Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Si](C(C)C)(C(C)C)[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:28])[CH:13]([N:15]2[CH2:20][CH2:19][C:18]([OH:27])([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)[CH3:14])=[CH:8][CH:7]=1)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:28])[CH:13]([N:15]2[CH2:16][CH2:17][C:18]([OH:27])([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:19][CH2:20]2)[CH3:14])=[CH:8][CH:7]=1
Reactant: CC(C(=O)c1ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc1)N1CCC(O)(c2ccccc2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C(=O)c1ccc(O)cc1)N1CCC(O)(c2ccccc2)CC1
Reaction time: 1 h
Yield: 112.3 %

Procedure:
1-(4-(Triisopropylsilyloxy)phenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanone (International Application Publication Number: WO 90/14088, Example 36 at page 41; 22.0 g, 45.7 mmol) was dissolved in dry tetrahydrofuran (500 mL). Tetrabutylammonium fluoride (55 ml, 55 mmol, 1N in tetrahydrofuran) was added dropwise to the stirred solution over 3 minutes. After stirring for 1 hour, the reaction mixture was concentrated and the concentrate flash chromatographed on silica gel (3×6 inches). The column was gradiently eluted with ethyl acetate/hexane, then sequentially with 100% ethyl acetate, 1:9 methanol:ethyl acetate and finally with 1:5 methanol:ethyl acetate. Product-containing fractions were stripped to yield 16.7 g (100%) of title product as a light yellow solid which was triturated with hexane; m.p. 95°-97° C.; 1H-NMR (CDCl3) delta (ppm) 8.08 (d, J=8.5 Hz, 2H), 7.48 (d, J=8 Hz, 2H), 7.34 (t, J=8 Hz, 2H), 7.28-7.25 (m, 1H partially obscured by CHCl3 from NMR solvent), 6.89 (d, J=8.5 Hz, 2H), 4.15 (q, J=7 Hz, 1H), 3.0-2.65 (m, 4H), 2.25-2.10 (m, 2H), 1.85-1.77 (m, 2H), 1.35 (d, J=7 Hz, 3H).
Reaction SMILES: O=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:4][C:3]1=2.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][CH2:25][NH2:26].[BH4-].[Na+].O>C(O)C>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][CH2:25][NH:26][CH:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:4][C:3]1=2
Reactant: COc1ccccc1CCN
Reactant: COC(=O)c1ccc2c(c1)CCCC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COC(=O)c1ccc2c(c1)CCCC2NCCc1ccccc1OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
15.2 g (74.5 mmol) of methyl 5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate [U. Gerlach and T. Wollmann, Tetrahedron Lett. 1992, 33 (38), 5499-5502] and 11.5 g (74.5 mmol) of 2-(2-methoxyphenyl)ethylamine in 50 ml of ethanol were heated under reflux for 2 h. The mixture was then concentrated to dryness under reduced pressure, the residue was taken up in 300 ml of methanol and 5.6 g (149 mmol) of sodium borohydride were, over 20 min, added a little at a time at RT with slight external cooling to the suspension. The brownish solution was stirred at RT for 24 h and then poured into 900 ml of water and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulphate and concentrated. The residue (24.5 g) was purified by flash chromatography on silica gel using the mobile phase cyclohexane/ethyl acetate 2:1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[N:13]=[CH:14][C:15]3[CH2:21][C:20](=[O:22])[NH:19][C:18]4[CH:23]=[C:24](I)[CH:25]=[CH:26][C:17]=4[C:16]=3[N:28]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:29]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:30]#[CH:31]>>[C:35]([O:34][C:33](=[O:39])[NH:32][CH2:29][C:30]#[C:31][C:24]1[CH:25]=[CH:26][C:17]2[C:16]3[N:28]=[C:12]([NH:11][C:5]4[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:13]=[CH:14][C:15]=3[CH2:21][C:20](=[O:22])[NH:19][C:18]=2[CH:23]=1)([CH3:38])([CH3:37])[CH3:36]
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: COc1ccc(Nc2ncc3c(n2)-c2ccc(I)cc2NC(=O)C3)cc1OC
Product: COc1ccc(Nc2ncc3c(n2)-c2ccc(C#CCNC(=O)OC(C)(C)C)cc2NC(=O)C3)cc1OC

Procedure:
In a manner similar to that described for Method O, 2-(3,4-dimethoxy-phenylamino)-9-iodo-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one (I-30) and tert-butyl prop-2-ynylcarbamate were converted to I-39 (31%): HRMS Calcd. for C29H29N5O5: 516.2246, Found 516.2244.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([O:10]C)=[S:9])[S:5][C:6]=1[CH3:7].[OH-].[Na+]>CO.O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=[S:9])[S:5][C:6]=1[CH3:7]
Reactant: COC(=S)c1cc(Br)c(C)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1sc(C(O)=S)cc1Br
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.9 %

Procedure:
To 1.0 g (3.7 mmol) of methyl 4-bromo-5-methylthiothiophene-2-carboxylate (as prepared in Example 241, step (a) dissolved in 25 ml of MeOH was added 450 mg of NaOH dissolved in 10 ml of H2O. The reaction was stirred for 5 hours at room temperature, and then the solvents were removed under vacuum. The residue of the reaction was extracted with ethyl acetate (2×50 mL) and 1N HCl. The organic layer was collected, dried (Na2SO4), filtered and concentrated under vacuum to yield 833 mg (89%) of 4-bromo-5-methylthiothiophene-2-carboxylic acid as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH:13]([C:15]([O:17]C)=[O:16])[CH2:12][CH2:11][N:10]1[C:19]([O:21][CH3:22])=[O:20].[Br-].[Li+].C(N(CC)CC)C.CC(OC)(C)C>C(#N)C.O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH:13]([C:15]([OH:17])=[O:16])[CH2:12][CH2:11][N:10]1[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)C1CCN(C(=O)OC)C(c2ccc(F)cc2Cl)C1
Agent: [Br-]
Agent: [Li+]
Solvent: COC(C)(C)C
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)N1CCC(C(=O)O)CC1c1ccc(F)cc1Cl
Yield: 89 %

Procedure:
Dimethyl 2-(2-chloro-4-fluorophenyl)piperidine-1,4-dicarboxylate (2.5 g, 7.58 mmol) was dissolved in acetonitrile (50 mL) and water (1 mL), then lithium bromide (5.27 g, 60.65 mmol) was added. Triethylamine (4.20 mL, 30.33 mmol) was added and the resulting suspension was heated under reflux for 7 h. MTBE (170 mL) and water (90 mL) were added, the phases separated and the organic layer was extracted with water. The combined aqueous layers were acidified with 3.8 M HCl and extracted with EtOAc. The combined organic layers were dried with Na2SO4 and evaporated. 2-(2-Chloro-4-fluorophenyl)-1-(methoxycarbonyl)-piperidine-4-carboxylic acid (2.130 g, 89%) was isolated as a brown solid. MS m/z 316 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[CH2:14][CH2:15][C:16](OC)=[O:17])[CH:5]=[CH:6][C:7]=1[F:8].[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[CH2:14][CH2:15][CH2:16][OH:17])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC(=O)CCc1cnoc1-c1ccc(F)c(F)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: OCCCc1cnoc1-c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
To a solution of methyl 3-[5-(3,4-difluorophenyl)-4-isoxazolyl]propionate (2.20 g) in tetrahydrofuran (30 ml) was gently added diisobutylaluminum hydride (1.0 M hexane solution, 20 ml) at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and 3-[5-(3,4-difluorophenyl)-4-isoxazolyl]propan-1-ol (1.88 g, yield 95%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). NMR (CDCl3) δ: 1.38 (1H, br s), 1.82–2.00 (2H, m), 2.72–2.84 (2H, m), 3.66–3.82 (2H, m), 7.21–7.38 (1H, m), 7.44–7.66 (2H, m), 8.22 (1H, s).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([NH:12][C:13](=[O:30])[CH:14]([NH:18][C:19](=[O:29])[CH2:20][C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=3)[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]2)[CH2:3][CH2:2]1.[C:31]([CH2:35][C:36](Cl)=[O:37])([CH3:34])([CH3:33])[CH3:32]>>[CH3:32][C:31]([CH3:34])([CH3:33])[CH2:35][C:36]([N:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([NH:12][C:13](=[O:30])[CH:14]([NH:18][C:19](=[O:29])[CH2:20][C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=3)[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]2)[CH2:3][CH2:2]1)=[O:37]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C2CCNCC2)cn1
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C2CCN(C(=O)CC(C)(C)C)CC2)cn1

Procedure:
Following the procedure for Example 21; 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid (1-piperidin-4-yl-1H-imidazol-4-yl)-amide was coupled with t-butylacetylchloride to afford the title compound: C13 NMR (100 MHz, CDCl3) 13.9, 18.9, 30.2, 31.6, 33.0, 33.8, 36.0, 40.6, 43.0, 44.9, 45.7, 53.0, 55.7, 102.6, 102.8, 103.1, 105.8, 112.3, 112.4, 112.5, 112.6, 131.5, 137.8, 138.8, 138.9, 161.8, 162.0, 164.3, 164.5, 169.3, 169.5, 170.6; MS 518.30 m/z (M+1).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]([OH:15])=[O:14].FC(F)(F)C(O[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)=O>N1C=CC=CC=1>[N+:27]([C:24]1[CH:25]=[CH:26][C:21]([O:14][C:13]([C:3]2[CH:4]=[N:5][C:6]3[C:11]([C:2]=2[OH:1])=[CH:10][CH:9]=[C:8]([CH3:12])[N:7]=3)=[O:15])=[CH:22][CH:23]=1)([O-:29])=[O:28]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Reactant: Cc1ccc2c(O)c(C(=O)O)cnc2n1
Solvent: c1ccncc1
Product: Cc1ccc2c(O)c(C(=O)Oc3ccc([N+](=O)[O-])cc3)cnc2n1
Reaction time: 2 h

Procedure:
A mixture of 1 g of 4-hydroxy-7-methyl-1,8-naphthyridine-3-carboxylic acid and 25 ml of anhydrous pyridine was heated on an oil bath at 50° to 60° C while stirring. Then, 1.38 g of p-nitrophenyl trifluoroacetate were added thereto and, after the heating was interrupted, stirring was carried out for 2 hours. The precipitated crystals were collected by filtration and washed with ethanol to give 4-hydroxy-7-methyl-1,8-naphthyridine-3-carboxylic acid p-nitrophenyl ester as pale yellow crystalline powder melting at 311 to 313° C (decomp.). Yield, 1.2 g. IR νC=O 1700 cm-1 ; νNO2 1520 cm-1, 1345 cm-1.
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:7]([NH:8][C:9]2[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][N:12]=[C:11]3[NH:18][CH:19]=[CH:20][C:10]=23)[CH2:6][C@@H:5]([NH:21][S:22]([CH:25]2[CH2:27][CH2:26]2)(=[O:24])=[O:23])[CH2:4]1)[CH3:2].[H-].[Na+].[CH3:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1>CN(C=O)C.CCOC(C)=O>[CH2:1]([C@H:3]1[C@@H:7]([NH:8][C:9]2[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][N:12]=[C:11]3[N:18]([S:37]([C:34]4[CH:35]=[CH:36][C:31]([CH3:30])=[CH:32][CH:33]=4)(=[O:39])=[O:38])[CH:19]=[CH:20][C:10]=23)[CH2:6][C@@H:5]([NH:21][S:22]([CH:25]2[CH2:27][CH2:26]2)(=[O:24])=[O:23])[CH2:4]1)[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC[C@@H]1C[C@H](NS(=O)(=O)C2CC2)C[C@@H]1Nc1c([N+](=O)[O-])cnc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC[C@@H]1C[C@H](NS(=O)(=O)C2CC2)C[C@@H]1Nc1c([N+](=O)[O-])cnc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Reaction time: 0.08 h
Yield: 126.8 %

Procedure:
To a solution of N-((1S,3R,4S)-3-ethyl-4-(5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)cyclopentyl)cyclopropanesulfonamide (0.123 g, 0.314 mmol) in DMF (3.0 mL) at about 0° C. was added NaH (60% in mineral oil, 0.015 g, 0.37 mmol). The reaction mixture was stirred for about 5 min. 4-Methylbenzene-1-sulfonyl chloride (0.060 g, 0.314 mmol) was added and the reaction mixture was stirred for about 30 min. Additional NaH (60% in mineral oil, 0.007 g, 0.18 mmol) was added and the reaction mixture was stirred for about 10 min. Additional NaH (60% in mineral oil, 0.005 g, 0.12 mmol) was added and the reaction mixture was stirred for about 15 min. Additional 4-methylbenzene-1-sulfonyl chloride (0.012 g, 0.063 mmol) was added and the reaction mixture was stirred for about 40 min. The reaction mixture was concd under reduced pressure. The residue was dissolved in EtOAc (25 mL) and washed with water (15 mL). The organic layer was separated, dried over anhydrous MgSO4, filtered and concd under reduced pressure to give N-((1S,3R,4S)-3-ethyl-4-(5-nitro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)cyclopentyl)-cyclopropanesulfonamide (0.218 g) as a red-orange oil containing 40 mol % DMF and 1 equivalent EtOAc: LC/MS (Table 1, Method n) Rt=0.88 min; MS m/z 548 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[F:10])[CH:5]=[O:6].O.[BH4-].[Na+].Cl>C(O)C.CCCCCC>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[F:10])[CH2:5][OH:6]
Reactant: O=Cc1cc(F)c(F)c(F)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCCCCC
Solvent: O
Product: OCc1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.6 %

Procedure:
Then, 37.91 g of 3,4,5-trifluorobenzaldehyde and 10 mL of water were dissolved in 50 mL of ethanol and cooled with ice, and 2.69 g of sodium tetrahydroborate was slowly added to the resultant solution. The mixture was stirred at room temperature for 2 hours, and 10% hydrochloric acid was added until the system became acidic, followed by stirring for 1 hour. Then, hexane was added to the mixture to separate an organic layer, and an aqueous layer was subjected to extraction with hexane. The hexane extract was combined with the organic layer and washed with saturated brine. The resultant mixture was dried by adding sodium sulfate, and then the solvent was distilled off under reduced pressure. Then, reduced-pressure distillation (3.9 kPa, b. p.=116° C. to 118° C.) yielded 26.73 g of 3,4,5-trifluorobenzyl alcohol (A).
Reaction SMILES: [CH2:1]([S-:3])[CH3:2].[Na+].ClC1C=CC(N[C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH2:24][CH2:25][CH2:26]Cl)=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][N:12]=2)=C(F)C=1>CN(C=O)C.O>[CH2:1]([S:3][CH2:26][CH2:25][CH2:24][O:23][C:17]1[CH:16]=[C:15]2[C:20]([CH:11]=[N:12][CH:13]=[N:14]2)=[CH:19][C:18]=1[O:21][CH3:22])[CH3:2]
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCCCl
Reactant: CC[S-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCSCCCOc1cc2ncncc2cc1OC
Temperature: 70 °C
Yield: 54.2 %

Procedure:
A mixture of sodium ethanethiolate (120 mg, 1.5 mmol) and 4-(4chloro-2-fluoroanilino)7-(3-chloropropoxy)-6-methoxyquinazoline (227 mg, 0.57 mmol) in DMF (10 ml) was stirred and heated at 70° C. for 3 hours. The reaction mixture was allowed to cool, was diluted with water and extracted with ethyl acetate (3×75 ml). The extracts were combined, washed with water (×2), and then brine, and dried (MgSO4). The solvent was removed by evaporation and the residue was recrystallised from ethyl acetate/hexane to give 4chloro-2-fluoroanilino)-7-(3-(ethylthio)propoxy)6-methoxyquinazoline (86 mg, 40%).
Reaction SMILES: BrC(Br)(Br)[C:3]([NH:5][C:6]1[C:15]2[C:10](=[C:11]([F:17])[CH:12]=[CH:13][C:14]=2[F:16])[N:9]=[C:8]([CH3:18])[CH:7]=1)=[O:4].[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[NH2:25]>N1C=CC=CC=1>[Cl:21][C:22]1[CH:23]=[C:24]([NH:25][C:3]([NH:5][C:6]2[C:15]3[C:10](=[C:11]([F:17])[CH:12]=[CH:13][C:14]=3[F:16])[N:9]=[C:8]([CH3:18])[CH:7]=2)=[O:4])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]
Reactant: Cc1cc(NC(=O)C(Br)(Br)Br)c2c(F)ccc(F)c2n1
Reactant: COc1ccc(N)cc1Cl
Solvent: c1ccncc1
Product: COc1ccc(NC(=O)Nc2cc(C)nc3c(F)ccc(F)c23)cc1Cl
Yield: 5.3 %

Procedure:
Title compound (0.005 g) was prepared according to the method of Example 66 from acetamide D23 (0.118 g) and 3-chloro-4-methoxyaniline (0.039 g) but using pyridine as solvent. m/z (API+): 378 (MH+). 1H NMR δ: 2.62 (3H, s), 3.83 (1H, s), 7.13 (1H, d, J=9.0 Hz ), 7.28-7.40 (2H, m), 7.50-7.60 (1H, m), 7.74 (1H, d, J=2.6 Hz), 8.29 (1H, s), 8.86 (1H, d), 9.93 (1H, s).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:14]#[N:15])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[CH:5]=1.[CH3:16][CH:17]([S:19](Cl)(=[O:21])=[O:20])[CH3:18]>C(N(CC)CC)C>[CH3:16][CH:17]([S:19]([O:1][N:2]=[C:3]([C:14]#[N:15])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[CH:5]=1)(=[O:21])=[O:20])[CH3:18]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: COc1ccc(C(C#N)=NO)cc1OC
Solvent: CCN(CC)CC
Product: COc1ccc(C(C#N)=NOS(=O)(=O)C(C)C)cc1OC
Yield: 87.6 %

Procedure:
As described under 1.2, 16.5 g (0.08 mol) of α-hydroxyimino-3,4-dimethoxybenzyl cyanide are reacted with 12.6 g (0.088 mol) of 2-propanesulfonyl chloride in the presence of triethylamine. Recrystallisation of the crude product from ethyl acetate/hexane yields 21.9 g (88%) of α-(2-propylsulfonyloxyimino)-3,4-dimethoxybenzyl cyanide in the form of beige crystals having a melting point of 90.5-93.5° C. The 1H-NMR spectrum of the compound shows that it is a pure stereoisomer. The UV spectrum (acetonitrile) of the substance shows a broad absorption band with a maximum at 346 nm (ε=1165034) that extends to 434 nm. Elemental analysis: C13H16N2O5S (312.34)
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[S:10][C:9]=1[C:20](=[O:22])[NH2:21])(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:7][C:8]1[CH:12]=[C:11]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[S:10][C:9]=1[C:20]([NH2:21])=[O:22]
Reactant: CC(C)(C)OC(=O)Nc1cc(-c2ccc(Cl)cc2)sc1C(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1sc(-c2ccc(Cl)cc2)cc1N

Procedure:
To a solution of 1c (250 mg, 0.71 mmol) in CH2Cl2 (10 mL) was added TFA (1 mL). The resultant solution was stirred for 1 h, then mixed with saturated NaHCO3 solution (60 mL), and extracted with ethyl acetate (50 mL, 3×). The combined organic phases were dried over MgSO4, filtered, and concentrated. Flash chromatography (hexanes/ethyl acetate, 1:1) then provided compound 1d as a yellow solid: MS (ES) 253 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(OCC)(=O)C>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: NCc1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(NCc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 126.3 %

Procedure:
To a solution of 4-chlorobenzylamine (859 mg, 6.07 mmol) in 1,2-dichloroethane (20 mL) was added t-butyl-4-oxo-piperidine-1-carboxylate (1.451 g, 7.282 mmol), acetic acid (400 uL), and sodium triacetoxyborohydride (1.800 g, 8.497 mmol). The mixture was stirred at rt under nitrogen for 2 h, diluted with ethyl acetate, washed thrice with saturated sodium bicarbonate solution and dried over magnesium sulfate. The extracts were filtered and concentrated to afford 4-(4-chloro-benzylamino)-piperidine-1-carboxylic acid tert-butyl ester (2.49 g, >100%) as a yellow oil, which was of sufficient purity by H-NMR to use without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:18])[NH:10][C:11]([CH3:17])([CH3:16])[C:12](OC)=[O:13])=[CH:4][C:3]=1[C:19]1[S:20][CH:21]=[CH:22][CH:23]=1.Cl>O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]([CH3:17])([CH3:16])[NH:10][C:9]2=[O:18])=[CH:4][C:3]=1[C:19]1[S:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)C(C)(C)NC(=O)Nc1ccc(F)c(-c2cccs2)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)NC(=O)N(c2ccc(F)c(-c3cccs3)c2)C1=O
Temperature: 80 °C
Reaction time: 2 h

Procedure:
0.62 g of compound 267.3 was dissolved at room temperature in 5 ml of dry tetrahydrofuran, admixed with 0.62 ml of concentrated hydrochloric acid and stirred at 80° C. for 2 h. The cooled reaction mixture was taken up in ethyl acetate and washed with saturated sodium hydrogencarbonate solution, and the organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was stirred with diisopropyl ether, filtered and dried. 3-(4-Fluoro-3-thiophen-2-yl-phenyl)-5,5-dimethylimidazolidine-2,4-dione (267.2) was obtained. Molecular weight 304.06 (C15H13FN2O2S); retention time Rt=2.25 min. [E]; MS (ESI): 346.09 (MH++CH3CN).
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]2[S:22][CH:23]([CH2:26][C:27]([OH:29])=O)[CH2:24][N:25]=2)=[CH:15]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[F:53][C:54]([F:58])([F:57])[CH2:55][NH2:56]>CN(C)C=O.CCCCCC.C(OCC)(=O)C.CO.O>[CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]2[S:22][CH:23]([CH2:26][C:27]([NH:56][CH2:55][C:54]([F:58])([F:57])[F:53])=[O:29])[CH2:24][N:25]=2)=[CH:15]3)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(Oc2ccc3[nH]c(C4=NCC(CC(=O)O)S4)cc3c2)cn1
Reactant: NCC(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(Oc2ccc3[nH]c(C4=NCC(CC(=O)NCC(F)(F)F)S4)cc3c2)cn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 64.5 %

Procedure:
To a solution of [2-(5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (150 mg) in N,N-dimethylformamide (5 mL) were added 1-hydroxybenzotriazole monohydrate (80 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (100 mg), and 2,2,2-trifluoroethylamine (69 mg), and the mixture was stirred at room temperature for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was subjected to basic silica gel column chromatography (methanol:ethyl acetate:hexane=0:0:100 to 10:90:0, volume ratio) and crystallized from acetonitrile to give the title compound (115 mg, yield 65%) as white crystals.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[CH3:26][O:27][CH2:28][CH2:29][C:30](O)=[O:31]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:30](=[O:31])[CH2:29][CH2:28][O:27][CH3:26])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: COCCC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: COCCC(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (34.2 mg, 60.3%), MS (ISP) m/z=417.5 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (50 mg, 0.136 mmol) and 3-methoxypropionic acid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[C:9]([F:12])[CH:10]=2)[CH:5]=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]([CH3:24])[CH3:23])=[CH:17][CH:16]=2)[N:3]=1.[F-:25].[Cs+]>CS(C)=O.C(OC(=O)C)C>[F:25][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[C:9]([F:12])[CH:10]=2)[CH:5]=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]([CH3:24])[CH3:23])=[CH:17][CH:16]=2)[N:3]=1
Reactant: COc1cc2cc(-c3ccc(OC(C)C)cc3)nc(Cl)c2cc1F
Reactant: [F-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1cc2cc(-c3ccc(OC(C)C)cc3)nc(F)c2cc1F
Temperature: 140 °C
Yield: 78.8 %

Procedure:
To a solution of 1-chloro-7-fluoro-3-(4-isopropoxyphenyl)-6-methoxyisoquinoline (1 g, 2.89 mmol) in DMSO (6 mL), was added CsF (0.879 g, 5.78 mmol) and the mixture was heated to 140° C. for 4 hrs. The reaction was diluted with Ethylacteate and washed with water, and brine. The organic phase was collected, dried over sodium sulfate, and concentrated under vacuum to give the crude product which was purified by silica gel chromatography using 50% DCM/Hexanes. The product fractions were collected and the solvent removed under vacuum to give 1,7-difluoro-3-(4-isopropoxyphenyl)-6-methoxyisoquinoline (750 mg, 79% yield). MS: MS m/z 330.1 (M++1).