Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:13])[C@H:7]([CH2:9][CH2:10][CH2:11][CH3:12])[NH2:8])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][C@H:7]([C:6]([OH:13])=[O:5])[CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCC[C@H](N)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCC[C@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
23.5 mg of L-N-[(2R or S) -5-ethylthio-2-(1-naphthylmethyl)pentanoyl]norleucine tert-butyl ester was dissolved in 0.2 ml of dichloromethane, and 0.1 ml of trifluoro acetic acid was added thereto. The mixture was stirred at room temperature for four hours. Then, the reaction solution was concentrated under reduced pressure to obtain 20.7 mg of L-N-[(2R or S)-5-ethylthio-2-(1-naphthylmethyl)pentanoyl]norleucine as colorless solid.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:7]1[O:8][CH:9]=[CH:10][CH:11]=1)[C:4]([OH:6])=[O:5].[Cl:12][CH:13]([Cl:17])[C:14](Cl)=[O:15]>C(Cl)Cl>[Cl:12][CH:13]([Cl:17])[C:14]([O:1][N:2]=[C:3]([C:7]1[O:8][CH:9]=[CH:10][CH:11]=1)[C:4]([OH:6])=[O:5])=[O:15]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: O=C(O)C(=NO)c1ccco1
Solvent: ClCCl
Product: O=C(O)C(=NOC(=O)C(Cl)Cl)c1ccco1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 63 %

Procedure:
2-Hydroxyimino-2-(fur-2-yl)acetic acid (1.38 g) mixture was added portionwise to an ice cold solution of dichloroacetyl chloride (2 8 mls.) in dry methylene chloride (14 mls.). After 15 mins stirring a white precipitate was formed which was collected, washed successively with cold dry methylene chloride and petrol (b.p. 40-60°) and dried to yield 2-dichloroacetoxyimino-2-(fur-2-yl)acetic acid (syn-isomer) (1.5 g, 63%).
Reaction SMILES: [BH4-].[Na+].[C:3]([CH2:6][C:7]1([C:26](O)=[O:27])[O:11][N:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:13]=2)[CH2:8]1)(O)=[O:4].FB(F)F.[OH-].[Na+]>O1CCCC1.C(OC(=O)C)C.O>[CH:21]1([O:20][C:14]2[CH:13]=[C:12]([C:9]3[CH2:8][C:7]([CH2:6][CH2:3][OH:4])([CH2:26][OH:27])[O:11][N:10]=3)[CH:17]=[CH:16][C:15]=2[O:18][CH3:19])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: COc1ccc(C2=NOC(CC(=O)O)(C(=O)O)C2)cc1OC1CCCC1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(C2=NOC(CO)(CCO)C2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of sodium borohydride (3 eq) in tetrahydrofuran, was added a solution of the compound obtained from step d above (1 eq) in tetrahydrofuran. To the resulting reaction mixture was added ethereal solution of trifluoroborane (3 eq) at 0° C. and stirred for 14-16 hours at ambient temperature. Sodium hydroxide (1N) solution was added at 0° C. and stirred for 1 hour. The reaction mixture was diluted with ethylacetate and water. The combined extract was washed with saturated solution of sodium chloride and concentrated under reduced pressure. The residue thus obtained was purified by column chromatography to furnish the title compound.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[N:8][CH:9]=1.Cl>[OH-].[Na+]>[Br:1][C:7]1[C:6]([OH:10])=[CH:5][C:4]([Cl:3])=[CH:9][N:8]=1
Reactant: Oc1cncc(Cl)c1
Reactant: BrBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Oc1cc(Cl)cnc1Br
Yield: 30.4 %

Procedure:
A solution of Bromine (8.82 g) in 10% of aqueous sodium hydroxide (53 mL) was added drop-wise to a solution of 5-chloropyridin-3-ol (7.2 g) with stirring in 10% aqueous sodium hydroxide (50 mL). After addition was completed, the mixture was cooled with ice-bath and neutralized with concentrated HCl. The product was precipitated, collected by filtration and washed with water to provide 3.5 g of 2-bromo-5-chloropyridin-3-ol was obtained. LCMS [M+H]+: 209.13.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([O:32][CH3:33])=[C:6]2[C:10]([C:11](=[O:31])[C:12]([N:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:24]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[N:23]=[N:22][N:21]=4)[CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:8][C:7]=12.C([Sn](CCCC)(CCCC)[C:39]1[CH:43]=[C:42]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[NH:41][N:40]=1)CCC>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:33][O:32][C:5]1[CH:4]=[N:3][C:2]([C:39]2[CH:43]=[C:42]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[NH:41][N:40]=2)=[C:7]2[NH:8][CH:9]=[C:10]([C:11](=[O:31])[C:12](=[O:13])[N:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:24]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:23]=[N:22][N:21]=4)[CH2:16][CH2:15]3)[C:6]=12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C(=O)OCC)[nH]n1
Reactant: COc1cnc(Cl)c2[nH]cc(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccc4)CC3)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(-c2ncc(OC)c3c(C(=O)C(=O)N4CCN(c5nnnn5-c5ccccc5)CC4)c[nH]c23)n[nH]1
Temperature: 120 °C

Procedure:
To a suspension of 1-(7-chloro-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione (2.50 g, 5.35 mmol) in 1,4-dioxane (60 mL) in a sealable flask was added ethyl 3-(tributylstannyl)-1H-pyrazole-5-carboxylate (2.30 g, 5.36 mmol) followed by tetrakis(triphenylphosphine)palladium(0) (1.86 g, 1.61 mmol). The mixture was flushed with N2, the flask was sealed, and the mixture was heated to 120° C. for 16 hr. The mixture was cooled to rt and diluted with MeOH (50 mL). The remaining solids were removed by filtering the mixture through a pad of celite and were washed with MeOH (25 mL). The remaining solvent was concentrated under reduced pressure. The resulting residue was dissolved in MeOH, and loaded onto a silica gel. After the silica was dry, a column was run using the biotage system with a 0 to 10% MeOH in CH2Cl2 gradient. After concentrating the desired fractions, 1.05 g of ethyl 3-(4-methoxy-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-pyrazole-5-carboxylate was recovered as an orange solid. LCMS: m/e 571.2 (M+H)+, ret time 2.01 min (method 2). 1H NMR (500 MHz, DMSO-D6) δ ppm 12.39-12.72 (m, 1H) 8.37 (s, 1H) 8.11 (s, 1H) 7.52-7.76 (m, 6H) 4.68-4.85 (m, 1H) 4.38 (q, J=7.02 Hz, 2H) 3.98-4.06 (m, 3H) 3.67-3.73 (m, 2H) 3.43-3.49 (m, 2H) 3.28-3.36 (m, 2H) 3.14-3.22 (m, 2H) 1.36 (t, J=7.17 Hz, 3H).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH:4]([CH2:7][CH:8]=O)[CH2:3]1.Cl.[CH3:11]N(C)C=O>[Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C)C=CC=CC=1>[CH2:7]([CH:4]1[CH2:5][CH2:6][CH:2]([OH:1])[CH2:3]1)[CH:8]=[CH2:11]
Reactant: CN(C)C=O
Reactant: O=CCC1CCC(O)C1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Br-]
Product: C=CCC1CCC(O)C1
Temperature: -60 °C
Reaction time: 2 h

Procedure:
A solution of 5 g of potassium tert.-butylate in 80 ml of dimethylformamide was added at -60° C. over 90 minutes to a solution of 5 g of 3-hydroxy-cyclopentyl-acetaldehyde, 15 g of triphenyl methyl phosphonium bromide and 100 ml of dimethylformamide and the resulting suspension was stirred at -60° C. for 2 hours after which the temperature was allowed to rise to 20° C. The mixture was poured into 2N hydrochloric acid solution and the mixture was extracted with isopropyl ether. The organic phase was dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with a 7-3 cyclohexane-ethyl acetate mixture to obtain 1.7 g of 3-(2-propenyl)-cyclopentanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:22])[CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl.Cl[CH2:27][CH2:28][N:29]([CH3:31])[CH3:30]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:22][CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])[CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:13][CH2:14]2)=[CH:6][CH:7]=1
Reactant: CN(C)CCCl
Reactant: CC(C)(C)OC(=O)N1CCC(C(O)c2ccc(Cl)cc2)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)CCOC(c1ccc(Cl)cc1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of tert-butyl 4-((4-chlorophenyl)(hydroxyl)methyl)piperidine-1-carboxylate (1.25 g, 3.84 mmol) in DMF (50 mL) was added sodium hydride 60% w/w dispersion on mineral oil (384 mg, 9.59 mmol). The reaction mixture was stirred for 10 minutes at room temperature then 2-chloro-N,N-dimethylethanamine hydrochloride (608 mg, 4.22 mmol) was added. The reaction mixture was stirred at 70° C. for 12 h. LC-MS of the reaction mixture showed no more starting material. The reaction mixture was cooled to room temperature and was diluted with EtOAc (50 mL) and washed with 10% LiCl in water (2×50 mL) followed by water (50 mL) and brine (50 mL). The organic layer was dried over Na2SO4, filtered and concentrated to yield tert-butyl 4-((4-chlorophenyl)(2-(dimethylamino)ethoxy)methyl)piperidine-1-carboxylate that was purified by reversed phase HPLC followed by separation on enantiomers by SFC. (253 mg and 246 mg, 33%) m/z: 397 (MH+)
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][N:16]([CH3:26])[CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O>[CH3:26][N:16]([CH3:15])[CH2:17][CH2:18][CH2:19][N:20]1[CH2:21][CH2:22][N:23]([CH:11]2[CH2:12][CH2:13][N:8]([CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:9][CH2:10]2)[CH2:24][CH2:25]1
Reactant: CN(C)CCCN1CCNCC1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CN(C)CCCN1CCN(C2CCN(Cc3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 27.8 g (0.15 mol) of 1-(phenylmethyl)-4-piperidinone and 26.5 g (0.15 mol) of 1-(3-dimethylaminopropyl)-piperazine in 500 ml of tetrahydrofuran were added 200 mg of p-toluenesulphonic acid and 13.5 g (0.225 mol) of glacial acetic acid, followed by 47.7 g (0.225 mol) of sodium triacetoxyborohydride, in small batches, and the mixture was stirred overnight at ambient temperature. 100 ml of water were added dropwise while stirring was continued and after 30 minutes sufficient potassium carbonate was added to produce a precipitate that could be filtered off. It was filtered and the filter cake was washed thoroughly with THF and diethylether in succession. The combined filtrates were concentrated by evaporation in vacuo, the residue was purified by column chromatography on 400 g of aluminium oxide (Al2O3—ICN, activity stage 3) using EE/MeOH (95/5 v/v) as eluant. A colourless oil, Rf 0.33 (El O), was obtained in a yield of 35.0 g (68% of theoretical). MS: ESI: (M+H)+=345
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:13].[F:14][C:15]1[CH:16]=[C:17]([CH2:22][C:23](O)=[O:24])[CH:18]=[C:19]([F:21])[CH:20]=1>>[Cl:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:13])[N:2]([NH:1][C:23](=[O:24])[CH2:22][C:17]2[CH:16]=[C:15]([F:14])[CH:20]=[C:19]([F:21])[CH:18]=2)[N:11]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: Nn1nc(Cl)c2ccccc2c1=O
Product: O=C(Cc1cc(F)cc(F)c1)Nn1nc(Cl)c2ccccc2c1=O

Procedure:
The product from Example 19A and 2-(3,5-difluorophenyl)acetic acid were processed using a method similar to that described in Example 17C to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 3.77 (s, 2H) 7.06-7.22 (m, 3H) 7.98-8.20 (m, 3H) 8.37 (d, J=7.32 Hz, 1H) 11.82 (s, 1H); MS (ESI) m/z 350 (M+H)+.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][NH:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:14][CH2:15][O:16][C:17]1[CH:18]=[C:19]([CH:25]=[CH:26][CH:27]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(#N)C>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:14][CH2:15][O:16][C:17]1[CH:18]=[C:19]([CH:25]=[CH:26][CH:27]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: C[C@@H]1CCCN1
Reactant: CCOC(=O)c1cccc(OCCBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cccc(OCCN2CCC[C@H]2C)c1
Temperature: 25 °C

Procedure:
To a suspension of (2R)-2-methylpyrrolidine (300 mg, 3.52 mmol) and potassium carbonate (974 mg, 7.05 mmol) in Acetonitrile (20 mL) stirred at room temperature was added ethyl 3-[(2-bromoethyl)oxy]benzoate D46 (962 mg). The reaction mixture was stirred at 80° C. for 24 hours. After cooled to room temperature the mixture was filtrated and the filtrate was concentrated. The crude product was added to a silica gel column and was eluted with Hexane/EtOAc/TEA in ratio 50/50/0.5. The relevant fractions were isolated and solvent evaporated to afford the title compound D50 in 900 mg as a yellow oil. LCMS Retention time=1.09 mins, [M+H]+278 (5 min run)
Reaction SMILES: [F:1][C:2]1([C:6]2[C:7]([O:15][C@@H:16]([CH3:21])[C:17]([F:20])([F:19])[F:18])=[CH:8][C:9]([C:12](O)=[O:13])=[N:10][CH:11]=2)[CH2:5][O:4][CH2:3]1.[NH2:22][C@@H:23]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:24]([NH:26][CH3:27])=[O:25]>>[CH3:29][C:28]([CH3:31])([CH3:30])[C@H:23]([NH:22][C:12]([C:9]1[CH:8]=[C:7]([O:15][C@@H:16]([CH3:21])[C:17]([F:19])([F:20])[F:18])[C:6]([C:2]2([F:1])[CH2:5][O:4][CH2:3]2)=[CH:11][N:10]=1)=[O:13])[C:24]([NH:26][CH3:27])=[O:25]
Reactant: C[C@H](Oc1cc(C(=O)O)ncc1C1(F)COC1)C(F)(F)F
Reactant: CNC(=O)[C@@H](N)C(C)(C)C
Product: CNC(=O)[C@@H](NC(=O)c1cc(O[C@@H](C)C(F)(F)F)c(C2(F)COC2)cn1)C(C)(C)C

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-(3-fluorooxetan-3-yl)-4-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine-2-carboxylic acid (example 142b) and (S)-2-Amino-3,3,N-trimethyl-butyramide (CAN 89226-12-0) as starting materials and isolated (40 mg, 57%); MS (ESI, m/z): 436.6 (M+H+).
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=3)[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:11]2=[O:28])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:29]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)([OH:31])=[O:30].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:35]4[CH:36]=[CH:37][C:32]([C:29]([OH:31])=[O:30])=[CH:33][CH:34]=4)=[CH:17][CH:16]=3)[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:11]2=[O:28])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1N(c2ccccc2)C(c2ccc(Br)cc2)CN1S(=O)(=O)c1ccccc1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1ccc(-c2ccc(C3CN(S(=O)(=O)c4ccccc4)C(=O)N3c3ccccc3)cc2)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 33 %

Procedure:
To a stirred solution of 1-benzenesulfonyl-4-(4-bromo-phenyl)-3-phenyl-imidazolidin-2-one (100 mg) and 4-carboxyphenylboronic acid (57 mg) in dioxane (0.6 mL) and water (0.4 mL) under argon were added a 2 M aqueous sodium carbonate solution (0.33 mL) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloromethane adduct (9 mg). The mixture was stirred at 80° C. for 3 h. After cooling to room temperature, the mixture was filtered. The filtrate was diluted with ethyl acetate and washed with 10% aqueous KHSO4 solution. The org. phase was dried (MgSO4), filtered and concentrated. The product was purified using column chromatography (SiO2, dichloromethane/methanol 1:0=>4:1) to give 4′-(1-benzenesulfonyl-2-oxo-3-phenyl-imidazolidin-4-yl)-biphenyl-4-carboxylic acid (36 mg) as an off-white solid. MS: 497.1 ([M−H]−)
Reaction SMILES: [O:1]=[S:2]1(=[O:20])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:12]=[CH:11][C:10]([CH:13]([O:18][CH3:19])[C:14]([O:16]C)=[O:15])=[CH:9][CH:8]=1.[OH-].[Na+]>CO>[O:1]=[S:2]1(=[O:20])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:8]=[CH:9][C:10]([CH:13]([O:18][CH3:19])[C:14]([OH:16])=[O:15])=[CH:11][CH:12]=1
Reactant: COC(=O)C(OC)c1ccc(N2CCCS2(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(C(=O)O)c1ccc(N2CCCS2(=O)=O)cc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 82.8 %

Procedure:
To a solution of methyl 2-(4-(1,1-dioxidoisothiazolidin-2-yl)phenyl)-2-methoxyacetate (0.48 g, 1.6 mmol) in MeOH (21 mL) was added 1 M NaOH (7 mL, 7 mmol) slowly. After stirring at room temperature for 23 hrs, the volatiles were removed in vacuo and the residue was dissolved in H2O. EtOAc was added to the aqueous solution and saturated aqueous NH4Cl and 1 M HCl were added slowly until the pH ˜3. The mixture was extracted with EtOAc then the aqueous layer was acidified to pH 1 and extracted with EtOAc again. The combined organics were washed with H2O and brine, dried over Na2SO4 and concentrated in vacuo to give 2-(4-(1,1-dioxidoisothiazolidin-2-yl)phenyl)-2-methoxyacetic acid as a yellow foam (0.378 g, 82% yield). The product was used in the next synthetic step without further purification.
Reaction SMILES: [N:1]#[C:2][NH2:3].CC(C)([O-])C.[K+].[F:10][C:11]1[CH:12]=[C:13]([CH:26]=[CH:27][C:28]=1[S:29][CH3:30])[CH2:14][N:15]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=[O:25].BrN1C(=O)CCC1=O>CO>[F:10][C:11]1[CH:12]=[C:13]([CH:26]=[CH:27][C:28]=1[S:29]([CH3:30])=[N:1][C:2]#[N:3])[CH2:14][N:15]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=[O:25]
Reactant: N#CN
Reactant: CSc1ccc(CN2C(=O)c3ccccc3C2=O)cc1F
Agent: CC(C)(C)[O-]
Agent: O=C1CCC(=O)N1Br
Agent: [K+]
Solvent: CO
Product: CS(=NC#N)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1F
Temperature: 25 °C

Procedure:
Cyanamide (350 mg, 8.20 mmol) and potassium tert-butoxide (860 mg, 7.60 mmol) are added to a solution of 2-(3-fluoro-4-methylsulfanyl-benzyl)-isoindole-1,3-dione (preparation 15a, 2.00 g, 6.31 mmol) in methanol (50 mL). N-Bromosuccinimide (1.70 g, 9.50 mmol) is added and the mixture is stirred at room temperature over night. All volatiles are removed under reduced pressure, and the residue is treated with dichloromethane (20 mL). The mixture is washed with saturated aqueous sodium chloride solution, dried over Na2SO4 and concentrated under reduced pressure. The residue is directly used in the next step without further purification. Yield: 1.61 g (60% of theory); ESI mass spectrum: [M+H]+=342; r.t. HPLC: 0.76 min (5-95AB).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[O:4][N:3]=1.O=S(Cl)Cl.[CH3:15]O>>[CH3:1][C:2]1[CH:6]=[C:5]([CH2:7][C:8]([O:10][CH3:15])=[O:9])[O:4][N:3]=1
Reactant: CO
Reactant: Cc1cc(CC(=O)O)on1
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1cc(C)no1
Temperature: 50 °C
Reaction time: 4 h
Yield: 92 %

Procedure:
To a 50 mL RB flask fitted with magnetic stirrer was charged with 10 mL of methanol. To the stirred solvent was added (3-methyl-1,2-oxazol-5-yl)acetic acid (1 g, 7 mmol), was added drop wise SOCl2 (1.25 g, 10.5 mmol) to the reaction mixture at 0° C. and stirred at 50° C. for 4 h. After completion of the reaction, the reaction mixture was concentrated to distill off the solvent; water (25 mL) was added and extracted with ethyl acetate (25 mL). The organic layer was washed with saturated NaHCO3 solution (10 mL) and brine solution (10 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The product was obtained as brown liquid (1 g, yield: 92%). 1H NMR (300 MHz, CDCl3): δ 6.03 (s, 1H), 3.73 (d, 2H), 3.69 (s, 3H), 2.23 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1[C:14]2[CH:15]=[C:16]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:17]=[C:18]([C:19]([O:21]C)=[O:20])[C:13]=2[N:12]=[C:11]1[CH3:29].[Li+].[OH-]>C1COCC1>[F:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1[C:14]2[CH:15]=[C:16]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:17]=[C:18]([C:19]([OH:21])=[O:20])[C:13]=2[N:12]=[C:11]1[CH3:29]
Reactant: COC(=O)c1cc(N2CCOCC2)cc2c1nc(C)n2Cc1cccc(C)c1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cccc(Cn2c(C)nc3c(C(=O)O)cc(N4CCOCC4)cc32)c1F
Temperature: 45 °C
Reaction time: 16 h
Yield: 70 %

Procedure:
A mixture of methyl 1-[(2-fluoro-3-methylphenyl)methyl]-2-methyl-6-(4-morpholinyl)-1H-benzimidazole-4-carboxylate, prepared as described in Example 28 (240 mg, 0.6 mmol) and 2 N LiOH (1.8 mL, 3.6 mmol) in THF (20 mL), was stirred at 45° C. for 16 h. The solution was filtered; the filter cake was then dissolved in water (20 mL) and added into formic acid to adjust the pH of the solution to 3-4. Then a filtration was performed to provide the product (160 mg, 70%), as a white solid. 1H NMR (300 MJz, DMSO-d6): δ ppm 2.24 (d, 3H, J=1.8 Hz), 2.50 (s, 3H), 3.12 (t, 4H, J=4.8 Hz), 3.75 (t, 4H, J=4.8 Hz), 5.57 (s, 2H), 6.74 (t, 1H, J=7.5 Hz), 7.03 (t, 1H, J=7.5 Hz), 7.24 (t, 1H, J=7.5 Hz), 7.40 (d, 1H, J=2.4 Hz), 7.42 (d, 1H, J=2.4 Hz); LC-MS: m/e=384 [M+1]+
Reaction SMILES: [NH2:1][C@H:2]([CH3:35])[C:3]([C:20]1[CH:25]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:23]=[CH:22][C:21]=1[O:30][CH2:31][CH2:32][CH2:33][CH3:34])([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[O:15][CH2:16][CH2:17][CH2:18][CH3:19])[OH:4].[CH:36](=O)[C:37]1[C:38](=[CH:40][CH:41]=[CH:42][CH:43]=1)[OH:39]>C(O)C.C1(C)C=CC=CC=1>[CH:36](=[N:1][C@H:2]([CH3:35])[C:3]([C:5]1[CH:10]=[C:9]([C:11]([CH3:13])([CH3:12])[CH3:14])[CH:8]=[CH:7][C:6]=1[O:15][CH2:16][CH2:17][CH2:18][CH3:19])([C:20]1[CH:25]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:23]=[CH:22][C:21]=1[O:30][CH2:31][CH2:32][CH2:33][CH3:34])[OH:4])[C:37]1[C:38](=[CH:40][CH:41]=[CH:42][CH:43]=1)[OH:39]
Reactant: CCCCOc1ccc(C(C)(C)C)cc1C(O)(c1cc(C(C)(C)C)ccc1OCCCC)[C@@H](C)N
Reactant: O=Cc1ccccc1O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCCOc1ccc(C(C)(C)C)cc1C(O)(c1cc(C(C)(C)C)ccc1OCCCC)[C@@H](C)N=Cc1ccccc1O
Yield: 99.5 %

Procedure:
0.968 g (2.0 mmol) of (R)-2-amino-1,1-di(2-butoxy-5-t-butylphenyl)-propanol and 0.244 g (2.0 mmol) of salicylaldehyde were dissolved in 20 ml of ethanol and 20 ml of toluene, the solution was heated at reflux for 1 hour. The solvent was distilled off from the reaction mixture and dried to obtain 1.17 g of (R)-N-salicyliden-2-amino-1,1-di(2-butoxy-5-t-butylphenyl)-propanol as a yellow solid.
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[O:9][C:8]([CH3:11])([CH3:10])[O:7][C@@H:6]([CH2:12][C:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[O:14])[CH2:5]1)#[N:2].N.[H][H]>CO.[Ni]>[NH2:2][CH2:1][CH2:3][C@H:4]1[O:9][C:8]([CH3:11])([CH3:10])[O:7][C@@H:6]([CH2:12][C:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[O:14])[CH2:5]1
Reactant: CCN(CC)C(=O)C[C@H]1C[C@@H](CC#N)OC(C)(C)O1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Product: CCN(CC)C(=O)C[C@H]1C[C@@H](CCN)OC(C)(C)O1
Temperature: 20 °C
Reaction time: 3 h
Yield: 91.3 %

Procedure:
A solution of (4R-cis)-6-(cyanomethyl)-N,N-diethyl-2,2-dimethyl-1,3-dioxane-4-acetamide (10.0 g, 0.037 mol) in methanol (220 mL) containing anhydrous ammonia (3.25 g) is reacted with hydrogen gas in a Parr shaker at 30° C. in a presence of a slurry of Raney nickel A-7000 (4.2 g). After 3 hours, uptake of hydrogen has ceased, the mixture is cooled to 20° C., the atmosphere is vented and exchanged for nitrogen, the slurry is filtered through celite, and concentrated at reduced pressure to give 9.2 g of (4R-cis)-6-(2-aminoethyl)-N,N-diethyl-2,2-dimethyl-1,3-dioxane-4-acetamide as an oil.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[CH:31][C:32](O)=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].CC(CC)=[O:37].C1(C)C(C)=CC=CC=1>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[CH:31][CH:32]=[C:33]([OH:37])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCC(C)=O
Reactant: CCCCc1nc2cc(O)ccc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: Cc1ccccc1C
Product: CCCCc1nc2c(O)cccc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1

Procedure:
tert.butyl 4'-[(2-n-butyl-5-hydroxy-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate oil, Rf value: 0.60 (Silica gel: methylethylketone/xylene=1:2)