Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:23][CH2:24][O:25][CH:26]=[O:27].O>CC(=O)CC>[CH2:24]([O:25][C:26](=[O:27])[NH:15][C:11]1[CH:10]=[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[N:14]=[CH:13][N:12]=1)[CH3:23]
Reactant: COc1ccccc1-c1cc(N)ncn1
Reactant: O=COCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CCOC(=O)Nc1cc(-c2ccccc2OC)ncn1
Temperature: 80 °C
Yield: 44.8 %

Procedure:
To a mixture of 6-(2-methoxy-phenyl)-pyrimidin-4-ylamine (XXIV) (1.0 g, 4.9 mmol) and potassium carbonate (4.0 g, 29 mmol) in 2-butanone (10 ml), chloroethylformate (0.50 ml, 4.9 mmol) was added and the mixture was refluxed for 3 hours at 80° C. The reaction was monitored by TLC. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated to provide 0.60 g of [6-(2-methoxy-phenyl)-pyrimidin-4-yl]-carbamic acid ethyl ester (XL).
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:12]2[N:11]([CH2:15][CH:16](OS(C)(=O)=O)[C:17]3[CH:22]=[N:21][CH:20]=[CH:19][N:18]=3)[C:10]3[CH2:9][CH2:8][N:7]4[CH2:28][CH2:29][CH2:30][CH:6]4[C:5]=3[C:4]=2[CH:3]=1.[CH3:31][NH:32][CH3:33]>O>[CH3:31][N:32]([CH3:33])[CH:16]([C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1)[CH2:15][N:11]1[C:10]2[CH2:9][CH2:8][N:7]3[CH2:28][CH2:29][CH2:30][CH:6]3[C:5]=2[C:4]2[CH:3]=[C:2]([CH3:1])[CH:14]=[CH:13][C:12]1=2
Reactant: Cc1ccc2c(c1)c1c(n2CC(OS(C)(=O)=O)c2cnccn2)CCN2CCCC12
Reactant: CNC
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CC(c2cnccn2)N(C)C)CCN2CCCC12
Temperature: 25 °C

Procedure:
Methanesulfonic acid 2-(9-methyl-1,2,3,4,5,10c-hexahydro-3a,6-diaza-cyclopenta[c]fluoren-6-yl)-1-pyrazin-2-yl-ethyl ester (300 mg, 0.70 mmol) in 40% dimethylamine in water (20 mL) was heated at 90° C. for 1 h. The reaction mixture was cooled to RT and extracted with DCM (12×50 mL) The combined organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by reverse phase chromatography to obtain 60 mg of dimethyl-[2-(9-methyl-1,2,3,4,5,10c-hexahydro-3a,6-diaza-cyclopenta[c]fluoren-6-yl)-1-pyrazin-2-yl-ethyl]-amine. 1H NMR (CD3OD, TFA salt): δ (ppm): 8.1 (s, 1H), 7.4 (s, 1H), 7.1 (d, 1H), 5.1 (t, 1H), 4.42 (m, 2H), 3.6 (m, 3H), 3.2 (m, 1H), 3.17 (m, 1H), 3.15 (s, 6H), 2.85 (m, 2H), 2.63 (m, 1H), 2.42 (s, 3H), 2.3 (m, 2H), 2.15 (m, 1H). Chiral HPLC separates the racemate into diastereomers II-7a-d.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[Cl:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([NH:28][C:29](=[O:31])[CH3:30])([CH3:27])[CH3:26])=[CH:21][CH:20]=1>>[ClH:17].[CH3:27][C:25]([NH:28][C:29](=[O:31])[CH3:30])([C:22]1[CH:23]=[CH:24][C:19]([CH2:18][N:14]2[CH2:13][CH2:12][N:11]([C:5]3[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:4]=3[F:3])[CH2:16][CH2:15]2)=[CH:20][CH:21]=1)[CH3:26]
Reactant: Fc1ccc(N2CCNCC2)c(F)c1
Reactant: CC(=O)NC(C)(C)c1ccc(CCl)cc1
Agent: Cl
Product: CC(=O)NC(C)(C)c1ccc(CN2CCN(c3ccc(F)cc3F)CC2)cc1

Procedure:
By similar reaction and treatment to that in Example 1(5) using 1-(2,4-difluorophenyl)piperazine dihydrochloride instead of phenylpiperazine and N-(1-(4-chloromethylphenyl)-1-methylethyl)acetamide instead of N-(4-chloromethylphenylmethyl)acetamide, the title compound was obtained as pale-brown crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH:4](Cl)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:20])([CH3:19])[O:13][SiH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:8][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].[F:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][SH:38])=[CH:32][CH:31]=1>CN(C=O)C>[CH3:1][O:2][C:3](=[O:22])[CH:4]([S:38][CH2:37][CH2:36][C:33]1[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:20])([CH3:19])[O:13][SiH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:8][CH:7]=1
Reactant: Fc1ccc(CCS)cc1
Reactant: COC(=O)C(Cl)Cc1ccc(C(C)(C)O[SiH2]C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccc(C(C)(C)O[SiH2]C(C)(C)C)cc1)SCCc1ccc(F)cc1
Reaction time: 18 h

Procedure:
To a solution of 3-[4-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-2-chloro-propionic acid methyl ester (6.56 g, 42 mmol) in anhydrous DMF (200 mL) was added Cs2CO3 (14.34 g, 44 mmol) at 0° C. After stirring for 30 min 2-(4-fluoro-phenyl)-ethanethiol (13.72 g, 40 mmol), dissolved in anhydrous DMF (100 mL), was added dropwise and the resulting organe mixture was stirred for 18 h without removing the cooling bath. The mixture was diluted with Et2O and extracted with three times with H2O. The organic phase was concentrated under reduced pressure and the residue was dissolved in Et2O again and repeatedly extracted with H2O. After drying the separated organic layer over MgSO4, the solvent was removed under reduced pressure to afford the crude product as an orange oil which was purified by chromatography using n-heptane/EtOAc 20:1 as the eluent. The desired product was obtained as an oil (4.93 g, 25.4%). 1H NMR (400 MHz, CDCl3): δ 7.16 (d, 2H), 7.06-6.99 (m, 4H), 6.88 (t, 2H), 4.62 (s, 2H), 3.58 (s, 3H), 3.41 (dd, 1H), 3.10 (dd, 1H), 2.82 (dd, 1H), 2.74-2.76 (m, 4H), 0.85 (s, 9H), 0.00 (s, 6H).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C@:13]1([OH:46])[CH2:21][C@H:20]([CH2:22]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:19][C@@H:18]2[C@H:14]1[CH2:15][N:16]([C:34](=[O:45])[C@H:35]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[O:43][CH3:44])[CH3:36])[CH2:17]2>CN(C)C=O.O>[N:1]([CH2:22][C@@H:20]1[CH2:19][C@@H:18]2[C@@H:14]([CH2:15][N:16]([C:34](=[O:45])[C@H:35]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[O:43][CH3:44])[CH3:36])[CH2:17]2)[C@@:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH3:5])([OH:46])[CH2:21]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccccc1[C@H](C)C(=O)N1C[C@@H]2C[C@@H](COS(=O)(=O)c3ccc(C)cc3)C[C@@](O)(c3ccccc3OC)[C@@H]2C1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1[C@H](C)C(=O)N1C[C@@H]2C[C@@H](CN=[N+]=[N-])C[C@@](O)(c3ccccc3OC)[C@@H]2C1
Temperature: 20 °C
Reaction time: 20 h
Yield: 99.4 %

Procedure:
1.68 g of sodium azide are added to a solution, which has been brought to 50° C., of 9.0 g (3aS,4S,6R,7aR)-4-(2-methoxyphenyl)-2-[(S)-2-(2-methoxyphenyl)propionyl]-6-tosyloxymethylperhydroisoindol-4-ol in 50 cm3 of dimethylformamide. The reaction mixture is stirred at 20° C. for 20 hours and then diluted with 350 cm3 of water and subjected to extraction with 100 cm3 of ethyl acetate. The organic phase is washed with 100 cm3 of water, dried over magnesium sulphate and then concentrated to dryness under reduced pressure (2.7 kPa). 7.0 g of (3aS,4S,6R,7aR)-6-azidomethyl-4-(2-methoxyphenyl)-2-[(S)-2-(2-methoxyphenyl)propionyl]perhydroisoindol-4-ol are obtained in the form of a thick white foam.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=3[O:30][CH3:31])[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[C:5]([F:32])=[CH:4][N:3]=1.[OH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:31][O:30][C:23]1[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:22]=1[CH2:21][N:15]([C:16]1[S:17][CH:18]=[CH:19][N:20]=1)[S:12]([C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[OH:33])=[N:3][CH:4]=[C:5]2[F:32])(=[O:13])=[O:14]
Reactant: OB(O)c1ccccc1O
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)ncc(F)c3c2)c(OC)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccccc4O)ncc(F)c3c2)c(OC)c1

Procedure:
A microwave vial was charged with 1-chloro-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (Intermediate PPP; 0.075 g, 0.152 mmol), (2-hydroxyphenyl)boronic acid (0.031 g, 0.228 mmol), tetrakis(triphenylphosphine)palladium(0) (0.018 g, 0.015 mmol), and potassium carbonate (0.105 g, 0.759 mmol). Dioxane (0.759 mL) and Water (0.253 mL) were added; the vial was flushed with argon and sealed, and microwaved at 100° C. for 30 minutes. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (RediSep Gold 12 g, gradient elution 0-100% EtOAc:Heptane) to afford N-(2,4-dimethoxybenzyl)-4-fluoro-1-(2-hydroxyphenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide. (ESI) 522.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[CH:11]=[C:10]([CH3:12])[O:9][C:8]=12.C1C(=O)N([Br:20])C(=O)C1>C(#N)C>[Br:20][C:6]1[CH:5]=[N:4][C:3]([O:2][CH3:1])=[C:8]2[O:9][C:10]([CH3:12])=[CH:11][C:7]=12
Reactant: COc1nccc2cc(C)oc12
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COc1ncc(Br)c2cc(C)oc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.2 %

Procedure:
A solution of 7-methoxy-2-methylfuro[2,3-c]pyridine (3.2 g, 19.6 mmol) in ACN (30 mL) was treated with NBS (3.5 g, 19.7 mmol). After the mixture was stirred at rt for 18 h, it was concentrated in vacuo and purified by silica gel chromatography (PE/EA=30:1˜5:1) to afford the title compound (3.0 g, 64%) as a yellow solid. LCMS (M+H)+=243.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1.C([Li])CCC.C([O:19][C:20](=[O:26])[CH2:21][CH2:22][C:23]([CH3:25])=O)C>C(OCC)C>[S:4]1[CH:5]=[CH:6][C:2]([C:23]2([CH3:25])[O:26][C:20](=[O:19])[CH2:21][CH2:22]2)=[C:3]1[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1
Reactant: Brc1ccsc1-c1cccs1
Reactant: CCOC(=O)CCC(C)=O
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC1(c2ccsc2-c2cccs2)CCC(=O)O1
Reaction time: 0.25 h
Yield: 32.4 %

Procedure:
3-Bromo-2,2′-bithiophene (1.00 g, 4.08 mmol) in dry diethylether (35 mL) was added slowly to a solution of n-butyllithium (1.6 M in hexane, 2.50 mL, 4.08 mmol) in dry diethylether (35 mL) at −78° C. over 2 h under N2. The mixture was stirred for 15 minutes at the same temperature. Freshly distilled ethyllevulinate (0.58 mL, 4.08 mmol) was added to the mixture at −78° C., followed by stirring overnight at room temperature. The reaction was quenched with an aqueous NH4Cl-solution (2.5 M, 20 mL) and water (80 mL) at 0° C. The organic phase was separated and the aqueous phase was extracted with diethylether. The combined organic phases were washed with brine, dried over MgSO4 and evaporated under reduced pressure to give a crude oil. The oily residue was purified by gradient column chromatography (eluent hexane/EtOAc 95:5) to afford the title compound as a yellow oil (0.35 g, 28%). 1H-NMR (CDCl3): δ=7.38 (dd, J=5.1 Hz, J=1.3 Hz, 1H), 7.27 (d, J=5.3 Hz, 1H), 7.15 (d, J=5.3 Hz, 1H), 7.09 (dd, J=3.7 Hz, J=1.3 Hz, 1H), 7.04 (dd, J=5.1 Hz, J=3.7 Hz, 1H), 2.59-2.40 (m, 2H), 2.19-2.12 (m, 2H), 1.69 (s, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][CH:11]([NH:20][C:21]([N:23]3[CH2:28][CH2:27][CH:26]([N:29]4[CH2:38][C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[NH:31][C:30]4=[O:39])[CH2:25][CH2:24]3)=[O:22])[C:12](=[O:19])[N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH3:40][CH:41]([CH2:44][CH3:45])[CH:42]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][CH:11]([NH:20][C:21]([N:23]3[CH2:24][CH2:25][CH:26]([N:29]4[CH2:38][C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[NH:31][C:30]4=[O:39])[CH2:27][CH2:28]3)=[O:22])[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:40][CH:41]([CH3:42])[CH2:44][CH3:45])[CH2:15][CH2:14]3)=[O:19])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(NC(Cc1ccc2[nH]ncc2c1)C(=O)N1CCNCC1)N1CCC(N2Cc3ccccc3NC2=O)CC1
Reactant: CCC(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: CCC(C)CN1CCN(C(=O)C(Cc2ccc3[nH]ncc3c2)NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)CC1
Reaction time: 1 h
Yield: 50 %

Procedure:
A stirred solution of 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [1-(1H-indazol-5-ylmethyl)-2-oxo-2-piperazin-1-yl-ethyl]-amide (100 mg, 0.188 mmol) in methanol (25 mL) was treated with 2-methyl-butyraldehyde (0.03 ml, 0.376 mmol). After 1 h at room temperature, sodium triacetoxyborohydride (80 mg, 0.316 mmol) was added. The mixture was allowed to stir overnight. The solution was filtered through an SCX cartridge. The cartridge was eluted first with methanol and then with a 1M solution of ammonia in methanol. The solvent was removed in vacuo to give the desired product in 50% yield. LC/MS: tR=1.31 min, 601(MH)+.
Reaction SMILES: [Cl:1]Cl.[OH:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1>C(O)(=O)C>[Cl:1][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:4]=1[OH:3])[CH:8]=[O:9]
Reactant: O=Cc1ccc(O)cc1
Reactant: ClCl
Solvent: CC(=O)O
Product: O=Cc1ccc(O)c(Cl)c1
Reaction time: 2 h
Yield: 74.5 %

Procedure:
Acetic acid (300 ml) was bubbled with chlorine gas to make 38.38 g (0.541 mol) of chlorine. 4-Hydroxybenzaldehyde (66.1 g, 0.541 mol) was dissolved in acetic acid (300 ml) and stirred, during which the acetic acid solution containing chlorine as prepared above was slowly added thereto over 2 hours. The resulting mixture was stirred for further 2 hours. After completion of reaction, the reaction solution was concentrated. To the residue was added water (1L), which was then filtered, washed with water (500 ml) and dried to give 63.16 g (0.403 mol, Yield 75%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C1(C[C:21](O)=[O:22])C=CC=CC=1.C=O>C1C=CC=CC=1>[OH:1][C:2]1[C:3]([CH2:21][OH:22])=[C:4]([CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: O=C(O)Cc1ccccc1
Reactant: COc1ccc(CC(=O)O)cc1O
Agent: C=O
Solvent: c1ccccc1
Product: COc1ccc(CC(=O)O)c(CO)c1O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 83 %

Procedure:
11.0 g of 3-hydroxy-4-methoxyphenylacetic acid is dissolved in 550 ml of benzene and refluxed to remove water as azeotrope. Then, 14.0 g of benzeneboronic acid is added thereto, and refluxed for approximately 1 hour while removing the water produced. (In this reaction, the starting phenylacetic acid works as the carboxylic acid catalyst). At 2-3 hour intervals, each 2-3 g of paraformaldehyde is added while continuing the removal of water, and after the lapse of 9 hours an additional 1.0 g of benzeneboronic acid is added thereto. The reaction is completed within a period of 20 hours, and the solvent is completely distilled off under reduced pressure. The crystalline residue after addition of 150 ml of water is kept on an oil bath at 90°-100° C. for 1.5 hours under stirring. The reaction mixture is cooled to room temperature, and the precipitated crystals are collected and recrystallized from acetone-ether to give 9.70 g (83% yield) of 3-hydroxy-2-hydroxymethyl-4-methoxyphenylacetic acid as the δ-lactone having mp. 183°-185° C. IR νmaxCHCl 3 3540, 1740, 1600, 1277, 1030, 983cm-1. NMR (d6 -DMSO) δ 3.80 (3H. singlet), 3.65 (2H, singlet), 5.32 (2H, singlet), 6.70, 6.90 (AB quartet, J = 8.0 Hz), 8.07 (1H, singlet) ppm. Anal. Aclcd. for C10H10O4 : C, 61.85; H, 5.19 (%). Found: C, 61.70; H, 5.17 (%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](Cl)=[C:10]([C:15]#[N:16])[CH:11]=[N:12]2)=[CH:7][C:6]=1[O:18][CH3:19].[OH:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[CH3:28])[NH2:24].Cl.N1C=CC=CC=1>C(OCCO)C>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:24][C:23]3[CH:25]=[CH:26][C:27]([CH3:28])=[C:21]([OH:20])[CH:22]=3)=[C:10]([C:15]#[N:16])[CH:11]=[N:12]2)=[CH:7][C:6]=1[O:18][CH3:19]
Reactant: Cc1ccc(N)cc1O
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1OCCCl
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc2c(Nc3ccc(C)c(O)c3)c(C#N)cnc2cc1OCCCl
Yield: 67.1 %

Procedure:
By using the above method, starting with 3 g of 7-(2-chloro-ethoxy)-4-chloro-6-methoxy-quinoline-3-carbonitrile, 1.37 g of 3-hydroxy-4-methyl-aniline, and 1.2 g of pyridine hydrochloride in 31 ml of 2-ethoxyethanol, 2.6 g of the title compound was obtained as a crystalline solid: mass spectrum (electrospray, m/e) M+H 383.9.
Reaction SMILES: O.[NH2:2]N.C[N:5](C)/[CH:6]=[CH:7]/[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]=[C:18]3[CH:23]=[CH:22][C:21]([I:24])=[CH:20][N:19]3[CH:25]=2)=[CH:12][CH:11]=1)=O>C(O)C>[I:24][C:21]1[CH:22]=[CH:23][C:18]2[N:19]([CH:25]=[C:16]([C:13]3[CH:14]=[CH:15][C:10]([C:8]4[CH:7]=[CH:6][NH:5][N:2]=4)=[CH:11][CH:12]=3)[N:17]=2)[CH:20]=1
Reactant: NN
Reactant: CN(C)/C=C/C(=O)c1ccc(-c2cn3cc(I)ccc3n2)cc1
Solvent: CCO
Solvent: O
Product: Ic1ccc2nc(-c3ccc(-c4cc[nH]n4)cc3)cn2c1

Procedure:
Hydrazine monohydrate (100 μL) was added to a solution (30 mL) of (E)-3-(dimethylamino)-1-[4-(6-iodoimidazo[1,2-a]pyridin-2-yl)phenyl]-2-propen-1-one (344 mg) in ethanol, and the mixture was refluxed for 3 hours. The reaction mixture was left to cool, and the precipitated matter was recovered through filtration and dried, to thereby yield the title compound (290 mg).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1[C:14]([CH2:30][S:31][C:32]2[NH:36][C:35]3[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=3[N:33]=2)=[N:15][CH:16]=[CH:17][C:18]=1[O:19][CH2:20][CH2:21][O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>ClCCl>[CH3:12][C:13]1[C:14]([CH2:30][S:31]([C:32]2[NH:33][C:34]3[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=3[N:36]=2)=[O:9])=[N:15][CH:16]=[CH:17][C:18]=1[O:19][CH2:20][CH2:21][O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1c(OCCOCc2ccccn2)ccnc1CSc1nc2ccccc2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(OCCOCc2ccccn2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 79.1 %

Procedure:
0.16 g of m-chloroperbenzoic acid was added to a solution of 0.38 g of 2-[{3-methyl-4-(2-pyridylmethoxyethoxy)pyridine-2-yl}methylthio]-1H-benzimidazole in 20 ml of dichloromethane at -60° C. in a nitrogen atmosphere to obtain a mixture. This mixture was stirred for 0.5 hour. After the completion of the reaction, 0.16 g of triethylamine was added to the reaction mixture. The obtained mixture was heated to -10° C., followed by the addition of 30 ml of a saturated aqueous solution of sodium hydrogencarbonate. The obtained mixture was stirred at a room temperature for 0.5 hour and extracted with 50 ml of dichloromethane thrice. The extract was dried over magnesium sulfate and filtered. The filtrate was concentrated and dried in a vacuum to obtain a crude product. This crude product was crystallized from dichloromethane/diethyl ether to obtain 0.31 g of 2-[{3-methyl-4-(2-pyridylmethoxyethoxy)pyridine-2-yl}methylsulfinyl]-1H-benzimidazole as a white crystal.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](Cl)[C:17]2[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=2)[C:5]1=[O:25])(=O)C.[CH3:26][N:27]([CH2:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1)[CH3:28].[OH-].[Na+]>CN(C=O)C.CO>[CH3:28][N:27]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([NH:34]/[C:16](=[C:6]2\[C:5](=[O:25])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=3)/[C:17]2[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=2)=[CH:35][CH:36]=1)[CH3:26]
Reactant: CC(=O)N1C(=O)C(=C(Cl)c2cccc(C)c2)c2cc([N+](=O)[O-])ccc21
Reactant: CN(C)Cc1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1cccc(/C(Nc2ccc(CN(C)C)cc2)=C2/C(=O)Nc3ccc([N+](=O)[O-])cc32)c1

Procedure:
Prepared analogously to Example 2 from 1-acetyl-3-[1-chloro-1-(m-tolyl)-methylidene)-5-nitro-2-indolinone and 4-dimethylaminomethyl-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)C.[CH2:8]([C:12]1[CH:17]=[CH:16][C:15]([C:18](=[CH2:22])[C:19](=[O:21])[CH3:20])=[CH:14][CH:13]=1)[CH2:9][CH2:10][CH3:11]>CN(C)C=O>[CH2:8]([C:12]1[CH:13]=[CH:14][C:15]([C:18]2([C:19](=[O:21])[CH3:20])[CH2:4][CH2:22]2)=[CH:16][CH:17]=1)[CH2:9][CH2:10][CH3:11]
Reactant: C=C(C(C)=O)c1ccc(CCCC)cc1
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1ccc(C2(C(C)=O)CC2)cc1
Temperature: 0 °C
Yield: 61.9 %

Procedure:
507 mg of sodium hydride (55% in paraffin oil) is introduced into 20 ml of dimethylformamide under nitrogen at 0° C., and 1.38 g of trimethylsulfonium iodide is added. After 30 minutes at this temperature, 1.06 g of ketone 52 is added in drops to 4 ml of dimethylformamide. It is stirred for 1 more hour at 0° C., then quenched with sodium chloride solution, extracted with ethyl acetate, dried on sodium sulfate and concentrated by evaporation. After chromatography on silica gel with ethyl acetate/hexane, 702 mg of title compound 53 is obtained as a colorless oil.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[N:10]=[CH:9][N:8]([CH2:12][CH2:13][O:14][CH3:15])[C:7]=2[C:6](=[O:16])[NH:5][C:4]1=[O:17])[CH3:2].Cl[CH2:19][CH2:20][CH:21]([CH3:25])[C:22](=[O:24])[CH3:23]>>[O:24]=[C:22]([CH3:23])[CH:21]([CH3:25])[CH2:20][CH2:19][N:5]1[C:6](=[O:16])[C:7]2[N:8]([CH2:12][CH2:13][O:14][CH3:15])[CH:9]=[N:10][C:11]=2[N:3]([CH2:1][CH3:2])[C:4]1=[O:17]
Reactant: CC(=O)C(C)CCCl
Reactant: CCn1c(=O)[nH]c(=O)c2c1ncn2CCOC
Product: CCn1c(=O)n(CCC(C)C(C)=O)c(=O)c2c1ncn2CCOC

Procedure:
1-(4-Oxo-3-methylpentyl)-3-ethyl-7-(2-methoxyethyl)-xanthine (melting point 83-84° C.) is prepared from 3-ethyl-7-(2-methoxyethyl)xanthine and 1-chloro-3-methylpentan-4-one.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)[C:5]([Cl:22])=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[Cl:22][C:5]1[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)=[N:7][C:2]([NH:23][C:24]2[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=2)=[N:3][CH:4]=1
Reactant: NC(=O)C1(c2ccccc2CCc2nc(Cl)ncc2Cl)CC1
Reactant: Cn1cc(N)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Product: Cn1cc(Nc2ncc(Cl)c(CCc3ccccc3C3(C(N)=O)CC3)n2)cn1
Temperature: 120 °C
Yield: 56 %

Procedure:
A solution of 1-(2-(2-(2,5-dichloropyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide A14 (1.50 g, 4.46 mmol) in 1,4-dioxane (25 mL) containing 4-amino-1-methylpyrazole (0.520 g, 5.35 mmol) and p-toluenesulfonic acid (0.085 g, 0.45 mmol) was heated under microwave irradiation at 120° C. for 7 hours. The volatiles were removed in vacuo and the residue was adsorbed onto silica gel and the product was separated using silica column chromatography (Combiflash Rf, 40 g SiO2 Cartridge, 60-100% EtOAc in cyclohexane and then 0-5% MeOH in DCM) to give the title compound 13 as a light orange foam (1.01 g, 56%). 1H NMR (300 MHz, d6-DMSO) δ 9.64 (s, 1H), 8.37 (s, 1H), 7.87 (s, 1H), 7.46 (s, 1H), 7.22-7.36 (m, 4H), 7.00 (brs, 1H), 6.01 (brs, 1H), 3.81 (s, 3H), 3.09 (brs, 4H), 1.45-1.44 (m, 2H), 1.00-0.99 (m, 2H). LCMS-B: rt 6.318 min; m/z 397 [M+H]+.