Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:41]=[CH:40][C:25]([O:26][C:27]2[CH:39]=[CH:38][C:30]([O:31][CH2:32][CH2:33][CH2:34][C:35](O)=[O:36])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C([O:45][C:46](=[O:50])[CH2:47][CH2:48][NH2:49])C>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([O:31][CH2:32][CH2:33][CH2:34][C:35]([NH:49][CH2:48][CH2:47][C:46]([OH:45])=[O:50])=[O:36])=[CH:38][CH:39]=2)=[CH:40][CH:41]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCCCC(=O)O)cc2)cc1
Reactant: CCOC(=O)CCN
Agent: Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCCCC(=O)NCCC(=O)O)cc2)cc1

Procedure:
The product from Example 233 and beta-alanine ethyl ester hydrochloride were processed as described in Example 251A and B to provide the titled compound. 1H NMR (500 MHz, DMSO-d6) δ11.91-12.41 (br.s, 1 H), 8.94 (s, 1 H), 7.90 (m, 1 H), 7.22 (m, 7 H), 6.88-7.09 (m, 7 H), 6.82 (d, 2 H), 4.04 (s, 2 H), 4.00 (s, 2 H), 3.92 (t, 2 H), 3.24 (dd, 2 H), 2.91 (s, 3 H), 2.38 (s, 3 H), 2.37 (t, 2 H), 2.21 (t, 2 H), 1.91 (m, 2 H); MS (ESI+) m/z 646 (M+H)+.
Reaction SMILES: C[O:2]C(C1C=CC=CC=1)C(O)=O.[CH:13]1([N:19]=[C:20]=[N:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C(OCC)(=O)C.CN(C)C1C=CN=CC=1>[CH:22]1([NH:21][C:20]([NH:19][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)=[O:2])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: COC(C(=O)O)c1ccccc1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(NC1CCCCC1)NC1CCCCC1

Procedure:
In 50 ml of ethyl acetate was dissolved with heating 1.0 g (2.73 mmole) of the compound obtained in step 1 of Example 1 above. To the resultant solution were added 0.68 g (4.10 mmole) of (-)-α-methoxyphenylacetic acid and then 0.67 g (3.28 mmole) of 1,3-dicyclohexyl carbodiimide at room temperature. Subsequently, 0.040 g (0.33 mmole) of 4-dimethylaminopyridine as a catalyst was added. The resultant mixture was stirred for 24 hours. Dicyclohexyl urea in the form of a white solid produced during the reaction as a side-product was removed by filtration, and the remaining filtrate was concentrated and purified by silica gel column chromatography using a mixture of hexane and ethyl acetate (1:1) as an eluent to obtain 0.70 g (1.36 mmole, yield 50%) of (+) dimethoxymethyl-3-(O-α-methoxy-α-phenylacethoxy)-4-(2'-oxo-1'-pyrrolidinyl)-6-cyano-3,4-dihydro-2H-1-benzopyran having Rf value of 0.23 and 0.54 g (1.05 mmole, yield 38%) of (-) dimethoxymethyl-3-(O-α-methoxy-α-phenylacethoxy)-4-(2'-oxo-1'-pyrrolidinyl)-6-cyano-3,4-dihydro-2H-1-benzopyran having Rf value of 0.30.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].C(O[C:13]([S-])=[S:14])C.[K+]>CN(C=O)C>[S:14]=[C:13]1[NH:1][C:2]2[S:3][CH:4]=[CH:5][C:6]=2[C:7](=[O:8])[NH:9]1
Reactant: NC(=O)c1ccsc1N
Reactant: CCOC(=S)[S-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1[nH]c(=S)[nH]c2sccc12
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 67.8 %

Procedure:
2-Aminothiophene-3-carboxamide (13 g, 92 mmol) and potassium ethylxanthate (48 g, 275 mmol) were mixed together and added to DMF (300 mL). The resulting mixture was heated to 150° C. for 6 hrs, then cooled to RT and concentrated on the rotovap under reduced pressure at 90° C. The residue was diluted with 300 mL of aqueous citric acid (5%) and cooled to 0° C. and stirred for 30 min. The tan powder was filtered and dried overnight to give (11.5 g) of the title compound MS (ES+): 185 (M+H)+.
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([NH2:10])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[C:11]1([O:17][C:18](Cl)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[C:1]([N:5]1[CH:9]=[C:8]([NH:10][C:18](=[O:19])[O:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1cc(N)cn1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)n1cc(NC(=O)Oc2ccccc2)cn1
Reaction time: 8 h
Yield: 89 %

Procedure:
To a solution containing 1-tert-butyl-1H-pyrazol-4-amine (0.995 g, 7.16 mmmol) in THF (20 mL), phenylchloroformate (1.00 mL, 8.02 mmol) and K2CO3 (1.32 g, 9.52 mmol) were added at room temperature. After stirring overnight, the mixture was filtered and the solid washed with THF. The filtrate was concentrated to dryness and the residue was dissolved in DCM and the organic solution was washed with brine and dried over MgSO4 to yield phenyl 1-tert-butyl-1H-pyrazol-4-ylcarbamate as a solid (1.65 g, 89%). 1H NMR (300 MHz, CDCl3) δ 7.85 (1H, s), 7.30 (6H, m), 1.60 (9H, s).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:7]=2[CH:6]=1)=[O:4].C([O-])([O-])=O.[Na+].[Na+].[Cl:21][CH2:22][C:23](Cl)=[O:24]>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[C:11]([NH:14][C:23](=[O:24])[CH2:22][Cl:21])[CH:12]=[CH:13][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc2ccc(N)cc2s1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2ccc(NC(=O)CCl)cc2s1
Reaction time: 18 h

Procedure:
To a mixture of 6-amino-benzo[b]thiophene-2-carboxylic acid methyl ester (1.0 g, 4.83 mmol) and Na2CO3 (2.05 g, 19.3 mmol) in DMF (10 mL) was added chloroacetylchloride (460 μL, 5.79 mmol.). After stirring for 18 h, the mixture was diluted with EtOAc, filtered and concentrated. The residue was purified by column:chromatography (2:8; EtOAc:hexanes) to give a pale-white solid. MS (EI): cal'd (MH+) 284.01, exp (MH+) 284.15. Also retained ˜50.5% of impure fractions.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C@H:4]([CH3:13])[NH:5][C:6](=[O:12])/[CH:7]=[CH:8]\[C:9]([OH:11])=[O:10].NC(N)=S.CS(O)(=O)=O>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:14])[C@H:4]([CH3:13])[NH:5][C:6](=[O:12])/[CH:7]=[CH:8]/[C:9]([OH:11])=[O:10]
Reactant: COC(=O)[C@H](C)NC(=O)/C=C\C(=O)O
Agent: CS(=O)(=O)O
Agent: NC(N)=S
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](C)NC(=O)/C=C/C(=O)O
Temperature: 25 °C
Yield: 74.2 %

Procedure:
This compound was isomerized to the fumaryl amide ester by the following procedure. (Z)-N-(3-Carboxy-1-oxo-2-propenyl) -L-alanine methyl ester (67.5 g.) was mixed with 1.28 g. thiourea and 2.18 ml. anhydrous methanesulfonic acid in 675 ml. dry ethyl acetate. The mixture was stirred at reflux for one hour and cooled to 25° C. After addition of 500 ml. water, the organic layer was separated and dried over anhydrous sodium sulphate. The solution was filtered and the solvent distilled under vacuum of 1-2 mm Hg leaving a solid residue that was dried to constant weight affording 50.1 g (74.2% yield) of the (E)N-(3-carboxy-1-oxo-2-propenyl)-L-alanine methyl ester. The NMR in d6 -dimethyl sulfoxide showed the product to be free of the Z-isomer.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.Br[C:7]1[CH:8]=[C:9]2[C:15]3([CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[CH2:14][N:13]([C:28]3[C:29]4[C@H:36]([CH3:37])[CH2:35][CH2:34][C:30]=4[N:31]=[CH:32][N:33]=3)[C:10]2=[CH:11][CH:12]=1>C1COCC1.CCOC(C)=O.[Zn+2].[Br-].[Br-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]1([C:7]2[CH:8]=[C:9]3[C:15]4([CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:17][CH2:16]4)[CH2:14][N:13]([C:28]4[C:29]5[C@H:36]([CH3:37])[CH2:35][CH2:34][C:30]=5[N:31]=[CH:32][N:33]=4)[C:10]3=[CH:11][CH:12]=2)[CH2:3][CH2:2]1
Reactant: Br[Mg]C1CC1
Reactant: C[C@@H]1CCc2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4cc(Br)ccc43)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@@H]1CCc2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4cc(C5CC5)ccc43)c21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
To a stirred suspension of ZnBr2 (41 mg, 0.18 mmol) in THF (0.5 mL) was added dropwise a 0.5 M solution of cyclopropylmagnesium bromide in THF (0.36 mL, 0.18 mmol) at about −78° C. under nitrogen. After being stirred at about −78° C. for about 30 min, the resulting solution was allowed to warm to about 0° C. A solution of (R)-tert-butyl 5-bromo-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (38 mg, 0.076 mmol) and Pd(PPh3)4 (4.4 mg, 0.0038 mmol) in THF (0.3 mL) was added. The resulting mixture was heated to about 60° C. overnight. After cooling, the mixture was diluted with EtOAc, washed with water and brine, dried and concentrated. The residue was purified by reverse phase preparative HPLC to give (R)-tert-butyl 5-cyclopropyl-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (20 mg, 57%). LCMS (APCI+) m/z 461 [M+H]+; Rt=3.24 min.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH:8]=O.[NH2:10][C:11]1[C:12]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:13][CH:14]=[C:15]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH:16]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(O)(=O)C>[F:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][C:15]2[CH:16]=[C:11]([NH:10][CH2:8][CH2:7][N:3]3[CH2:4][CH2:5][CH2:6][C:2]3=[O:1])[C:12]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:13][CH:14]=2)=[CH:19][CH:20]=1
Reactant: O=CCN1CCCC1=O
Reactant: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1NCCN1CCCC1=O
Temperature: 2.5 °C
Reaction time: 0.25 h

Procedure:
(2-Oxopyrrolidin-1-yl)acetaldehyde (2.00 g, 15.7 mmol) and ethyl 3-amino-5-(4-fluorobenzyl)-2-pyridinecarboxylate (2.00 g, 7.32 mmol) were combined in 1:1 dichloroethane/acetic acid (10 mL) and cooled under nitrogen to 0-5° C. Sodium trisacetoxyborohydride (3.10 g, 14.6 mmol) was added and the reaction was stirred for 15 min. Two additional portions of aldehyde (1.0 g, 7.8 mmol) plus sodium triacetoxyborohydride (1.65 g, 7.8 mmol) separated by 15 min. increments were made. The reaction mixture was evaporated in vacuo, dissolved in CH2Cl2, and treated with aqueous K2CO3 (5% w/v). After separating the layers, the aqueous phase was back-extracted twice with CH2Cl2. The combined organic phases were dried over MgSO4, filtered, evaporated in vacuo and purified on silica gel eluting with 0-3% MeOH in EtOAc to provide an oil: 1H NMR (CDCl3) δ 7.89 (1H, d, J=1.4 Hz), 7.83 (1H, br t, J˜6 Hz), 7.15 (2H, dd, J˜9, 6 Hz), 6.98 (2H, t, J˜9 Hz), 6.92 (1H, s), 4.42 (2H, q, J=7 Hz), 3.92 (2H, s), 3.49 (2H, m), 3.41 (2H, t, J=7 Hz), 3.35 (2H, q, J=6 Hz), 2.36 (2H, t, J=8 Hz), 1.99 (2H, m), 1.42 (3H, t, J=7 Hz); ES+ MS: 386 (M+H+).
Reaction SMILES: [Na].[N:2](OCCC(C)C)=[O:3].O.[CH3:11][C@:12]12[C:20](=[O:21])[CH2:19][C@H:15]([C:16]1([CH3:18])[CH3:17])[CH2:14][CH2:13]2>C(OCC)C>[OH:3][N:2]=[C:19]1[CH:15]2[C:16]([CH3:17])([CH3:18])[C:12]([CH3:11])([CH2:13][CH2:14]2)[C:20]1=[O:21]
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)C(=O)C2
Reactant: CC(C)CCON=O
Agent: [Na]
Solvent: CCOCC
Solvent: O
Product: CC12CCC(C(=NO)C1=O)C2(C)C

Procedure:
In 600 ml of dried diethyl ether was dissolved 130 g (0.854 mol) of commercially available D-camphor, and 20.4 g of metallic sodium was added thereto. The solution was kept at 0° C. with stirring, and 123 ml (0.916 mol) of isoamyl nitrite was added thereto to conduct a reaction for 14 hours. After completion of the reaction, 200 ml of water was added to the reaction mixture, and the aqueous layer was separated. To the aqueous layer was added 400 ml of 10% hydrochloric acid, and the solid thus formed was extracted with diethyl ether. The ether layer was dried and concentrated to obtain 51 g of 3-hydroxyiminocamphor.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:17]1[S:18][C:19]([C:23]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[O:24])=[C:20]([CH3:22])[N:21]=1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:17]2[S:18][C:19]([C:23]([NH:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[O:24])=[C:20]([CH3:22])[N:21]=2)[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Reactant: Cc1nc(Br)sc1C(=O)NCc1ccc(F)cc1
Product: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)NCc1ccc(F)cc1
Yield: 92 %

Procedure:
Following the procedure as described in Example 3, making variations only as required to use 4-(benzyloxy)pyridin-2(1H)-one in place of 4-aminopyridin-2(1H)-one to react with 2-bromo-N-(4-fluorobenzyl)-4-methylthiazole-5-carboxamide in place of N-benzyl-2-bromo-4-methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 92% yield: mp 223-225° C. (hexane/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 8.67 (t, J=8.1 Hz, 1H), 7.38-7.35 (m, 5H), 7.32-7.27 (m, 2H), 7.01 (t, J=8.6 Hz, 2H), 6.23 (dd, J=8.1, 2.3 Hz, 1H), 6.11 (t, J=5.5 Hz, 1H), 6.06 (d, J=2.3 Hz, 1H), 5.03 (s, 2H), 4.54 (d, J=5.5 Hz, 2H), 2.67 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 167.4, 163.9, 162.2, 160.6, 153.5, 152.3, 134.5, 133.6, 131.5, 129.6, 128.8, 128.7, 127.7, 122.1, 115.8, 104.1, 97.3, 70.8, 43.3, 17.3; (ES+) m/z 450.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][NH:12][C:13](=O)[CH2:14][C@@H:15]2[CH2:19][CH2:18][N:17]([C:20]([O:22]C(C)(C)C)=O)[CH2:16]2)=[O:10])=[C:4]([F:28])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:35]1(C(Cl)=O)[CH2:37][CH2:36]1>O.ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]([CH2:14][C@@H:15]3[CH2:19][CH2:18][N:17]([C:20]([CH:35]4[CH2:37][CH2:36]4)=[O:22])[CH2:16]3)=[N:12][NH:11][C:9]2=[O:10])=[C:4]([F:28])[CH:3]=1
Reactant: O=C(Cl)C1CC1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CC(=O)NNC(=O)Nc2ccc(Br)cc2F)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(Br)cc2F)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1,1-dimethylethyl (3S)-3-[2-(2-{[(4-bromo-2-fluorophenyl)amino]carbonyl}hydrazino)-2-oxoethyl]-1-pyrrolidinecarboxylate (3.59 mmol) in water (150 mL) was treated with potassium carbonate (17.96 mmol). The reaction was heated to reflux and was stirred overnight. A white solid had formed on the top of the aqueous solution. The reaction was allowed to cool to room temperature. Analysis by LCMS indicated complete consumption of the starting material and the mixture was concentrated to dryness in vacuo. The crude material was dissolved in dichloromethane (100 mL) and was treated with a solution of cyclopropanecarbonyl chloride (3.59 mmol) in dichloromethane (5 mL). After 30 min of stirring, LCMS analysis indicated that the intermediate amine had converted to a mixture of the desired product and a product that corresponded to bis-acylated product. The reaction solution was concentrated to dryness in vacuo and was dissolved in methanol (50 mL). The suspension was stirred at room temperature for 30 min. Analysis by LCMS indicated that the majority of the material now existed as a mixture of the desired product and the intermediate amine. Additional portions of cyclopropanecarbonyl chloride (3.59 mmol) were added to the reaction mixture twice (30 min apart). Analysis by LCMS indicated the complete conversion of the intermediate amine. The reaction mixture was diluted with water (100 mL) and acidified to pH˜4 using 1N aq HCl. The methanol was removed in vacuo, and the resulting aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated aq sodium bicarbonate, washed with brine, dried over MgSO4, filtered and concentrated in vacuo to dryness. The resulting solid was purified by flash chromatography (0-10% methanol/dichloromethane) to give the title compound as a white amorphous solid (850 mg, 58% yield). MS(ES)+ m/e 409/411 [M+H]+ (bromide isotope pattern).
Reaction SMILES: [F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][N:15]=3)[S:13][C:6]=12.[CH3:29][O:30][CH2:31][CH2:32][NH2:33].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]=[CH:16][C:17]([CH2:18][NH:33][CH2:32][CH2:31][O:30][CH3:29])=[CH:20][CH:21]=3)[S:13][C:6]=12
Reactant: COCCN
Reactant: O=Cc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COCCNCc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)nc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 52.9 %

Procedure:
To a solution of 25 (2.864 g, 7.24 mmol) in DCM (30 mL) was added 2-methoxyethylamine (8) (0.756 mL, 8.69 mmol). After 45 min, sodium triacetoxyborohydride (2.149 g, 10.14 mmol) was added and the reaction mixture was stirred at r.t. for 18 h. More sodium triacetoxyborohydride (2.149 g, 10.14 mmol) was added and the mixture was stirred for an additional 2 h. The reaction mixture was quenched with saturated aqueous NaHCO3 and the phases were separated. Organic phase was collected and the aqueous layer was extracted with DCM (3×100 mL). The combined organic solutions were concentrated and the residue was purified by flash column chromatography (eluent DCM/MeOH) to afford, intermediate 26 (1.742 g, 53% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.62 (d, J=5.6 Hz, 1H), 8.55 (d, J=1.2 Hz, 1H), 8.48 (dd, J=10.2, 2.6 Hz, 1H), 8.37 (s, 1H), 8.26-8.23 (m, 1H), 8.21 (ddd, J=8.8, 2.8, 1.2 Hz, 1H), 7.90 (dd, J=8.4, 2.0 Hz, 1H), 7.71 (dd, J=9.0, 8.2 Hz, 1H), 6.97 (dd, J=5.6, 0.4 Hz, 1H), 3.78 (s, 2H), 3.40 (t, J=5.6 Hz, 2H), 3.24 (s, 3H), 2.65 (t, J=5.6 Hz, 2H). MS (m/z): 455.2 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([SH:18])[N:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:14]=2[CH:25]=1.[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)(O)[O-].[K+].C1CC2OCCOCCOC3C(OCCOCCOC2CC1)CCCC3>CN(C)C=O>[CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([S:18][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:15]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:14]=2[CH:25]=1
Reactant: COC(=O)CCCCCOc1ccc2nc(S)n(-c3ccccc3)c2c1
Reactant: BrCc1ccccc1
Agent: C1CCC2OCCOCCOC3CCCCC3OCCOCCOC2C1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCOc1ccc2nc(SCc3ccccc3)n(-c3ccccc3)c2c1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
490 mg of 6-[(2-mercapto-1-phenyl-1H-benzimidazol-6-yl)oxy]hexanoic acid methyl ester was dissolved in 7 ml of N,N-dimethylformamide, mixed with 0.19 ml of benzyl bromide, 278 mg of potassium bicarbonate and 49 mg of dicyclohexano-18-crown-6, and the mixture was stirred for 15 hours at 20° C. It was filtered, and the filtrate was concentrated by evaporation in a vacuum. The residue was purified by column chromatography on silica gel. 548 mg was obtained.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].[C:12]([NH:20][NH2:21])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH:6]1([CH2:4][N:1]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)/[C:4](=[N:21]/[NH:20][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)/[C:2]2=[O:3])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: O=C1Nc2ccccc2C1=O
Reactant: NNC(=O)c1ccccc1
Product: O=C(N/N=C1\C(=O)N(CC2CCCCC2)c2ccccc21)c1ccccc1
Yield: 71.4 %

Procedure:
The title compound was prepared as a yellow solid, using isatin 7 and benzhydrazide according to the synthetic method D. The resulting solid was washed with ethanol. Yield: 71.4%. 1H NMR (DMSO-d6): δ 1.05-1.09 (m, 2H), 1.18-1.20 (m, 3H), 1.61-1.79 (m, 6H), 3.65 (d, J=7.5 Hz, 2H), 7.22 (t, J=8 Hz, 1H), 7.28 (d, J=8 Hz, 1H), 7.52 (t, J=7.5 Hz, 1H), 7.66-7.70 (m, 3H), 7.75 (t, J=7 Hz, 1H), 7.96 (d, J=7 Hz, 2H), 13.97 (br s, 1H). 13C NMR (DMSO-d6): δ 25.68 (CH2), 26.26 (CH2), 30.71 (CH2), 36.40 (CH), 45.90 (CH2), 110.95 (CH), 119.57 (C), 121.19 (CH), 123.67 (CH), 127.87 (CH), 129.68 (CH), 132.19 (CH), 132.44 (C), 133.40 (CH), 137.70 (C), 143.94 (C═N), 161.90 (C═O), 163.42 (C═O). HRMS (ES+) calcd for C22H24N3O2 (M+H+), m/e, 362.1872. found, 362.1863.
Reaction SMILES: [CH2:1]([S:5](Cl)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].[I:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1>N1C=CC=CC=1>[I:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][S:5]([CH2:1][CH2:2][CH2:3][CH3:4])(=[O:7])=[O:6])=[CH:12][CH:11]=1
Reactant: Nc1ccc(I)cc1
Reactant: CCCCS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCCCS(=O)(=O)Nc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.8 %

Procedure:
Butanesulphonyl chloride (7.8 g) was added dropwise to a stirred solution of 4-iodobenzeneamine (10 g) in pyridine (50 ml) at 0°, the mixture was stirred at room temperature for 1 h, concentrated, and partitioned between 2 N hydrochloric acid (100 ml) and EA (100 ml). The organic layer was washed with 2 N hydrochloric acid, water and brine, dried and concentrated to a solid which was recrystallised from cyclohexane to give the title compound (10.5 g) m.p. 80°-81°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9](N)=[O:10])[CH:6]=[CH:5][C:4]=1[C:12]1[NH:20][C:19]2[C:14](=[N:15][CH:16]=[N:17][CH:18]=2)[N:13]=1.[CH2:21]([OH:23])[CH3:22]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([O:23][CH2:21][CH3:22])=[O:10])[CH:6]=[CH:5][C:4]=1[C:12]1[NH:20][C:19]2[C:14](=[N:15][CH:16]=[N:17][CH:18]=2)[N:13]=1
Reactant: COc1cc(C(N)=O)ccc1-c1nc2ncncc2[nH]1
Reactant: CCO
Product: CCOC(=O)c1ccc(-c2nc3ncncc3[nH]2)c(OC)c1

Procedure:
A quantity of 0.42 gm of 8-(2'-methoxy-4'-chlorocarbonyl-phenyl)-purine hydrochloride (see Example 43) was refluxed in 30 ml of ethanol for 45 minutes. The solvent was evaporated off, and the residue was purified over a silica gel column [eluant:methylene chloride/ethanol (50:1 to 19:1)].
Reaction SMILES: C([C:3]1[N:8]=[C:7]([C:9]#[N:10])[C:6]([C:11]([O:13][CH3:14])=[O:12])=[C:5]([NH:15][C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[N:4]=1)#N.C(N(CC)C(C)C)(C)C.[CH:32]1([NH2:38])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.C([O-])(O)=O.[Na+]>CN(C=O)C>[C:9]([C:7]1[C:6]([C:11]([O:13][CH3:14])=[O:12])=[C:5]([NH:15][C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[N:4]=[C:3]([NH:38][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[N:8]=1)#[N:10]
Reactant: NC1CCCCC1
Reactant: COC(=O)c1c(C#N)nc(C#N)nc1Nc1cccc(C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1c(C#N)nc(NC2CCCCC2)nc1Nc1cccc(C)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 89.9 %

Procedure:
A mixture of methyl 2,4-dicyano-6-(m-tolylamino)pyrimidine-5-carboxylate (102.3 mg, 0.349 mmol), N,N-diisopropylethylamine (0.075 mL, 0.429 mmol) and cyclohexylamine (0.05 mL, 0.437 mmol) in DMF (2 mL) was stirred at RT for 14 h. Saturated aq NaHCO3 was added and the mixture was extracted with EtOAc. The organic layers were washed with aq NaHCO3, water, and brine, and were filtered through SiO2. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (SiO2, hexanes/EtOAc=4/1) to give the title compound as a yellow oil (114.7 mg, 90%). 1H NMR (500 MHz, CDCl3) δ ppm 1.19-1.45 (m, 5H), 1.64-1.67 (m, 1H), 1.73-1.80 (m, 2H), 2.00-2.05 (m, 2H), 2.38 (s, 3H), 3.75-3.82 (m, 1H), 3.98 (s, 3H), 5.57-5.58 (br d, J=7.9 Hz, 1H), 6.97-6.98 (m, 1H), 7.27-7.29 (m, 1H), 7.46-7.51 (m, 2H), 10.62 (br s, 1H). [M+H] calc'd for C20H24N5O2, 366. found, 366.