Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([CH3:29])([CH3:28])[CH2:19][C:20]([OH:27])([C:23]([F:26])([F:25])[F:24])[CH2:21][OH:22])=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]([CH3:29])([CH3:28])[CH2:19][C:20]([OH:27])([C:23]([F:25])([F:26])[F:24])[CH:21]=[O:22])=[CH:16][CH:17]=1
Reactant: CC(C)(CC(O)(CO)C(F)(F)F)c1ccc(Cl)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(CC(O)(C=O)C(F)(F)F)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 53.9 %

Procedure:
0.674 ml of oxalyl chloride in 16.8 ml of dichloromethane is mixed at −78° C. with 1.15 ml of DMSO in 3.4 ml of dichloromethane. After 5 minutes, 2 g of 4-(4-chlorophenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentan-1-ol in 6.8 ml of dichloromethane is added in drops at −78° C. After 15 minutes, it is mixed with 4.7 ml of triethylamine and slowly heated to room temperature. It is washed with water and brine, dried with sodium sulfate and concentrated by evaporation in a vacuum. After chromatography on silica gel (hexane/ethyl acetate 98:2), 1.07 g of 4-(4-chlorophenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanal is obtained as a colorless oil. 300 mg thereof was heated with 194 mg of 5-amino-2-methylquinoline in 9 ml of glacial acetic acid for 4.5 hours to 130° C. After toluene is added, it is concentrated by evaporation in a vacuum. The residue is taken up in methanol and mixed at 0° C. with 153 mg of sodium borohydride. It is allowed to stir for 5 hours at room temperature, and water is added. The batch is concentrated by evaporation in a vacuum, extracted with ethyl acetate, washed with water and brine, dried with sodium sulfate and concentrated by evaporation in a vacuum. After chromatography on silica gel (hexane/ethyl acetate 100:0->85:15), 163 mg of the title compound is obtained as a yellow solid.
Reaction SMILES: CC1C=C[C:5]([C:6]([OH:8])=[O:7])=[C:4]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)N=1.Br[C:17]1[C:18](C(O)=O)=[N:19]C=C[CH:22]=1.ClC1N=C(C)C=CC=1C(O)=O>>[N:15]1[N:11]([C:4]2[C:5]([C:6]([OH:8])=[O:7])=[N:19][CH:18]=[CH:17][CH:22]=2)[N:12]=[CH:13][CH:14]=1
Reactant: O=C(O)c1ncccc1Br
Reactant: Cc1ccc(C(=O)O)c(-n2nccn2)n1
Agent: Cc1ccc(C(=O)O)c(Cl)n1
Product: O=C(O)c1ncccc1-n1nccn1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 70 substituting 3-bromo-2-pyridinecarboxylic acid for 2-chloro-6-methylnicotinic acid. MS (ESI): mass calculated for C8H6N4O2, 190.10; m/z found 191.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.77 (d, J=4.3 Hz, 1H), 8.26 (dt, J=6.5, 3.3 Hz, 1H), 7.88 (s, 2H), 7.65 (dd, J=8.2, 4.7 Hz, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]([CH3:26])=[CH:11][C:12]([NH:15][C:16]([N:18]3[CH2:22][CH2:21][N:20]([CH2:23][CH3:24])[C:19]3=[O:25])=[O:17])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH3:27][C:28]1[N:29]=[CH:30][NH:31][CH:32]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O1CCOCC1.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]>[CH2:23]([N:20]1[CH2:21][CH2:22][N:18]([C:16]([NH:15][C:12]2[CH:11]=[C:10]([CH3:26])[C:9]([O:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([N:31]4[CH:32]=[C:28]([CH3:27])[N:29]=[CH:30]4)[CH:7]=3)=[CH:14][N:13]=2)=[O:17])[C:19]1=[O:25])[CH3:24]
Reactant: CCN1CCN(C(=O)Nc2cc(C)c(Oc3ccnc(Cl)c3)cn2)C1=O
Reactant: Cc1c[nH]cn1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CCN1CCN(C(=O)Nc2cc(C)c(Oc3ccnc(-n4cnc(C)c4)c3)cn2)C1=O
Temperature: 25 °C
Yield: 33.3 %

Procedure:
A solution of Pd2(dba)3 (0.029 g, 0.032 mmol) and Me4t-BuXPhos (0.034 g, 0.072 mmol) in toluene (0.6 mL) and dioxane (1.2 mL) was heated at 120° C. for 3 min, cooled to RT, added to a degassed suspension of N-(5-((2-chloropyridin-4-yl)oxy)-4-methylpyridin-2-yl)-3-ethyl-2-oxoimidazolidine-1-carboxamide (0.3 g, 0.798 mmol), 4-methyl imidazole (0.085 g, 1.038 mmol) and K3PO4 (0.339 g, 1.597 mmol) in toluene (1.2 mL) and dioxane (2.4 mL) and heated at 110° C. overnight. The mixture was treated with additional catalyst (synthesized from Pd2(dba)3 (0.029 g, 0.032 mmol) and Me4t-BuXPhos (0.034 g, 0.072 mmol) in toluene (0.6 mL) and dioxane (1.2 mL) as above) and heated at 110° C. overnight. The mixture was cooled to RT, treated with satd. NaHCO3, extracted with EtOAc (5×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified twice via silica gel chromatography (MeOH/DCM). The material was further purified via reverse-phase chromatography (MeCN/H2O with 0.1% TFA); the organics were removed under reduced pressure and the aqueous residue was treated with satd. NaHCO3 and extracted with DCM (3×). The combined organics were dried over Na2SO4 and concentrated to dryness to afford 3-ethyl-N-(4-methyl-5-((2-(4-methyl-1H-imidazol-1-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide (112 mg, 32%). 1H NMR (400 MHz, DMSO-d6): δ 10.93 (s, 1 H), 8.39 (d, J=1.4 Hz, 1 H), 8.30 (d, J=5.8 Hz, 1 H), 8.13 (s, 1 H), 8.02 (s, 1 H), 7.64 (s, 1 H), 7.33 (d, J=2.2 Hz, 1 H), 6.73 (dd, J=5.8, 2.2 Hz, 1 H), 3.80 (t, J=8.3 Hz, 2H), 3.46 (t, J=8.2 Hz, 2 H), 3.26-3.25 (q, J=7.2 Hz, 2 H), 2.15 (s, 3 H), 2.13 (s, 3 H), 1.09 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 422.2 (M+H+).
Reaction SMILES: [OH-].[Na+].C(O)C.[CH3:6][O:7][C:8]1[CH:32]=[CH:31][C:11]([C:12]([NH:14][C:15]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:22]=[CH:21][C:16]=2[C:17]([O:19]C)=[O:18])=[O:13])=[CH:10][CH:9]=1.Cl>C(OCC)(=O)C>[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([NH:14][C:15]2[CH:24]=[C:23]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:22]=[CH:21][C:16]=2[C:17]([OH:19])=[O:18])=[O:13])=[CH:31][CH:32]=1
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(C(=O)Nc2cc(-c3ccccc3)ccc2C(=O)O)cc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
1.0 mL of 2.0 mol/L aqueous sodium hydroxide and 3.0 mL of ethanol were added to the obtained methyl 2-(4-methoxybenzamido)-4-phenylbenzoate and stirred at 40° C. for 2 hours. After the reaction mixture was cooled to room temperature, 8.0 mL of 0.38 mol/L hydrochloric acid and 10 mL of ethyl acetate were added. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified with reversed-phase silica gel column chromatography [eluent; 55-100% acetonitrile /0.1% trifluoroacetic acid aqueous solution] to obtain 6.1 mg of 2-(4-methoxybenzamido)-4-phenylbenzoic acid as white solid.
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[F:12][CH:13]([CH2:15][C:16](Cl)=[S:17])[F:14]>ClCCl>[F:12][CH:13]([CH2:15][C:16]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[S:17])[F:14]
Reactant: CC(C)(C)O
Reactant: FC(F)CC(=S)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=S)CC(F)F
Yield: 48.6 %

Procedure:
To a stirred and ice cooled solution of t-butanol (1.2 equivalents) and pyridine (1.3 equivalents) in dichloromethane (5 parts by weight) is dropwise added difluoromethylthioacetyl chloride, and the mixture is stirred for 4 hours. The mixture is washed with water, dried and concentrated in vacuum. The residual liquid is distilled to give t-butyl difluoromethylthioacetate as an oil. Yield: 48.6%.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12](=[O:44])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]3[CH2:25][CH2:24][CH:23]([O:26][Si](C(C)(C)C)(C4C=CC=CC=4)C4C=CC=CC=4)[CH2:22][CH2:21]3)=[CH:15][CH:14]=1)[CH2:8]2.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12](=[O:44])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]3[CH2:21][CH2:22][CH:23]([OH:26])[CH2:24][CH2:25]3)=[CH:15][CH:14]=1)[CH2:8]2
Reactant: CC(C)(C)[Si](OC1CCC(Oc2ccc(C(=O)NC3C4CC5CC(C4)CC3C5)cc2)CC1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(NC1C2CC3CC(C2)CC1C3)c1ccc(OC2CCC(O)CC2)cc1
Reaction time: 48 h
Yield: 27.1 %

Procedure:
To a solution of N-adamantan-2-yl-4-[4-(t-butyl-diphenyl-silanyloxy)-cyclohexyloxy]-benzamide (4.73 g, 7.78 mmol) in dry THF (50 mL) was added a 1N TBAF solution in THF (31, 12 mL) and the mixture was stirred for 48 hrs. at room temperature. The volatiles were evaporated in vacuo and the residue redissolved in AcOEt (50 mL) and washed with 5% aqueous citric acid and vand. The organic phase was dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue was purified using a Combi Flash Sq16× with a solvent gradient starting from AcOEt/heptan (20:80) to (85:15). Desired fractions were collected and the solvent evaporated in vacuo affording 780 mg (27%) of N-adamantan-2-yl-4-(4-hydroxy-cyclohexyloxy)-benzamide as a solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[C:5]([CH3:7])[N:6]=1.C(N(CC)C(C)C)(C)C.Cl[CH2:28][CH2:29][N:30]=[C:31]=[O:32].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCOCC1>[CH2:11]([NH:10][C:8]([C:4]1[S:3][C:2]([N:1]2[CH2:28][CH2:29][NH:30][C:31]2=[O:32])=[N:6][C:5]=1[CH3:7])=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C=NCCCl
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1nc(N2CCNC2=O)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 60 %

Procedure:
To a solution of 2-amino-N-benzyl-4-methylthiazole-5-carboxamide (3.00 g, 12.1 mmol) in tetrahydrofuran (70 mL) was added N,N-diisopropylethylamine (3.13 g, 24.3 mmol), followed by the addition of 2-chloroethyl isocyanate (1.66 g, 15.76 mmol) at ambient temperature. The resulting reaction mixture was stirred at ambient temperature for 2 days. The solvent was removed in vacuo and the residue was washed with water (100 mL) and t-butyl methyl ether (200 mL). The resulting white solid was added to a suspension of potassium carbonate (2.01 g, 14.55 mmol) and tetrabutylammonium iodide (0.16 g, 0.44 mmol) in dioxane (50 mL). The reaction mixture was refluxed for 24 hours. The solvent was removed in vacuo, and the residue was washed with water (200 mL) and ethyl acetate (50 mL). The residue was recrystallized in methanol to afford the title compound as a colorless solid in 60% yield (2.3 g): mp 226-228° C. (methanol); 1H NMR (300 MHZ, DMSO-d6) δ 8.45 (t, J=5.8 Hz, 1H), 7.71 (s, 1H), 7.31-7.16 (m, 5H), 4.33 (d, J=5.8 Hz, 2H), 3.99 (m, 2H), 3.46 (m, 2H), 2.43 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 162.2, 157.6, 157.1, 151.4, 140.1, 128.6, 127.6, 127.1, 118.1, 44.5, 43.0, 37.7, 17.5; MS (ES+) m/z 317.2 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:18])[CH2:10][NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])=[CH:5][CH:4]=1)#[N:2].[N:19]([Sn](CCCC)(CCCC)CCCC)=[N+:20]=[N-:21].Cl>>[NH:19]1[C:1]([C:3]2[CH:8]=[CH:7][C:6]([CH:9]([CH3:18])[CH2:10][NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:13])=[O:14])=[CH:5][CH:4]=2)=[N:2][N:21]=[N:20]1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(C#N)cc1
Agent: Cl
Product: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.8 %

Procedure:
0.2 g (0.8 mmol) of material from Example 53 and 0.5 g (1.5 mmol) of azidotributylstannane were heated to 80° C. for 72 hours. The mixture was cooled to ambient temperature, 5 mL of a saturated methanolic HCl solution was added, the mixture stirred for 30 minutes and was concentrated in vacuo. The residue was dissolved in 10 mL of acetonitrile and extracted four times with 5 mL each of hexane. The acetonitrile layer was concentrated in vacuo and the resulting solid was suspended in 10 mL of ethyl ether, filtered and dried in vacuo at 60° C. to afford 0.2 g (89%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][C:8]2[CH:10]=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:7]=2[O:6]1)=[O:4].[CH3:16]N(P(N(C)C)(N(C)C)=O)C.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.CI>C1COCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1([CH3:16])[CH2:9][C:8]2[CH:10]=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:7]=2[O:6]1)=[O:4]
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Reactant: COC(=O)C1Cc2cc(OC)ccc2O1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CI
Product: COC(=O)C1(C)Cc2cc(OC)ccc2O1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-methoxy-2,3-dihydro-benzofuran-2-carboxylic acid methyl ester (0.44 g, 2.0 mmol) and HMPA (0.20 mL) in THF (15 mL) at −78° C. was added LiHMDS (1M in THF, 3.0 mL, 3.0 mmol). After 15 min, methyl iodide (0.42 g, 3.0 mmol) was added and the reaction was gradually warmed to 25° C. overnight. The reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous solution of NH4Cl. The organic phase was dried and concentrated. The residue was chromatographed on silica gel eluting with 8:2 hexane:ethyl acetate to give 0.32 g 5-methoxy-2-methyl-2,3-dihydro-benzofuran-2-carboxylic acid methyl ester.
Reaction SMILES: [CH:1]1([CH:7]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]([OH:27])=O)=[N:23][CH:24]=2)[C:8]2[S:9][C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH2:29]([O:31][C:32](=[O:36])[CH2:33][CH2:34][NH2:35])[CH3:30].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl-].[NH4+]>CN(C)C=O.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]([NH:35][CH2:34][CH2:33][C:32]([O:31][CH2:29][CH3:30])=[O:36])=[O:27])=[N:23][CH:24]=2)[C:8]2[S:9][C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CCN
Reactant: Cc1c(C(Nc2ccc(C(=O)O)nc2)C2CCCCC2)sc2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)CCNC(=O)c1ccc(NC(c2sc3ccccc3c2C)C2CCCCC2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a mixture of 5-{[cyclohexyl(3-methyl-1-benzothiophen-2-yl)methyl]amino}pyridine-2-carboxylic acid (247 mg) synthesized in Example A59(2), β-alanine ethyl ester hydrochloride (149 mg), 1-hydroxybenzotriazole monohydrate (149 mg), triethylamine (270 μL) and N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (186 mg), and the mixture was stirred at room temperature overnight. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30-70% ethyl acetate/hexane) to give the title object compound (274 mg, 88%) as a colorless oil.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]([F:13])([F:12])[F:11])=[CH:5][N:4]=1.C(Cl)(Cl)Cl.[Br:18]N1C(=O)CCC1=O>O>[Br:18][C:8]1[C:3]([NH:2][CH3:1])=[N:4][CH:5]=[C:6]([S:9][C:10]([F:11])([F:13])[F:12])[CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CNc1ccc(SC(F)(F)F)cn1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CNc1ncc(SC(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.5 %

Procedure:
To a mixture of methyl-(5-trifluoromethylsulfanylpyridine-2-yl)-amine (1.52 g) and chloroform (24 mL), N-bromosuccinimide (1.43 g) was added, and stirred at room temperature for 1 hour. Into the reaction mixture, water was poured, and extracted with chloroform. The combined organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 1.96 g of (3-bromo-5-trifluoromethylsulfanylpyridine-2-yl)-methylamine.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][N:8]2[C:14](=[O:15])[C@H:13]3[CH2:16][CH2:17][CH2:18][C@H:12]3[NH:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[CH:5][CH:4]=1.[C:25]1(=[O:39])[N:29]([CH2:30][C:31](Cl)=[O:32])[C:28](=[O:34])[C:27]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:26]12.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][N:8]2[C:14](=[O:15])[C@H:13]3[CH2:16][CH2:17][CH2:18][C@H:12]3[N:11]([C:31](=[O:32])[CH2:30][N:29]3[C:28](=[O:34])[C:27]4=[CH:35][CH:36]=[CH:37][CH:38]=[C:26]4[C:25]3=[O:39])[C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[CH:5][CH:4]=1
Reactant: O=C1[C@H]2CCC[C@H]2Nc2ccccc2N1Cc1ccc(Cl)cc1
Reactant: O=C(Cl)CN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1CC(=O)N1c2ccccc2N(Cc2ccc(Cl)cc2)C(=O)[C@H]2CCC[C@H]21
Yield: 14.8 %

Procedure:
(3aR*,10aS*)-9-(4-Chlorobenzyl)-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one hydrochloride (426 mg, 1.2 mmol) and phthalimidoacetyl chloride (389 mg, 1.7 mmol) were suspended in toluene (4 mL). The suspension was refluxed for 16 hours. To the reaction mixture was added a saturated aqueous solution of sodium hydrogencarbonate, which was subjected to extraction with chloroform. The extract solution was washed with water and a saturated aqueous solution of sodium hydrogencarbonate, which was dried and subjected to filtration. The filtrate was concentrated under reduced pressure. The concentrate was crystallized from ethanol-hexane to give 91 mg (yield 15%) of the titled compound, m.p. 205°-206° C.
Reaction SMILES: C1(C2N=C(C(C(N[C:15]([CH:17]([NH:26][C:27]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[O:28])[CH2:18][S:19]([CH2:22][CH:23]([CH3:25])[CH3:24])(=[O:21])=[O:20])=[O:16])CC)=O)ON=2)CC1.C1(N=C=N)CCCCC1.C1C=CC2N(O)N=NC=2C=1.[NH2:54][CH:55]([CH2:69][CH3:70])[C@@H:56]([C:58]1[N:62]=[C:61]([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[O:60][N:59]=1)[OH:57].C(O)C(N)(CO)CO>C(Cl)Cl>[CH:23]1([CH2:22][S:19]([CH2:18][CH:17]([NH:26][C:27]([N:29]2[CH2:30][CH2:31][O:32][CH2:33][CH2:34]2)=[O:28])[C:15](=[O:16])[NH:54][CH:55]([CH:56]([OH:57])[C:58]2[N:62]=[C:61]([C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)[O:60][N:59]=2)[CH2:69][CH3:70])(=[O:20])=[O:21])[CH2:24][CH2:25]1
Reactant: CCC(NC(=O)C(CS(=O)(=O)CC(C)C)NC(=O)N1CCOCC1)C(=O)c1nc(C2CC2)no1
Reactant: CCC(N)[C@H](O)c1noc(-c2ccccc2)n1
Agent: N=C=NC1CCCCC1
Agent: NC(CO)(CO)CO
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCC(NC(=O)C(CS(=O)(=O)CC1CC1)NC(=O)N1CCOCC1)C(O)c1noc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 109.2 %

Procedure:
A suspension of (R)-3-cyclopropylmethanesulfonyl-2-[(morpholine-4-carbonyl)-amino]-propionic acid (110 mg, 0.344 mmol, Reference Example 4) in methylene chloride (10 mL) was treated with PS-bound N-cyclohexylcarbodiimide (HL 200-400 mesh cross linked with 2% DVB) from Novabiochem (320 mg, 0.618 mmol, 1.93 mmol/g loading) and stirred at room temperature for 10 minutes. HOBt (43 mg, 0.319 mmol) was added followed by (S)-2-amino-1-(5-phenyl-1,2,4-oxadiazol-3-yl)-butan-1-ol (73 mg, 0.313 mmol, Reference Example 12) and the reaction mixture was stirred at room temperature overnight. PS-trisamine from Argonaut Technologies (413 mg, 1.549 mmol, 3.75 mmol/g loading) was added and the reaction was stirred for another 3 hours. The mixture was filtered and the filtrate was evaporated under reduced pressure to give morpholine-4-carboxylic acid (2-cyclopropylmethanesulfonyl-1-{1-[hydroxy-(5-phenyl-1,2,4-oxadiazol-3-yl)-methyl]-propylcarbamoyl}-ethyl)-amide as an orange solid (183 mg). MS: 536 (MH+)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][C:11]([O:14]CC3C=CC=CC=3)=[CH:10][C:9]2=[O:22])=[CH:4][C:3]=1[F:23]>CO.[Pd]>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]2=[O:22])=[CH:4][C:3]=1[F:23]
Reactant: Nc1ccc(-n2ccc(OCc3ccccc3)cc2=O)cc1F
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(-n2ccc(O)cc2=O)cc1F
Reaction time: 3 h
Yield: 96.7 %

Procedure:
A solution of 580 mg (1.87 mmol) 1-(4-amino-3-fluoro-phenyl)-4-benzyloxy-1H-pyridin-2-one (example 144, step 1) in 20 ml of MeOH was treated with 140 mg of Pd/C (10%) and hydrogenated at atmospheric pressure under vigorous stirring for 3 hrs. Filtration and evaporation of the solvent gave 398 mg (97%) of 1-(4-Amino-3-fluoro-phenyl)-4-hydroxy-1H-pyridin-2-one. Light brown solid. MS: 221 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)(=[O:7])=[O:6].Cl.CCN(CC)CC.[C:27](Cl)(=[O:29])[CH3:28]>C(Cl)Cl>[Br:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:27](=[O:29])[CH3:28])[CH2:10][CH2:9]1)(=[O:6])=[O:7]
Reactant: CC(=O)Cl
Reactant: NC1CCN(S(=O)(=O)Cc2ccccc2Br)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC1CCN(S(=O)(=O)Cc2ccccc2Br)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
To a mixture of 1-(2-bromobenzylsulfonyl)piperidin-4-amine.HCl (200 mg, 0.54 mmol) and Et3N (164 mg, 1.62 mmol) in dry DCM (20 mL) was added acetyl chloride (85 mg, 1.1 mmol) drop-wise at rt. The reaction mixture was stirred at rt for 2 hours before concentrating to dryness and purifying the residue by HPLC to give the title compound (180 mg, 89%). MS (ESI): mass calcd. for C14H19BrN2O3S, 374.03; m/z found, 374.8 [M+H]+.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][N:37]4[CH:42]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][N:37]4[CH:42]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(-c3cn4ccccc4n3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2c(C)cc(-c3cn4ccccc4n3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.-butyl 4'-[[2-n-propyl-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [CH:1]([NH:4][NH:5][C:6]([CH:8]1[CH2:13][CH2:12][S:11][CH2:10][CH2:9]1)=[O:7])([CH3:3])[CH3:2].[Br:14][C:15]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:16]=1[O:17][CH2:18][C:19](O)=[O:20].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C>CN(C=O)C>[Br:14][C:15]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:16]=1[O:17][CH2:18][C:19]([N:4]([CH:1]([CH3:3])[CH3:2])[NH:5][C:6]([CH:8]1[CH2:9][CH2:10][S:11][CH2:12][CH2:13]1)=[O:7])=[O:20]
Reactant: CC(C)NNC(=O)C1CCSCC1
Reactant: O=C(O)COc1ccc(F)cc1Br
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)N(NC(=O)C1CCSCC1)C(=O)COc1ccc(F)cc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 18.1 %

Procedure:
A solution of tetrahydro-thiopyran-4-carboxylic acid N′-isopropyl-hydrazide (300 mg, 1.48 mmol) and (2-bromo-4-fluoro-phenoxy)-acetic acid (369 mg, 1.48 mmol) in DMF (6 ml) was treated at rt with HOBT (240 mg, 1.78 mmol), EDCI (341 mg, 1.78 mmol), and triethylamine (0.620 ml, 4.45 mmol). The reaction mixture was stirred at room temperature for 18 hours and then partitioned between 1N HCl solution and ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate, filtered and concentrated under vacuum. The crude was purified by RP HPLC to afford the product as a solid (116 mg, 18.1%).