Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+:2].[C:3]([CH:5]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27]/[C:28](=[N:35]/[O:36][CH3:37])/[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:22][CH:21]=2)=[CH:14][CH:13]=1)[CH2:6][C:7]([O:9]CC)=[O:8])#[N:4]>>[C:3]([CH:5]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27]/[C:28](=[N:35]/[O:36][CH3:37])/[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:22][CH:21]=2)=[CH:16][CH:17]=1)[CH2:6][C:7]([O-:9])=[O:8])#[N:4].[Na+:2]
Reactant: CCOC(=O)CC(C#N)c1ccc(OCc2ccc(OC/C(=N/OC)c3ccccc3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Product: CO/N=C(/COc1ccc(COc2ccc(C(C#N)CC(=O)[O-])cc2)cc1)c1ccccc1
Yield: 67.38 %

Procedure:
Compound 53 was synthesized from sodium hydroxide (0.05 g, 1.27 mmol) and ethyl 3-cyano-3-{4-[(4-{[(2E)-2-(methoxyimino)-2-phenylethyl]oxy}benzyl)oxy]phenyl}propanoate (0.3 g, 0.64 mmol) by following the procedure described in scheme 12 (0.2 g, yield: 67.38%); Purity: 89.99%.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[Br:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:9]=1.CCN(CC)CC.O>C(Cl)Cl>[Br:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([N:14]([C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:5])[C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:18])[CH3:20])[CH:9]=1
Reactant: O=C(Cl)C1CC1
Reactant: CC(C)(C)OC(=O)Nc1cc(Br)ccn1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(C(=O)C1CC1)c1cc(Br)ccn1
Yield: 98.8 %

Procedure:
Add cyclopropanecarbonyl chloride (1.42 g, 13.68 mmol) slowly to a solution of tert-butyl N-(4-bromo-2-pyridyl)carbamate (1.24 g, 4.6 mmol), Et3N (1.38 g, 13.68 mmol) in DCM (15 mL) at 0° C. After addition, stir the reaction at room temperature for 2 hrs. Pour the reaction mixture to water (50 mL), extract with EtOAc (15 mL×3), combine the organic layers and wash with brine (100 mL). Dry over anhydrous Na2SO4; concentrate under reduced pressure to give the crude product (1.55 g) which is used without further purification. MS: (M+1): 241.0
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][C:28]([C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)=[O:29].C(=O)([O-])[O-].[K+].[K+]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:24][CH2:25][CH2:26][CH2:27][C:28]([C:30]3[CH:31]=[CH:32][C:33]([OH:36])=[CH:34][CH:35]=3)=[O:29])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: O=C(CCCCBr)c1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCC(=O)c2ccc(O)cc2)CC1
Yield: 55.9 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (5.20 g) as a starting compound, 5-bromo-1-(4-hydroxyphenyl)-1-pentanone (3.60 g) and potassium carbonate (8.7 g) were reacted and purified in the same manner as in Example 172 to give 3.71 g of 4-amino-5-chloro-2-methoxy-N-((1-(5-(4-hydroxyphenyl)-5-oxopentyl)-piperidin-4-yl)methyl)benzamide, m.p. 154°-156° C.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.COC1C=C(OC)C=CC=1C[NH:18][C:19](=[O:46])[C:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:30]=[C:29]([C:31]3[CH:36]=[CH:35][C:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[CH3:43])=[C:33]([CH3:44])[CH:32]=3)[O:28][N:27]=2)=[CH:22][C:21]=1[F:45]>C1(C)C=CC=CC=1>[CH3:44][C:33]1[CH:32]=[C:31]([C:29]2[O:28][N:27]=[C:26]([C:23]3[CH:24]=[CH:25][C:20]([C:19]([NH2:18])=[O:46])=[C:21]([F:45])[CH:22]=3)[N:30]=2)[CH:36]=[CH:35][C:34]=1[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[CH3:43]
Reactant: COc1ccc(CNC(=O)c2ccc(-c3noc(-c4ccc(-c5ccccc5C)c(C)c4)n3)cc2F)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccccc1-c1ccc(-c2nc(-c3ccc(C(N)=O)c(F)c3)no2)cc1C
Temperature: 110 °C

Procedure:
Toluene-4-sulfonic acid monohydrate (141.53 mg; 0.74 mmol) was added to a mixture of N-(2,4-dimethoxybenzyl)-4-[5-(2,2′-dimethylbiphenyl-4-yl)-1,2,4-oxadiazol-3-yl]-2-fluorobenzamide, obtained in step 1 and toluene (2 mL). The mixture was heated at 110° C. The reaction was quenched with water (3 mL) and extracted with EtOAc (3×5 mL). The organic layer was then dried over magnesium sulfate, filtered and concentrated. The crude was purified with MD Autoprep, to afford the title compound as a white solid. LC/MS (Method B): 388.3 (M+H)+. HPLC (Method A) Rt 5.20 min (Purity: 100.0%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:15]2[O:19][N:18]=[C:17]([C:20]3[N:25]=[C:24]([C:26]([O:28]C)=[O:27])[CH:23]=[CH:22][CH:21]=3)[N:16]=2)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CCOCC>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:15]2[O:19][N:18]=[C:17]([C:20]3[N:25]=[C:24]([C:26]([OH:28])=[O:27])[CH:23]=[CH:22][CH:21]=3)[N:16]=2)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1cccc(-c2noc(C(=O)CCCCCCc3ccccc3)n2)n1
Solvent: CCOCC
Product: O=C(O)c1cccc(-c2noc(C(=O)CCCCCCc3ccccc3)n2)n1
Yield: 26.4 %

Procedure:
The title compound was prepared from 9f (4.0 mg, 0.01 mmol) following general procedure A. Tritration with hexanes and Et2O afforded the title compound (1.0 mg, 25%) as a white solid: 1H NMR (acetone-d6, 600 MHz) δ 8.45 (dd, 1H, J=1.2, 7.7 Hz), 8.37 (dd, 1H, J=1.2, 7.8 Hz), 8.33 (t, 1H, J=7.7 Hz), 7.26 (t, 2H, J=7.5 Hz), 7.21 (d, 2H, J=6.9 Hz), 7.15 (t, 1H, J=7.3 Hz), 3.29 (t, 2H, J=7.2 Hz), 2.63 (t, 2H, J=7.7 Hz), 1.80 (m, 2H), 1.66 (m, 2H), 1.50 (m, 2H), 1.43 (m, 2H); 13C NMR (acetone-d6, 150 MHz) δ 188.9, 172.7, 169.9, 166.3, 150.5, 147.3, 144.5, 141.5, 130.2, 130.1, 128.7, 128.4, 127.4, 42.0, 37.4, 33.2, 31.3, 30.4, 24.6; HRMS-ESI-TOF m/z 380.1608 ([M+H]+, C21H21N3O4 requires 380.1605).
Reaction SMILES: O.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]2[CH2:15][OH:16])=[CH:5][CH:4]=1.[C:17]([OH:26])(=[O:25])[C@@H:18]([C@H:20]([C:22]([OH:24])=[O:23])[OH:21])[OH:19].CO>C(O)(C)C>[C:22]([C@@H:20]([C@H:18]([C:17]([O-:26])=[O:25])[OH:19])[OH:21])([O-:24])=[O:23].[F:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]2[CH2:15][OH:16])=[CH:5][CH:4]=1
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: OC[C@@H]1CNCC[C@H]1c1ccc(F)cc1
Solvent: CO
Solvent: CC(C)O
Solvent: O
Product: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Yield: 35.5 %

Procedure:
Subsequently, 10.00 g (44.0 mmol) of the trans-(−)-4-(4-fluorophenyl)-3-hydroxymethylpiperidine monohydrate, 6.60 g (44.0 mmol) of L-tartaric acid, and 50 ml of methanol were mixed together, and 50 ml of isopropanol was added to the resulting mixture under ice-cooling. The mixture was allowed to stand to precipitate crystals, and the resulting crystals were filtered. The crystals were washed with a 10 ml mixed solvent of 5 ml of methanol and 5 ml of isopropanol and dried, to give 5.60 g (15.6 mmol) of L-tartrate of trans-(−)-4-(4-fluorophenyl)-3-hydroxymethylpiperidine (yield: 35.5%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[O:11][C:12]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH2:22][CH2:23][NH:24][CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[C:13]=3[C:14]=2[CH3:15])=[CH:4][CH:3]=1.[OH:32]O.N>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:9][C:10]2[O:11][C:12]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH2:22][CH2:23][NH:24][CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[C:13]=3[C:14]=2[CH3:15])=[O:32])=[CH:4][CH:3]=1
Reactant: OO
Reactant: Cc1c(CSc2ccc(F)cc2)oc2cccc(OCCCNCc3cccnc3)c12
Agent: N
Solvent: ClCCl
Product: Cc1c(CS(=O)c2ccc(F)cc2)oc2cccc(OCCCNCc3cccnc3)c12
Reaction time: 1 h

Procedure:
To a solution of {3-[2-(4-fluoro-phenylsulfanylmethyl)-3-methyl-benzofuran-4-yloxy]-propyl}-pyridin-3-ylmethyl-amine (16 mg) and bis(2,4-pentanedionato)-vanadium oxide (9.8 mg) in dichloromethane (2 ml) was added 30% hydrogenperoxide aqueous solution (20 μl) at room temperature and the mixture was stirred for 1 hour. After the addition of ammonia solution (2 ml) the whole mixture was vigorously stirred until the sticky precipitation disappeared, then extracted with ethyl acetate, washed with brine and dried over anhydrous sodium sulfate. The mixture was separated by silica gel column chromatography developed by dichloromethane and methanol. {3-[2-(4-fluoro-benzenesulfinylmethyl)-3-methyl-benzofuran-4-yloxy]-propyl}-pyridin-3-ylmethyl-amine (5 mg) was obtained as a white solid: ESI-MS: m/z 453 (MH+); 1H-NMR (CDCl3): δ 1.98 (3H, s), 2.00-2.09 (2H, m), 2.85 (2H, t, J=6.9 Hz), 4.01 (1H, d, J=13.5 Hz), 4.13 (2H, t, J=5.9 Hz), 4.32 (1H, d, J=13.5 Hz), 6.59 (1H, d, J=7.9 Hz), 6.94 (1H, d, J=8.2 Hz), 7.10-7.25 (4H, m), 7.44-7.49 (2H, m), 7.65-7.69 (1H, m), 8.49-8.59 (2H, m). {3-[2-(4-fluoro-benzenesulfonylmethyl)-3-methyl-benzofuran-4-yloxy]-propyl}-pyridin-3-ylmethyl-amine (11 mg) was obtained as a colorless oil:. ESI-MS: m/z 469 (MH+); 1H-NMR (CDCl3): δ 1.99-2.09 (2H, m), 2.12 (3H, s), 2.86 (2H, t, J=7.3 Hz), 3.84 (2H, s), 4.13 (2H, t, J=5.9 Hz), 4.50 (2H, s), 6.59 (1H, d, J=8.3 Hz), 6.89 (1H, d, J=8.2 Hz), 7.11-7.69 (7H, m), 7.69-8.57 (2H, m).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:26])[NH:10][C@@H:11]([CH3:25])[CH:12]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:13][CH2:14][CH2:15]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.O>O1CCCC1>[Si:18]([O:17][CH:12]1[CH2:13][CH2:14][CH2:15][N:10]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:26])[C@H:11]1[CH3:25])([C:21]([CH3:23])([CH3:22])[CH3:24])([CH3:19])[CH3:20]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(CCCO)O[Si](C)(C)C(C)(C)C
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: C[C@H]1C(O[Si](C)(C)C(C)(C)C)CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 30 h
Yield: 63.5 %

Procedure:
To a solution (15 mL) of benzyl((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-5-hydroxy-1-methylpentyl)carbamate (430 mg) in tetrahydrofuran were added triethylamine (0.235 mL) and methanesulfonyl chloride (0.105 mL) under ice-cooling, and the mixture was stirred at room temperature for 30 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL). Potassium tert-butoxide (152 mg) was added under ice-cooling, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with 0.1N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: hexane:ethyl acetate=9:1→2:1) to give the title compound (yield: 260 mg) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:33]OS(C)(=O)=O)[CH:5]=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:17]=[C:16]([N:27]3[CH2:31][CH2:30][CH2:29][CH:28]3[CH3:32])[N:15]=2)[CH2:10][CH2:9]1.[CH3:39][NH:40][CH3:41]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:33][N:40]([CH3:41])[CH3:39])[CH:5]=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:17]=[C:16]([N:27]3[CH2:31][CH2:30][CH2:29][CH:28]3[CH3:32])[N:15]=2)[CH2:10][CH2:9]1
Reactant: CNC
Reactant: CC1CCCN1c1nc(-c2ccc(F)cc2)cc(N2CCN(c3ncc(COS(C)(=O)=O)cc3Cl)CC2)n1
Product: CC1CCCN1c1nc(-c2ccc(F)cc2)cc(N2CCN(c3ncc(CN(C)C)cc3Cl)CC2)n1

Procedure:
Heat a mixture of methanesulfonic acid 5-chloro-6-{4-[6-(4-fluoro-phenyl)-2-(2-methyl-pyrrolidin-1-yl)-pyrimidin-4-yl]-piperazin-1-yl}-pyridin-3-ylmethyl ester with an excess of dimethylamine (1M in THF) in a sealed tube at 80° C. for 2 h. Concentrate under reduced pressure then partition between EtOAc and 10% NaOH solution. Dry the organic layer (Na2SO4) and concentrate under reduced pressure. Purify the resulting residue using flash chromatography (10:90:1/MeOH:DCM:NH4OH eluent) to give the title compound.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[CH3:12][NH:13][C:14](=[O:36])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]1[C:32]2[C:31]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[N:25]=[CH:24][C:23]=2[N:22]=[C:21]1[CH2:33][CH2:34][CH3:35].[OH-].[NH4+:38].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[NH2:38][C:24]1[C:23]2[N:22]=[C:21]([CH2:33][CH2:34][CH3:35])[N:20]([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:14]([NH:13][CH3:12])=[O:36])[C:32]=2[C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N:25]=1
Reactant: [NH4+]
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCCCC(=O)NC
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCCc1nc2c(N)nc3ccccc3c2n1CCCCCC(=O)NC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
mCPBA (5.0 g, 29.03 mmol) was added to a solution of N-methyl-6-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)hexanamide (3.42 g, 9.67 mmol) in chloroform (100 mL). The reaction was stirred for two hours at ambient temperature and then washed with 10% aqueous sodium hydroxide. Ammonium hydroxide (40 mL) and p-toluenesulfonyl chloride (2.39 g, 12.6 mmol) were sequentially added, and the reaction was stirred vigorously for two hours. The organic layer was separated and washed sequentially with 10% sodium hydroxide, saturated aqueous sodium bicarbonate, and brine; dried over magnesium sulfate; filtered; and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with 95:5 dichloromethane:methanol) followed by recrystallization from methanol:water to provide 1.055 g of 6-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-N-methylhexanamide as beige needles, mp 158-159° C.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH:5]1([CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=2[O:19][CH:20]([F:22])[F:21])[C:13](O)=[O:14])[CH2:7][CH2:6]1>C1(C)C=CC=CC=1>[CH:5]1([CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=2[O:19][CH:20]([F:22])[F:21])[C:13]([Cl:3])=[O:14])[CH2:7][CH2:6]1
Reactant: O=C(O)c1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Yield: 100 %

Procedure:
Thionyl chloride (25 ml, 344 mmol) was added dropwise to a solution of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (12 g, 48 mmol) in toluene (100 ml) and the reaction mixture was heated to reflux for 2 hours, then the solvent was evaporated to dryness under vacuum and the residue was used without further purification (13.2 g, 48 mmol, 100% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([N:22]2[C:30]3[CH:29]=[C:28]4[C:31]5([CH2:37][O:38][C:27]4=[CH:26][C:25]=3[CH2:24][CH2:23]2)[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]5)=[O:21])=[CH:16][CH:15]=1.Br[CH2:40][CH2:41][CH3:42]>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([N:22]2[C:30]3[CH:29]=[C:28]4[C:31]5([CH2:37][O:38][C:27]4=[CH:26][C:25]=3[CH2:24][CH2:23]2)[CH2:36][CH2:35][N:34]([CH2:40][CH2:41][CH3:42])[CH2:33][CH2:32]5)=[O:21])=[CH:16][CH:15]=1
Reactant: CCCBr
Reactant: Cc1cc(N2CCCC2=O)ccc1-c1ccc(C(=O)N2CCc3cc4c(cc32)C2(CCNCC2)CO4)cc1
Product: CCCN1CCC2(CC1)COc1cc3c(cc12)N(C(=O)c1ccc(-c2ccc(N4CCCC4=O)cc2C)cc1)CC3

Procedure:
The title compound was prepared from 5-[2'-methyl-4'-(2-oxopyrrolidin-1-yl)biphenyl-4-carbonyl]-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (E18) and 1-bromopropane using a similar procedure to Example 19, as a colourless oil (78%). This was converted to its hydrochloride salt and crystallised from acetone.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1.Cl.[CH3:19][NH:20][O:21][CH3:22].C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:20]([O:21][CH3:22])[CH3:19])=[O:7])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1
Reactant: O=C(O)c1ccc(F)cc1Nc1ccccc1
Reactant: CNOC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccc(F)cc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.9 %

Procedure:
To a solution of 4-fluoro-2-phenylamino-benzoic acid (10 g, 43.2 mmol) in DMF (100 mL) was added O-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluorophosphate (HBTU) (32.8 g, 86.5 mmol), N,O-dimethylhydroxylamine hydrochloride (5.3 g, 86.5 mmol), and triethylamine (26.0 g, 36.2 mL, 259 mmol) at room temp. The resulting mixture was stirred for 24 hr at room temperature. The reaction mixture was diluted with ethyl acetate and the organic layer was washed with water and brine. The organic layer was dried over anhydrous Na2SO4 and volatiles were removed under reduced pressure. The crude material was purified using silica gel column chromatography (100% hexanes ramped to 30% ethyl acetate in hexanes). Further purification was accomplished by recrystallization from 10% ethyl acetate in petroleum ether. The product 4-fluoro-N-methoxy-N-methyl-2-phenylamino-benzamide (9.35 g, 79%) was obtained as an off-white solid.
Reaction SMILES: CS(O[C:6]1([CH3:23])[CH2:9][N:8]([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7]1)(=O)=O.[C:24]([NH2:28])([CH3:27])([CH3:26])[CH3:25].[ClH:29]>C(O)(C)C.CCOCC>[ClH:29].[C:24]([NH:28][C:6]1([CH3:23])[CH2:9][N:8]([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7]1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC1(OS(C)(=O)=O)CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CC(C)(C)N
Agent: Cl
Solvent: CC(C)O
Solvent: CCOCC
Product: CC(C)(C)NC1(C)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 74 %

Procedure:
To a solution of 1-benzhydryl-3-methylazetidin-3-yl methanesulfonate (2.00 g, 6.23 mmol) in iso-propanol (10 ml) was added tert-butyl amine (1.36 g, 18.63 mmol). The mixture was heated at 80° C. for 3 h. The reaction mixture was then allowed to cool to room temperature and concentrated. The residue was slurried with ethyl acetate and filtered, washing with further ethyl acetate and then concentrated to give a solid. The solid was slurried in ether and hydrochloric acid (20 ml, 2M in ether) was added, then stirred for 10 mins and filtered to provide the title compound as a tan solid (1.69 g, 74%). 1H NMR (DMSO) 1.40 (9H, s), 1.99 (3H, s), 3.85 (2H, brs), 4.11 (2H, brs), 4.71 (1H, brs), 7.35-7.50 (6H, m), 7.70-7.81 (4H, m), 10.23 (1H, s).
Reaction SMILES: [CH3:1][CH:2]1[C:10](=[O:11])[C:6]2[CH:7]=[CH:8][S:9][C:5]=2[CH2:4][CH2:3]1.I[CH2:13]C>>[CH2:1]([CH:2]1[C:10](=[O:11])[C:6]2[CH:7]=[CH:8][S:9][C:5]=2[CH2:4][CH2:3]1)[CH3:13]
Reactant: CCI
Reactant: CC1CCc2sccc2C1=O
Product: CCC1CCc2sccc2C1=O

Procedure:
Following the procedure for the preparation of 5-methyl-6,7-dihydro-1-benzothiophen-4(5H)-one but substituting iodoethane and making non-critical variations provided the title compound as a oil: 1H NMR (300 MHz, CDCl3) δ) 7.40, 7.07, 3.18–2.96, 2.43–2.27, 2.09–1.94, 1.59, 1.02. HRMS (FAB) calcd for C10H12OS+H 181.0687, found 181.0684. Anal. Calcd for C10H12OS: C, 66.63; H, 6.71. Found: C, 66.50; H, 6.75.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([N:16]2[CH2:20][C@@H:19]([N:21]([CH:32]3[CH2:34][CH2:33]3)[C:22]([O:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:23])[C@H:18]([C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=3)[CH2:17]2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>>[F:31][C:28]1[CH:29]=[CH:30][C:25]([O:24][C:22](=[O:23])[N:21]([C@H:19]2[C@H:18]([C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=3)[CH2:17][N:16]([C:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[O:15])[CH2:20]2)[CH:32]2[CH2:34][CH2:33]2)=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)N2C[C@@H](N(C(=O)Oc3ccc(F)cc3)C3CC3)[C@H](c3ccc(Cl)cc3)C2)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(C1CCNCC1)N1C[C@@H](N(C(=O)Oc2ccc(F)cc2)C2CC2)[C@H](c2ccc(Cl)cc2)C1

Procedure:
In analogy to the procedure described for the synthesis of [(3R,4S)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester the title compound was prepared from 4-{(3R,4S)-3-(4-Chloro-phenyl)-4-[cyclopropyl-(4-fluoro-phenoxycarbonyl)-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid tert-butyl ester through cleavage of the protecting group with TFA. The title compound was obtained as light yellow foam. MS m/e: 486.4 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:37])[CH2:5][CH2:6][N:7]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:8]1([C:16](=[O:19])[NH:17][OH:18])[CH2:14][CH:13]2[CH2:15][CH:10]([CH2:11][CH2:12]2)[O:9]1)C.C1(C)C=CC=CC=1.O.[OH-].[Na+]>ClCCl>[F:36][C:33]1[CH:34]=[CH:35][C:30]([O:29][C:26]2[CH:27]=[CH:28][C:23]([S:20]([N:7]([C:8]3([C:16](=[O:19])[NH:17][OH:18])[CH2:15][CH:10]4[O:9][CH:13]([CH2:12][CH2:11]4)[CH2:14]3)[CH2:6][CH2:5][C:4]([OH:3])=[O:37])(=[O:22])=[O:21])=[CH:24][CH:25]=2)=[CH:31][CH:32]=1
Reactant: CCOC(=O)CCN(C1(C(=O)NO)CC2CCC(C2)O1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)CCN(C1(C(=O)NO)CC2CCC(C1)O2)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of (15.1 mmol) of the product from Step G in dichloromethane is concentrated by rotary evaporation with the addition of 75 mL of toluene. This solution is treated with 75 mL of water, cooled to 0° C., and treated with 6.05 g (151 mmol, 10 equivalents) of sodium hydroxide pellets over 10 minutes with vigorous stirring. This mixture is stirred for 15 minutes at 0° C. and warmed to ambient temperature over one hour. The aqueous phase is separated, diluted with 7.5 mL of tetrahydrofuran, cooled to 0° C., and treated with 33 mL of 6N aqueous hydrochloric acid over 20 minutes. This mixture is stirred with 75 mL of ethyl acetate at 0° C. to ambient temperature, and the ethyl acetate phase is separated and washed with water. The ethyl acetate solution was concentrated to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:20]([CH2:21]I)[CH2:19][C:18]3[C:23]4[C:10]2=[N:11][CH:12]=[N:13][C:14]=4[CH:15]=[C:16]([O:26][CH3:27])[C:17]=3[O:24][CH3:25])[CH:5]=[CH:6][C:7]=1[F:8].C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:20]([CH3:21])=[CH:19][C:18]3[C:23]4[C:10]2=[N:11][CH:12]=[N:13][C:14]=4[CH:15]=[C:16]([O:26][CH3:27])[C:17]=3[O:24][CH3:25])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1cc2ncnc3c2c(c1OC)CC(CI)N3c1ccc(F)c(Cl)c1
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc2ncnc3c2c(c1OC)C=C(C)N3c1ccc(F)c(Cl)c1
Temperature: 120 °C

Procedure:
To a solution of 4-(3-chloro-4-fluoro-phenyl)-5-iodomethyl-7,8-dimethoxy-5,6-dihydro-4H-1,3,4-triaza-phenalene (0.125 g, 0.25 mmol) (from Example 18, Step F, supra) in toluene (25 mL) was added DBU (0.37 mL, 2.5 mmol) (Fluka). The reaction mixture was heated at 120° C. for 1 hours. The mixture was then diluted with chloroform (100 mL) and washed with H2O. The organic layer was separated, dried over Na2SO4, and concentrated. The residue was purified by chromatography using EtOAc/CH2Cl2/Et3N (3:1:0.05) as eluent to give the desired 4-(3-chloro-4-fluoro-phenyl)-7,8-dimethoxy-5-methyl-4H-1,3,4-triaza-phenalene as a white solid. (Yield 0.093 g, 100%).