Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.Cl[C:11]1[C:20]([C:21]2[N:29]=[C:28]([CH3:30])[N:27]=[C:26]3[C:22]=2[N:23]=[CH:24][N:25]3[CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>O1CCOCC1>[CH3:9][O:8][C:5]1[N:6]=[CH:7][C:2]([NH:1][C:11]2[C:20]([C:21]3[N:29]=[C:28]([CH3:30])[N:27]=[C:26]4[C:22]=3[N:23]=[CH:24][N:25]4[CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][O:32]3)=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)=[CH:3][CH:4]=1
Reactant: Cc1nc(-c2cc3ccccc3nc2Cl)c2ncn(C3CCCCO3)c2n1
Reactant: COc1ccc(N)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1COCCO1
Product: COc1ccc(Nc2nc3ccccc3cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A solution of 5-amino-2-methoxypyridine (50 mg, 0.41 mmol, Aldrich, St. Louis, Mo.) and 2-chloro-3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)quinoline (77 mg, 0.20 mmol) in dioxane (4 mL) at 0° C. was treated with LiHMDS (1 M in THF, 0.51 mL, 0.51 mmol). The reaction mixture was stirred at 0° C. for 1 h and 18 h at room temperature. Then an additional amount of LiHMDS (1 M in THF, 0.51 mL, 0.51 mmol) was added and the reaction mixture stirred at room temperature for 2 h. The reaction was quenched by the addition of MeOH (2 mL) and the solvents were removed under vacuum. Purification of the crude reaction mixture by silica gel chromatography (2 to 3% MeOH/CH2Cl2) provided the title compound as a dark orange solid. m/z (ESI, +ve ion) 468 (M+H)+.
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[F:16][C:17]([F:25])([C:21]([F:24])([F:23])[F:22])[CH2:18][CH2:19]O>>[F:13][C:10]([F:11])([F:12])[S:7]([O:6][CH2:19][CH2:18][C:17]([F:25])([F:16])[C:21]([F:24])([F:23])[F:22])(=[O:8])=[O:9]
Reactant: OCCC(F)(F)C(F)(F)F
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Product: O=S(=O)(OCCC(F)(F)C(F)(F)F)C(F)(F)F
Temperature: 56 °C
Reaction time: 2 h

Procedure:
198.49 g (703.51 mmol) of trifluoromethanesulphonic anhydride were initially charged under argon. The reaction flask was immersed into an oil bath at 70° C. and heated to internal temperature 56° C. 88.2 ml (738.68 mmol) of 3,3,4,4,4-pentafluorobutanol were added dropwise to the reaction mixture within 35 min and the mixture was stirred at bath temperature 70-73° C. and internal temperature 69° C. for two hours. The reaction mixture was concentrated on a rotary evaporator and the residue was taken up in 1500 ml of dichloromethane. The residue was washed once with 300 ml of cold water, once with 300 ml of cold saturated aqueous sodium hydrogencarbonate solution and once with 300 ml of cold water. The organic phase was dried with magnesium sulphate, filtered and concentrated. This gave 192.86 g (92.6% of theory) of the target compound.
Reaction SMILES: Cl.[NH2:2][OH:3].O=[C:5]([C:10]1[O:11][CH:12]=[CH:13][CH:14]=1)[C:6]([O:8][CH3:9])=[O:7]>CO>[OH:3][N:2]=[C:5]([C:10]1[O:11][CH:12]=[CH:13][CH:14]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: NO
Reactant: COC(=O)C(=O)c1ccco1
Agent: Cl
Solvent: CO
Product: COC(=O)C(=NO)c1ccco1
Reaction time: 3 h

Procedure:
Hydroxylamine hydrochloride (0.951 g) was added to a stirred solution of methyl 2-oxo-2-(2-furanyl)acetate (2.107 g) in methanol (30 ml). The mixture was stirred for 3 h, then the solvent was evaporated and the residue partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over magnesium sulphate and evaporated. The title oxime was isolated by column chromatography of the residue using gradient elution (Kieselgel:3:1 to 1:1 hexane:ethyl acetate). (Found: M+, 169.0378. C7H7NO4 requires M, 169.0375). νmax (CHCl3 /cm-1 3555, 3278 and 1739. δH (250 MHz, CDCl3), 3.95 (3H, s), 6.57 (1H, dd, J 1.58 and 3.48), 7.45 (1H, d, J 3.22), 7.58 (1H, d, J 2.11), 9.75 (1H, br.s), m/z (EI) 169 (M+).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][Cl:8])=[CH:5][CH:4]=1.S(=O)(=O)(O)O.[CH3:16][C:17](=[CH2:19])[CH3:18].[OH-].[Na+]>ClCCl.O>[C:17]([O:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][Cl:8])=[CH:5][CH:4]=1)([CH3:19])([CH3:18])[CH3:16]
Reactant: C=C(C)C
Reactant: OCc1ccc(CCl)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OCc1ccc(CCl)cc1
Yield: 45 %

Procedure:
A 5-gallon stirred pressure reactor was charged with p-hydroxymethylbenzyl chloride (600 g, 3.83 moles) in dichloromethane (6 liters). Concentrated sulfuric acid (60 mL) was charged to the reactor. Isobutylene gas was charged to the stirred solution for 2 hours at 10 psi. The temperature of the reaction was maintained at 20°-25° C. At the end of 24 hours the reaction was about 85% complete. The reaction mixture was diluted with water and the mixture adjusted to pH 7 by addition of 25% aqueous sodium hydroxide. The dichloromethane extract was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was fractionally distilled on a 24 cm Vigreux column to provide 312 g (45% yield) of the desired product. The boiling point of the product was 115°-125° C. (2-3 mm Hg). 1H NMR spectral data were as follows: (CDCl3, 300 MHz): δ7.4 (s, 4H), 4.58 (s, 2H), 4.45 (s, 2H), 1.3 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:16])([CH2:12][CH2:13][CH2:14][CH3:15])[C:3](=[O:11])[CH2:4]P(=O)(OC)OC.[H-].[Na+].[C:19]([O:22][C@@H:23]1[C@H:27]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C@@H:26]([CH:38]=O)[C@H:25]([O:40][CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43][O:42]2)[CH2:24]1)(=[O:21])[CH3:20]>C1COCC1>[C:19]([O:22][C@@H:23]1[C@H:27]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C@@H:26](/[CH:38]=[CH:4]/[C:3](=[O:11])[C:2]([F:1])([F:16])[CH2:12][CH2:13][CH2:14][CH3:15])[C@H:25]([O:40][CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43][O:42]2)[CH2:24]1)(=[O:21])[CH3:20]
Reactant: COC(=O)CCCCCC[C@@H]1[C@@H](C=O)[C@H](OC2CCCCO2)C[C@@H]1OC(C)=O
Reactant: CCCCC(F)(F)C(=O)CP(=O)(OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCC(F)(F)C(=O)/C=C/[C@@H]1[C@@H](CCCCCCC(=O)OC)[C@@H](OC(C)=O)C[C@H]1OC1CCCCO1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of dimethyl (3,3-difluoro-2-oxoheptyl)phosphonate (1) (0.453 g, 1.75 mmol) in anhydrous THF (7 ml), sodium hydride (60%, dispersion in mineral oil, 70 mg, 1.75 mmol) was added and stirred for 15 minutes at room temperature. A solution of methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-formyl-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (2) (0.175 g, 439 mmol) in anhydrous THF (3 ml) was added thereto, and the mixed solution was heat refluxed for approximately 4 hours. Only a trace amount of the target product (3) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][C:3]=1[N:16]=[C:17]=S.[NH2:19][C:20]1[C:25]([NH2:26])=[CH:24][C:23]([N:27]2[CH2:31][CH2:30][CH:29]([C:32]#[N:33])[CH2:28]2)=[C:22]([Cl:34])[CH:21]=1.CC(C)N=C=NC(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][C:3]=1[NH:16][C:17]1[NH:26][C:25]2[CH:24]=[C:23]([N:27]3[CH2:31][CH2:30][CH:29]([C:32]#[N:33])[CH2:28]3)[C:22]([Cl:34])=[CH:21][C:20]=2[N:19]=1
Reactant: N#CC1CCN(c2cc(N)c(N)cc2Cl)C1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(Nc2nc3cc(Cl)c(N4CCC(C#N)C4)cc3[nH]2)c1

Procedure:
The title compound was prepared from N-(4-chloro-3-isothiocyanatobenzyl)-2,2-dimethyl-propionamide (66 mg, 0.2 mmol), 1-(4,5-diamino-2-chloro-phenyl)-pyrrolidine-3-carbonitrile (55 mg, 0.2 mmol) in DMF (2 mL) and DIC (39 μL, 0.2 mmol) in analogy to example 6 step (c).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl.C(N=C=NCCCN(C)C)C.[NH2:26][CH:27]1[CH2:32][CH2:31][CH:30]([O:33][C:34](=[O:36])[CH3:35])[CH2:29][CH:28]1[C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([O:45][CH2:46][CH3:47])[CH:38]=1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][O:2][C:3]1[C:4]([C:5]([NH:26][CH:27]2[CH2:32][CH2:31][CH:30]([O:33][C:34](=[O:36])[CH3:35])[CH2:29][CH:28]2[C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([O:45][CH2:46][CH3:47])[CH:38]=2)=[O:7])=[CH:8][CH:9]=[C:10]([O:12][CH3:13])[N:11]=1
Reactant: COc1ccc(C(=O)O)c(OC)n1
Reactant: CCOc1cc(C2CC(OC(C)=O)CCC2N)ccc1OC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCOc1cc(C2CC(OC(C)=O)CCC2NC(=O)c2ccc(OC)nc2OC)ccc1OC
Temperature: 40 °C
Reaction time: 42 h
Yield: 102.6 %

Procedure:
555 mg of 2,6-dimethoxynicotinic acid and 581 mg of N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride are placed in a flask under nitrogen. 778 mg of acetic acid (1RS,3RS,4RS)-4-amino-3-(3-ethoxy-4-methoxyphenyl)cyclohexyl ester (compound B1) and 2 mg of 4-dimethylaminopyridine both as solution in dichloromethane are added and the solution stirred for 1 h at 40° C., than 42 h at room temperature. The reaction is quenched with 5 ml of water. After phase separation the organic layer is washed with 2.5 ml of saturated potassium hydrogencarbonate solution. After drying the organic layer with magnesium sulfate the solvent is removed to give 1.227 g of the crude title compound which are used for the following step without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH:11]12[CH2:17][CH2:16][CH:15]1[CH2:14][NH:13][CH2:12]2.C(N(CC)CC)C>O1CCOCC1>[CH:11]12[CH2:17][CH2:16][CH:15]1[CH2:14][N:13]([C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1)[CH2:12]2
Reactant: C1CC2CNCC12
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(N2CC3CCC3C2)nc1
Temperature: 65 °C
Yield: 87.6 %

Procedure:
A mixture of 0.1 g (0.63 mmol) of 2-chloro-5-nitropyridine, 0.1 g (0.75 mmol) of 3-aza-bicyclo[3.2.0]heptane (J. Med. Chem. 1967, 10(4), 621) and 0.26 mL (0.19 mmol) of triethylamine in 10 mL of dioxane, is heated at 65° C. for 4 h. The reaction mixture is then poured into 50 mL of ice water. The mixture is stirred until the ice has melted completely, then a yellow precipitate is collected by filtration and is dried at reduced pressure. In this way we isolate 0.121 g of the expected product in the form of a yellow powder.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][NH2:14])[CH2:7][CH2:6]1.[CH3:15][O:16][C:17]1[C:24]([O:25][CH3:26])=[C:23]([O:27][CH3:28])[C:22]([O:29][CH3:30])=[C:21]([CH3:31])[C:18]=1[CH:19]=O>>[CH3:15][O:16][C:17]1[C:24]([O:25][CH3:26])=[C:23]([O:27][CH3:28])[C:22]([O:29][CH3:30])=[C:21]([CH3:31])[C:18]=1[CH2:19][NH:14][CH2:13][CH2:12][CH2:11][N:8]1[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][CH2:2][NH:1][CH2:19][C:18]2[C:21]([CH3:31])=[C:22]([O:29][CH3:30])[C:23]([O:27][CH3:28])=[C:24]([O:25][CH3:26])[C:17]=2[O:16][CH3:15])[CH2:10][CH2:9]1
Reactant: COc1c(C)c(C=O)c(OC)c(OC)c1OC
Reactant: NCCCN1CCN(CCCN)CC1
Product: COc1c(C)c(CNCCCN2CCN(CCCNCc3c(C)c(OC)c(OC)c(OC)c3OC)CC2)c(OC)c(OC)c1OC

Procedure:
The title compound was prepared by a similar way as in Preparation Example 1, except that 1,4-bis(3-aminopropyl)piperazine was used instead of trans-1,2-cyclohexane diamine and 2,3,4,5-tetramethoxy-6-methylbenzaldehyde was used instead of veratraldehyde.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[CH:18]=[C:19]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])[CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[N:10](S(C2C=CC(C)=CC=2)(=O)=O)[CH:9]=1.[OH-].[K+]>CO.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[CH:18]=[C:19]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])[CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[NH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccccc3F)c3cc(-c4cccc(C(=O)N5CCOCC5)c4)cnc32)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(c1cccc(-c2cnc3[nH]cc(-c4ccccc4F)c3c2)c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21 %

Procedure:
Crude (3-(3-(2-fluorophenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)(morpholino)methanone from last step was dissoled in methanol (1 mL) and potassium hydroxide (50% w/v, 0.038 mL, 0.136 mmol) was added to the solution. The resulting mixture was stirred at room temperature for 30 minutes before being diluted with water and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to dryness. The crude product was then dissolved in DMSO and purified by mass triggered reverse phase HPLC to afford pure (3-(3-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)(morpholino)methanone (5.6 mg, 21% yield from (3-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)(morpholino)methanone) as light brown syrup. 1H NMR (500 MHz, DMSO-d6) δ 3.60 (m, br, 8H), 7.33 (m, 3H), 7.39 (m, 1H), 7.55 (t, J=7.5 Hz, 1H), 7.74 (m, 1H), 7.84 (m, 3H), 8.28 (m, 1H), 8.61 (d, J=2.5 Hz, 1H), 12.17 (s, 1H). MS: m/z 402.1 (M+H+).
Reaction SMILES: CO[C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([CH3:12])([CH3:11])[NH:8][C:7]=2[CH:13]=1.[BH4-].[Na+].[C:16](O)(=[O:18])C>C(COC)OC.C(O)(C)C>[CH:9]([NH:8][C:7]1[CH:13]=[CH:3][C:4]([O:18][CH3:16])=[CH:5][C:6]=1[SH:10])([CH3:11])[CH3:12]
Reactant: CC(=O)O
Reactant: COc1ccc2c(c1)NC(C)(C)S2
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: COCCOC
Product: COc1ccc(NC(C)C)c(S)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 5-methoxy-2,2-dimethylbenzothiazolidine (14.6 gm; 75 mmoles) in 50 ml dimethoxyethane and 5 ml isopropanol was added sodium borohydride (4.0 gm; 0.1 mole). The reaction mixture was stirred at room temperature for 1 hour. The mixture was then poured over 5 N acetic acid, extracted with methylene chloride, washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was recrystallized from hexane to yield the title compound, m.p. 68°-69° C. in nearly quantitative yield.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][C:11]([Cl:15])=[CH:12][CH:13]=2)[NH:8][C:7]=1[C:16](=[O:24])[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)C.[OH-].[Na+]>CO.O>[Cl:15][C:11]1[CH:10]=[C:9]2[C:14]([C:6]([CH2:5][C:4]([OH:25])=[O:3])=[C:7]([C:16](=[O:24])[C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)[NH:8]2)=[CH:13][CH:12]=1
Reactant: CCOC(=O)Cc1c(C(=O)c2ccc(Cl)cc2)[nH]c2cc(Cl)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)Cc1c(C(=O)c2ccc(Cl)cc2)[nH]c2cc(Cl)ccc12
Reaction time: 24 h
Yield: 81 %

Procedure:
To a solution of [6-chloro-2-(4-chloro-benzoyl)-1H-indol-3-yl]-acetic acid ethyl ester (200 mg, 0.532 mmol) in methanol (2 ml) and water (0.8 ml) was added sodium hydroxide (137 mg, 3.43 mmol). The reaction mixture was stirred 24 hours, and was concentrated to a low volume. Water (4 ml) was added, the material was transferred to a separatory fumnel and was washed with dichloromethane (5 ml). The aqueous layer was acidified to pH 1 with 1N hydrochloric acid and was extracted with ethyl acetate (15 ml). The organic layer was dried over magnesium sulfate, filtered, and concentrate to afford [6-chloro-2-(4-chloro-benzoyl)-1H-indol-3-yl]-acetic acid (150 mg, 81%). The 1H NMR spectrum was identical with the one obtained for the compound prepared by the method described in example 2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[S:12])[N:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[C:7]2=[O:19].[C:20]([O-])([O-])=O.[K+].[K+].CI>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([S:12][CH3:20])[N:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[C:7]2=[O:19]
Reactant: O=C([O-])[O-]
Reactant: O=c1c2cccc(Br)c2[nH]c(=S)n1-c1ccccn1
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: CSc1nc2c(Br)cccc2c(=O)n1-c1ccccn1
Temperature: 25 °C
Yield: 90.2 %

Procedure:
A mixture of 8-bromo-3-(pyridin-2-yl)-2-thioxo-2,3-dihydroquinazolin-4(1H)-one (330 mg, 0.987 mmol, 415b), K2CO3 (59.6 mg, 0.987 mmol), and THF (9.9 mL) was set stirring under nitrogen at RT. MeI (61.3 pt, 0.987 mmol) was added, and the mixture was set stirring at 75° C. for 4 h. The reaction was cooled to RT and filtered, rinsing with chilled THF. The filtrate was concentrated under reduced pressure to give 310 mg of a waxy yellow-brown solid that contained the product. m/z (ESI, +ve) 349.7 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[O:18][CH2:19][CH2:20][CH2:21]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[O:18][CH2:19][CH2:20][CH2:21][C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:5][CH2:6][C:2]1=[O:1]
Reactant: CCOC(=O)C1CCCC1=O
Reactant: BrCCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1(CCCOC2CCCCO2)CCCC1=O
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 2.0 g (12.8 mmol) ethyl 2-oxocyclopentanecarboxylate, 5.71 g (25.6 mmol) 1-(tetrahydropyranyl- oxy)-3-bromopropane, 7.08 g (57.2 mmol) powdered potassium carbonate and 60 mL acetone is heated to 60° C. under nitrogen with stirring for 8 hours. The reaction mixture is cooled to room temperature, filtered and evaporated to give a yellow orange liquid which is purified by flash chromatograhy using 1:9 ethyl acetate, hexane to yield 2-[3-(tetrahydropyranyloxy)propyl]-2-carbethoxycyclopentanone; IR (neat): 1750 cm-1 1724 cm-1.
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:11]1([C:10]2[C:9]3[C:4](=[CH:5][C:6]([C:17]([O:19][CH3:20])=[O:18])=[CH:7][CH:8]=3)[NH:3][C:2]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3)[nH]c2c1
Temperature: 90 °C
Reaction time: 6 h
Yield: 49 %

Procedure:
To a solution of methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (from Step 3) in DME and EtOH (0.2 M, 3:1, v/v) was added phenyl-boronic acid (1.2 eq.) followed by 2 M aqueous Na2CO3 (8.5 eq,). The mixture was degassed with ultrasound for 30 min, then Pd(PPh3)4 (0.1 eq.) was added and mixture degassed with ultrasound for a further 30 min. The reaction was stirred under nitrogen at 90° C. for 6 h and then cooled to RT. Water was added and the solids filtered off. They were washed with Et2O to give the title compound (49%). The combined mother liquors together with the reaction solvents were washed with water (150 ml) and after phase-cut the organic phase was dried over Na2SO4 and evaporated to dryness. The residual solid was crystallized from boiling CHCl3 to give more title compound (38%, 87% total yield). 1H NMR (400 MHz, DMSO-d6, 300 K) δ 1.21-1.48 (m, 3H), 1.65-1.80 (m, 5H), 1.90-2.05 (m, 2H), 2.79-2.95 (m, 1H), 3.88 (s, 3H), 7.2-7.34 (m, 1H), 7.40-7.50 (m, 1H), 7.51-7.60 (m, 3H), 7.60 (d, J 7.6, 1H), 7.84 (d, J 7.6, 1H), 8.00 (s, 1H); MS (ES+) m/z 334 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[CH:21]=[CH:20][C:8]([O:9][Si:10]([CH:17]([CH3:19])[CH3:18])([CH:14]([CH3:16])[CH3:15])[CH:11]([CH3:13])[CH3:12])=[CH:7][CH:6]=1.[OH:22][C:23]1[CH:40]=[CH:39][C:38]([C:41]([O:43][CH3:44])=[O:42])=[CH:37][C:24]=1[C:25]([N:27]1[CH2:32][CH2:31][CH:30]([C:33]([O:35][CH3:36])=[O:34])[CH2:29][CH2:28]1)=[O:26]>>[CH3:44][O:43][C:41]([C:38]1[CH:39]=[CH:40][C:23]([O:22][CH2:2][CH2:3][CH2:4][C:5]2[CH:21]=[CH:20][C:8]([O:9][Si:10]([CH:17]([CH3:19])[CH3:18])([CH:14]([CH3:16])[CH3:15])[CH:11]([CH3:13])[CH3:12])=[CH:7][CH:6]=2)=[C:24]([CH:37]=1)[C:25]([N:27]1[CH2:28][CH2:29][CH:30]([C:33]([O:35][CH3:36])=[O:34])[CH2:31][CH2:32]1)=[O:26])=[O:42]
Reactant: COC(=O)c1ccc(O)c(C(=O)N2CCC(C(=O)OC)CC2)c1
Reactant: CC(C)[Si](Oc1ccc(CCCBr)cc1)(C(C)C)C(C)C
Product: COC(=O)c1ccc(OCCCc2ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc2)c(C(=O)N2CCC(C(=O)OC)CC2)c1

Procedure:
Methyl 1-[5-(methoxycarbonyl)-2-(3-{4-[(triisopropylsilyl)oxy]phenyl}propoxy)-benzoyl]piperidine-4-carboxylate is prepared by the process described in Example XLI from [4-(3-bromopropyl)phenoxy](triisopropyl)silane and methyl 1-[2-hydroxy-5-(methoxycarbonyl)benzoyl]-4-piperidinecarboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([N+]([O-])=O)[CH:3]=1.[OH:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:25])[CH3:24])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1)[O:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:23](=[O:25])[CH3:24])=[CH:20][CH:21]=1
Reactant: CC(=O)Nc1ccc(CO)cc1
Reactant: O=[N+]([O-])c1cc(Cl)cc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1ccc(COc2cc(Cl)cc([N+](=O)[O-])c2)cc1
Temperature: 25 °C
Yield: 29.9 %

Procedure:
The product from Example 193a (1.00 g, 4.9 mmol), and the product from Example 197b (0.90 g, 5.4 mmol) and K2CO3 (0.86 g, 6.2 mmol) in DMF (20 mL) were heated at 100° C. for 10 hours. The reaction mixture was cooled to room temperature, diluted with H2O. The resulting solid was collected by filtration, washed with H2O, and dried in vacuum to give brown crystal, which was purified by silica gel column chromatography eluting with 5:2 EtOAc/hexane to give the title compound as a dark orange crystal (0.47 g, 30%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12](=[O:15])[NH:13][CH:14]=2)=[CH:5][CH:4]=1.[CH2:16]([O:18][C:19](=[O:22])[CH2:20]Br)[CH3:17]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12](=[O:15])[N:13]([CH2:20][C:19]([O:18][CH2:16][CH3:17])=[O:22])[CH:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2ccc(=O)[nH]c2)cc1
Reactant: CCOC(=O)CBr
Product: CCOC(=O)Cn1cc(-c2ccc(OC)cc2)ccc1=O
Temperature: 60 °C
Reaction time: 12 h
Yield: 90.6 %

Procedure:
According to Scheme 9 Step 1: The title compound was prepared from 5-(4-methoxyphenyl)pyridin-2(1H)-one (1 eq, 3.73 mmol, 0.75 g, Example 7 Step 1) and ethylbromoacetate (1.2 eq, 4.47 mmol, 0.50 mL) according to the procedure described for Example 1 Step 2. The reaction was stirred at 60° C. for 12 hours. The reaction was filtered and concentrated under reduced pressure to yield a yellow oil. The product was triturated from diisopropyl ether to afford ethyl 2-(5-(4-methoxyphenyl)-2-oxopyridin-1(2H)-yl)acetate (3.38 mmol, 0.97 g, 91%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N+:15]([O-:18])=[CH:14][CH:13]=[C:12]([CH3:19])[C:11]=2[C:10](=O)[CH2:9]1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].Cl.Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N+:15]([O-:18])=[CH:14][CH:13]=[C:12]([CH3:19])[C:11]=2[C:10](=[N:25][NH:24][C:21]([NH2:23])=[NH:22])[CH2:9]1
Reactant: Cc1cc[n+]([O-])c2c1C(=O)CC(c1ccccc1Cl)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Product: Cc1cc[n+]([O-])c2c1C(=NNC(=N)N)CC(c1ccccc1Cl)C2
Temperature: 25 °C
Yield: 144.8 %

Procedure:
To a mixture of 7-(2-chlorophenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one-1-oxide (0.23 g) and aminoguanidine hydrochloride (100 mg) were added ethanol (6 ml) and concentrated hydrochloric acid (0.1 ml), and the mixture was refluxed for 3 hours. The reaction solution was cooled to room temperature, and the resulting crystals were filtered and dried to give 7-(2-chlorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline-1-oxide hydrochloride (Compound 157) (220 mg) as colorless crystals.