Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:9]2)[CH:5]=[N:4][C:3]=1[C:22]#[N:23].[H-].[Na+].I[CH3:27]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:14]([CH3:27])[C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20])[CH2:9]2)[CH:5]=[N:4][C:3]=1[C:22]#[N:23]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2cnc(C#N)c(Cl)n2)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)[C@@H]1CCCN(c2cnc(C#N)c(Cl)n2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(R)-tert-Butyl 1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-ylcarbamate (87, 550 mg, 1.63 mmol) was dissolved in 20 mL DMF. To it was added NaH (60% in mineral oil, 98 mg, 2.45 mmol). The mixture was stirred at RT for 30 min, and then iodomethane (305 μL, 4.89 mmol) was added. It was stirred for 1.5 hour, diluted with 120 mL EtOAc, washed with water ×3, dried, concentrated, and subjected to flash column using 0 to 50% EtOAc in hexane to isolate (R)-tert-butyl 1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-yl(methyl)carbamate (293). It was treated with 20 mL commercial 4N HCl in dioxane at RT for 1 hour, and the mixture was concentrated in vacuo to dryness. It was dissolved in 5 mL DMF and 15 mL dioxane. To it were added DIEA (1.45 mL, 8.15 mmol) and then dimethylcarbamoyl chloride (300 μL, 3.26 mmol). The mixture was stirred at RT for overnight, diluted with 120 mL EtOAc, washed with water ×2, dried, concentrated, and subjected to silica flash column using 0 to 5% MeOH in DCM to isolate (R)-1-(1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-yl)-1,3,3-trimethylurea (294, 490 mg, 93% overall) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](Cl)[C:3]=1[CH:4]=[O:5].[CH3:11][S-:12].[Na+].O>CN(C)C=O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([S:12][CH3:11])[C:3]=1[CH:4]=[O:5]
Reactant: C[S-]
Reactant: O=Cc1c(Cl)cccc1Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1cccc(Cl)c1C=O
Temperature: 25 °C

Procedure:
To a solution of 2,6-dichlorobenzaldehyde (20 g, 114.28 mmol) in N,N-dimethylformamide (200 ml), sodium thiomethoxide (8.81 g, 125.7 mmol) was added at 0° C. The reaction mixture was allowed to warm to room temperature overnight, then poured into water. A yellow precipitate was collected by vacuum filtration and dried to afford 2-chloro-6-(methylthio)benzaldehyde (11. g), as a light yellow solid. (This method is general for other 2-haloaldehydes). 1H NMR (300 MHz, CDCl3): 10.6 (s, 1H), 7.4 (t, 1H), 7.2 (dd, 2H), 2.4 ppm (s, 3H). MW=187 confirmed by LC-MS, tr=13.18 min (Method Y) MH+=188.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:22])([CH3:21])[C:14]2[O:15]CC(C)(C)N=2)=[CH:9][CH:8]=1)=[O:6].Cl.[O:24]1CCOCC1>>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:8]=[CH:9][C:10]([C:13]([CH3:22])([CH3:21])[C:14]([OH:15])=[O:24])=[CH:11][CH:12]=1)=[O:6]
Reactant: CC1(C)COC(C(C)(C)c2ccc(C(=O)CCCCl)cc2)=N1
Reactant: C1COCCO1
Agent: Cl
Product: CC(C)(C(=O)O)c1ccc(C(=O)CCCCl)cc1

Procedure:
A mixture of 4-(4-chloro-1-oxobutyl)-α,α-dimethyl-α-(4,4-dimethyloxazolin-2-yl)toluene, prepared according to Example 3, (47.8 g, 0.15 mole), 150 mL concentrated hydrochloric acid, and 150 mL 1,4-dioxane is brought to reflux for 18 hours. The mixture is extracted three times with ethyl acetate. The organics are washed with saturated NaCl solution, dried over MgSO4, and concentrated. Crude product is purified by column chromatography using silica gel, and eluting with hexane/ethyl acetate/acetic acid. Cleaner fractions are combined and recrystallized from methylene chloride/hexanes to afford 4-(4-chloro-1-oxobutyl)-α,α-dimethylphenylacetic acid.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH:3]([NH2:14])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.[C:17]1([S:27](Cl)(=[O:29])=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1>N1C=CC=CC=1.CCOCC>[F:16][C:2]([F:1])([F:15])[CH:3]([NH:14][S:27]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)(=[O:29])=[O:28])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: NC(Cc1c[nH]c2ccccc12)C(F)(F)F
Solvent: c1ccncc1
Solvent: CCOCC
Product: O=S(=O)(NC(Cc1c[nH]c2ccccc12)C(F)(F)F)c1cccc2ccccc12
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A mixture of 100 mg (0.44 mmol) of 2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethylamine and 99 mg (0.44 mmol) of 1-naphthylsulfonyl chloride in 4 mL of pyridine was warmed at 70° C. After 3 hours, the mixture was cooled and concentrated to afford a thick oily residue. The residue was diluted with ether and washed twice with 10% aqueous acetic acid and brine, dried over sodium sulfate, decanted and concentrated in vacuo. The crude material was crystallized from ether-hexanes to afford 102 mg (55%) as off white needles, MS: m/z 419.3 (M+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH3:18][C:19]1[C:23]([C:24]([N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)=[O:25])=[C:22]([CH3:33])[NH:21][C:20]=1[CH:34]=O>C(O)C.N1CCCCC1>[CH3:18][C:19]1[C:23]([C:24]([N:26]2[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]2)=[O:25])=[C:22]([CH3:33])[NH:21][C:20]=1[CH:34]=[C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[CH:16][C:8]=2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[NH:12][C:11]1=[O:17]
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCN(C)CC1
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(F)c4)c32)c(C)c1C(=O)N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 56.7 %

Procedure:
To a solution of 4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide 3-[3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-(3-fluoro-phenyl)1,3-dihydro-indol-2-one as a yellow solid (65 mg, 57%)
Reaction SMILES: [CH2:1]([NH:10][CH2:11][CH2:12][NH:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:20](N1C=CN=C1)(N1C=CN=C1)=[O:21]>>[CH2:1]([N:10]1[CH2:11][CH2:12][N:13]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[C:20]1=[O:21])/[CH:2]=[CH:3]/[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C(=C/c1ccccc1)\CNCCNc1cccnc1
Product: O=C1N(C/C=C/c2ccccc2)CCN1c1cccnc1
Yield: 70.3 %

Procedure:
By treating 2.53 g of (E)-N-cinnamyl-N'-(3-pyridyl)ethylenediamine and 1.63 g of carbonyldiimidazole in the same manner as in Example 106-(2), 1.96 g of (E)-1-cinnamyl-3-(3-pyridyl)-2-imidazolidinone was obtained.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:35])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]2[CH:33]=[N:32][CH:31]=[N:30]2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:14][C:12]1[C:11]([C:15]([F:16])([F:18])[F:17])=[CH:10][C:9]2[NH:19][C:20](=[O:35])[CH2:21][C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N:29]4[CH:33]=[N:32][CH:31]=[N:30]4)[CH:24]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3cncn3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3cncn3)c1)=N2

Procedure:
The title compound was prepared from {5-methyl-2-[3-oxo-3-(3-[1,2,4]triazol-1-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M51) (0.41 g, 0.81 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (255 mg, 81%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH:23]1[CH2:27][CH2:26][CH2:25][C:24]1=[O:28]>CC(=O)CC.[I-].[K+]>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH:23]2[CH2:27][CH2:26][CH2:25][C:24]2=[O:28])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: O=C1CCCC1Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C1CCCC1Oc1ccc(OCc2ccccc2)cc1
Yield: 34 %

Procedure:
To a mixture of 4-benzyloxyphenol (5 g, 25 mmol), potassium iodide (125 mg), and potassium carbonate (4.48 g, 32.5 mmol) in 2-butanone (30 ml) was added 2-chlorocyclopentanone (5.9 g, 50 mmol). The mixture was heated at reflux for 5 h, filtered and concentrated in vacuo. The residue was dissolved in diethyl ether and washed successively with 10% aqueous sodium hydroxide, water and brine. After drying over magnesium sulfate, solvents were removed in vacuo and the residue subjected to flash chromatography on silica gel eluting with 30% diethyl ether in hexanes to afford the title compound as a pale orange solid (2.4 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]2[C:7](=[N:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]([O:17][CH3:18])=[CH:5][CH:4]=1.N1C(C)=CC=CC=1C.[F:27][C:28]([F:41])([F:40])[S:29]([O:32]S(C(F)(F)F)(=O)=O)(=[O:31])=[O:30]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[C:16]2[C:7](=[N:8][C:9]3[C:14]([C:15]=2[O:32][S:29]([C:28]([F:41])([F:40])[F:27])(=[O:31])=[O:30])=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]([O:17][CH3:18])=[CH:5][CH:4]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COc1ccc(OC)c2nc3ccccc3cc12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COc1ccc(OC)c2c(OS(=O)(=O)C(F)(F)F)c3ccccc3nc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
To a solution of 1,4-dimethoxyacridine (prepared as described in Ionescu and Mester (1969)) (1.0 g, 3.9 mmol) in dry CH2Cl2 (18 ml) under N2 were successively added DMAP (95 mg, 0.8 mmol), 2,6-lutidine (0.6 ml, 55 mmol) and trifluoromethane-sulfonic anhydride (0.8 ml, 4.7 mmol) and the reaction mixture was stirred at 0° C. for 2 h and then for 1 h at rt. The solution was washed with H2O, dried and evaporated. The residue was purified by column chromatography when elution with hexane/CH2Cl2 (1:1) to give the title compound (1.3 g, 87%), as a yellow solid. IR (KBr): ν/cm−1=1253 (s, SO), 1030 (s, SO); 1H NMR (200 MHz, CDCl3): δH/ppm=4.04 (s, 3H, OCH3), 4.14 (s, 3H, OCH3), 6.83 (d, J=8.4 Hz, 1H, H-2), 7.01 (d, J=8.4 Hz, 1H, H-3), 7.68 (dd, J=8.5 and 7.8 Hz, 1H, H-7), 7.86 (dd, J=8.5 and 7.8 Hz, 1H, H-6), 8.22 (d, J=8.5 Hz, 1H, H-5), 8.43 (d, J=8.5 Hz, 1H, H-8); 13C NMR (50.3 MHz, CDCl3): δC/ppm=55.2 (q, OCH3) 56.3 (q, OCH3), 104.2 (d, C-2), 106.6 (d, C-3), 113.3 (s, C-9a), 118.5 (q, CF3), 119.1 (s, C-8a), 120.7 (d, C-7), 122.5 (s, C-4a), 127.6 (d, C-6), 129.8 (d, C-8), 130.9 (d, C-5), 144.2 (s, C-10a), 147.2 (s, C-1), 148.7 (s, C-4), 148.8 (s, C-9); MS (EI); m/z (%)=388 [M+1] (9), 387 [M+] (42), 254 (100), 226 (69); HRMS: calcd. for C16H12F3NO5S 387.0388; found 387.0394.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11]([O:15][C:16]([NH:18][CH:19]1[C:25](=[O:26])[NH:24][C:23]2[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=2[NH:21][CH2:20]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].Br[CH2:32][C:33]([O:35][CH3:36])=[O:34]>C1COCC1.C(OCC)(=O)C>[CH3:36][O:35][C:33](=[O:34])[CH2:32][N:24]1[C:25](=[O:26])[C@@H:19]([NH:18][C:16]([O:15][C:11]([CH3:14])([CH3:12])[CH3:13])=[O:17])[CH2:20][NH:21][C:22]2[CH:30]=[CH:29][CH:28]=[CH:27][C:23]1=2
Reactant: COC(=O)CBr
Reactant: CC(C)(C)OC(=O)NC1CNc2ccccc2NC1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CNc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
A 1.0 M solution of lithium bis(trimethylsilyl)amide (3.4 ml, 3.4 mmol) in THF was added dropwise to a −78° C. solution of 3-tert-butoxycarbonylamino-1,3,4,5-tetrahydrobenzo[b][1,4]diazepin-2-one (0.94 g, 3.38 mmol) in 20 ml of anhydrous tetrahydrofuran and stirred for 30 minutes. Methyl bromoacetate (o0.44 ml, 4 mmol) was added dropwise to the reaction mixture then warmed to room temperature. The reaction was diluted with 100 ml of ethyl acetate and washed with 0.3N potassium hydrogen sulfate (50 ml), water (2×50 ml), and brine. The combined organics were dried over anhydrous sodium sulfate, filtered, and evaporated to afford a gum that was purified by flash chromatography eluting with 3:7 EtOAc/Hex. to give 0.98 g (83%) of the title compound as a white solid. 1H NMR (CDCl3) δ7.15-7.07 (2H, m), 6.98-6.94 (1H, m), 6.88-6.84 (1H, d), 5.62-5.55 (1H, d), 4.71-4.65 (1H, d), 4.65-4.6 (1H, m), 4.33-4.27 (1H, d), 3.96-3.90 (1H, m), 3.78 (3H, s), 3.44-3.37 (1H, m), 1.4 (9H, s).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].CCN(CC)CC.Cl.[NH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[C:24]2[B:25]([OH:32])[O:26][CH:27]([CH2:28][N+:29]([O-:31])=[O:30])[C:23]=2[CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[OH:32][B:25]1[C:24]2[C:19]([O:18][CH2:17][CH2:16][CH2:15][NH:14][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:20][CH:21]=[CH:22][C:23]=2[CH:27]([CH2:28][N+:29]([O-:31])=[O:30])[O:26]1
Reactant: CS(=O)(=O)Cl
Reactant: NCCCOc1cccc2c1B(O)OC2C[N+](=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)NCCCOc1cccc2c1B(O)OC2C[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
MsCl (0.99 mL, 13 mmol) was added slowly to a solution of Et3N (2.85 mL, 20.5 mmol) and 7-(3-amino-propoxy)-3-nitromethyl-3H-benzo[c][1,2]oxaborol-1-ol hydrochloride (1.55 g, 5.12 mmol) in CH2Cl2 (50 mL) at 0° C. (bath temp). The reaction mixture was stirred at rt for 1 h and then quenched with H2O (50 mL). The mixture was extracted with CH2Cl2 and the organic fractions were dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (30% EtOAc in hexane) to give the title compound as a viscous liquid: yield 500 mg (28%).
Reaction SMILES: [CH2:1]([S:8][CH:9]([CH:38]=O)[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([O:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:18][C:17]=2[NH:28][S:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)(=[O:31])=[O:30])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:40]1[CH2:45][CH2:44][S:43][CH2:42][CH2:41]1.O1CCCC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[CH2:1]([S:8][CH:9]([CH2:38][N:40]1[CH2:45][CH2:44][S:43][CH2:42][CH2:41]1)[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([O:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:18][C:17]=2[NH:28][S:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)(=[O:31])=[O:30])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CSCCN1
Reactant: COCCOc1cc(NS(=O)(=O)c2ccccn2)c2[nH]c(C(=O)NCC(C=O)SCc3ccccc3)cc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCCOc1cc(NS(=O)(=O)c2ccccn2)c2[nH]c(C(=O)NCC(CN3CCSCC3)SCc3ccccc3)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.9 %

Procedure:
A mixture of N-[2-(benzylthio)-3-oxopropyl]-5-(2-methoxyethoxy)-7-[(pyridin-2-ylsulfonyl)amino]-1H-indole-2-carboxamide (800 mg), thiomorpholine (290 mg) and tetrahydrofuran (30 mL) was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (450 mg) was added at room temperature, and the mixture was stirred at room temperature for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (3:2-1:4, volume ratio) to give the title compound (590 mg, yield 64%) as colorless crystals. The crystals were recrystallized from acetone-hexane to give colorless prism crystals. melting point 160-161° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[CH:12]1([CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([F:29])=[C:21]3[C:26]=2[NH:25][CH:24]=[C:23]([I:27])[C:22]3=[O:28])[CH2:14][CH2:13]1.[CH2:30](I)[CH3:31]>O>[CH:12]1([CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([F:29])=[C:21]3[C:26]=2[N:25]([CH2:30][CH3:31])[CH:24]=[C:23]([I:27])[C:22]3=[O:28])[CH2:13][CH2:14]1
Reactant: CCI
Reactant: O=c1c(I)c[nH]c2c(OCC3CC3)ccc(F)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1cc(I)c(=O)c2c(F)ccc(OCC3CC3)c21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 76.6 %

Procedure:
Potassium carbonate (450 mg, 3.26 mmol) was added to a DMF solution (5 ml) of 8-cyclopropylmethoxy-5-fluoro-3-iodo-1H-quinolin-4-one (910 mg, 2.53 mmol). The mixture was stirred for 15 minutes at room temperature. Ethyl iodide (0.31 ml, 3.87 mmol) was added thereto, and the resulting mixture was stirred at 60° C. for 2 hours. After the reaction mixture was cooled to room temperature, water was added, and the resulting mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure and the residue was then purified by silica gel column chromatography (dichloromethane:ethyl acetate=40:1→15:1). The purified product was concentrated to dryness under reduced pressure to thereby obtain 750 mg of powdery pale dark brown 8-cyclopropylmethoxy-1-ethyl-5-fluoro-3-iodo-1H-quinolin-4-one (yield: 77%).
Reaction SMILES: [CH2:1]([OH:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl.[CH3:11][N:12]([CH3:16])[CH2:13][CH2:14]Cl.O>CN(C=O)C>[CH3:11][N:12]([CH3:16])[CH2:13][CH2:14][O:7][CH2:1][C:2]1[O:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccco1
Reactant: CN(C)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCOCc1ccco1
Reaction time: 0.25 h
Yield: 24.3 %

Procedure:
Furfuryl alcohol (10.0 g, 102 mmol) was dissolved in DMF (200 ml) and sodium hydride (60% dispersion in oil, 9.00 g, 225 mmol) was added under ice-cooling. The mixture was stirred for 15 min at the same temperature. Then, 2-dimethylaminoethyl chloride hydrochloride (15.4 g, 107 mmol) was added under ice-cooling and the mixture was stirred at the same temperature for 30 min and at room temperature for 3.5 hr. Water (200 ml) was added to the reaction mixture under ice-cooling and the mixture was extracted with diethyl ether (2×500 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography (20:1 chloroform-methanol) to give the title compound (4.19 g, 24%) as a red-brown liquid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.[CH:12](O)([CH3:14])[CH3:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:12]([CH3:14])[CH3:13])=[C:4]([Cl:11])[N:3]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: CC(C)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)n1cnc2c(Cl)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 77 %

Procedure:
2,6-Dichloropurine (2 mmol), isopropanol (8 mmol) and triphenylphosphine (4 mmol) were taken up in 40 ml anhydrous tetrahydrofuran and diisoproplyazidodicarboxylate (4 mmol) was added drop wise at room temperature over a period of 30 min. The reaction mixture was then stirred at room temperature for a further 24 h. The reaction was periodically monitored by TLC or LC-MS. The reaction mixture was poured in to a beaker containing ice-cold water. Extraction of the aqueous layer, using 3×100 ml portions of ethyl acetate, afforded the crude product. This was purified by chromatography on a silica gel column (10-80% ethyl acetate in petroleum ether, gradient elution), to give 2,6-dichloro-9-isopropyl-9H-purine in a yield of 77%.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([OH:35])([C:29]2[N:33]([CH3:34])[CH:32]=[N:31][CH:30]=2)[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:20])[C:15](=[O:21])[CH:14]=[C:13]3[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)=[CH:5][CH:4]=1.[NH:36]1[CH:40]=[CH:39][N:38]=[CH:37]1.C([O-])([O-])=O.[K+].[K+].O>CC#N>[Cl:28][C:24]1[CH:23]=[C:22]([C:13]2[C:12]3[C:17](=[CH:18][CH:19]=[C:10]([C:9]([OH:35])([C:6]4[CH:7]=[CH:8][C:3]([CH2:2][N:36]5[CH:40]=[CH:39][N:38]=[CH:37]5)=[CH:4][CH:5]=4)[C:29]4[N:33]([CH3:34])[CH:32]=[N:31][CH:30]=4)[CH:11]=3)[N:16]([CH3:20])[C:15](=[O:21])[CH:14]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: Cn1cncc1C(O)(c1ccc(CCl)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cn1cncc1C(O)(c1ccc(Cn2ccnc2)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Yield: 13.4 %

Procedure:
A mixture of (±)-6-[[4-(chloromethyl)phenyl]hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone (described in Example B14) (0.00039 mol), 1-H-imidazole (0.00079 mol) and K2CO3 (0.0016 mol) in CH3CN (2 ml) was stirred and refluxed for 4 hours, poured out into H2O and extracted with CH2Cl2. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue (0.2 g) was purified twice by column chromatography over kromasil (eluent: CH2Cl2/CH3OH/NH4OH 97/3/0.5 then CH3OH/H2O 60/40; 10 μm). The pure fractions were collected and the solvent was evaporated, yielding 0.028 g (13%) of (±)-4-(3-chlorophenyl)-6-[hydroxy[4-(1H-imidazol-1-ylmethyl)phenyl](1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)-quinolinone, as a white foam, MS (ESI) m/z:536, 538 (MH+).
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([CH:24]4[CH2:28][CH2:27][C:26](=O)[CH2:25]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:4][CH2:3]1.C[CH2:32][N:33](CC)[CH2:34]C.CNC.C1COCC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:30][C:2]1([F:1])[CH2:3][CH2:4][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([CH:24]4[CH2:28][CH2:27][CH:26]([N:33]([CH3:34])[CH3:32])[CH2:25]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:6][CH2:7]1
Reactant: CCN(CC)CC
Reactant: O=C1CCC(c2ccc3c(C(=O)NCC4(O)CCC(F)(F)CC4)c(Cl)ccc3n2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CNC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)C1CCC(c2ccc3c(C(=O)NCC4(O)CCC(F)(F)CC4)c(Cl)ccc3n2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.4 %

Procedure:
To a stirred solution of 6-chloro-2-(3-oxo-cyclopentyl)-quinoline-5-carboxylic acid (4,4-difluoro-1-hydroxycyclohexylmethyl)-amide (0.30 g, 0.28 mmol, 1.00 eq) in DCM (15.00 ml, 50.00 V) were added Et3N (0.09 g, 0.84 mmol, 3.00 eq) and dimethylamine solution 2.0 M in THF (0.70 mL, 1.40 mmol, 5.00 eq) at 0° C., and warmed to room temperature. The reaction mixture was stirred at RT for 1 h and sodium triacetoxyborohydride (0.09 g, 0.42 mmol, 1.50 eq) was added and the reaction mixture was stirred at RT for 16 h and the solvent was removed under vacuum. The crude product was purified by prep HPLC to provide 6-chloro-2-(3-dimethylaminocyclopentyl)-quinoline-5-carboxylic acid (4,4-difluoro-1-hydroxy-cyclohexyl methyl)-amide (0.03 g, 0.06 mmol, 22.3%, Brown solid). 1H NMR (400 MHz, DMSO-d6): δ 8.81 (t, J=5.82 Hz, 1H), 8.01-7.96 (m, 2H), 7.76-7.74 (m, 1H), 7.60-7.56 (m, 1H), 7.56-3.28 (m, 1H), 3.27-3.25 (m, 2H), 2.68-2.57 (m, 1H), 2.56-2.48 (m, 1H), 2.25-2.16 (m, 1H), 2.15-2.07 (m, 6H), 2.06-1.96 (m, 5H), 1.96-1.90 (m, 4H), 1.88-1.83 (m, 2H), 1.78-1.72 (m, 1H), 1.30-1.24 (m, 2H). m/z: 450.2 [M+H]+