Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([O:23][CH3:24])[C:5]([N:8](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[N:6][CH:7]=1.[F:25][CH:26]([F:48])[CH2:27][N:28]1[CH:32]=[C:31]([C:33]2[CH:38]=[CH:37][N:36]=[C:35]([NH:39][CH2:40][C@@H:41]([OH:43])[CH3:42])[N:34]=2)[C:30]([Sn](C)(C)C)=[N:29]1>CN(C=O)C.CO.O.[Cu](I)I>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:30]2[C:31]([C:33]3[CH:38]=[CH:37][N:36]=[C:35]([NH:39][CH2:40][C@@H:41]([OH:43])[CH3:42])[N:34]=3)=[CH:32][N:28]([CH2:27][CH:26]([F:48])[F:25])[N:29]=2)=[N:3][C:4]=1[O:23][CH3:24]
Reactant: C[C@H](O)CNc1nccc(-c2cn(CC(F)F)nc2[Sn](C)(C)C)n1
Reactant: COc1nc(Br)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: I[Cu]I
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: COc1nc(-c2nn(CC(F)F)cc2-c2ccnc(NC[C@H](C)O)n2)cnc1N
Temperature: 10 °C
Yield: 34.6 %

Procedure:
A mixture of di-tert-butyl (5-bromo-3-methoxypyrazin-2-yl)imidodicarbonate (517 mg, 1.28 mmol), (2S)-1-({4-[1-(2,2-difluoroethyl)-3-(trimethylstannyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-ol (570 mg, 1.28 mmol), Copper iodide (5 mg, 0.026 mmol) in DMF (13 mL) was deoxygenated with a N2 bubbler for a few minutes before adding Tetrakis(triphenylphoshine)palladium (0) (74 mg, 0.064 mmol). The mixture was sealed in a microwave vial and heated in an oil bath at 10° C. for 18 hrs. This mixture was then heated in the microwave at 170° C. for 20 minutes to themolyze the tert-butoxycarbonyl groups. The mixture was partitioned between ethyl acetate and saturated aqueous NaCl. Some dark insoluble solids did not go into either phase and were removed by filtration. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organics were washed once each with water and saturated aqueous NaCl, dried over Magnesium sulfate and reduced to minimum volume. The residue was then purified on silica gel using a gradient of 0-8% methanol (containing 10% ammonium hydroxide) in a mixture of tert-butyl methyl ether and dichloromethane (1:1) as eluent. A small amount of the product still containing the tert-butoxycarbonyl groups was recovered from the column. This material was treated with 10% hydrochloric acid in methanol at 70° C. for 2 hours to complete the deprotection. The mixture was partitioned between aqueous Sodium bicarbonate and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate. The combined organics were washed with water (1×), saturated aqueous NaCl (1×), dried over MgSO4 and reduced to minimum volume. The residue was then purified on silica gel in a similar fashion to obtain a second batch of product. The batched were combined and dissolved in a mixture of methanol and water then lyophilized to give 180 mg (33%) (2S)-1-({4-[3-(5-amino-6-methoxypyrazin-2-yl)-1-(2,2-difluoroethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-ol (I-1) as a fluffy white solid. 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 8.05-8.15 (m, 2H), 7.83 (s, 1H), 6.65 (d, J=5.31 Hz, 1H), 6.27 (tt, J=54.95, 3.79 Hz, 1H), 5.73 (br. t, J=4.93 Hz, 1H), 5.34 (br. s., 2H), 4.58 (td, J=14.72, 3.66 Hz, 2H), 3.81 (br. s., 1H), 3.76 (s, 3H), 3.54 (br. s., 1H), 3.27-3.41 (br. m, 1H), 3.06-3.23 (br. m, 1H), 1.08 (d, J=6.32 Hz, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](=[O:33])[NH:29][CH:30]([CH3:32])[CH3:31])=[C:24]([F:34])[CH:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C>O1CCOCC1>[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[NH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:33])[NH:29][CH:30]([CH3:32])[CH3:31])=[C:24]([F:34])[CH:23]=1
Reactant: CC(C)NC(=O)c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)OC(C)(C)C)CC3)cc1F
Solvent: C1COCCO1
Product: CC(C)NC(=O)c1ccc(CNc2c(Cl)ccc3c2CCNCC3)cc1F
Yield: 100 %

Procedure:
Use a method similar to the General Procedure 1-4 to deprotect 3-tert-butoxycarbonyl-7-chloro-6-(3-fluoro-4-isopropylcarbamoyl-benzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.406 g, 0.83 mmol) in 1,4-dioxane (12.8 mL). Purify by SCX chromatography eluting with dichloromethane and dichloromethane/2M ammonia in methanol (1:1) followed by chromatography on silica gel (40 g RediSep column) eluting with dichloromethane/2M ammonia in methanol (99:1 to 90:10 over 30 min) and then dichloromethane/2M ammonia in methanol (90:10 over 30 min; 35 mL/min) to afford 7-chloro-6-(3-fluoro-4-isopropylcarbamoyl-benzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a colorless oil (0.3237 g). MS (ES+) m/z: 390.1 (M+H)+. Use a method similar to the General Procedure 2-1, using 7-chloro-6-(3-fluoro-4-isopropylcarbanzoyl-benzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.301 g, 0.772 mmol) to provide the title compound as a beige solid (0.328 g, 84%). MS (ES+) m/z: 390.1 (M+H)+.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([C:22](=[O:39])[CH:23]([N:25]2[CH2:30][CH2:29][C:28]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=3)([OH:31])[CH2:27][CH2:26]2)[CH3:24])[CH:7]=[C:8]([F:21])[C:9]=1[O:10][Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13]>C(O)C>[F:3][C:4]1[CH:5]=[C:6]([C@@H:22]([OH:39])[C@H:23]([N:25]2[CH2:26][CH2:27][C:28]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=3)([OH:31])[CH2:29][CH2:30]2)[CH3:24])[CH:7]=[C:8]([F:21])[C:9]=1[O:10][Si:11]([CH:15]([CH3:17])[CH3:16])([CH:12]([CH3:14])[CH3:13])[CH:18]([CH3:20])[CH3:19]
Reactant: CC(C(=O)c1cc(F)c(O[Si](C(C)C)(C(C)C)C(C)C)c(F)c1)N1CCC(O)(c2ccc(Cl)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)[Si](Oc1c(F)cc([C@@H](O)[C@@H](C)N2CCC(O)(c3ccc(Cl)cc3)CC2)cc1F)(C(C)C)C(C)C
Reaction time: 0.17 h
Yield: 56.2 %

Procedure:
A mixture of sodium borohydride (0.058 g, 1.40 mmol) and ethanol (5 mL) was stirred 10 min and then 1-(3,5-difluoro-4-triisopropylsilyloxyphenyl)-2-(4-(-4-chlorophenyl)-4-hydroxypiperidin-1-yl)-propan-1-one (0.76 g, 1.38 mmol in 20 mL of ethanol) was added. The reaction was stirred at ambient temperature over the weekend. The white solid which precipitated was collected by filtration and dried to yield 0.43 g (57%) of (1R*,2R*)-1-(3,5-difluoro-4-triisopropylsilyloxyphenyl)-2-(4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)-propan-1-ol which was suitable for use without further purification and had: mp 192-192.5° C. Analysis calculated for C29H42ClF2NO3Si.0.25 H2O: C, 62.35; H, 7.67; N, 2.51. Found: C, 62.37; H, 7.81; N, 2.73.
Reaction SMILES: [H-].[K+].[CH2:3]([OH:11])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.I[CH2:13][Sn:14]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH2:17][CH3:18]>C1COCC1>[CH2:23]([Sn:14]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:13][O:11][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:24][CH2:25][CH3:26]
Reactant: OCCc1ccccc1
Reactant: CCCC[Sn](CI)(CCCC)CCCC
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)COCCc1ccccc1
Temperature: 0 °C
Yield: 87.7 %

Procedure:
Potassium hydride (35 wt % in mineral oil, 2.29 g, 20.0 mmol, 2.0 equiv) was stirred in hexanes (10 mL) for 5 min, and then stirring was stopped and the solid allowed to settle. Most of the hexanes layer was removed by pipette, and the residual solvent removed under vacuum. The resulting dry KH powder was suspended in THF (20 mL) and phenethyl alcohol (1.22 g, 10.0 mmol, 1 equiv) was added (causing gas evolution). After stirring at 23° C. for 2.5 h, a thick precipitate formed. The mixture was cooled to 0° C. and a solution of iodomethyltributyltin (prepared according to Seitz, et al., Synth. Commun. (1983), vol. 13, 129) (6.46 g, 15.0 mmol, 1.5 equiv) in THF (15 mL) was added via cannula over 10 min. The mixture was warmed to 23° C. for 3.5 h, and then cooled to −78° C. The reaction was quenched with saturated aqueous NH4Cl solution (25 mL), warmed to 23° C., and extracted with Et2O (200 mL). The organic extracts were dried over MgSO4, filtered, and concentrated. Purification of the residue by flash column chromatography (hexanes) afforded tributyl-phenethyloxymethyl-stannane (3.73 g, 88% yield) as a colorless liquid. Rf=0.63 (4% EtOAc in hexanes). IR (cm−1) 2955, 2924, 2852, 1464, 1082. 1H NMR (CDCl3) δ0.90 (t, J=7.2, 15H), 1.31 (sextet, J=7.4, 6H), 1.50 (quintet, J=7.4, 6H), 2.86 (t, J=7.0, 2H), 3.54 (t, J=7.0, 2H), 3.75 (s, 2H), 7.15-7.33 (m, 5H). 13C NMR (CDCl3) δ9.01, 13.66, 27.28, 29.12, 36.36, 61.94, 76.38, 125.94, 128.17, 128.91, 139.50.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][C:9]1=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)CCCN=C=NCC.N1(O)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:48][CH2:49][C:50]1[C:59](=[O:60])[C:58]2[C:53](=[N:54][CH:55]=[CH:56][CH:57]=2)[N:52]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[C:51]=1[C:67]1[O:68][CH:69]=[CH:70][N:71]=1>C(Cl)Cl>[O:68]1[CH:69]=[CH:70][N:71]=[C:67]1[C:51]1[N:52]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[C:53]2[C:58]([C:59](=[O:60])[C:50]=1[CH2:49][NH:48][C:14]([C:11]1[CH:12]=[CH:13][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:9](=[O:17])[CH:10]=1)=[O:16])=[CH:57][CH:56]=[CH:55][N:54]=2
Reactant: O=C(O)c1ccn(Cc2ccccc2)c(=O)c1
Reactant: NCc1c(-c2ncco2)n(-c2ccccc2)c2ncccc2c1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCc1c(-c2ncco2)n(-c2ccccc2)c2ncccc2c1=O)c1ccn(Cc2ccccc2)c(=O)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
In a 50 mL round-bottomed flask, 1-benzyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid (21 mg, 0.93 mmol), 1-(3-dimethylaminopropyl-3-ethylcarbodiimide (23.0 mg, 0.148 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (20.0 mg, 0.148 mmol) and N,N-diisopropylethylamine were combined with methylene chloride (5 mL). The reaction mixture was stirred at room temperature for 10 min. After this time, 3-(aminomethyl)-2-(oxazol-2-yl)-1-phenyl-1,8-naphthyridin-4(1H)-one (intermediate B) was added. The reaction mixture was stirred at room temperature over the weekend. The reaction mixture was partitioned between methylene chloride and water. The organic phase was dried over sodium sulfate, then filtered and concentrated. The crude product was purified using flash chromatography (Isco, 0% ethyl acetate-hexanes ramped to 70% ethyl acetate-hexanes) to afford 1-Benzyl-2-oxo-1,2-dihydro-pyridine-4-carboxylic acid (2-oxazol-2-yl-4-oxo-1-phenyl-1,4-dihydro-[1,8]naphthyridin-3-ylmethyl)-amide as a light brown powder (12 mg). MS calcd. for C31H24N5O4 [(M+H)+] 530.2, obsd. 530.3
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]2[C:7](=[C:8]([CH3:14])[C:9]([OH:13])=[CH:10][CH:11]=2)[O:6][C:5](=[O:15])[CH:4]=1.[CH3:16][O-:17].[Na+].Cl>CO.C(O)(C)C>[OH:13][C:9]1[C:8]([CH3:14])=[C:7]2[C:12]([C:3]([CH2:2][O:17][CH3:16])=[CH:4][C:5](=[O:15])[O:6]2)=[CH:11][CH:10]=1
Reactant: C[O-]
Reactant: Cc1c(O)ccc2c(CCl)cc(=O)oc12
Agent: Cl
Agent: [Na+]
Solvent: CC(C)O
Solvent: CO
Product: COCc1cc(=O)oc2c(C)c(O)ccc12
Temperature: 25 °C

Procedure:
A mixture of 4-chloromethyl-7-hydroxy-8-methylcoumarin (2.00 g, 8.90 mmol) and sodium methoxide (12.0 g, 222 mmol) in methanol (400 mL) was refluxed overnight. The solution was allowed to cool to room temperature, acidified to pH 0-1 with 5-6N HCl in isopropanol and evaporated. The residue was azeotroped with toluene several times to give crude product 7-hydroxy-4-methoxymethyl-8-methylcoumarin, a yellow oil. 1H NMR (CD3OD): δ 7.38 (d, J=8.5 Hz, 1H), 6.82 (d, J=8.8 Hz, 1H), 6.29 (s, 1H), 4.66 (s, 2H), 3.51 (s, 3H), 2.26 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[S:11](=[O:13])(=[O:12])[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]([OH:14])=[C:3]1[C:15]([NH:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][N:23]=1)=[O:16].[C:24](=[O:36])([O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[O:25][CH:26](Cl)[CH3:27]>>[CH:30]1([O:29][C:24]([O:25][CH:26]([O:14][C:4]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=3[S:11](=[O:13])(=[O:12])[N:2]([CH3:1])[C:3]=2[C:15]([NH:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][N:23]=2)=[O:16])[CH3:27])=[O:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CC(Cl)OC(=O)OC1CCCCC1
Reactant: CN1C(C(=O)Nc2ccccn2)=C(O)c2ccccc2S1(=O)=O
Product: CC(OC(=O)OC1CCCCC1)OC1=C(C(=O)Nc2ccccn2)N(C)S(=O)(=O)c2ccccc21

Procedure:
By the procedure of Example 6, piroxicam (3.00 g, 9.1 mmol) and alpha-chloroethyl cyclohexyl carbonate (5.37 g, 26.1 mmol) were converted to chromatographed title product, 3.85 g pale yellow foam (7.7 mmol, 84.7%) which gave 2.45 g white crystals from toluene/hexane: mp 142°-144° C.; IR (KBr) 1749, 1682 cm-1 ; 1H NMR (CDCl3) delta 0.99-1.93 (br m, 10 H), 1.76 (d, J=6 Hz, 3H), 3.11 (s, 3H), 4.40-4.58 (br m, 1H), 6.36 (q, J=6 Hz, 1H), 7.06-7.18 (m, 1H), 7.62-7.97 (m, 5H), 8.32-8.43 (m, 2H), 9.40 (br s, 1H); precise mass calcd for C24H27N3O7S m/e 501.1576, found 501.1613.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:11]1[C:12]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)=[CH:21][C:13]=2[S:14][C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]>CN(C)C=O>[O:7]([C:11]1[C:12]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)=[CH:21][C:13]=2[S:14][C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: CCOC(=O)c1sc2cc(OCc3cccnc3)ccc2c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc2cc(OCc3cccnc3)ccc2c1Oc1ccccc1
Temperature: 75 °C
Yield: 17 %

Procedure:
Phenol (108 mg, 1.15 mmol) was added to a stirred suspension of sodium hydride (46 mg of 60% dispersion in mineral oil, 1.15 mmol) in anhydrous dimethylformamide (1 ml), under a nitrogen atmosphere. Ethyl 3-chloro-6-(3-pyridylmethoxy)benzo[b]thiophene-2-carboxylate (Preparation 4, 200 mg, 0.58 mmol) was added to the mixture after 30 minutes, and the mixture was then heated to 75° C. for 48 hours. The reaction was partitioned between ethyl acetate and water. The organics were separated and washed with water, dried (magnesium sulfate) and evaporated under reduced pressure. The residue was flash chromatographed on silica gel using diethyl ether as eluant. The isolated product was crystallised from hexane to give the title compound as a colourless solid (40 mg).
Reaction SMILES: CO[C:3]1[N:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([C:21]1[S:22][CH:23]=[CH:24][CH:25]=1)[C:7](C1C=CC(C=O)=CC=1)=[N:8]2.Cl.Cl.N1CCC(C2N=C(C3C=CC=CN=3)NN=2)CC1.C(N(CC)CC)C.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>[Cl-].[NH4+].CN(C=O)C>[S:22]1[CH:23]=[CH:24][CH:25]=[C:21]1[C:6]1[CH:7]=[N:8][C:9]2[C:4]([CH:5]=1)=[CH:3][N:12]=[CH:11][CH:10]=2
Reactant: COc1nccc2nc(-c3ccc(C=O)cc3)c(-c3cccs3)cc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: c1csc(-c2cnc3ccncc3c2)c1
Temperature: 23 °C
Reaction time: 8 h

Procedure:
A 25 ml RB flask with a stirring bar was charged with 4-[5-methoxy-3-(2-thienyl)-1,6-naphthyridin-2-yl]benzaldehyde (1-5) (62 mg, 0.18 mmol), followed by 2-(3-piperidin-4-yl-1H-1,2,4-triazol-5-yl)pyridine dihydrochloride (1-6) (82 mg, 0.36 mmol), anhydrous DMF (1.0 mL), triethylamine (72 mg, 0.716 mmol), and acetic acid (107 mg, 1.79 mmol). Then sodium triacetoxyborohydride (76 mg, 0.36 mmol) was added in one portion, and the resulting pale yellow solution was stirred at 23° C. overnight. The mixture was diluted with sat. ammonium chloride solution (10 mL), extracted twice with ethyl acetate (10 mL). The crude mixture was purified by column chromatography on silica gel (0-30% methanol/dichloromethane) to give 5-methoxy-2(4-{[4-5-pyridin-2-yl-4H-1,2,4-triazol)piperidin-1-yl]methyl}phenyl)-3-(2-thienyl)-1,6-naphthyridine (1-7). 1H NMR (CDCl3, ppm) δ: 8.54 (bs, 1H), 8.51 (s,1H), 8.10 (d, J=6.0 Hz, 1H), 8.01 (d, J=7.8 Hz, 1H), 7.68 (t, J=7.7 Hz, 1H), 7.42 (d, J=8.0 Hz, 2H), 7.37 (d, J=6.9 Hz, 1H), 7.29 (d, J=8.0 Hz, 2H), 7.25 (t, J=3.4 Hz, 1H), 7.19 (d, J=5.1 Hz, 1H), 7.15 (s, 1H), 6.81 (t, J=3.6 Hz, 1H), 6.68 (d, J=3.1 Hz, 1H), 4.05 (s, 3H), 3.98 (s, 2H), 3.35 (s, 1H), 3.25 (bs, 2H), 3.02 (bs, 2H), 2.75 (bs, 2H), 2.19 (bs, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14]([C:16]2[S:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[CH:17]=2)=[O:15])[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)([O-])=O.[CH:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:26]1([C:25]2[NH:10][C:9]3[CH:8]=[CH:7][C:6]([NH:13][C:14]([C:16]4[S:20][C:19]5[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=5[CH:17]=4)=[O:15])=[CH:5][C:4]=3[N:1]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=Cc1ccccc1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1cc2ccccc2s1
Product: O=C(Nc1ccc2[nH]c(-c3ccccc3)nc2c1)c1cc2ccccc2s1

Procedure:
Compound 201 was prepared according to the procedure similar to that described in Scheme III from N-(3,4-dinitrophenyl)benzo[b]thiophene-2-carboxamide and benzaldehyde. 1H NMR (500 MHz, CD3OD) δ 8.18 (d, J=2 Hz, 1H), 8.14 (s, 1H), 8.06 (d, J=8 Hz, 2H), 7.91 (m, 2H), 7.85 (d, J=8.5 Hz, 1H), 7.73 (d, J=8.5 Hz, 1H), 7.60 (d, J=8.5 Hz, 1H), 7.53 (m, 3H), 7.44 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][N:14](C(=O)C4C(Cl)=CC=CC=4Cl)[C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1.N.C(O)(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:28])=[O:29])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(C(=O)c3c(Cl)cccc3Cl)c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Agent: N
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Temperature: 100 °C

Procedure:
To a high pressure vessel is added compound 9 (1.70 kg, 2.567 mol) in THF (5 L), followed by an ammonia/isopropyl alcohol solution (30.80 mol of ammonia in 12 L of isopropyl alcohol). The mixture is heated to 100° C. overnight. When the reaction is completed, the solvents are removed in vacuum and the residue is dissolved in isopropanol. Compound 10 is isolated and further purified by recrystallization using a mixture of THF (7 L) and isopropanol (14 L). Yield: 0.763 kg (60.7%).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([CH2:13][N:14]3[C:23]4[N:19]([C:20]([C:24]5[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=5)=[N:21][N:22]=4)[CH2:18][CH2:17][CH2:16][CH2:15]3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:30][N:31](C=O)C>[C-]#N.[Zn+2].[C-]#N>[N:27]1[CH:28]=[CH:29][C:24]([C:20]2[N:19]3[C:23]([N:14]([CH2:13][C:10]4[N:11]=[N:12][N:8]([C:4]5[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=5)[C:30]#[N:31])[N:9]=4)[CH2:15][CH2:16][CH2:17][CH2:18]3)=[N:22][N:21]=2)=[CH:25][CH:26]=1
Reactant: CN(C)C=O
Reactant: Ic1cccc(-n2nnc(CN3CCCCn4c(-c5ccncc5)nnc43)n2)c1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cccc(-n2nnc(CN3CCCCn4c(-c5ccncc5)nnc43)n2)c1

Procedure:
The title compound is prepared from 8-[2-(3-iodo-phenyl)-2H-tetrazol-5-ylmethyl]-3-pyridin-4-yl-5,6,7,8-tetrahydro-4H-1,2,3a,8-tetraaza-azulene (1 mmol), zinc cyanide (1.1 mmol), palladium (0) tetrakis-triphenylphosphine (0.05 mmol) in DMF (5 mL) at 80° C. overnight.
Reaction SMILES: [Br:1]Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:22]([C:24]1[CH:29]=[C:28]([CH2:30]O)[CH:27]=[CH:26][N:25]=1)#[N:23]>C(Cl)Cl>[C:22]([C:24]1[CH:29]=[C:28]([CH2:30][Br:1])[CH:27]=[CH:26][N:25]=1)#[N:23]
Reactant: N#Cc1cc(CO)ccn1
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: N#Cc1cc(CBr)ccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
Bromine (6.88 g, 43.1 mmol) is added dropwise to a solution of triphenylphosphine (11.3 g, 43.1 mmol) in 280 mL of CH2Cl2 at 0° C. The mixture is tirred for 30 minutes at 0° C. At this time, 2-cyano-4-(hydroxymethyl)-pyridine (4.82 g, 35.9 mmol) is added and the resulting mixture is stirred for 2 hours at room temperature. The reaction mixture is diluted with CH2Cl2 and washed with water (2x) and saturated NaCl solution. The organic layer is dried with MgSO4, filtered and concentrated. The crude product is purified by column chromatography eluting in a gradient of 20% EtOAc/hexanes to 30% EtOAc/hexanes to afford the title compound (6.40 g, 32.5 mmol) as an oil.
Reaction SMILES: Br[C:2]1[C:6]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)=[N:5][NH:4][C:3]=1[NH2:12].[C:13]([N:21]=[C:22]=[S:23])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCOCC1>[S:8]1[CH:9]=[CH:10][CH:11]=[C:7]1[C:6]1[C:2]2[S:23][C:22]([NH:21][C:13](=[O:20])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[N:12][C:3]=2[NH:4][N:5]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Nc1[nH]nc(-c2cccs2)c1Br
Solvent: C1COCCO1
Product: O=C(Nc1nc2[nH]nc(-c3cccs3)c2s1)c1ccccc1
Temperature: 90 °C
Reaction time: 17 h
Yield: 80.7 %

Procedure:
To a stirring solution of 4-bromo-5-thiophen-2-yl-2H-pyrazol-3-ylamine (50 mg, 0.205 mmol) in dioxane (1 mL) was added benzoylisothiocyanate (30 μL, 0.225 mmol) dropwise. The reaction mixture was stirred at 90° C. for 17 h. It was then cooled to room temperature and partitioned between ethyl acetate and a saturated aqueous solution of sodium bicarbonate. The organic layer was washed twice with a saturated aqueous solution of sodium bicarbonate, then with brine, and adsorbed on silica gel. Purification on silica gel with 0-80% ethyl acetate in hexane as eluent provided 54 mg (80%) of N-(3-thiophen-2-yl-1H-pyrazolo[3,4-d]thiazol-5-yl)-benzamide as a beige solid. 1H-NMR (d6-DMSO) δ: 13.5 and 13.6 (2 broad s, 1H, NH+tautomer), 12.9 (broad s, 1H, NH), 8.1 (d, 2H), 7.68 and 7.85 (2 dd, 1H, tautomers), 7.66 (t, 1H), 7.58 (t, 2H), 7.34 and 7.53 ( 2 d, 1H, tautomers), 7.17 and 7.22 (2 t, 1H, tautomers); HPLC/MS m/z: 327 [MH]+.
Reaction SMILES: C(O)C1C=CC=CC=1.[N+](C1C=C(C=CC=1)C(Cl)=O)([O-])=O.[N+:21]([C:24]1[CH:25]=[C:26]([CH:37]=[CH:38][CH:39]=1)[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])([O-])=O>CCOCC.C(O)C.[Pt]=O>[NH2:21][C:24]1[CH:25]=[C:26]([CH:37]=[CH:38][CH:39]=1)[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28]
Reactant: O=C(OCc1ccccc1)c1cccc([N+](=O)[O-])c1
Agent: O=[Pt]
Agent: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: CCO
Solvent: OCc1ccccc1
Solvent: CCOCC
Product: Nc1cccc(C(=O)OCc2ccccc2)c1
Temperature: 25 °C

Procedure:
Benzyl alcohol (10 g, 92.6 mmole) was treated with a solution of m-nitrobenzoyl chloride (17.5 g, 94.5 mmole) in ether (50 ml) added dropwise. The mixture was stirred at room temperature for eighteen hours, then washed twice with aqueous sodium bicarbonate, dried over sodium sulfate, and filtered. The filtrate was evaporated to dryness in vacuo and the residue chromatographed on silica gel eluted with 1:1 CH2Cl2 :hexane. The product fractions were combined and evaporated to dryness in vacuo. A portion (5.2 g, 20.2 mmole) of the resulting benzyl m-nitrobenzoate was dissolved in ethanol and hydrogenated over platinum oxide (70 mg) at 50 psi of H2. The resulting mixture was filtered and evaporated to dryness in vacuo to give benzyl m-aminobenzoate.