Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CON(C)[C:39]([C:41]1[N:46]=[CH:45][CH:44]=[CH:43][N:42]=1)=[O:40]>>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[C:22]([C:44]2[CH:43]=[N:42][C:41]([CH:39]=[O:40])=[N:46][CH:45]=2)[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2Cl)C[C@H](C)O1
Reactant: CON(C)C(=O)c1ncccn1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(-c3cnc(C=O)nc3)c(F)c2Cl)C[C@H](C)O1

Procedure:
Starting materials: (2R,6S)-4-[6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-chloro-3-fluorophenyl]-2,6-dimethylmorpholine (Intermediate 42) and N-methoxy-N-methylpyrimidine-2-carboxamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[N:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[CH:20][CH:19]=2)=[N:10]1.[NH:29]1[CH:33]=[CH:32][N:31]=[CH:30]1.N[C@@H]1CCCC[C@H]1N.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.[Cu]I.O>[F:1][C:2]1[CH:7]=[C:6]([N:29]2[CH:33]=[CH:32][N:31]=[CH:30]2)[CH:5]=[CH:4][C:3]=1[N:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[CH:20][CH:19]=2)=[N:10]1
Reactant: COc1cn(-c2ccc(I)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Reactant: c1c[nH]cn1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COc1cn(-c2ccc(-n3ccnc3)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Yield: 7.7 %

Procedure:
A suspension of 1-(2-fluoro-4-iodophenyl)-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (244 mg, 0.5 mmol), imidazole (40.8 mg, 0.6 mmol), CuI (9.5 mg, 0.05 mmol), trans-1,2-diaminocyclohexane (0.012 mL, 0.1 mmol), and Cs2CO3 (326 mg, 1.0 mmol) in 1,4-dioxane (2 mL) was refluxed for 4 h under Ar atmosphere. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with AcOEt/THF (1/0-0/1) and crystallized from MeOH to give the title compound (16.5 mg, 8% yield) as a white solid: mp 235-236° C. (dec); 1H NMR (300 MHz, CDCl3): δ ppm 3.93 (3H, s), 6.49 (1H, t, J=8.7 Hz), 7.03 (1H, ddd, J=1.1, 2.3, 8.7 Hz), 7.22-7.27 (3H, m), 7.35 (1H, d, J=1.9 Hz), 7.38-7.49 (5H, m), 7.80 (1H, d, J=1.9 Hz), 7.82 (1H, d, J=2.6 Hz), 7.86 (1H, t, J=1.1 Hz). LC-MS (ESI) m/z 429 [M+H]+. Anal. Calcd for C23H17FN6O2: C, 64.48; H, 4.00; N, 19.62. Found: C, 64.35H, 3.90; N, 19.43.
Reaction SMILES: N=O.[NH:3]([C:7]1[S:8][CH:9]=[C:10]([CH2:12][S:13][CH2:14][CH2:15][C:16]#[N:17])[N:11]=1)[C:4]([NH2:6])=[NH:5].[S:18]([NH2:22])([NH2:21])(=[O:20])=[O:19]>>[CH:9]1[S:8][C:7]([NH:3][C:4]([NH2:6])=[NH:5])=[N:11][C:10]=1[CH2:12][S:13][CH2:14][CH2:15][C:16]([NH:21][S:18]([NH2:22])(=[O:20])=[O:19])=[NH:17]
Reactant: NS(N)(=O)=O
Reactant: N#CCCSCc1csc(NC(=N)N)n1
Agent: N=O
Product: N=C(N)Nc1nc(CSCCC(=N)NS(N)(=O)=O)cs1
Yield: 78.8 %

Procedure:
An inproved method is disclosed in the European Patent Application No. 128,736 of the same company, where the chromatographic purification could be avoided only by preparing and using an iminoether base of substantially higher purity. From 3-(2-guanidino-thiazol-4-yl-methylthio)-propionitrile solid iminoether base was prepared with a yield of 78.8%, which was reacted with 2.2 molar equivalents of sulfamide in a methanolic medium, at 20° to 30° C. for three days. The crude product obtained with a yield of 62% was recrystallized from aqueous dimethyl formamide, and the obtained material was again precipitated with a base, after dissolution in a mixture of water and acetic acid. The total yield for crude famotidine was accordingly merely 48.8%. The main disadvantage of this process is the high consumption of sulfamide, the many and cumbersome steps involved in the process and that it is very time consuming.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.[NH3:13]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([S:8]([NH2:13])(=[O:10])=[O:9])[CH:7]=1
Reactant: Cc1ccc(Cl)cc1S(=O)(=O)Cl
Reactant: N
Solvent: C1CCOC1
Product: Cc1ccc(Cl)cc1S(N)(=O)=O
Temperature: 25 °C
Yield: 70.3 %

Procedure:
A solution of 3810.5 g of 5-chloro-2-methylbenzenesulfonyl chloride in 10.8 L of tetrahydrofuran was cooled to 0°-5° C. and 720 g of anhydrous ammonia was added while maintaining the temperature at 0°-5° C. When addition was complete, the suspension was stirred several hours at 0°-5° C., then allowed to warm to ambient temperature overnight. The precipitated ammonium chloride was filtered and washed with tetrahydrofuran. The filtrate was concentrated in vacuo until solids were formed. The solids were collected, washed with 1-chlorobutane and dried to give 2449 g of the title compound, m.p. 142°-145° C.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][CH2:9][C:10]2[S:11][C:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:13][CH:14]=2)=[O:7])=[CH:4][N:3]=1.C1C=C2C(C=C(NCNCCCC(O)=O)C=C2)=CC=1.C=O.[C:45]([O:48][CH2:49]C)(=O)C>CO>[CH2:15]([C:12]1[S:11][C:10]([CH2:9][NH:8][C:6](=[O:7])[C:5]2[CH:22]=[CH:23][C:2]([NH:1][CH2:45][O:48][CH3:49])=[N:3][CH:4]=2)=[CH:14][CH:13]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Nc1ccc(C(=O)NCc2ccc(Cc3ccccc3)s2)cn1
Reactant: CCOC(C)=O
Agent: C=O
Agent: O=C(O)CCCNCNc1ccc2ccccc2c1
Solvent: CO
Product: COCNc1ccc(C(=O)NCc2ccc(Cc3ccccc3)s2)cn1
Reaction time: 1 h
Yield: 87.6 %

Procedure:
To a solution of 6-amino-N-(5-benzylthiophen-2-ylmethyl)-nicotinamide described in Example A-144 (210 mg, 0.65 mmol) and 5,5-dimethylimidazo phospho-2,4-dione (92 mg, 0.71 mmol) in methanol (15 mL) was added an aqueous solution of 37% formaldehyde (2.5 mL) under reflux in three time, and the solution was stirred for 1 hour. NH silica gel was added to the reaction solution, the solvent was evaporated in vacuo for adsorption, purification was carried out by NH silica gel column chromatography (hexane:ethyl acetate=1:1, then ethyl acetate), and the title compound (210 mg, 0.57 mmol, 87.6%) was obtained as a white solid.
Reaction SMILES: [C:1]1([C:7]2[C:14]3[S:13][C:12]([NH2:15])=[N:11][C:10]=3[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][O:17][CH2:18][CH2:19][O:20][CH2:21][C:22](Cl)=[O:23].C(O)C(N)(CO)CO>CN(C1C=CN=CC=1)C.C1COCC1>[CH3:16][O:17][CH2:18][CH2:19][O:20][CH2:21][C:22]([NH:15][C:12]1[S:13][C:14]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8][NH:9][C:10]=2[N:11]=1)=[O:23]
Reactant: COCCOCC(=O)Cl
Reactant: Nc1nc2[nH]nc(-c3ccccc3)c2s1
Agent: CN(C)c1ccncc1
Agent: NC(CO)(CO)CO
Solvent: C1CCOC1
Product: COCCOCC(=O)Nc1nc2[nH]nc(-c3ccccc3)c2s1
Temperature: 70 °C
Reaction time: 24 h
Yield: 65 %

Procedure:
To a vial charged with 3-phenyl-1H-pyrazolo[3,4-d]thiazol-5-ylamine (30 mg, 0.139 mmol), PS-DMAP (Argonaut resin, 6 equiv.), and a stirring bar was added THF (2 mL) and 2-(2-methoxyethoxy)acetyl chloride (106 μL, ca. 5 equiv.). The reaction mixture was stirred at 70° C. for 24 h, then cooled to room temperature and treated with PS-trisamine (Argonaut resin, 20 equiv.) for 1.5 h. The resin was filtered, washed with THF and the solvent was evaporated. The residue was treated with a (5:1:1) mixture of THF/H2O/Et3N (2 mL) at 50° C. for 24 h, then the solution was directly adsorbed on silica gel. Purification on silica gel with 0-10% MeOH in CH2Cl2 as eluent provided 30 mg (65%) of 2-(2-methoxy-ethoxy)-N-(3-phenyl-1H-pyrazolo[3,4-d]thiazol-5-yl)-acetamide as a white solid. 1H-NMR (d6-DMSO) δ: 13.5 and 13.6 (2 broad s, 1H, NH+tautomer), 12.2 (broad s, 1H, NH), 7.74 (m, 2H, tautomers), 7.54 (m, 2H, tautomers), 7.38 (m, 1H, tautomers), 4.28 (s, 2H), 3.68 (t, 2H), 3.51 (t, 2H), 3.29 (s, 3H); HPLC/MS m/z: 333 [MH]+.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:12]2[C:11](=[O:13])[CH2:10][C:9]([CH3:15])([CH3:14])[CH2:8][C:7]=2[NH:6][CH:5]=1.F[C:17]1[C:26]([F:27])=[C:25]2[C:20]([C:21]([NH2:28])=[N:22][CH:23]=[N:24]2)=[CH:19][CH:18]=1>CN(C=O)C>[NH2:28][C:21]1[C:20]2[C:25](=[C:26]([F:27])[C:17]([N:6]3[C:7]4[CH2:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11](=[O:13])[C:12]=4[C:4]([CH3:3])=[CH:5]3)=[CH:18][CH:19]=2)[N:24]=[CH:23][N:22]=1
Reactant: Nc1ncnc2c(F)c(F)ccc12
Reactant: Cc1c[nH]c2c1C(=O)CC(C)(C)C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cn(-c2ccc3c(N)ncnc3c2F)c2c1C(=O)CC(C)(C)C2
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (60% suspension in mineral oil, 50 mg, 1.3 mmol) is added to a solution of 3,6,6-Trimethyl-1,5,6,7-tetrahydro-indol-4-one (50 mg, 0.29 mmol) in anhydrous DMF (1 mL). This mixture is stirred at room temperature for 5 minutes before 7,8-Difluoro-quinazolin-4-ylamine (75 mg, 0.41 mmol) is added. After 10 minutes at room temperature, the reaction mixture is heated at 50° C. overnight. The cooled reaction mixture is partitioned between ethyl acetate and water to remove DMF, and the organic layer is concentrated to dryness via Rotovap. The resulting crude residue is further purified through two consecutive silica gel columns (0%-8% of methanol in DCM, gradient) to afford 1-(4-Amino-8-fluoro-quinazolin-7-yl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one (15 mg, not optimized) as white solid. LC/MS m/z=339 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24](F)[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].IC1C(=O)C2C(=CC=C([O:49][C:50]([F:53])([F:52])[F:51])C=2)OC=1C1C=CC=CC=1>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([O:49][C:50]([F:53])([F:52])[F:51])[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Reactant: O=c1c(I)c(-c2ccccc2)oc2ccc(OC(F)(F)F)cc12
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(OC(F)(F)F)cc4c3=O)cc2)CCC1
Yield: 100 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 3-iodo-2-phenyl-6-trifluoromethoxy-chromen-4-one was reacted to give the title compound as a pale yellow oil (90 mg, 100%). LCMS (Method B): RT=5.07 min, [M+Na]+=574.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]([N:5]([CH2:17][CH2:18][O:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1)[C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:7]=1)=[O:4].[N:32]#[C:33]Br.C(Cl)Cl.[Cl-].[Al+3].[Cl-].[Cl-]>O>[F:1][C:2]([F:30])([F:31])[C:3]([N:5]([CH2:17][CH2:18][O:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([C:33]#[N:32])=[CH:22][CH:21]=1)[C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:7]=1)=[O:4]
Reactant: N#CBr
Reactant: CCOC(=O)c1ccc(N(CCOc2cccc3ccccc23)C(=O)C(F)(F)F)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1ccc(N(CCOc2ccc(C#N)c3ccccc23)C(=O)C(F)(F)F)cc1
Reaction time: 5 h

Procedure:
To a solution of 5.4 g. of ethyl 4-[N-trifluoroacetyl-2-(1-naphthyloxy)ethylamino]benzoate and 1.5 g. of cyanogen bromide in 200 ml. of methylene chloride at -5° C. is added 5.7 g. of anhydrous aluminum chloride. The solution is allowed to stand at room temperature for 5 hours and then poured into 200 ml. of ice and water. After addition of 20 ml. of concentrated hydrochloric acid, the organic layer is seperated, washed with water, dried and evaporated to dryness. Recrystallization from 75% aqueous acetonitrile gives material, m.p. 150°-151° C.
Reaction SMILES: ClC1C(Cl)=CC2OC3C=C(Cl)C(Cl)=CC=3OC=2C=1.[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[C:23]([Cl:27])=[CH:22][C:21]=1[OH:28].Cl[CH2:30][C:31]([OH:33])=[O:32]>>[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[C:23]([Cl:27])=[CH:22][C:21]=1[O:28][CH2:30][C:31]([OH:33])=[O:32]
Reactant: Oc1cc(Cl)c(Cl)cc1Cl
Reactant: O=C(O)CCl
Agent: Clc1cc2c(cc1Cl)Oc1cc(Cl)c(Cl)cc1O2
Product: O=C(O)COc1cc(Cl)c(Cl)cc1Cl

Procedure:
The above objects have been achieved by the synthesis of 2,4,5-trichlorophenoxyacetic acid and its intermediate, 2,4,5-trichlorophenol, which are free from contamination with 2,3,7,8-tetrachloro-dibenzo-p-dioxin (TCDD). The synthesis involves the nitration of 1,2,4-trichlorobenzene to form 1,2,4-trichloro-5-nitrobenzene, which is reduced (usually with hydrogen) to produce 2,4,5-trichloroaniline. The 2,4,5-trichloroaniline is reacted with sulfuric acid and a nitrite to form 2,4,5-trichlorobenzenediazonium sulfate, which is reacted with water and distilled to produce 2,4,5-trichlorophenol which is analytically free of TCDD. The 2,4,5-trichlorophenol is reacted with monochloroacetic acid in the presence of aqueous base, followed by acidification, to produce 2,4,5-trichlorophenoxyacetic acid which also is analytically free of TCDD.
Reaction SMILES: C[C:2]1([N:9]=[N:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[CH:16][CH:17]=3)[CH:12]=2)[C:6](=O)[CH:5]=[C:4](C)[O:3]1.Cl>C(O)(=O)C>[OH:3][C:2]1[CH:6]=[C:5]([CH3:4])[N:10]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[CH:16][CH:17]=3)[CH:12]=2)[N:9]=1
Reactant: COc1ccc2ccc(N=NC3(C)OC(C)=CC3=O)cc2c1
Agent: Cl
Solvent: CC(=O)O
Product: COc1ccc2ccc(-n3nc(O)cc3C)cc2c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
2,5-dimethyl-2-(7-methoxynaphthalen-2-yldiazenyl)furan-3-one (3.4 g, 11.48 mmol) dissolved in acetic acid (20 ml) was added dropwise over hydrochloric acid 6N (3.5 ml) and was heated to a temperature of 60° C. The mixture was kept stirring at 60° C. during 2 hours. The solution was cooled, poured over a mixture of water/ice (400 ml) and the solid precipitate was filtered and washed with water. It was dried and a solid crude remained, which was purified by means of crystallization in toluene, thereby resulting in 1.23 g (42%) of 3-hydroxy-5-methyl-1-(7-methoxynaphthalen-2-yl)-1H-pyrazol in the form of a white-greyish coloured solid.
Reaction SMILES: [C:1](=[NH:23])([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:14]=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=2)=[CH:8][CH:7]=1)[NH2:2].[CH:24]([CH:26]([CH2:31][C:32]1[CH:33]=[N:34][N:35]([CH3:37])[CH:36]=1)[C:27](OC)=O)=[O:25].C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[CH3:37][N:35]1[CH:36]=[C:32]([CH2:31][C:26]2[C:24](=[O:25])[N:23]=[C:1]([O:3][CH2:4][CH2:5][C:6]3[CH:7]=[CH:8][C:9]([O:12][C:13]4[CH:14]=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=4)=[CH:10][CH:11]=3)[NH:2][CH:27]=2)[CH:33]=[N:34]1
Reactant: N=C(N)OCCc1ccc(Oc2ccc(C(F)(F)F)nc2)cc1
Reactant: COC(=O)C(C=O)Cc1cnn(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Cn1cc(Cc2c[nH]c(OCCc3ccc(Oc4ccc(C(F)(F)F)nc4)cc3)nc2=O)cn1
Temperature: 130 °C
Yield: 24.6 %

Procedure:
To the solution of 2-(4-{[6-(trifluoromethyl)-3-pyridinyl]oxy}phenyl)ethyl imidocarbamate (200 mg, 0.456 mmol) and methyl 2-formyl-3-(1-methyl-1H-pyrazol-4-yl)propanoate (107 mg, 0.548 mmol) in NMP (3 mL) was added K2CO3 (252 mg, 1.825 mmol). The mixture was heated with a microwave reactor at 130° C. for 0.5 h. Purification via MDAP then afforded the title compound (53 mg, 0.112 mmol, 24.64% yield). LCMS: rt=2.92 min, [M+H+]=472
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1.[N-:13]=[N+:14]=[N-:15].[Na+]>CN(C=O)C>[N:13]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1)=[N+:14]=[N-:15]
Reactant: [N-]=[N+]=[N-]
Reactant: O=c1cc(Cl)c2ccccc2o1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1cc(=O)oc2ccccc12
Temperature: 0 °C

Procedure:
4-chloro coumarin, (100 mg, 0.54 mmol) was dissolved in 2 mL of DMF at room temperature and followed by the addition of NaN3 (40 mg, 0.62 mmol) and stirring for twelve hours. The reaction mixture was poured onto 10 g of ice, and then stirred for 30 minutes at room temperature. Filtration and drying afforded white powder; yield (80 mg, 80%); mp 159-160° C. 1H-NMR (300 MHz, CDCl3): δ 7.2-7.7 (m, 5H).
Reaction SMILES: CC(O)=O.[NH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([CH3:16])[C:10]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:9]2[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[CH2:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][C:31]1=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH2:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH:31]1[NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([CH3:16])[C:10]([C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])=[C:9]2[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1nc2ccc(N)cc2c(-c2ccccc2)c1C(=O)OC(C)(C)C
Reactant: O=C1Cc2ccccc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1nc2ccc(NC3Cc4ccccc4C3)cc2c(-c2ccccc2)c1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.6 %

Procedure:
A method of Abdel-Magid et al (J. Org. Chem., 61, 3849, 1996) was used: Glacial AcOH (0.25 ml) was added to a solution of the product of Step 2 (1.46 g, 4.4 mmol), 1H-inden-2(3H)-one (0.46 g, 4.5 mmol) and NaBH(OAc)3 (1.4 g, 6.55 mmol) in anhydrous 1,2-dichloroethane (17 ml). The resulting mixture was stirred overnight at room temperature under N2 and to it more of NaBH(OAc)3 (0.4 g, 1.9 mmol) was added. After 2 h of stirring at room temperature, the mixture was quenched by addition of 1N NaOH aq (5 ml). This was diluted to 60 ml with Et2O and washed with H2O and brine. The organic phase was dried over anhydrous MgSO4, filtered and filtrate evaporated to dryness under reduced pressure. The residue was purified by flash column chromatography (SiO2, CH2Cl2) to give pure product as a creamy solid (1.4 g, 71%). 1H NMR (300 MHz, CDCl3) δ 7.83 (d, J=9.0 Hz, 1H), 7.34-7.5(m, 5H), 7.12-7.21(m, 4H), 7.05(dd, J=2.6, 9.0 Hz, 1H), 6.49(d, J=2.6 Hz, 1H), 4.17(m, 1H), 4.08(m, 1H), 3.19-3.27(m 2H), 2.73-2.83(m, 2H), 2.7(s, 3H), 1.22(s, 9H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([CH2:12][CH2:13][CH2:14][CH:15]1[C:20](=[O:21])[NH:19][C:18]2[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=2[S:16]1)=O)C.O>CCOCC>[OH:9][CH2:10][CH2:12][CH2:13][CH2:14][CH:15]1[C:20](=[O:21])[NH:19][C:18]2[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=2[S:16]1
Reactant: CCOC(=O)CCCC1Sc2ccccc2NC1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: O=C1Nc2ccccc2SC1CCCCO
Reaction time: 1 h
Yield: 55.2 %

Procedure:
To a suspension of 0.46 g of lithium aluminum hydride in 50 ml of ether was added dropwise, with ice-cooling, a solution of 1.6 g of 2-(3-ethoxycarbonylpropyl)-2H-1,4-benzothiazin-3(4H)-one in ether (30 ml). After the mixture was stirred for one hour, water was added dropwise thereto. The resultant white precipitates were filtered off, and the filtrate was dried (MgSO4). The solvent was evaporated off, and the residue was subjected to a column chromatography on silica-gel (70 g). From the eluate with hexane-ethyl acetate (1:1, v/v) was obtained 0.75 g (55.6%) of 2-(4-hydroxybutyl)-2H-1,4-benzothiazin-3(4H)-one. Recrystallization from ethyl acetate gave prisms, m.p. 101°-102° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:14](=[O:25])[O:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)[CH2:7]1.ClC1C=C(C=CC=1Cl)CN1CCO[C@@H](CN)C1.C1C([N+]([O-])=O)=CC=C([Cl-]C([O-])=O)C=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][C@@H:8]([CH2:12][NH:13][C:14](=[O:25])[O:15][C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)[CH2:7]1
Reactant: O=C(NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)Oc1ccc([N+](=O)[O-])cc1
Agent: NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Product: O=C(NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)Oc1ccc([N+](=O)[O-])cc1

Procedure:
Intermediate 13 was prepared in an analogous manner to Intermediate 10 from Intermediate 11 (0.225 g) and 4-nitrophenylchloroformate (0.182 g) to yield the title compound (0.2 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5](=[O:14])[CH2:4][CH2:3]1.C(O[CH:19](OCC)[N:20]([CH3:22])[CH3:21])C>>[CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5](=[O:14])[C:4](=[CH:19][N:20]([CH3:22])[CH3:21])[CH2:3]1
Reactant: CCOC(OCC)N(C)C
Reactant: COc1ccc2c(c1)C(=O)CCC2(C)C
Product: COc1ccc2c(c1)C(=O)C(=CN(C)C)CC2(C)C

Procedure:
The 3,4-dihydro-4,4-dimethyl-2-dimethylaminomethylene-7-methoxy-1 (2H) naphthalenone was prepared from 4,4-dimethyl-7-methoxy-1-tetralone [2.3 g; H. Hart et al J. Chem. Soc. 85, 3260, (1963)] and N,N-dimethylformamide diethylacetal (6 ml) in a method analogous to that used in Example 1, to give the desired product as a yellow solid (2.26 g) m.p. 108-110°. MS (ES+) 260 (MH+, 100%).
Reaction SMILES: [Br:1][C:2]1[C:3]([S:11][C:12]2[NH:13][C:14]3[C:19]([N:20]=2)=[C:18]([NH2:21])[N:17]=[CH:16][N:15]=3)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.Br[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N+:31]([O-:33])=[O:32])[CH:26]=1>>[Br:1][C:2]1[C:3]([S:11][C:12]2[N:13]=[C:14]3[C:19]([N:20]=2)=[C:18]([NH2:21])[N:17]=[CH:16][N:15]3[CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([N+:31]([O-:33])=[O:32])[CH:26]=2)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: O=[N+]([O-])c1cccc(CCBr)c1
Reactant: Nc1ncnc2[nH]c(Sc3cc4c(cc3Br)OCO4)nc12
Product: Nc1ncn(CCc2cccc([N+](=O)[O-])c2)c2nc(Sc3cc4c(cc3Br)OCO4)nc1-2

Procedure:
The title compound was prepared from 8-(6-bromo-benzo[1,3]dioxol-5-ylsulfanyl)-9H-purin-6-ylamine and 1-(2-bromo-ethyl)-3-nitro-benzene by a procedure similar to examples 1 and 2. The compound was purified by preparative HPLC. 1H NMR (DMSO-d6) δ 8.29 (s, 1H), 7.99-7.95 (m, 1H), 7.56-7.42 (m, 2H), 7.33 (s, 1H), 7.10-7.05 (m, 1H), 6.72 (s, 1H), 6.10 (s, 2H), 4.60 (t, J=6.9 Hz, 2H), 3.36 (t, J=7.0 Hz, 2H); LC-MS [M+H]+ 516.0.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:13][N:12]([C:14]2[C:18]([N+:19]([O-])=O)=[CH:17][N:16]([CH3:22])[N:15]=2)[C:11](=[O:23])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1COCC1>[C].[Pd].CO>[NH2:19][C:18]1[C:14]([N:12]2[CH2:13][C@@H:9]([O:8][Si:1]([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2])[CH2:10][C:11]2=[O:23])=[N:15][N:16]([CH3:22])[CH:17]=1
Reactant: Cn1cc([N+](=O)[O-])c(N2C[C@@H](O[Si](C)(C)C(C)(C)C)CC2=O)n1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1cc(N)c(N2C[C@@H](O[Si](C)(C)C(C)(C)C)CC2=O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.4 %

Procedure:
A mixture of (4S)-4-((tert-butyl(dimethyl)silyl)oxy)-1-(1-methyl-4-nitro-1H-pyrazol-3-yl)pyrrolidin-2-one (2.7 g), 10% palladium-carbon (0.85 g), THF (27 mL) and methanol (27 mL) was stirred at room temperature for 2 hr under hydrogen atmosphere. The reaction mixture was filtered through a membrane filter, and the filtrate was concentrated under reduced pressure to give the title compound (2.3 g).