Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C.[CH3:5][C:6]([CH3:55])([CH3:54])[CH2:7][O:8][C:9](=[O:53])[C:10]([CH3:52])([CH3:51])[C:11]([O:13][CH2:14][O:15][C:16]1[N:17]([C:45]2[N:50]=[CH:49][CH:48]=[CH:47][N:46]=2)[N:18]=[C:19]([CH:21]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([C:42](=[NH:44])[NH2:43])=[CH:38][CH:37]=2)[C:22]2[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH2:31][CH2:32][OH:33])[C:23]=2[F:34])[N:20]=1)=[O:12].[N+](C1C=CC([O:65][C:66](=O)[O:67][CH2:68][C:69]([CH3:73])([CH3:72])[CH2:70][CH3:71])=CC=1)([O-])=O.C1COCC1.C(N(CC)CC)C>C(O)(=O)C>[CH3:5][C:6]([CH3:55])([CH3:54])[CH2:7][O:8][C:9](=[O:53])[C:10]([CH3:52])([CH3:51])[C:11]([O:13][CH2:14][O:15][C:16]1[N:17]([C:45]2[N:46]=[CH:47][CH:48]=[CH:49][N:50]=2)[N:18]=[C:19]([CH:21]([NH:35][C:36]2[CH:37]=[CH:38][C:39]([C:42]([NH2:43])=[N:44][C:66]([O:67][CH2:68][C:69]([CH3:73])([CH3:72])[CH2:70][CH3:71])=[O:65])=[CH:40][CH:41]=2)[C:22]2[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH2:31][CH2:32][OH:33])[C:23]=2[F:34])[N:20]=1)=[O:12]
Reactant: COc1cc(OCCO)c(F)c(C(Nc2ccc(C(=N)N)cc2)c2nc(OCOC(=O)C(C)(C)C(=O)OCC(C)(C)C)n(-c3ncccn3)n2)c1
Reactant: CCC(C)(C)COC(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CCC(C)(C)COC(=O)N=C(N)c1ccc(NC(c2nc(OCOC(=O)C(C)(C)C(=O)OCC(C)(C)C)n(-c3ncccn3)n2)c2cc(OC)cc(OCCO)c2F)cc1
Temperature: 25 °C
Reaction time: 26 h

Procedure:
To a mixture of 2,2-dimethylmalonic acid 5-{(4-carbamimidoylphenylamino)-[2-fluoro-3-(2-hydroxyethoxy)-5-metho xyphenyl]methyl}-2-pyrimidin-2-yl-2H-[1,2,4]triazol-3-yloxymethyl ester 2,2-dimethylpropyl ester acetate (270 mg), carbonic acid 2,2-dimethylbutyl ester 4-nitrophenyl ester (141 mg), and THF (10 mL), triethylamine (0.17 mL) was added, and the resulting mixture was stirred at room temperature for 26 hours. Acetic acid (0.3 mL) was added to the reaction solution, and the resulting mixture was concentrated under reduced pressure. The residue obtained was purified by NAM silica gel column chromatography (mixed solvent of methanol-ethyl acetate) to obtain the captioned compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([CH2:12][C:13]1[CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH:17]=1)=O)C.C(OCC)(=O)C.O>O1CCCC1>[OH:9][CH2:10][CH2:12][C:13]1[CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH:17]=1
Reactant: CCOC(=O)CC1=CCN(C(=O)OC(C)(C)C)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC=C(CCO)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 1.22 g (32.1 mM) of lithium aluminum hydride in 150 ml of tetrahydrofuran was added a solution of 8.201 g (32.122 mM) of tert-butyl 3-(ethoxycarbonylmethyl)-2,5-dihydropyrrole-1-carboxylate in 50 ml of tetrahydrofuran dropwise under ice-cooling and the mixture was stirred at room temperature for 1 hour. To this reaction mixture was added ethyl acetate with ice-cooling to decompose the excess lithium aluminum hydride, and water was added until a white precipitate had formed. The precipitate was filtered off with the aid of celite and the celite was washed with ethyl acetate. The filtrate and washes were pooled and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1 to 1/1) to provide the title compound.
Reaction SMILES: O[C@:2]12[CH2:21][CH2:20][C@@:19]3([CH3:22])[C@@H:12]([CH2:13][CH2:14][C@@H:15]3[C:16](=[O:18])[CH3:17])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:24])[CH2:4][CH2:5][C:6](=[O:23])[CH:7]=1.O.C(OCC)(=O)C>S(=O)(=O)(O)O>[CH3:17][C:16](=[O:18])[C@@H:15]1[C@:19]2([CH3:22])[C@H:12]([C@H:11]3[C:2](=[CH:21][CH2:20]2)[C@:3]2([CH3:24])[C:8](=[CH:7][C:6](=[O:23])[CH2:5][CH2:4]2)[CH2:9][CH2:10]3)[CH2:13][CH2:14]1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@@]3(O)CC[C@]12C
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)C3=CC[C@]12C

Procedure:
A solution of 9α-hydroxypregn-4-ene-3,20-dione (218 mg) in 70% (v/v) aqueous sulfuric acid was stirred at room temperature for 1 hour after which the reaction mixture was added dropwise to a stirred mixture of water (5 ml) and ethyl acetate (5 ml). The organic layer was washed with a 5% aqueous potassium carbonate solution, then with water to neutral pH, dried (MgSO4) and concentrated under reduced pressure. The crude product (149 mg), still containing some starting material, was purified by chromatography (silica gel, toluene/acetone 3/1) to afford the title compound.
Reaction SMILES: Cl.C[N:3]([CH3:15])[C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].[C:16]([O:20][C:21]([NH:23][CH2:24][C@H:25]1[CH2:30][CH2:29][C@H:28]([C:31](O)=[O:32])[CH2:27][CH2:26]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>ClCCl.O>[CH3:15][NH:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[NH:6][C:31]([C@H:28]1[CH2:27][CH2:26][C@H:25]([CH2:24][NH:23][C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])[CH2:30][CH2:29]1)=[O:32]
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CN(C)C(=O)[C@@H](N)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H]1CC[C@H](CNC(=O)OC(C)(C)C)CC1
Reaction time: 2 h

Procedure:
To the compound (I) (19.00 g), 4 N hydrogen chloride/1,4-dioxane solution (325 ml) was added under room temperature, and the mixture was stirred at the same temperature for 30 minutes. The mixture was concentrated under a reduced pressure, and L-phenylalanine dimethylamide hydrochloride (II) was obtained quantitatively as a white powder. Subsequently, to a solution of the compound (II), trans-4-(t-butoxycarbonylaminomethyl)cyclohexylcarboxylic acid (16.70 g) and triethylamine (9.75 ml) in dry dichloromethane (200 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (13.69 g) was added under ice-cooling, the mixture was stirred for 2 hours, and again stirred at room temperature for 2 hours. To the reaction water was added to obtain an organic layer, which was washed with 10% aqueous citric acid, water, 5% aqueous sodium hydrogen carbonate, and water, in this order, followed by drying over anhydrous sodium sulfate. The solids were filtered off, the filtrate concentrated under a reduced pressure and the residue was washed with diethyl ether, followed by filtration to give N-[trans-4-(t-butoxycarbonylaminomethyl)cyclohexylcarbonyl]-L-phenylalanine dimethylamide (III) (21.90 g). The structure was confirmed by NMR.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:18]([CH:20]1[O:22][CH2:21]1)Br>C(#N)C>[CH3:7][NH:6][C:4](=[O:5])[C:3]1[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=1[O:1][CH2:18][CH:20]1[CH2:21][O:22]1
Reactant: CNC(=O)c1ccccc1O
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CNC(=O)c1ccccc1OCC1CO1
Temperature: 50 °C
Yield: 62.7 %

Procedure:
To a solution of 2-Hydroxy-N-methyl-benzamide (0.5 g, 3.31 mmol prepared according to Cohen, Seth M et al J. Am. Chem. Soc., (1998), 120(25), 6277-6286.) and cesium carbonate (2.16 g, 6.62 mmol) in acetonitrile was added epibromohydrin (0.274 ml, 3.31 mmol). The mixture was heated at 50° C. for 2 hours and then after cooling to room temperature partitioned between water(50 ml) and dichloromethane (100 ml). The dichloromethane was dried and evaporated. Chromatography (EtOAc) gave 0.43 g (64%) of the product as a solid.
Reaction SMILES: [N:1]1([C:6]2[CH:25]=[CH:24][C:9]([CH2:10][C:11]3C(O)=[N:13][C:14]4[C:19]([C:20]=3O)=[CH:18][C:17]([I:22])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.P(Cl)(Cl)([Cl:28])=O.Cl[CH2:32][Cl:33].C(=O)(O)[O-].[Na+]>C(#N)C>[N:1]1([C:6]2[CH:25]=[CH:24][C:9]([CH2:10][C:11]3[C:32]([Cl:33])=[N:13][C:14]4[C:19]([C:20]=3[Cl:28])=[CH:18][C:17]([I:22])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Oc1nc2ccc(I)cc2c(O)c1Cc1ccc(-n2ccnc2)cc1
Reactant: ClCCl
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: Clc1nc2ccc(I)cc2c(Cl)c1Cc1ccc(-n2ccnc2)cc1
Temperature: 23 °C
Reaction time: 16 h

Procedure:
A mixture containing 3-(4-(1H-imidazol-1-yl)benzyl)-6-iodoquinoline-2,4-diol (3.0 g, 6.8 mmol, Intermediate 17: step a) and phosphorus oxychloride (1.9 mL, 20 mmol) in acetonitrile (34 mL) was heated to 100° C. After 16 hours, the flask was allowed to cool to 23° C. Dichloromethane (200 mL) and saturated aqueous sodium bicarbonate solution were added in sequence and the resulting biphasic mixture was stirred for 30 minutes. The biphasic mixture was filtered through Celite® and the layers of the biphasic filtrate were separated. The organic layer was dried with magnesium sulfate and the dried solution was filtered. Silica gel (7 g) was added to the filtrate and the solvent was removed by rotary evaporation to afford a free-flowing powder. The powder was loaded onto a column of silica gel for purification. Elution with dichloromethane initially, grading to 5% methanol-dichloromethane provided the title compound as a solid.
Reaction SMILES: C(O[C:5]1[C:6]([O:12][CH3:13])=[CH:7][C:8]([CH3:11])=[N:9][CH:10]=1)(=O)C.C[O-:15].[Na+]>CO>[OH:15][CH2:11][C:8]1[CH:7]=[C:6]([O:12][CH3:13])[CH:5]=[CH:10][N:9]=1
Reactant: COc1cc(C)ncc1OC(C)=O
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccnc(CO)c1
Yield: 41 %

Procedure:
Starting with 2-methyl-4-methoxypyridine-1-oxide (2.1 g) in the procedure of Part (ii) afforded 2.5 g of 2-acetoxymethyl-4-methoxypyridine which was contaminated with about 25% of 5-acetoxy-2-methyl-4-methoxypyridine. This mixture was dissolved in methanol (10 ml) containing 1.118 g (20.7 mmole) sodium methoxide and stirred at reflux for one hour. The methanol was evaporated in vacuo, the residue diluted with water, neutralized with dilute hydrochloric acid, and extracted with chloroform. The organic layer was washed with brine, dried (MgSO4) and concentrated in vacuo to give 853 mg (41%) 2-hydroxymethyl-4-methoxypyridine. 1H--NMR(CDCl3)ppm (delta): 3.9 (s, 3H), 4.72 (s, 2H), 5.35 (bs, 1H), 6.7 (dd, 1H), 6.95 (d, 1H), 8.3 (d, 1H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([N:11]2[N:15]=[C:14]3[CH:16]=[CH:17][C:18]([C:20]([F:23])([F:22])[F:21])=[CH:19][C:13]3=[N:12]2)[C:4]=1[OH:24].C(N(CC)CC)C.[C:32](Cl)(=[O:36])[C:33]([CH3:35])=[CH2:34]>C1COCC1>[C:32]([O:1][CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([N:11]2[N:15]=[C:14]3[CH:16]=[CH:17][C:18]([C:20]([F:23])([F:22])[F:21])=[CH:19][C:13]3=[N:12]2)[C:4]=1[OH:24])(=[O:36])[C:33]([CH3:35])=[CH2:34]
Reactant: COc1cc(CO)c(O)c(-n2nc3ccc(C(F)(F)F)cc3n2)c1
Reactant: C=C(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=C(C)C(=O)OCc1cc(OC)cc(-n2nc3ccc(C(F)(F)F)cc3n2)c1O
Temperature: -10 °C
Reaction time: 1 h

Procedure:
In a 250 ml round bottom flask equipped with a magnetic stirrer and nitrogen inlet was dissolved 1.15 g (3.39 mmol) 2-(hydroxymethyl)-4-methoxy-6-(5-(trifluoromethyl)-2H-benzo[d][1,2,3]triazol-2-yl)phenol from Example 3 in 50 ml anhydrous THF containing BHT inhibitor (Aldrich). Triethylamine (1.4 ml, 11 mmol) was added and the mixture was cooled to −10° C. Methacryloyl chloride (0.436 g, 4.17 mmol) was added dropwise and the mixture was stirred for 1 hr at −10° C. followed by 20 hours at ambient temperature. The solid was filtered and rinsed with 100 ml diethyl ether. The filtrate was poured into 100 ml diethyl ether and washed with 0.5 N HCl and water. The organic layer was dried with magnesium sulfate, filtered, and then concentrated via rotary evaporation to give the desired product as a dark yellow oil which was recrystallized in methanol to give 0.35 g product (25%). [M+H+]=408.1. 1H NMR (CDCl3) delta: 10.97 (s, 1H, Ar—OH), 8.30 (s, 1H, Ar—H benzotriazole), 8.07 (d, 1H, Ar—H benzotriazole), 7.91 (s, 1H, Ar—H phenol), 7.69 (d, 1H, Ar—H benzotriazole), 7.10 (s, 1H, Ar—H phenol), 6.21 (s, 1H, C═C—H trans), 5.62 (s, 1H, C═C—H cis), 5.40 (s, 2H, Ar—CH2), 3.90 (s, 3H, Ar—OCH3), 2.01 (s, 3H, C═C—CH3). Elemental analysis: calculated % C (56.02), % H (3.96), % N (10.32), % F (13.99). found % C (56.11), % H (3.96), % N (10.24), % F (14.37).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH:9]=[C:8]([N+:10]([O-])=O)[N:7]=[C:6]2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:3][CH2:2]1.[H][H]>C1COCC1.[Ni]>[NH2:10][C:8]1[N:7]=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:5]([CH2:4][CH:1]2[CH2:2][CH2:3]2)[CH:9]=1
Reactant: CCOC(=O)c1nc([N+](=O)[O-])cn1CC1CC1
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(N)cn1CC1CC1

Procedure:
3.89 g (16.26 mmol) of ethyl 1-(cyclopropylmethyl)-4-nitro-1H-imidazole-2-carboxylate are dissolved in 50 ml of THF, and a spatula tip of Raney nickel is added. In a hydrogenation apparatus, the reaction mixture is hydrogenated with hydrogen at room temperature. The catalyst is filtered off and the filtrate is concentrated in vacuo. The concentration residue is directly used further for the next reaction.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].CCN(C(C)C)C(C)C.[CH2:19](Cl)[O:20][CH3:21].[NH4+].[Cl-]>ClCCl>[I:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][O:5][CH2:19][O:20][CH3:21]
Reactant: OCc1ccccc1I
Reactant: COCCl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOCc1ccccc1I
Temperature: 23 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
To stirring solution of 2-iodobenzyl alcohol (6.02 g, 25.72 mmol) in dichloromethane (40 mL) was added sequentially Hunig's base (6.8 mL, 38.51 mmol) followed by MOMCl (3.0 mL, 39.13 mmol), and stirred at 23° C. overnight. The reaction was treated with saturated NH4Cl (30 mL), stirred vigorously for several minutes, then the phases separated. The organic phase was extracted with dichloromethane (2×). The combined organics were dried (MgSO4), filtered and concentrated to an amber oil which was purified on Biotage Horizon (10-100% (7:3 hexane:EtOAc)/hexane, 40+M, SiO2) to afford the product (6.06 g) as an oil: 1H NMR (400 MHz, CDCl3) δ ppm 7.83 (dd, J=7.83, 1.26 Hz, 1H), 7.45 (dd, J=7.70, 1.64 Hz, 1H), 7.35 (td, J=7.52, 1.14 Hz, 1H), 6.99 (td, J=7.58, 1.77 Hz, 1H), 4.76 (s, 2H), 4.59 (s, 2H), 3.43 (s, 3H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH2:9])=[O:8])[CH2:3][CH2:2]1.C(Cl)(=O)[C:11](Cl)=[O:12].[NH2:16][C:17]1[N:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][N:27]=[C:26]([NH:30][C:31](=[O:33])[CH3:32])[CH:25]=2)=[CH:19][CH:18]=1>ClCCCl.C1COCC1>[C:31]([NH:30][C:26]1[CH:25]=[C:24]([O:23][C:20]2[CH:19]=[CH:18][C:17]([NH:16][C:11]([NH:9][C:7]([CH:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)=[O:8])=[O:12])=[N:22][CH:21]=2)[CH:29]=[CH:28][N:27]=1)(=[O:33])[CH3:32]
Reactant: NC(=O)C1CCOCC1
Reactant: CC(=O)Nc1cc(Oc2ccc(N)nc2)ccn1
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CC(=O)Nc1cc(Oc2ccc(NC(=O)NC(=O)C3CCOCC3)nc2)ccn1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 52.4 %

Procedure:
A solution of Example B5 (0.095 g, 0.737 mmol) in DCE (3 mL) was treated with oxalyl chloride (0.129 mL, 1.474 mmol) and heated at 80° C. for 3 h. The mixture was cooled to RT, concentrated to dryness, treated with a solution of Example A2 (0.09 g, 0.368 mmol) and TEA (0.205 mL, 1.474 mmol) in THF (4 mL) and stirred at RT for 0.5 h. The mixture was treated with satd. NaHCO3, extracted with EtOAc (2×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM). The material was suspended in MeCN/H2O, frozen and lyophilized to afford N-((5-((2-acetamidopyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)tetrahydro-2H-pyran-4-carboxamide (77 mg, 52%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.05 (s, 1H), 10.88 (s, 1H), 10.56 (s, 1H), 8.24 (d, J=2.9 Hz, 1H), 8.18 (d, J=5.7 Hz, 1H), 8.07 (d, J=9.0 Hz, 1H), 7.72 (dd, J=9.0, 2.9 Hz, 1H), 7.64 (d, J=2.4 Hz, 1H), 6.68 (dd, J=5.7, 2.4 Hz, 1H), 3.87 (m, 2H), 3.29-3.25 (m, 2H), 2.72-2.64 (m, 1H), 2.02 (s, 3H), 1.71 (m, 2H), 1.66-1.54 (m, 2H); MS (ESI) m/z: 400.2 (M+H+).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C:16]1[C:21]([NH2:22])=[CH:20][CH:19]=[CH:18][N:17]=1.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][C:33](=O)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>ClC(Cl)C>[NH2:15][C:16]1[C:21]([NH:22][CH:33]2[CH2:34][CH2:35][N:30]([C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29])[CH2:31][CH2:32]2)=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: Nc1cccnc1N
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(Nc2cccnc2N)CC1
Reaction time: 5 h
Yield: 33.2 %

Procedure:
Sodium triacetoxyborohydride (14.5 g, 68.7 mmol) was added to a solution of 2,3-diaminopyridine (5.00 g, 45.8 mmol) and N-(t-butoxycarbonyl)-4-piperidone (9.58 g, 48.1 mmol) in dichloroethane (75 mL) at room temperature. After 5 h, additional sodium triacetoxyborohydride was added (1.8 g) and again after another 2.5 h. The reaction was stirred overnight, and quenched with 5% aqueous sodium hydroxide. This was extracted with methylene chloride, and washed with 5% aqueous sodium hydroxide, water and saturated sodium chloride solution. After drying over sodium sulfate, the solution was filtered and evaporated to give the crude product. This was purified by chromatorgraphy (silica gel, 3 to 5% methanol in methylene chloride gradient elution), which gave the title compound (4.44 g). MS 293 (M+1)
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:11]([CH3:13])[CH3:12])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23]Br>CN(C)C=O>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:23][C:22]2[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=2[F:20])=[C:4]([N:11]([CH3:13])[CH3:12])[N:3]=1
Reactant: CN(C)c1nc(Cl)nc2[nH]cnc12
Reactant: Fc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)c1nc(Cl)nc2c1ncn2Cc1ccccc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3.31 g (16.8 mmol) of 2-chloro-6-(N,N-dimethylamino)-9H-purine are dissolved in 60 ml of N,N-dimethylformamide. 4.16 g (30.2 mmol) of potassium carbonate and 2.02 ml (16.8 mmol) of 2-fluorobenzyl bromide are added to the solution. The reaction mixture is then stirred for 3 hours at room temperature and then ice water is added and the whole is extracted three times with dichloromethane. The combined organic phases are washed twice with water, dried over magnesium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel with toluene/ethyl acetate (3:1) as eluant. The eluate is concentrated by evaporation and the residue obtained is recrystallised from ethyl acetate/diethyl ether. In this manner 2-chloro-6-(N,N-dimethylamino)-9-(2-fluorobenzyl)-9H-purine is obtained in the form of colourless needles having a melting range of from 130° to 131°.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].CS[CH:17](SC)[CH2:18][N+:19]([O-:21])=[O:20]>C(#N)C>[CH3:3][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:17]([NH:2][CH2:4][CH2:5][O:9][CH3:8])=[CH:18][N+:19]([O-:21])=[O:20])=[CH:7][CH:6]=1)[CH3:1]
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: CSC(C[N+](=O)[O-])SC
Solvent: CC#N
Product: COCCNC(=C[N+](=O)[O-])NCCSCc1ccc(CN(C)C)o1
Yield: 55.9 %

Procedure:
2-[[[5-(Dimethylamino)methyl-2-furanyl]methyl]thio]ethanamine (2.14 g) and 1,1-bis(methylthio)-2-nitroethane (1.65 g) were refluxed in acetonitrile for 8 hr. Solvents were removed and an ethanolic solution of 2-methoxyethylamine (0.75 g) added. After refluxing for a further 8 hr, removal of solvents gave an oil. This was purified by column chromatography to give N-[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N'-(2-methoxyethyl)-2-nitro-1,1-ethenediamine (1.0 g). NMR τ (CDCl3) 7.73 s (6H); 7-7.5 m (2H); 6.2-7 m (11H); 6.23 s (2H); 3.81 s (2H); 3.42 s (1H).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][C@H:4]([C:7]([O-:9])=[O:8])[C@H:3]1[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1.C[C@H]([NH3+])C1C=CC=CC=1.Cl.CCO>O>[OH:1][C@@H:2]1[CH2:6][CH2:5][C@H:4]([C:7]([OH:9])=[O:8])[C@H:3]1[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1
Reactant: O=C([O-])[C@H]1CC[C@@H](O)[C@@H]1c1ccc(F)cc1
Agent: C[C@H]([NH3+])c1ccccc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C(O)[C@H]1CC[C@@H](O)[C@@H]1c1ccc(F)cc1

Procedure:
The salt from Step B was dissolved in water and acidified with 2N HCl and was extracted with 3 portions of EtOAc. The organic layers were washed with a portion of brine, combined, dried over sodium sulfate and evaporated to give a white solid. [α]D (EtOH)=+21.6 (c=2.55).
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]2[CH2:6][CH2:7][C:8]3[C:9]([C:23]([NH2:25])=[O:24])=[N:10][N:11]([C:13]4[CH:18]=[CH:17][C:16]([O:19][O:20][S:21][NH2:22])=[CH:15][CH:14]=4)[C:12]=3[C:4]=2[CH:3]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29].N1C=CC=CC=1>CN(C=O)C.O>[C:28]([NH:1][C:2]1[CH:27]=[CH:26][C:5]2[CH2:6][CH2:7][C:8]3[C:9]([C:23]([NH2:25])=[O:24])=[N:10][N:11]([C:13]4[CH:14]=[CH:15][C:16]([O:19][O:20][S:21][NH2:22])=[CH:17][CH:18]=4)[C:12]=3[C:4]=2[CH:3]=1)(=[O:30])[CH3:29]
Reactant: NSOOc1ccc(-n2nc(C(N)=O)c3c2-c2cc(N)ccc2CC3)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2c(c1)-c1c(c(C(N)=O)nn1-c1ccc(OOSN)cc1)CC2
Reaction time: 8 h
Yield: 90 %

Procedure:
To the material of Example 4b (1.0 g, 0.0026 mol) in DMF (15 mL) was added dropwise a mixture of acetic anhydride (0.283 mL, 0.003 mol) and pyridine (0.243 mL, 0.003 mol) in DMF (5 mL). Contents were stirred overnight, diluted with water (75 mL), and filtered to give the desired as a white solid, 1.0 g (90% yield). FABHRMS m/z 426.1235 (M+H, C20H20N5O4S requires 426.1236). 1H NMR (DMSO-d6/300 MHz) 9.80 (s, 1H); 8.00 (d, 2H); 7.75 (d, 2H); 7.60 (s, 1H); 7.48 (s, 2H); 7.39 (s, 1H); 7.30 (d, 1H); 7.15 (s, 1H); 2.90 (s, 4H); 1.92 (s, 3H). Anal. Calcd for C20H19N5O4S (1H2O): C, 54.17; H, 4.77; N, 15.79. Found: C, 54.20; H, 4.97; N, 15.77.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].[C:7](Cl)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+]>C(Cl)(Cl)Cl>[C:7]([O:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN(C)CCO
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CN(C)CCOC(=O)c1ccccc1

Procedure:
In accordance with the procedure of Example 10, 89.1 g of 2-dimethylaminoethanol and 140.5 g of benzoyl chloride are reacted in altogether 300 ml of CHCl3. The reaction mixture is neutralised with 210 ml of 20% NaOH. Yield: 187.7 g (97.1%) of analytically pure product (analysis by gas chromatography) with a boiling point of 127° C./9 torr.
Reaction SMILES: C(O[C:6]1[C:7](=[O:25])[C:8](=[O:24])[C:9]=1[NH:10][CH2:11][C:12]1[O:13][C:14]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:15]=2[CH:16]=1)CCC.[C:26]([NH2:30])([CH3:29])([CH3:28])[CH3:27]>C(O)C>[C:26]([NH:30][C:6]1[C:7](=[O:25])[C:8](=[O:24])[C:9]=1[NH:10][CH2:11][C:12]1[O:13][C:14]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:15]=2[CH:16]=1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CCCCOc1c(NCc2cc3cc([N+](=O)[O-])ccc3o2)c(=O)c1=O
Reactant: CC(C)(C)N
Solvent: CCO
Product: CC(C)(C)Nc1c(NCc2cc3cc([N+](=O)[O-])ccc3o2)c(=O)c1=O
Temperature: 70 °C
Reaction time: 18 h
Yield: 80.1 %

Procedure:
To 3-butoxy-4-[(5-nitro-benzofuran-2-ylmethyl)amino]-cyclobut-3-ene-1,2-dione (0.25 g, 0.727 mmol), as prepared in Example 8, in ethanol (5 mL) was added tert-butylamine (0.51 mL, 4.85 mmol). The reaction was stirred at 70° C. for 18 hours and then at room temperature for 48 hours. Workup in a manner identical to Example 9 afforded 0.20 g (80%) of 3-tert-butylamino-4-[(5-nitro-benzofuran-2-ylmethyl)-amino]-cyclobut-3-ene-1,2-dione as an off-white solid: mp>300° C.; 1H NMR (DMSO-d6): δ 8.61 (d, 1H), 8.20 (dd, 1H), 7.91 (br t, 1H), 7.81 (d, 1H), 7.59 (br s, 1H), 7.07 (s, 1H), 4.98 (d, 2H), 1.36 (s, 9H). IR (KBr): 3220, 2930, 1800, 1675 cm-1 ; MS (m/z) 344.3 [M+H]+.