Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:14])[C:12]2[C:7](=[CH:8][C:9]([OH:13])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1.Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>O1CCCC1>[CH3:3][C:4]1([CH3:14])[C:12]2[C:7](=[CH:8][C:9]([O:13][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1
Reactant: CCOC(=O)CBr
Reactant: CC1(C)CCc2cc(O)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc2c(c1)CCC2(C)C
Reaction time: 0.25 h
Yield: 67 %

Procedure:
To a stirred suspension of 60% sodium hydride (240 mg, 5.87 mmol) in anhydrous tetrahydrofuran (5 ml) was added a solution of crude 1,1-dimethylindan-5-ol (878 mg) in anhydrous tetrahydrofuran (10 ml) dropwise at 0° C. After 15 minutes at 0° C., to this was added ethyl bromoacetate (1.16 g, 6.94 mmol) via a syringe at 0° C. After 2 hours at ambient temperature, the mixtute was quenched with water (15 ml) and extracted with ethyl acetate. The combined solution was washed with brine, dried over sodium sulfate. After filtration to separate solvent and sodium sulfate, the solvent was removed under reduced pressure to give a residue, which was applied to a silica gel chromatography column and eluted with hexane/ethyl acetate=8/1–6/1 to furnish 890 mg (67% yield in 2 steps) of the title compound as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[N:7]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=3[O:17][CH3:18])[NH:9][C:5]=2[CH:4]=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[N:7]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([O:16][S:22]([CH3:21])(=[O:24])=[O:23])=[CH:12][C:11]=3[O:17][CH3:18])[NH:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2nc(-c3ccc(O)cc3OC)[nH]c2c1
Reactant: CS(=O)(=O)Cl
Product: COc1ccc2nc(-c3ccc(OS(C)(=O)=O)cc3OC)[nH]c2c1

Procedure:
Prepared analogously to Example 1 from 5-methoxy-2-(2'-methoxy-4'-hydroxy-phenyl)-benzimidazole and methanesulfonic acid chloride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH:7]=1.Cl.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[S:35](Cl)(=[O:37])=[O:36]>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:19][CH:20]=2)[S:35]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=2)(=[O:37])=[O:36])[CH:7]=1
Reactant: O=S(=O)(Cl)c1ccccn1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(-c3ccccc3)cc2)c1
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc(-c3ccccc3)cc2)S(=O)(=O)c2ccccn2)c1

Procedure:
The title compound of Step B was prepared following the method described in Step B of Example 1 from 3-(3-{[(biphenyl-4-ylmethyl)-amino]-methyl}-phenyl)-propionic acid methyl ester, prepared in Step A of Example 12m and pyridine-2-sulfonyl chloride hydrochloride, of Preparation 47, using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 8.65 (d, 1H), 7.95 (d, 1H), 7.83 (m, 1H), 7.51 (dd, 2H), 7.45-7.29 (m, 6H), 7.16-7.10 (m, 3H), 7.08-6.90 (m, 3H), 4.50 (s, 2H), 4.48 (s, 2H), 3.64 (s, 3H), 2.79 (t, 2H), 2.49 (t, 2H); MS 501 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:20][O:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][C:31]=1[O:32][CH2:33][CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)[N:28]=[CH:27][N:26]=[C:25]2[O:40][C:41]1[CH:42]=[C:43]2[C:47](=[CH:48][CH:49]=1)[NH:46][C:45]([CH3:50])=[CH:44]2.C(=O)([O-])O.[Na+]>C(Cl)Cl.CO>[CH3:20][O:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][C:31]=1[O:32][CH2:33][CH:34]1[CH2:39][CH2:38][N:37]([CH2:4][CH2:3][O:2][CH3:1])[CH2:36][CH2:35]1)[N:28]=[CH:27][N:26]=[C:25]2[O:40][C:41]1[CH:42]=[C:43]2[C:47](=[CH:48][CH:49]=1)[NH:46][C:45]([CH3:50])=[CH:44]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCC1CCNCC1
Reactant: COCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COCCN1CCC(COc2cc3ncnc(Oc4ccc5[nH]c(C)cc5c4)c3cc2OC)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 47.3 %

Procedure:
Methoxyacetaldehyde (368 mg, 3.47 mmol) (freshly distilled) followed by sodium triacetoxyborohydride (552 mg, 2.6 mol) were added to a solution of 6-methoxy-4-(2-methylindol-5-yloxy)-7-(piperidin-4-ylmethoxy)quinazoline (726 mg, 1.74 mmol), (prepared as described in Example 70), in a mixture of methylene chloride (15 ml) and methanol (15 ml). After stirring for 1.5 hours at ambient temperature, saturated sodium hydrogen carbonate was added. The volatiles were removed under vacuum and the residue was partitioned between methylene chloride and water. The organic layer, was separated, washed with water, brine, dried (MgSO4) and the volatiles were removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (80/20). After removal of the solvent, the residue was triturated with ether, collected by filtration, washed with ether and dried under vacuum at 60° C. to give 6-methoxy-7-(1-(2-methoxyethyl)piperidin-4-ylmethoxy)-4-(2-methylindol-5-yloxy)quinazoline (392 mg, 47%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[O:13][C:14]2[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1)[CH2:9][C:10]#[CH:11]>>[F:24][C:21]([F:22])([F:23])[C:20]1[C:14]2[O:13][C:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)=[N:16][C:15]=2[CH:17]=[CH:18][CH:19]=1
Reactant: C#CCCc1nc2cccc(C(F)(F)F)c2o1
Reactant: Ic1ccccn1
Product: FC(F)(F)c1cccc2nc(CCC#Cc3ccccn3)oc12
Yield: 52.6 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-iodopyridine (77 mg, 0.38 mmol) and 2-(but-3-ynyl)-7-(trifluoromethyl)benzo[d]oxazole (90 mg, 0.38 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1 to DCM/MeOH 99:1) to yield 63 mg (0.20 mmol, 53%) of 7-(trifluoromethyl)-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as a brown solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2[CH:7]=[C:8]([S:15](=[O:18])(=[O:17])[NH2:16])[CH:9]=[C:10]([C:11]([O:13]C)=O)[C:4]=2[O:3]1.[CH2:19]([N:26]1[CH2:30][CH2:29][CH2:28][CH:27]1[CH2:31][NH2:32])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>C(O)COCCO>[CH2:19]([N:26]1[CH2:30][CH2:29][CH2:28][CH:27]1[CH2:31][NH:32][C:11]([C:10]1[C:4]2[O:3][CH:2]([CH3:1])[CH2:6][C:5]=2[CH:7]=[C:8]([S:15](=[O:18])(=[O:17])[NH2:16])[CH:9]=1)=[O:13])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCC1CCCN1Cc1ccccc1
Reactant: COC(=O)c1cc(S(N)(=O)=O)cc2c1OC(C)C2
Solvent: OCCOCCO
Solvent: O
Product: CC1Cc2cc(S(N)(=O)=O)cc(C(=O)NCC3CCCN3Cc3ccccc3)c2O1
Temperature: 25 °C
Reaction time: 30.5 h

Procedure:
A suspension of 4.0 g of methyl 2-methyl-5-sulfamoyl-2,3-dihydrobenzofuran-7-carboxylate and 3.37 g of 1-benzyl-2-aminomethyl-pyrrolidine in 15 ml of diethylene glycol is heated at 120°-130° C. and stirred for 30-31 hours. The reaction solution is cooled to room temperature, poured into 150-200 ml of water, and extracted with ethyl acetate three times. The ethyl acetate extract is washed with water followed by sodium chloride saturated water. The product is dried over magnesium sulfate and the solvent is distilled off under diminished pressure. The resulting residue is recrystallized from isopropanol by the use of decolorizing charcoal to give crystals of N-(1-benzyl-2-pyrrolidinylmethyl)-2-methyl-5-sulfamoyl-2,3-dihydrobenzofuran-7-carboxamide, m.p. 161°-167° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:29][C:35]2[CH:36]=[CH:37][C:32]([O:31][CH3:30])=[CH:33][CH:34]=2)[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(Cl)cc3)CC2)c1
Reactant: COc1ccc(O)cc1
Product: COc1ccc(OC(CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccc(Cl)cc2)cc1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-chlorophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-methoxyphenol: ESMS m/e: 520.8 (M+H)+.
Reaction SMILES: [CH:1]1([C:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]([CH2:17][CH2:18][CH3:19])[C:9](=[O:20])[CH:8]([NH:21]C(OCC3C=CC=CC=3)=O)[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br.CCOCC>C(O)(=O)C>[NH2:21][CH:8]1[N:7]=[C:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([CH2:17][CH2:18][CH3:19])[C:9]1=[O:20]
Reactant: CCCN1C(=O)C(NC(=O)OCc2ccccc2)N=C(C2CCCC2)c2ccccc21
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCCN1C(=O)C(N)N=C(C2CCCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
To 5-cyclopentyl-1,3-dihydro-1-propyl-3(R,S)-[(benzyloxycarbonyl)amino]-2H-1,4-benzodiazepin-2-one (507 mg, 1.21 mmol) was added 45% hydrobromic acid in acetic acid (1 ml) and the mixture stirred at room temperature for 2 h. Anhydrous ether (10 ml) was then added and the mixture was stirred for 1.5 h before removing the solvent by pipette. The resulting solid was washed with more ether, filtered off and washed again with ether, before partitioning between dichloromethane (30 ml) and 2N sodium hydroxide solution (30 ml). The aqueous layer was re-extracted with more dichloromethane (2×30 ml), the organic extracts combined, dried (Na2SO4) and evaporated to leave the title compound (333 mg, 96%) as a colourless oil. 1H NMR (360 MHz, CDCl3) δ 0.81 (3H, t, J=7.4 Hz), 1.25-1.94 (9H, m); 2.16 (1H, m), 3.29 (1H, m), 3.56 (1H, m), 4.28 (1H, s), 4.30 (1H, m), 7.24 (1H, t, J=7.3 Hz), 7.31 (1H, d, J=7.9 Hz), 7.46 (1H, t of d, J=7.8 and 1.5 Hz), 7.53 (1H, dd, J=7.8 and 1.4 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH3:13][N:14]([CH3:23])[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(O)(=O)C>[CH3:13][N:14]([CH3:23])[C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CN(C)c1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)c1ccc(NCc2ccc(N(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 64.4 %

Procedure:
To a solution of ethyl 4-aminobenzoate (10 g) and 4-(dimethylamino)benzaldehyde (9.0 g) in methylene chloride (200 mL) is added sodium triacetoxyborohydride (18.9 g) and acetic acid (3.47 mL) under ice-cooling, and the mixture is stirred at room temperature for 2 days. To the reaction mixture is added a saturated sodium hydrogencarbonate solution and extracted with chloroform (×2). The extract is concentrated in vacuo and the residue is triturated in n-hexane/ethyl acetate to give ethyl 4-[4-(dimethylamino)benzylamino]benzoate (11.6 g, yield; 64%) as powder. MS (APCI) m/z; 299 [M+H]+
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7](/[CH:11]=[CH:12]/[CH2:13][C@H:14](O)[CH3:15])[CH:8]=[N:9][CH:10]=1)([CH3:3])[CH3:2].[CH3:17][NH2:18]>C(O)C>[CH3:17][NH:18][C@H:14]([CH2:13]/[CH:12]=[CH:11]/[C:7]1[CH:8]=[N:9][CH:10]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:6]=1)[CH3:15]
Reactant: CC(C)Oc1cncc(/C=C/C[C@@H](C)O)c1
Reactant: CN
Solvent: CCO
Product: CN[C@@H](C)C/C=C/c1cncc(OC(C)C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 31 %

Procedure:
A mixture of (2R)-(4E)-5-(5-isopropoxy-3-pyridyl)-4-penten-2-ol ptoluenesulfonate (11.00 g, 29.33 mmol), methylamine (200 mL, 40% solution in water), and ethyl alcohol (10 mL) was stirred at ambient temperature for 18 h. The resulting solution was extracted with chloroform (3×100 mL). The combined chloroform extracts were dried over sodium sulfate, filtered, and concentrated by rotary evaporation. The crude product was purified by column chromatography over aluminum oxide, eluting with ethyl acetate-methanol (7:3, v/v). Selected fractions were combined and concentrated by rotary evaporation, producing an oil. Further purification by vacuum distillation furnished 2.10 g (31.0%) of a colorless oil, bp 90-100° C. at 0.5 mm Hg.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][CH:7]=[C:8]3[C:13]=2[N:12]=[C:11]([C:14]([N:16]2[CH2:21][CH2:20][C:19]4([CH2:30][C:29](=[O:31])[C:28]5[C:23](=[CH:24][CH:25]=[C:26]([C:32]6[CH:33]=[N:34][CH:35]=[C:36]([CH:40]=6)[C:37]([OH:39])=[O:38])[CH:27]=5)[O:22]4)[CH2:18][CH2:17]2)=[O:15])[CH:10]=[C:9]3[O:41][CH3:42])[CH2:3][CH2:2]1.[OH-].[Na+:44]>O>[CH:1]1([C:4]2[CH:5]=[CH:6][CH:7]=[C:8]3[C:13]=2[N:12]=[C:11]([C:14]([N:16]2[CH2:21][CH2:20][C:19]4([CH2:30][C:29](=[O:31])[C:28]5[C:23](=[CH:24][CH:25]=[C:26]([C:32]6[CH:33]=[N:34][CH:35]=[C:36]([CH:40]=6)[C:37]([O-:39])=[O:38])[CH:27]=5)[O:22]4)[CH2:18][CH2:17]2)=[O:15])[CH:10]=[C:9]3[O:41][CH3:42])[CH2:3][CH2:2]1.[Na+:44]
Reactant: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4cncc(C(=O)O)c4)ccc2O3)nc2c(C3CC3)cccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4cncc(C(=O)[O-])c4)ccc2O3)nc2c(C3CC3)cccc12

Procedure:
5-{1′-[(8-Cyclopropyl-4-methoxy-quinolin-2-yl)carbonyl]-4-oxospiro[chroman-2,4′-piperidin]-6-yl}nicotinic acid (3.53 g, 6.26 mmol) was suspended in H2O (35 mL) and 1N NaOH (6.26 mL) was added at 0° C. The resulted solution was purified by ODS column chromatography (eluent: H2O/MeOH=10/0 to 40/60) to afford sodium 5-{1′-[(8-Cyclopropyl-4-methoxy-quinolin-2-yl)carbonyl]-4-oxospiro[chroman-2,4′-piperidin]-6-yl}nicotinate as a colorless solid. 1H-NMR (400 MHz, DMSO-d6) δ: 8.91 (1.0H, d, J=1.7 Hz), 8.74 (1.0H, d, J=2.4 Hz), 8.30-8.28 (1.0H, m), 7.98-7.93 (3.0H, m), 7.49 (1.0H, dd, J=8.5, 7.3 Hz), 7.27-7.23 (2.0H, m), 7.20 (1.0H, s), 4.43-4.30 (1.0H, m), 4.07 (3.0H, s), 3.94-3.85 (1.0H, m), 3.61-3.46 (1.0H, m), 3.35-3.27 (1.0H, m), 3.12-3.03 (1.0H, m), 2.97 (2.0H, s), 2.17-2.06 (1.0H, m), 2.04-1.79 (3.0H, m), 1.15-1.03 (2.0H, m), 0.89-0.69 (2.0H, m). MS [M+Na]+=586.
Reaction SMILES: [CH3:1][C:2]1([N:6]=[C:7]=[N:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH2:5][CH2:4][CH2:3]1.C([N:19]=[C:20]=[N:21]C1C=NC=CC=1)(C)(C)C>>[C:20]([N:21]=[C:7]([NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)[NH:6][C:2]1([CH3:1])[CH2:3][CH2:4][CH2:5]1)#[N:19]
Reactant: CC(C)(C)N=C=Nc1cccnc1
Reactant: CC1(N=C=Nc2cccnc2)CCC1
Product: CC1(NC(=NC#N)Nc2cccnc2)CCC1

Procedure:
By following the procedure of Example 1, but substituting N-1-methylcyclobutyl-N'-3-pyridylcarbodiimide for the N-tert-butyl-N'-3-pyridylcarbodiimide, the desired compound was obtained with a melting point of 210.5°-211.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:28]=[CH:27][C:12]([O:13][CH2:14][C@@H:15]3[CH2:19][CH2:18][CH2:17][N:16]3[C:20](=[O:26])[CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:30]>CO.C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:28]=[CH:27][C:12]([O:13][CH2:14][C@@H:15]3[CH2:19][CH2:18][CH2:17][N:16]3[C:20](=[O:26])[CH2:21][CH2:22][C:23]([O:25][CH3:30])=[O:24])=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)CCC(=O)N1CCC[C@H]1COc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)CCC(=O)N1CCC[C@H]1COc1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
To a solution of 4-{(S)-2-[4-(4-chloro-phenyoxy)-phenoxymethyl]-pyrrolidin-1-yl}-4-oxo-butyric acid (d4) (500 mg, 1.2 mmol, 1 eq.) in a mixture of methanol (6 ml) and benzene (5 ml) was added dropwise TMSCHN2 (2 M in hexane, 3 ml, 6 mmol, 3 eq.) with stirring. The mixture was stirred until the starting acid was consumed by indication of yellow color persists). Then volatile material was removed under reduced pressure. The crude product thus obtained was forwarded to the next step without further purification.
Reaction SMILES: C([C@H]1[O:9][C:8](=[O:10])[C@@:7]([C:17]2(O)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:6]1)(C)(C)C.S(Cl)(Cl)=O.N1C=CC=CC=1.[OH-].[K+]>C1COCC1>[C:17]1([C@:7]([OH:6])([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:8]([OH:10])=[O:9])[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=1
Reactant: CC(C)(C)[C@H]1OC(=O)[C@](c2ccccc2)(C2(O)CCCCC2)O1
Agent: [K+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(O)[C@](O)(C1=CCCCC1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(2R,5S)-2-tert-Butyl-5-(1-hydroxy-cyclohexyl)-5-phenyl-[1,3]dioxolan-4-one (176 g, 0.553 mol) in THF (1.56 litres) is cooled to 0° C. and treated dropwise with thionyl chloride (109 ml, 1.49 mol) followed by pyridine (191 ml, 2.35 mol) over 40 minutes. After stirring at 0° C. for 30 minutes, the reaction is quenched by dropwise addition of saturated ammonium chloride solution (2000 ml) ensuring the temperature does not exceed 25° C. Water (300 ml) is added and the organic portion is separated. The aqueous is extracted with EtOAc (1000 ml) and the combined organic layers are washed with brine and concentrated in vacuo. To the resulting crude material is added MeOH (333 ml) followed by water (586 ml). The mixture is stirred and treated with potassium hydroxide (221.2 g, 5.53 mol) maintaining the temperature below 50° C. The reaction mixture is heated to reflux for 3.5 hour and then allowed to cool to room temperature. The methanol is removed in vacuo and the aqueous is cooled to 0° C. The solution is acidified to pH1 with 5M HCl and then diluted with water (1 litre). The solution is extracted with EtOAc (2×1 litre) and the combined organic portions are dried (Na2SO4) and concentrated in vacuo to afford the titled product.
Reaction SMILES: [CH2:1]([S:3]([O-])=[S:4])[CH3:2].S[CH2:7][CH2:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])=[O:10].[OH-].[Na+]>C(O)C.O>[CH2:1]([S:3][S:4][CH2:7][CH2:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])=[O:10])[CH3:2]
Reactant: CCS([O-])=S
Reactant: O=C(O)[C@@H]1CCCN1C(=O)CCS
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCSSCCC(=O)N1CCC[C@H]1C(=O)O

Procedure:
A solution of ethylthiosulfinate (8.4 g) in ethanol (50 ml) is added to an aqueous solution of 3-mercaptopropanoyl-L-proline (10 g) maintained at pH 6-7 by careful addition of sodium hydroxide. The mixture is stirred vigorously at room temperature until negative thiol reaction. The mixture is diluted with water, adjusted to pH 8 and extracted with ethyl acetate, the aqueous phase is acidified to pH 3 and extracted again with ethyl acetate. This latter extract is washed with water, dried and concentrated to dryness to yield 1-[3-(ethyldithio)propanoyl]-L-proline.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:9]=[C:10]2[CH:16]=[C:15]([C:17](OCC)=[O:18])[NH:14][C:11]2=[CH:12][N:13]=1>O1CCCC1>[Cl:7][C:8]1[CH:9]=[C:10]2[CH:16]=[C:15]([CH2:17][OH:18])[NH:14][C:11]2=[CH:12][N:13]=1
Reactant: CCOC(=O)c1cc2cc(Cl)ncc2[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cc2cc(Cl)ncc2[nH]1
Temperature: 0 °C
Yield: 67.3 %

Procedure:
Lithium aluminum hydride (105 mg, 2.77 mmol) was added in three portions to a solution of ethyl 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (410 mg, 1.83 mmol) in tetrahydrofuran (15 mL) under stirring at 0° C. under a nitrogen atmosphere. The reaction mixture was warmed to room temperature and then heated to 60° C. for 3 h. The reaction mixture was quenched by the gradual addition of hydrated sodium sulfate. The sodium sulfate was removed by filtration and washed thoroughly with tetrahydrofuran to give a yellow filtrate, which was concentrated to a brown solid. After sonication in diethyl ether for 20 minutes, the solid was collected by filtration and dried to give (5-chloro-1H-pyrrolo[2,3-c]pyridin-2-yl)methanol (225 mg, 67%) as a brown solid: 1H NMR (300 MHz, Acetone-d6) δ4.52-4.89 (3H, m), 6.38 (1H, s), 7.47 (1H, s), 8.49 (1H, s), 10.88 (1H, br s).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:17])[N:10]2[CH2:13][C@H:14]2[CH2:16][O:15]2)=[CH:5][CH:4]=1.[N+](C1C=C(S(OC[C@H]2CO2)(=O)=O)C=CC=1)([O-])=O.[NH:35]1[CH2:40][CH2:39][CH:38]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:37][CH2:36]1>CN(C=O)C>[OH:15][C@@H:14]([CH2:13][N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:12]=2)[CH2:7][CH2:8][C:9]1=[O:17])[CH2:16][N:35]1[CH2:36][CH2:37][CH:38]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:46])([CH3:45])[CH3:47])[CH2:39][CH2:40]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: COc1ccc2c(n1)N(C[C@H]1CO1)C(=O)CC2
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@H]2CO2)c1
Solvent: CN(C)C=O
Product: COc1ccc2c(n1)N(C[C@H](O)CN1CCC(NC(=O)OC(C)(C)C)CC1)C(=O)CC2
Temperature: 110 °C

Procedure:
A mixture of 7-(methyloxy)-1-[(2S)-2-oxiranylmethyl]-3,4-dihydro-1,8-naphthyridin-2(1H)-one (made according to the general method of Example 5(f) but using (2R)-2-oxiranylmethyl 3-nitrobenzenesulfonate) (3.1 g, 13.3 mmol) and 1,1-dimethylethyl 4-piperidinylcarbamate (2.7 g, 13.3 mmol) in DMF (3 ml) was heated at 110° C. for 1 h. DMF was then evaporated. The crude product was purified by silica chromatography using a 0-10% methanol/dichlormethane gradient to provide the desired compound as a pale yellow solid, presumed R enantiomer (3.9 g; 89%; 90% purity).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:32]([F:35])([F:34])[F:33])[O:14][N:13]=[C:12]([C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]([C:25]([NH:27][CH2:28][CH2:29][S:30][CH3:31])=[O:26])=[CH:17][CH:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].ClC1C=C(C2(C(F)(F)F)ON=C(C3C4C(=CC=CC=4)C(C(NCCSC)=O)=CC=3)C2)C=C(Cl)C=1.[F:70][C:71]([F:76])([F:75])[C:72]([NH2:74])=[O:73].C(OI(C1C=CC=CC=1)OC(=O)C)(=O)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:32]([F:33])([F:34])[F:35])[O:14][N:13]=[C:12]([C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]([C:25]([NH:27][CH2:28][CH2:29][S:30]([CH3:31])=[N:74][C:72](=[O:73])[C:71]([F:76])([F:75])[F:70])=[O:26])=[CH:17][CH:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8]
Reactant: CSCCNC(=O)c1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Reactant: NC(=O)C(F)(F)F
Agent: CC(=O)OI(OC(C)=O)c1ccccc1
Agent: CSCCNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Solvent: ClCCl
Product: CS(CCNC(=O)c1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)c2ccccc12)=NC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
To a stirred suspension of 4-[4,5-dihydro-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-(methylthio)ethyl]-1-naphthalenecarboxamide (prepared analogously as described for the compound of Example 3, Step A) (200 mg), 2,2,2-trifluoroacetamide (80 mg), MgO (57 mg), and Rh2(OAc)4 (4 mg) in dichloromethane (4 mL) was added PhI(OAc)2 (172 mg) at room temperature. The resulting mixture was stirred overnight at room temperature, then filtered through a short pad of Celite® diatomaceous filter aid, and rinsed with ethyl acetate. The filtrate was concentrated, and the residue was purified by column chromatography on silica gel using hexanes/ethyl acetates (1:1 to 1:4) as eluent to afford the title compound as a semisolid (70 mg, 30% yield).
Reaction SMILES: [OH-].[K+].[CH2:3]([O:5][C:6](=[O:14])[CH:7]([F:13])[C:8]([O:10]CC)=[O:9])C>CO>[CH3:3][O:5][C:6](=[O:14])[CH:7]([F:13])[C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)C(F)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)C(F)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.4 %

Procedure:
KOH (38 mg, 0.67 mmol) was added to a solution 2-fluoro-malonic acid diethyl ester (100 mg, 0.563 mmol) in methanol (0.7 mL). The reaction mixture was stirred for 4 hours at ambient temperature then concentrated. The residue was diluted with water, acidified with conc. HCl, and the product was extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford 70 mg (77%) of 2-fluoro-malonic acid monomethyl ester