Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][N:16]=2)[CH2:11][CH2:10]1)=O)(C)(C)C.Cl>C(OCC)(=O)C>[NH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][N:16]=2)[CH2:11][CH2:10]1
Reactant: CCOC(=O)c1ccc(N2CCC(NC(=O)OC(C)(C)C)CC2)nc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(N2CCC(N)CC2)nc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
The product of stage b) is dissolved in ethyl acetate, a 3N solution of hydrochloric acid in ethyl acetate is added and the mixture is left stirring at ambient temperature for 10 hours. The product is filtered off and washed with acetone. The title product is obtained. M.p.: 148-150° C.
Reaction SMILES: [K+].[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:19]2[S:20][CH:21]=[CH:22][N:23]=2)[O:10][CH:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([O-:14])=O)=[CH:5][CH:4]=1.Cl.[NH2:25][CH2:26][C:27]#[N:28]>>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([C:19]2[S:20][CH:21]=[CH:22][N:23]=2)[O:10][CH:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([NH:28][CH2:27][C:26]#[N:25])=[O:14])=[CH:7][CH:8]=1
Reactant: N#CCN
Reactant: CC(C)CC(OC(c1ccc(Br)cc1)c1nccs1)C(=O)[O-]
Agent: Cl
Agent: [K+]
Product: CC(C)CC(OC(c1ccc(Br)cc1)c1nccs1)C(=O)NCC#N

Procedure:
Using the same protocol as described in example 17, step 3, 2-[(4-bromophenyl)(1,3-thiazol-2-yl)methoxy]-4-methylpentanoic acid potassium salt from step 3 (427 mg, 1.11 mmol) was coupled with aminoacetonitrile HCl Salt. The crude residue obtained was chromatographed on silica gel using 50% ethyl acetate in hexanes to afford the title compound.
Reaction SMILES: [CH2:1]([C:3]1([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18]C)[CH:13]=2)[CH2:9][CH2:8][CH:7]([CH3:10])[CH2:6][N:5]([CH3:11])[CH2:4]1)[CH3:2].[BrH:20]>>[BrH:20].[CH2:1]([C:3]1([C:12]2[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=2)[CH2:9][CH2:8][CH:7]([CH3:10])[CH2:6][N:5]([CH3:11])[CH2:4]1)[CH3:2]
Reactant: CCC1(c2cccc(OC)c2)CCC(C)CN(C)C1
Agent: Br
Product: CCC1(c2cccc(O)c2)CCC(C)CN(C)C1

Procedure:
The distilled oil from Example 3 (1.1 g.) was heated under reflux with 48% hydrobromic acid (10 ml.) for 2 hours. The product was isolated by a procedure analogous to that described in Example 6 to give the title compound (1.07 g.), m.p. 210°-211° C. (Found: C, 58.35; H, 8.0; N, 4.2% C16H25NO HBr requires: C, 58.5; H, 8.0; N, 4.3%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.O.ON1C2C=CC=CC=2N=N1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30][NH2:31]>CN(C=O)C>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30][NH:31][C:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[N:7][CH:6]=2)[N:1]=1)=[O:13]
Reactant: O=C(O)c1ccc2cnccc2n1
Reactant: COc1cccc(CN)c1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(CNC(=O)c2ccc3cnccc3n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To a stirring mixture of 2-[1,6]naphthyridinecarboxylic acid (50 mg, 0.287 mmol) in anhydrous DMF (1.0 mL) at room temperature was added sequentially 1-hydroxybenzotriazole hydrate (42.7 mg, 0.316 mmol), 3-methoxybenzylamine (56.6 μL, 0.431 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarboiimide hydrochloride (61.8 mg, 0.316 mmol). The resulting mixture was allowed to stir at room temperature overnight and it was found to be clear. The solvent was removed under vacuum. Flash column chromatography of the residue (50% hexane/ethyl acetate to 100% ethyl acetate) afforded the desired product as a clear oil (79.1 mg, 94%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([C:9]2[CH:13]=[C:12]([CH2:14][CH2:15][OH:16])[O:11][N:10]=2)=[O:8])=[CH:5][CH:4]=1.[OH:19]S(O)(=O)=O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([C:9]2[CH:13]=[C:12]([CH2:14][C:15]([OH:19])=[O:16])[O:11][N:10]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)c2cc(CCO)on2)cc1
Reactant: O=S(=O)(O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Solvent: ClCCl
Product: COc1ccc(C(=O)c2cc(CC(=O)O)on2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a mixture of 24.7 g of 2-[3-(4-methoxybenzoyl)-isoxazol-5-yl]ethanol and a few crystals of tetrabutylammonium hydrogen sulfate in 2 liter of CH2Cl2 was added 300 ml of 9M H2SO4. To this was added 29.4 g of pulverized K2Cr2O7 and the mixture was stirred at room temperature for 15 minutes. The organic phase was separated from the aqueous phase and washed with water. The acid product was extracted from the organic phase using 300 ml of 3% NaHCO3. The alkaline solution was washed with CH2Cl2 several times, and the solution was then acidified slowly with 5% HCl until all the acid precipitated. The solid was filtered, washed with water, and dried to give 2.6 g of a powder. Recrystallization from 50 ml of toluene yielded 2.3 g (9%) of needles, m.p. 119°-121°.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.C(N(CC)CC)C.Cl>C1(C)C=CC=CC=1>[I:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:19][C:16]2[CH:17]=[CH:18][C:13]([CH3:12])=[CH:14][CH:15]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Reactant: Cc1ccc(O)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(OS(=O)(=O)c2ccc(I)cc2)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
4-Iodobenzenesulfonyl chloride (604 g, 2 mol) was added with stirring to a solution of 4-methylphenol (227 g, 2.1 mol) and triethylamine (222 g, 2.2 mol) in toluene (1.5 l). The suspension was stirred at 60° C. for 2 h. The reaction mixture was added to excess dilute hydrochloric acid. The precipitate was filtered off and washed with ethanol. A second crop was obtained by concentrating the toluene mother liquor and collecting the solid material in the same manner. The combined crops were recrystallized from 2-propanol (2.5 l). Yield 680 g, 91%.
Reaction SMILES: [CH2:1]([O:13][C:14]1[CH:15]=[C:16]([CH:21]=[C:22]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:23]=1)[C:17]([O:19]C)=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[OH-].[K+]>CCO>[CH2:25]([O:24][C:22]1[CH:21]=[C:16]([CH:15]=[C:14]([O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:23]=1)[C:17]([OH:19])=[O:18])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCCCCCCOc1cc(OCCCCCCCCCCCC)cc(C(=O)OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCCOc1cc(OCCCCCCCCCCCC)cc(C(=O)O)c1
Yield: 85 %

Procedure:
Methyl 3,5-bis-dodecyloxybenzoate (8 g) was refluxed for 6 h with EtOH (25 mL) and 10% KOH. Then, the mixture was cooled and poured onto ice H2O and extracted with MC, then the organic layer was stored over dry MgSO4. The solvent was removed; the crude was recrystallized in EtOH to yield 85% of the benzoic acid product as a white solid. 1H-NMR (300 MHz, CDCl3) δ 7.1 (d, 2H), 6.6 (t, 1H), 4.0 (t, 4H), 1.7-1.8 (m, 4H), 1.4-1.6 (m, 4H), 1.2-1.3 (m, 32H), 0.9 (t, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]([C:19]1[S:23][N:22]=[CH:21][N:20]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13](F)=[CH:12][C:11]=1[F:18])(=[O:9])=[O:8].[C:30]1([C@H:36]2[CH2:41][CH2:40][CH2:39][CH2:38][C@@H:37]2[OH:42])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[H-].[Na+]>CS(C)=O>[CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]([C:19]1[S:23][N:22]=[CH:21][N:20]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:42][C@H:37]2[CH2:38][CH2:39][CH2:40][CH2:41][C@@H:36]2[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:12][C:11]=1[F:18])(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(F)cc2F)c(OC)c1
Reactant: O[C@H]1CCCC[C@@H]1c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(O[C@H]3CCCC[C@@H]3c3ccccc3)cc2F)c(OC)c1
Yield: 32.7 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1a by using N-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (WO 2010/079443; 126 mg, 0.283 mmol), (1S,2R)-2-phenylcyclohexanol (50.0 mg, 0.284 mmol), sodium hydride (63%; 21.6 mg, 0.567 mol) and DMSO (2.0 mL), to yield the title compound (55.7 mg, 33%) as a colorless oil.
Reaction SMILES: [C:1]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][N:7]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH:6]([C:25](O)=[O:26])[CH2:5]1)(=[O:3])[CH3:2].[OH:28][N:29]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.NO>CN(C)C=O.O.C(OCC)(=O)C.CO>[OH:28][NH:29][C:25]([CH:6]1[N:7]([S:15]([C:18]2[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:4]([C:1](=[O:3])[CH3:2])[CH2:5]1)=[O:26]
Reactant: CC(=O)N1CC(C(=O)O)N(S(=O)(=O)c2ccc(O)cc2)Cc2ccccc21
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NO
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: CC(=O)N1CC(C(=O)NO)N(S(=O)(=O)c2ccc(O)cc2)Cc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a crude mixture of 1-acetyl-4-(4-hydroxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid (0.55 g) and N-hydroxybenzotriazole (0.414 g) in 5 ml of N,N-dimethylformamide was added 0.684 g of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride. The mixture was stirred at room temperature for 1 hr and then 750 μL of hydroxylamine in water (50%) was added and the mixture stirred at room temperature overnight. The mixture was diluted with ethyl acetate and then washed with H2O, 2N citric acid, brine and dried (Na2SO4). The solvent was removed under vacuum to give a solid. Chromatography on silica gel with 10% methanol in ethyl acetate as solvent gave a solid which was dried at 78° C under vacuum overnight to give an off-white foam; Mass spectrum (ES) 406.1 (M+H); Anal. Calcd. For C18H19N3O6S; C, 53.3; H, 4.7; N, 10.4. Found: C, 52.6; H, 5.2; N, 10.4.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27](=[O:39])[NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([CH3:38])([CH3:37])[CH3:36])[CH:30]=3)=[CH:23][CH:22]=2)[CH2:17][CH2:16]1)=O)(C)(C)C.C(C1C=CC(NC(=O)C2C=CC(N3CCNCC3)=NC=2)=CC=1)(C)(C)C>>[C:35]([C:31]1[CH:30]=[C:29]([NH:28][C:27](=[O:39])[C:24]2[CH:23]=[CH:22][C:21]([CH:18]3[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]3)=[CH:26][CH:25]=2)[CH:34]=[CH:33][CH:32]=1)([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)Nc3cccc(C(C)(C)C)c3)cc2)CC1
Agent: CC(C)(C)c1ccc(NC(=O)c2ccc(N3CCNCC3)nc2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1cccc(NC(=O)c2ccc(C3CCNCC3)cc2)c1

Procedure:
N-(3-tert-Butyl-phenyl)-4-piperidin-4-yl-benzamide was synthesized by the TFA deprotection of 4-[4-(3-tert-butyl-phenylcarbamoyl)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester in a manner similar to the one described in the synthesis of N-(4-tert-butyl-phenyl)-6-piperazin-1-yl-nicotinamide. LCMS calcd for C22H28N2O (m/e) 336, obsd 337 (M+H).
Reaction SMILES: C(OC([N:8]1[C:12]2=[N:13][C:14]([N:17]3[CH2:22][CH2:21][CH:20]([N:23]([CH3:25])[CH3:24])[CH2:19][CH2:18]3)=[CH:15][CH:16]=[C:11]2[N:10]=[CH:9]1)=O)(C)(C)C.C[O:27][C:28](=O)[C:29]1[CH:34]=[CH:33][N:32]=[C:31]([Br:35])[CH:30]=1.[Li+].CC([N-]C(C)C)C>>[CH3:25][N:23]([CH3:24])[CH:20]1[CH2:19][CH2:18][N:17]([C:14]2[N:13]=[C:12]3[NH:8][C:9]([C:28]([C:29]4[CH:34]=[CH:33][N:32]=[C:31]([Br:35])[CH:30]=4)=[O:27])=[N:10][C:11]3=[CH:16][CH:15]=2)[CH2:22][CH2:21]1
Reactant: COC(=O)c1ccnc(Br)c1
Reactant: CN(C)C1CCN(c2ccc3ncn(C(=O)OC(C)(C)C)c3n2)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: CN(C)C1CCN(c2ccc3nc(C(=O)c4ccnc(Br)c4)[nH]c3n2)CC1
Yield: 39.8 %

Procedure:
Starting with 5-(4-dimethylamino-piperidin-1-yl)-imidazo[4,5-b]pyridin-3-carboxylic acid tert-butyl ester [Example 135, Step 4 (Step 4)] (711 mg, 2.05 mmol) and methyl-2-bromo-isonicotinate (445 mg, 2.05 mmol), the reaction was performed by following General procedure J (LDA metallation) followed by work up method D. Purification by SiO2 chromatography (CH2Cl2/MeOH) gave [5-(4-dimethylamino-piperidin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl]-[2-bromo-pyridin-4-yl]-methanone (350 mg, 40%). 1H NMR (400 MHz, CD3OD) δ 1.43 (m, 2H), 1.93 (m, 2H), 2.26 (s, 6H), 2.47 (m, 1H), 2.87 (m, 2H), 4.53 (m, 2H), 6.95 (d, J=9.54 Hz, 1H), 7.83 (d, J=9.03 Hz, 1H), 8.14 (d, 5.03 Hz, 1H), 8.42 (s, 1H), 8.47 (d, J=5.02 Hz, 1H). MS(ESI) m/z 430 [M+H]+.
Reaction SMILES: Cl.[F:2][C:3]1[S:7][C:6]([C:8]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])=[CH:5][CH:4]=1.O=[CH:17][CH2:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([NH:25][C:26](=[O:28])[CH3:27])[CH2:21][CH2:20]1>>[F:2][C:3]1[S:7][C:6]([C:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:17][CH2:18][C@H:19]3[CH2:24][CH2:23][C@H:22]([NH:25][C:26](=[O:28])[CH3:27])[CH2:21][CH2:20]3)[CH2:12][CH2:11]2)=[O:9])=[CH:5][CH:4]=1
Reactant: O=C(c1ccc(F)s1)C1CCNCC1
Reactant: CC(=O)N[C@H]1CC[C@H](CC=O)CC1
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@H](CCN2CCC(C(=O)c3ccc(F)s3)CC2)CC1

Procedure:
From (5-fluoro-thiophen-2-yl)-piperidin-4-yl-methanone hydrochloride (17 mg) and N-[trans-4-(2-oxo-ethyl)-cyclohexyl]-acetamide (20 mg, intermediate AG) by procedure A.2. Yield: 19 mg (73%). White solid. MS (m/z): 381.3 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=O.O1CCCC1.S([O-])([O-])(=O)=O.[OH:21][NH3+:22].O[NH3+].C(=O)(O)[O-].[Na+]>O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=[N:22][OH:21]
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: [NH3+]O
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: ON=Cc1c(Cl)cccc1Cl
Temperature: 40 °C
Reaction time: 3 h

Procedure:
50.0 g (0.286 mol) of 2,6-dichlorobenzaldehyde were added to 250 ml of tetrahydrofuran and 250 ml of water, and 26.0 g (0.159 mol) of hydroxylammonium sulfate were added. The mixture was then stirred at 40° C. for 3 h, keeping the pH at 4-5 by adding sodium bicarbonate solution. The tetrahydrofuran was then distilled off under reduced pressure, and the residue was extracted with methyl tert-butyl ether, and the solution was dried over sodium sulfate and concentrated under reduced pressure. Yield 54.3 g (99.9%) of solid of melting point 150° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[C:5](C)=[CH:6][CH:7]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C(C2C=CC=CC=2)CC(Cl)=O)C=CC=CC=1>[OH:9][C:4]1[CH:3]=[C:2]([CH3:1])[C:7]([C:2]([CH3:1])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:3][C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:9])=[CH:6][CH:5]=1
Reactant: Clc1ccccc1
Reactant: Cc1ccc(C)c(O)c1
Agent: O=C(Cl)CC(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1cc(O)ccc1C(C)(CC(=O)c1ccccc1)c1ccccc1

Procedure:
Twenty-four and four-tenths grams of 3,6-dimethylphenol and 26.6 grams of aluminum chloride are dissolved in 250 mls chlorobenzene and 48.9 grams of 3,3-diphenylpropionic acid chloride, dissolved in 150 mls chlorobenzene, are added while stirring. The stirring is continued for several days at 100° C. The chlorobenzene is evaporated in vacuo, the residue is mixed with ice and ether and washed several times with water. After drying with sodium sulfate, the ether is evaporated. Fifteen and one-tenth grams of 4-hydroxy-3,6-dimethyl-β,β-diphenylpropiophenone are obtained.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[Cl:15][C:16]1[C:21]([Cl:22])=[C:20]([O:23][CH3:24])[CH:19]=[CH:18][C:17]=1[S:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C:27]1=O>O>[Cl:22][C:21]1[C:20]([O:23][CH3:24])=[CH:19][C:18]2[C:27]3[CH2:28][CH2:29][CH2:30][CH2:31][C:26]=3[S:25][C:17]=2[C:16]=1[Cl:15]
Reactant: COc1ccc(SC2CCCCC2=O)c(Cl)c1Cl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Product: COc1cc2c3c(sc2c(Cl)c1Cl)CCCC3
Reaction time: 2 h

Procedure:
A mixture of "super" polyphosphoric acid is freshly prepared by mixing 7.0 g of phosphorous pentoxide and 40 g of polyphosphoric acid. The mixture is heated to 135°-140° and, with efficient stirring, is added 5.5 g of finely pulverized 2-[2,3-dichloro-4-methoxyphenylthio]cyclohexanone. Stirring is continued at 140° for 2 hours and the mixture is cooled, dilued with water and filtered. The crude product is filtered, air-dried and purified by passing it through a silica column. Elution with ether-hexane (50:50) yields 4.3 g of 3,4-dichloro-6,7,8,9-tetrahydro-2-methoxydibenzothiophene as off-white crystals, mp 123°-125°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18]C(OCC2C=CC=CC=2)=O)[CH2:11][CH2:10]1>[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:13][CH2:14]1
Reactant: COc1ccccc1N1CCN(CCCNC(=O)OCc2ccccc2)CC1
Agent: [Pd]
Product: COc1ccccc1N1CCN(CCCN)CC1
Reaction time: 1.33 h
Yield: 92.8 %

Procedure:
A mixture of benzyl 3-[4-(2-methoxyphenyl)piperazin-1-yl]propylamino-formate (384.4 g, I mol) and 10% palladium on carbon (38.4 g) in 3.5L of nitrogen-purged ethanol was hydrogenated at atmospheric pressure for 80 minutes while cooled such that the reaction temperature remained below 30° C. The mixture was filtered and the filtrate was concentrated under reduced pressure to give 3-[4-(2-methoxyphenyl)piperazin-1-yl]propylamine (230.8 g, 0.93 mol) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=O)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH2:31][CH2:30][N:29]([CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH2:28][CH2:27]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([N:26]4[CH2:31][CH2:30][N:29]([CH:32]5[CH2:33][CH2:34][O:35][CH2:36][CH2:37]5)[CH2:28][CH2:27]4)=[C:22]([C:23]#[N:24])[CH:25]=3)=[O:16])[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(C(=O)O)cnn1-c1cccc(Cl)c1
Reactant: N#Cc1cc(N)ccc1N1CCN(C2CCOCC2)CC1
Product: Cc1c(C(=O)Nc2ccc(N3CCN(C4CCOCC4)CC3)c(C#N)c2)cnn1-c1cccc(Cl)c1
Yield: 41 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-(3-chlorophenyl)-5-methylpyrazole-4-carboxylic acid (0.8 g) and 5-amino-2-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]benzonitrile (1.0 g), the title compound (0.7 g) was obtained, melting point: 230° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CN(C=O)C.[Br:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[C:19](F)[CH:18]=1>C1COCC1>[CH2:3]([O:10][C:19]1[CH:18]=[C:17]([Br:16])[CH:22]=[C:21]([F:23])[CH:20]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCc1ccccc1
Reactant: Fc1cc(F)cc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Fc1cc(Br)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.3 %

Procedure:
Sodium hydride (80% oil dispersion, 6.0 g, 201 mmol) was added slowly to a solution of benzyl alcohol (16 mL, 155 mmol) in THF (310 mL) at 0° C. DMF (300 mL) was added slowly and the reaction mixture was stirred until all of the NaH dissolved and gas evolution ceased. A solution of 1-bromo-3,5-difluorobenzene (30 g, 155 mmol) in THF (30 mL) was added and the reaction mixture was stirred for 30 min at ambient temperature. The reaction was quenched with saturated aqueous NH4Cl, and the reaction mixture was extracted 3 times with ethyl acetate. The combined organic layers were washed with saturated aqueous NH4Cl and brine, dried over MgSO4, filtered, and concentrated in vacuo to give a yellow liquid. 3-benzyloxy-5-fluorobromobenzene (28 g) was isolated by chromatography on silica gel (5% ethyl acetate, hexanes). Step 2. 4-[(3-benzyloxy-5-fluorophen-1-yl)oxomethyl]tetrahydropyran.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[F:21][C:22]([F:38])([F:37])[O:23][C:24]1[CH:25]=[C:26]([C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)[CH:27]=[CH:28][CH:29]=1.[OH-].[Na+]>>[CH3:19][O:18][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:36][C:33]2[CH:34]=[CH:35][C:30]([C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([O:23][C:22]([F:21])([F:37])[F:38])[CH:25]=3)=[CH:31][CH:32]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:20]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Reactant: Oc1ccc(-c2cccc(OC(F)(F)F)c2)cc1
Agent: [Na+]
Agent: [OH-]
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(-c3cccc(OC(F)(F)F)c3)cc2)cc1)C(=O)O

Procedure:
(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 173, Step A was treated with 3′-Trifluoromethoxy-biphenyl-4-ol from Step A under the Standard Procedure J. The compound thus obtained was allowed to react under Standard hydrolysis procedure C (NaOH) to give the title compound. MS(ES) for C26H25F3O6 [M+Na]+: 513, [M+H]+: 491.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:16][CH2:15][C:10]2([NH:14][CH2:13][CH2:12][CH2:11]2)[C:9]1=[O:17].[CH:18](=O)[CH:19]([CH3:21])[CH3:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:16][CH2:15][C:10]2([N:14]([CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:13][CH2:12][CH2:11]2)[C:9]1=[O:17]
Reactant: O=C1N(c2ccccc2Cl)CCC12CCCN2
Reactant: CC(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)CN1CCCC12CCN(c1ccccc1Cl)C2=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
7-(2-Chlorophenyl)-1,7-diazaspiro[4.4]nonan-6-one (20 mg, 0.00008 mol) was dissolved in anhydrous DCM (2 mL). To this mixture was added isobutyraldehyde (8.0 μL, 0.000088 mol) and sodium triacetoxyborohydride (3.0E1 mg, 0.00014 mol). The resulting solution was stirred at RT for 16 h. The volatiles were removed in vacuo and the resulting residue was dissolved in acetonitrile/H2O and purified by prep.-LC/MS chromatography to afford the desired product. LC-MS: 307.1 (M+1H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:8][CH:7]1[C:9]1[CH:10]=[C:11]2[CH:17]=[CH:16][N:15](S(C3C=CC(C)=CC=3)(=O)=O)[C:12]2=[N:13][CH:14]=1)=[O:5])[CH3:2].[O-]CC.[Na+].[Cl-].[NH4+]>C(O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:8][CH:7]1[C:9]1[CH:10]=[C:11]2[CH:17]=[CH:16][NH:15][C:12]2=[N:13][CH:14]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CC1c1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1
Agent: CC[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)C1CC1c1cnc2[nH]ccc2c1
Temperature: 70 °C

Procedure:
2-[1-(Toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl ]-cyclopropanecarboxylic acid ethyl ester, (153 mg, 0.4 mmol), was added to 2 mL ethanol and sodium ethoxide solution, (˜2.68M, 300 μL, 0.8 mmol), was added. The mixture was heated to 70° C. for 3 hours. The mixture was cooled to rt and several mL sat. ammonium chloride solution were added. The mixture was extracted with dichloromethane and the organic layers evaporated affording 85 mg essentially pure 2-(1H-Pyrrolo[2,3-b]pyridin-5-yl)-cyclopropanecarboxylic acid ethyl ester, which was used without further purification. MS ES+231.1.