Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([Br:8])[CH:2]=1.CN(C)C=O.N1C=CN=C1.[CH3:19][C:20]([Si:23]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)Cl)([CH3:22])[CH3:21]>O>[Br:8][C:3]1[CH:4]=[CH:5][C:6]([O:7][Si:23]([C:20]([CH3:22])([CH3:21])[CH3:19])([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:1][CH:2]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: Oc1ccc(Br)cc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](Oc1ccc(Br)cc1)(c1ccccc1)c1ccccc1
Yield: 95.1 %

Procedure:
80.89 g of p-bromophenol, 400 ml of dimethylformamide, 31.18 g of imidazole and 125.89 g of 1,1-dimethyl-ethyl-diphenylchlorosilane were stirred for 2 hours at ambient temperature and the reaction medium was poured into 2 liters of water. Extraction was carried out with ethyl acetate, followed by decanting, drying and evaporating under reduced pressure. After crystallization from pentane, separation was carried out, followed by drying to obtain 179.24 g of the expected product with a Rf=0.53 (thin layer chromatography, support: silica, eluant: cyclohexane/AcOEt 95/5) and a melting point of 56° C.
Reaction SMILES: [Br:1][C:2]1[C:3](O[C:6](=[O:8])[CH:7]=1)=[O:4].C([O-])(=O)C.[Na+].O.[NH2:15][NH2:16].O>C(O)(=O)C.O>[Br:1][C:2]1[C:3](=[O:4])[NH:15][NH:16][C:6](=[O:8])[CH:7]=1
Reactant: O=C1C=C(Br)C(=O)O1
Reactant: NN
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=c1cc(Br)c(=O)[nH][nH]1
Temperature: 100 °C
Yield: 37 %

Procedure:
A mixture of bromomaleic anhydride (50 g, 283 mmol) and sodium acetate (76.5 g, 562 mmol) in 40% acetic acid/water (750 ml) was treated with hydrazine monohydrate (16.5 ml, 339 mmol) at room temperature under nitrogen. The brown solution was stirred and heated at 100° C. for 18 hours. Upon cooling the mixture was poured into water (1 l) and extracted with ethyl acetate (6×500 ml). The combined extracts were dried (MgSO4), filtered and evaporated to afford the title compound (20 g, 37%) as an orange solid. 1H NMR (250 MHz, d6-DMSO) δ 7.68 (1H, br s). MS (ES+) m/e 193 [MH]+, 191 [MH]+. This material was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[H-].[Na+].F[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1>CC(N(C)C)=O>[CH3:1][C:2]1[N:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: Fc1ccccn1
Reactant: Cc1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1nc2ccccc2n1-c1ccccn1
Temperature: 100 °C
Reaction time: 0.83 h
Yield: 71.3 %

Procedure:
To a stirred solution of 2-methyl-1H-benzimidazole (6.61 g, 50 mmol) in dimethylacetamide (40 ml) at room temperature under a nitrogen atmosphere was added sodium hydride (2.40 g, 60 mmol) in portions during 15 min. At the point where the reaction mixture was too viscous to stir, the reaction was diluted with 100 ml of dimethylacetamide. After 50 min., a solution of 2-fluoropyridine (5.83 g, 60 mmol) in dimethylacetamide (30 ml) was added during 15 min. The resulting mixture was heated at 100° C. for 2 h and then to reflux for about 4 h. Volatiles were removed by evaporation under reduced pressure. The residue was dissolved into ethyl acetate (200 ml) and washed consecutively with water (3×100 ml) and brine (100 ml). The organic layer was dried (magnesium sulfate) and concentrated to dryness. Purification by column chromatography (silica gel, 300 g; n-hexane/ethyl acetate (17/3)) yielded 7.46 g (71%) of the titled compound as a light yellow liquid. 1H-NMR (CDCl3) δ: 8.72-8.67 (1H, m), 7.95 (1H, ddd, J=7.7, 7.7, 1.8 Hz), 7.78-7.74 (1H, m), 7.49-7.36 (3H, m), 7.32-7.20 (2H, m), 2.69 (3H, s).
Reaction SMILES: CS([C:4]1[S:5][C:6]2[CH:12]=[C:11]([CH2:13][N:14]3[C:18]4=[N:19][CH:20]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:22]=[C:17]4[N:16]=[CH:15]3)[CH:10]=[CH:9][C:7]=2[N:8]=1)=O.CS(C1SC2C=C(CN3C4=NC=C(C(OC)=O)C=C4N=C3)C=CC=2N=1)(=O)=O.[NH2:54][C@@H:55]1[CH2:60][CH2:59][CH2:58][CH2:57][C@H:56]1[OH:61].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[OH:61][C@@H:56]1[CH2:57][CH2:58][CH2:59][CH2:60][C@H:55]1[NH:54][C:4]1[S:5][C:6]2[CH:12]=[C:11]([CH2:13][N:14]3[C:18]4=[N:19][CH:20]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:22]=[C:17]4[N:16]=[CH:15]3)[CH:10]=[CH:9][C:7]=2[N:8]=1
Reactant: COC(=O)c1cnc2c(c1)ncn2Cc1ccc2nc(S(C)=O)sc2c1
Reactant: N[C@@H]1CCCC[C@H]1O
Agent: COC(=O)c1cnc2c(c1)ncn2Cc1ccc2nc(S(C)(=O)=O)sc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cnc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Temperature: 100 °C
Reaction time: 19 h

Procedure:
A 2:1 mixture of methyl 3-((2-(methylsulfinyl)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-carboxylate and methyl 3-((2-(methylsulfonyl)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-carboxylate (360 mg) from Step 4 of this Example was dissolved in anhydrous DMA (10 mL), and (1R,2R)-(−)-2-aminocyclohexanol (322 mg, 2.79 mmol) and DIEA (360 mg, 2.79 mmol) were added. The reaction vessel was sealed and the mixture was heated with stirring at 100° C. for 19 h. LCMS indicated the reaction was not complete. To the reaction mixture was added additional (1R,2R)-(−)-2-aminocyclohexanol (100 mg, 0.870 mmol) and the reaction vessel was sealed and the mixture was heated at 100° C. for a further 15 h. After the reaction mixture was cooled to rt, one half of the reaction mixture was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenyl column as the stationary phase to afford methyl 3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-carboxylate (19 mg) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.96 (d, J=7.3 Hz, 1H), 8.76 (m, 1H), 8.54 (m, 1H), 7.99 (br s, 1H), 7.66 (d, J=7.2 Hz, 1H), 7.16-7.33 (m, 2H), 5.51 (br s, 2H), 4.76 (br s, 1H), 3.89 (s, 3H), 3.30-3.50 (m, 2H), 2.02 (m, 1H), 1.86 (m, 1H), 1.50-1.70 (m, 2H), 1.10-1.30 (m, 4H). LCMS (ESI) m/z 438 (M+H)+.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH2:32][CH3:33])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[NH2:77][CH:78]1[CH2:83][CH2:82][N:81]([C:84]([O:86][C:87]([CH3:90])([CH3:89])[CH3:88])=[O:85])[CH2:80][CH2:79]1>CN(C)C=O>[C:87]([O:86][C:84]([N:81]1[CH2:80][CH2:79][CH:78]([NH:77][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:22]([NH:21][C:19]3[N:18]=[CH:17][C:8]4[N:9]([CH3:16])[C:10](=[O:15])[C:11]([F:13])([F:14])[CH2:12][N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[C:7]=4[N:20]=3)=[C:23]([O:31][CH2:32][CH3:33])[CH:24]=2)[CH2:83][CH2:82]1)=[O:85])([CH3:90])([CH3:89])[CH3:88]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CCOc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.17 h
Yield: 85.7 %

Procedure:
To a mixture of 0.0905 g (0.196 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethoxy-benzoic acid (I-214) and 6 mL of dimethylformamide was added 0.0418 g (0.310 mmole) of 1-hydroxybenzotriazole, 0.1146 g (0.302 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.1484 g (1.148 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0624 g (0.299 mmole) of 4-amino-1-Boc-piperidine was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-90:10) gave 0.1081 g of 4-[4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethoxy-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester (I-221) as a white solid.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[OH:28][C:29]1([CH2:33][C:34](OCC)=[O:35])[CH2:32][CH2:31][CH2:30]1>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:34](=[O:35])[CH2:33][C:29]5([OH:28])[CH2:32][CH2:31][CH2:30]5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: CCOC(=O)CC1(O)CCC1
Agent: Cl
Product: O=C(CC1(O)CCC1)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (58 mg, 52%), MS (ISP) m/z=443.5 [(M+H)+], mp 155° C., was prepared in accordance with the general method of example 2 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and ethyl 2-(1-hydroxy-cyclobutyl)-acetate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH3:9][C:10]1([CH3:24])[C:15]2[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][C:14]=2[NH:13][C:12](=[O:23])[O:11]1>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:17]2[CH:18]=[CH:19][C:14]3[NH:13][C:12](=[O:23])[O:11][C:10]([CH3:24])([CH3:9])[C:15]=3[CH:16]=2)=[CH:6][CH:7]=1
Reactant: Nc1ccc(Br)cn1
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Product: CC1(C)OC(=O)Nc2ccc(-c3ccc(N)nc3)cc21

Procedure:
Prepared according to procedure B from 2-amino-5-bromopyridine and (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid. White crystals, mp 257-259° C. 1H-NMR (DMSO-d6) δ 10.20 (s, 1H), 8.22 (d, 1H, J=2.38 Hz) 7.69, 7.66 (dd, 1H, J=2.5, 2.5 Hz), 7.42 (m, 2H), 6.89 (d, 1H, J=8.8 Hz), 6.49 (d, 1H, J=8.64 Hz), 6.02 (s, 2H), 1.64 (s, 6H), MS m/z 269 M+. Anal. Calcd. For C15H15N3O2.17H2O: C, 66.15; H, 5.68; N, 15.43. Found: C, 66.10; H, 5.81; N, 15.02.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]1[N:8]=[CH:7][N:6]=[C:5]([CH2:9][N:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=3)[C:12]([C:20](O)=[O:21])=[CH:11]2)[C:4]=1[CH3:23].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.Cl.[F:51][CH2:52][CH2:53][NH2:54]>C(Cl)Cl>[CH3:24][N:2]([CH3:1])[C:3]1[N:8]=[CH:7][N:6]=[C:5]([CH2:9][N:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=3)[C:12]([C:20]([NH:54][CH2:53][CH2:52][F:51])=[O:21])=[CH:11]2)[C:4]=1[CH3:23]
Reactant: NCCF
Reactant: Cc1cnc2c(C(=O)O)cn(Cc3ncnc(N(C)C)c3C)c2c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cnc2c(C(=O)NCCF)cn(Cc3ncnc(N(C)C)c3C)c2c1
Temperature: 25 °C
Yield: 14.1 %

Procedure:
See FIG. 23(d). 1-((6-(dimethylamino)-5-methylpyrimidin-4-yl)methyl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (75 mg, 0.23 mmol) was taken in a thermal reactor. DCM (5 mL) was added to get a suspension. Triethyl amine (0.064 mL, 0.46 mmol) was added followed by the addition of 1-Propanephosphonic acid cyclic anhydride (0.274 mL, 0.46 mmol). 2-fluoroethanamine hydrochloride (22.94 mg, 0.23 mmol) was added and stirred at RT for ON. After the completion of the reaction, reaction mixture was concentrated and dissolved in DCM:MeOH. This crude compound was subjected for reverse phase purification. The final compound obtained 1-((6-(dimethylamino)-5-methylpyrimidin-4-yl)methyl)-N-(2-fluoroethyl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (12.00 mg, 14.05%) as a white solid. ES+MS m/z: 371 (M+). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.27 (s, 3 H ) 2.40 (s, 3 H ) 2.95 (s, 6 H ) 3.66 (d, J=5.46 Hz, 1 H ) 3.75 (d, J=5.27 Hz, 1 H ) 4.49 (t, J=4.99 Hz, 1 H ) 4.65 (t, J=4.99 Hz, 1 H ) 5.54 (s, 2 H ) 7.75 (s, 1 H ) 8.13 (s, 1 H ) 8.22 (s, 1 H ) 8.34 (s, 1 H ) 8.88 (t, J=5.84 Hz, 1 H).
Reaction SMILES: [Se](=O)=O.[O:4]1CCOCC1.[O:10]=[C:11]1[NH:15][C:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][S:12]1>O>[O:10]=[C:11]1[NH:15][C:14]([C:16](=[O:4])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][S:12]1
Reactant: C1COCCO1
Reactant: CCOC(=O)Cc1csc(=O)[nH]1
Agent: CCOC(=O)Cc1csc(O)n1
Agent: O=[Se]=O
Solvent: O
Product: CCOC(=O)C(=O)c1csc(=O)[nH]1

Procedure:
To a solution prepared by heating a mixture of selenium dioxide (0.33 g.), dioxane (15 ml.) and water (0.3 ml.) at 110° C. with stirring was added ethyl 2-(2-oxo-2,3-dihydro-1,3-thiazol-4-yl)acetate, which can be represented as ethyl 2-(2-hydroxy-1,3-thiazol-4-yl)acetate, (0.56 g.) without heating, and then the mixture was stirred for 30 minutes at 110° C. After the reaction, the reaction liquid was separated and the residue was washed with a small amount of dioxane. The reaction liquid and the washings were combined together, and the solvents were distilled off. To the residue was added ethyl acetate, and the mixture was washed with water and dried over magnesium sulfate. The solvent was distilled off from the mixture to give a solid of ethyl 2-(2-oxo-2,3-dihydro-1,3-thiazol-4-yl)-glyoxylate, which can be represented as ethyl 2-(2-hydroxy-1,3-thiazol-4-yl)glyoxylate, (0.55 g.)
Reaction SMILES: S(=O)(=O)(O)[OH:2].[S:6]1[C:10]2[CH:11]=[C:12]([NH:15][C:16](=[O:20])[CH:17]=NO)[CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1>O>[S:6]1[C:10]2[C:9](=[CH:14][CH:13]=[C:12]3[C:11]=2[C:17](=[O:2])[C:16](=[O:20])[NH:15]3)[N:8]=[CH:7]1
Reactant: O=S(=O)(O)O
Reactant: O=C(C=NO)Nc1ccc2ncsc2c1
Solvent: O
Product: O=C1Nc2ccc3ncsc3c2C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
To a 1-L flask was added a magnetic stir bar, 85 g of sodium sulfate, and 100 mL of water. The mixture was magnetically stirred until all the solids were dissolved. To the resultant aqueous solution was added a solution of 6-aminobenzothiazole (4.96 g, 33.0 mmol) in 50 mL of 1N aqueous hydrochloric acid and 10 mL of ethanol. The mixture was stirred, and chloral (6.0 g, (36 mmol) was added. To the resultant solution was added a solution of hydroxyl amine hydrochloride (7.50 g, 108 mmol) in 30 mL of water. The final mixture was heated with stirring to a gentle boil until all solids dissappeared, and heating was continued for an additional 15 min. The flask was removed from the heat, and the solution was poured onto 500 g of ice. The mixture was stirred as the product precipatated from solution. The precipatate was collected by suction filtration, washed thoroughly with water, filtered, and air dried to provide 6.9 g (94%) of N-benzothiazol-6-yl-2-hydroxyimino-acetamide: 1H NMR (DMSO-d6): δ 12.2 (s, 1H), 10.4 (s, 1H), 9.2 (s, 1H), 8.5 (s, 1H), 7.9 (d, 1H), 7.7 (m, 1H), 7.7 (s, 1H); APCI-MS m/z 220 (M−H)−. To a 1-L 3-neck round bottom flask was placed a magnetic stir bar and 100 ml of concentrated sulfuric acid. The flask was fitted with a thermometer to monitor the temperature of the reaction. The sulfuric acid was heated to 100° C., and 10.0 g (45.2 mmol) of N-benzothiazol-6-yl-2-hydroxyimino-acetamide was added slowly. The solution was heated for ˜1 h, and the reaction mixture was poured into 750 g of ice and water. The residual reaction mixture in the reaction vessel was washed out with an additional 20 mL of cold water. The aqueous slurry was stirred for about 1 h and filtered. The solid was washed thoroughly with water, filtered, and air dried to yield 4.3 g (46%) of 6-H-1-thia-3,6-diaza-as-indacen-7,8-dione: 1H NMR (DMSO-d6): δ 11.1 (s, 1H), 9.2 (s, 1H), 8.2 (d, 1H), 7.0 (d, 1H); APCI-MS m/z 203 (M−H)−.
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[C:10]([C:22]#[N:23])=[C:11]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:12]2=[C:13]([CH:21]=1)[CH2:14][O:15][CH2:16]3.C(Cl)[Cl:25]>C(#N)C.[Cu](Cl)Cl>[Cl:25][C:9]1[C:10]([C:22]#[N:23])=[C:11]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:12]2=[C:13]([CH:21]=1)[CH2:14][O:15][CH2:16]3
Reactant: ClCCl
Reactant: N#Cc1c(N)cc2c3c(cccc13)COC2
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: N#Cc1c(Cl)cc2c3c(cccc13)COC2
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl nitrite (27.5 ml, 208 mmol) was added to a suspension of copper (II) chloride (22.5 g, 167 mmol) in anhydrous acetonitrile (500 mL) at room temperature under nitrogen atmosphere. The resulting dark green suspension was heated to the internal temperature of 65° C., and a solution of 5-amino-6-cyano-1H,3H benzo[de]isochromene (29.2 g, 139 mmol) in anhydrous acetonitrile (1000 mL) was added thereto. The reaction solution was stirred at 65° C. for 30 minutes, and then allowed to return to room temperature. The reaction solution was diluted with methylene chloride. The mixture was washed in succession with 1N aqueous hydrochloric acid solution and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography using methylene chloride, and dried under reduced pressure. The title compound was obtained as yellow solid material (27.7 g, 87%).
Reaction SMILES: N1C=CC=CC=1.C(B1OB(C=C)OB([CH:17]=[CH2:18])O1)=C.[OH:19][C:20]1[C:21]([N+:30]([O-:32])=[O:31])=[C:22]([CH:27]=[CH:28][CH:29]=1)[C:23]([O:25][CH3:26])=[O:24].N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[N+:30]([C:21]1[C:20]([O:19][CH:17]=[CH2:18])=[CH:29][CH:28]=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24])([O-:32])=[O:31]
Reactant: C=CB1OB(C=C)OB(C=C)O1
Reactant: COC(=O)c1cccc(O)c1[N+](=O)[O-]
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=COc1cccc(C(=O)OC)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 120 h
Yield: 75.1 %

Procedure:
A mixture of copper (II) acetate (11.98 g, 65.9 mmol) and dichloromethane (80 mL) were stirred at room temperature for 10 minutes, before the addition of 2,4,6-trivinyl-1,3,5,2,4,6-trioxatriborinane compound with pyridine (1:1) (10.63 g, 44.2 mmol, 0.67 eq), methyl 3-hydroxy-2-nitrobenzoate (U.S. Publication No. 2012/0035194 A1 [0202]) (13 g, 65.9 mmol), pyridine (26.7 mL, 330 mmol), and molecular sieves (1 g). The resulting deep blue mixture was stirred at room temperature for 5 days, with the reaction mixture opened to the air. The reaction mixture was filtered through a pad of CELITE®, washing with some dichloromethane. The filtrate was washed with 3M aqueous ammonium acetate (2×), water, brine, and then dried, filtered and concentrated in vacuo. The crude product mixture was purified via ISCO (0% to 20% of EtOAc/DCM in 15 minutes, 120 g column) to give methyl 2-nitro-3-(vinyloxy)benzoate (7.42 g, 33.2 mmol, 50.4% yield). HPLC: RT=2.487 min (H2O/MeOH with TFA, SunFire C18 3.5 μm, 2.1×30 mm, gradient=4 min, wavelength=220 nm); MS(ES):m/z=246 [M+Na]+; 1H NMR (400 MHz, chloroform-d) δ 7.77 (dd, J=7.8, 1.2 Hz, 1H), 7.55 (t, J=8.1 Hz, 1H), 7.38 (dd, J=8.4, 1.3 Hz, 1H), 6.61 (dd, J=13.6, 5.9 Hz, 1H), 4.95 (dd, J=13.6, 2.4 Hz, 1H), 4.69 (dd, J=5.9, 2.4 Hz, 1H), 3.93 (s, 3H), 1.56 (s, 1H), 0.03 (s, 1H).
Reaction SMILES: [NH:1]1[CH2:3][CH:2]1[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.[Cl:15][C:16]1[S:20][C:19]([C:21](Cl)=[O:22])=[CH:18][CH:17]=1>C(Cl)Cl>[Cl:15][C:16]1[S:20][C:19]([C:21]([N:1]2[CH2:3][CH:2]2[C:4]([O:6][CH3:7])=[O:5])=[O:22])=[CH:18][CH:17]=1
Reactant: COC(=O)C1CN1
Reactant: O=C(Cl)c1ccc(Cl)s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1CN1C(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 4.40 g (43.5 mmol) methyl aziridine-2-carboxylate and 13.5 ml (97.3 mmol) triethylamine in 30 ml methylene chloride is combined with 8.80 g (48.6 mmol) 5-chlorothiophenecarboxylic acid chloride in 30 ml methylene chloride while cooling with ice and subsequently after removal of the cooling bath stirred for 3 h at room temperature. Then the mixture is diluted with water, extracted with methylene chloride, dried with sodium sulphate, concentrated and purified by chromatography (silica gel, petroleum ether/ethyl acetate 80/15->80/20) to obtain the slightly contaminated title compound.
Reaction SMILES: O[C:2]1[C:3]([C:12]([OH:14])=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>>[NH:15]([C:2]1[C:3]([C:12]([OH:14])=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)c1cc2ccccc2cc1O
Reactant: Nc1ccccc1
Agent: Cl
Product: O=C(O)c1cc2ccccc2cc1Nc1ccccc1
Temperature: 170 °C
Reaction time: 16 h
Yield: 6.8 %

Procedure:
A mixture of 3-hydroxy-2-naphthoic acid (Aldrich cat. # H4600-7) (376 g, 2.0 mol) and aniline (376 ml, 4.1 mol) was heated at 170° C. with stirring under nitrogen for 16 hours. The resulting mixture, when hot, was poured into 1N HCl (2.5 ml), heated to 100° C., and stirred at this temperature for 5 minutes. The mixture, when hot, was filtrated and the solid was washed with 0.2N HCl (600 ml). The wet material was boiled and mechanically stirred with 0.5N sodium carbonate solution (6.0 ml) for 10 minutes, cooled and filtered. The reddish filtrate was treated dropwise with 5N HCl with stirring to ~pH 7. The resulting yellow precipitate was collected, washed with small amount of water and crystallized from ethanol (400 ml) to give 3-anilino-2-naphthoic acid (36 g, 7%). Rf 0.6 (silica gel, EM Art. 5715, 20% methanol/chloroform). MS (EI): m/z 264 (M).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[N:14]([CH3:17])[C:13](SC)=[N:12]3)[CH2:10][CH:9]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[O:8][C:5]2=[CH:6][CH:7]=1.[NH4+:27].[I-]>N.CCO>[NH2:27][C:13]1[N:14]([CH3:17])[C:15](=[O:16])[C:11]2([C:4]3[C:5](=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[O:8][CH:9]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[CH2:10]2)[N:12]=1
Reactant: CSC1=NC2(CC(c3ccc(Cl)cc3)Oc3ccc(Br)cc32)C(=O)N1C
Reactant: [NH4+]
Agent: N
Agent: [I-]
Solvent: CCO
Product: CN1C(=O)C2(CC(c3ccc(Cl)cc3)Oc3ccc(Br)cc32)N=C1N
Yield: 12.4 %

Procedure:
A solution of 6-bromo-2-(4-chlorophenyl)-1′-methyl-2′-(methylthio)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (300 mg, 0.67 mmol) and NH4I (194 mg, 1.33 mmol) in NH3/EtOH (5 mL, 1.5 N) was heated at 110° C. in a tube in a microwave reactor for 2-2.5 h. After cooling, the mixture was concentrated in vacuo to give a residue, which was purified by preparative TLC to afford 2′-amino-6-bromo-2-(4-chlorophenyl)-1′-methylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (35 mg, 12%). 1H-NMR (MeOD): 2.19 (m, 1H), 2.41 (m, 1H), 3.11 (m, 3H), 5.15 (m, 0.5H), 5.38 (m, 0.5H), 6.78 (m, 1H), 6.82 (m, 0.5H), 7.02 (m, 0.5H), 7.23 (m, 1H), 7.31 (m, 3H), 7.44 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[S:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=3)=[N:10][C:9]=2[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=2)[CH:5]=[C:4]([CH3:28])[N:3]=1.ClC1C=CC=C(C(OO)=[O:37])C=1.[OH-].[Na+]>CN(C)C=O>[CH3:28][C:4]1[CH:5]=[C:6]([C:8]2[S:12][C:11]([C:13]3[CH:14]=[CH:15][C:16]([S:19]([CH3:20])=[O:37])=[CH:17][CH:18]=3)=[N:10][C:9]=2[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=2)[CH:7]=[C:2]([CH3:1])[N:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(-c2nc(-c3cccc(C)c3)c(-c3cc(C)nc(C)c3)s2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1cccc(-c2nc(-c3ccc(S(C)=O)cc3)sc2-c2cc(C)nc(C)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To a solution of 5-(2,6-dimethyl-4-pyridyl)-4-(3-methylphenyl)-2-[4-(methylthio)phenyl]-1,3-thiazole (0.41 g, 1.0 mmol) in N,N-dimethylformamide (15 mL) was added m-chloroperbenzoic acid (0.25 g, 1.0 mmol), and the mixture was stirred for 1 hour at room temperature. A 8N aqueous sodium hydroxide solution was poured into the reaction mixture, and extracted with ethyl acetate. The extracted solution was washed with brine, dried, then, the solvent was distilled off. The residue was purified by column chromatography (filler: Chromatorex NH DM1020 (trade name, manufactured by Fuji Silysia Chemical Lte.), hexane-ethyl acetate=1:2), to obtain a title compound (0.41 g, yield 97%).