Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([CH2:10][OH:11])[CH2:7][C:6]=2[CH:12]=1.CC1(C)N([O])C(C)(C)CCC1.[O-:24]Cl.[Na+].Cl>O.CC#N>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([C:10]([OH:24])=[O:11])[CH2:7][C:6]=2[CH:12]=1
Reactant: OCC1Cc2cc(Cl)ccc2O1
Reactant: [O-]Cl
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C(O)C1Cc2cc(Cl)ccc2O1
Temperature: 0 °C
Yield: 74 %

Procedure:
To a solution of (5-chloro-2,3-dihydro-1-benzofuran-2-yl)methanol (2 g, 11 mmol), KHCO3 (4.32 g, 43 mmol, 4 eq) and TEMPO (20 mg, 0.13 mmol, 0.1 eq) in water (8 ml) and CH3CN (18 ml) was added NaOCl (20 ml, aq. 15%, ˜4 eq) dropwise with stirring at 0° C. and stirred for 1 hour. The mixture was diluted with water (200 ml) and adjusted to pH˜4 with hydrogen chloride (2N). After extraction with ethyl acetate (3×200 ml), the organic layers were combined, washed with brine (200 ml), dried over anhydrous sodium sulfate, filtered, and then concentrated under vacuum. The crude material was purified by silica gel chromatography using 1% methanol in dichloromethane to elute. The product-containing fractions were combined and concentrated under vacuum to afford 5-chloro-2,3-dihydro-1-benzofuran-2-carboxylic acid as a yellow solid (1.6 g, 74%). 1H NMR (300 MHz, CDCl3): δ 7.05-7.22 (m, 2H), 6.83 (d, J=8.4 Hz, 1H), 5.20-5.30 (m, 1H), 3.56-3.65 (m, 1H), 3.33-3.45 (m, 1H)
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[C:9]([OH:11])[CH:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[N:6]=1)([CH3:3])[CH3:2].P(OCC)(OCC)OCC.[CH3:26][O:27][CH:28]=[C:29]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:40]Br)[C:30]([O:32][CH3:33])=[O:31].S>CCCCCCCC.O.[Cu].[Cu].O>[CH3:26][O:27][CH:28]=[C:29]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:40][O:11][C:9]1[CH:8]=[C:7]([C:12]([F:14])([F:15])[F:13])[N:6]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[N:10]=1)[C:30]([O:32][CH3:33])=[O:31]
Reactant: CC(C)Oc1nc(O)cc(C(F)(F)F)n1
Reactant: COC=C(C(=O)OC)c1ccccc1CBr
Agent: [Cu]
Agent: CCOP(OCC)OCC
Agent: S
Solvent: O
Solvent: CCCCCCCC
Product: COC=C(C(=O)OC)c1ccccc1COc1cc(C(F)(F)F)nc(OC(C)C)n1
Temperature: 100 °C
Reaction time: 5 h
Yield: 57.7 %

Procedure:
2.22 g of 2-isopropoxy-6-trifluoromethyl-4-hydroxypyrimidine and 0.86 g of copper suboxide were suspended in 30 ml of octane. The suspension was refluxed until no water was recognized to form, while formed water was being taken into a quantitative water receiver. 1.86 g of triethyl phosphite was added, and, 30 minutes later, 3.65 g of methyl 3-methoxy-2-(2-bromomethylphenyl)acrylate was added at an instance. The reaction was carried out for 5 hours at reflux of octane. The solution was cooled down to 100° C. Hydrogen sulfide gas was blown into the solution at a rate of 15-30 ml/min for an hour. The resultant was stirred for 30 minutes. The formed precipitate was filtrated and washed with 9 ml of octane. The mixed solution of the obtained filtrate and washing was analyzed with high-performance liquid chromatography. The reaction yield was 72%. Octane was concentrated under reduced pressure. To the residue were added 10.3 ml of ethanol and 3.9 ml of water, and heated to 64° C. to dissolve. The resulting solution was left to cool over night. 2.8 ml of a mixed solution of ethanol/water (7/1) was added to it and cooled down to 5° C. to deposit crystals fully. The crystals were filtrated, washed with 1.4 ml of a mixed solution of ethanol/water (7/1) twice to give 2.46 g (yield 67%) of the target compound with melting point of 109˜110° C.
Reaction SMILES: [CH:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]([OH:11])=[O:10])[CH:5]=1)([CH3:3])[CH3:2].[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[CH:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]([OH:11])=[O:10])[C:5]=1[N+:12]([O-:14])=[O:13])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(C)c1cc(C(=O)O)n[nH]1
Agent: O=S(=O)(O)O
Product: CC(C)c1[nH]nc(C(=O)O)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To an ice-cooled and stirred solution of 2.9 g (18.8 mmol) 5-isopropylpyrazol-3-carboxylic acid II (lit.: Baraldi P. G. et al: Farmaco, 46, 1337 (1991); mp=136-140° C.) in fuming sulphuric acid (65%) the nitric acid (65%) was added portion wise. The stirring was continued for 1 h at room temperature and then another 3 h at 104° C. temperature and then poured into ice-water. The white precipitate of product was filtered and crystallized from water; (yield 76%); mp=139-142° C.; 1H NMR (300 MHz, DMSO): 1.22 d (6H, 7.1 Hz), 2.94 sept (1H, 7.1 Hz), 3.33 s (1H), 6.45 bs (1H); CHN required: C=42.02%; H=4.56%; N=21.09; found: C=42.41%; H=4.49%; N=21.01%.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:28]([O:30]C)=[O:29])=[CH:12][C:13]=3[N:14]3[C:20]=2[C:19]2[CH:21]=[CH:22][CH:23]=[C:24]4[N:25]=[C:26]([CH3:27])[N:17]([C:18]=24)[CH2:16][CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>O.CO.C1COCC1.O[Li].O>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:28]([OH:30])=[O:29])=[CH:12][C:13]=3[N:14]3[C:20]=2[C:19]2[CH:21]=[CH:22][CH:23]=[C:24]4[N:25]=[C:26]([CH3:27])[N:17]([C:18]=24)[CH2:16][CH2:15]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCn1c(C)nc2cccc-3c21
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc2cccc3c2n1CCn1c-3c(C2CCCCC2)c2ccc(C(=O)O)cc21
Temperature: 60 °C
Yield: 68 %

Procedure:
Methyl 14-cyclohexyl-5-methyl-7,8-dihydroimidazo[4,5,1-jk]indolo[1,2-d][1,4]benzodiazepine-11-carboxylate was dissolved in a mixture of H2O/MeOH/THF (1/1/1) (0.015 M) and LiOH.H2O added (4.4 eq). The reaction was stirred with heating at 60° C. for 3 h, before being allowed to cool to RT, acidified with 1N HCl (aq). The volatiles were removed in vacuo and the residue purified by RP-HPLC (stationary phase: column WATERS X-TERRA prep. C18, 5 microns. Mobile phase: MeCN/H2O buffered with 0.1% TFA). Fractions containing the pure compound were combined and freeze dried to afford the title compound as a white powder (68%). 1H NMR (400 MHz, DMSO-d6, 300 K) δ 8.30 (s, 1H), 7.99 (d, 1H, J 8.6), 7.79 (d, 1H, J 7.6), 7.68 (d, 1H, J 8.6), 7.67-7.56 (m, 2H), 5.39-5.29 (m, 1H), 4.80-4.72 (m, 1H), 4.38-4.29 (m, 1H), 4.23-4.14 (m, 1H), 3.14-3.06 (m, 1H), 2.73 (s, 3H), 2.19-2.06 (m, 3H), 1.98-1.90 (m, 1H), 1.78-1.72 (m, 2H), 1.55-1.42 (m, 3H), 1.24-1.14 (m, 1H); MS (ES+) m/z 400 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:7]([CH2:20][CH3:21])[N:8]=[C:9]2[C:18]=1[C:17]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:11]=[C:10]2[NH2:19].[C:22]([O-:25])(=[O:24])[CH3:23].[K+].[I-].[Na+].CN(C=O)C>O>[C:22]([O:25][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:7]([CH2:20][CH3:21])[N:8]=[C:9]2[C:18]=1[C:17]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:11]=[C:10]2[NH2:19])(=[O:24])[CH3:23]
Reactant: CC(=O)[O-]
Reactant: CCn1nc2c(N)nc3ccccc3c2c1CCCCCl
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1nc2c(N)nc3ccccc3c2c1CCCCOC(C)=O
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 1.3 %

Procedure:
1-(4-Chlorobutyl)-2-ethyl-2H-pyrazolo[3,4-c]quinolin-4-amine (3.8 g, 12.5 mmol, prepared as described in Example 19) was combined with potassium acetate (3.68 g, 37.5 mmol), sodium iodide (470 mg, 3.12 mmol), and DMF (21 mL). The mixture was heated at 90° C. for 2 hours, allowed to cool to ambient temperature, diluted with water (100 mL), stirred for 20 minutes, and then filtered to remove a black solid. The filtrate was allowed to stand for 1 week at which time crystals had formed. The crystals were isolated by filtration, purified by chromatography on a HORIZON HPFC system (25+M cartridge eluting with chloroform/CMA in a gradient from 100:0 to 70:30), and then recrystallized from acetonitrile to provide 55 mg of 4-(4-amino-2-ethyl-2H-pyrazolo[3,4-c]quinolin-1-yl)butyl acetate as a tan crystalline solid, mp 128-129° C. MS (APCI) m/z 327 (M+H)+;
Reaction SMILES: [S:1]([C:16]1[CH:21]=[C:20]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:19]([OH:28])=[CH:18][C:17]=1[CH3:29])[C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[C:5]([OH:14])=[CH:4][C:3]=1[CH3:15].OO.[OH2:32].C(O)(=[O:35])C>>[S:1]([C:16]1[CH:21]=[C:20]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:19]([OH:28])=[CH:18][C:17]=1[CH3:29])([C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[C:5]([OH:14])=[CH:4][C:3]=1[CH3:15])(=[O:35])=[O:32]
Reactant: Cc1cc(O)c(C2CCCCC2)cc1Sc1cc(C2CCCCC2)c(O)cc1C
Reactant: O
Reactant: CC(=O)O
Agent: OO
Product: Cc1cc(O)c(C2CCCCC2)cc1S(=O)(=O)c1cc(C2CCCCC2)c(O)cc1C
Reaction time: 6 h

Procedure:
The semi-solid oily 4,4'-thiobis(6-cyclohexyl-3-methylphenol) is dissolved in acetic acid (100 ml), to which 35% hydrogen peroxide (9.7 g) is added at 40° C. over a period of 2 hours. Further, 35% hydrogen peroxide (20 g) is added thereto at 50°-60° C. over a period of 6 hours. After the reaction, water is added thereto and the water layer is decanted off. Dichloroethane is added to the resulting oily substance to allow precipitation. The crystals are filtered off and recrystallized from ethanol to give 4,4'-sulfonylbis(6-cyclohexyl-3-methylphenol), m.p. 301° C. (decomposition).
Reaction SMILES: Br[CH:2]([CH3:6])[C:3]([NH2:5])=[O:4].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([NH:17][C:18]2[CH:19]=[N:20][CH:21]=[C:22]([C:24]([C:26]3[C:34]4[CH:33]=[N:32][CH:31]=[N:30][C:29]=4[NH:28][CH:27]=3)=[O:25])[CH:23]=2)=[O:16])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([NH:17][C:18]2[CH:23]=[C:22]([C:24]([C:26]3[C:34]4[CH:33]=[N:32][CH:31]=[N:30][C:29]=4[N:28]([CH:2]([CH3:6])[C:3]([NH2:5])=[O:4])[CH:27]=3)=[O:25])[CH:21]=[N:20][CH:19]=2)=[O:16])=[CH:10][CH:9]=1
Reactant: CC(Br)C(N)=O
Reactant: O=C(Cc1ccc(Cl)cc1)Nc1cncc(C(=O)c2c[nH]c3ncncc23)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C(N)=O)n1cc(C(=O)c2cncc(NC(=O)Cc3ccc(Cl)cc3)c2)c2cncnc21
Temperature: 60 °C
Reaction time: 3 h
Yield: 34 %

Procedure:
2-bromopropionamide (46.5 mg, 0.31 mmol) was added to a mixture of 2-(4-chlorophenyl)-N-[5-(7H-pyrrolo[2,3-d]pyrimidin-5-ylcarbonyl)pyridin-3-yl]acetamide (Example 308, 100 mg, 0.26 mmol) and cesium carbonate (150 mg, 0.46 mmol) in DMF (1.3 mL). The mixture was stirred at 60° C. for 3 hours. The reaction mixture was cooled and water (10 mL) was added. The mixture was extracted with EtOAc (3×10 mL) and the combined organic phases were passed through a phase separator and evaporated in vacuo. Purification by preparative HPLC gave the title compound as a white solid in 34% yield, 15 mg.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH2:10][CH2:11][C:12](=[O:59])[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH2:21][N:22]([CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH2:23][C@@H:24]([C:33]2[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[C:39]3[C:34]=2[CH:35]=[CH:36][C:37](=[O:51])[NH:38]3)[O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH:15]=1)C)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:52]([N:22]([CH2:23][C@@H:24]([C:33]1[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[C:39]2[C:34]=1[CH:35]=[CH:36][C:37](=[O:51])[NH:38]2)[O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:27])[CH3:28])[CH2:21][CH2:20][C:16]1[CH:15]=[C:14]([NH:13][C:12](=[O:59])[CH2:11][CH2:10][CH2:9][NH:7][CH3:6])[CH:19]=[CH:18][CH:17]=1)[C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1
Reactant: CN(CCCC(=O)Nc1cccc(CCN(Cc2ccccc2)C[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(OCc3ccccc3)c3[nH]c(=O)ccc23)c1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCCCC(=O)Nc1cccc(CCN(Cc2ccccc2)C[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(OCc3ccccc3)c3[nH]c(=O)ccc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.6 %

Procedure:
To a stirred solution of {3-[3-(2-{benzyl-[(R)-2-(8-benzyloxy-2-oxo-1,2-dihydroquinolin-5-yl)-2-(tert-butyldimethylsilanyloxy)ethyl]amino}ethyl)-phenylcarbamoyl]propyl}methylcarbamic acid tert-butyl ester (276 mg, 0.331 mmol) in DCM (3 mL) at room temperature was added trifluoroacetic acid (2 mL, 20 mmol) and the resulting mixture was stirred at room temperature overnight. LC-MS (Method 2-90) showed product was present (Rt 2.69 min; m/z 7.33.4 [M+H]−). The reaction mixture was concentrated under reduced pressure and the residue was dissolved in DCM. This solution was washed with aqueous saturated sodium bicarbonate solution (2×), dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (249 mg, 100% yield) as a yellow-brown oil, which was used in the next reaction without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([O:6][C:7]1[C:8]([CH3:22])=[N:9][CH:10]=[C:11]([CH2:20]O)[C:12]=1[CH2:13][O:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5])[CH3:2].S(Cl)([Cl:25])=O>C1C=CC=CC=1>[ClH:25].[Cl:25][CH2:20][C:11]1[C:12]([CH2:13][O:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:7]([O:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:8]([CH3:22])=[N:9][CH:10]=1
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)OCc1c(CO)cnc(C)c1OC(=O)OCC
Solvent: c1ccccc1
Product: CCOC(=O)OCc1c(CCl)cnc(C)c1OC(=O)OCC
Product: Cl

Procedure:
To a solution of 0.1 mole of 3-ethoxycarbonyloxy-4-ethoxycarbonyloxymethyl-5-hydroxymethyl-2-methylpyridine in 200 ml. of benzene is added dropwise with stirring and cooling 0.15 moles of thionyl chloride. The reaction mixture is stirred for 1 hour and then filtered to give 5-chloromethyl-3-ethoxycarbonyloxy-4-ethoxycarbonyloxymethyl-2-methylpyridine hydrochloride.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:22][CH:21]=1)=[O:19])[C:13]([C:35]1[CH:40]=[CH:39][C:38]([O:41]CC3C=CC=CC=3)=[CH:37][CH:36]=1)=[C:12]2[CH3:49])C1C=CC=CC=1.C(O)C.C1CCC=CC=1>C1COCC1.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18]([C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH2:28][N:29]3[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]3)=[CH:24][CH:25]=1)=[O:19])[C:13]([C:35]1[CH:36]=[CH:37][C:38]([OH:41])=[CH:39][CH:40]=1)=[C:12]2[CH3:49]
Reactant: Cc1c(-c2ccc(OCc3ccccc3)cc2)n(C(=O)c2ccc(OCCN3CCCCC3)cc2)c2ccc(OCc3ccccc3)cc12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Solvent: C1=CCCC=C1
Product: Cc1c(-c2ccc(O)cc2)n(C(=O)c2ccc(OCCN3CCCCC3)cc2)c2ccc(O)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.1 %

Procedure:
To a solution of 0.78 g (0.00120 mol) of [5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-indol-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone (described above) in 5 mL of dry THF, and 5 mL of punctilious ethanol, under N2, was added 1.4 mL (0.0120 mol) of cyclohexadiene and 0.39 g (one-half the mass of the benzyloxy starting material) of 10% Pd/C, and stirred at room temperature overnight. The reaction mixture was filtered and evaporated to dryness in a rotary evaporator. 100 mL of ethyl acetate was added to the crude product. This organic phase was washed with water (2×50 mL), saturated brine, removed, dried over magnesium sulfate, filtered and evaporated to dryness in a rotary evaporator. The crude product when subjected to HPLC gave 0.30 g of pale-yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])=[N:5][CH:6]=[CH:7][CH:8]=1.[N+](N[C:18]1[NH:23][C:22](=[O:24])[C:21]([CH2:25][C:26]2[CH:31]=[C:30]([CH2:32][N:33]([CH3:35])[CH3:34])[CH:29]=[CH:28][N:27]=2)=[C:20]([CH3:36])[N:19]=1)([O-])=O>>[CH3:1][O:2][C:3]1[C:4]([CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:18]2[NH:23][C:22](=[O:24])[C:21]([CH2:25][C:26]3[CH:31]=[C:30]([CH2:32][N:33]([CH3:34])[CH3:35])[CH:29]=[CH:28][N:27]=3)=[C:20]([CH3:36])[N:19]=2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccnc1CCCCN
Reactant: Cc1nc(N[N+](=O)[O-])[nH]c(=O)c1Cc1cc(CN(C)C)ccn1
Product: COc1cccnc1CCCCNc1nc(C)c(Cc2cc(CN(C)C)ccn2)c(=O)[nH]1

Procedure:
Reaction of 4-(3-methoxypyridyl)butylamine with 2-nitroamino-5-(4-dimethylaminomethyl-2-pyridylmethyl)-6-methyl-4-pyrimidone gives 2-[4-(3-methoxypyridyl)butyl-amino]-5-(4-dimethylaminomethyl-2-pyridylmethyl)-6-methyl-4-pyrimidone.
Reaction SMILES: [CH3:1][C:2]([OH:6])([CH3:5])[CH:3]=[CH2:4].[CH2:7]([SiH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[CH3:8]>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl.C(O)CCC>[CH3:1][C:2]([OH:6])([CH3:5])[CH2:3][CH2:4][Si:9]([CH2:12][CH3:13])([CH2:10][CH3:11])[CH2:7][CH3:8]
Reactant: CC[SiH](CC)CC
Reactant: C=CC(C)(C)O
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: CCCCO
Product: CC[Si](CC)(CC)CCC(C)(C)O
Temperature: 80 °C
Yield: 81.1 %

Procedure:
Into a four-necked 500 mL-flask equipped with a stirring apparatus, a thermometer and a dropping funnel, 81.2 g (0.943 mole) of 3-methyl-1-buten-3-ol and 0.2 g of an n-butanol solution containing chloroplatinic acid at a concentration of 2 weight % were charged, and they were heated to 80° C. with stirring. From the dropping funnel, 109.6 g (0.943 mole) of triethylsilane was dropwise added into the four-necked flask. After the completion of the addition, they were heated and stirred for about 20 hours. Meanwhile, the proceeding of reaction was traced by gas chromatography analysis. At the stage when the proceeding of the reaction stopped, an additional mount of the above n-butanol solution containing chloroplatinic acid was added for the proceeding of the reaction. The reaction mixture was distilled under reduced pressure to obtain 154.9 g (0.765 mole) of 1,1-dimethyl-3-(triethylsilyl)propyl alcohol as a fraction at 105° C./14-16 torr.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH:27]=[CH:26][NH:25][C:24]2=[O:28])=[CH:19][CH:18]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:25]1[CH:26]=[CH:27][N:23]([C:20]2[CH:19]=[CH:18][C:17]([O:16][CH3:15])=[CH:22][CH:21]=2)[C:24]1=[O:28])[CH3:13]
Reactant: COc1ccc(-n2cc[nH]c2=O)cc1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Product: COc1ccc(-n2ccn([C@H](C)[C@@]3(c4ccc(F)cc4F)CO3)c2=O)cc1
Yield: 25 %

Procedure:
In the same manner as in Reference Example 5, starting from 1.66 g of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 1.26 g of 1-(4-methoxyphenyl)-2(1H,3H)-imidazolone, 1-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-3-(4-methoxyphenyl)-2(1H,3H)-imidazolone (617 mg) was obtained as colorless prisms.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[Cl:10][CH2:11][C:12]([CH2:14]Cl)=O.C(COC)OC>C(O)C>[Cl:9][C:5]1[CH:6]=[C:7]([Cl:8])[C:2]2[N:3]([CH:14]=[C:12]([CH2:11][Cl:10])[N:1]=2)[CH:4]=1
Reactant: O=C(CCl)CCl
Reactant: Nc1ncc(Cl)cc1Cl
Solvent: CCO
Solvent: COCCOC
Product: ClCc1cn2cc(Cl)cc(Cl)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
A mixture of 2-amino-3,5-dichloropyridine (Aldrich; 5.12 g), 1,3-dichloroacetone (Aldrich; 4.68 g), and dimethoxyethane (28 mL) is stirred overnight at room temperature. Ethanol (28 mL) is then added and the mixture is refluxed for 7.5 h and then stirred overnight at room temperature. The mixture is then refluxed for an additional 24 h and is then concentrated under reduced pressure and partitioned between saturated aq. sodium bicarbonate and dichloromethane. The combined organic layers are washed with brine, dried with MgSO4, and concentrated under reduced pressure. The residue is adsorbed to silica gel and chromatographed on silica gel using ethyl acetate/chloroform (10/90), followed by a second chromatography of the combined product fractions using methanol/dichloromethane (2/98), to give 2.22 g of 6,8-dichloro-2-(chloromethyl)imidazo[1,2-a]pyridine in three crops after crystallization from methanol/dichloromethane; mp 162-163° C.; MS m/z 234, 236, 238; IR (mineral oil) 994, 808, 861, 1522, 3056 cm-1, 1H NMR (CDCl3) δ 4.79, 7.69, 8.10.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH:13]1([C:17](O)=[O:18])[CH2:16][CH2:15][CH2:14]1.C(N(CC)CC)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.O[Li].O>C(Cl)Cl.O>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:17]([CH:13]3[CH2:16][CH2:15][CH2:14]3)=[O:18])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: O=C(O)C1CCC1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li]O
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)C1CCC1
Temperature: 25 °C
Reaction time: 42 h
Yield: 71.2 %

Procedure:
A mixture of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.869 mmol, Example 1, Step H), cyclobutanecarboxylic acid (218 mg, 2.17 mmol) and triethylamine (606 μL, 4.35 mmol) in CH2Cl2 (10 mL) at room temperature was treated with BOP-Cl (203 mg, 2.17 mmol). The reaction was stirred at room temperature for 42 hours. The reaction mixture was then treated with 2M LiOH.H2O (2 mL) and stirred at room temperature for 18 hours. Water (10 mL) was added to the reaction mixture, and the solid formed was filtered, washed with additional water, and dried to provide N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclobutanecarboxamide (193 mg, 71% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 12.04 (br s, 1H), 9.33 (s, 1H), 8.33 (d, 1H), 7.57 (s, 1H), 3.29-3.24 (m, 1H), 2.25-2.18 (m, 2H), 2.15-2.08 (m, 2H), 1.98-1.88 (m, 1H), 1.86-1.78 (m, 1H); LCMS (APCI+) m/z 311.9, 314.0 (M+H)+, Retention time=2.96 minutes (Method 2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[C:27]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])[CH:26]=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.[CH3:37][O:38][N:39]([CH3:49])[C:40](=[O:48])[CH2:41][N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:45]3[CH2:44][CH2:43][N:42]([CH2:41][C:40]([N:39]([O:38][CH3:37])[CH3:49])=[O:48])[CH2:47][CH2:46]3)=[O:21])[C:10]([C:23]3[CH:28]=[C:27]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])[CH:26]=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CON(C)C(=O)CN1CCNCC1
Reactant: CCOc1ccc(C(C)(C)C#N)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1ccc(C(C)(C)C#N)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N(C)OC)CC1

Procedure:
2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-[5-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl}-piperazin-1-yl)-N-methoxy-N-methyl-acetamide was prepared from (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-[5-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl chloride (example 12e) and N-methoxy-N-methyl-2-piperazin-1-yl-acetamide (example 16b) in an analogous manner as described in example 25. LR-MS: 691.3 [(M+H)+]
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([SH:11])[C:5]=2[CH:4]=[CH:3][N:2]=1.Cl[C:13]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][C:16]2[N:17]([CH2:21][CH3:22])[C:18]([CH3:20])=[N:19][C:15]=2[CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:21]([N:17]1[C:16]2[CH:23]=[C:24]([N+:25]([O-:27])=[O:26])[C:13]([S:11][C:6]3[CH:7]=[CH:8][CH:9]=[C:10]4[C:5]=3[CH:4]=[CH:3][N:2]=[CH:1]4)=[CH:14][C:15]=2[N:19]=[C:18]1[CH3:20])[CH3:22]
Reactant: Sc1cccc2cnccc12
Reactant: CCn1c(C)nc2cc(Cl)c([N+](=O)[O-])cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1c(C)nc2cc(Sc3cccc4cnccc34)c([N+](=O)[O-])cc21
Temperature: 130 °C
Reaction time: 3 h
Yield: 42.5 %

Procedure:
5-Isoquinolinethiol 500 mg (3.1 mmol) was dissolved in DMF 20 ml, 5-chloro-1-ethyl-2-methyl-6-nitro-1H-benzo[d]imidazole 910 mg (3.1 mmol) and potassium carbonate 1.29 g (9.3 mmol) were added, and the mixture was stirred for 3 hours at 130° C. The reaction mixture was concentrated under reduced pressure, the residue was crystallized with ethyl acetate, and 1-ethyl-5-(5-isoquinolylsulfanyl)-2-methyl-6-nitro-1H-benzo[d]imidazole 480 mg (42.3%) was obtained.