Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl[S:15]([C:18]1[CH:27]=[CH:26][C:25]2[NH:24][C:23](=[O:28])[C:22]3[NH:29][CH:30]=[C:31]([C:32]([OH:34])=[O:33])[C:21]=3[C:20]=2[CH:19]=1)(=[O:17])=[O:16]>ClCCl.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>[O:28]=[C:23]1[C:22]2[NH:29][CH:30]=[C:31]([C:32]([OH:34])=[O:33])[C:21]=2[C:20]2[CH:19]=[C:18]([S:15](=[O:17])(=[O:16])[NH:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:27]=[CH:26][C:25]=2[NH:24]1
Reactant: O=C(O)c1c[nH]c2c(=O)[nH]c3ccc(S(=O)(=O)Cl)cc3c12
Reactant: Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(O)c1c[nH]c2c(=O)[nH]c3ccc(S(=O)(=O)Nc4ccccc4)cc3c12
Temperature: 25 °C
Reaction time: 5 h
Yield: 43.5 %

Procedure:
30 μL (0.37 mmol) of pyridine and 20 μL (0.22 mmol) of aniline are added to 60 mg (0.18 mmol) of 8-chlorosulfonyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid suspended in 4 mL of anhydrous dichloromethane and 1 mL of anhydrous dimethylformamide. The reaction mixture is stirred for 5 hours at room temperature then diluted with a 10% aqueous solution of potassium carbonate and dichloromethane. The phases are separated and the aqueous phase is acidified with acetic acid to pH of 4. The product is extracted with dichloromethane. The organic phase is dried over magnesium sulfate, filtered then evaporated. The residue is diluted with water (5 mL) then the solid is filtered and dried under vacuum to give 30 mg (42%) of 4-oxo-8-phenylsulfamoyl-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid in the form of a beige solid.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH2:14][CH:15]1[CH2:19][CH2:18][CH2:17][O:16]1)C.[NH2:22][C:23]([NH2:25])=[S:24].C([O-])([O-])=O.[K+].[K+].Cl>COCCO.O>[O:16]1[CH2:17][CH2:18][CH2:19][CH:15]1[CH2:14][O:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:6]1[NH:25][C:23](=[S:24])[NH:22][C:4](=[O:3])[CH:5]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1OCC1CCCO1
Reactant: NC(N)=S
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCO
Product: O=c1cc(-c2ccccc2OCC2CCCO2)[nH]c(=S)[nH]1
Yield: 64 %

Procedure:
To a solution of 3-oxo-3-[2-(tetrahydro-furan-2-ylmethoxy)-phenyl]-propionic acid ethyl ester (0.9 g, 3.08 mmol) in 2-methoxyethanol (5 mL) was added thiourea (0.31 g, 4.08 mmol) and K2CO3 (0.56 g, 4 mmol). The reaction mixture refluxed 5-6 h. After cooling, a mixture poured into water (10 mL), adjusted to pH 3 with 10% HCl and extracted with ethyl acetate (2×10 mL). Organic layers were combined, washed with water (10 mL), then dried over anhydrous sodium sulfate, concentrated and triturated with diethyl ether to obtained 0.6 g (64%) 6-[2-(tetrahydro-furan-2-ylmethoxy)-phenyl]-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one as a beige solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].Cl.Cl.[CH3:19][N:20]([CH3:28])[C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24].C(N(CC)CC)C.C>CCOC(C)=O>[CH3:19][N:20]([CH3:28])[C:21]1[CH:22]=[C:23]([NH:24][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:15]#[N:16])[CH:25]=[CH:26][CH:27]=1
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Cl
Reactant: CN(C)c1cccc(N)c1
Agent: C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CN(C)c1cccc(Nc2c(C#N)cnc3ccc([N+](=O)[O-])cc23)c1

Procedure:
Prepared from 5.00 g of 4-chloro-6-nitroquinoline-3-carbonitrile, 5.38 g of 3-dimethylaminoaniline dihydrochloride and 5.17 g of triethylamine in the same manner as EXAMPLE 377. The crude product was taken up in EtOAc, treated with Darco, filtered through Celite, evaporated and dried in vacuo (50° C.). The yield of 4-(3-dimethylaminophenylamino)-6-nitroquinoline-3-carbonitrile was 5.62 g as brick red crystals: mass spectrum (electrospray, m/e): M+H 334.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[C:6]([C:8]1[N:9]=[C:10]([C:13]2[CH:27]=[CH:26][C:16]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:15][CH:14]=2)[S:11][CH:12]=1)=[O:7].[H-].[Na+].I[CH3:38]>CN(C=O)C>[CH3:38][N:18]([CH2:17][C:16]1[CH:15]=[CH:14][C:13]([C:10]2[S:11][CH:12]=[C:8]([C:6](=[O:7])[C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:30]([O:31][CH3:32])=[C:29]([O:33][CH3:34])[CH:28]=3)[N:9]=2)=[CH:27][CH:26]=1)[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22]
Reactant: CI
Reactant: COc1cc(C(=O)c2csc(-c3ccc(CNC(=O)OC(C)(C)C)cc3)n2)cc(OC)c1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C(=O)c2csc(-c3ccc(CN(C)C(=O)OC(C)(C)C)cc3)n2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.3 %

Procedure:
At 0° C., to a solution of compound 68a (100 mg, 0.2 mmol) in 5 mL DMF was added sodium hydride (10 mg, 0.2 mmol), then iodomethane (77 mg, 0.4 mmol) was added to the reaction mixture and stirred at RT overnight. The mixture was quenched with a sat. NaHCO3 solution, extracted with ethyl acetate and dried with MgSO4. The solvent was removed under reduced pressure to yield a crude product, which was purified by column chromatography to obtain pure compound 71a. Yield: 61.3%. 1H NMR (500 MHz, DMSO-d6) δ 8.30 (s, 1H), 8.02 (d, 2H, J=8.0 Hz), 7.82 (s, 2H), 7.36 (br, 2H), 4.50 (s, 2H), 4.00 (s, 3H), 3.98 (s, 6H), 2.90 (d, br, 3H), 1.50 (s, 9H). MS (ESI) m/z 521.2 (M+Na)+, 496.9 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11]C)[C:3]=1/[CH:4]=[N:5]/O.S(Cl)(Cl)(=O)=[O:14]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]2[C:4](=[O:14])[NH:5][S:11][C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: CSc1cccc(Cl)c1/C=N/O
Solvent: Cc1ccccc1
Product: O=c1[nH]sc2cccc(Cl)c12
Temperature: 80 °C

Procedure:
(E)-2-Chloro-6-(methylthio)benzaldehyde oxime (12.37 g) was dissolved in toluene (35 mL). Sulfuryl chloride (5.4 ml, 66.24 mmol) was added, dropwise to the solution at 0° C., followed by heating at 80° C. for 1 h. After the completion of the reaction, the reaction mixture was cooled to room temperature and a white precipitate formed. The solid was collected by vacuum filtration, washed with toluene and air dried to 4-chlorobenzo[d]isothiazol-3(2H)-one (6 g). (This method is general for other 2-(methythio) benzaldehyde oximes.) 1H NMR (300 MHz, DMSO-d6): 7.90 (t, 1H), 7.55 (t, 1H), 7.41 ppm (d, 1H). MW=186 confirmed by LC-MS, tr=2.38 min (Method B) MH+=187.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:20]([O:22][P:23]([C:28]([P:30](=[O:37])([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])=[CH2:29])(=[O:27])[O:24][CH2:25][CH3:26])[CH3:21].[Cl:38]N1C(=O)CCC1=O>C1COCC1>[CH2:35]([O:34][P:30]([C:28]([P:23](=[O:27])([O:24][CH2:25][CH3:26])[O:22][CH2:20][CH3:21])([Cl:38])[CH2:29][CH2:2][C:1](=[O:3])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:37])[O:31][CH2:32][CH3:33])[CH3:36]
Reactant: C=C(P(=O)(OCC)OCC)P(=O)(OCC)OCC
Reactant: CC(=O)c1ccccc1
Reactant: O=C1CCC(=O)N1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(Cl)(CCC(=O)c1ccccc1)P(=O)(OCC)OCC
Reaction time: 0.5 h

Procedure:
Acetophenone (1.17 ml) is dissolved in THF (20 ml), cooled to -78° and treated with lithium bis(trimethylsilyl)amide. The solution is stirred for 30 minutes and a solution of ethenylidenebisphosphonic acid tetraethyl ester (I, 2.7g) in THF (5 ml) is added. The solution is stirred for several minutes then warmed to 0° for 1 hour. N-Chlorosuccinimide (1.33 g) is added and the solution was stirred at 22° for 18 hours. The reaction is quenched with aqueous ammonium chloride and concentrated. The residue is diluted with ethyl acetate and washed with sulfuric acid (2N, 2×), water, sodium bicarbonate, saline and dried with magnesium sulfate and concentrated. The resultant mixture is chromatographed eluting with ethyl acetate, slowly increased from 1 to 5% ethanol/ethyl acetate. The appropriate fractions are pooled and concentrated to give the title compound, MS (m/e) 454, 426, 322 and 105; IR (neat) 1686, 1599, 1581, 1448, 1391, 1368, 1259, 1214 and 1163 cm-1 ; NMR (CDCl3) 8.02-7.99, 7.59-7.54, 7.49-7.44, 4.37-4.25, 3.50, 2.78-2.64 and 1.38 δ. Another compound is formed by the reaction which is not within the scope of the invention.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[C:30]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][N:41]3[C:45]4=[CH:46][CH:47]=[CH:48][CH2:49][CH:44]4[NH:43][CH2:42]3)=[CH:31][CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[C:30]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][N:41]3[C:45]4=[CH:46][CH:47]=[CH:48][CH2:49][CH:44]4[NH:43][CH2:42]3)=[CH:31][CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(C)ccc(OCCCCCN3CNC4CC=CC=C43)c2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCc1nc2c(C)ccc(OCCCCCN3CNC4CC=CC=C43)c2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.-butyl 4'-[[2-n-butyl-4-methyl-7-[5-(tetrahydrobenzimidazol-1-yl)-pentyloxy]-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([CH:15]=1)[N:7](C)[C:8](=[O:13])[C:9]([F:12])([F:11])[F:10].N([O-])=[O:18].[Na+].NC(N)=O>O>[F:16][C:5]1[CH:4]=[CH:3][C:2]([OH:18])=[CH:15][C:6]=1[NH:7][C:8](=[O:13])[C:9]([F:12])([F:11])[F:10]
Reactant: O=N[O-]
Reactant: CN(C(=O)C(F)(F)F)c1cc(N)ccc1F
Agent: NC(N)=O
Agent: [Na+]
Solvent: O
Product: O=C(Nc1cc(O)ccc1F)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Compound 32-NH2—H (248 mg, 1.12 mmol) was dissolved in 35% aq. H2 SO4 (2 mL) cooled to 0° C., and NaNO2 (96.6 mg 1.4 mmol) in water (1 mL) was added carefully through a Teflon® tube to the bottom of the flask. An exothermic reaction was observed and the brown gas evolved. The mixture was stirred for 5 min, several crystals of urea were added to the reaction mixture, and then the reaction solution was transferred into the blue solution of Cu(NO3)2*3H2O (3.75 g, 15.5 mmol) in water (36 mL). The color of the solution changed to green. With vigorous stirring, the powder of Cu2O (132 mg, 0.920 mmol) was added, and the evolution of nitrogen was complete in several minutes. The reaction mixture was extracted with ether (3×200 mL); combined organic solutions were washed with brine (100 mL) and dried. The solvent was removed in vacuo, and the residue was filtered through SiO2 (50 mL), eluting with CH2 Cl2/EtOAc mixture (4:1). The title compound was isolated as a brown solid (116 mg, 52%) with m.p. 151-153° C. (ether/hexane). This procedure may be easily scaled-up. 1H NMR (CD3OD, 300 MHz, ppm): δ=6.70 (ddd, 4JHH=3.0, 4JHF=3.9, 3JHH=9.0, 1H, H-4), 7.03 (dd, 3JHH=9.0, 3JHF=10.1, 1H, H-3), 7.08 (dd, 4JHH=3.0, 4JHF=6.2, 1H, H-6); 13C NMR (CD3 OD, δ5.5 MHz, ppm): δ=113.4 (s, C-4/6), 115.4 (d, 3JCF=7.2, C-6/4), 117.2 (d, 2JCF=21.3, C-3), 117.4 (q, 1JCF=298, CF3), 124.4 (d, 2JCF=13.8, C-1), 150.5 (d, 1JCF=239, C-2), 154.8 (s, C-5), 157.1 (q, 2JCF=37.7, CO); EI-MS: m/z (rel. int., %)=223 (100) [M], 154 (21), 126(22), 99 (22); elemental analysis (%): C, 42.92; H, 2.44; N, 6.54 (found); C, 43.07; H, 2.26; N, 6.28 (calc.).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[F:7][C:8]1[CH:13]=[CH:12][C:11]([SH:14])=[CH:10][CH:9]=1.I[C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19]([OH:21])=[O:20]>[Cu]=O.CN1CCCC1=O>[F:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:16]2[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=2)[C:19]([OH:21])=[O:20])=[CH:10][CH:9]=1
Reactant: O=C(O)c1cccc(I)c1
Reactant: Fc1ccc(S)cc1
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: O=C(O)c1cccc(Sc2ccc(F)cc2)c1
Temperature: 160 °C
Reaction time: 8 h
Yield: 81.5 %

Procedure:
Copper(II) oxide (4.01 g) and cesium carbonate (19.7 g) were added in that order to an N-methylpyrrolidinone (100 mL) solution of 4-fluorobenzenethiol (3.10 g) and 3-iodobenzoic acid (5.00 g), and stirred overnight at 160° C. After left cooled, the solid in the reaction solution was removed through filtration. 1 M hydrochloric acid was added to the filtrate, extracted three times with ethyl acetate and dried with sodium sulfate. The drying agent was removed through filtration, and the solvent was evaporated off under reduced pressure. The residue was suspended in a mixed solvent of chloroform/hexane, and the solid was collected through filtration to give the intended product (4.08 g, 82%) as a white solid.
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]([CH3:28])[C:14](=[O:27])[C:15]3[CH:20]=[CH:19][C:18]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[CH:9][CH:8]=2)[C:3]1=[O:29].[CH:30]1([CH2:33][NH2:34])[CH2:32][CH2:31]1>>[CH:21]1([C:18]2[CH:19]=[CH:20][C:15]([C:14]([N:13]([C:10]3[CH:11]=[CH:12][C:7]([N:4]4[CH2:5][CH2:6][CH:2]([NH:34][CH2:33][CH:30]5[CH2:32][CH2:31]5)[C:3]4=[O:29])=[CH:8][CH:9]=3)[CH3:28])=[O:27])=[CH:16][CH:17]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: NCC1CC1
Reactant: CN(C(=O)c1ccc(C2CCCCC2)cc1)c1ccc(N2CCC(Br)C2=O)cc1
Product: CN(C(=O)c1ccc(C2CCCCC2)cc1)c1ccc(N2CCC(NCC3CC3)C2=O)cc1

Procedure:
N-[4-(3-Bromo-2-oxopyrrolidin-1-yl)phenyl]-4-cyclohexyl-N-methylbenzamide was reacted with cyclopropylmethylamine by method L. This resulted in the product with the molecular weight of 445.61 (C28H35N3O2); MS (ESI): 446 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:17]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:18])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3.[CH2:19]([O:21][C:22](=[O:30])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH2:29])[CH:24]=1)[CH3:20]>>[CH2:19]([O:21][C:22](=[O:30])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:2]2[CH:17]=[C:6]3[C:7]4[C:12]([CH2:13][CH2:14][N:5]3[C:4](=[O:18])[N:3]=2)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=4)[CH:24]=1)[CH3:20]
Reactant: COc1ccc2c(c1)CCn1c-2cc(Cl)nc1=O
Reactant: CCOC(=O)c1cccc(N)c1
Product: CCOC(=O)c1cccc(Nc2cc3n(c(=O)n2)CCc2cc(OC)ccc2-3)c1

Procedure:
The title compound was prepared from 2-chloro-9-methoxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one (4) and 3-amino-benzoic acid ethyl ester as in Example 1 d. 1H-NMR (400 MHz, d0-DMSO) δ 9.84 (s, 1H), 8.26 (s, 1H), 8.21 (d, 1H), 7.70 (d, 1H), 7.62 (d, 1H), 7.49 (t, 1H), 7.05-6.97 (2H), 6.36 (s, 1H), 4.33 (q, 2H), 3.99 (t, 2H), 3.85 (s, 3H), 2.97 (t, 2H) and 1.34 (t, 3H); MS (ESI) (M+H)+ 392.
Reaction SMILES: CC(C[AlH]CC(C)C)C.[CH3:10][C:11]1[CH:18]=[C:17]([C:19]2[S:20][C:21]3[C:26]([N:27]=2)=[CH:25][CH:24]=[C:23]([C:28]2([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:30][CH2:29]2)[N:22]=3)[CH:16]=[CH:15][C:12]=1[C:13]#N.C(C(C(C([O-])=O)O)O)([O-])=[O:38]>C(Cl)Cl>[CH3:10][C:11]1[CH:18]=[C:17]([C:19]2[S:20][C:21]3[C:26]([N:27]=2)=[CH:25][CH:24]=[C:23]([C:28]2([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:30][CH2:29]2)[N:22]=3)[CH:16]=[CH:15][C:12]=1[CH:13]=[O:38]
Reactant: O=C([O-])C(O)C(O)C(=O)[O-]
Reactant: Cc1cc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)ccc1C#N
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: Cc1cc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)ccc1C=O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
DIBAL-H (1.0M in hexanes; 132 μL, 132 μmol) was added to a solution of 2-methyl-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)benzonitrile (44.2 mg, 120 μmol) in CH2Cl2 (2.0 mL) at 25° C., and the resulting solution was stirred at 25° C. for 45 min. Saturated aqueous Na/K tartrate solution (2.0 mL) was then added, and the resulting mixture was stirred for 15 min, then partitioned between CH2Cl2 (20 mL) and water (10 mL). The organic layer was separated, and the aqueous layer was extracted with CH2Cl2. The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 15% EtOAc/hexanes) provided 2-methyl-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)benzaldehyde as a light yellow solid. MS (ESI) m/z: Calculated: 370.1; Observed: 371.2 (M++1).
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].[CH3:9][S:10](Cl)(=[O:12])=[O:11].C(N(CC)CC)C.O>ClCCl>[CH3:9][S:10]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7])(=[O:12])=[O:11]
Reactant: C=CCCCCCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: C=CCCCCCS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 100.3 %

Procedure:
This example illustrates a synthesis of 1-(6,7-Oxidoheptyl)-3,7-dimethylxanthine (inventive compound no. 1586). To a solution of 6-hepten-1-ol (6.00 g, 52.6 mmol) in dichloromethane (120 mL) at 0° C. was added methanesulfonyl chloride (6.07 g, 4.0 mL, 53.0 mmol), followed by triethylamine (7.79 g, 77.0 mmol). After stirring for 10 minutes at 0° C., the reaction was allowed to warm to 25° C. and then stirred for 2 hours. The reaction was poured into water (100 mL) and extracted with dichloromethane (2×100 mL). The organic portions were combined, dried over magnesium sulfate, and evaporated to give the 7-methanesulfonyl-1-heptene as a yellow oil (9.30 g, 93%), which was used without further purification.
Reaction SMILES: [H-].[Na+].[CH:3]1([C:6]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[NH:17][CH:16]=[C:15]4[I:21])[CH:9]=[N:8][CH:7]=2)[CH2:5][CH2:4]1.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.O>C1COCC1>[CH:3]1([C:6]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[N:17]([S:28]([C:25]3[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=3)(=[O:30])=[O:29])[CH:16]=[C:15]4[I:21])[CH:9]=[N:8][CH:7]=2)[CH2:5][CH2:4]1
Reactant: Ic1c[nH]c2ccc(-c3cncc(C4CC4)n3)cc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4cncc(C5CC5)n4)ccc32)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 97.4 %

Procedure:
NaH (60% in mineral oil) (34 mg, 0.85 mmol) was added to a solution of 5-(6-cyclopropylpyrazin-2-yl)-3-iodo-1H-indole (280 mg, 0.78 mmol) in THF (4 mL) at 0° C. The mixture was stirred for 10 min at 0° C. and p-toluenesulfonyl chloride (163 mg, 0.85 mmol) was added and the mixture was warmed to RT. After 1 h, water was added and the mixture was extracted with EtOAc (3×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to afford 5-(6-cyclopropylpyrazin-2-yl)-3-iodo-1-tosyl-1H-indole (394 mg, 0.76 mmol, 99% yield) as a yellow solid. MS (ESI, pos. ion) m/z: 516.0 (M+1).
Reaction SMILES: C([O-])([O-])[O:2][CH2:3][CH3:4].B(F)(F)F.[CH3:11][O:12][N:13]=[C:14]([C:19](=[O:21])[CH3:20])[C:15]([O:17][CH3:18])=[O:16].C(=O)(O)[O-].[Na+].[CH:27](OC(C)C)(C)[CH3:28]>C(O)C>[CH3:11][O:12][N:13]=[C:14]([C:19]([O:2][CH2:3][CH3:4])([O:21][CH2:27][CH3:28])[CH3:20])[C:15]([O:17][CH3:18])=[O:16]
Reactant: CON=C(C(C)=O)C(=O)OC
Reactant: CC(C)OC(C)C
Reactant: CCOC([O-])[O-]
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(C)(OCC)C(=NOC)C(=O)OC
Temperature: 70 °C
Reaction time: 4 h

Procedure:
Ethyl orthoformate (14.0 g) and borontrifluoride diethyletherate (0.45 g) were added to a solution of methyl 2-methoxyimino-3-oxobutyrate (syn isomer, 10 g) in ethanol (20 ml) and stirred at 70° C. for 4 hours. To the resultant mixture were added a saturated aqueous solution of sodium bicarbonate (20 ml) and diisopropyl ether (30 ml). After separating the organic solution, the aqueous solution was extracted with diisopropyl ether (30 ml). The organic layer and the extract were combined, washed with water and a saturated aqueous solution of sodium chloride (30 ml) in turn and dried over magnesium sulfate. The solution was evaporated in vacuo to give methyl 2-methoxyimino-3,3-diethoxybutyrate (syn isomer, 13.9 g.).
Reaction SMILES: [CH3:1][C@@:2]12[C:10]3[NH:11][C:12]4[CH:13]=[CH:14][CH:15]=[C:16]([C:18]([O:20]C)=O)[C:17]=4[C:9]=3[C:8](=O)[CH2:7][N:6]1[CH2:5][CH2:4][CH2:3]2.C(O)(=O)C.O.[NH2:28][NH2:29].O>CO>[CH3:1][C@:2]12[CH2:3][CH2:4][CH2:5][N:6]1[CH2:7][C:8]1[C:9]3[C:17]4[C:16]([C:18](=[O:20])[NH:28][N:29]=1)=[CH:15][CH:14]=[CH:13][C:12]=4[NH:11][C:10]=32
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CN1CCC[C@]31C
Reactant: NN
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: C[C@]12CCCN1CC1=NNC(=O)c3cccc4[nH]c2c1c34
Reaction time: 7 h

Procedure:
A solution of compound (R)-methyl 11b-methyl-6-oxo-2,3,5,6,11,11b-hexahydro-1H-indolizino[8,7-b]indole-7-carboxylate (58 mg, 0.19 mmol), acetic acid (0.4 mL), and hydrazine hydrate (0.2 mL) in methanol (10 mL) was heated at reflux. After 7 h, the reaction was cooled and water (5 mL) was added. The mixture was extracted with EtOAc (3×5 mL) and the combined organic layers were washed with brine (10 mL) and dried over MgSO4. The mixture was filtered, evaporated to dryness, and the residue was purified by Pre-TLC using CH2Cl2 as eluent to give 40 mg of (R)-10a-methyl-7,8,9,10,10a, 11-hexahydro-5,6,7a,11-tetraazacyclohepta[def]cyclopenta[a]fluoren-4(5H)-one. 1H NMR (DMSO-d6) δ 12.9 (s, 1H), 10.6 (s, 1H), 7.50-7.52 (m, 2H), 7.12 (t, 1H, J=7.8 Hz), 3.24-3.26 (m, 1H), 2.91 (d, 1H, J=18.4 Hz), 2.37-2.38 (m, 1H), 2.30-2.32 (m, 1H), 2.20-2.21 (m, 1H), 1.95-1.96 (m, 1H), 1.41-1.43 (m, 1H), 1.34 (s, 3H), and 1.18-1.19 (m 1H). MS (ESI) m/e [M+1]+ 281.0.
Reaction SMILES: [CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[C:12]2=[N:19]C1C=CC=CC=1.[C:26]([NH:34]N)(=[O:33])[C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1>>[CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[C:12]2=[N:19][NH:34][C:26]([C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1)=[O:33]
Reactant: CC1SC(=O)NN=C1c1ccc2c(c1)C(=Nc1ccccc1)C(=O)N2
Reactant: NNC(=O)c1ccncc1
Product: CC1SC(=O)NN=C1c1ccc2c(c1)C(=NNC(=O)c1ccncc1)C(=O)N2
Yield: 68 %

Procedure:
Starting from 1,3-dihydro-5-(3,6-dihydro-6-methyl-2-oxo -2H-1,3,4-thiadiazin-5-yl)-3-phenylimino-2H-indol-2-one, and isonicotinic acid hydrazide and following the method described in Example 21, the desired compound was obtained.