Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]([C:10]([O:12]C)=O)[CH2:5][C:6](OC)=[O:7])[C:2]#[CH:3].[NH3:14]>>[CH2:1]([N:4]1[CH2:5][C:6](=[O:7])[NH:14][C:10]1=[O:12])[C:2]#[CH:3]
Reactant: N
Reactant: C#CCN(CC(=O)OC)C(=O)OC
Product: C#CCN1CC(=O)NC1=O

Procedure:
3.0 g of methyl N-propargyl-N-methoxycarbonylglycinate were dissolved in 40 ml of 28% aqueous ammonia. Then the mixture was maintained under the pressure of 10-13 kg/cm2 at 100°-110° C. for an hour. Then the solvent was evaporated off from the reaction mixture. The resulting mixture was subjected to a column chromatography on silica gel (5:1 ethyl acetate:methanol as eluent) to obtain 0.65 g of 1-propargyl-2,4-dioxoimidazolidine.
Reaction SMILES: [F:1][C:2]([F:18])([C:8]([F:17])([F:16])[C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])[CH2:3][CH2:4][C:5](O)=[O:6].CO>O1CCCC1>[F:1][C:2]([F:18])([C:8]([F:16])([F:17])[C:9]([F:14])([F:15])[C:10]([F:11])([F:12])[F:13])[CH2:3][CH2:4][CH2:5][OH:6]
Reactant: O=C(O)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: C1CCOC1
Solvent: CO
Product: OCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.1 %

Procedure:
Borane-methyl sulfide complex (5.2 ml, 52.2 mmol) was slowly added to a solution of 4,4,5,5,6,6,7,7,7-nonafluoroheptanoic acid (5.10 g, 17.4 mmol) in anhydrous tetrahydrofuran (50 ml) at −50° C. The reaction mixture was stirred for 4 hours at room temperature and cooled to 0° C., followed by addition of methanol. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/5→1/3) to give 4,4,5,5,6,6,7,7,7-nonafluoroheptan-1-ol (4.7 g, Yield 97%) as a colorless oil.
Reaction SMILES: [S:1]([O-:4])([O-])=[O:2].[Na+].[Na+].[Cl:7][C:8]1[CH2:16][C:15]([Cl:21])(S(Cl)(=O)=O)[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].[OH-].[Na+]>O>[Cl:21][C:15]1[CH:16]=[C:8]([Cl:7])[C:9]([C:10]([OH:12])=[O:11])=[CH:13][C:14]=1[S:1]([OH:4])=[O:2]
Reactant: O=C(O)C1=C(Cl)CC(Cl)(S(=O)(=O)Cl)C=C1
Reactant: O=S([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc(S(=O)O)c(Cl)cc1Cl

Procedure:
This compound is prepared following substantially the same procedure described in Example 1, Step A, using the following substances:sodium sulfite 75 g.water 200 ml.2,4-dichloro-4-chlorosulfonylbenzoic acid 58 g.10N sodium hydroxide 50 ml.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2([C:15]([O:17]C)=[O:16])[CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.O[Li].O>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2([C:15]([OH:17])=[O:16])[CH2:14][CH2:13]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)C1(NS(=O)(=O)c2ccc(F)cc2)CC1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1(NS(=O)(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.1 %

Procedure:
Compound 13A (645 mg, 2.36 mmol) dissolved in THF (10 ml) and water (5 ml) was added with LiOH.H2O (3 equiv., 297 mg) and the reaction was stirred at rt 3 hours. The reaction was concentrated under vacuum. Water was added and 10% HCl till precipitation of the acid. The acid was extracted with ethyl acetate and the organic phase was washed with Brine, dried over sodium sulfate and concentrated under vacuum to give 600 mg of 15C as a white solid. Yield=98%. 1HNMR (DMSO, 200 MHz) δ 1.38 (2H, m), 1.35 (2H, bs), 7.42 (2H, m), 7.80 (2H, m), 8.80 (1H, bs), 12.46 (1H, bs)
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH:21]4[CH2:26][C:25]([CH3:28])([CH3:27])[NH:24][C:23]([CH3:30])([CH3:29])[CH2:22]4)[N:15]=3)[S:11][C:10]=2[CH:31]=1.[CH:32]([NH2:35])([CH3:34])[CH3:33]>C(O)C>[CH:32]([NH:35][CH2:3][CH:2]([OH:1])[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH:21]4[CH2:26][C:25]([CH3:28])([CH3:27])[NH:24][C:23]([CH3:29])([CH3:30])[CH2:22]4)[N:15]=3)[S:11][C:10]=2[CH:31]=1)([CH3:34])[CH3:33]
Reactant: CC1(C)CC(Nc2nccc(-c3cc4ccc(OCC5CO5)cc4s3)n2)CC(C)(C)N1
Reactant: CC(C)N
Solvent: CCO
Product: CC(C)NCC(O)COc1ccc2cc(-c3ccnc(NC4CC(C)(C)NC(C)(C)C4)n3)sc2c1
Temperature: 70 °C
Reaction time: 24 h

Procedure:
Compound of Example 156 (44 mg, 0.1 mmol) was dissolved in 2 ml ethanol and 100 mg (1.7 mmol) isopropylamine added. This mixture was stirred for 24 hours at 70° C. After evaporation the crude was purified by chromatography on silicagel (DCM/MeOH/ammonia:85/15/1.5). Yield: 38 mg (78%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]([NH:11][S:12]([C:15]1[C:16]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][N:28]3[C:32]([CH2:33][OH:34])=[C:31]([Cl:35])[N:30]=[C:29]3[CH2:36][CH2:37][CH2:38][CH3:39])=[CH:23][CH:22]=2)=[CH:17][CH:18]=[CH:19][CH:20]=1)(=[O:14])=[O:13])=[O:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][C:9]([NH:11][S:12]([C:15]1[C:16]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][N:28]3[C:32]([CH2:33][OH:34])=[C:31]([Cl:35])[N:30]=[C:29]3[CH2:36][CH2:37][CH2:38][CH3:39])=[CH:23][CH:22]=2)=[CH:17][CH:18]=[CH:19][CH:20]=1)(=[O:13])=[O:14])=[O:10]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)CNC(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)CN)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
To a DCM (500 μL) solution of intermediate (1d) (600 mg, 1.0 mmol) was added TFA (500 μL, 6.4 mmol). The mixture was stirred at room temperature for 30 minutes. Volatiles were removed under vacuum and the TFA salt of the product was lyophilized in 50/50 water/acetonitrile to give the title compound as a white solid (418 mg). Anal. HPLC: retention time=1.2 minutes. Gradient conditions: 25% solvent B/75% solvent A to 95% solvent B/5% solvent B over 6 minutes. MS m/z: [M+H]+ calcd for C23H27ClN4O4S, 491.15; found 473.1 [M+H]+ −18.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15]S(C3C=CC(C)=CC=3)(=O)=O)=[C:11]([C:26]3[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:36][C:37](=[CH2:41])[CH2:38][CH2:39]O.N>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:39][CH2:38][C:37]([CH3:41])=[CH2:36])=[C:11]([C:26]3[CH:27]=[CH:28][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:30][CH:31]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3ccc(F)cc3)c2=O)cc1
Reactant: C=C(C)CCO
Agent: N
Product: C=C(C)CCOc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)cc2)c1=O

Procedure:
The title compound was prepared according to the method of Example 335, substituting 2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-(3-chlorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting 3-methyl-3-butene-1-ol in place of isobutanol (yield: 0.1327 g, 91%). mp 109–111° C. 1H NMR (300 MHz, DMSO d6) δ 1.61 (s, 3H), 2.32 (t, J=7 Hz, 2H), 3.30 (s, 3H), 4.56 (t, J=7 Hz, 2H), 4.63 (bs, 1H), 4.68 (bs, 1H), 7.37 (m, 2H), 7.66 (m, 2H), 7.90 (m, 2H), 8.05 (m, 2H), 8.19 (s, 1H). MS (DCI/NH3) m/z 429 (M+H)+, 446 (M+NH4)+. Anal. calc. for C22H21FN2O4S: C, 61.67; H, 4.94; N, 6.54. Found: C, 61.50; H, 5.00; N, 6.45.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C1(=O)O[CH2:13][CH2:12][O:11]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.ClCCl>[N:1]1([CH2:13][CH2:12][OH:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=C1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: OCCn1ccc2ccccc21

Procedure:
A mixture of indole (5.71 g, 48.7 mmol), ethylene carbonate (4.72 g, 53.6 mmol) and K2CO3 (6.73 g, 48.7 mmol) in DMF (20 mL) was heated under reflux for 2 h. The reaction mixture was diluted with dichloromethane, filtered, and concentrated in vacuo. The light brown oily residue was purified by chromatography on silica gel (13×6 cm) using n-hexane/ethyl acetate (1:1) as eluent. This gave 1.78 g (23%) of the title compound as a beige oil. HRMS m/z calcd for C10H11NO (M)+ 161.0841, found 161.0849. Anal. (C10H11NO.0.1H2O) C, H, N. *Previously described in a) J. Med. Chem. 1992, 35, 994-1001; b) ibid. 1998, 41, 1619-1630.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:5]([C:6]([OH:8])=[O:7])[C:4]=1[C:12]([OH:14])=[O:13].Cl.[CH3:16]O>O.CO.Cl[Cu]>[CH3:16][O:7][C:6](=[O:8])[C:5]1[C:4](=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][CH:9]=1)[C:12]([OH:14])=[O:13]
Reactant: CO
Reactant: COc1cccc(C(=O)O)c1C(=O)O
Agent: Cl[Cu]
Agent: Cl
Solvent: O
Product: COC(=O)c1cccc(OC)c1C(=O)O
Yield: 63 %

Procedure:
A solution of methoxyphthalic acid obtained as per Example 5 (0.1 mol) in 100 ml methanol was added with CuCl (0.1 mol) and HCl (0.1 mol). The solution was heated to reflux for 30 min. The clear solution obtained was evaporated to dryness under reduced pressure. The residue obtained was dissolved in a 1:3 water-methanol mixture and acidified. The product was separated by cooling, collected by filtration and air dried. The product yield was 63-66%.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:13][C:14]([O:16]CC)=[O:15]>>[OH:11][CH:10]([CH2:9][CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:13][C:14]([OH:16])=[O:15]
Reactant: CCOC(=O)CBr
Reactant: O=CCCOc1ccccc1
Product: O=C(O)CC(O)CCOc1ccccc1

Procedure:
Magnetic microcapsules 71 were obtained in the same manner as in Example 64 except that the purified enzyme solution (1) in Example 64 was replaced by the crude enzyme solution (3) and (R)-3-hydroxybutyryl CoA was replaced by (R,S)-3-hydroxy-5-phenoxyvaleryl CoA (prepared by hydrolyzing 3-hydroxy-5-phenoxy valerate obtained through a Reformatsky reaction with zinc using 3-phenoxypropanal and ethyl bromoacetate as raw materials, which were synthesized according to a procedure described in J. Org. Chem., 55, 1490-1492, 1990, to produce 3-hydroxy-5-phenoxy valeric acid and then following a procedure described in Eur. J. Biochem., 250, 432-439, 1997). The drug content in the microcapsules is shown in Table 9.
Reaction SMILES: Cl[C:2]([CH2:4][C:5]([CH3:11])([OH:10])[CH:6]=[C:7]([CH3:9])[CH3:8])=[CH2:3].[OH-].[K+].C(O)(=O)C>CN(C)C=O>[CH3:11][C:5]([CH2:6][C:7]([CH3:9])=[CH2:8])([CH2:4][C:2]#[CH:3])[OH:10]
Reactant: C=C(Cl)CC(C)(O)C=C(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: C#CCC(C)(O)CC(=C)C

Procedure:
10.00 Grams of the 2-chloro-4,6-dimethyl-1,5-heptadien-4-ol obtained above were dissolved in 94 g of N,N-dimethylformamide, and 9.65 g of potassium hydroxide in a flake form were added. The resultant mixture was stirred at room temperature for 4 hours and neutralized with a 20% acetic acid aqueous solution, and the resultant mixture was subjected to extraction with toluene. The toluene phase was washed with water and then dried over magnesium sulfate. The desiccant was filtered off, and then the toluene was distilled off under reduced pressure. The resultant oily substance was purified by silica gel column chromatography to give 6.32 g of methyl 2-methylallylpropargylcarbinol; nD25 =1.496, FI-MS m/e 138 (M+) (Propargyl compound/allene compound=100.0/0.0).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[CH:10]=[C:9](OC)[C:8](=[O:15])[NH:7][C:6]=2[CH:16]=1.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CO>[CH2:17]([NH:24][C:9]1[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[C:11](=[O:12])[CH:10]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COc1cc(=O)c2ccc(Cl)cc2[nH]c1=O
Reactant: NCc1ccccc1
Solvent: CO
Product: O=c1[nH]c2cc(Cl)ccc2c(=O)cc1NCc1ccccc1

Procedure:
To a stirred solution of 8-chloro-3-methoxy-2,5-dioxo-2,5-dihydro-1H-benz[b]azepine (0.5 g) in methanol (15 mL) was added benzylamine (0.3 mL). The mixture was heated to reflux for 24 hours. The solvent was evaporated to give a solid. The solid was recrystallized from dimethylformamide (5 mL) and water, washed (water) and vacuum dried (100° C., 15 Pa) to give the title compound (0.181 g); mp 309.1°-313.9° C.; NMR: 5.73 (s,1); MS: m/z=313(M+1). Analysis for C17H13ClN2O2 : Calculated: C, 65.29; H, 4.19; N, 8.96; Found: C, 65.02; H, 3.96; N, 8.61.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[C:18]([S:26][CH3:27])=[CH:19][N:20]=[CH:21]3)[CH2:11][CH2:10]1)=O)(C)(C)C.[ClH:28].CO>>[ClH:28].[CH3:27][S:26][C:18]1[C:17]2[C:22](=[CH:23][CH:24]=[CH:25][C:16]=2[NH:15][CH:12]2[CH2:13][CH2:14][CH:9]([NH2:8])[CH2:10][CH2:11]2)[CH:21]=[N:20][CH:19]=1
Reactant: CSc1cncc2cccc(NC3CCC(NC(=O)OC(C)(C)C)CC3)c12
Agent: Cl
Solvent: CO
Product: CSc1cncc2cccc(NC3CCC(N)CC3)c12
Temperature: 25 °C

Procedure:
According to the method of Example 1, Step C, deprotection was performed (50° C., 2 hours) by using Intermediate 78 (341 mg) and 10% hydrogen chloride/methanol solution (5 ml). The reaction mixture was cooled to room temperature, and then the solvent was evaporated under reduced pressure. The residue was added with methanol (2 ml) and diethyl ether (6 ml). The deposited precipitates were collected by filtration and washed with diethyl ether to obtain the title compound (279 mg).
Reaction SMILES: Cl[CH2:2][C:3](=O)[C:4](=[N:10][OH:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:13]([NH2:21])(=[S:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1C=CC=CC=1>[N:10](=[C:4]([C:3]1[N:21]=[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[S:20][CH:2]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[OH:11]
Reactant: NC(=S)c1ccccc1
Reactant: CCOC(=O)C(=NO)C(=O)CCl
Solvent: c1ccccc1
Product: CCOC(=O)C(=NO)c1csc(-c2ccccc2)n1
Reaction time: 4 h
Yield: 107.9 %

Procedure:
A solution of ethyl γ-chloro-α-oximinoacetoacetate (2.10 g, 10.8 mmol) and thiobenzamide (1.49 g, 10.8 mmol) in dry benzene (15 mL) was heated to reflux. After 4 hours, the reaction mixture was poured onto NaHCO3 (sat., aq., 50 mL); The resulting mixture was extracted with ethyl acetate (2×50 mL); and the combined extracts dried over MgSO4 and evaporated under reduced pressure. Flash chromatography (ethyl acetate:hexane 1:4, Rf 0.30) then afforded impure ethyl α-oximino-2-phenylthiazole-4-acetate (3.22 g). The crude oxime was then dissolved in methanol (15 mL) and formic acid (50% aq., 15 mL) was added. The mixture was cooled to 0° C. and zinc dust (2.00 g, 30.6 mmol) was added portionwise over 30 minutes. The reaction mixture was allowed to warm to room temperature, and stirred for 6 hours. The solution was then filtered, basified to pH 9 with solid NaHCO3, and extracted with ethyl acetate (3×80 mL). The combined extracts were then dried and evaporated to afford D/L-2-phenylthiazol-4-ylglycine ethyl ester (1.43 g, 5.45 mmol, 50% from the chloro-oxime). The ester (194 mg, 0.74 mmol) was then dissolved in tetrahydrofuran (5 mL). Triethylamine (120 μL, 87 mg, 0.86 mmol) was added, followed by di-t-butyl dicarbonate (180 mg, 0.82 mmol). After stirring at room temperature for 4 days, water (20 mL) was added and the solution extracted with dichloromethane (2×20 mL). The combined extracts were evaporated and purified by flash column chromatography (ethyl acetate:hexane 1:4, Rf 0.45) to afford N-t-butyloxycarbonyl-D/L-2-phenylthiazol-4-ylglycine ethyl ester (158 mg, 0.44 mmol, 59%) as a clear oil. The oil was dissolved in tetrahydrofuran (2 mL) and LiOH.H2O (80 mg as a solution in 2 mL water) was added. After stirring at room temperature for 2 hours, water (10 mL) was added, and the solution extracted with ethyl acetate (5 mL). The aqueous layer was then acidified to pH 4 with 2N HCl, and extracted with ethyl acetate (2×20 mL); The latter extracts were combined and evaporated to afford N-BOC-D/L-2-phenylthiazol-4-ylglycine (116 mg, 0.35 mmol, 75%) as a white powder.
Reaction SMILES: [S:1]1[C:5]2=[CH:6][CH:7]=[CH:8][C:9]([S:10]([NH:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)(=[O:12])=[O:11])=[C:4]2[N:3]=C1.O.NN>CCO>[NH2:3][C:4]1[C:5]([SH:1])=[CH:6][CH:7]=[CH:8][C:9]=1[S:10]([NH:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1)(=[O:11])=[O:12]
Reactant: O=C(O)c1ccc(NS(=O)(=O)c2cccc3scnc23)cc1
Agent: NN
Solvent: CCO
Solvent: O
Product: Nc1c(S)cccc1S(=O)(=O)Nc1ccc(C(=O)O)cc1
Temperature: 130 °C
Reaction time: 1.5 h
Yield: 92.3 %

Procedure:
To a solution of 4-(benzo[d]thiazole-4-sulfonamido)benzoic acid (500 mg, 1.5 mmol) in 6 mL of EtOH was added hydrazine hydrate (479 mg, 15 mmol) at r.t. The reaction mixture was then stirred at 130° C. in microwave for 1.5 h. The resulting mixture was then cooled, and partitioned between water and EtOAc. The organic phase was washed with brine, dried over anhy. Na2SO4 and concentrated in vacuo to afford the title compound (449.0 mg). LC-MS: m/z 323.4 (M+H)+
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.C([Li])CCC.[CH:17]1([N:22]([CH:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)[C:23](=[O:32])[C:24]2[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH:17]1([N:22]([CH:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)[C:23](=[O:32])[C:24]2[CH:31]=[CH:30][C:27]([CH:28]([C:2]3[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH3:11])[CH:3]=3)[OH:29])=[CH:26][CH:25]=2)[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: COc1ccc(Br)cc1OC
Reactant: O=Cc1ccc(C(=O)N(C2CCCC2)C2CCCC2)cc1
Agent: [Li]CCCC
Product: COc1ccc(C(O)c2ccc(C(=O)N(C3CCCC3)C3CCCC3)cc2)cc1OC

Procedure:
The reaction and workup were carried out in the same manner as described in Example 8 using 4-bromoveratrole (1.29 mL, 10 mmol), n-butyl lithium (6.25 mL of 1.6 M solution in hexane), terephthalaldehydic acid N,N-dicyclopentyl amide (Example 29) (2.6 g, 9.1 mmol). The crude product was chromatographed on silica gel using mixtures of ethyl acetate and hexane to give the title compound as an oil that crystallized under ethyl ether: m. pt. 137-138° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8](=O)[CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.O.[NH2:12][NH2:13]>CCCCO>[CH3:9][C:8]1[C:7]2[C:2](=[N:3][CH:4]=[CH:5][CH:6]=2)[NH:13][N:12]=1
Reactant: NN
Reactant: CC(=O)c1cccnc1Cl
Solvent: CCCCO
Solvent: O
Product: Cc1n[nH]c2ncccc12
Temperature: 120 °C
Reaction time: 0.83 h

Procedure:
To a solution of the above crude 1-(2-chloropyridin-3-yl)ethanone (XIII) in n-BuOH (512 L) was added 85% hydrazine hydrate (78 L, 1360 mol). The reaction was heated at refluxed (˜120° C.) for 48 hours. The reaction was cooled and evaporated under vacuum. The crude material was taken up in DCM (834 L) and washed with 2× aqueous 25% NaCl (214 L) by adding aqueous 25% NaCl, stirring for 50 min, allowing to stand for 50 min, separating the layers and then repeating. The organic layer was evaporated to produce 3-methyl-1H-pyrazolo[3,4-b]pyridine (XIV) as a solid (13.2 Kg, 99 mol, 94.1% purity, 36.3% assay yield for 3 steps). 1H NMR (DMSO-d6, 400 MHz) δ ppm 2.50 (s, 3H), 7.13 (dd, J=4.4 Hz, J=8 Hz, 1H), 8.19 (dd, J=1.2 Hz, J=8 Hz, 1H), 8.47 (dd, J=1.6 Hz, J=4.8 Hz, 1H), 13.18 (brs, 1H); ESIMS found C7H7N3 m/z 133.8 (M+H).
Reaction SMILES: [C:1](OC1C2C(=CC=C(C)C=2)N(CC)C1=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:28](=[O:41])[C:27]2=[O:42]>>[C:1]([O:42][CH:27]1[C:26]2[C:30](=[CH:31][CH:32]=[C:24]([Cl:23])[CH:25]=2)[N:29]([CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:28]1=[O:41])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN1C(=O)C(OC(=O)c2ccccc2)c2cc(C)ccc21
Reactant: O=C1C(=O)N(CCc2ccccc2)c2ccc(Cl)cc21
Product: O=C(OC1C(=O)N(CCc2ccccc2)c2ccc(Cl)cc21)c1ccccc1

Procedure:
Was made in an analogous fashion to 1-ethyl-5-methyl-2-oxoindolin-3-yl benzoate using 5-chloro-1-phenethylindoline-2,3-dione. 1H-NMR δ 8.11 (dd, 2H), 7.60 (dt, 1H), 7.47 (m, 2H), 7.41 (dd, 1H), 7.34-7.24 (m, 6H), 6.68 (d, 1H), 6.07 (s, 1H), 3.97 (dd, 2H), 3.02 (t, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](Cl)=[C:6](Cl)[CH:5]=1)([O-:3])=[O:2].[S-:12][C:13]1[CH:18]=[CH:17][CH:16]=CC=1.[Na+]>>[S:12]1[CH:16]=[CH:17][CH:18]=[C:13]1[C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=1[C:16]1[S:12][CH:13]=[CH:18][CH:17]=1
Reactant: [S-]c1ccccc1
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Agent: [Na+]
Product: O=[N+]([O-])c1ccc(-c2cccs2)c(-c2cccs2)c1
Yield: 31 %

Procedure:
The procedure was as previously mentioned using 1-nitro-3,4-dichlorobenzene (10 g, 0.052 M) and sodium thiophenoxide (13.75 g, 0.104 M). mp = 97°-101°. Yield 31%. The reaction product was characterized by NMR, 13CNMR, ir, and Mass Spectra (M+ = 339).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[N+:17]([C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1)([O-:19])=[O:18]>CN(C)C=O>[N+:8]([C:5]1[CH:4]=[CH:3][C:2]([O:26][C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([N+:17]([O-:19])=[O:18])[CH:21]=2)=[CH:7][N:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(Oc2ccc([N+](=O)[O-])nc2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 54.1 %

Procedure:
To a solution of 5-bromo-2-nitropyridine (20.5 g, 101 mmol) and cesium carbonate (50 g, 153 mmol) in N,N-dimethylformamide (200 mL) was added dropwise a solution of 3-nitrophenol (15.5 g, 111 mmol) in N,N-dimethylformamide (100 mL) for 1 hr, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was diluted with water (300 mL) and extracted with ethyl acetate (600 mL). The organic layer was washed with 5% aqueous sodium hydrogen carbonate solution (300 mL) and saturated brine (300 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=90/10→60/40), and fractions containing the object product was concentrated under reduced pressure to give the title compound (14.28 g, 54%) as colorless crystals.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:16][CH2:17][CH3:18])[CH:8]=1)=O.Cl.[N+:21]([C:24]1[CH:25]=[C:26]([NH:30][C:31]([NH2:33])=[NH:32])[CH:27]=[CH:28][CH:29]=1)([O-:23])=[O:22]>>[N+:21]([C:24]1[CH:25]=[C:26]([NH:30][C:31]2[N:33]=[C:5]([C:7]3[C:15]4[C:10](=[N:11][CH:12]=[CH:13][CH:14]=4)[N:9]([CH2:16][CH2:17][CH3:18])[CH:8]=3)[CH:4]=[CH:3][N:32]=2)[CH:27]=[CH:28][CH:29]=1)([O-:23])=[O:22]
Reactant: CCCn1cc(C(=O)/C=C/N(C)C)c2cccnc21
Reactant: N=C(N)Nc1cccc([N+](=O)[O-])c1
Agent: Cl
Product: CCCn1cc(-c2ccnc(Nc3cccc([N+](=O)[O-])c3)n2)c2cccnc21

Procedure:
Prepared by treatment of (E)-3-(dimethylamino)-1-(1-propyl-1H-pyrrolo[2,3-b]pyridin-3-yl)prop-2-en-1-one with 1-(3-nitrophenyl)guanidine hydrochloride. 1H-NMR (DMSO-d6) δ: 0.90 (t, 3H, J=7.2 Hz, CH3), 1.93 (t, 2H, J=7.6 Hz, CH2), 4.33 (t, 2H, J=6.8 Hz, CH2), 7.26 (q, 1H, J=4.4 Hz, Ar—H), 7.40 (d, 1H, J=5.6 Hz, Pyrimidin-H), 7.61 (t, 1H, J=8.4 Hz, Ph-H), 7.81 (m, 1H, Ph-H), 8.12 (m, 1H, Ph-H), 8.37 (m, 1H, Ar—H), 8.48 (d, 1H, J=5.6 Hz, Pyrimidin-H), 8.64 (s, 1H, Ar—H), 8.92 (d, 1H, J=8.0 Hz, Ar—H), 9.00 (s, 1H, NH). MS (ESI+) m/z 375.1519 (M+H)+.