Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].S(Cl)([Cl:18])(=O)=O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:5]=[C:6]([Cl:18])[C:7]=1[OH:8]
Reactant: COC(=O)CCc1ccc(O)c(Br)c1
Reactant: O=S(=O)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COC(=O)CCc1cc(Cl)c(O)c(Br)c1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
A solution of Intermediate 5 (516 mg) in chloroform (5 ml) was added with sulfuryl chloride (177 μl), and stirred at room temperature for 21 hours. The reaction mixture was poured into aqueous saturated sodium hydrogencarbonate (20 ml), and extracted with ethyl acetate. The organic layer was successively washed with saturated aqueous sodium hydrogencarbonate, saturated aqueous ammonium chloride, and saturated brine and dried, and then the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (Quad, hexane:ethyl acetate=10:1) to obtain the title compound (Intermediate 6, 290 mg).
Reaction SMILES: Br.O[CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[CH:6][CH:5]=1.S(Cl)([Cl:16])=O>>[ClH:16].[Cl:16][CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[CH:6][CH:5]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccnc2ccccc12
Agent: Br
Product: Cl
Product: ClCc1ccnc2ccccc12
Yield: 80.7 %

Procedure:
A reaction mixture of 4-(hydroxymethyl)-quinoline hydrobromide (2.0 g, 12.6mmol) and thionylchloride (20 mL) was heated to reflux for 2 hours. This was allowed to cool and then concentrated in vacuum. The green solid was treated with ethyl ether, filtered, washed with ethyl ether and dried in vacuum to yield 4-(chloromethyl)-quinoline hydrochloride (2.17 g, 80.7%).
Reaction SMILES: C(O)(=O)C.[NH:5]1[CH2:10][CH2:9][CH:8]([CH:11]([NH:13][CH:14]=[O:15])[CH3:12])[CH2:7][CH2:6]1.[Cl:16][C:17]1[N:22]=[C:21](Cl)[CH:20]=[CH:19][N:18]=1.C(N(C(C)C)C(C)C)C>C(O)C>[Cl:16][C:17]1[N:22]=[C:21]([N:5]2[CH2:10][CH2:9][CH:8]([CH:11]([NH:13][CH:14]=[O:15])[CH3:12])[CH2:7][CH2:6]2)[CH:20]=[CH:19][N:18]=1
Reactant: CC(NC=O)C1CCNCC1
Reactant: Clc1ccnc(Cl)n1
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(NC=O)C1CCN(c2ccnc(Cl)n2)CC1

Procedure:
N-(1-Piperidin-4-yl-ethyl)-formamide; compound with acetic acid (350 mg, 1.61 mmol), 2,4-dichloro-pyrimidine (265 mg, 1.78 mmol) and ethyl-diisopropyl-amine (848 mg, 6.56 mmol) in 20 ml of ethanol were heated under reflux for 5 hours. The mixture was evaporated and the residue dissolved in water and extracted with ethyl acetate. The organic layer was dried with MgSO4 and evaporated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH:13]=O)=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16].N1CCCCC1.C(O)(=O)[CH2:26][C:27]([OH:29])=[O:28].Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11](/[CH:13]=[CH:26]/[C:27]([OH:29])=[O:28])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:15]([F:16])([F:17])[F:18]
Reactant: O=Cc1ccc(-c2ccc(Cl)c(C(F)(F)F)c2)o1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)/C=C/c1ccc(-c2ccc(Cl)c(C(F)(F)F)c2)o1
Temperature: 0 °C
Yield: 500.2 %

Procedure:
5-(4-chloro-3-(trifluoromethyl)phenyl)furan-2-carbaldehyde (3.32 g, 13.4 mmol) was dissolved in pyridine (16.6 ml) and piperidine (0.66 ml) was added. Malonic acid (1.67 g, 1.61 mmol) was added and the reaction mixture was refluxed for 4 h. Cooled reaction mixture was poured into a solution of ice (100 ml) water (100 ml) and conc. HCl (100 ml). The precipitate was filtered and washed with cold water and recrystallised from ethanol to afford 2.55 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 6.44 (d, 1H), 7.08 (d, 1H), 7.40 (m, 1H), 7.43 (d, 1H), 7.81 (d, 1H), 8.14 (m, 1H), 8.21 (m, 1H), 12.44 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([F:9])=[C:7]([F:10])[C:6]([N+:11]([O-])=O)=[C:5]([N:14]2[C:18](=[O:19])[C:17]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]3[C:15]2=[O:24])[C:4]=1[F:25].[H][H]>C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[C:8]([F:9])=[C:7]([F:10])[C:6]([NH2:11])=[C:5]([N:14]2[C:18](=[O:19])[C:17]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]3[C:15]2=[O:24])[C:4]=1[F:25]
Reactant: COc1c(F)c(F)c([N+](=O)[O-])c(N2C(=O)c3ccccc3C2=O)c1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1c(F)c(F)c(N)c(N2C(=O)c3ccccc3C2=O)c1F
Yield: 75.8 %

Procedure:
1.3 g of 5% w/w palladium-on-carbon was added to a solution of 4.2 g (0.012 mole) of 4-methoxy-2-phthalimido-3,5,6-trifluoro-1-nitrobenzene (XXXIV) [prepared as described in Step (F1) above] in 150 ml of acetic acid, and the mixture was agitated vigorously for 1 hour in an atmosphere of hydrogen. At the end of this time, the reaction mixture was filtered, the filtrate was concentrated by evaporation under reduced pressure. and the solid which separated was washed with toluene, to afford 2.93 g of 4-methoxy-2-phthalimido-3,5,6-trifluoroaniline (XXXV) as colorless sandy crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=O)=O)=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.Cl.C(CCP(CCC(O)=O)CCC(O)=O)(O)=O>O1CCOCC1.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[C:4]([C:12]([F:15])([F:13])[F:14])[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1C(F)(F)F
Agent: Cl
Agent: O=C(O)CCP(CCC(=O)O)CCC(=O)O
Solvent: O
Solvent: C1COCCO1
Product: FC(F)(F)c1cc(Br)ccc1S
Yield: 93.9 %

Procedure:
To a mixture of 4-bromo-2-trifluoromethyl-benzene sulfonyl chloride (9.38 g, 29 mmol) in dioxane (45 mL) and water (10 mL) was added tris-(2-carboxyethyl)phosphine hydrochloride (34.4 g, 118 mmol) and the reaction mixture was refluxed for 5 h, then cooled down, and partitioned between water and dichloromethane. The aqueous layer was extracted with dichloromethane and combined organic layers were washed with water then dried over sodium sulfate and concentrated in vacuo to afford the title compound (7.00 g, 94%) as a colorless liquid. MS (EI): 254.9 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[CH2:6][CH2:5]2.Cl.[CH3:13][O:14][NH2:15]>N1C=CC=CC=1>[CH3:13][O:14][N:15]=[C:7]1[C:8]2[C:4](=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: O=C1CCc2cc(Br)ccc21
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Product: CON=C1CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5-Bromo-1-indanone and O-methylhydroxylamine hydrochloride were combined in pyridine and stirred at ambient temperature for 16 hours. The mixture was concentrated under reduced pressure and the residue was suspended in diethyl ether. The suspension was filtered and the filter cake was washed with diethyl ether. The filtrate was washed with water, 1N HCl, water, and concentrated to provide the title compound. 1H NMR (300 MHz, d6-DMSO) 7.63 (m, 2H), 7.48 (m, 2H), 3.90 (s, 3H), 3.00 (m, 2H), 2.80 (m, 2H); MS (DCI/NH3) m/e 240 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=2[F:32])[CH2:12][CH2:13][N:14]([CH2:22][CH2:23][OH:24])C(=O)OC(C)(C)C)(=[O:10])=[O:9])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl.C(OCC)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]([C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=2[F:32])[CH2:12][CH2:13][NH:14][CH2:22][CH2:23][OH:24])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N(CCO)CCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cl
Product: O=S(=O)(c1ccc(Cl)cc1)C(CCNCCO)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 190.8 %

Procedure:
In dichloromethane (5 ml) was dissolved t-butyl N-[3-[(4-chlorophenyl)sulfonyl]-3-(2,5-difluorophenyl)propyl]-N-(2-hydroxyethyl)carbamate (300 mg, 0.607 mmol) and trifluoroacetic acid (0.5 ml) was added dropwise to the resulting solution under ice cooling. After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure. To the residue was added a 1N solution (5 ml) of hydrochloric acid in ethanol, followed by concentration under reduced pressure to give a white solid. The solid thus obtained was washed with diethyl ether, whereby the title compound (249 mg, 0.579 mmol, 95%) was obtained as a white powder.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C([Li])CCC.CN(C)[CH:17]=[O:18]>O1CCCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:17]=[O:18]
Reactant: CN(C)C=O
Reactant: c1ccc2scnc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 69.6 %

Procedure:
A solution of freshly distilled (b.p. 82° C., 2 torr) benzothiazole (10 g, 0.074 mole) in 250 ml tetrahydrofuran was colloed under nitrogen to -78° C. and stirred at this temperature for 15 minutes. To this was added dropwise over 15 minutes 29.6 ml (0.074 mole) 2,5M n-butyl-lithium, stirring continued for 25 minutes, and 8.6 ml (0.111 mole) dimethylformamide was added and the reaction mixture stirred for an hour. The mixture was allowed to warm to room temperature, 200 g ice was added and the solvent evaporated in vacuo. The aqueous residue was extracted with 5×100 ml ethyl acetate, the extractes dried (MgSO4), concentrated to a small volume and chromatographed on a silica gel column, eluting with 96:4 chloroform/ethyl acetate to yield 8.4 g of the desired aldehyde, m.p. 74.5-75° C. 1 -H--NMR(CDCl3)ppm (delta): 7.54 (m, 2H), 7.97 (m, 1H), 8.21 (m, 1H), 10.1 (s,1H.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[O:8][C:9]3[CH2:14][CH2:13][N:12](CC4C=CC(OC)=CC=4)[CH:11]([CH2:24][F:25])[C:10]=3[C:6]=2[CH:5]=[C:4]([S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH:3]=1>O.CC(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]2[O:8][C:9]3[CH2:14][CH2:13][NH:12][CH:11]([CH2:24][F:25])[C:10]=3[C:6]=2[CH:5]=[C:4]([S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:27])=[O:28])[CH:3]=1
Reactant: COc1ccc(CN2CCc3oc4c(Cl)cc(S(=O)(=O)c5ccccc5)cc4c3C2CF)cc1
Solvent: O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccccc1)c1cc(Cl)c2oc3c(c2c1)C(CF)NCC3
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 11.7 %

Procedure:
A solution of ceric ammonium nitrate (800 mg, 1.46 mmol) in water (1 mL) was added to a solution of the product obtained in step C (90 mg, 0.18 mmol) in acetone (10 mL). The resulting red solution was stirred at ambient temperature for 1.5 h, diluted with ethyl acetate, washed sequentially with saturated aqueous NaHCO3 and brine then dried over anhydrous MgSO4. The solution was filtered and the filtrate concentrated in vacuo to give the crude product which was purified by flash column chromatography (SiO2, 9:1 to 1:1 hexanes/ethyl acetate) providing 6-chloro-1-(fluoromethyl)-8-(phenylsulfonyl)-1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridine (8 mg, 12%) as a colorless oil: 1H NMR (CDCl3, 300 MHz) δ 8.14 (d, J=1.5 Hz, 1H), 7.98-7.95 (m, 2H), 7.85 (d, J=1.8 Hz, 1H), 7.57-7.48 (m, 3H), 5.72-5.54 (m, 1H), 3.68-3.58 (m, 1H), 3.42-3.28 (m, 2H), 3.26-3.18 (m, 1H), 3.13-3.00 (m, 2H).
Reaction SMILES: [NH:1]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[C@H:2]([C:5]([OH:7])=O)[CH2:3][OH:4].[C:18]1([Mg]Br)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl.CCCCCC>C1COCC1.C(OCC)(=O)C>[OH:4][CH2:3][C@H:2]([NH:1][C:8](=[O:9])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5](=[O:7])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(N[C@@H](CO)C(=O)O)OCc1ccccc1
Reactant: Br[Mg]c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(N[C@@H](CO)C(=O)c1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 20 %

Procedure:
To a stirred solution of Z-L-Ser-OH (6.00 g, 25.08 mmol) in 32 mL of anhydrous THF at 0° C. under nitrogen was added dropwise 1 M phenylmagnesium bromide in THF (32 mL, 200 mmol). (The symbol Z designates a benzylcarbamoyl group). The mixture was stirred 15 h at RT under nitrogen. A solution of 2 M HCl (100 mL) was slowly added at 0° C. and the mixture was partitioned between ethyl acetate (750 mL) and acidic water. The organic layer was washed with water (2×20 mL), 1 N aqueous sodium bicarbonate (2×20 mL), brine (2×20 mL) and dried over MgSO4. After removing ethyl acetate by evaporation at 30-35° C., the crude product (4.50 g, 60% yield) was cristallized in a mixture of ethyl acetate:hexane=25 mL:20 mL to give benzyl (S)-3-hydroxy-1-oxo-1-phenylpropan-2-ylcarbamate TTA 08010B as a white solid (1.40 g, 20% yield).
Reaction SMILES: N[CH:2]1[CH2:11][CH:10]2[N:5]([CH2:6][CH2:7][C:8]3[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:9]=32)[CH2:4][CH2:3]1.ClC1C=CC2C3[N:27](CCC=2C=1)CCC(=O)C3.[C:33]1([N:39]=[C:40]=[O:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[Cl:16][C:14]1[CH:13]=[CH:12][C:9]2[CH:10]3[N:5]([CH2:6][CH2:7][C:8]=2[CH:15]=1)[CH2:4][CH2:3][CH:2]([C:33]1([NH:39][C:40]([NH2:27])=[O:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH2:34]1)[CH2:11]3
Reactant: O=C=Nc1ccccc1
Reactant: NC1CCN2CCc3cc(Cl)ccc3C2C1
Reactant: O=C1CCN2CCc3cc(Cl)ccc3C2C1
Product: NC(=O)NC1(C2CCN3CCc4cc(Cl)ccc4C3C2)C=CC=CC1

Procedure:
2-Amino-9-chloro-1,3,4,6,7,11b-hexahydro-2H-benzo[a]quinolizine [prepared from 9-chloro-1,3,4,6,7,11b-hexahydro-2H-benzo[a]quinolizin-2-one (Neth.Appln. No. 6,508,468) by reduction of the oxime] is reacted with phenyl isocyanate by a procedure analogous to that of Example 1 to give the title compound.
Reaction SMILES: C(N1C2C(=CC=CC=2)CC1=O)C1C=CC=CC=1.[F:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23](=[O:35])[C:22]2=O.CCOCC>CCCCCC>[CH2:28]([N:24]1[C:25]2[C:21](=[CH:20][C:19]([F:18])=[CH:27][CH:26]=2)[CH2:22][C:23]1=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C1C(=O)N(Cc2ccccc2)c2ccc(F)cc21
Agent: O=C1Cc2ccccc2N1Cc1ccccc1
Solvent: CCOCC
Solvent: CCCCCC
Product: O=C1Cc2cc(F)ccc2N1Cc1ccccc1
Yield: 75.2 %

Procedure:
The title compound was prepared in a manner similar to the method of N-Benzyl-oxindole using 5-fluoro-N-benzylisatin (14.5 g, 56.8 mmol). Trituration using Et2O: hexane yielded the title compound as a pale yellow solid (10.3 g, 75%). 1H NMR (400 MHz, CDCl3) δ 7.30-7.26 (m, 5H), 7.00 (d, J=7.6 Hz, 1H), 6.87 (t, 1H), 6.63 (m, 1H), 4.91 (s, 2H), 3.63 (s, 2H); MS ESI 241.9 [M+H]+, calcd for [C15H10FNO2+H]+ 241.09.
Reaction SMILES: [CH3:1][O:2][C:3](=[NH:8])[NH:4][N+:5]([O-:7])=[O:6].Cl.N[CH2:11][C:12]1[S:16][C:15]([Cl:17])=[N:14][CH:13]=1>O>[CH3:1][O:2][C:3](=[N:4][N+:5]([O-:7])=[O:6])[NH:8][CH2:11][C:12]1[S:16][C:15]([Cl:17])=[N:14][CH:13]=1
Reactant: NCc1cnc(Cl)s1
Reactant: COC(=N)N[N+](=O)[O-]
Agent: Cl
Solvent: O
Product: COC(=N[N+](=O)[O-])NCc1cnc(Cl)s1
Temperature: 25 °C
Reaction time: 6 h
Yield: 55.4 %

Procedure:
To a mixture of O-methyl-N-nitroisourea (3.0 g, 0.0252 mol), 36% hydrochloric acid (2.2 ml), and water (50 ml) was added 5-aminomethyl-2-chlorothiazole (93% purity, 4.4 g, 0.0275 mol) at 20° C. This mixture was stirred at room temperature for 6 hours and then extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate and concentrated to provide 3.5 g (55.4% yield) of O-methyl-N-(2-chloro-5-thiazolylmethyl)-N'-nitroisourea.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:29]#[N:30])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][C:21]3([CH3:27])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:17](O)=[O:18])[C:10](=[O:28])[CH:9]=2)[CH:7]=1.[NH2:31][C:32]1[CH:42]=[CH:41][C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:34][CH:33]=1.CC(C)N=C=NC(C)C.C(#N)C.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:29]#[N:30])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][C:21]3([CH3:27])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:17]([NH:31][C:32]3[CH:33]=[CH:34][C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:41][CH:42]=3)=[O:18])[C:10](=[O:28])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CC2(C)CCOCC2)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: CC(C)N=C=NC(C)C
Solvent: O
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCOC(=O)c1ccc(NC(=O)C(CC2(C)CCOCC2)n2cc(OC)c(-c3cc(Cl)ccc3C#N)cc2=O)cc1

Procedure:
206 mg (478 μmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(4-methyltetrahydro-2H-pyran-4-yl)propanoic acid (racemate), 79 mg (0.48 mmol) of ethyl 4-aminobenzoate, 6.8 mg (48 μmol) of Oxima and 74 μl (0.48 mmol) of DIC in 4.8 ml of dimethylformamide were reacted according to General Method 5B. Preparative HPLC (acetonitrile/water gradient) gave the title compound. Yield: 70 mg (purity 95%, 24% of theory)
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:42]=[C:43]([CH:52]=[CH:53][CH:54]=2)[O:44][CH2:45][CH2:46][O:47]S(C)(=O)=O)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:55][N:56]1[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]1.C1C[O:65]CC1>>[CH:46]([OH:47])=[O:65].[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:54]=[CH:53][CH:52]=[C:43]([O:44][CH2:45][CH2:46][N:59]3[CH2:60][CH2:61][N:56]([CH3:55])[CH2:57][CH2:58]3)[CH:42]=2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN1CCNCC1
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCOS(C)(=O)=O)c4)c4ccccc43)cn12
Reactant: C1CCOC1
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCN5CCN(C)CC5)c4)c4ccccc43)cn12
Product: O=CO

Procedure:
A solution of Intermediate 154a (50.5 mg, 0.067 mmol) and 1-methylpiperazine (37 μL, 0.33 mmol) in THF (1 mL) was stirred at 60° C. for 20 h in a sealed tube. The mixture was concentrated in vacuo and the residue purified by MDAP (Method 7). The title product was isolated as an off-white solid (28 mg, 55%). LCMS (Method 5): Rt 3.62 min, m/z 761.6 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.91 (3H, d, J=8.0 Hz), 1.28 (9H, s), 1.47-1.56 (2H, m), 1.61-1.73 (2H, m), 1.74-1.97 (4H, m), 2.00-2.19 (5H, m), 2.21-2.35 (4H, m,), 2.36-2.49 (4H, m), 2.66 (2H, t, J=8.0 Hz), 2.86-2.95 (1H, m), 3.12-3.19 (1H, m, obscured by water), 3.27-3.35 (1H, m, obscured by water), 4.10 (2H, t, J=8.0 Hz), 4.78-4.86 (1H, m), 5.52 (1H, t, J=4.0 Hz), 6.33 (1H, s), 6.94-6.98 (1H, m), 7.05-7.13 (3H, m), 7.19 (1H, dd, J=8.0 Hz, 4.0 Hz), 7.24-7.42 (5H, m), 7.64 (1H, d, J=8.0 Hz), 7.69 (1H, d, J=4.0 Hz), 8.13 (1H, s), 8.17 (1.4H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([CH3:23])([CH3:22])[N:10](CC3C=CC(OC)=CC=3)[C:11](=[O:12])[C:6]2=[CH:5][CH:4]=1.O.CCOC(C)=O>CC#N>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([CH3:23])([CH3:22])[NH:10][C:11](=[O:12])[C:6]2=[CH:5][CH:4]=1
Reactant: COc1ccc(CN2C(=O)c3ccc(OC)nc3C2(C)C)cc1
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc2c(n1)C(C)(C)NC2=O
Yield: 62.4 %

Procedure:
To solution of 2-methoxy-6-(4-methoxy-benzyl)-7,7-dimethyl-6,7-dihydro-pyrrolo[3,4-b]pyridin-5-one (0.31 g, 1.0 mmol) in CH3CN (5 mL) was added ceric ammonium nitrate (1.64 g, 3.0 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 hours before water and EtOAc were added into the mixture. The organic layer was separated, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product which was then purified by silica gel column chromatography to give the title compound (0.12 g, 63%) as a solid. MS: 193.1 (M+H+).
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[C:10]([CH3:23])=[C:11]([C:14]([O:19][CH2:20][CH2:21][OH:22])=[C:15]([CH3:18])[C:16]=1[CH3:17])[CH2:12]Cl.[CH3:24][NH:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][C:30]=1[CH:36]([CH3:38])[CH3:37]>CN(C)C=O>[OH:8][C:9]1[C:10]([CH3:23])=[C:11]([C:14]([O:19][CH2:20][CH2:21][OH:22])=[C:15]([CH3:18])[C:16]=1[CH3:17])[CH2:12][N:25]([CH2:26][CH2:27][O:28][C:29]1[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][C:30]=1[CH:36]([CH3:38])[CH3:37])[CH3:24]
Reactant: Cc1c(C)c(OCCO)c(CCl)c(C)c1O
Reactant: CNCCOc1cc(C)ccc1C(C)C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(C(C)C)c(OCCN(C)Cc2c(C)c(O)c(C)c(C)c2OCCO)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.5 %

Procedure:
Triethylamine (2.1 ml) was added dropwise to a solution of 3-hydroxy-6-(2-hydroxyethoxy)-2,4,5-trimethylbenzyl chloride (2.45 g) and N-methyl-2-(2-isopropyl-5-methylphenoxy)ethylamine (2.07 g) in N,N-dimethylformamide (30 ml), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was poured on ice water and extracted with ethyl acetate. The obtained extract was purified by silica gel column chromatography (eluent; ethyl acetate/benzene=1/1) and recrystallized from methanol-water to give 2.51 g of the title compound (colorless needle crystals).
Reaction SMILES: [OH-].[CH2:2]([N+:4]([CH2:9][CH3:10])([CH2:7][CH3:8])[CH2:5][CH3:6])[CH3:3].[C:11]([OH:14])(=[O:13])[CH3:12]>>[C:11]([O-:14])(=[O:13])[CH3:12].[CH2:2]([N+:4]([CH2:9][CH3:10])([CH2:7][CH3:8])[CH2:5][CH3:6])[CH3:3]
Reactant: CC(=O)O
Agent: CC[N+](CC)(CC)CC
Agent: [OH-]
Product: CC(=O)[O-]
Temperature: 25 °C

Procedure:
An aqueous tetraethylammonium hydroxide solution (1 mol) was charged into a flask and, while the solution was cooled so as to maintain it at room temperature, acetic acid (1 mol) was added thereto to obtain a tetraethylammonium acetate salt. Thereafter, ethylene glycol was added as a solvent so as to be a predetermined concentration and then water was removed by evaporation using an evaporator to obtain a solution of 50% of tetraethylammonium acetate and 50% of ethylene glycol.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([CH3:17])=[CH:11]2.[OH-].[Na+].[CH3:20][C:21](N(C)C)=[O:22]>O>[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([CH3:17])=[C:11]2[C:21](=[O:22])[CH3:20]
Reactant: COc1ccc2[nH]c(C)cc2c1
Reactant: CC(=O)N(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2[nH]c(C)c(C(C)=O)c2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 67.2 %

Procedure:
Dimethylacetamide (17.5 ml, 188.4 mmol) is added dropwise with stirring to phosphorous oxychloride (12.9 ml, 138.2 mmol) at 0° C. Stirring is maintained for 45 minutes, at which time the bath is removed and 5-methoxy-2-methylindole (20.25 g, 125.6 mmol) in 15 ml of dimethylacetamide is added dropwise over a period of 75 minutes. The resulting mixture is warmed to 40°-45° C. for 4 hours. The reaction mixture is cooled to 0° C., and 100 g of ice water is added followed by dropwise addition of a solution of sodium hydroxide (50 g) in water (75 ml). The first 1/3 of this sodium hydroxide solution is added slowly and the remainder is added quickly. The exothermic reaction is quickly warmed to boiling for 15 minutes, cooled to room temperature and refrigerated overnight. The resulting crystals are collected by filtration and rinsed four times with water. Recrystallization from ethanol/water gives 17.2 g (67.2%) of pure 1-(5-methoxy-2-methyl-lH-indol-3-yl)ethanone; mp 229.0°-230.5° C.