Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].N1[CH2:16][CH2:15][CH2:14][CH2:13]C1.C1(C=O)CC1>CO>[CH:15]1([CH:16]=[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]2=[O:10])[CH2:13][CH2:14]1
Reactant: C1CCNCC1
Reactant: O=C1Cc2ccccc2N1
Agent: O=CC1CC1
Solvent: CO
Product: O=C1Nc2ccccc2C1=CC1CC1

Procedure:
2.0 g (15 mmol) 1,3-dihydro-indol-2-one and 0.20 mL piperidine were placed in 20 mL methanol. 1.1 mL (15 mmol) cyclopropanecarboxaldehyde were added dropwise, the reaction mixture was refluxed for 3 h and then concentrated to dryness by rotary evaporation. The residue was triturated with diisopropylether and the solid remaining was suction filtered and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][C:5]1[S:9][C:8]([NH2:10])=[N:7][CH:6]=1.[Br:15][CH:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:17](O)=[O:18].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(#N)C>[Br:15][CH:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:17]([NH:10][C:8]1[S:9][C:5]([CH2:4][C:3]2[CH:11]=[CH:12][CH:13]=[CH:14][C:2]=2[Cl:1])=[CH:6][N:7]=1)=[O:18]
Reactant: Nc1ncc(Cc2ccccc2Cl)s1
Reactant: O=C(O)C(Br)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(Nc1ncc(Cc2ccccc2Cl)s1)C(Br)c1ccccc1
Reaction time: 16 h
Yield: 75 %

Procedure:
5-(2-Chloro-benzyl)-thiazol-2-ylamine (450 mg, 2.0 mmol) and bromo-phenyl-acetic acid (430 mg, 2.0 mmol) were dissolved in acetonitrile (20 mL) containing triethylamine (280 μL, 2.0 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (836 mg, 2.2 mmol) was added and the solution was allowed to stir for 16 hours. The crude product was purified by silica gel chromatography using a gradient of 10-30% ethyl acetate in hexanes to yield a pale yellow solid (633 mg, 1.50 mmol, 75.0%). ESI-MS m/z calc. 420.0. found 421.2 (M+1)+ Retention time 3.63 minutes.
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([S:12]([NH:15][CH2:16][CH2:17][N:18]([C:23](=[O:34])[CH2:24][N:25]3[CH:33]=[C:31]([CH3:32])[C:29](=[O:30])[NH:28][C:26]3=[O:27])[CH2:19][C:20]([OH:22])=O)(=[O:14])=[O:13])=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN1CCOCC1.ClC(OCC(C)C)=O>O1CCCC1>[C:1]1([C:7]2[S:11][C:10]([S:12]([N:15]3[CH2:16][CH2:17][N:18]([C:23](=[O:34])[CH2:24][N:25]4[CH:33]=[C:31]([CH3:32])[C:29](=[O:30])[NH:28][C:26]4=[O:27])[CH2:19][C:20]3=[O:22])(=[O:14])=[O:13])=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1cn(CC(=O)N(CCNS(=O)(=O)c2nnc(-c3ccccc3)s2)CC(=O)O)c(=O)[nH]c1=O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: Cc1cn(CC(=O)N2CCN(S(=O)(=O)c3nnc(-c4ccccc4)s3)C(=O)C2)c(=O)[nH]c1=O
Temperature: -20 °C
Yield: 90 %

Procedure:
To a solution of N-[2-(5-phenyl-1,3,4-thiadiazole-2-sulfonylamino)-ethyl]-N-[(thymin-1-yl)-acetyl]-glycine (1.02 g, 2 mmol) in tetrahydrofuran (50 mL) was added N-methylmorpholine (3.3 mL, 3 mmol) and then the mixture was cooled to −20° C. After stirring for 5 min at the same temperature, isobutyl chloroformate (3.4 mL, 26 mmol) was added to the reaction mixture. The resulting mixture was slowly warmed to 0° C. for 1 hour. Then the reaction mixture was evaporated in vacuo and dissolved in a mixture of ethyl acetate and acetonitrile. The solution was washed with brine and dried over sodium sulfate and filtered. The filtrate was evaporated in vacuo and triturated with tetrahydrofuran-ethyl ether (1/1, v/v) to precipitate solid. The solid was filtered off, washed with ethyl ether, and dried in vacuo to give the titled compound (883 mg, 90%). 1H NMR (500 MHz; DMSO-d6) δ 11.30 (s, 0.6H), 11.29 (s, 0.4H), 8.10 (d, 2H), 7.68–7.57 (m, 3H), 7.33 (s, 0.6H), 7.27 (s, 0.4H), 4.66 (s, 1.2H), 4.58 (s, 0.8H), 4.43 (s, 0.8H), 4.30 (s, 1.2H), 4.17 (t, 1.2H), 4.02 (t, 0.8H), 3.95 (t, 1.2H), 3.85 (t, 0.8H), 1.73(s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C([O:19][CH:20]=[C:21]([C:27](OCC)=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23])C.CN(C)C=O>O>[O:19]=[C:20]1[N:3]2[CH:4]=[N:5][C:6]3[CH:7]=[CH:8][C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:10][C:11]=3[C:2]2=[N:1][CH:27]=[C:21]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CS(=O)(=O)Nc1ccc2ncnc(N)c2c1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2c3cc(NS(C)(=O)=O)ccc3ncn2c1=O
Temperature: 155 °C
Reaction time: 2.5 h
Yield: 55 %

Procedure:
A mixture of 4-amino-6-methanesulfonamidoquinazoline (6.89 g), diethyl ethoxymethylenepropanediate (15.5 g) and N,N-dimethylformamide (55 ml) was stirred at 155° C. for 2.5 hours. The reaction mixture was cooled to ambient temperature. To the mixture was added water to give precipitates, which were separated by filtration and washed with water. To the crystals was added a mixture of methanol and chloroform (1:4) (400 ml). After stirring under heating, insoluble materials (6.95 g) were filtered off and recrystallized from N,N-dimethylformamide to give crystalline ethyl 4-oxo-10-methanesulfonamido-4H-pyrimido [1,2-c]quinazoline-3-carboxylate (5.76 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]#[N:10])=[CH:4][N:3]=1.[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH2:20][CH2:21][NH2:22])=[CH:12]1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:8][C:6]1[C:5]([C:9]#[N:10])=[CH:4][N:3]=[C:2]([NH:22][CH2:21][CH2:20][C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:11][CH:12]=2)[N:7]=1
Reactant: N#Cc1cnc(Cl)nc1Cl
Reactant: NCCc1c[nH]c2ccccc12
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cnc(NCCc2c[nH]c3ccccc23)nc1Cl
Temperature: 50 °C
Reaction time: 3 h
Yield: 38.4 %

Procedure:
A mixture of 2,4-dichloro-pyrimidine-5-carbonitrile (2.0 g, 11.5 mmol), 2-(1H-indol-3-yl)-ethylamine (1.83 g, 11.4 mmol), and DIEA (1.94 g, 15.0 mmol) in THF (50 mL) was stirred at 50° C. for 3 h. After cooling to room temperature, the reaction mixture was concentrated and the residue was diluted with ethyl acetate (150 mL). The organic layer was washed with saturated aqueous ammonium chloride, brine, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated in vacuum to give the crude product, which was purified by silica gel column chromatography (20% ethyl acetate in petroleum ether) to afford the title compound as a brown solid (1.3 g, 4.38 mmol, 38% yield). MS (ESI) m/z 298.1 [M+H]+.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([NH2:14])[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8].[CH3:15][O:16][CH2:17][C:18](Cl)=[O:19]>N1C=CC=CC=1>[CH3:15][O:16][CH2:17][C:18]([NH:3][C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([NH:14][C:18](=[O:19])[CH2:17][O:16][CH3:15])[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])=[O:19]
Reactant: COC(=O)c1cc(N)cc(N)c1
Reactant: COCC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: COCC(=O)Nc1cc(NC(=O)COC)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 3,5-diaminobenzoate dihydrochloride (7.2 g) in pyridine (100 ml) is added dropwise methoxyacetyl chloride (6.0 ml) at room temperature. The mixture is stirred at room temperature for 2 hours, and thereafter, pyridine is distilled off under reduced pressure. To the residue is added water and chloroform. The organic layer is separated and washed with water and then with aqueous saturated sodium chloride solution, dired over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent. The resulting solid substance is recrystallized from ethanol to give the title compound (5.2 g) having the following physical properties.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([NH2:15])=[CH:13][C:12]([C:16]([CH3:19])([CH3:18])[CH3:17])=[N:11]2)=[CH:6][CH:5]=1.Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C1COCC1>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:14]([NH:15][C:22]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:23])=[CH:13][C:12]([C:16]([CH3:17])([CH3:19])[CH3:18])=[N:11]2)=[CH:8][CH:9]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COC(=O)c1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.3 %

Procedure:
To a solution of 4-(5-amino-3-tert-butyl-pyrazol-1-yl)-benzoic acid methyl ester (5.3 g, 19.4 mmol) in anhydrous THF (200 mL) was slowly added phenyl chloroformate (6.81 mL, 54.3 mmol), followed by sodium carbonate (2.1 g, 19.4 mmol). The mixture was stirred at room temperature overnight. Ethyl acetate (500 mL) was added, followed by saturated sodium carbonate (300 mL). The organic layer was washed with saturated sodium carbonate (3×) and brine (1×), dried over MgSO4, and concentrated at reduced pressure. The residue was washed with ether to give 4.3 g (56%) of the desired product. 1H-NMR (DMSO-d6) δ 10.19 (s, 1H), 8.10 (d, J=9.0 Hz, 2H), 7.73 (d, J=9.0 Hz, 2H), 7.38-7.11 (m, 5H), 6.41 (s, 1H), 3.87 (s, 3H), 1.27 (s, 1H); MS LC-MS [M+H]+=394.1, RT=3.53 min.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:17])[C:15]3[C@@H:14]4[C:18]([CH3:20])([CH3:19])[C@@:11]([CH3:21])([CH2:12][CH2:13]4)[C:10]=3[NH:9]2)=[CH:4][CH:3]=1.I[CH3:23]>CN(C)C=O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:17])[C:15]3[C@@H:14]4[C:18]([CH3:20])([CH3:19])[C@@:11]([CH3:21])([CH2:12][CH2:13]4)[C:10]=3[N:9]2[CH3:23])=[CH:4][CH:3]=1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccc(O)cc3)c(=O)c12
Reactant: CI
Solvent: CN(C)C=O
Product: Cn1c2c(c(=O)n1-c1ccc(O)cc1)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 100 °C
Yield: 75.4 %

Procedure:
A mixture of (4S,7R)-2-(4-hydroxy-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 41; 1.60 g, 5.6 mmol) and iodomethane (1.1 mL, 17.7 mmol) in dimethylformamide (50 mL) was heated in a sealed tube at about 100° C. for 2.5 h. The reaction mixture was allowed to cool to room temperature. The tube was carefully opened, and the contents were allowed to stand at room temperature over a weekend. The solvent was evaporated and dichloromethane (250 mL) was added. The solution was washed with water (100 mL), saturated sodium thiosulfate (100 mL), water (100 mL), and brine (100 mL). The organic layer was dried (magnesium sulfate), filtered, and evaporated. The residue was triturated with ethyl acetate and the solid was filtered off and washed with 20% ethyl acetate/hexanes and then hexanes, and then purified using a Biotage 40M system, eluting with 3-5% methanol/dichloromethane to give (4S,7R)-2-(4-Hydroxy-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (1.26 g, 75%) as a light yellow solid. APCI(+)-MS (M+H) 299.
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH2:15][CH3:16])[CH:7]=1)[CH2:3][C:4]#[N:5].CCN(CC)CC.C[O:25][C:26](=O)[C:27]1[C:32]([NH:33][C:34]([CH:36]2[CH2:38][CH2:37]2)=[O:35])=[CH:31][CH:30]=[C:29]([Cl:39])[C:28]=1[CH2:40]Br>CN(C=O)C>[Cl:39][C:29]1[CH:30]=[CH:31][C:32]([NH:33][C:34]([CH:36]2[CH2:37][CH2:38]2)=[O:35])=[C:27]2[C:28]=1[CH2:40][N:1]([CH:2]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH2:15][CH3:16])[CH:7]=1)[CH2:3][C:4]#[N:5])[C:26]2=[O:25]
Reactant: COC(=O)c1c(NC(=O)C2CC2)ccc(Cl)c1CBr
Reactant: CCOc1cc(C(N)CC#N)ccc1OC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1cc(C(CC#N)N2Cc3c(Cl)ccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Temperature: 90 °C
Yield: 75.5 %

Procedure:
To the DMF solution (20 ml) of 3-Amino-3-(3-ethoxy-4-methoxy-phenyl)-propionitrile (1.55 g, 7 mmol) was added Et3N (1.6 ml, 12 mmol) followed by 2-bromomethyl-3-chloro-6-(cyclopropanecarbonyl-amino)-benzoic acid methyl ester (2.42 g, 7 mmol). The mixture was heated at 90° C. for 12 hrs then cooled to room temperature. The mixture was extracted with EtOAc (50 ml) and water (50 ml). The organic layer was washed with water (50 ml) and brine (50 ml), dried over Na2SO4 and concentrated in vacuo. The resulted oil was purified by silica gel chromatography to give cyclopropanecarboxylic acid {7-chloro-2-[2-cyano-1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide as white solid (2.4 g, 80%): mp 200-202° C.; 1H NMR (CDCl3)δ 0.90-0.94 (m, 2H, c-CH2), 1.09-1.14 (m, 2H, c-CH2), 1.45 (t, J=7.0 Hz, 3H, CH3), 1.64-1.70(m, 1H, c-CH), 3.12-3.32(m, 2H; CH2CN), 3.89(s, 3H), 3.99-4.12 (m, 3H, OCH2CH3+CHHN), 4.37 (d, J=18 Hz, 1H. CHHN), 5.62-5.68 (m, 1H, NCH), 6.87-6.98 (m, 3H, Ar), 7.40 (d, J=9 Hz, 1H, Ar), 8.47 (t, J=9 Hz, 1H, Ar), 10.34 (s, 1H, NH); 3C NMR (CDCl3) δ 8.5, 14.7, 16.2, 21.2, 46.4, 51.8, 56.0, 64.7, 111.7, 112.2, 116.9, 118.4, 119.1, 119.8, 121.9, 127.9, 133.3, 136.9, 138.9, 149.9, 150.0, 169.0, 172.7; Anal Calcd for C24H24ClN3O4: C, 63.50; H, 5.33; N, 9.26. Found: C, 63.43; H, 5.31; N, 9.01
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:3][CH2:2]1.[C:22]([BH3-])#N.[Na+].C=O.CC(O)=O.C([O-])(O)=O.[Na+]>CO>[CH3:22][N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:3][CH2:2]1
Reactant: [BH3-]C#N
Reactant: c1ccc(-c2[nH]c3ccccc3c2C2CCNCC2)cc1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN1CCC(c2c(-c3ccccc3)[nH]c3ccccc23)CC1
Reaction time: 2 h
Yield: 24.1 %

Procedure:
3-(Piperidin-4-yl)-2-phenyl-1H-indole (200 mg, 0.7 mmol), sodium cyanoborohydride (51 mg, 0.8 mmol), formaldehyde (60 μl, 40% in H2O, 0.8 mmol) and AcOH (97 μl, 1.7 mmol) were stirred in MeOH (5 ml) at 0° C. for 1 h, then room temperature for 2 h. The solution was poured into saturated NaHCO3 solution and extracted with EtOAc. The organic layer was washed with water and brine, dried, and evaporated in vacuo to give white crystals (49 mg, 23%), mp 245-246° C. (from EtOH); δH (360 MHz, d6-DMSO) 1.88 (2H, d, J 13, NCH2CHAHB), 2.60-2.80 (2H, m, NCH2CHAHB), 2.76 (3H, s, CH3), 3.00-3.20 (3H, m, CH2CH and NCHAHB), 3.44 (2H, d, J 12, NCHAHB), 6.99 (1H, t, J 7, indole-H), 7.09 (1H, t, J 7, indole-H), 7.20-7.50 (6H, m, ArH), 7.98 (1H, d, J 7, ArH), 11.20 (1H, br s, indole NH); m/z (ES+) 291 (M++H).
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: O=C(O)C1CCC1
Reactant: CS(=O)(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Solvent: CCOCC
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: [N+]([C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[CH:10][CH:11]=1)[C:8]#[N:9])([O-])=O.[C:14]1([CH3:21])[C:19]([OH:20])=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[C:14]1([CH3:21])[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=1[O:20][C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[CH:10][CH:11]=1)[C:8]#[N:9]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Reactant: Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1Oc1ccc(C#N)c(C#N)c1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
A mixture of 4-nitrophthalonitrile (10.6 g, 60.0 mmol), o-cresol (7.9 g, 72.0 mmol) and K2CO3 (16.6 g, 120.0 mmol) in DMF (70 mL) was heated to 60° C. under a nitrogen atmosphere for 3 hours. The crude reaction was then poured into H2O (300 mL). The resulting mixture was extracted twice with EtOAc. The combined organic layers were washed with sat'd NaHCO3 solution, dried over MgSO4 and concentrated in vacuo. The residue was then dissolved in EtOH (60 mL). After storing for 5 hours at room temperature, the precipitate was collected by filtration and the filter cake was washed with cold EtOH to give the title compound in 8.9 g. MS: (+) m/z 235.46 (M+1).
Reaction SMILES: [OH-].[Na+].CO.[CH:5]1([CH2:11][N:12]2[C:17](=[O:18])[C:16]([C:19]([O:21]CC)=[O:20])=[CH:15][C:14]3[CH2:24][S:25][CH2:26][CH2:27][C:13]2=3)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.Cl>O>[CH:5]1([CH2:11][N:12]2[C:17](=[O:18])[C:16]([C:19]([OH:21])=[O:20])=[CH:15][C:14]3[CH2:24][S:25][CH2:26][CH2:27][C:13]2=3)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: CCOC(=O)c1cc2c(n(CC3CCCCC3)c1=O)CCSC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc2c(n(CC3CCCCC3)c1=O)CCSC2

Procedure:
4M sodium hydroxide solution (15.2 mL, 60.8 mM) was added to a methanol (30 mL) solution of ethyl 1-cyclohexylmethyl-2-oxo-1,5,7,8,tetrahydro-2H-thiopyrano[4,3-b]pyridine-3-carboxylate (AA08, 8.16 g, 24.3 mmol), which had been obtained in Example 8, at room temperature, and the mixture was heated and refluxed for 30 minutes. The reaction mixture was diluted with water (100 mL) and washed with ether (100 mL). 5M hydrochloric acid (13 mL, 65 mmol) was added to the water layer, the precipitated crystal was separated by filtration and washed with water, and the brown crystal of 1-cyclohexylmethyl-2-oxo-1,5,7,8,tetrahydro-2H-thiopyrano[4,3-b]pyridine-3-carboxylic acid (6.78 g) was obtained. The crystal was recrystallized from ethanol-water to give light brown crystalline powder (AA09, 6.30 g, 84.3%).
Reaction SMILES: O[C:2]1[N:10]=[C:9]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([N+:21]([O-:23])=[O:22])[CH:14]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.P(Cl)(Cl)([Cl:26])=O.CN(C)C1C=CC=CC=1>O1CCOCC1>[Cl:26][C:2]1[N:10]=[C:9]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([N+:21]([O-:23])=[O:22])[CH:14]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2
Reactant: COc1ccc(CSc2nc(O)c3nc[nH]c3n2)cc1[N+](=O)[O-]
Reactant: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Solvent: CN(C)c1ccccc1
Product: COc1ccc(CSc2nc(Cl)c3nc[nH]c3n2)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 2 h
Yield: 35.2 %

Procedure:
6-hydroxy-2-(4-methoxy-3-nitrobenzylsulfanyl)-9H-purine (14.67 g, 44 mmol) was suspended in dioxane (30 ml), phosphorus oxychloride (12.3 ml, 132 mmol) and dimethylaniline (8.3 ml, 66 mmol) were added and heated and stirred at 100° C. for 2 hours. The reaction solution was poured into ice water and extracted twice with ethyl acetate. After combining the ethyl acetate layers and washing with a saturated saline solution, it was dried with MgSO4 and the solvent was distilled away under reduced pressure. Separation and purification were performed by silica gel column chromatography (dichloromethane: methanol=20:1) to obtain 5.45 g (35% yield) of 6-chloro-2-(4-methoxy-3-nitrobenzylsulfanyl)-9H-purine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:10])[CH:5]=[N:6][C:7]=1[O:8][CH3:9].CCN(C(C)C)C(C)C.Br[CH2:21][CH2:22][O:23][CH2:24][CH2:25]Br>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ncc(N)cc1Br
Reactant: BrCCOCCBr
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ncc(N2CCOCC2)cc1Br
Temperature: 120 °C
Yield: 53 %

Procedure:
To a solution of 5-bromo-6-methoxypyridin-3-amine (1.0 equiv.) in DMF was added DIEA (3.0 equiv.) and 1-bromo-2-(2-bromoethoxy)ethane (1.0 equiv.). The solution was heated to 120° C. for 24 hours. Upon cooling to room temperature, the reaction was partitioned between water and ethyl acetate, the aqueous phase was extracted three times with ethyl acetate, the organics were combined, dried with sodium sulfate, filtered and concentrated. The crude material was purified via silica gel column chromatography eluting with 0-50% ethyl acetate in heptanes. The pure fractions were concentrated to yield 4-(5-bromo-6-methoxypyridin-3-yl)morpholine in 53% yield as an orange oil. LCMS m/z (M+H)=273/275, Rt=0.61 min. 1H NMR (400 MHz, <cdcl3>) δ ppm 2.93-3.18 (m, 4H) 3.80-4.05 (m, 7H) 7.50 (d, J=2.74 Hz, 1H) 7.74 (d, J=2.74 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[NH2:9].C(#N)C.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>C(Cl)Cl>[Cl:8][C:6]1[N:5]=[N:4][C:3]([NH2:9])=[C:2]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:7]=1
Reactant: C1COCCN1
Reactant: Nc1nnc(Cl)cc1Br
Solvent: ClCCl
Solvent: CC#N
Product: Nc1nnc(Cl)cc1N1CCOCC1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
4-Bromo-6-chloropyridazin-3-amine (2.0 g, 9.6 mmol) was placed in an 8 mL vial equipped with a stir bar, and ACN (5 mL) and morpholine (8.3 mL, 96 mmol) were added. The mixture was stirred at 70° C. for 18 h. The reaction was cooled to rt, the suspension obtained was filtered, and the filtercake was washed with ACN (10 mL). The filtrate was concentrated under reduced pressure and the residue obtained was dissolved in DCM (50 mL) and washed with saturated NaHCO3 solution (2×30 mL). The aqueous washings were combined and extracted with DCM (3×30 mL). The combined organic extracts were dried over MgSO4 and filtered. The solvent was removed under reduced pressure. The crude residue was triturated with EtOAc (30 mL) then the solid was isolated by filtration to give compound 19a. Mass Spectrum (LCMS, ESI pos.): Calcd. for C8H11ClN4O: 215.1 (M+H). found: 215.1.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31]O)=[C:26]([N+:33]([O-:35])=[O:34])[CH:25]=1.N1C=CC=CC=1>C(Cl)Cl>[Br:20][CH2:31][CH2:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][C:26]=1[N+:33]([O-:35])=[O:34]
Reactant: COc1ccc(CCO)c([N+](=O)[O-])c1
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(CCBr)c([N+](=O)[O-])c1
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 80.7 %

Procedure:
A suspension of triphenylphosphine (26 g, 1 mol) in DCM (100 mL) under nitrogen atmosphere at 25-26° C. is cooled down to 0-5° C. A solution of bromine (15.9 g, 0.1 mol) in DCM (150 mL) is added over 30 min at the same temperature. The reaction mixture is stirred for 15 min at 0-5° C. A solution of 2-(4-methoxy-2-nitrophenyl)ethanol (14 g, 0.07 mol) and pyridine (7.8 g, 0.1 mol) in DCM (100 mL) is added to the above reaction mixture over 30 min at 0-5° C. The resulting reaction mixture is warmed up to 25-26° C. and stirred for 3 h. The reaction is quenched by addition of cold water (250 mL). The crude product is extracted with DCM (2×200 mL). The organic layer is washed with water and brine (200 mL each), dried over Na2SO4 and concentrated to dryness. The crude residue obtained is purified by column chromatography (60-120 mesh silica gel, eluent: 5% EtOAc in petrol ether) to give 14.7 g (79%) of the title compound as a yellow solid. 1H NMR (DMSO-d6, 400 MHz) δ 7.51-7.49 (m, 2H), 7.30-7.27 (m, 1H), 3.83 (s, 3H), 3.82-3.68 (m, 2H), 3.32-3.27 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10](Cl)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH:14]([NH:17][CH2:18][CH2:19][NH:20][CH:21]([CH3:23])[CH3:22])([CH3:16])[CH3:15]>>[CH3:15][CH:14]([N:17]([CH2:18][CH2:19][NH:20][CH:21]([CH3:23])[CH3:22])[S:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)(=[O:12])=[O:11])[CH3:16]
Reactant: CC(C)NCCNC(C)C
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Product: CC(C)NCCN(C(C)C)S(=O)(=O)c1cccc([N+](=O)[O-])c1

Procedure:
Following the procedure of Example 1, m-nitrobenzenesulfonyl chloride was reacted with N,N'-diisopropyl ethylene diamine to give N-(1-methylethyl)-N-[2-[(1-methylethyl)amino]ethyl]-3-nitrobenzene sulfonamide.