refluxed for 7 hours. Once the reaction complete, the temperature was lowered to 20° C., water (2.5 volumes) was added and the phases separated. The organic phase was stored at RT until used in the next step.