Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]([F:15])([F:14])[C:4]1[CH:13]=[CH:12][C:11]2[CH2:10][NH:9][CH2:8][CH2:7][C:6]=2[N:5]=1.[CH3:16][S:17]([C:20]1[CH:21]=[CH:22][C:23]([O:29][C@@H:30]([CH3:35])[C:31]([F:34])([F:33])[F:32])=[C:24]([CH:28]=1)[C:25](O)=[O:26])(=[O:19])=[O:18]>>[CH3:16][S:17]([C:20]1[CH:21]=[CH:22][C:23]([O:29][C@@H:30]([CH3:35])[C:31]([F:32])([F:33])[F:34])=[C:24]([C:25]([N:9]2[CH2:8][CH2:7][C:6]3[N:5]=[C:4]([C:3]([F:2])([F:14])[F:15])[CH:13]=[CH:12][C:11]=3[CH2:10]2)=[O:26])[CH:28]=1)(=[O:19])=[O:18]
Reactant: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Reactant: FC(F)(F)c1ccc2c(n1)CCNC2
Agent: Cl
Product: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCc2nc(C(F)(F)F)ccc2C1)C(F)(F)F

Procedure:
Prepared in analogy to example 1.1 from 2-trifluoromethyl-5,6,7,8-tetrahydro-[1,6]naphthyridine hydrochloride (CA [741736-98-1]; WO2004069162) and 5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (example 2.2).
Reaction SMILES: [CH:1]([S:4](Cl)(=[O:6])=[O:5])([CH3:3])[CH3:2].[CH2:8]1[O:17][C:11]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[O:10][CH2:9]1.C(N(CC)CC)C>ClCCl>[CH2:8]1[O:17][C:11]2([CH2:16][CH2:15][N:14]([S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])[CH2:13][CH2:12]2)[O:10][CH2:9]1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: C1CC2(CCN1)OCCO2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)S(=O)(=O)N1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.6 %

Procedure:
Isopropylsulphonyl chloride (5.6 ml, 50 mmol) was added dropwise to an ice-cooled solution of 4-piperidone ethylene ketal (6.4 ml, 50 mmol) and triethylamine (7.7 ml, 55 mmol) in dichloromethane (100 ml), and the reaction stirred at room temperature for 3 hours. The mixture was washed with water (2×), dried (MgSO4), filtered and evaporated in vacuo. The residue was crystallised from ether/pentane to afford the title compound as a solid, (10.55 g, 85%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.N1(C2C=C[C:23]([CH:24]=[O:25])=CC=2)C=CC=N1>>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:14]=[CH:13][C:10](/[CH:11]=[CH:23]/[CH:24]=[O:25])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(-c2ccncc2)cc1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: O=C/C=C/c1ccc(-c2ccncc2)cc1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(4-pyridinyl)-benzaldehyde (prepared as described in WO 9828264) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 210 (M+H)+.
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.[CH3:9][O:10][C:11](=[O:31])[C:12]1[C:17]([O:18][CH3:19])=[CH:16][C:15]([C:20]2[C:25]([CH2:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:21]=2[CH2:28][CH3:29])=[N:14][C:13]=1[CH3:30].CI>>[CH3:9][O:10][C:11](=[O:31])[C:12]1[C:17]([O:18][CH3:19])=[CH:16][C:15]([C:20]2[C:25]([CH2:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:21]=2[CH2:28][CH3:29])=[N:14][C:13]=1[CH2:30][CH3:2]
Reactant: CC(C)[N-]C(C)C
Reactant: CCc1cccc(CC)c1-c1cc(OC)c(C(=O)OC)c(C)n1
Agent: [Li+]
Solvent: CI
Product: CCc1cccc(CC)c1-c1cc(OC)c(C(=O)OC)c(CC)n1
Temperature: 78 °C
Reaction time: 0.5 h

Procedure:
LDA (19 mg, 89 μL of 2 M solution in THF, 0.18 mmol) at −78° C. is added to a solution of 6-(2,6-diethyl-phenyl)-4-methoxy-2-methyl-nicotinic acid methyl ester (27 mg, 0.086 mmol). The mixture is stirred for 30 minutes at 78° C. Methyl iodide (15 μL, 0.24 mmol) is added and the resulting yellow mixture is stirred for 10 minutes at −78° C. After quenching with saturated NH4Cl the mixture is extracted with EtOAc. The combined extracts are dried, concentrated, and purified by flash-chromatography to give 6-(2,6-diethyl-phenyl)-2-ethyl-4-methoxy-nicotinic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([OH:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18](F)[C:15]=1[C:16]#[N:17]>CN(C)C=O.O>[F:13][C:14]1[CH:21]=[CH:20][C:19]([O:10][C@@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH3:9])=[CH:18][C:15]=1[C:16]#[N:17]
Reactant: N#Cc1c(F)cccc1F
Reactant: C[C@@H](O)c1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](Oc1ccc(F)c(C#N)c1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.2 %

Procedure:
A solution of (R)-1-(3-chlorophenyl)ethanol (0.730 g, 4.66 mmol) in dimethylformamide (5 mL) was added to a 0° C. slurry of sodium hydride (0.207 g, 5.18 mmol) in dimethylformamide (5 mL) under nitrogen atmosphere. The reaction mixture was warmed to room temperature, stirred for 3 hour, and then cooled with an ice bath. The cold orange solution was added dropwise to a 0° C. solution of 2,6-difluorobenzonitrile (0.720 g, 5.18 mmol) in dimethylfomamide (5 mL). After the reaction was stirred at ambient temperature for around 18 hours, the reaction was diluted with water and extracted with EA. The organic layer was washed with water and brine, dried over MgSO4, and concentrated in vacuo to a yellow semi-solid. Flash chromatography purification (silica gel, 50% hexane in DCM) afforded the 2-fluoro-5-[(R)-1-(3-chlorophenyl)ethoxy]benzonitrile as a pale yellow oil (0.645 g, 50%).
Reaction SMILES: CO[C:3](=[O:22])[CH:4]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1.[CH3:23][NH:24][C:25]([NH2:27])=[O:26].C[O-].[Mg+2].C[O-]>CO>[CH3:21][S:18]([C:15]1[CH:14]=[CH:13][C:12]([CH:4]([CH2:5][CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][O:7]2)[C:3]([NH:27][C:25]([NH:24][CH3:23])=[O:26])=[O:22])=[CH:17][CH:16]=1)(=[O:19])=[O:20]
Reactant: CNC(N)=O
Reactant: COC(=O)C(CC1CCCCO1)c1ccc(S(C)(=O)=O)cc1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: CNC(=O)NC(=O)C(CC1CCCCO1)c1ccc(S(C)(=O)=O)cc1
Yield: 5.9 %

Procedure:
A solution of 2-(4-methanesulfonyl-phenyl)-3-(tetrahydro-pyran-2-yl)-propionic acid methyl ester (75 mg, 0.23 mmol), methylurea (34 mg, 0.46 mmol), and a solution of magnesium methoxide in methanol (7.4 wt. %, 0.49 mL, 0.35 mmol) and methanol (0.5 mL) was heated at 100° C. for 8 h. Over time, the reaction mixture turned cloudy in appearance. At this time, the reaction was concentrated in vacuo. The residue was dissolved in ethyl acetate (10 mL) and then filtered through a pad of silica gel. The filtrate was concentrated in vacuo. Biotage chromatography (FLASH 12M, Silica, 30/70 hexanes/ethyl acetate) afforded 1-[2-(4-methanesulfonyl-phenyl)-3-(tetrahydro-pyran-2-yl)-propionyl]-3-methyl-urea (5 mg, 6%) as a colorless oil: FAB-HRMS m/e calcd for C17H24N2O5S (M+H)+ 369.1484, found 369.1495.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1.C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33]>C1COCC1>[C:32]([NH:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1)(=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CN)C1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NC[C@@H]1CN(C(=O)OC(C)(C)C)CCO[C@H]1c1ccc(Cl)c(Cl)c1
Yield: 97.1 %

Procedure:
To a solution of tert-butyl (6R,7R)-6-(aminomethyl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (150 mg) in THF (2 ml) were added triethylamine (0.084 mL) and acetyl chloride (47 mg), and the mixture was stirred at under ice-cooling for 2 hr. The solvent was evaporated under reduced pressure, distilled water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (162 mg).
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:7])[CH:4]([CH3:6])[CH3:5].[CH3:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[CH:20][C:21]3[O:25][CH:24]([CH:26]4[CH2:31][CH2:30][N:29]([C:32]#N)[CH2:28][CH2:27]4)[CH2:23][C:22]=3[CH:34]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10]>O1CCCC1.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH:4]([C:3]1[N:7]=[C:32]([N:29]2[CH2:28][CH2:27][CH:26]([CH:24]3[CH2:23][C:22]4[CH:34]=[C:18]([C:15]5[CH:16]=[CH:17][C:12]([S:9]([CH3:8])(=[O:11])=[O:10])=[CH:13][CH:14]=5)[CH:19]=[CH:20][C:21]=4[O:25]3)[CH2:31][CH2:30]2)[O:1][N:2]=1)([CH3:6])[CH3:5]
Reactant: CS(=O)(=O)c1ccc(-c2ccc3c(c2)CC(C2CCN(C#N)CC2)O3)cc1
Reactant: CC(C)C(=N)NO
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)c1noc(N2CCC(C3Cc4cc(-c5ccc(S(C)(=O)=O)cc5)ccc4O3)CC2)n1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A 0.5 M solution of zinc chloride in tetrahydrofuran (0.78 mL) is diluted with tetrahydrofuran (5 mL) and added dropwise at room temperature to a mixture of N-hydroxy-isobutyramidine (40 mg) and 4-[5-(4-methanesulfonyl-phenyl)-2,3-dihydro-benzofuran-2-yl]-piperidine-1-carbonitrile (100 mg) in ethyl acetate (5 mL). The reaction mixture is stirred at 50° C. for 4 h and cooled to room temperature. The precipitate is filtered off and heated to 100° C. for 2 h in a mixture of ethanol (5 mL) and glacial acetic acid (2.5 mL). The solvents are evaporated and the residue is mixed with dichloromethane and 10% aqueous K2CO3 solution. The organic phase is washed with brine, dried over MgSO4 and concentrated in vacuo. The residue is triturated with diethyl ether to give the title compound. LC (method 2): tR=1.12 min; Mass spectrum (ESI+): m/z=468 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)[C:5]([CH3:15])=[CH:4][N:3]=1.[CH2:16]([O:18][C:19](=[O:31])[CH2:20][C@H:21]1[C:29]2[C:24](=[CH:25][C:26](O)=[CH:27][CH:28]=2)[CH2:23][CH2:22]1)[CH3:17].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1>[CH2:16]([O:18][C:19](=[O:31])[CH2:20][C@H:21]1[C:29]2[C:24](=[CH:25][C:26]([O:14][CH:11]3[CH2:10][CH2:9][N:8]([C:6]4[C:5]([CH3:15])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=4)[CH2:13][CH2:12]3)=[CH:27][CH:28]=2)[CH2:23][CH2:22]1)[CH3:17]
Reactant: Cc1cnc(Cl)nc1N1CCC(O)CC1
Reactant: CCOC(=O)C[C@@H]1CCc2cc(O)ccc21
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@H]1CCc2cc(OC3CCN(c4nc(Cl)ncc4C)CC3)ccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 81.4 %

Procedure:
To a solution of 1-(2-chloro-5-methyl-4-pyrimidinyl)-4-piperidinol (Example 458, 2.01 g, 8.81 mmol) and ethyl[(1S)-5-hydroxy-2,3-dihydro-1H-inden-1-yl]acetate (Example 6, 970 mg, 4.40 mmol) in THF (35 mL) were added PPh3 (2.31 g, 8.81 mmol) and ADDP (2.22 g, 8.81 mmol). The reaction mixture was vigorously stirred at rt for 24 h. The precipitate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was then purified by silica gel chromatography (9:1 to 3:1 hexanes/EtOAc) to give the title product (1.54 g, 81%). 1H NMR (400 MHz, CDCl3) δ 1.28 (t, 3H), 1.74-1.80 (m, 1H), 1.91-1.95 (m, 2H), 2.02-2.07 (m, 2H), 2.22 (s, 3H), 2.38-2.46 (m, 2H), 2.71-2.88 (m, 3H), 3.50-3.55 (m, 3H), 3.75-3.81 (m, 2H), 4.18 (q, 2H), 4.52-4.54 (m, 1H), 6.73 (d, 1H), 6.80 (s, 1H), 7.07 (d, 1H), 7.93 (s, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:24][CH3:25])=[C:13]([O:16][CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:14]=2)[C:9]([C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH:34]([CH3:36])[CH3:35])[CH:28]=2)=[N:8][CH:7]=1)=[O:5])C.[OH-].[Na+]>C(O)C.O1CCCC1>[CH:34]([O:33][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=1)[C:26]([C:9]1[C:10]2[C:15](=[CH:14][C:13]([O:16][CH2:17][CH2:18][N:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)=[C:12]([O:24][CH3:25])[CH:11]=2)[C:6]([C:4]([OH:5])=[O:3])=[CH:7][N:8]=1)=[O:37])([CH3:36])[CH3:35]
Reactant: CCOC(=O)c1cnc(C(=O)c2cccc(OC(C)C)c2)c2cc(OC)c(OCCN3CCCC3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc2c(C(=O)c3cccc(OC(C)C)c3)ncc(C(=O)O)c2cc1OCCN1CCCC1
Temperature: 60 °C
Yield: 41.8 %

Procedure:
To a stirred solution of 6-hydroxy-1-(3-isopropoxy-benzoyl)-7-methoxy-isoquinoline-4-carboxylic acid ethyl ester (70 mg, 0.17 mmol) in N,N dimethylformamide (2 mL) was added potassium carbonate (237 mg, 1.71 mmol) and 2-chloro-N,N-dimethyl-acetamide (0.088 mL, 0.86 mmol) at room temperature. The reaction mixture was heated 85° C. for 2 hrs. The solvent was evaporated and the crude product was diluted with ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (3×20 mL). The combined extracts were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 30% ethyl acetate/hexane) afforded 6-dimethylcarbamoylmethoxy-1-(3-isopropoxy-benzoyl)-7-methoxy-isoquinoline-4-carboxylic acid ethyl ester. To a stirred solution of 1-(3-isopropoxy-benzoyl)-7-methoxy-6-(2-pyrrolidin-1-yl-ethoxy)-isoquinoline-4-carboxylic acid ethyl ester (73.0 mg, 0.14 mmol) in ethanol (1.0 mL) and tetrahydrofuran (0.5 mL) was added 4N aqueous sodium hydroxide (0.144 mL, 0.56 mmol) at room temperature. The mixture was heated at 60° C. for 1 h. The solvent was evaporated and the residue was diluted with dichloromethane and water. The aqueous phase was acidified to pH=3 by addition of 1N hydrochloride solution and then was extracted with dichloromethane (3×20 mL). The combined extracts were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude product recrystallized from ethyl acetate to afford 1-(3-isopropoxy-benzoyl)-7-methoxy-6-(2-pyrrolidin-1-yl-ethoxy)-isoquinoline-4-carboxylic acid as a light brown solid (28 mg, 37% yield). HR-MS m/e calcd for C23H21N1O6 (M−H+) 440.1340, found 440.1347; 1H NMR (300 MHz) compatible.
Reaction SMILES: Cl[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[C:12]([Cl:14])=[CH:13][C:4]=2[N:3]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[Cl:14][C:12]1[C:11]([N+:15]([O-:17])=[O:16])=[CH:10][C:5]2[N:6]([CH:7]([CH3:9])[CH3:8])[C:2]([N:22]3[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]3)=[N:3][C:4]=2[CH:13]=1
Reactant: CC(C)n1c(Cl)nc2cc(Cl)c([N+](=O)[O-])cc21
Reactant: CN1CCNCC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)n1c(N2CCN(C)CC2)nc2cc(Cl)c([N+](=O)[O-])cc21
Yield: 84.7 %

Procedure:
2,5-Dichloro-1-isopropyl-6-nitrobenzimidazole (4.6 g) was suspended in toluene (31 ml) and to the suspension was added dropwise N-methylpiperazine (8.4 g) and then the mixture was refluxed for 30 minutes. To the reaction solution was added ethyl acetate and the mixture was washed with water and then extracted with 2N hydrochloric acid. The water layer was separated and made basic with an aqueous sodium hydroxide solution and then extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate and then the solvent was distilled off under reduced pressure to give 5-chloro-1-isopropyl-2-(4-methyl-1-piperazinyl)-6-nitrobenzimidazole (4.8 g). A part of the obtained product was recrystallized from acetonitrile, which showed the physical properties consistent with those in Preparation 8.
Reaction SMILES: [CH3:1][C:2]([CH3:39])([CH3:38])[C:3]([O:5][CH2:6][C:7]1[NH:16][C:15](=[O:17])[C:14]2[C:9](=[CH:10][C:11]3[CH2:20][CH2:19][CH:18]([N:21]([C:25]4[CH:37]=[CH:36][C:28]([C:29]([O:31]C(C)(C)C)=[O:30])=[CH:27][CH:26]=4)[CH2:22][C:23]#[CH:24])[C:12]=3[CH:13]=2)[N:8]=1)=[O:4]>FC(F)(F)C(O)=O>[CH3:1][C:2]([CH3:39])([CH3:38])[C:3]([O:5][CH2:6][C:7]1[NH:16][C:15](=[O:17])[C:14]2[C:9](=[CH:10][C:11]3[CH2:20][CH2:19][CH:18]([N:21]([C:25]4[CH:26]=[CH:27][C:28]([C:29]([OH:31])=[O:30])=[CH:36][CH:37]=4)[CH2:22][C:23]#[CH:24])[C:12]=3[CH:13]=2)[N:8]=1)=[O:4]
Reactant: C#CCN(c1ccc(C(=O)OC(C)(C)C)cc1)C1CCc2cc3nc(COC(=O)C(C)(C)C)[nH]c(=O)c3cc21
Solvent: O=C(O)C(F)(F)F
Product: C#CCN(c1ccc(C(=O)O)cc1)C1CCc2cc3nc(COC(=O)C(C)(C)C)[nH]c(=O)c3cc21
Yield: 114 %

Procedure:
A solution of tert-butyl 4-[N-((6RS)-2-(2,2-dimethylpropionyloxymethyl)-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-N-(prop-2-ynyl)amino]-benzoate (80 mg, 0.15 mmol) in trifluoroacetic acid (5 ml) was stirred at room temperature with protection from the light for 1.5 h. The solvent was removed in vacuo and the residue triturated with 1:1 diethyl ether and hexane to yield the desired product as a white solid (81 mg, TFA salt); m.p. 133° C., 1H-NMR (DMSO-d6) δ 1.23 (s, 9H, CO2CMe3), 2.22 (m, 1H, 7-H), 2.50 (m, 1H, 7-H), 3.03 (m, 2H, 8-H), 3.14 (s, 1H, propargyl CH), 3.97 (AB system, J=18.8 Hz, 2H, propargyl CH2), 4.95 (s, 2H, 2-CH2), 5.79 (t, J=8.6 Hz, 1H, 6-H), 7.03 (d, J=9.0 Hz, 2H, 3′-H, 5′-H), 7.51 (s, 1H, 9-H), 7.81 (d, J=6.6 Hz, 2H, 2′-H, 6′-H), 7.83 (s, 1H, 5-H).
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH2:9][CH:10]=[O:11])[CH2:3][C:4]([O:6]CC)=[O:5].[OH-].[K+].Cl>CO.O>[CH3:1][C:2]([CH3:12])([CH2:9][CH:10]=[O:11])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)CC(C)(C)CC=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(CC=O)CC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
To a solution of 1.50 g (8.71 mmol) of ethyl 3,3-dimethyl-5-oxopentanoate in 50 mL of methanol and 1 mL of water was added 1.0 g (17.8 mmol) of potassium hydroxide. The reaction mixture was stirred at room temperature for 411/2 hours. The reaction mixture was diluted with water and then made acidic by the addition of aqueous hydrochloric acid. The resulting solution was extracted with methylene chloride repeatedly. The combined organic layer was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. Removal of the solvent afforded 1.05 g of 3,3-dimethyl-5-oxopentanoic acid, 84% crude yield. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.I[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18]>>[N+:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)([O-:19])=[O:18]
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=[N+]([O-])c1ccccc1I
Product: O=[N+]([O-])c1ccccc1-n1ccc2ccccc21

Procedure:
Prepared by Procedure C and Scheme O using 1H-indole and 1-iodo-2-nitrobenzene: ESMS m/e: 238.2 (M+H)+.
Reaction SMILES: Cl.[C:2]([NH:5][C@@H:6]1[CH2:10][NH:9][C@@H:8]([CH3:11])[CH2:7]1)(=[O:4])[CH3:3].C(N(CC)CC)C.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[C:2]([NH:5][C@@H:6]1[CH2:10][N:9]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@@H:8]([CH3:11])[CH2:7]1)(=[O:4])[CH3:3]
Reactant: CC(=O)N[C@@H]1CN[C@@H](C)C1
Reactant: BrCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N[C@H]1C[C@H](C)N(Cc2ccccc2)C1

Procedure:
(2S,4S)-4-acetamido-2-methylpyrrolidine hydrochloride from the previous step is suspended in methylene chloride, triethylamine and benzyl bromide are added and the mixture heated at reflux. The product is obtained after washing and evaporation of the solvent.
Reaction SMILES: [CH2:1]([C:3]1([CH3:13])[CH:8]([CH3:9])[CH2:7][CH2:6][C:5]([CH2:11][CH3:12])([CH3:10])[NH:4]1)[CH3:2].[C:14](Cl)(=[O:17])[CH:15]=[CH2:16].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:14]([N:4]1[C:5]([CH2:11][CH3:12])([CH3:10])[CH2:6][CH2:7][CH:8]([CH3:9])[C:3]1([CH2:1][CH3:2])[CH3:13])(=[O:17])[CH:15]=[CH2:16]
Reactant: C=CC(=O)Cl
Reactant: CCC1(C)CCC(C)C(C)(CC)N1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=CC(=O)N1C(C)(CC)CCC(C)C1(C)CC
Reaction time: 18 h

Procedure:
36.7 g of 2,6-diethyl-2,3,6-trimethylpiperidine (Compound No. 1) are dissolved in 200 ml toluene. A solution of 19 g acrylic chloride in 50 ml toluene is added slowly within an hour and the mixture is stirred at 70°-75° C. for 18 hours. After addition of 21.2 g of triethylamine the stirring is continued for another 24 hours. After cooling the reaction mixture is washed twice with 100 ml water each. The toluene solution is dried over sodium sulfate and evaporated. The residue is distilled in vacuo and there is obtained the 1-acryloyl-2,6-diethyl-2,3,6-trimethylpiperidine (Compound No. 12) as distillate at 133°-135° C./0.6 mm Hg.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[C:30]2[CH:29]=[CH:28][C:16]3[C:17](=[O:27])[N:18]([CH2:24][CH2:25]O)[C:19](=[O:23])[C:20]4=[CH:21][CH:22]=[C:13]([C:14]=2[C:15]=34)[C:12]1=[O:31])([CH3:4])([CH3:3])[CH3:2].P(Br)(Br)[Br:33]>C(Cl)(Cl)Cl>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[C:30]2[CH:29]=[CH:28][C:16]3[C:17](=[O:27])[N:18]([CH2:24][CH2:25][Br:33])[C:19](=[O:23])[C:20]4=[CH:21][CH:22]=[C:13]([C:14]=2[C:15]=34)[C:12]1=[O:31])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccccc1N1C(=O)c2ccc3c4c(ccc1c24)C(=O)N(CCO)C3=O
Reactant: BrP(Br)Br
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1ccccc1N1C(=O)c2ccc3c4c(ccc1c24)C(=O)N(CCBr)C3=O

Procedure:
0.92 g (2.22 mmol) of 1-(2-tert. butylphenyl)-6-(2-hydroxyethyl)-1H-indolo[5,4,3-def]isoquinoline-2,5,7(6H)-trione was dissolved in 60 mL of chloroform and heated to a boil. Then, 15 mL (15.54 mmol) of phosphorus tribromide was added dropwise within 20 minutes and the solution was heated at reflux for 2 hours. The reaction mixture was then poured onto ice, and the aqueous phase was extracted with chloroform. The combined organic phases were dried over magnesium sulfate. The purification was carried out by column chromatography on silica gel with toluene as the developing solvent.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:20])=[CH:4][C:5]([F:19])=[C:6]([N:8]2[C:12](=[O:13])[C:11]3[CH2:14][CH2:15][CH2:16][CH2:17][C:10]=3[C:9]2=[O:18])[CH:7]=1.Br[CH:22]([CH3:35])[C:23]([O:25][CH:26]1[CH:30]([O:31][C:32](=[O:34])[CH3:33])[CH2:29][O:28][CH2:27]1)=[O:24].C(=O)([O-])O.[Na+].C1(C)C(C)=CC=CC=1>C(OCC)(=O)C>[C:32]([O:31][CH:30]1[CH2:29][O:28][CH2:27][CH:26]1[O:25][C:23]([CH:22]([NH:1][C:2]1[C:3]([Cl:20])=[CH:4][C:5]([F:19])=[C:6]([N:8]2[C:12](=[O:13])[C:11]3[CH2:14][CH2:15][CH2:16][CH2:17][C:10]=3[C:9]2=[O:18])[CH:7]=1)[CH3:35])=[O:24])(=[O:34])[CH3:33]
Reactant: Nc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Reactant: CC(=O)OC1COCC1OC(=O)C(C)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: CC(=O)OC1COCC1OC(=O)C(C)Nc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Reaction time: 4 h
Yield: 32.9 %

Procedure:
A mixture of 8.84 g of N-(5-amino-4-chloro-2-fluorophenyl)-3,4,5,6-tetrahydrophthalimide, 12.6 g of 4-acetoxytetrahydrofuran-3-yl 2-bromopropionate, 3.02 g of sodium hydrogencarbonate and 3 ml of xylene was heated under stirring at 150° to 160° C. for 4 hours. Adding ethyl acetate to the reaction mixture while it remained warm, the resulting mixture was washed with water, subsequently with aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by chromatography on a silica gel column (development solvent: ethyl acetate/hexane=1/2), to obtain 4.88 g of a compound described in Table 1 (No. 10) (33 %).
Reaction SMILES: [OH:1][CH2:2][C:3]1([N:16]2[CH2:21][CH2:20][CH2:19][NH:18][C:17]2=[O:22])[CH2:8][CH2:7][N:6](CC2C=CC=CC=2)[CH2:5][CH2:4]1.[H][H]>CO.[Pd]>[OH:1][CH2:2][C:3]1([N:16]2[CH2:21][CH2:20][CH2:19][NH:18][C:17]2=[O:22])[CH2:4][CH2:5][NH:6][CH2:7][CH2:8]1
Reactant: [H][H]
Reactant: O=C1NCCCN1C1(CO)CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: O=C1NCCCN1C1(CO)CCNCC1
Yield: 47.7 %

Procedure:
A mixture of intermediate (16) (0.0059 mol) in methanol (100 ml) was hydrogenated with palladium on carbon (1 g) as a catalyst. After uptake of hydrogen (1 equivalent), the catalyst was filtered off, the filtrate was evaporated and crystallized from ACN, yielding 0.6 g of tetrahydro-1-[4(hydroxymethyl)-4-piperidinyl]-2(1H)-pyrimidinone (intermediate 17, mp. 162° C.).