Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:5]([OH:7])=[O:6])[CH2:4][CH2:3][CH2:2]1.C1CCC(N=C=NC2CCCCC2)CC1.CS(O[C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([C:38](=[NH:40])[NH2:39])[CH:34]=2)[CH:29]=1)(=O)=O.C(OCC)C>N1C=CC=CC=1>[CH:1]1([C:5]([O:7][C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[CH:31][CH:32]=[C:33]([C:38](=[NH:39])[NH2:40])[CH:34]=3)[CH:29]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Reactant: O=C(O)C1CCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOCC
Solvent: c1ccncc1
Product: N=C(N)c1ccc2cc(OC(=O)C3CCC3)ccc2c1
Reaction time: 0.5 h
Yield: 68.4 %

Procedure:
To a solution of 1.8 g of cyclobutanecarboxylic acid in 50 ml of anhydrous pyridine, while being cooled in ice and stirred, was added 4.4 g of DCC. After 30 minutes, 5.0 g of 6-amidino-2-naphthol methanesulfonate was added to the mixture and the mixture was further stirred for 24 hours at room temperature. The precipitate formed on addition of ethyl ether was collected by filtration, dissolved in dimethylformamide, and filtered to remove the insolubles. Ethyl ether was added to the filtrate and the precipitate which was formed was collected by filtration and recrystallized from a dimethylformamide-ethyl ether mixture to yield 3.3 g of a white powder of 6-amidino-2-naphthyl cyclobutanecarboxylate methanesulfonate.
Reaction SMILES: [CH:1]1([N:7]2[CH:16](O)[CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)C.Cl>O>[CH:1]1([N:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1c2ccccc2CC(O)N1C1CCCCC1
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=c1c2ccccc2ccn1C1CCCCC1
Yield: 88.3 %

Procedure:
The compound (22 mg) obtained in step (b) just above was stirred in a mixed solution of ethanol:concentrated hydrochloric acid=10:1 at room temperature for 30 min. Water was added to the reaction solution. The mixture was extracted with ethyl acetate, and then dried over anhydrous magnesium sulfate. The solvent was then removed by distillation. The residue was purified by chromatography on silica gel (hexane ethyl acetate=1:1) to give 2-cyclohexyl-2H-isoquinolin-1-one (18 mg).
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][C:14]#[CH:15])=[N+]=[N-].O.[Na+].[Cl-].C(Cl)Cl>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1>[NH2:1][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][C:14]#[CH:15]
Reactant: C#CCOCCOCCOCCN=[N+]=[N-]
Agent: [Cl-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: C#CCOCCOCCOCCN
Temperature: 25 °C
Reaction time: 3 h

Procedure:
in a 50 mL flask, 3 (150 mg, 0.7 mmol), Ph3P were dissolved in 10 mL THF. The reaction mixture was stirred at rt for 3 hr. To the reaction mixture was added H2O (1 mL) the resultant mixture was stirred for 36 hr at rt. The solvent was evaporated and the residue was purified by FCC to afford 4 as slightly yellow oil (131 mg, quant.). 1H NMR (400 MHz, CDCl3): δ 1.46 (br, 2H), 2.35 (t, J=1.6 Hz, 1H), 2.73 (t, J=5.2 Hz, 2H), 3.38 (t, J=5.2 Hz, 2H) 3.50-3.59 (m, 10H), 4.08 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 41.72, 58.34, 69.04, 70.21, 70.36, 70.54, 73.36, 74.63, 79.60. ESIMS calcd for C9H18NO3 [M+H]+ 188.13, found: 188.16. FTIR (NaCl plate, CH2Cl2): 1118 (C—O str), 2111 (C≡C str), 2869 (C—H str), 3249 (N—H str).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:16][CH:15]3[CH:11]([CH2:12][NH:13][CH2:14]3)[CH2:10]2)[N:3]=1.[N:17]1[N:18]=[C:19]([C:22]2[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=2[C:24](O)=[O:25])[NH:20][CH:21]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(OCC)(=O)C.CN(C=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:16][CH:15]3[CH:11]([CH2:12][N:13]([C:24]([C:23]4[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=4[C:19]4[NH:18][N:17]=[CH:21][N:20]=4)=[O:25])[CH2:14]3)[CH2:10]2)[N:3]=1
Reactant: O=C(O)c1ccccc1-c1nnc[nH]1
Reactant: Cc1cc(C)nc(N2CC3CNCC3C2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)nc(N2CC3CN(C(=O)c4ccccc4-c4ncn[nH]4)CC3C2)n1
Yield: 55 %

Procedure:
A mixture of 2-(4,6-dimethyl-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole (60.0 mg, 0.28 mmol), 2-(4H-[1,2,4]triazol-3-yl)benzoic acid (57.2 mg, 0.30 mmol), HATU (156.8 mg, 0.41 mmol) and DIPEA (107.0 mg, 0.83 mmol) was stirred into DMF (5.0 mL) at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate (60.0 mL) and washed with water (2×100 mL). The organic phase was dried (Na2SO4), filtered and concentrated to dryness. The crude product was purified using Agilent HPLC (basic system) to yield pure title compound (60.0 mg, 56%). MS (ESI) mass calcd. for O21H23N7O, 389.46; m/z found 390.2 [M+H]+. 1H NMR (CDCl3): 8.12 (d, J=7.5, 1H), 8.05 (s, 1H), 7.53-7.39 (m, 2H), 7.37-7.31 (m, 1H), 6.28 (s, 1H), 3.95-3.77 (m, 2H), 3.76-3.55 (m, 3H), 3.48-3.33 (m, 2H), 3.19-3.03 (m, 1H), 3.02-2.95 (m, 1H), 2.91-2.82 (m, 1H), 2.36-2.19 (m, 6H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[NH2:9][C@H:10]([C:13]([OH:15])=[O:14])[CH2:11][SH:12].C>C(O)C>[N:1]1[CH:2]=[CH:3][C:4]([CH:7]2[NH:9][CH:10]([C:13]([OH:15])=[O:14])[CH2:11][S:12]2)=[CH:5][CH:6]=1
Reactant: N[C@@H](CS)C(=O)O
Reactant: O=Cc1ccncc1
Solvent: CCO
Product: O=C(O)C1CSC(c2ccncc2)N1
Yield: 57.1 %

Procedure:
Pyridine-4-carbaldehyde (1.07 g) and 1.21 g of L-cysteine were heated in 60% ethanol at a refluxing temperature for 4 hours. Activated charcoal (100 mg) was added to the reaction mixture while it was warm. The mixture was filtered. After cooling, the resultant crystalline precipitate was collected by filtration and washed with ethanol to give 1.2 g of 2-(4-pyridyl)thiazolidine-4-carboxylic acid. Melting point 171°-173° C.
Reaction SMILES: Cl.[C:2]1([C:8]2([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:12]3[CH2:13][N:14]([C:17]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[O:18])[CH2:15][CH2:16][N:11]3[C:10](=[O:25])[O:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41]>O1CCCC1.O>[O:25]=[C:10]1[N:11]2[CH2:16][CH2:15][N:14]([C:17]([CH:19]3[CH2:24][CH2:23][N:22]([CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:21][CH2:20]3)=[O:18])[CH2:13][CH:12]2[C:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[O:9]1
Reactant: O=C(C1CCNCC1)N1CCN2C(=O)OC(c3ccccc3)(c3ccccc3)C2C1
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CN1CCC(C(=O)N2CCN3C(=O)OC(c4ccccc4)(c4ccccc4)C3C2)CC1
Temperature: 0 °C
Reaction time: 20 h
Yield: 90.4 %

Procedure:
To a solution of hexahydro-1,1-diphenyl-7-[(4-piperidinyl)carbonyl]-3H-oxazolo[3,4-a]pyrazin-3-one hydrochloride (0.20 g, 0.45 mmol) and potassium carbonate (0.16 g, 1.2 mmol) in tetrahydrofuran (5 mL) was added ethyl bromoacetate (0.055 mL, 0.50 mmol) at 0° C., and the mixture was stirred at 0° C. for 2 hours and at room temperature for 20 hours. The reaction solution was diluted with water and then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solid was filtered off, and the filtrate was concentrated and dried to a solid. The residue was purified with silica gel column chromatography (ethyl acetate to ethyl acetate:methanol=9:1) to obtain the title compound (0.20 g, yield 90%).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[C:10]([CH3:23])=[C:11]([CH3:22])[C:12]3[O:17][C:16]([CH3:19])(O)[CH2:15][CH2:14][C:13]=3[C:20]=2[CH3:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:24]>CCOCC>[Cl:24][C:16]1([CH3:19])[CH2:15][CH2:14][C:13]2[C:20]([CH3:21])=[C:9]([O:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:10]([CH3:23])=[C:11]([CH3:22])[C:12]=2[O:17]1
Reactant: Cl
Reactant: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CCC(C)(O)O2
Solvent: CCOCC
Product: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CCC(C)(Cl)O2
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 92.8 %

Procedure:
To a solution of 5 g (16 mmol) of rac-3,4-dihydro-6-(phenylmethoxy)-2,5,7,8-tetramethyl-2H-1-benzopyran-2-ol in 50 mL of anhydrous ether was added 5 g of 4A molecular sieves. The mixture was stirred mechanically with ice-bath cooling while HCl gas was bubbled in for 30 min. Stirring was continued at 0° C. for 30 min and then the solvent was removed in vacuo. The residue was treated with 500 mL of hexane and the solution was decanted. The hexane solution was then treated with 10 g of anhydrous CaCl2 and the mixture stirred for 2 hr. The solids were filtered and the filtrate was concentrated in vacuo to a volume of ca. 20 mL. Crystallization was induced by cooling to -10° C. and stirring, then the remaining solvent was removed in vacuo giving 4.9 g (92.8% yield) of rac-2-chloro-3,4-dihydro-2,5,7,8-tetramethyl-6-(phenylmethoxy)-2H-1-benzopyran as a colorless solid. The chlorochroman decomposed upon attempted column or thin layer chromatography. It was stored at 0° C.
Reaction SMILES: C([Li])CCC.[I:6]I.S([O-])([O-])(=O)=S.[Na+].[Na+].[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1[F:23]>C1COCC1>[I:6][C:19]1[CH:20]=[CH:21][C:16]([F:15])=[C:17]([F:23])[C:18]=1[F:22]
Reactant: II
Reactant: Fc1cccc(F)c1F
Agent: O=S([O-])([O-])=S
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: Fc1ccc(I)c(F)c1F
Temperature: -60 °C
Reaction time: 2 h

Procedure:
In a nitrogen atmosphere, 1,2,3-trifluorobenzene was dissolved into THF, and cooled to −60° C. Then, butyllithium (1.56 M hexane solution) was added dropwise for 30 minutes, and stirred for 2 hours. Then, the THF solution containing iodine was added dropwise for 1 hour, and warmed to room temperature. After the reaction solution was poured into a sodium thiosulfate aqueous solution and stirred for a while, an organic layer was separated, and an aqueous layer was extracted with toluene. After the extract and the organic layer were mixed together, washed using water and a saturated saline solution in that order, and dried using anhydrous sodium sulfate, the solvent was evaporated under a reduced pressure to obtain 4-iodo-1,2,3-trifluorobenzene.
Reaction SMILES: [C:1]1(=[O:6])[O:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[C:9]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)(=[O:11])[CH3:10].C(O)C>CS(C)=O.O1CCCC1>[OH:5][CH2:4][CH2:3][CH2:2][C:1](=[O:6])[CH2:10][C:9]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[O:11]
Reactant: CC(=O)c1cccnc1
Reactant: O=C1CCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(CCCO)CC(=O)c1cccnc1
Yield: 110 %

Procedure:
A solution of γ-butyrolactone (1.92 mL, 2.15 g, 25.0 mmol), 60% suspension of sodium hydride in mineral oil (300 mg, 7.50 mmol) and 3-acetylpyridine (551 μL, 606 mg, 5.00 mmol) in dimethylsulfoxyde (4 mL) and tetrahydrofuran (36 mL) was stirred overnight at 25° C. Ethanol (4 mL) was added to destroy excess sodium hydride and the reaction mixture was adsorbed on silica gel (10 g). Flash chromatography on silica gel (75 g), eluting with DCM/MeOH/NH4OH (96/4/1), gave 1.14 g of a yellow oil containing compound 3-A (0.62 g, 60%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:8][C:9]1[CH:10]=[C:11](B(O)O)[CH:12]=[CH:13][CH:14]=1.C(COC)OC.C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C.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>[Br:8][C:9]1[CH:14]=[C:13]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: Brc1ccccn1
Reactant: OB(O)c1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: Brc1cccc(-c2ccccn2)c1
Yield: 75 %

Procedure:
A mixture of 2-bromopyridine (4.8 g, 30.33 mmol), 3-bromophenyl boronic acid (4.06 g, 20.22 mmol), glyme (35 mL), tetrakis(triphenylphosphine)palladium(0) (0.4 g) and a solution of potassium carbonate (7.6 g, 55 mmol) in water (35 mL) was stirred well at reflux under nitrogen overnight. After cooling, the reaction mixture was diluted with ethyl acetate (600 mL) and washed with water (3×200 mL). The solvent and excess 2-bromopyridine were removed on a rotary evaporator (bath temperature=75° C.) and the crude product was purified by chromatography on silica (110 g) with 2% ethyl acetate in heptane (6 L) to produce 1 (3.55 g, 75%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[C:13]([CH:18]=[O:19])=[N:14][CH:15]=[CH:16][CH:17]=2)[N:4]=1.[CH:20]([O-])([O-])[O:21]CC.[Cl-].[NH4+].[CH3:28]O>>[CH3:28][O:19][CH:18]([O:21][CH3:20])[C:13]1[C:12]([O:11][C:5]2[N:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[N:6]=2)=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: CO
Reactant: COc1cc(OC)nc(Oc2cccnc2C=O)n1
Reactant: CCOC([O-])[O-]
Agent: [Cl-]
Agent: [NH4+]
Product: COc1cc(OC)nc(Oc2cccnc2C(OC)OC)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
A mixture consisting of 53.0 g of 3-(4,6-dimethoxy-2-pyrimidinyloxy)-2-formylpyridine, 30.7 g of ethyl orthoformate, 0.48 g of ammonium chloride and 500 ml of methanol was heated under stirring at a reflux point for 5 hours. After the reaction mixture was cooled to room temperature, the precipitate was filtered off. The filtrate was concentrated under reduced pressure so that 56.1 g of 3-(4,6-dimethoxy-2-pyrimidinyloxy-2-pyridinecarboxaldehyde dimethylacetal were obtained (yield: 90%). A purified product was obtained by chromatography on a silica gel column.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]4[CH:28]=[C:27]([O:29][CH3:30])[C:26]([Cl:31])=[C:25]([O:32][CH3:33])[CH:24]=4)[CH:18]=3)[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.[Cl:34][C:35]1[C:40]([O:41][CH3:42])=[CH:39][C:38]([C:43]2[CH:48]=[C:47]([CH2:49]Cl)[CH:46]=[CH:45][N:44]=2)=[CH:37][C:36]=1[O:51][CH3:52]>>[ClH:31].[ClH:34].[ClH:31].[Cl:31][C:26]1[C:25]([O:32][CH3:33])=[CH:24][C:23]([C:19]2[CH:18]=[C:17]([CH2:16][N:13]3[CH2:12][CH2:11][CH:10]([N:9]([CH2:49][C:47]4[CH:46]=[CH:45][N:44]=[C:43]([C:38]5[CH:39]=[C:40]([O:41][CH3:42])[C:35]([Cl:34])=[C:36]([O:51][CH3:52])[CH:37]=5)[CH:48]=4)[C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[CH2:15][CH2:14]3)[CH:22]=[CH:21][N:20]=2)=[CH:28][C:27]=1[O:29][CH3:30]
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1Cl
Reactant: COc1ccc(NC2CCN(Cc3ccnc(-c4cc(OC)c(Cl)c(OC)c4)c3)CC2)cc1
Product: COc1ccc(N(Cc2ccnc(-c3cc(OC)c(Cl)c(OC)c3)c2)C2CCN(Cc3ccnc(-c4cc(OC)c(Cl)c(OC)c4)c3)CC2)cc1
Product: Cl

Procedure:
4-(p-Anisidino)-1-[[2-(4-chloro-3,5-dimethoxyphenyl)pyridin-4-yl]methyl]piperidine (271 mg) and 2-(4-chloro-3,5-dimethoxyphenyl)-4-chloromethylpyridine (173 mg) were condensed in the same manner as described in Example 9. The title compound was obtained as yellow powder after converting a free base to a trihydrochloride.
Reaction SMILES: [OH:1][CH:2]1[O:7][C:6]([CH3:9])([CH3:8])[C:5]2[S:10][C:11](=S)[S:12][C:4]=2[C:3]1=[O:14].[OH2:15]>CC(C)=O.C(O)(=O)C.[Hg](OC(C)=O)OC(C)=O>[OH:1][CH:2]1[O:7][C:6]([CH3:9])([CH3:8])[C:5]2[S:10][C:11](=[O:15])[S:12][C:4]=2[C:3]1=[O:14]
Reactant: CC1(C)OC(O)C(=O)c2sc(=S)sc21
Reactant: O
Agent: CC(=O)O[Hg]OC(C)=O
Solvent: CC(C)=O
Solvent: CC(=O)O
Product: CC1(C)OC(O)C(=O)c2sc(=O)sc21
Reaction time: 0.17 h

Procedure:
13 mg (0.05 mmol) of 6-hydroxy-4,4-dimethyl-2-thioxo-4H-[1,3]dithiolo[4,5-c]pyran-7(6H)-one 6 was dissolved in acetone (5 mL) and added to a solution of Hg(OAc)2 (50 mg, 0.15 mmol) in 1 ml of acetic acid. The color of the reaction mixture changed very fast from yellow to white. The solution was stirred for 10 minutes and then 20 mL of water was added. The resulting mixture was extracted with CH2Cl2 (3×5 mL). The organic layer was separated and then was washed with saturated aqueous NaHCO3 (10 mL). The organic layer was separated again and the aqueous layer was re-extracted again with CH2Cl2 (2×5 mL). The organic layers were combined and evaporated to get 6-hydroxy-4,4-dimethyl-4H-[1,3]dithiolo[4,5-c]pyran-2,7(6H)-dione 8 as a pale beige oil. Yield: 7 mg (0.03 mmol, 57%). 1H NMR in CDCl3 (δ, ppm): 5.51 (1H, s, hemiacetal), 1.74 (3H, s, CH3), 1.68 (3H, s, CH3). 13C NMR in CDCl3 (δ, ppm): 187.09, 181.81, 159.93, 124.38, 91.15, 76.16, 31.47, 28.27. IR (neat, cm−1): 3419, 2978, 2929, 2864, 1670, 1625, 1548.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11](O)=O)=[CH:5][CH:4]=1)#[N:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:26][NH:27][C:28]1[CH:44]=[CH:43][C:31]([CH2:32][N:33]2[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=3[N:35]=[C:34]2[CH3:42])=[CH:30][C:29]=1[NH2:45].N>O1CCCC1.O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11]2[N:27]([CH3:26])[C:28]3[CH:44]=[CH:43][C:31]([CH2:32][N:33]4[C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=5[N:35]=[C:34]4[CH3:42])=[CH:30][C:29]=3[N:45]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(NCC(=O)O)cc1
Reactant: CNc1ccc(Cn2c(C)nc3ccccc32)cc1N
Agent: N
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc2ccccc2n1Cc1ccc2c(c1)nc(CNc1ccc(C#N)cc1)n2C

Procedure:
A mixture of 1.94 g (11.0 mmol) of N-(4-cyanophenyl)-glycine and 1.78 g (11.0 mmol) of carbonyldiimidazole is refluxed in 80 ml of absolute tetrahydrofuran for 15 minutes. After the addition of 2.7 g (10.46 mmol) of 1-(4-methylamino-3-aminobenzyl)-2-methyl-benzimidazole the mixture is refluxed for a further 16 hours. Then the solution is evaporated to dryness, the residue is mixed with 80 ml glacial acetic acid and refluxed for 1 hour. It is then evaporated to dryness once more, the residue thus obtained is mixed with 50 ml of water and made alkaline with conc. ammonia (about pH 10). The product which crystallises out is suction filtered, washed with a little water and dried.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[O:12])=[C:7]([O:13]C(=O)C)[CH:6]=1)(=[O:3])[CH3:2].[OH-].[Na+].Cl>C(O)C.O.C(OCC)(=O)C>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[O:12])=[C:7]([OH:13])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(C=O)c(OC(C)=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(=O)Oc1ccc(C=O)c(O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.5 %

Procedure:
To a solution of 4-formylbenzene-1,3-diyl diacetate (5.56 g, 25.08 mmol) in ethanol (20 mL) was added a solution of sodium hydroxide (1.00 g, 25.08 mmol) in water (12 mL). The reaction was stirred overnight at room temperature. The reaction was carefully neutralized with 2.0 N aqueous solution of hydrochloric acid (12.8 mL) at 0° C. and diluted with ethyl acetate (400 mL). The organic layer was washed with water (60 mL) and saturated aqueous sodium chloride (50 mL), dried over magnesium sulfate, filtered, and concentrated to afford, the product (2.01 g, 44% yield) as a gray solid: 1H NMR (400 MHz, d-MeOH): δ 9.90 (s, 1H), 7.68 (d, 1H), 6.80 (d, 1H), 6.75 (s, 1H), 4.82 (br s, 1H), 2.20 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[C:14](=[O:15])[CH:13]=[C:12]([OH:16])[CH:11]2[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(O)(=O)C.[BH4-].[Na+].O>C(#N)C>[Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[C:14](=[O:15])[CH2:13][C@H:12]([OH:16])[C@@H:11]2[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[CH:22][CH:23]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(CC2C(O)=CC(=O)N2c2ccc(C#N)c(Cl)c2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CC#N
Product: N#Cc1ccc(C[C@H]2[C@@H](O)CC(=O)N2c2ccc(C#N)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.7 %

Procedure:
To a mixture of 2-chloro-4-[2-(4-cyanobenzyl)-3-hydroxy-5-oxo-2,5-dihydro-1H-pyrrol-1-yl]benzonitrile (300 mg) and acetic acid (0.54 mL) in acetonitrile (10 mL) was added sodium borohydride (81 mg) at 0° C. in small portions. The mixture was warmed to room temperature and stirred for 1 hr. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (eluent: hexane:ethyl acetate=4:1→ethyl acetate), and recrystallized from tetrahydrofuran-hexane to give the title compound as colorless crystals (yield: 162 mg, 54%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][CH3:17])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5](Br)[N:6]2[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH-:26].[Na+].[CH3:28]O>>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][CH3:17])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:26][CH3:28])[N:6]2[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CO
Reactant: [OH-]
Reactant: CCOCCCOc1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Agent: [Na+]
Product: CCOCCCOc1nc(N)c2nc(OC)n(Cc3ccccc3)c2n1
Reaction time: 2 h
Yield: 85 %

Procedure:
To 6-amino-9-benzyl-8-bromo-2-(3-ethoxypropoxy)purine (250 mg, 0.36 mmol) in 20 ml of methanol was added 1N aqueous sodium hydroxide (80 ml). The mixture was refluxed on heating under stirring for 2 hours. The reaction mixture was concentrated in vacuo to dryness. To the residue was added water and the mixture was extracted with chloroform. The organic layer was dried on sodium sulfate and the solvent was removed. The residue was purified with silica gel chromatography (2% methanol/chloroform) to give the subject compound (187 mg, yield 85%).
Reaction SMILES: [C:1](O)(=O)C.C=O.C([BH3-])#N.[Na+].[Cl:11][C:12]1[CH:52]=[CH:51][C:15]([CH2:16][CH:17]2[N:22]3[C:23](=[O:46])[CH:24]([NH:38][C:39]([CH:41]4[CH2:45][CH2:44][CH2:43][NH:42]4)=[O:40])[CH2:25][N:26]([S:27]([C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=4[Cl:37])(=[O:29])=[O:28])[CH:21]3[CH2:20][N:19]([CH:47]([CH3:49])[CH3:48])[C:18]2=[O:50])=[CH:14][CH:13]=1>CO>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:16][CH:17]2[N:22]3[C:23](=[O:46])[CH:24]([NH:38][C:39]([CH:41]4[CH2:45][CH2:44][CH2:43][N:42]4[CH3:1])=[O:40])[CH2:25][N:26]([S:27]([C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=4[Cl:37])(=[O:29])=[O:28])[CH:21]3[CH2:20][N:19]([CH:47]([CH3:49])[CH3:48])[C:18]2=[O:50])=[CH:51][CH:52]=1
Reactant: CC(=O)O
Reactant: CC(C)N1CC2N(C(=O)C(NC(=O)C3CCCN3)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)N1CC2N(C(=O)C(NC(=O)C3CCCN3C)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.5 %

Procedure:
0.3 ml (5.2 mmol) of acetic acid, 0.25 ml (3.33 mmol) of formaldehyde (37% in water) and 1.5 ml (1.5 mmol) of sodium cyanoborohydride (1M in THF) were added to a solution of 93 mg (0.142 mmol) of the amine from Example 40 in 7.5 ml of methanol. The reaction mixture was stirred at room temperature for 2 hours and concentrated in vacuo. The residue was diluted with 10 ml of DCM, basified with 7N—NH3 in methanol, filtered and concentrated. This residue was purified by preparative RP-HPLC. 50 mg of the desired compound were obtained. LC/MS (calculated, monoisotopic MW=669; measured value (M+H)=670)