Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C@H:18]3[CH2:22][O:21][C:20]([CH3:24])([CH3:23])[O:19]3)=[CH:12][CH:11]=2)[C:5]([C:25]#[N:26])=[C:4]([SH:27])[N:3]=1.Cl.Cl[CH2:30][C:31]1[CH:36]=[CH:35][N:34]=[C:33]([C:37]([NH:39][CH3:40])=[O:38])[CH:32]=1.C(=O)(O)[O-].[Na+].O>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([S:27][CH2:30][C:31]2[CH:36]=[CH:35][N:34]=[C:33]([C:37]([NH:39][CH3:40])=[O:38])[CH:32]=2)[C:5]([C:25]#[N:26])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C@H:18]3[CH2:22][O:21][C:20]([CH3:23])([CH3:24])[O:19]3)=[CH:12][CH:11]=2)[C:7]=1[C:8]#[N:9]
Reactant: CNC(=O)c1cc(CCl)ccn1
Reactant: CC1(C)OC[C@H](COc2ccc(-c3c(C#N)c(N)nc(S)c3C#N)cc2)O1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(CSc2nc(N)c(C#N)c(-c3ccc(OC[C@H]4COC(C)(C)O4)cc3)c2C#N)ccn1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
450 mg (1.178 mmol) of 2-amino-4-(4-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}phenyl)-6-mercaptopyridine-3,5-dicarbonitrile (Example 18A), 286 mg (1.29 mmol) of 4-(chloromethyl)-N-methylpyridine-2-carboxamide hydrochloride (Example 41A) and 395 mg (4.71 mmol) of sodium bicarbonate were dissolved in 7.1 ml of DMF and the mixture was stirred at RT for 1.5 h. Water was added to the reaction mixture. The precipitate was filtered off and washed with water.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:15][CH:14]2[CH2:16][CH:7]([C:8]3[C:13]2=[CH:12][C:11]([N+:17]([O-])=O)=[CH:10][CH:9]=3)[CH2:6]1)(=[O:4])=[O:3].[H][H]>CCO.C(Cl)Cl.[Pd]>[CH3:1][S:2]([N:5]1[CH2:15][CH:14]2[CH2:16][CH:7]([C:8]3[C:13]2=[CH:12][C:11]([NH2:17])=[CH:10][CH:9]=3)[CH2:6]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)N1CC2CC(C1)c1cc([N+](=O)[O-])ccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: CS(=O)(=O)N1CC2CC(C1)c1cc(N)ccc12
Yield: 103.7 %

Procedure:
10-methanesulfonyl-4-nitro-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-triene (170 mg, 0.60 mmol) in 8 ml EtOH and 2 ml methylene chloride in a Parr bottle was treated with 50 mg 10% Pd/C and subjected to hydrogen (g) at 40 psi for 2 h. The suspension was filtered and the solvent removed under reduced pressure to yield 10-methanesulfonyl-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-trien-4-ylamine (157 mg, 99%). 1H-NMR (CDCl3) δ 7.03, (d, J=7.8 Hz, 1H), 6.64 (s, 1H), 6.52 (dd, J=7.8, 2.3 Hz, 1H), 3.77-3.68 (m, 1H), 3.67-3.54 (m, 3H), 3.36 (dd, J=12.6, 6.8 Hz, 2H), 3.13-3.05 (m, 2H), 2.38-2.28 (m, 1H), 2.03 (s, 3H), 1.78 (d, J=10.9 Hz, 1H), 1.24 (t, J=7.0 Hz, 3H); LC/MS (ESI+): 253 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([Cl:26])=[CH:10][C:11]([O:24][CH3:25])=[C:12]([NH:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[O:17])[CH:13]=1.CCN(CC)CC.[C:34](Cl)(=[O:37])[CH:35]=[CH2:36]>C(Cl)Cl>[Cl:26][C:9]1[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[CH:13][C:12]([NH:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:34](=[O:37])[CH:35]=[CH2:36])[CH2:20][CH2:19]2)=[O:17])=[C:11]([O:24][CH3:25])[CH:10]=1
Reactant: C=CC(=O)Cl
Reactant: COc1cc(Cl)c(-c2ccccc2Cl)cc1NCC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)N1CCN(C(=O)CNc2cc(-c3ccccc3Cl)c(Cl)cc2OC)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.7 %

Procedure:
To a solution of the crude 2-(5-(2-Chlorophenyl)-4-chloro-2-methoxyphenylamino)-1-(piperazin-1-yl)ethanone (0.304 mmol) and Et3N in DCM (5 mL) at 0° C., acryloyl chloride (27.5 mg, 0.304 mmol) was slowly added and the resulting mixture was stirred at room temperature for 1 h. The mixture was quenched with saturated NaHCO3 solution and extracted with DCM. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel to afford the desired product (80 mg, 58.7% yield, 2 steps). 1H NMR (400 MHz, DMSO-d6) δ: 7.55-7.52 (m, 1H), 7.45-7.39 (m, 2H), 7.32-7.29 (m, 1H), 6.97 (s, 1H), 6.80 (dd, J=10.4, 16.4 Hz, 1H), 6.54 (s, 1H), 6.12 (dd, J=2.0, 16.8 Hz, 1H), 5.70 (dd, J=2.0, 10.4 Hz, 1H), 5.35 (bs., 1H), 3.93 (d, J=4.0 Hz, 2H), 3.89 (s, 1H), 3.55-3.49 (m, 8H). ESI-MS m/z: 448.2[M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH3:14])[C:7]([CH:15]1[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]1)=[C:6]2[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C.[C:36](Cl)(=[O:38])[CH3:37].C(=O)(O)[O-].[Na+]>ClCCl>[C:36]([N:17]1[CH2:18][CH2:19][CH2:20][CH:15]([C:7]2[N:8]([CH3:14])[C:9](=[O:13])[C:10]3[C:5]([C:6]=2[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=3)[CH2:16]1)(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: COc1ccc2c(=O)n(C)c(C3CCCNC3)c(-c3ccccc3)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(=O)n(C)c(C3CCCN(C(C)=O)C3)c(-c3ccccc3)c2c1

Procedure:
To a dichloromethane (0.100 mL) solution of (±)-6-methoxy-2-methyl-4-phenyl-3-piperidin-3-ylisoquinolin-1(2H)-one (30 mg, 0.086 mmol) and N,N-diisopropylethylamine (0.017 mL, 0.095 mmol) was added acetyl chloride (0.007 mL, 0.095 mmol). After 24 hours saturated sodium bicarbonate and additional dichloromethane were added. The layers were separated and the organic phase dried with anhydrous magnesium sulfate. Evaporation of the solvent in vacuo followed by trituration with ether-EtOAc gave a white solid which was isolated by vacuum filtration to give the titled product. ESI+MS: 391.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:16]([C:18](=[O:21])[CH2:19][CH3:20])[CH3:17]>CN(C)C=O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:16]([C:18](=[O:21])[CH2:19][CH3:20])[CH3:17])=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: CCC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(=O)C(C)Oc1ccc(F)cc1
Temperature: 70 °C
Yield: 40.8 %

Procedure:
To a solution of 4-fluorophenol (8.0 g, 71.4 mmol) in dimethylformamide (130.0 mL) was added potassium carbonate (13.5 g, 97.4 mmol) and 2-bromopentan-3-one (836) (10.7 g, 64.9 mmol). The suspension was heated at 70° C. for 18 h, cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (2×25 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography (0-20% EtOAc in hexanes) to provide the desired 2-(4-fluorophenoxy)pentan-3-one (837) (5.2 g, 40.8%) as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][NH:12][C@@H:13]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:14][CH:15]=[CH2:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([CH3:31])[CH:30]=1)[C:25](Cl)=[O:26]>>[CH2:1]([O:8][C:9]([NH:11][N:12]([C@@H:13]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:14][CH:15]=[CH2:16])[C:25](=[O:26])[C:24]1[CH:28]=[C:29]([CH3:31])[CH:30]=[C:22]([CH3:21])[CH:23]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC[C@@H](NNC(=O)OCc1ccccc1)C(C)(C)C
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Product: C=CC[C@@H](N(NC(=O)OCc1ccccc1)C(=O)c1cc(C)cc(C)c1)C(C)(C)C

Procedure:
Briefly, benzyl carbazate (compound A) was reacted with pivaldehyde to give (E)-N′-(2,2-dimethyl-propylidene)-hydrazinecarboxylic acid benzyl ester (compound B). Compound B was reacted with (S,S)-2-allyl-2-chloro-3,4-dimethyl-5-phenyl-[1,3,2]oxazasilolidine (Compound C; see Leighton et al., J. Am. Chem. Soc. 125:9596 (2003) and WO 03/074534) to give (R)—N′-(1-tert-butyl-but-3-enyl)-hydrazinecarboxylic acid benzyl ester (compound D). Compound D was reacted with 3,5-dimethyl benzoyl chloride to give (R)—N′-(1-tert-butyl-but-3-enyl)-N′-(3,5-dimethyl-benzoyl)-hydrazinecarboxylic acid benzyl ester (compound B). Compound E was hydrogenated to give (R)-3,5-dimethyl-benzoic acid N-(1-tert-butyl-butyl)-hydrazide (compound F). Compound F was reacted with 2-ethyl-3-methoxybenzoyl chloride to give Compound 1. The crude material was triturated first with ether (2% ethanol) and then with 1:1 hexanes:ether in a fritted glass Büchner funnel. The product was then washed with deionized water with thorough mixing and allowed to dry in air. Compound 1 was isolated as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:12])[C:6](=[CH:10][CH:11]=1)[C:7]([OH:9])=[O:8].[CH3:13][Si](C=[N+]=[N-])(C)C>CO.O1CCCC1>[NH2:12][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][C:6]=1[C:7]([O:9][CH3:13])=[O:8]
Reactant: COc1ccc(C(=O)O)c(N)c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC)cc1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-methoxyanthranilic acid (5.0 g, 30.0 mmol) in a mixture of 10% methanol in tetrahydrofuran (100 mL) was added dropwise (trimethylsilyl)diazomethane (2.0 M solution in diethyl ether, 18.0 mL, 36.0 mmol) at 0° C. The reaction mixture was stirred for 16 hours at room temperature then quenched by the addition of glacial acetic acid (0.1 mL). The reaction mixture was concentrated and the residue was partitioned between saturated sodium bicarbonate (50 mL) and ethyl acetate (250 mL). The organic layer was separated and washed with water (50 mL), saturated sodium bicarbonate (50 mL) and brine (50 mL), dried over sodium sulfate, filtered and concentrated to give methyl 2-amino-4-methoxybenzoate as an oil (5.4 g, quantitative). MS (EI) for C9H11NO3: 182 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:14]([CH:17]=O)=[CH:13][C:10]=2[C:11]#[N:12])=[CH:4][C:3]=1[C:19]([F:22])([F:21])[F:20].[NH3:23]>CO.[Pd]>[NH2:23][CH2:17][C:14]1[CH:15]=[CH:16][C:9]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:19]([F:22])([F:21])[F:20])[CH:4]=2)=[C:10]([CH:13]=1)[C:11]#[N:12]
Reactant: N
Reactant: N#Cc1cc(C=O)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Product: N#Cc1cc(CN)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.9 %

Procedure:
To a suspension of 2-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}-5-formylbenzonitrile (1.0 g, 3.07 mmol) and ammonia (10 mL, 70.0 mmol) (7M in MeOH) in methanol (50 mL), was added Pd/C (0.327 g, 3.07 mmol). The reaction mixture was stirred at rt overnight under H2 atmosphere, filtered and concentrated. Purification via MDAP afforded the title compound (500 mg). LC-MS (ESI): m/z 327 [M+H]+; 2.49 min (ret time).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:23])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[C:19]([CH3:20])=[N:18][N:17]=[C:16]1[CH2:21]O.P(Br)(Br)[Br:25]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:23])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[C:19]([CH3:20])=[N:18][N:17]=[C:16]1[CH2:21][Br:25]
Reactant: BrP(Br)Br
Reactant: Cc1nnc(CO)n1-c1ccccc1C(=O)c1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: Cc1nnc(CBr)n1-c1ccccc1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Example 5, 2'-chloro-2-[3-(hydroxymethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone is treated with phosphorus tribromide in chloroform to give 2'-chloro-2-[3-(bromomethyl)-5-methyl-4H-1,2,4-triazol-4yl]benzophenone.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:3]=1[CH:4]=[O:5].Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1c(O)cccc1Cl
Reactant: CCCCCCCCCBr
Product: CCCCCCCCCOc1cccc(Cl)c1C=O

Procedure:
2-chloro-6-hydroxy-benzaldehyde was alkylated with 1-bromononane as in Example 1 to give 2-chloro-6-nonyloxy benzaldehyde. Reduction with sodium borohydroxide as in Example 1 gave 2-chloro-6-nonyloxy benzyl alcohol which on treatment with triphenylphosphine hydrobromide in acetonitrile as in Example 1 yielded [[2-chloro-6-nonyl-oxy]phenyl]methyl]triphenyl phosphonium bromide. Condensation with 7-formyl-3-methyl-2,4,6-octatrienoic acid ethyl ester as described in Example 3 produced (All E)-9-[2-chloro-6-(nonyloxy)phenyl]-3,7-dimethyl-2,4,6,8-nonatetraenoic acid ethyl ester. The ester was subjected to hydrolysis, as in Example 5, to produce (All-E)-9-[2-chloro-6-(nonyloxy)phenyl]-3,7-dimethyl-2,4,6,8-nonatetraenoic acid mp 129°-131° (from ethyl acetate/hexane mixture).
Reaction SMILES: F[C:2]1[C:3]([CH3:15])=[C:4]([CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12])[C:5]([OH:7])=[O:6].[CH2:16]([O:18][CH:19]([O:22][CH2:23][CH3:24])[CH2:20][NH2:21])[CH3:17].OS(O)(=O)=O>>[CH2:16]([O:18][CH:19]([O:22][CH2:23][CH3:24])[CH2:20][NH:21][C:2]1[C:3]([CH3:15])=[C:4]([CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12])[C:5]([OH:7])=[O:6])[CH3:17]
Reactant: Cc1c(C(=O)O)ccc(S(C)(=O)=O)c1F
Reactant: CCOC(CN)OCC
Agent: O=S(=O)(O)O
Product: CCOC(CNc1c(S(C)(=O)=O)ccc(C(=O)O)c1C)OCC
Temperature: 120 °C
Reaction time: 48 h

Procedure:
5.1 g (22 mmol) of 3-fluoro-2-methyl-4-(methylsulfonyl)benzoic acid were dissolved in 30 ml (218 mmol) of aminoacetaldehyde diethyl acetal. The mixture was heated at 120° C. with stirring for 2 days, cooled to RT, acidified with 10% strength H2SO4 and extracted twice with ethyl acetate. The combined organic phases were dried over MgSO4, and the solvent was removed under reduced pressure. This gave 4.0 g of a yellow oil of a purity of 91%.
Reaction SMILES: CC(C)(S([NH:6][CH:7]([C:16]1[C:21]([O:22][CH3:23])=[CH:20][CH:19]=[CH:18][C:17]=1[F:24])[CH2:8][CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=O)C.Cl.O1CCOCC1>CCO>[NH2:6][CH:7]([C:16]1[C:21]([O:22][CH3:23])=[CH:20][CH:19]=[CH:18][C:17]=1[F:24])[CH2:8][CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(C)CC(NS(=O)C(C)(C)C)c1c(F)cccc1OC
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)C(C)CC(N)c1c(F)cccc1OC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A cooled (0° C.) solution of ethyl 4-(1,1-dimethylethylsulfinamido)-4-(2-fluoro-6-methoxyphenyl)-2-methylbutanoate (1.060 g; 2.84 mmol) in EtOH (15 ml) was treated dropwise with a solution of 4 M HCl in 1,4-dioxane (1.5 ml; 6.00 mmol). The resulting mixture was further stirred at 0° C., under nitrogen, for 10 min., and then at rt for 30 min. The reaction mixture was then concentrated to dryness under reduced pressure and the oily residue was further dried under HV to give the chlorhydrate salt of ethyl 4-amino-4-(2-fluoro-6-methoxyphenyl)-2-methylbutanoate. LC-MS (conditions A): tR=0.50 min. and [M+H]+: 270.33 g/mol.
Reaction SMILES: O.[NH2:2][C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][C:6]([C:12]2[N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:14]=[CH:15][CH:16]=2)=[C:5]([O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)[CH:4]=1>[Pt].[C].CC(O)C>[NH2:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([CH:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:5]([O:24][C:25]2[CH:26]=[CH:27][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:29][CH:30]=2)[CH:4]=1
Reactant: CC(C)(C)OC(=O)n1cccc1-c1cc([N+](=O)[O-])c(N)cc1Oc1ccc(S(C)(=O)=O)cc1
Agent: [Pt]
Solvent: CC(C)O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC1c1cc(N)c(N)cc1Oc1ccc(S(C)(=O)=O)cc1
Temperature: 70 °C
Reaction time: 48 h

Procedure:
20 ml of water and 4 g of 5% platinum-carbon catalyst were added to a 2-propanol (200 ml) solution of 12 g of t-butyl 2-(4-amino-2-(4-methanesulfonyl-phenoxy)-5-nitro-phenyl)-pyrrole-1-carboxylate, and the reaction liquid was stirred under a hydrogen atmosphere of 50 kgf/cm2 at 70° C. for 2 days. The catalyst was removed through filtration through Celite, the solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: chloroform/methanol=50/1) to obtain the entitled compound as a dark brown oily substance.
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:15](=[O:17])[NH2:16])[CH:10]=[C:9]2[NH:18][C:19]([N:21]1[C@H:26]([C:27](=[O:38])[NH:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=2[F:37])[CH2:25][C@@H:24]2[C@H:22]1[CH2:23]2)=[O:20].[OH-].[Na+]>C1COCC1.O>[C:15]([N:11]1[C:12]2[C:8](=[CH:7][C:6]([O:5][CH2:4][C:3]([OH:39])=[O:2])=[CH:14][CH:13]=2)[C:9]([NH:18][C:19]([N:21]2[C@H:26]([C:27](=[O:38])[NH:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=3[F:37])[CH2:25][C@@H:24]3[C@H:22]2[CH2:23]3)=[O:20])=[CH:10]1)(=[O:17])[NH2:16]
Reactant: COC(=O)COc1ccc2c(c1)c(NC(=O)N1[C@@H]3C[C@@H]3C[C@H]1C(=O)NCc1cccc(Cl)c1F)cn2C(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)n1cc(NC(=O)N2[C@@H]3C[C@@H]3C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2cc(OCC(=O)O)ccc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of (1-carbamoyl-3-{[(1R,3S,5R)-3-(3-chloro-2-fluoro-benzylcarbamoyl)-2-aza-bicyclo[3.1.0]hexane-2-carbonyl]-amino}-1H-indol-5-yloxy)-acetic acid methyl ester Example 133 (85 mg, 0.145 mmol) in THF (1.2 mL) and H2O (120 μL) was added NaOH 1N (290 μL, 0.29 mmol) and the reaction mixture was stirred at RT for 20 min. The crude was directly purified using trimethylaminopropyl cartridge (Mega Bond Elut-SAX, 1 g from Varian) pre-washed with CH3CN (10 mL) and the compound was released with 10 mL of HCl 0.1N in CH3CN. The resulting solution was concentrated and purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 19×50 mm, eluent: 20% to 100% CH3CN in H2O in 15 min, CH3CN and H2O containing 0.1% HCOOH, flow: 20 mL/min) to give the desired material after lyophilization of the purified fractions. MS (UPLC-MS): 544.3/546.3 [M+H]+, 566.4/568.3 [M+Na]+, 542.3/544.4 [M−H]−; tR (HPLC conditions f): 1.72 min.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([CH2:10][O:11][CH:12]2[CH2:15][CH2:14][CH2:13]2)=[CH:4][C:3]=1[O:16][CH3:17].C([Li])CCC.[B:23](OC)([O:26]C)[O:24]C.[Cl-].[NH4+]>C(OCC)(=O)C.C1COCC1>[CH:12]1([O:11][CH2:10][C:5]2[CH:6]=[C:7]([O:8][CH3:9])[C:2]([B:23]([OH:26])[OH:24])=[C:3]([O:16][CH3:17])[CH:4]=2)[CH2:15][CH2:14][CH2:13]1
Reactant: COB(OC)OC
Reactant: COc1cc(COC2CCC2)cc(OC)c1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(COC2CCC2)cc(OC)c1B(O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.8 %

Procedure:
To a mixture of 2-bromo-5-[(cyclobutyloxy)methyl]-1,3-dimethoxybenzene (2.39 g, 7.94 mmol) and THF (20 mL) was added n-butyllithium (2.73M n-hexane solution: 3.49 mL, 9.53 mmol) at −78° C. (internal temperature), and the mixture was stirred for one hour. To the mixture was added trimethyl borate (1.07 mL, 9.53 mmol) and the mixture was gradually warmed to room temperature while stirring. Thereafter, a saturated aqueous solution of ammonium chloride was added to the mixture while cooling on ice, and then ethyl acetate was added. After thoroughly shaking the mixture, the organic layer was separated, and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The mixture was filtered, and then the solvent in the filtrate was distilled off under reduced pressure. To the residue, heptane (30 mL) was added, the precipitated solid was filtered and then dried under reduced pressure to obtain the title compound (905 mg, 3.40 mmol).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[CH:6]1.[Cl:14][C:15]1[CH:30]=[CH:29][C:18]2[N:19]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[C:20](=[O:22])[NH:21][C:17]=2[CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[N:5]1([CH2:4][CH2:3][CH2:2][N:26]2[CH2:25][CH2:24][CH:23]([N:19]3[C:18]4[CH:29]=[CH:30][C:15]([Cl:14])=[CH:16][C:17]=4[NH:21][C:20]3=[O:22])[CH2:28][CH2:27]2)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[CH:6]1
Reactant: O=c1[nH]c2cc(Cl)ccc2n1C1CCNCC1
Reactant: ClCCCn1cnc2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: O=c1[nH]c2cc(Cl)ccc2n1C1CCN(CCCn2cnc3ccccc32)CC1
Yield: 14 %

Procedure:
A mixture of 9 parts of 1-(3-chloropropyl)-1H-benzimidazole, 10 parts of 5-chloro-1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one, 7.4 parts of sodium carbonate and 200 parts of 4-methyl-2-pentanone is stirred and refluxed overnight. The reaction mixture is cooled, water is added and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is crystallized from 4-methyl-2-pentanone, yielding 2.9 parts (14%) of 1-{1-[3-(1H-benzimidazol-1-yl)propyl]-4-piperidinyl}-5-chloro-1,3-dihydro-2H-benzimidazol-2-one; mp. 224° C.
Reaction SMILES: B(Br)(Br)Br.ClCCl.[F:8][C:9]([F:38])([F:37])[C:10]1[CH:11]=[C:12]([NH:20][C:21](=[O:36])[C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:24][C:23]=2[O:34]C)[CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1>ClCCl.C(OCC)(=O)C>[F:8][C:9]([F:37])([F:38])[C:10]1[CH:11]=[C:12]([NH:20][C:21](=[O:36])[C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:24][C:23]=2[OH:34])[CH:13]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:15]=1
Reactant: COc1cc(-c2ccccc2)ccc1C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccc(-c2ccccc2)cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
1M Boron tribromide-dichloromethane solution (0.71 mL, 0.71 mmol) was added to a solution of N-[3,5-bis(trifluoromethyl)phenyl]-2-methoxy-4-phenylbenzamide (100 mg, 0.24 mmol) in dichloromethane (5 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with water and brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=5:1) to give the title compound (69.3 mg, 71.6%) as a white powder.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[F:14].C([Li])CCC.[CH:20](N1CCOCC1)=[O:21].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[F:14][C:3]1[C:4]2[O:9][CH2:8][CH2:7][O:6][C:5]=2[C:10]([O:12][CH3:13])=[CH:11][C:2]=1[CH:20]=[O:21]
Reactant: COc1cc(Br)c(F)c2c1OCCO2
Reactant: O=CN1CCOCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(C=O)c(F)c2c1OCCO2
Temperature: -72 °C
Reaction time: 0.5 h

Procedure:
To a solution of 549 mg of 6-bromo-5-fluoro-8-methoxy-2,3-dihydrobenzo[1,4]dioxine in 15 ml of THF there was added dropwise 0.86 ml of n-butyllithium (2.55 M, hexane solution) at −70° C. under a nitrogen atmosphere. After stirring at −72° C. for 30 minutes, 0.3 ml of N-formylmorpholine was added and the temperature was raised from −78° C. to 0° C. over a period of 30 minutes. Saturated aqueous ammonium chloride was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (247 mg) as a solid.