Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]2[CH2:8][CH2:9][O:10][C:6]=2[C:5]([NH2:11])=[CH:4][C:3]=1[CH3:12].[N:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C.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>[CH3:12][C:3]1[CH:4]=[C:5]([NH2:11])[C:6]2[O:10][CH2:9][CH2:8][C:7]=2[C:2]=1[C:16]1[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=1
Reactant: Cc1cc(N)c2c(c1Br)CCO2
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(N)c2c(c1-c1ccncc1)CCO2
Temperature: 135 °C
Reaction time: 1 h

Procedure:
A mixture of 4-bromo-5-methyl-2,3-dihydrobenzofuran-7-amine (1e) (0.80 g, 3.5 mmol), pyridin-4-ylboronic acid (0.86 g, 7 mmol), Cs2CO3 (2.84 g, 8.7 mmol), Pd(PPh3)4 (0.40 g, 0.346 mmol) and water (7 mL) in DMF (35 mL) was stirred at 135° C., under N2 for 1 h. It was cooled to ambient temperature, poured into water (50 mL), extracted with EtOAc (150 mL), washed with water, brine, dried and concentrated. The residue was purified by column chromatography on silica gel eluting with hexanes/EtOAc (20:1 to 5:1 to 1:1) to give the title compound (1f) as a yellow solid. MS-ESI (m/z): 227 (M+1)+.
Reaction SMILES: [H-].[Na+].O[C@H:4]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:5][C:6]([O:8][CH3:9])=[O:7].BrC(CCCCCC)C(Cl)=O>O1CCCC1>[CH3:9][O:8][C:6](=[O:7])[CH2:5][CH2:4][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCC[C@@H](O)CC(=O)OC
Agent: CCCCCCC(Br)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCC(=O)OC
Reaction time: 0.42 h

Procedure:
98 mg (3.3 mmol) Sodium hydride (80% in mineral oil) was added to a solution of 764 mg (2.96 mmol) methyl(R)-3-hydroxytetradecanoate in 20.0 mL tetrahydrofuran. After 25 minutes, a solution of 732 mg (3.03 mmol) 2-bromooctanoyl chloride in 10.0 mL tetrahydrofuran was added dropwise via syringe to the cloudy off-white mixture. After 10 minutes at 0° C., the reaction flask was removed from the cold bath for 24 hours. The mixture was poured into 100 mL 10% NaHCO3 and extraction with ether (3×50 mL) was performed. Drying over MgSO4 and removal of the solvent by rotary evaporation gave yellow oil. Purification by flash chromatography (3×24 cm column, 50% CH2Cl2 /hexane) gave 407 mg (30% yield based on methyl (R)-3-hydroxytetradecanoate) (R)-3-[2-bromo-1-oxooctyl)oxy]tetradecanoic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[OH:12][C:13]1[C:14]([O:21][CH3:22])=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=[O:17].C(=O)([O-])[O-].[Cs+].[Cs+].[OH-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:12][C:13]2[CH:20]=[CH:19][CH:18]=[C:15]([CH:16]=[O:17])[C:14]=2[O:21][CH3:22])[CH:3]=1
Reactant: N#Cc1cc(F)c(Cl)cc1F
Reactant: COc1c(O)cccc1C=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1c(C=O)cccc1Oc1cc(Cl)c(F)cc1C#N
Yield: 41.5 %

Procedure:
4-Chloro-2,5-difluorobenzonitrile (0.45 g, 2.6 mmol), 3-hydroxy-2-methoxybenzaldehyde (0.39 g, 2.6 mmol) and cesium carbonate (0.84 g, 2.6 mmol) were heated with stirring in dry DMF (5 mL) at 50° C. for 18 h. The reaction mixture was cooled, poured into 0.1N sodium hydroxide solution and extracted with ethyl acetate. The ethyl acetate layer was separated, washed with 0.1N sodium hydroxide solution (1×), water (2×), brine (1×), and dried over MgSO4. After filtration, the solvent was removed in vacuo, and purified by chromatography to yield 4-chloro-5-fluoro-2-(3-formyl-2-methoxyphenoxy)benzonitrile (0.33 g, 42%) as a pale yellow solid.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([O:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22](O)[CH2:23][CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:18][CH:17]=2)[CH:5]=[CH:4][C:3]=1[C:33](=[O:35])[CH3:34].[SH:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40].CCOC(C)=O.[OH-].[Na+:49]>ClCCCl.CC(O)=O.CCO>[Na+:49].[C:33]([C:3]1[CH:4]=[CH:5][C:6]([O:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]([S:36][CH2:37][CH2:38][C:39]([O-:41])=[O:40])[CH2:23][CH2:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[CH:18][CH:17]=2)=[C:7]([CH2:8][CH2:9][CH3:10])[C:2]=1[OH:1])(=[O:35])[CH3:34]
Reactant: CCCc1c(OCCCOc2ccc(C(O)CCCc3ccccc3)cc2)ccc(C(C)=O)c1O
Reactant: O=C(O)CCS
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCCc1c(OCCCOc2ccc(C(CCCc3ccccc3)SCCC(=O)[O-])cc2)ccc(C(C)=O)c1O
Reaction time: 1 h

Procedure:
To a 0° C. solution of the alcohol from Step 2 (275 mg) and 3-mercaptopropionic acid (64 mg) in 1,2-dichloroethane (10 mL) was added BF3 ·OEt2 (355 mg). After 1 hr. at 0° C., the reaction mixture was poured on 25% aqueous NH4OAc containing AcOH (3 drops) and EtOAc. The organic layer was separated and the aqueous further extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine, dried with MgSO4 and solvents were removed under reduced pressure to yield an oil which was spectroscopically pure. The oil was dissolved in EtOH and 2N NaOH (1 equivalent) was added. Ethanol was removed under reduced pressure and the residue was dissolved in H2 0 and freeze dried to yield the title compound as a hemihydrate.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][C:13]([CH2:15][CH2:16][C:17]([O:19]CC)=[O:18])=[N:12][N:11]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.C(O)C.[OH-].[Na+].Cl>O1CCCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][C:13]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[N:12][N:11]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: CCOC(=O)CCc1nnc(-c2ccc3c(c2)CCO3)o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)CCc1nnc(-c2ccc3c(c2)CCO3)o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.3 %

Procedure:
To a mixture of ethyl 3-[5-(2,3-dihydro-1-benzofuran-5-yl)-1,3,4-oxadiazol-2-yl]propionate (5.20 g, 18.04 mmol), ethanol (30 mL) and tetrahydrofuran (15 mL) was added 1 M aqueous sodium hydroxide solution (20 mL), and the resulting mixture was stirred at room temperature for 3 hr. The reaction mixture was neutralized with 5 M hydrochloric acid, and extracted with ethyl acetate/tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from methanol/diethyl ether to give the title compound (3.63 g, yield 77%) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[CH:6][N:5]=2.ClC1C=CC=C(C(OO)=[O:19])C=1.[OH-].[Na+]>C(Cl)Cl>[CH3:1][C:2]1[S:3][C:4]2[C:9]([N+:10]=1[O-:19])=[CH:8][CH:7]=[CH:6][N:5]=2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1nc2cccnc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1sc2ncccc2[n+]1[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product of Step 2 (8.00 g) in 400 mL of CH2Cl2 was added m-chloroperbenzoic acid (26.0 g) and the mixture was stirred at room temperature overnight. NaOH 0.5M was added and the product was extracted in CH2Cl2 (6×), dried over Na2SO4, and purified by flash chromatography on silica with acetone: toluene 70:30 and acetone: toluene: methanol 40:40:20.
Reaction SMILES: I[C:2]1[C:7]2[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:9]=[N:10][C:6]=2[CH:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.C(B(CC)[C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)C.C(=O)(O)[O-].[Na+].C(O)C>O.C(COC)OC.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>[C:11]1([N:8]2[C:7]3[C:2]([C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)=[CH:3][C:4]([C:17]([F:20])([F:19])[F:18])=[CH:5][C:6]=3[N:10]=[CH:9]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: FC(F)(F)c1cc(I)c2c(c1)ncn2-c1ccccc1
Reactant: CCB(CC)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: FC(F)(F)c1cc(-c2cccnc2)c2c(c1)ncn2-c1ccccc1

Procedure:
A mixture of 7-iodo-1-phenyl-5-trifluoromethylbenzimidazole (370 mg, 1 mmol), diethyl 3-pyridylborane (220 mg, 1.5 mmol), sodium bicarbonate (420 mg, 5 mmol) and tetrakis(triphenylphosphine)palladium(0) (29 mg, 0.025 mmol) in a mixture of water (5 ml) and dimethoxyethane (10 ml) was stirred at reflux overnight The cooled reaction mixture was partitioned between ethyl acetate and water, and the organic extract was purified by column chromatography on silica gel eluting with a mixture of dichloromethane and acetone (9:1, v/v). The product was isolated by removal of solvent from appropriate eluate fractions followed by trituration of the residue with a mixture of water and ethanol. Yield: 130 mg (38%), m/z, 340.1 (M+H)+.
Reaction SMILES: [N:1]([C@@H:4]([CH:44]1[CH2:46][CH2:45]1)[C@H:5]([OH:43])[C@@H:6]([NH:14][C:15](=[O:42])[C@@H:16]([NH:23][C:24](=[O:41])[C@@H:25]([CH2:33][S:34]([C:37]([CH3:40])([CH3:39])[CH3:38])(=[O:36])=[O:35])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:17][C:18]1[N:19]=[CH:20][NH:21][CH:22]=1)[CH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[N+]=[N-]>CO.[Pd]>[NH2:1][C@@H:4]([CH:44]1[CH2:46][CH2:45]1)[C@@H:5]([OH:43])[C@@H:6]([NH:14][C:15](=[O:42])[C@@H:16]([NH:23][C:24](=[O:41])[C@@H:25]([CH2:33][S:34]([C:37]([CH3:40])([CH3:39])[CH3:38])(=[O:36])=[O:35])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:17][C:18]1[N:19]=[CH:20][NH:21][CH:22]=1)[CH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)S(=O)(=O)C[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](N=[N+]=[N-])C1CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)S(=O)(=O)C[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@H](O)[C@@H](N)C1CC1
Reaction time: 4 h
Yield: 61.7 %

Procedure:
A suspension of 60 mg (0.09 mmol) of (S)-N-[(1S,2R,3S)-3-azido-1-(cyclohexylmethyl)-3-cyclopropyl-2-hydroxypropyl]-α-[(S)-α-[(tert-butylsulphonyl)methyl]hydrocinnamamido]imidazole-4-propionamide and 20 mg of palladium/carbon (5%) in 15 ml of methanol is hydrogenated at room temperature for 4 hours. After filtering off the catalyst the solvent is evaporated under reduced pressure. For purification, the crude product (40 mg) is chromatographed on 10 g of silica gel using a 80:10:1 mixture of methylene chloride, methanol and ammonia as the eluent. There are obtained 35 mg of (S)-N-[(1S,2R,3S)-3-amino-1-(cyclohexylmethyl)-3-cyclopropyl-2-hydroxypropyl]-α-[(S)-α-[(tert-butylsulphonyl)methyl]hydrocinnamamido]imidazole-4-propionamide as a colourless solid; MS: 630 (M+H)+.
Reaction SMILES: [CH3:1][C@H:2]1[N:7]([CH2:8][C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[N:12]=[N:11][N:10]=2)[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.Cl.O1CCOCC1>CO>[CH3:1][C@@H:2]1[CH2:3][NH:4][CH2:5][CH2:6][N:7]1[CH2:8][C:9]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=2)[N:12]=[N:11][N:10]=1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1Cc1nnnn1-c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: C[C@@H]1CNCCN1Cc1nnnn1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
To a solution of 1,1-dimethylethyl (3R)-3-methyl-4-({1-[3-(trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl)-1-piperazinecarboxylate (527 mg, 1.236 mmol, Intermediate 13) in methanol was added 4M hydrogen chloride in 1,4-dioxane (7 mL, 28.0 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo to give white crystals. The crude product was poured onto a 5 g SCX cartridge, washed with methanol (2 column volumes) and eluted with ammonia in methanol (2 column volumes). The ammonia in methanol fractions were concentrated and dried in vacuo to yield the title compound as a yellow oil (389 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH3:27])=[C:7]2[N:12]([CH:13]=1)[N:11]=[CH:10][N:9]=[C:8]2[NH:14][C:15]1[CH:20]=[C:19]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH:18]=[CH:17][C:16]=1[CH3:26])=[O:4].O>N1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:6]([CH3:27])=[C:7]2[N:12]([CH:13]=1)[N:11]=[CH:10][N:9]=[C:8]2[NH:14][C:15]1[CH:16]=[CH:26][C:18]([CH3:17])=[C:19]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH:20]=1)=[O:4]
Reactant: COC(=O)c1cn2ncnc(Nc3cc(NS(C)(=O)=O)ccc3C)c2c1C
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)c1cn2ncnc(Nc3ccc(C)c(NS(C)(=O)=O)c3)c2c1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 34.7 %

Procedure:
To a solution of Example 53 (16 mg, 51 μmol) in pyridine (1 mL) at 0° C. was added 4-methyl-3-[(methylsulfonyl)aniline (4.4 μL, 87 μmol). The reaction mixture was stirred for 1 hr at 0° C. and then warmed to 25° C. and stirred for 4 hrs. Water (5 mL) was added and the mixture was extracted with ethyl acetate (3×5 mL). The combined organic extracts were washed with water (10 mL) and brine (10 mL) and dried (Na2SO4). The crude material was purified by chromatography on silica gel eluting with 2% methanol in chloroform to provide 6.9 mg (30%) of solid. MS: [M+H]+=390.2; 1H NMR (CDCl3): δ 7.93 (s, 1H), 7.86 (s, 1H), 7.77 (s, 1H), 7.35 (d, J=8.2 Hz, 1H), 7.27 (s, 1H), 7.18 (d, J=8.2 Hz, 1H), 6.25 (s, 1H), 3.82 (s, 3H), 3.03 (s, 3H), 2.86 (s, 3H), 2.24 (s, 3H)
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:6][CH2:7][C:8](=O)[CH2:9][CH3:10]>CCCCC.[Ti](Cl)(Cl)(Cl)Cl>[CH2:9]([C:8]([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[CH:7][CH3:6])[CH3:10]
Reactant: CCC(=O)CC
Reactant: C1CCNC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCCCC
Product: CC=C(CC)N1CCCC1
Temperature: 0 °C
Yield: 68.6 %

Procedure:
99 g (1.39 mole) of pyrrolidine dissolved in 460 ml of n-pentane were added clropwise to 40 g (0.464 mole) of 3-pentanone dissolved in 1600 ml of n-pentane, and the solution was cooled to 0° C. in an ice bath. 48.4 g (0.255 mole) of titanium tetrachloride dissolved in 480 ml of n-pentane were added dropwise at 0° C.-10° C. within one hour, the mixture was stirred for two further hours at RT, and the suspension was filtered. The filtrate was concentrated by evaporation on a rotary evaporator (500 to 10 mbar), and 44.3 g of 1-(1-ethylpropenyl)pyrrolidine (68.6% of theory) were obtained in this way.
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[Cl:11].[NH3:12].Cl>CO>[NH2:12][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[Cl:11]
Reactant: N
Reactant: N#Cc1ccc(CBr)c(Cl)c1
Agent: Cl
Solvent: CO
Product: N#Cc1ccc(CN)c(Cl)c1
Temperature: 18 °C
Reaction time: 17 h

Procedure:
To a mixture of 4-(bromomethyl)-3-chlorobenzonitrile (11 g, 49 mmol, 1.0 equiv) and 6 M NH3 in methanol (200 mL) was stirred at 18° C. for 17 h. Aqueous HCl (1 M, 200 mL) was added, and the water layer was washed with ethyl acetate. The aqueous phase was adjusted to pH 9-10 with 1 M NaOH and extracted with ethyl acetate. The organic layer was washed with water, dried with magnesium sulfate, and concentrated. The residue was purified on silica gel to afford 2.71 g of the title compound. MS (ES+): m/e 167.0 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]([CH2:8][O:9]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:6][CH:5]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:4]1=[O:36])[CH3:2]>C(#N)C.C(O)=O>[CH2:1]([N:3]1[CH:7]([CH2:8][OH:9])[CH2:6][CH:5]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:4]1=[O:36])[CH3:2]
Reactant: CCN1C(=O)C(Cc2ccccc2)CC1COC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O=CO
Solvent: CC#N
Product: CCN1C(=O)C(Cc2ccccc2)CC1CO
Reaction time: 3 h
Yield: 66.2 %

Procedure:
1-Ethyl-3-(phenylmethyl)-5-{[(triphenylmethyl)oxy]methyl}-2-pyrrolidinone (0.561 g, 1.1 mmol) was stirred for 24 hrs at room temperature in a mixture of acetonitrile (21 ml) and formic acid (3 ml). The reaction was not complete at this stage so the solvent was evaporated and replaced with formic acid (10 ml) and stirring was continued for 3 hrs. Reaction was still not complete so the mixture was concentrated in vacuo (azeotroping with methanol to remove all of the formic acid) and then dissolved in methanol (20 ml). Amberlyst 15® was then added to the mixture and stirring was continued at room temperature overnight. The resin was filtered off, washing with more methanol, and the filtrate was concentrated to a gum (0.625 g). The gum was purified by automated flash silica-gel column chromatography (Biotage SP4), eluting with a 0-100% gradient of ethyl acetate in hexane, to give 1-ethyl-5-(hydroxymethyl)-3-(phenylmethyl)-2-pyrrolidinone (0.170 g) which was used in the next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([S:19](=[O:22])(=[O:21])[NH2:20])=[CH:15][CH:14]=2)[C:10]#N)[CH:5]=[CH:6][C:7]=1[F:8].O=[CH:24][C:25](=C)[CH3:26]>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19](=[O:22])(=[O:21])[NH2:20])=[CH:15][CH:14]=3)[CH:24]=[C:25]([CH3:26])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C=C(C)C=O
Reactant: N#CC(Nc1ccc(S(N)(=O)=O)cc1)c1ccc(F)c(F)c1
Product: Cc1cc(-c2ccc(F)c(F)c2)n(-c2ccc(S(N)(=O)=O)cc2)c1

Procedure:
Following a procedure similar to that described in Example 1(iii), but using α-(3,4-difluorophenyl)-α-(4-sulfamoylanilino)acetonitrile [prepared as described in step (ii) above] and methacrolein as starting materials, the title compound was obtained as a pale yellow powder (yield 51%), melting at 177-1 79° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[CH3:14].[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]2[CH:30]=[CH:29][N:28]=[C:27]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[CH:26]=2)=[O:24])=[CH:18][C:17]=1B1OC(C)(C)C(C)(C)O1>>[CH3:14][C:3]1[CH:4]=[C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)[CH:6]=[CH:7][C:2]=1[C:17]1[C:16]([CH3:15])=[CH:21][CH:20]=[C:19]([NH:22][C:23]([C:25]2[CH:30]=[CH:29][N:28]=[C:27]([N:31]3[CH2:32][CH2:33][CH2:34][CH2:35]3)[CH:26]=2)=[O:24])[CH:18]=1
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCCC3)c2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1nnc(-c2ccc(Br)c(C)c2)o1
Product: Cc1nnc(-c2ccc(-c3cc(NC(=O)c4ccnc(N5CCCC5)c4)ccc3C)c(C)c2)o1

Procedure:
Example 10 was prepared using 2-(4-bromo-3-methylphenyl)-5-methyl-1,3,4-oxadiazole and N-[4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)phenyl]-2-(1-pyrrolidinyl)-4-pyridinecarboxamide (Intermediate 20).
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.Cl.[CH2:12]([O:16][C:17](=[O:21])[C@H:18]([CH3:20])[NH2:19])[CH:13]([CH3:15])[CH3:14]>>[CH2:12]([O:16][C:17](=[O:21])[C@H:18]([CH3:20])[NH:19][C:8](=[O:10])[CH2:7][C:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: O=C(O)CC1=CCCCC1
Reactant: CC(C)COC(=O)[C@H](C)N
Agent: Cl
Product: CC(C)COC(=O)[C@H](C)NC(=O)CC1=CCCCC1

Procedure:
Following General Procedure BB above, and using cyclohex-1-enyl acetic acid (Alfa) and L-alanine iso-butyl ester hydrochloride (from Example BB above), the title compound was prepared as a solid having a melting point of 49° C.-51° C. The reaction was monitored by tlc on silica gel (Rf=0.40 in 1:3 EtOAc:hexane) and purification was by extraction with Et2O followed by washes with aqueous K2CO3 and aqueous HCl.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]2[N:14]=[C:15]3[CH:21]=[C:20]([C:22]4[CH:23]=[N:24][N:25]([CH2:27][C:28]([OH:30])=O)[CH:26]=4)[N:19](S(C4C=CC=CC=4)(=O)=O)[C:16]3=[N:17][CH:18]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH3:40][NH:41][CH3:42].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH2:11][CH2:12][C:13]2[N:14]=[C:15]3[CH:21]=[C:20]([C:22]4[CH:23]=[N:24][N:25]([CH2:27][C:28]([N:41]([CH3:42])[CH3:40])=[O:30])[CH:26]=4)[NH:19][C:16]3=[N:17][CH:18]=2)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: CNC
Reactant: COc1cc(CCc2cnc3c(cc(-c4cnn(CC(=O)O)c4)n3S(=O)(=O)c3ccccc3)n2)cc(OC)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(CCc2cnc3[nH]c(-c4cnn(CC(=O)N(C)C)c4)cc3n2)cc(OC)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 35.2 %

Procedure:
To a stirred solution of {4-[2-[2-(3,5-dimethoxyphenyl)ethyl]-5-(phenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazin-6-yl]-1H-pyrazol-1-yl}acetic acid (10.0 mg, 18.3 μmol) in N,N-dimethylformamide (1.0 mL), N,N-dimethylamine (2.0 M in THF, 13.7 μL, 27.4 μmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (8.33 mg, 21.9 mmol) and N,N-diisopropylethylamine (12.7 μL, 73.0 μmol) were added sequentially at ambient temperature. After 1 hour, the reaction was quenched with saturated aqueous NH4Cl, extracted with methylene chloride. The combined organic layers were dried over MgSO4, and then concentrated. The residue was dissolved in methanol (2.0 mL) and potassium carbonate (5.05 mg, 36.5 μmol) was added. The reaction mixture was then warmed up to 60° C. After 2 hours, the crude mixture was cooled to ambient temperature and purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 30 mL/min) to give the desired product (2.8 mg) as its TFA salt. LCMS calculated for C23H27N6O3 (M+H)+: m/z=435.2. Found: 435.3.
Reaction SMILES: FC(F)(F)C([O-])=O.[C:8]([CH2:11][N:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[NH+:14]=[CH:13]1)([OH:10])=O.[F:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[CH3:29])[NH2:25]>>[N:12]1([CH2:11][C:8]([NH:25][C:24]2[CH:26]=[CH:27][C:28]([CH3:29])=[C:22]([F:21])[CH:23]=2)=[O:10])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[CH:13]1
Reactant: O=C(O)Cn1c[nH+]c2ccccc21
Reactant: Cc1ccc(N)cc1F
Agent: O=C([O-])C(F)(F)F
Product: Cc1ccc(NC(=O)Cn2cnc3ccccc32)cc1F

Procedure:
The title compound was synthesised according to the procedure described in Example 89, from 3-carboxymethyl-3H-benzoimidazol-1-ium trifluoro-acetate and 3-fluoro-4-methyl-aniline. Yield 12 mg (35%). Calculated for C16H14FN3O m/z: 283.3, found 284.3 [M+H]+. 1H NMR (400 MHz, CD3OD) δ ppm 2.2 (s, 3H), 5.1 (s, 2H), 7.1 (m, 2H), 7.3 (m, 2H), 7.4 (d, J=11.6 Hz, 1H), 7.5 (d, J=8.6 Hz, 1H), 7.7 (m, 1H), 8.1 (s, 1H).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]1)(C)(C)C.[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18]>ClCCl>[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[NH2:7][C@@H:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H]1CC[C@H](O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a round-bottomed flask, (cis-3-hydroxy-cyclopentyl)-carbamic acid tert-butyl ester (320 mg, 1.59 mmol) was dissolved in dichloromethane (10 ml) and trifluoroacetic acid (3.6 ml, 46.7 mmol) was slowly added. The reaction mixture was stirred at room temperature for 2 h then concentrated to afford cis-3-amino-cyclopentanol trifluoroacetate as a light yellow oil which was used without further purification.