Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[C:3]([N:6]1[C:16]2[C:11](=[CH:12][C:13]([I:17])=[CH:14][CH:15]=2)[C:9](=O)[C:7]1=[O:8])(=[O:5])[CH3:4].N1C2C(=CC=CC=2)C=CC1=[O:28].Cl>O>[I:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[NH:6][C:3](=[O:5])[CH:4]=[C:9]2[C:7]([OH:28])=[O:8]
Reactant: O=c1ccc2ccccc2[nH]1
Reactant: CC(=O)N1C(=O)C(=O)c2cc(I)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc(=O)[nH]c2ccc(I)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
To a solution of sodium hydroxide (0.77 g, 19.3 mmol) in water (46.5 mL), was added N-acetyl-5-iodoisatine (107) (2.50 g, 7.86 mmol) (Aeschlimann, J. A. The relative stability of the quinolone and indolinone rings. J. Chem. Soc. 1926, 2908). The mixture was refluxed for 3 h. After cooling to room temperature and then 0° C., a 6 N aqueous hydrochloric acid solution was added (pH=1). The precipitate was filtered and suspended in a saturated aqueous sodium bicarbonate solution (10 mL). The remaining precipitate was filtered and the filtrate was extracted with dichloromethane (6×50 mL). The aqueous layer was acidified up to pH=1 with a 6 N aqueous hydrochloric acid solution and left 1 h at 0° C. The precipitate formed was filtered and dried under vacuum at 35° C. to give compound 108 (0.90 g, 2.86 mmol) as an ocher solid. Yield 36%; mp 361-363° C.; IR (KBr) ν 1219, 1636, 1701, 2800-3150, 3200-3500 cm−1; 1H NMR (200 MHz, DMSO-d6) δ 6.92 (s, 1H), 7.18 (d, 1H, J=8.7 Hz), 7.84 (dd, 1H, J=1.8, 8.7 Hz), 8.57 (d, 1H, J=1.8 Hz), 12.17 (s, 1H), 14.00 (m, 1H); ESI-MS m/z 313.7 [M−H].
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].Cl[C:16]1[CH:21]=[N:20][CH:19]=[CH:18][N:17]=1>>[CH3:8][C:7]1[O:6][N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]=1[C:1]#[C:2][C:16]1[CH:21]=[N:20][CH:19]=[CH:18][N:17]=1
Reactant: C#Cc1c(-c2ccccc2)noc1C
Reactant: Clc1cnccn1
Product: Cc1onc(-c2ccccc2)c1C#Cc1cnccn1
Yield: 60 %

Procedure:
As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (92 mg, 0.50 mmol) was converted (using 2-chloropyrazine instead of 2-chloro-4-iodopyridine) to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 78 mg, 60%) which was obtained as a light yellow solid. MS: m/e=262.1 [M+H]+.
Reaction SMILES: C([N:8]1[C@@H:13]2[CH2:14][CH2:15][C@@:9]1([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C@H:10]([O:16][CH2:17][C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=1)[CH2:11][CH2:12]2)C1C=CC=CC=1>[Pd].C(O)C>[F:26][C:24]([F:25])([F:27])[C:22]1[CH:23]=[C:18]([CH2:17][O:16][C@@H:10]2[CH2:11][CH2:12][C@@H:13]3[NH:8][C@@:9]2([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:15][CH2:14]3)[CH:19]=[C:20]([C:28]([F:31])([F:29])[F:30])[CH:21]=1
Reactant: FC(F)(F)c1cc(CO[C@@H]2CC[C@H]3CC[C@]2(c2ccccc2)N3Cc2ccccc2)cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CCO
Product: FC(F)(F)c1cc(CO[C@@H]2CC[C@H]3CC[C@]2(c2ccccc2)N3)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 46.9 %

Procedure:
A mixture of (1R,2R,5R)-8-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8-azabicyclo[3.2.1]octane (Example 180; 165 mg), 10% palladium on charcoal (215 mg) and ethanol (15 ml) was stirred under hydrogen atmosphere (1 atm) at +65° C. for 45 minutes. The reaction mixture was cooled to room temperature, flushed with nitrogen gas and filtered through a pad of Celite™. The filtrate was concentrated. The residue was purified by chromatography on silica gel (dichloromethane:methanol:ammonia) to give the title compound (64 mg, 59%). The hydrochloride salt of the title compound was prepared by treatment with ethereal HCl.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:7]=[C:8]([CH:23]([CH3:25])[CH3:24])[C:9]=1[N:10]1[CH:14]=[CH:13][N:12]=[C:11]1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21]C)[CH:16]=1)([CH3:3])[CH3:2].Cl.N1C=CC=CC=1>>[CH:23]([C:8]1[CH:7]=[C:6]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:9]=1[N:10]1[CH:14]=[CH:13][N:12]=[C:11]1[C:15]1[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1)([CH3:24])[CH3:25]
Reactant: COc1cccc(-c2nccn2-c2c(C(C)C)cc(-c3ccccc3)cc2C(C)C)c1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)c1cc(-c2ccccc2)cc(C(C)C)c1-n1ccnc1-c1cccc(O)c1
Temperature: 200 °C
Reaction time: 13 h
Yield: 95.2 %

Procedure:
A mixture of 1-(3,5-diisopropyl-[1,1′-biphenyl]-4-yl)-2-(3-methoxyphenyl)-1H-imidazole (5.57 g, 13.57 mmol) and pyridine hydrochloride (9.41 g, 81 mmol) were fused with stirring at 200° C. for 13 h. After the reaction was complete, the mixture was partitioned between water and AcOEt. AcOEt layer was separated, washed with water (3×) and brine, and then purified by silica gel column chromatography using DCM/MeOH (96/4) as eluant to afford an off-white solid (5.12 g, 95%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](Cl)=[CH:6][C:5]=1[C:11]([F:14])([F:13])[F:12])([O-:3])=[O:2].[CH3:15][C:16]1([CH3:23])[NH:20][C:19](=[O:21])[NH:18][C:17]1=[O:22].[OH-].[K+]>CS(C)=O>[F:12][C:11]([F:14])([F:13])[C:5]1[CH:6]=[C:7]([N:18]2[C:17](=[O:22])[C:16]([CH3:23])([CH3:15])[NH:20][C:19]2=[O:21])[CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: CC1(C)NC(=O)NC1=O
Reactant: O=[N+]([O-])c1ccc(Cl)cc1C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC1(C)NC(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C1=O
Temperature: 110 °C

Procedure:
30 ml of dimethylsulfoxide and 24.8 grams of 2-nitro-5-chloro trifluoromethylbenzene were introduced at 20° C. with stirring into 100 ml of dimethylsulfoxide, 12.80 grams of 5,5-dimethyl-hydantoin and 6.28 grams of potassium hydroxide in the form of flakes. The mixture was heated to 110° C. for a period of time variable between 3 and 18 hours. The product was characterized and determined by thin layer chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.C([O:12][C:13](=[O:31])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=1/[CH:23]=[C:24]1/[C:25](=[O:30])[NH:26][C:27](=[O:29])[S:28]/1)C>>[Br:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][CH2:14][C:13]([OH:31])=[O:12])=[C:17]([CH2:23][CH:24]2[S:28][C:27](=[O:29])[N:26]([CH2:5][C:4]3[CH:7]=[CH:8][CH:9]=[C:2]([Cl:1])[CH:3]=3)[C:25]2=[O:30])[CH:18]=1
Reactant: CCOC(=O)COc1ccc(Br)cc1/C=C1\SC(=O)NC1=O
Reactant: Clc1cccc(CBr)c1
Product: O=C(O)COc1ccc(Br)cc1CC1SC(=O)N(Cc2cccc(Cl)c2)C1=O

Procedure:
Prepared from 3-chlorobenzyl bromide and 4-bromo-2-[2,4-dioxothiazolidin-(5Z)-ylidenemethyl]phenoxyacetic acid ethyl ester according to GP13, GP14 and GP16: LC/MS (an10p8): Rt 2.6 min, m/z 484 [M+H]+. 1H NMR (DMSO-d6): δ 3.02-3.10 (m, 1H), 3.54-3.60 (m, 1H), 4.69 (s, 2H), 4.75 (s, 2H), 5.09-5.14 (m, 1H), 6.89-6.92 (m, 1H), 7.18 (m, 1H), 7.33-7.43 (m, 5H), 13.01 (br s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]([C:16]2([C:21]([F:24])([F:23])[F:22])[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]([F:25])=[CH:4][N:3]=1.[F:26][C:27]1[CH:28]=[C:29]2[C:35](B3OC(C)(C)C(C)(C)O3)=[CH:34][N:33]([S:45]([C:48]3[CH:53]=[CH:52][C:51]([CH3:54])=[CH:50][CH:49]=3)(=[O:47])=[O:46])[C:30]2=[N:31][CH:32]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1COCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:25][C:5]1[C:6]([NH:8][CH:9]([C:16]2([C:21]([F:24])([F:23])[F:22])[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:7][C:2]([C:35]2[C:29]3[C:30](=[N:31][CH:32]=[C:27]([F:26])[CH:28]=3)[N:33]([S:45]([C:48]3[CH:53]=[CH:52][C:51]([CH3:54])=[CH:50][CH:49]=3)(=[O:46])=[O:47])[CH:34]=2)=[N:3][CH:4]=1
Reactant: CCOC(=O)CC(Nc1nc(Cl)ncc1F)C1(C(F)(F)F)CCCC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(F)cnc32)cc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CC(Nc1nc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(F)cc23)ncc1F)C1(C(F)(F)F)CCCC1

Procedure:
To a solution of racemic ethyl 3-(2-chloro-5-fluoropyrimidin-4-ylamino)-3-(1-(trifluoromethyl)cyclopentyl)propanoate, 196a, (0.084 g, 0.219 mmol) in THF (10 mL) and water (1 mL) was added 5-fluoro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine, 7a, (0.137 g, 0.328 mmol) and potassium phosphate (0.140 g, 0.657 mmol). The resulting mixture was degassed under a stream of nitrogen for 10 minutes. To the reaction was then added X-Phos (0.010 g, 0.021 mmol) and Pd2(dba)3 (0.010 g, 0.011 mmol). The reaction was irradiated for 15 minutes at 135° C. in a microwave. The resulting mixture was concentrated in vacuo to a brown oil which was purified by silica gel chromatography (EtOAc/CH2Cl2) to afford 80 mg of the desired product as a pale yellow solid: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=4.22 minutes (M+H) 638.42.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2(O)[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1ccc(C2(O)CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCOc1ccc(C2CCNCC2)cc1
Reaction time: 16 h
Yield: 60.9 %

Procedure:
To a stirring solution of tert-butyl 4-(4-(heptyloxy)phenyl)-4-hydroxypiperidine-1-carboxylate (388 mg, 0.99 mmol) and triethylsilane (791 μl, 4.95 mmol) in DCM (2 mL) cooled to −30° C. was slowly added 2,2,2-trifluoroacetic acid (379 μl, 4.95 mmol) in a drop-wise fashion. The reaction mixture was allowed to warm slowly and stirring continued for 16 h. The reaction mixture was poured onto ice-water/NaOH (50 mL/5 mL, 2 M) and extracted with DCM (3×20 mL). The combined organic extracts were washed successively with water (50 mL) and NaHCO3 (20 mL), dried over MgSO4 and evaporated to afford 166 mg (58%) of 4-(4-(heptyloxy)phenyl)piperidine INT-19 as a white, waxy solid. LCMS-ESI (m/z) calculated for C18H29NO: 275.4. found 276.0 [M+H]+, tR=2.88 min. (Method 11).
Reaction SMILES: [Cl:1][C:2]1[C:12](Cl)=[C:11]([C:14](=[N:22][OH:23])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7].[H-].[Na+].Cl>C1C=CC=CC=1.CN(C)C=O>[Cl:1][C:2]1[C:12]2[O:23][N:22]=[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])[C:11]=2[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: O=C(O)COc1ccc(C(=NO)c2ccccc2F)c(Cl)c1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: O=C(O)COc1ccc2c(-c3ccccc3F)noc2c1Cl

Procedure:
A mixture of 0.3 g of 2,3-dichloro-4-(2-fluorobenzohydroximoyl)phenoxyacetic acid and 0.05 g of sodium hydride in 5 ml of benzene and 5 ml of dimethylformamide is refluxed for 3 hours. To the mixture, after it has been permitted to cool there is added 5% hydrochloric acid causing the benzene to separate. The benzene is evaporated in vacuo and the resulting precipitate is collected by filtration and recrystallized from aqueous ethyl alcohol to yield the product {[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid having a melting point of 188° to 189° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C@H:12]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:13][CH2:14][CH2:15][OH:16])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:8]=2)[N:3]=1.CC(C)=[O:32].OS(O)(=O)=O.O=[Cr](=O)=O.OS(O)(=O)=O.O>CC(C)=O>[NH2:1][C:2]1[C:11]([C@H:12]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:13][CH2:14][C:15]([OH:32])=[O:16])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:8]=2)[N:3]=1
Reactant: Nc1nc2ccc(Oc3ccccc3)cc2cc1[C@@H](CCCO)C1CCCCC1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: Nc1nc2ccc(Oc3ccccc3)cc2cc1[C@@H](CCC(=O)O)C1CCCCC1
Temperature: 0 °C

Procedure:
To an ice cold solution of 4-(2-amino-6-phenoxy-quinoline-3-yl)-4-(S)-cyclohexyl-butan-1-ol (0.44 g, 1.12 mmol) in acetone (15 mL) was added Jones reagent (0.7 M solution in a 0.12:1 mixture of concentrated H2SO4:H2O, 16.0 mL, 11.3 mmol) dropwise, and the reaction mixture was stirred for 3.0 h. The excess reagent was quenched by adding isopropyl alcohol, and the resulting slurry was filtered through Celite®. The crude material obtained by removal of the solvent was purified by silica gel column chromatography using 30% MeOH in CHCl3 to yield 4-(2-amino-6-phenoxy-quinoline-3-yl)-4-(S)-cyclohexyl-butyric acid.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[CH:13]([OH:20])[CH2:14][N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1>C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC.C1C=CC=CC=1>[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[CH:13]([O:20][C:3](=[O:4])[NH:2][CH3:1])[CH2:14][N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: CN=C=O
Reactant: OC(Cn1ccnc1)c1ccc(Cl)cc1Cl
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: c1ccccc1
Product: CNC(=O)OC(Cn1ccnc1)c1ccc(Cl)cc1Cl
Yield: 81.2 %

Procedure:
5.7 g (0.1 mol) of methyl isocyanate and a few drops of dibutyl-tin dilaurate were added to 25.8 g (0.1 mol) of 1-(2,4-dichlorophenyl)-1-hydroxy-2-(imidazol-1-yl)-ethane in 250 ml of benzene, while stirring. The mixture was stirred overnight at 60°-65° C. It was then allowed to cool and the crystalline precipitate was filtered off and rinsed with ether. 25.5 g (81% of theory) of 1-(2,4-dichlorophenyl)-2-(imidazol-1-yl)-methylcarbamoyloxy-ethane of melting point 106°-108° C. were obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][S:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:24]([O:26][C:27]([C@@H:29]1[CH2:31][C@H:30]1[C:32]1[CH:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][CH:33]=1)=[O:28])[CH3:25]>>[CH2:24]([O:26][C:27]([C@@H:29]1[CH2:31][C@H:30]1[C:32]1[CH:37]=[CH:36][C:35]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[C:9]=3[CH2:14][S:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:4][CH:3]=2)=[CH:34][CH:33]=1)=[O:28])[CH3:25]
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CSCCc1ccccc1
Product: CCOC(=O)[C@@H]1C[C@H]1c1ccc(-c2ccc(-c3onc(C)c3CSCCc3ccccc3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using 5-(4-bromo-phenyl)-3-methyl-4-phenethylsulfanylmethyl-isoxazole and (trans)-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[S:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][C:5]12[C:21](=[O:22])[NH:20][C:19](=O)[NH:18]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[S:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][C:5]12[C:21](=[O:22])[NH:20][C:19](=[S:33])[NH:18]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1NC(=O)C2(CC(c3ccccc3)Sc3ccc(Br)cc32)N1
Solvent: C1COCCO1
Product: O=C1NC(=S)NC12CC(c1ccccc1)Sc1ccc(Br)cc12
Temperature: 25 °C
Yield: 80.9 %

Procedure:
A solution of 6′-bromo-2′-phenylspiro[imidazolidine-4,4′-thiochroman]-2,5-dione (237 mg, 0.61 mmol) and Lawesson's reagent (246 mg, 0.61 mmol) in 1,4-dioxane (3 mL) in a 10 mL CEM microwave test tube is heated in a CEM microwave reactor at 110° C. for 30 min. After cooled to rt, the solvent is removed in vacuo, and the residue is purified by flash chromatography column to give 6′-bromo-2′-phenyl-2-thioxospiro[imidazolidine-4,4′-thiochroman]-5-one (200 mg, 81%). MS ESI +ve m/z 405 (M+H)+.
Reaction SMILES: C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH3:25][S:26]([C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32]([OH:34])=O)(=[O:28])=[O:27].Cl.Cl.[N:40]1([CH:47]2[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)[CH2:45][CH2:44][CH:43]([OH:46])[CH2:42][CH2:41]1.CCN(C(C)C)C(C)C>ClCCl.CO>[OH:46][CH:43]1[CH2:42][CH2:41][N:40]([CH:47]2[CH2:52][CH2:51][N:50]([C:32]([C:31]3[CH:35]=[CH:36][CH:37]=[C:29]([S:26]([CH3:25])(=[O:27])=[O:28])[CH:30]=3)=[O:34])[CH2:49][CH2:48]2)[CH2:45][CH2:44]1
Reactant: CS(=O)(=O)c1cccc(C(=O)O)c1
Reactant: OC1CCN(C2CCNCC2)CC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: CS(=O)(=O)c1cccc(C(=O)N2CCC(N3CCC(O)CC3)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.4 %

Procedure:
PyBrOP™ (25.3 g) was added to a stirred solution of 3-methanesulphonyl benzoic acid (10 g), [1,4′]bipiperidinyl-4-ol dihydrochloride (13 g, see Method D) and Hunig's base (34 ml) in dichloromethane (500 ml). The resulting mixture was stirred at RT overnight, then washed with saturated NaHCO3 solution (300 ml) followed by saturated brine (300 ml). The organic layer was dried (MgSO4) and evaporated to leave an oily residue. Column chromatography (silica, 20% methanol in DCM) gave the product as a white solid (16 g; MS: APCI+(M+H) 367).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].[C:5]([N:9]1[C:13](=[O:14])[C:12](Cl)=[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:10]1(=[O:23])=[O:22])([CH3:8])([CH3:7])[CH3:6]>>[C:5]([N:9]1[C:13](=[O:14])[C:12]([NH:1][CH2:2][CH2:3][OH:4])=[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:10]1(=[O:23])=[O:22])([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: NCCO
Product: CC(C)(C)N1C(=O)C(NCCO)=C(c2ccccc2)S1(=O)=O
Yield: 55 %

Procedure:
The title compound was prepared as described for Example 49 from 2-aminoethanol and 2-tert-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide. The residue was purified by silica gel column chromatography (Horizons Biotage) using DCM as eluent to give the title compound (1.788 g, 55%) as an oil. 1H NMR (500 MHz): δ 7.50-7.44 (m, 5H), 6.81 (t, 1H), 4.69 (t, 1H), 3.29-3.22 (m, 2H), 3.86-2.80 (m, 2H), 1.64 (s, 9H); 13C NMR (125 MHz DMSO-d6): 159.9, 136.1, 132.1, 130.0, 129.2, 125.9, 105.4, 61.2, 59.5, 46.6, 27.8; Mass Spectrum: M+H+ 325.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6](Br)[CH:5]=1.[OH:13][C:14]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)=[O:15].C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]([C:19]2[CH:20]=[CH:21][C:16]([C:14]([OH:15])=[O:13])=[CH:17][CH:18]=2)[C:7]([CH3:10])=[CH:8][CH:9]=1)=[O:12]
Reactant: COC(=O)c1ccc(C)c(Br)c1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: COC(=O)c1ccc(C)c(-c2ccc(C(=O)O)cc2)c1
Yield: 96.1 %

Procedure:
A mixture of 3-bromo-4-methyl-benzoic acid methyl ester (3 g), 4-hydroxycarbonyl-phenyl boronic acid (2.21 g), cesium carbonate (4.26 g) and tetrakis(triphenylphosphine)palladium0 (catalytic quantity), in 1:2 aqueous DME (75 ml) was heated to reflux for 18 h. The cooled reaction was then evaporated to dryness and the residue purified on silica gel. Elution with dichloromethane:ethanol:0.880 ammonia; 800:8:1 to 100:8:1 gave a yellow crystalline solid (3.4 g)
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:30]=[CH:29][C:13]([CH2:14][C@H:15]2[CH2:19][O:18]C(C)(C)[N:16]2C(OC(C)(C)C)=O)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CO.C(OCC)(=O)C>[NH2:16][C@H:15]([CH2:19][OH:18])[CH2:14][C:13]1[CH:12]=[CH:11][C:10]([NH:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2ccc(NC(=O)c3ccccc3)cc2)COC1(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: N[C@H](CO)Cc1ccc(NC(=O)c2ccccc2)cc1
Reaction time: 4 h
Yield: 55 %

Procedure:
To a solution of tert-butyl (S)-4-[4-(benzoylamino)benzyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (690 mg) in methanol (20 ml) was added 4N hydrogen chloride in ethyl acetate (5 ml) at room temperature, and the solution was stirred at the same temperature for 4 hours. The mixture was evaporated in vacuo, and the residue was partitioned between chloroform and saturated sodium bicarbonate solution. The organic layer was separated, washed with brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated to give (S)-N-[4-(2-amino-3-hydroxypropyl)phenyl]benzamide (250 mg) as a colorless solid.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][C:6]([C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=1)([CH:9]([CH3:11])[CH3:10])[C:7]#[N:8].[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([CH2:27][CH2:28]Cl)=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([CH2:27][CH2:28][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][C:6]([C:12]2[CH:13]=[C:14]([O:20][CH3:21])[CH:15]=[C:16]([O:18][CH3:19])[CH:17]=2)([CH:9]([CH3:11])[CH3:10])[C:7]#[N:8])=[CH:25][CH:24]=1
Reactant: ClCCc1ccc(Cl)cc1
Reactant: CNCCCC(C#N)(c1cc(OC)cc(OC)c1)C(C)C
Product: COc1cc(OC)cc(C(C#N)(CCCN(C)CCc2ccc(Cl)cc2)C(C)C)c1
Yield: 65 %

Procedure:
29.0 g (0.1 mole) of 5-methylamino-2-(3,5-dimethoxyphenyl)-2-isopropylvaleronitrile and 21.0 g (0.12 mole) of 4-chlorophenethyl chloride were reacted similarly to Example 5, and 27.9 g (60%) of base were isolated after chromatographic purification. The base was converted to the amidosulfonate. Mp. 122°-123° C.
Reaction SMILES: C([O:3][C:4](=[O:45])[CH2:5][CH2:6][N:7]1[CH2:13][CH2:12][CH2:11][N:10]([C:14](=[O:44])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C@@H:21]([N:29]3[CH2:34][C@@H:33]([CH3:35])[N:32]([CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH2:31][C@@H:30]3[CH3:43])[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=3)[CH:16]=2)[CH2:9][CH2:8]1)C.[OH-].[Na+].Cl>C1COCC1>[CH2:36]([N:32]1[C@H:33]([CH3:35])[CH2:34][N:29]([C@@H:21]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=2)[C:17]2[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=2)[C:14]([N:10]2[CH2:11][CH2:12][CH2:13][N:7]([CH2:6][CH2:5][C:4]([OH:45])=[O:3])[CH2:8][CH2:9]2)=[O:44])[C@@H:30]([CH3:43])[CH2:31]1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CCOC(=O)CCN1CCCN(C(=O)c2cccc([C@H](c3cccc(O)c3)N3C[C@@H](C)N(Cc4ccccc4)C[C@@H]3C)c2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@@H]1CN([C@@H](c2cccc(O)c2)c2cccc(C(=O)N3CCCN(CCC(=O)O)CC3)c2)[C@@H](C)CN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.8 %

Procedure:
To the compound of Example 12 (215 mg) in THF (4 mL) was added 1N NaOH solution (1 mL). The reaction was stirred at room temperature for overnight. The reaction solution was neutralized by the addition of 1 N HCl solution (1 mL). The mixture was put under rotary evaporator for the removal of THF. The remaining water layer was diluted by water (3 mL). The water layer was extracted by n-butanol (5 mL×3). The combined n-butanol layer was washed by water (5 mL×2) and concentrated to give crude product (200 mg), which was purified by silica gel chromatography conducted on CombiFlash™ Sq 16× (gradient: 100% CH2Cl2 to 30% MeOH in CH2Cl2) to give 3-(4-{3-[(R)-((2S,5R)-4-benzyl-2,5-dimethyl-piperazin-1-yl)-(3-hydroxy-phenyl)-methyl]-benzoyl }-[1,4]diazepan-1-yl)-propionic acid (133 mg; 65%). 1H NMR (300 MHz, DMSO-d6) δ 9.36 (s, 1H), 7.36-7.17 (m, 9H), 7.12 (dd, 1H, J=7.5, 7.5 Hz), 6.67 (m, 3H), 4.97 (s, 1H), 3.76 (m, 1H), 3.57 (m, 2H), 3.42-3.16 (m, 3H), 2.75 (m, 2H), 2.69-2.49 (m, 8H), 2.37 (m, 1H), 2.31 (m, 1H), 1.98 (m, 1H), 1.90 (m, 1H), 1.79 (m, 1H), 1.63 (m, 1H), 1.01 (m, 6H).