Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O)#[N:26]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[C:25]#[N:26])[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: N#Cc1ccccc1B(O)O
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(-c4ccccc4C#N)cc32)N=C1N
Temperature: 120 °C
Yield: 13.3 %

Procedure:
Pd(PPh3)2Cl2 (10 mg, 0.01 mmol) in a 10 mL flask under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 2-cyanophenylboronic acid (15.3 mg, 0.104 mmol). The mixture was heated at 120° C. under Ar in a microwave reactor for 30 min. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative HPLC twice to give pure 2-(2′-amino-1′-methyl-5′-oxo-2-phenyl-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile (2.83 mg, 13%). 1H-NMR (MeOD): 2.48-2.60 (m, 2H), 3.33 (s, 3H), 5.26 & 5.88 (m, 1H), 7.17 (m, 1H), 7.37-7.60 (m, 9H), 7.70 (m, 1H), 7.81 (m, 1H).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][N:13]3[C:18]([C:20]3[N:21]=[C:22]([CH3:32])[S:23][C:24]=3[C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:19])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cu][C:34]#[N:35].O>CN1CCCC1=O>[C:34]([C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][N:13]3[C:18]([C:20]3[N:21]=[C:22]([CH3:32])[S:23][C:24]=3[C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)=[O:19])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)#[N:35]
Reactant: Cc1nc(C(=O)N2CCCCC2Cc2nc3c(Br)cccc3[nH]2)c(-c2ccc(F)cc2)s1
Reactant: N#C[Cu]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1nc(C(=O)N2CCCCC2Cc2nc3c(C#N)cccc3[nH]2)c(-c2ccc(F)cc2)s1
Yield: 3 %

Procedure:
A mixture of (RS)-1-[2-(4-bromo-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluorophenyl)-2-methylthiazol-4-yl]methanone, E66 (216 mg, 0.42 mmol) and copper(I)cyanide (76 mg, 0.84 mmol) in N-methylpyrrolidinone (15 ml) was heated at reflux for 3 h. The reaction mixture was cooled, poured into water and extracted with ethyl acetate (2×). Solid sodium chloride was added to the aqueous layer which was further extracted with ethyl acetate (2×). The combined organic extracts were washed with brine, dried (Na2SO4) and the solvent removed in vacuo. The residue was Chromatographed (silica gel, 10-100% ethyl acetate-hexane then 1-20% methanol-ethyl acetate). Further purification by HPLC (Supercosil ABZ+, 5-95% acetonitrile containing 0.1% trifluoroacetic acid-water containing 0.1% trifluoroacetic acid) afforded the title compound as a pale brown amorphous solid (5.3 mg, 3%).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH2:6]Br.[P:17]([O:24]CC)([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20]>>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH2:6][P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20]
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)OCC
Temperature: 160 °C
Yield: 40.5 %

Procedure:
A mixture of 3,5-bis-trifluoromethylbenzyl bromide (5.0 g, 16 mmol) and triethyl phosphite (3.4 g, 20 mmol) was heated at 160° C. for 20 hours. The reaction mixture was cooled and distilled at 83° C. (0.03 mm Hg) to give 2.36 g of the product as a colorless oil in 48% yield. D.C.I.M.S. [MH+, 365].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2OC(=O)[S:10][N:9]=2)=[C:4]([O:14][CH3:15])[CH:3]=1.[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])#[N:17]>ClC1C=CC=CC=1Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[S:10][N:9]=2)=[C:4]([O:14][CH3:15])[CH:3]=1
Reactant: CCOC(=O)C#N
Reactant: COc1cc(Cl)ccc1-c1nsc(=O)o1
Solvent: Clc1ccccc1Cl
Product: CCOC(=O)c1nc(-c2ccc(Cl)cc2OC)ns1
Temperature: 150 °C
Yield: 19.1 %

Procedure:
To a solution of 5-(4-chloro-2-methoxyphenyl)-1,3,4-oxathiazol-2-one (1.32 g, 5.42 mmol) in 1,2-dichlorobenzene (5 ml) was added ethyl cyanoformate (2.20 ml, 21.67 mmol). The resulting reaction mixture was refluxed for 24 h at 150° C. After the completion of the reaction (TLC monitoring), the reaction mass was as such (direct loading) purified through flash chromatography (100-200 M silica, 5% EtOAc-Hexane) to get the desired product (0.31 g, 19%). LCMS: 299.29 (M+H)+, 98.99%.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C(=O)(O)[O-].[Cs+].[CH2:20](Br)[CH2:21][CH2:22][CH3:23]>C1COCC1.CCOC(C)=O>[CH2:20]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCCBr
Reactant: COC(=O)c1ccc2c(c1)NCCC2
Agent: O=C([O-])O
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCN1CCCc2ccc(C(=O)OC)cc21
Temperature: 25 °C
Yield: 67.1 %

Procedure:
To a stirred solution of methyl 1,2,3,4-tetrahydroquinoline-7-carboxylate (180 mg, 0.94 mmol) and cesium bicarbonate (1.5 g, 4.7 mmol) in THF (2 mL) was added n-butyl bromide (1.0 mL, 9.4 mmol), and the reaction mixture was heated at reflux for 48 h. The reaction mixture was cooled to room temperature, and diluted with EtOAc. The organic layer was washed with water, and brine, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 1:3 ethyl acetate/hexanes) afforded methyl 1-butyl-1,2,3,4-tetrahydroquinoline-7-carboxylate (156 mg): ESI MS m/z 248 [M+H]+.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Cl:11][C:12]1[C:13]([CH3:28])=[N:14][N:15]2[C:20]([Cl:21])=[C:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:18]([CH3:27])=[N:17][C:16]=12.C1(C2[O:37]N2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1>C1COCC1>[Cl:11][C:12]1[C:13]([CH3:28])=[N:14][N:15]2[C:20]([Cl:21])=[C:19]([CH:22]([OH:37])[C:23]([O:25][CH3:26])=[O:24])[C:18]([CH3:27])=[N:17][C:16]=12
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Reactant: COC(=O)Cc1c(C)nc2c(Cl)c(C)nn2c1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C(O)c1c(C)nc2c(Cl)c(C)nn2c1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 52.6 %

Procedure:
To a stirred solution of KHMDS (0.5 M in toluene, 1.04 mL) in THF (5 mL) at −78° C. was added a solution of methyl 2-(3,7-dichloro-2,5-dimethylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (0.15 g, 0.5 mmol) in THF (5 mL) over 20 mins. The reaction mixture was stirred at −78° C. for 30 min. A solution of 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (0.16 g, 0.63 mmol) in THF (5 mL) was added over 10 min and the resulted reaction mixture was stirred for an additional 30 min at −78° C. The reaction mixture was quenched with saturated NH4Cl aqueous solution (2 mL). The mixture was allowed to warm up to room temperature and diluted with EtOAc (100 mL). The organic phase was washed with water and brine and dried with sodium sulfate. The solvent was evaporated. Purification by silica gel chromatography provided the title compound (80 mg, 30%). Used as is in the next step.
Reaction SMILES: C([N:8]1[C@H:22]([CH3:23])[CH2:21][N:11]2[C:12](=[O:20])[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[CH2:19][C@@H:10]2[CH2:9]1)C1C=CC=CC=1.[H][H]>[Pd].CO>[CH3:23][C@@H:22]1[CH2:21][N:11]2[C:12](=[O:20])[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[CH2:19][C@@H:10]2[CH2:9][NH:8]1
Reactant: [H][H]
Reactant: C[C@@H]1CN2C(=O)c3ccccc3C[C@@H]2CN1Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1CN2C(=O)c3ccccc3C[C@@H]2CN1
Yield: 99.6 %

Procedure:
(3R,11aR)-1,2,3,4,11,11a-Hexahydro-2-benzyl-3-methyl-pyrazino[1,2-b]isoquinolin-6-one (81 mg, 0.26 mmol) and 10% palladium on carbon (25 mg) in methanol (6.5 ml) was stirred under a balloon of hydrogen for 19 h. Evapoaration of the filtrate after filtration through Celite® afforded pure (3R,11aR)-1,2,3,4,11,11a-hexahydro-3-methyl-pyrazino[1,2-b]isoquinolin-6-one (56 mg, 83% yield). MS (ESI) 217 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[I-].[CH2:45]([N+:49]1[N:53]=[C:52]([CH3:54])[S:51][C:50]=1[CH3:55])[CH2:46][CH2:47][CH3:48]>>[CH2:45]([N:49]1[N:53]=[C:52]([CH3:54])[S:51]/[C:50]/1=[CH:55]\[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[CH3:1])=[O:6])[CH2:46][CH2:47][CH3:48]
Reactant: Cc1ccccc1C(=O)O
Reactant: CCCC[n+]1nc(C)sc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1N=C(C)S/C1=C\C(=O)c1ccccc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 2-methylbenzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.84-0.93 (m, 3 H) 1.27-1.37 (m, 2 H) 1.67-1.75 (m, 2 H) 2.36, (s, 3 H) 2.47 (s, 3 H) 4.11-4.17 (m, 2 H) 6.19-6.25 (m, 1 H) 7.17-7.26 (m, 2 H) 7.26-7.33 (m, 1 H) 7.43-7.51 (m, 1 H); MS (ESI) m/z 289 (M+H)+.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([C:7]([OH:9])=O)=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:44]1[CH2:49][CH2:48][O:47][CH2:46][CH:45]1[C:50]1[C:58]2[S:57][C:56]([NH2:59])=[N:55][C:54]=2[C:53]([O:60][CH3:61])=[CH:52][CH:51]=1>C1COCC1.C(Cl)(Cl)Cl>[O:44]1[CH2:49][CH2:48][O:47][CH2:46][CH:45]1[C:50]1[C:58]2[S:57][C:56]([NH:59][C:7](=[O:9])[C:4]3[CH:3]=[CH:2][C:1]([CH3:10])=[CH:6][CH:5]=3)=[N:55][C:54]=2[C:53]([O:60][CH3:61])=[CH:52][CH:51]=1
Reactant: Cc1ccc(C(=O)O)cc1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccc(C)cc3)nc12

Procedure:
From para-toluic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+35.1° (c=0.84, CHCl3), ES-MS m/e (%): 385 (M+H+, 100).
Reaction SMILES: C(O)(=O)C.[N:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:23])=[CH:12][C:13]([O:15]CC2C=CC=CC=2)=[O:14])=[CH:7][CH:6]=1>CO>[N:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:23])[CH2:12][C:13]([OH:15])=[O:14])=[CH:7][CH:6]=1
Reactant: CC(=CC(=O)OCc1ccccc1)c1ccncc1
Solvent: CO
Solvent: CC(=O)O
Product: CC(CC(=O)O)c1ccncc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.6 %

Procedure:
Next, methanol (31 ml) and acetic acid (0.71 ml, 12.4 mmol) were added to benzyl 3-(4-pyridyl)-2-butenate (1.75 g, 6.20 mmol), and a nitrogen gas was bubbled through the mixture at room temperature for 10 minutes. A catalytic amount of 10%-palladium on carbon was added to the mixture, and the whole was stirred under a hydrogen atmosphere at room temperature overnight. The resulting insoluble matter was filtered out, and the filtrate was concentrated under reduced pressure. The resulting crystals were filtered off with acetone to give 3-(4-pyridyl)butyric acid (0.61 g, 60%) as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[Cl:18][C:19]1[CH:20]=[C:21]([NH2:33])[CH:22]=[CH:23][C:24]=1[O:25][CH2:26][CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH3:30]>>[Cl:18][C:19]1[CH:20]=[C:21]([NH:33][C:6](=[O:8])[CH2:5][O:4][C:3]2[CH:9]=[CH:10][C:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[CH:12][C:2]=2[Cl:1])[CH:22]=[CH:23][C:24]=1[O:25][CH2:26][CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH3:30]
Reactant: O=C(O)COc1ccc(-c2cccs2)cc1Cl
Reactant: CCN(CC)CCOc1ccc(N)cc1Cl
Product: CCN(CC)CCOc1ccc(NC(=O)COc2ccc(-c3cccs3)cc2Cl)cc1Cl

Procedure:
The product was prepared according to general working method I from 2-chloro-4-thiophen-2-yl-phenoxy)-acetic acid (131b) and 3-chloro-4-(2-diethylamino-ethoxy)-phenylamine (Z1b).
Reaction SMILES: [C:1]([CH:6]([C:18](O)=[O:19])[NH:7]C(OCC1C=CC=CC=1)=O)([O:3][CH2:4][CH3:5])=[O:2].P(Cl)(Cl)(Cl)(Cl)Cl.[NH2:27][C:28]1[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:29]=1[C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=O.Br>C(O)(=O)C.C(Cl)Cl.CN(C)C=O>[CH2:4]([O:3][C:1]([CH:6]1[N:7]=[C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[NH:27][C:18]1=[O:19])=[O:2])[CH3:5]
Reactant: Nc1cc(Cl)ccc1C(=O)c1ccccc1
Reactant: CCOC(=O)C(NC(=O)OCc1ccccc1)C(=O)O
Agent: Br
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)C1N=C(c2ccccc2)c2ccc(Cl)cc2NC1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A suspension of 45.0 g. of 2-carbethoxy-N-(benzyloxycarbonyl)glycine in 120 ml. of dry methylene chloride, cooled to -20° C., is treated portionwise with 30 g. of phosphorus pentachloride and stirred for 30 minutes at -20° C. to -10° C. To the now clear solution, there is added at the same temperature a solution of 27.7 g. of 2-amino-4-chlorobenzophenone and 1 ml. of dimethylformamide in 120 ml. of dry methylene chloride. The mixture is concentrated under reduced pressure at 40°-45° C. The residue in partitioned between methylene chloride and 10% aqueous soda solution and the methylene chloride phase is dried over sodium sulfate and evaporated to dryness. There is obtained a reddish-colored resin of crude 2'-benzoyl-2-[(benzyloxycarbonyl)amino]-2-carbethoxy-5'-chloroacetanilide, which is then immediately reacted with 130 ml. of a 33% solution of hydrobromic acid in glacial acetic acid. After stirring at room temperature for 90 minutes, the obtained solution is concentrated at 45° C. and the oily residue partitioned between water and ether. The aqueous solution is made weakly alkaline with solid sodium bicarbonate while cooling with ice. The separated base is extracted with methylene chloride and the extracts are dried over sodium sulfate and evaporated to dryness. The resulting oil is dissolved in a mixture of 180 ml. of toluene and 180 ml. of glacial acetic acid and heated at 80° C. for 90 minutes. The solution is concentrated to an oil and is crystallized from ether so that there is obtained 8-chloro-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-carboxylic acid ethyl ester, having a melting point of 214°-217° C. (decomposition). Recrystallization from acetonitrile does not increase the melting point.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]#[N:27])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([O:22][CH2:23][CH3:24])[C:17]([O:19]CC)=[O:18])[C:10](=[O:25])[CH:9]=2)[CH:7]=1.[OH-].[Li+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]#[N:27])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([O:22][CH2:23][CH3:24])[C:17]([OH:19])=[O:18])[C:10](=[O:25])[CH:9]=2)[CH:7]=1
Reactant: CCOC(=O)C(OCC)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Agent: [Li+]
Agent: [OH-]
Product: CCOC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
277 mg (0.69 mmol) of ethyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl](ethoxy)acetate (racemate) were hydrolysed with lithium hydroxide according to General Method 6B. Yield: 180 mg (71% of theory)
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH:40]([CH3:42])[CH3:41]>CN(C=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH:40]([CH3:42])[CH3:41])[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)I
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(O)cc2n1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)C)n(Cc3ccccc3)c2c1

Procedure:
Following General Procedure A, 1-benzyl-N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 8, 8.0 mg, 0.018 mmol) in DMF (1.0 ml) was reacted with K2CO3 (8.0 mg, 0.055 mmol) and 2-iodopropane (9.0 μl, 0.092 mmol) to yield the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[CH2:13][N:12]([CH:17]([CH:22]([CH3:24])[CH3:23])[C:18]([O:20][CH3:21])=[O:19])[CH2:11]3)=[CH:4][CH:3]=1.[CH2:25]([C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1)[CH2:26][CH2:27][CH2:28][CH3:29]>>[CH3:23][CH:22]([CH3:24])[CH:17]([N:12]1[CH2:11][C:10]2[C:14](=[CH:15][CH:16]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:34](=[O:35])[C:33]4[CH:37]=[CH:38][C:30]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:31][CH:32]=4)=[CH:7][CH:6]=3)[CH:9]=2)[CH2:13]1)[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)C(C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1
Reactant: CCCCCc1ccc(C(=O)Cl)cc1
Product: CCCCCc1ccc(C(=O)Nc2ccc(-c3ccc4c(c3)CN(C(C(=O)OC)C(C)C)C4)cc2)cc1
Yield: 22 %

Procedure:
The compound of example 675 was prepared analogous to the compound of example 663 by reaction of compound of example 673 with 4-(n-pentyl)benzoyl chloride.
Reaction SMILES: [C:1]([C:3]1[CH:23]=[CH:22][C:6]([CH2:7][C:8]2([OH:21])[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:5][CH:4]=1)#[N:2].[ClH:24].O1CCOCC1>O1CCOCC1>[ClH:24].[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:8]2([OH:21])[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[CH:22][CH:23]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(Cc2ccc(C#N)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1ccc(CC2(O)CCNCC2)cc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a solution of tert-butyl 4-(4-cyanobenzyl)-4-hydroxypiperidine-1-carboxylate (19 g) in 1,4-dioxane (50 mL) was added 4.0 M HCl/1,4-dioxane solution (76 mL) at 0° C., and the mixture was stirred at room temperature for 10 hr. The resulting solid was collected by filtration, washed with ethyl acetate (100 mL) and diethyl ether (200 mL), and dried under reduced pressure to give the title compound (9.3 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][O:28][CH2:29][CH3:30])=[O:24])[C:5]1=[O:31].C(N(C(C)C)CC)(C)C.[Cl-].[CH3:42][N:43]([CH:45]=[O:46])[CH3:44]>>[CH3:42][N:43]([CH3:44])[C:45]([NH:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][O:28][CH2:29][CH3:30])=[O:24])[C:5]1=[O:31])=[O:46]
Reactant: CCOCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN)c1=O
Reactant: CN(C)C=O
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Product: CCOCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCNC(=O)N(C)C)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1-(2-aminoethyl)-N-[2-(ethyloxy)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (0.02 g, 0.047 mmol) and diisopropyl ethylamine (0.041 mL, 0.24 mmol) in DMF (5 mL) under nitrogen was treated with N,N-dimethyl carbonyl chloride (0.0043 mL, 0.047 mmol) at ambient temperature. After 2 h, an additional 0.001 mL of the chloride was added and the was stirred at ambient temperature for an additional 6 h. The reaction was concentrated in vacuo and the resulting residue suspended in DMSO and water, filtered, then washed with water and Et2O before drying in vacuo to provide the title compound as an off-white solid: 1H NMR (400 MHz, DMSO-D6) δ ppm 1.1 (t, J=7.0 Hz, 3 H), 2.7 (s, 6 H), 3.3 (d, J=7.0 Hz, 2 H), 3.5 (q, J=7.0 Hz, 2 H), 3.5 (s, 4 H), 4.1 (s, 2 H), 4.2 (t, J=6.1 Hz, 2 H), 6.6 (m, 1 H), 7.1 (t, J=8.9 Hz, 2 H), 7.4 (dd, J=8.8, 5.5 Hz, 2 H), 8.3 (s, 1 H), 8.5 (s, 1 H), 10.4 (s, 1 H); ES+ MS: 500 (M+H+).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](Br)[CH:13]=1)(=[O:3])[CH3:2].[Cl:27][C:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[CH:30][N:29]=1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:32]2[CH:31]=[CH:30][N:29]=[C:28]([Cl:27])[CH:33]=2)[CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(Br)c1
Reactant: OB(O)c1ccnc(Cl)c1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(-c2ccnc(Cl)c2)c1

Procedure:
By carrying out the operation analogously to example 1, starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IX, and 2-chloro-4-pyridineboronic acid, the desired product is obtained in the form of an ecru solid (yield=55%).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1[CH3:12])[CH3:2].[Cl-].C[Al+]C.[CH3:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([C:28](Cl)=[O:29])=[CH:20][CH:19]=1>ClCCl>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:28]([C:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:18]([CH3:17])=[CH:19][CH:20]=2)=[O:29])=[C:4]1[CH3:12])[CH3:2]
Reactant: Cc1ccc(C(=O)Cl)c2ccccc12
Reactant: CCn1c(C)cc2ccccc21
Agent: C[Al+]C
Agent: [Cl-]
Solvent: ClCCl
Product: CCn1c(C)c(C(=O)c2ccc(C)c3ccccc23)c2ccccc21
Reaction time: 0.75 h

Procedure:
To a solution of 0.20 g (1.26 mmol) of 1-ethyl-2-methylindole in 4 mL of dry dichloromethane at 0° C. under argon, was added dropwise 0.17 g (1.89 mmol) of dimethylaluminum chloride. The solution was stirred at this temperature for 45 min and then 0.39 g (1.88 mmol) of 4-methyl-1-napthoyl chloride in 6 mL of dry dichloromethane was added, and the solution stirred at 0° C. for 4 hrs. The solution was carefully quenched by the addition of 1M HCl and extracted with dichloromethane (2×20 mL). The combined organic extract were washed with a saturated solution of NaHCO3, H2O, brine, dried (MgSO4), filtered and concentrated in vacuo. The oil was purified by chromatography (ethyl acetate/petroleum ether 1:9) to afford the desired compound as an orange solid 0.16 g (40%), recrystallization from petroleum ether/ether provided white crystals, mp 136-137° C.: 1H NMR (300 MHz, CDCl3) δ 1.42 (t, J=7.3 Hz, 3H), 2.51 (s, 3H), 2.80 (s, 3H), 4.25 (q, J=7.3 Hz, 2H), 6.92-7.05 (m, 1H), 7.17-7.29 (m, 2H), 7.32-7.39 (m, 2H), 7.46-7.53 (m, 2H), 7.54-7.61 (m, 1H), 8.11 (d, J=8.3 Hz, 1H), 8.21 (d, J=8.3 Hz, 1H); 13C NMR (300 MHz, CDCl3) δ 12.3, 14.75, 19.9, 38.0, 109.2, 115.1, 121.4, 121.9, 122.2, 124.3, 125.8, 126.1, 126.3, 126.5, 127.3, 130.5, 132.9, 135.6, 136.7, 138.9, 145.1, 193.6; GC/MS (EI) m/z (rel intensity) 327 (100), 312 (80), 186 (60), 115 (20). Anal. Calcd for C23H21NO: C, 84.37; H, 6.46; N, 4.28. Found C23H21NO: C, 84.23; H, 6.48; N, 4.29.