Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]([C:5]1[S:9][C:8]([NH:10]C(=O)OC(C)(C)C)=[N:7][C:6]=1[CH2:18][CH2:19][O:20]C1CCCCO1)([CH3:4])[CH3:3].Cl.[OH-].[Na+]>O1CCCC1>[CH3:4][C:2]1([CH3:3])[C:5]2[S:9][C:8]([NH2:10])=[N:7][C:6]=2[CH2:18][CH2:19][O:20]1
Reactant: CC(C)(C)OC(=O)Nc1nc(CCOC2CCCCO2)c(C(C)(C)O)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1(C)OCCc2nc(N)sc21

Procedure:
To a solution of Example 251D (4.6 g, 11 mmol) in tetrahydrofuran was added concentrated HCl (6.9 mL). The reaction mixture was heated at reflux for overnight and then cooled. The mixture was basified with 5N NaOH (17 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography (SiO2, 0-10% methanol in CH2Cl2) to afford the title compound. MS (ESI+) m/z 185 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[C:19]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[N:34]=[CH:33][CH:32]=[N:31]2.C(N(C(C)C)C(C)C)C>CC#N>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[O:12][C:13]3[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH2:27][C:28]5[CH:29]=[C:30]6[C:35](=[CH:36][CH:37]=5)[N:34]=[CH:33][CH:32]=[N:31]6)[CH2:22][CH2:21]4)=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(-c2nc3cccc(N4CCNCC4)c3o2)cc1
Reactant: BrCc1ccc2nccnc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)c1ccc(-c2nc3cccc(N4CCN(Cc5ccc6nccnc6c5)CC4)c3o2)cc1
Temperature: 95 °C
Yield: 69.4 %

Procedure:
To a suspension of 2-(4-tert-butylphenyl)-7-piperazin-1-yl-1,3-benzooxazole 23.5 mg, 0.070 mmol) and 6-bromomethylquinoxaline (17.2 mg, 0.077 mmol) in CH3CN (anh., 10 mL) was added ethyldiisopropylamine (0.015 mL, 0.084 mmol). The mixture was heated in a 95° C. bath overnight. The reaction was cooled to room temperature and concentrated in vacuo. The residue was adsorbed onto silica gel. Silica gel chromatography using a gradient of 25% EtOAc/hexane to 50% EtOAc/hexane then 100% EtOAc afforded the title compound (23.2 mg) as an ivory powder. MS (ESI) m/z 478 [M+H]+; HPLC Method C, r.t.=10.9 min (98.9% @210-370 nm; 97.4% @ 236 nm).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]12[CH2:15][CH2:14][CH2:13][CH2:12]1.[C:16]([O:20][C:21]([N:23]1[CH:27]=[CH:26][CH:25]=[C:24]1B(O)O)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.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>[O:11]=[C:6]1[C:5]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([C:24]3[N:23]([C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])[CH:27]=[CH:26][CH:25]=3)[CH:3]=2)[NH:7]1
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Reactant: O=C1Nc2ccc(Br)cc2C12CCCC2
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: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)n1cccc1-c1ccc2c(c1)C1(CCCC1)C(=O)N2
Temperature: 80 °C
Yield: 83.2 %

Procedure:
A solution of 5′-bromospiro[cyclopentane-1,3′-[3H] indol]-2′(1′H)-one (2.0 g, 7.5 mmol) and tetrakis(triphenylphosphine)palladium(0) (430 mg, 0.3 mmol) in ethylene glycol dimethyl ether (50 mL) was stirred under a flow of nitrogen for 15 min. To the solution was added sequentially 1-t-butoxycarbonylpyrrole-2-boronic acid (2.1 g, 9.7 mmol) and potassium carbonate (2.4 g, 17 mmol) in water (10 mL). The mixture was heated to 80° C. for 3 h and allowed to cool. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (3×50 mL). The organic layers were combined, washed with brine (30 mL) and dried over magnesium sulfate. The solution was filtered and concentrated in vacuo. Crystallization from 20% ethyl acetate/hexane gave 2-(1′,2′-dihydro-2′-oxospiro[cyclopentane-1,3′-[3H]indol ]-5′yl)-1H-pyrrole-1-carboxylic acid, tert-butyl ester (2.2 g, 83%) as a white powder, mp 179-180.5° C. 1H NMR (DMSO-d6, 400 MHz) δ 1.30 (s, 9H), 1.75-1.98 (m, 8 H), 6.16 (dd, 1H, J=1.8, 3.3 Hz), 6.22 (‘t’, 1 H, J=3.3, 3.3 Hz), 6.79 (d, 1 H, J=7.9 Hz), 7.08 (dd, 1 H, J=1.8, 7.9 Hz), 7.14 (‘d’, 1 H, J=1.5 Hz), 7.28 (dd, J=1.9, 3.3 Hz),10.30 (s, 1 H). MS (EI) m/z 352 [M+]. Anal. Calcd for C21H24N2O3: C, 71.57; H, 6.86; N, 7.95. Found: C, 71.08; H, 6.83; N, 7.74.
Reaction SMILES: C(O[C:4]([O:13]CC)([CH3:12])[CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])C.[CH:16](OCC)=[O:17].[Na].O>C1C=CC=CC=1>[CH:16]([CH:6]([CH2:5][C:4]([CH3:12])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:17]
Reactant: CCOC(=O)CCC(C)(OCC)OCC
Reactant: CCOC=O
Agent: [Na]
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)C(C=O)CC(C)=O
Reaction time: 3 h

Procedure:
A mixture of 106.3 g (0.489 mol) of ethyl 4,4-diethoxypentanoate and 80 ml (73.6 g, 0.99 mol) of ethyl formate was added dropwise to a vigorously stirred suspension of 12.7 g (0.55 gram atom) of sodium (shavings) in 300 ml of anhydrous benzene at 10-15° C. over 3 h. Stirring was continued for a further 3 h, and the reaction mixture was left to stand overnight. 250 ml of water were added with vigorous stirring, and this was continued for a further 15 min. The water layer was separated off, and the benzene layer was extracted with 70 ml of water. The combined aqueous extracts were acidified to pH 2 and extracted with ethyl acetate (5×50 ml), and the organic extracts were dried over calcium chloride.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:21]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][S:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:21])[N:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cccc(CSc2ccccc2)n1
Product: Cc1cccc(CS(=O)c2ccccc2)n1

Procedure:
A solution of 2-methyl-6-((phenylthio)methyl)pyridine is reacted with m-chloroperoxybenzoic acid according to the method of Example 18 to give the title compound.
Reaction SMILES: [I:1][C:2]1[C:3]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:4][C:5]([S:13][CH3:14])=[C:6]([CH:12]=1)[C:7](OCC)=[O:8].[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[OH:8][CH2:7][C:6]1[C:5]([S:13][CH3:14])=[CH:4][C:3]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])=[C:2]([I:1])[CH:12]=1
Reactant: CCOC(=O)c1cc(I)c(NS(C)(=O)=O)cc1SC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: CSc1cc(NS(C)(=O)=O)c(I)cc1CO
Temperature: 0 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
To a solution of ethyl 5-iodo-4-(methylsulfonamido)-2-(methylthio)benzoate (crude, from step 2) in dry toluene (200 mL) at 0° C. was added diisobutylaluminium hydride (1.0 M in toluene, 100 mL, 100 mmol) slowly. After addition, the mixture was stirred at 0° C. for 3 h and quenched with methanol/H2O (1/1). The reaction mixture was poured into a vigorously stirred solution of potassium sodium tartrate (1M, 300 mL) and stirred vigorously for 2 h, after which time it settled to two clear phases. The organic layer was separated, and the aq layer was extracted with EtOAc (3×200 mL). The combined organic solution was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (0-40% EtOAc/Hexanes) afford N-(4-(hydroxymethyl)-2-iodo-5-(methylthio)phenyl)methanesulfonamide (11.9 g, 80% yield for two steps). LC-MS m/z 356 [M+H]+. 1H NMR (400 MHz, CDCl3): δ 7.82 (s, 1H), 7.49 (s, 1H), 4.67 (s, 2H), 2.99 (s, 3H), 2.50 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:5])[CH3:4].F[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]3[CH2:26][CH2:25][CH2:24][N:16]3[C:17]=2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:9][CH:8]=1>CN(C)C=O>[CH2:3]([S:5][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]3[CH2:26][CH2:25][CH2:24][N:16]3[C:17]=2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:9][CH:8]=1)[CH3:4]
Reactant: Fc1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Reactant: CCS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCSc1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Temperature: 95 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60%) (0.75 g, 19 mmol) was added to a solution of ethanethiol (2.1 ml, 1.7 g, 28 mmol) in N,N-dimethylformamide (15 ml) at 0° C. under an argon atmosphere. After stirring for 0.5 hours, 2-(4-fluorophenyl)-3-(4-pyridyl)-6,7-dihydro-[5H]-pyrrolo[1,2-a]-imidazole (3.5 g, 12.5 mmol) of Example 2 was added and the resulting solution heated to 95° C. for 6 hours. The cooled reaction mixture was evaporated under reduced pressure and the residue partitioned between 1N aqueous sodium hydroxide and dichloromethane. The organic layer was washed successively with water and brine, dried (magnesium sulfate) and concentrated. The residue was chromatographed on silica gel eluting with 25:1 chloroform/methanol. Fractions containing product were combined, the solvent evaporated and the residue recrystallized from ethyl acetate to afford the titled compound; mp. 124°-125° C. Anal. Calcd. for C19H19N3S: C,70 99; H, 5.96; N, 13.08; S, 9.97: Found: C, 70.99; H, 5.92; N, 13.07; S, 9.81.
Reaction SMILES: [OH:1][C:2]1([CH2:37][CH2:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:7][CH2:6][N:5]([CH2:8][C@@H:9]2[C@@H:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][N:11]([C@H:20]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[C:21]([O:23]CC3C=CC=CC=3)=[O:22])[CH2:10]2)[CH2:4][CH2:3]1.[H][H]>[Pd].CO>[OH:1][C:2]1([CH2:37][CH2:38][CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH2:7][CH2:6][N:5]([CH2:8][C@@H:9]2[C@@H:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][N:11]([C@H:20]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[C:21]([OH:23])=[O:22])[CH2:10]2)[CH2:4][CH2:3]1
Reactant: O=C(OCc1ccccc1)[C@@H](C1CCCCC1)N1C[C@H](CN2CCC(O)(CCCc3ccccc3)CC2)[C@@H](c2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C(O)[C@@H](C1CCCCC1)N1C[C@H](CN2CCC(O)(CCCc3ccccc3)CC2)[C@@H](c2ccccc2)C1
Yield: 99.4 %

Procedure:
A mixture of 20 mg (0.032 mmol) 2-(R)-(3-(S)-((4-hydroxy-4-(3-phenylpropyl)piperidin-1-yl)methyl)-4-(S)-phenylpyrrolidin-1-yl)-2-(cyclohexyl)acetic acid, benzyl ester (from EXAMPLE 1, Step J) and 3 mg of 10% palladium on carbon in 0.5 mL of MeOH was stirred under one atmosphere of hydrogen for 18 h. The reaction was filtered through a 0.45 nylon filter and concentrated to give 16.5 mg (97%) of the title compound: ESI-MS 519 (M+H); HPLC B: 5.07 min.
Reaction SMILES: [I:1][C:2]1[CH:12]=[N:11][C:5]2[NH:6][CH2:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.[F:13][C:14]1[CH:15]=[CH:16][C:17]([C:22]([F:25])([F:24])[F:23])=[C:18]([CH:21]=1)[CH2:19]Br>>[F:13][C:14]1[CH:15]=[CH:16][C:17]([C:22]([F:23])([F:24])[F:25])=[C:18]([CH:21]=1)[CH2:19][N:9]1[C:8](=[O:10])[CH2:7][NH:6][C:5]2[N:11]=[CH:12][C:2]([I:1])=[CH:3][C:4]1=2
Reactant: O=C1CNc2ncc(I)cc2N1
Reactant: Fc1ccc(C(F)(F)F)c(CBr)c1
Product: O=C1CNc2ncc(I)cc2N1Cc1cc(F)ccc1C(F)(F)F
Yield: 51 %

Procedure:
7-Iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (1.07 g) was reacted with 5-fluoro-2-trifluoromethylbenzyl bromide as in General Procedure 1 to give the title compound as an off-white solid (51% yield). M.p. 244-245° C., LCMS: m/z=453.03 (M+H+), 1H-NMR (DMSO-d6, 400 MHz) δ 4.21 (s, 2H), 5.15 (s, 2H), 6.97 (s, 1H0, 7.12 (d, J=9.8 Hz, 1H), 7.25 (s, 1H), 7.36 (dd, J=8.3 Hz, 1H), 7.84 (s, 1H), 7.88-7.94 (m, 1H).
Reaction SMILES: CS([O:5][C@@H:6]1[CH2:10][CH:9]=[CH:8][C@H:7]1[CH2:11][C:12]([O-:14])=[O:13])(=O)=O.O1CCCC1.[OH-].[Na+:21]>O>[OH:5][C@H:6]1[CH2:10][CH:9]=[CH:8][C@H:7]1[CH2:11][C:12]([O-:14])=[O:13].[Na+:21]
Reactant: CS(=O)(=O)O[C@@H]1CC=C[C@H]1CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C([O-])C[C@@H]1C=CC[C@@H]1O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 0.290 g. (0.00124 mole) of racemic trans-2-methylsulfonyloxy-4-cyclopentene-1-acetate in 10 ml. of tetrahydrofuran and 4 ml. of water at 0° C. was added dropwise, 1.00 ml. (0.0020 mole) of 2 N sodium hydroxide solution. The two-phased solution was vigorously stirred at 0° C. for 1 hr. and at room temperature for 16 hrs. to form racemic sodium cis-2-hydroxy-4-cyclopentene-1-acetate in admixture with racemic cis-2-hydroxy-4-cyclopentene-1-acetic acid lactone.
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[NH:7][C@H:8]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:9][N:10]1[C:15](=[O:16])[C:14]([NH:17][C:18](=[O:23])[CH2:19][CH2:20][CH2:21]Cl)=[CH:13][N:12]([CH2:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])[C:11]1=[O:33])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.ClCCl>[C:1]([O:5][C:6](=[O:40])[NH:7][C@H:8]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:9][N:10]1[C:15](=[O:16])[C:14]([N:17]2[CH2:21][CH2:20][CH2:19][C:18]2=[O:23])=[CH:13][N:12]([CH2:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])[C:11]1=[O:33])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cn1c(=O)c(NC(=O)CCCCl)cn(Cc2c(F)cccc2F)c1=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cn1c(=O)c(N2CCCC2=O)cn(Cc2c(F)cccc2F)c1=O)c1ccccc1
Yield: 88.9 %

Procedure:
{(R)-2-[5-(4-chloro-butyrylamino)-3-(2,6-difluoro-benzyl)-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethyl}-carbamic acid tert-butyl ester (30 mg, 0.052 mmol) and potassium carbonate (30 mg, 0.217 mmol) were dissolved at room temperature for 6 hrs in DMF (1 mL) with stirring. The solution was diluted with dichloromethane and washed with water to separate an organic layer. After concentration of the organic layer, the residue was purified using silica gel chromatography (eluent: dichloromethane/methanol, 30/1) and dried in a vacuum to afford 25 mg of the compound as a colorless oil (yield 90%). 1H NMR (300 MHz, CDCl3) δ 1.34 (9H, s), 2.15 (2H, p), 2.51 (2H, t), 3.80 (2H, m), 4.03 (1H, m), 4.27 (1H, m), 4.98-5.13 (3H, m), 5.57 (1H, d), 6.97 (2H, m), 7.22-7.40 (6H, m), 7.62 (1H, s)
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH2:13][CH2:14][OH:15].[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Br.ClCCl.[OH-].[Na+]>CCOCC>[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:15][CH2:14][CH2:13][CH2:12][CH2:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1
Reactant: OCCCCc1ccc2ccccc2n1
Reactant: BrCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: ClCCl
Product: BrCCCCCCOCCCCc1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2-quinolinebutanol (2.56 g), 1,6-dibromohexane (5 ml), dichloromethane (2 ml), TAB (150 mg) and 50% aqueous sodium hydroxide (5 ml) was stirred at room temperature for 18 h. Ether (40 ml) was added and the organic phase separated, washed with water (20 ml), brine (20 ml), dried and evaporated in vacuo to an oil. The oil was purified by chromatography over a column of silica (Merck 60, Art. 7734). Elution with hexane and hexane-ether (9:1) followed by hexane-ether (1:1) afforded the title compound (2.12 g) as a colourless oil, t.l.c. (diethyl ether), Rf 0.50.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][C@H:14]([O:16][CH3:17])[CH3:15])[N:8]=[C:7]([CH3:18])[CH:6]=[CH:5]2.[O:19]1CCOCC1>O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][C@H:14]([O:16][CH3:17])[CH3:15])[N:8]=[C:7]([CH:18]=[O:19])[CH:6]=[CH:5]2
Reactant: CO[C@H](C)COc1cc2nc(C)ccc2cc1F
Reactant: C1COCCO1
Solvent: O
Product: CO[C@H](C)COc1cc2nc(C=O)ccc2cc1F
Yield: 74 %

Procedure:
To a solution of (R)-6-fluoro-7-(2-methoxypropoxy)-2-methylquinoline (0.281 g, 1.13 mmol) in dioxane (4 mL) and water (0.04 mL) was added SeO2 (0.138 g, 1.24 mmol). The reaction mixture was heated at reflux for 3 hours. After cooling, the mixture was filtered through Celite®. The filtrate was concentrated. The residue was purified by flash chromatography on silica gel (hexanes:EtOAc, 4:1) to give (R)-6-fluoro-7-(2-methoxypropoxy)quinoline-2-carbaldehyde (0.219 g, 74%) as a solid.
Reaction SMILES: [CH2:1]1[O:3][CH:2]1[CH2:4][OH:5].CCOCC.[F:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15]>N1C=CC=CC=1>[F:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([O:5][CH2:4][CH:2]1[O:3][CH2:1]1)=[O:15]
Reactant: O=C(Cl)c1ccccc1F
Reactant: OCC1CO1
Solvent: c1ccncc1
Solvent: CCOCC
Product: O=C(OCC1CO1)c1ccccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.9 %

Procedure:
A mixture containing 37 g (0.5 mole) of glycidol, 500 ml of anhydrous ether, 500 ml of pyridine and 80 g (0.5 mole) of o-fluoro-benzoyl chloride was stirred at 0° C. for 1 hour and 25° C. for 2 hours. The mixture was filtered and the ethanol filtrate was washed with 100 ml of 5% HCl. Evaporation of the ether gave an oil which was distilled to give 69.5 g (71%) of product, b.p. 115° C./0.5 mmHg. The NMR and IR spectra were consistent with the assigned structure.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:11](=O)[CH3:12].N1CCCCC1.Cl.[Cl-].[Na+]>C(OCC)(=O)C>[CH:11](=[C:4]([C:3](=[O:10])[CH2:2][Cl:1])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:12]
Reactant: CC=O
Reactant: CCOC(=O)CC(=O)CCl
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCNCC1
Solvent: CCOC(C)=O
Product: CC=C(C(=O)CCl)C(=O)OCC
Temperature: -75 °C
Reaction time: 2 h

Procedure:
50 parts by weight of ethyl 4-chloroacetoacetate and 76 parts by volume of ethyl acetate are taken, covered with a layer of nitrogen and cooled to -75° C. 33 parts by weight of acetaldehyde are added to the cold solution and a solution of 0.43 part by volume of piperidine in 3 parts by volume of ethyl acetate is then allowed to run in over a period of 50 minutes. The solution is now warmed to 0° C. in the course of 40 minutes and is stirred at this temperature for 2 hours. After addition of 121 parts by volume of 1N hydrochloric acid and 16 parts by weight of sodium chloride, the mixture is worked up. The organic phase is separated off and the aqueous phase is extracted again with 45 parts by volume of ethyl acetate. The combined organic phases are extracted twice with a solution of in each case 16 parts by weight of sodium chloride in 55 parts by volume of water and dried. After the solvent has been stripped off, 51.9 parts by weight of product remain, which can be further processed in the crude form.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7](O)[C:8]([CH3:24])([CH3:23])[CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[CH:17]=3)[NH:10][C:11]=2[CH:12]=[C:13]([F:15])[CH:14]=1)=[O:4].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]([C:5]1[C:6]2[CH2:7][C:8]([CH3:24])([CH3:23])[CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[CH:17]=3)[NH:10][C:11]=2[CH:12]=[C:13]([F:15])[CH:14]=1)=[O:4]
Reactant: COC(=O)c1cc(F)cc2c1C(O)C(C)(C)C(c1cccc(Br)c1)N2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(F)cc2c1CC(C)(C)C(c1cccc(Br)c1)N2
Temperature: 25 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
To a stirred mixture solution of 2-(3-bromo-phenyl)-7-fluoro-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid methyl ester (63.0 g, 154 mmol) and triethylsilane (60 mL) at 25° C. was added trifluoroacetic acid (30 mL) dropwise. The resulting mixture solution was stirred at 25° C. for 3 hours. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with saturated aqueous sodium bicarbonate solution (4×100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was triturated with methanol. The resulting precipitate was collected, dried in vacuo to afford 2-(3-bromo-phenyl)-7-fluoro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid methyl ester (30.2 g, 50%) as a yellow oil: LC/MS m/e calcd for C19H19BrFNO2 (M+H)+: 393.27, observed: 392.0 & 394.0.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([S:23][C:24]4[CH:44]=[CH:43][C:27]5[N:28]=[C:29]([NH:31][C:32]([NH:34][CH2:35][CH2:36][N:37]6[CH2:42][CH2:41][O:40][CH2:39][CH2:38]6)=[O:33])[S:30][C:26]=5[CH:25]=4)=[N:21][N:22]=3)[N:19]=2)=[CH:10][CH:9]=1.I([O-])(=O)(=O)=[O:46].[Na+]>O.C(O)(=O)C>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([S:23][C:24]4[CH:44]=[CH:43][C:27]5[N:28]=[C:29]([NH:31][C:32]([NH:34][CH2:35][CH2:36][N+:37]6([O-:46])[CH2:42][CH2:41][O:40][CH2:39][CH2:38]6)=[O:33])[S:30][C:26]=5[CH:25]=4)=[N:21][N:22]=3)[N:19]=2)=[CH:10][CH:9]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: O=C(NCCN1CCOCC1)Nc1nc2ccc(Sc3nnc4ccc(-c5ccc(F)cc5)nn34)cc2s1
Agent: [Na+]
Agent: [Na]
Solvent: CC(=O)O
Solvent: O
Product: O=C(NCC[N+]1([O-])CCOCC1)Nc1nc2ccc(Sc3nnc4ccc(-c5ccc(F)cc5)nn34)cc2s1
Temperature: 20 °C
Reaction time: 8 h
Yield: 75.3 %

Procedure:
116 mg of periodate of sodium in 0.5 cm3 of water are added to a mixture of 200 mg of 1-(6-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulphanyl}-1,3-benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyl]urea in 5 cm3 of acetic acid at 20° C. After an overnight period, the precipitate is filtered off. The white powder obtained is a mixture containing oxidized product and starting product. This mixture is taken up in 10 cm3 of acetic acid with 155 mg of sodium periodate dissolved in 1 cm3 of water. The mixture is left to stir overnight at 20° C. The precipitate is then filtered off and then washed successively with diisopropyl ether and with diethyl ether. 155 mg of white powder of 1-(6-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulphanyl}-1,3-benzothiazol-2-yl)-3-[2-(4-oxidomorpholin-4-yl)ethyl]urea are obtained, the characteristics of which are as follows:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][S:8]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)(=[O:10])=[O:9])[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[O:30]([CH2:37][C:38](Cl)=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl>[O:30]([CH2:37][C:38]([N:1]1[CH2:2][CH2:3][CH:4]([NH:7][S:8]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)(=[O:10])=[O:9])[CH2:5][CH2:6]1)=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=S(=O)(NC1CCNCC1)c1ccc2ccccc2c1
Reactant: O=C(Cl)COc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(COc1ccccc1)N1CCC(NS(=O)(=O)c2ccc3ccccc3c2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
N-(Piperidin-4-yl)naphthalene-2-sulfonamide (50 mg, 0.17 moles) was dissolved in 10 mL DCM and to that di-isopropyl ethyl amine (0.1 mL, 0.34 moles) was added under nitrogen at 0° C. The reaction was allowed to stir for 10 min and phenoxy acetyl chloride (33 mg, 0.19 moles) was added at 0° C. and warmed room temperature and stirred for 3 h. After completion of the reaction as monitored by TLC, reaction was quenched with cold water and extracted with ethyl acetate (2×25 mL). The combined organic phase was washed with bicarbonate solution and brine and dried over sodium sulphate. The solvent was filtered and evaporated on rotavap to obtain a crude compound which was washed further with hexane to yield the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)=[CH:5][CH:4]=1.C(O)C.Cl.[NH2:22][OH:23].C([O-])(=O)C.[Na+]>O>[CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=[N:22][OH:23])=[CH:5][CH:4]=1
Reactant: COc1ccc(Oc2cccc(C=O)c2)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(Oc2cccc(C=NO)c2)cc1
Temperature: 85 °C
Yield: 102.8 %

Procedure:
3-(4-Methoxyphenoxy)benzaldehyde (Aldrich, Cat. #195898) (0.10 g, 0.44 mmol) was dissolved in ethanol (2.1 mL, 37 mmol) and water (0.43 mL) at r.t., and the hydroxylamine hydrochloride (0.061 g, 0.88 mmol) and sodium acetate (0.072 g, 0.88 mmol) were added. The reaction was heated in a sealed tube to 85° C. for 2 h., and allowed to cool to r.t. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give 3-(4-methoxyphenoxy)benzaldehyde oxime (0.11 g, 100%) as an oily residue.