Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH2:5][CH2:4][N:3]2[C:6]([C:9]3[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=3)=[CH:7][N:8]=[C:2]12.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[Cl:40][C:41]1[CH:51]=[CH:50][C:44]2[NH:45][C:46]([CH2:48][NH2:49])=[N:47][C:43]=2[CH:42]=1.ClCl>CN(C)C=O.C(OCC)(=O)C.C(O)C.C(N(CC)CC)C>[Cl:40][C:41]1[CH:51]=[CH:50][C:44]2[NH:45][C:46]([CH2:48][NH:49][C:13](=[O:15])[C:12]3[CH:11]=[CH:10][C:9]([C:6]4[N:3]5[C:2]([S:1][CH2:5][CH2:4]5)=[N:8][CH:7]=4)=[CH:17][CH:16]=3)=[N:47][C:43]=2[CH:42]=1
Reactant: O=C(O)c1ccc(-c2cnc3n2CCS3)cc1
Reactant: NCc1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(-c2cnc3n2CCS3)cc1
Yield: 73 %

Procedure:
Prepared analogously to Example 1g from 4-(2,3-dihydroimidazo[2,1-b]thiazol-5-yl)benzoic acid, TBTU, triethylamine and (5-chloro-1H-benzimidazol-2-yl)methylamine in N,N-dimethylformamide. Yield: 73%; Rf value: 0.50 (silica gel; ethyl acetate/ethanol=9:1); C20H16ClN5OS (409.90); mass spectrum: (M+H)+=410/412 (chlorine isotope).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[C:13]([CH3:17])[CH:12]=1)=O.[CH2:18]([CH:20]([CH2:26][CH3:27])[C:21](=O)[CH2:22][C:23]#[N:24])[CH3:19]>>[Cl:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:21]([CH:20]([CH2:26][CH3:27])[CH2:18][CH3:19])[C:22]([C:23]#[N:24])=[C:9]2[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([CH3:17])[CH:12]=1
Reactant: Cc1cc(C(=O)c2cc(Cl)ccc2N)ccn1
Reactant: CCC(CC)C(=O)CC#N
Product: CCC(CC)c1nc2ccc(Cl)cc2c(-c2ccnc(C)c2)c1C#N

Procedure:
The title compound was prepared in analogy to example 101 step B from (2-amino-5-chloro-phenyl)-(2-methyl-pyridin-4-yl)-methanone (prepared in analogy to example 126 step B) and 4-ethyl-3-oxo-hexanenitrile (prepared as described in example 101 step A). Yellow solid. MS (ESI): 350.5 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:9][C:8](=[O:10])[N:7]([C:11]([CH3:13])=[CH2:12])[C:6]=2[CH:14]=1.[OH-].[Na+].Br[CH2:18][CH2:19][CH2:20][Cl:21]>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C>[Cl:21][CH2:20][CH2:19][CH2:18][N:9]1[C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:14][C:6]=2[N:7]([C:11]([CH3:13])=[CH2:12])[C:8]1=[O:10]
Reactant: ClCCCBr
Reactant: C=C(C)n1c(=O)[nH]c2ccc(C)cc21
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Product: C=C(C)n1c(=O)n(CCCCl)c2ccc(C)cc21
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a stirred and hot (50° C.) mixture of 47 parts of 1,3-dihydro-6-methyl-1-(1-methylethenyl)-2H-benzimidazol-2-one and 5 parts of N,N,N-triethylbenzenemethanaminium chloride in 300 parts of a sodium hydroxide solution 50% are added 79 parts of 1-bromo-3-chloropropane. The whole is heated to 60° C.: exothermic reaction (temperature rises to 75° C.). Stirring is continued for one hour while cooling to keep the temperature between 60° and 70° C. The reaction mixture is cooled and poured onto crushed ice. The product is extracted with methylbenzene. The extract is washed three times with water, dried, filtered and evaporated. The oily residue is distilled, yielding 1-(3-chloropropyl)-1,3-dihydro-5-methyl-3-(1-methylethenyl)-2H-benzimidazol-2-one; bp. 140° C. at 0.015 mm. pressure.
Reaction SMILES: [CH2:1]([N:3]([CH2:43][CH3:44])[CH2:4][CH2:5][CH2:6][S:7]([N:10]([CH2:39][CH:40]([CH3:42])[CH3:41])[NH:11][C:12](=[O:38])[C@@H:13]([C@@H:18]([C:28](=[O:37])[NH:29][O:30]C1CCCCO1)[CH2:19]/[CH:20]=[CH:21]/[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:14][CH:15]([CH3:17])[CH3:16])(=[O:9])=[O:8])[CH3:2].O.[C:46]1([CH3:56])[CH:51]=[CH:50][C:49]([S:52]([OH:55])(=[O:54])=[O:53])=[CH:48][CH:47]=1>CO>[C:46]1([CH3:56])[CH:47]=[CH:48][C:49]([S:52]([OH:55])(=[O:53])=[O:54])=[CH:50][CH:51]=1.[CH2:43]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][S:7]([N:10]([CH2:39][CH:40]([CH3:42])[CH3:41])[NH:11][C:12](=[O:38])[C@@H:13]([C@@H:18]([C:28](=[O:37])[NH:29][OH:30])[CH2:19]/[CH:20]=[CH:21]/[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:14][CH:15]([CH3:17])[CH3:16])(=[O:9])=[O:8])[CH3:44]
Reactant: CCN(CC)CCCS(=O)(=O)N(CC(C)C)NC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: CCN(CC)CCCS(=O)(=O)N(CC(C)C)NC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.6 %

Procedure:
A solution of 0.16 g of (E)-2′-[3-(diethylamino)propylsulphonyl]-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide in 4 ml of methanol was treated with 0.057 g of p-toluenesulphonic acid monohydrate. The mixture was stirred for 2 hours at room temperature and evaporated. Trituration of the residue with diethyl ether gave 0.125 g of (E)-2′-[3-(diethylamino)propylsulphonyl]-2(R)-[1(S)-(hydroxycarbamoyl)-4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide p-toluenesulphonate in the form of an off-white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[Cl:14][C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[C:19](Cl)[C:18]([CH3:25])=[C:17]([CH3:26])[N:16]=1.C(N(CC)CC)C>CN(C)C=O>[Cl:14][C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[C:19]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[C:18]([CH3:25])=[C:17]([CH3:26])[N:16]=1
Reactant: CC(C)(C)OC(=O)NCCCCN
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)c1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(Cl)c([N+](=O)[O-])c(NCCCCNC(=O)OC(C)(C)C)c1C
Reaction time: 8 h
Yield: 48 %

Procedure:
A solution of tert-butyl 4-aminobutylcarbamate (8.52 g, 45.24 mmol) in N,N-dimethylformamide was added to a solution of 2,4-dichloro-5,6-dimethyl-3-nitropyridine (10.00 g, 45.24 mmol) and triethylamine (12.6 mL, 90.5 mmol) in N,N-dimethylformamide (320 mL). The reaction mixture was stirred overnight and then concentrated under reduced pressure. The residue was partitioned between water and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The organics were combined, washed with brine and then concentrated under reduced pressure to provide a brown oily residue. This material was purified by flash chromatography (400 mL silica gel, eluting initially with 10% ethyl acetate in hexane and then increasing the gradient to 15% and then to 25%) to provide 8.1 g of tert-butyl 4-[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]butylcarbamate as a yellow solid.
Reaction SMILES: O[CH2:2][CH2:3][O:4][CH2:5][N:6]1[CH:11]=[C:10]([CH3:12])[C:9](=[O:13])[NH:8][C:7]1=[O:14].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)(Cl)(Cl)[Cl:35]>N1C=CC=CC=1.C(OCC)(=O)C.CO>[Cl:35][CH2:2][CH2:3][O:4][CH2:5][N:6]1[CH:11]=[C:10]([CH3:12])[C:9](=[O:13])[NH:8][C:7]1=[O:14]
Reactant: Cc1cn(COCCO)c(=O)[nH]c1=O
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cn(COCCCl)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
150 mg (0.75 mmol) 1-[(2-hydroxyethoxy)methyl]-5-methyl-2,4(1H,3H)-pyrimidinedione were dissolved in 10 ml pyridine and 1 g PS-triphenylphosphine resin (3 mmol/g) and 147 μl carbontetrachloride were added. The reaction was stirred at room temperature for 3 days. The reaction mixture was diluted with a mixture of ethyl acetate and methanol and centrifuged. The supernatant was decanted and the solvent was evaporated under reduced pressure. The residue, dissolved in ethyl acetate and a small amount of methanol, was purified by flash chromatography on silica gel (ethyl acetate). The fractions containing the product were pooled and the volume was reduced to about 3 ml. Upon addition of hexane the product crystallized to give 97 mg of white crystals. MS (ISP): 217.1 (M−H+). 1H-NMR (DMSO-d6): 1.77 (d, 3H), 3.69–3.77 (m, 4H), 5.10 (s, 2H), 7.59 (d, 1H), 11,32 (s, br, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[F:10][C:11]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:12]=1[C:13]([C:15](=[CH:21]OCC)[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:14]>C(Cl)(Cl)Cl>[F:10][C:11]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:12]=1[C:13]([C:15](=[CH:21][NH:4][C:3]1[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:2]=1[Cl:1])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:14]
Reactant: Nc1ccc(F)cc1Cl
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)cc1F
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(=CNc1ccc(F)cc1Cl)C(=O)c1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
With ice cooling, 5 ml of a chloroform solution containing 1.2 ml of 2-chloro-4-fluoroaniline was added dropwise to 13 ml of a chloroform solution containing 2.46 g of ethyl 2-(2,4,5-trifluorobenzoyl)-3-ethoxyacrylate and stirred overnight at room temperature. The solvent was distilled off then to the residue, ethanol was added. The resulting crystals were collected by filtration and washed with diethyl ether, to give ethyl 2-(2,4,5-trifluorobenzoyl)-3-(2-chloro-4-fluorophenylamino)acrylate. To 15 ml of a N,N-dimethylformamide solution containing 3.00 g of ethyl 2-(2,4,5-trifluorobenzoyl)-3-(2-chloro-4-fluorophenylamino)acrylate was added 1.03 g of potassium carbonate. The solution was stirred for 90 minutes at room temperature. The reaction solution was poured into ice water, the precipitated solid was collected by filtration and washed with ethanol and diethyl ether, to give 2.74 g of the title compound.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:7]1[N:8]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[C:9](/[CH:12]=[C:13](\CC2C=CC=CC=2)/[CH2:14][OH:15])=[CH:10][N:11]=1)[CH2:4][CH2:5][CH3:6].Br[CH2:32][C:33]([O:35]C)=[O:34]>C(COC)OC>[CH2:3]([C:7]1[N:8]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[C:9]([CH2:12]/[CH:13]=[CH:14]/[O:15][CH:32]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:33]([OH:35])=[O:34])=[CH:10][N:11]=1)[CH2:4][CH2:5][CH3:6]
Reactant: COC(=O)CBr
Reactant: CCCCc1ncc(/C=C(/CO)Cc2ccccc2)n1Cc1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCCCc1ncc(C/C=C/OC(Cc2ccccc2)C(=O)O)n1Cc1ccccc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (2.3 mml)in 5 mL of glyme is added portionwise (E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-benzyl-2-propenol prepared by the method of Example 18(i) from the methyl ester of the compound of Example 2. After stirring for 30 minutes, methyl bromoacetate (2.2 mmol) is added dropwise The reaction is stirred overnight at room temperature and then the mixture is poured into ice/water. The product is extracted into ethyl acetate (3×). The combined organic extracts are washed with water and brine and dried with anhydrous magnesium sulfate. The solvent is removed in vacuo. The residue is chromatographed on silica gel to give the esters of the title compound as an oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:7]([C:11]1[N:16]=[C:15](Cl)[CH:14]=[C:13]([CH:18]2[CH2:20][CH2:19]2)[N:12]=1)([CH3:10])([CH3:9])[CH3:8]>C(O)C>[C:7]([C:11]1[N:16]=[C:15]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[CH:14]=[C:13]([CH:18]2[CH2:20][CH2:19]2)[N:12]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)c1nc(Cl)cc(C2CC2)n1
Reactant: C1CNCCN1
Solvent: CCO
Product: CC(C)(C)c1nc(C2CC2)cc(N2CCNCC2)n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
25.1 g of piperazine (291.4 mmol) were dissolved in 100 ml of ethanol and heated to 50° C. 17 g of 2-tert-butyl-4-chloro-6-cyclopropyl-pyrimidine (81 mmol), dissolved in 100 ml of ethanol, were added dropwise within 2 h. After heating to reflux at 70° C. for 5 h the reaction mixture was stirred at room temperature overnight. The ethanol was evaporated and the residue suspended in 200 ml of water. The aqueous phase was extracted 4 times with 100 ml of dichloromethane each. Drying over magnesium sulfate, filtration, and evaporation to dryness gave 19.2 g (90.9%) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:41]([O:43]C)=[O:42])=[N:11][C:12]([C:15]2[C:16]([N:35]([CH3:40])[S:36]([CH3:39])(=[O:38])=[O:37])=[CH:17][C:18]3[O:22][C:21]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)=[C:20]([C:30](=[O:33])[NH:31][CH3:32])[C:19]=3[CH:34]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[Li].O>O1CCOCC1.O>[CH2:1]([O:8][C:9]1[C:10]([C:41]([OH:43])=[O:42])=[N:11][C:12]([C:15]2[C:16]([N:35]([CH3:40])[S:36]([CH3:39])(=[O:37])=[O:38])=[CH:17][C:18]3[O:22][C:21]([C:23]4[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=4)=[C:20]([C:30](=[O:33])[NH:31][CH3:32])[C:19]=3[CH:34]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(OCc4ccccc4)c(C(=O)OC)n3)cc12
Agent: [Li]O
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(OCc4ccccc4)c(C(=O)O)n3)cc12
Temperature: 100 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
A mixture of methyl 3-(benzyloxy)-6-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)picolinate (540 mg, 0.87 mmol), LiOH.H2O (110 mg, 2.62 mmol) in 1,4-dioxane/H2O (15 mL/5 mL) under N2 was stirred at 100° C. for 1 h. After being filtrated and acidified with HCl to pH=5, the mixture was extracted with EtOAc, the organic phases were dried and concentrated to afford 3-(benzyloxy)-6-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)picolinic acid (520 mg, yield: 98%). 1H-NMR (DMSO-d6, 400 MHz) δ 8.56 (d, J=4.8 Hz, 1H), 7.94˜8.07 (m, 3H), 7.73˜7.85 (m, 3H), 7.50 (d, J=7.2 Hz, 2H), 7.42 (t, J=7.6 Hz, 4H), 7.35 (br s, 1H), 5.30 (s, 2H), 3.20 (s, 3H), 2.94 (s, 3H), 2.82 (d, J=4.4 Hz, 3H). MS (M+H)+: 604.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=3)[O:11][CH2:10][C:9]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:4][CH:3]=1>C(O)C.[Pd]>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=3)[O:11][CH2:10][C@H:9]2[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc2c(c1)OCC(c1ccccc1)=C2c1ccc(O)cc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc2c(c1)OC[C@@H](c1ccccc1)[C@H]2c1ccc(O)cc1
Reaction time: 8 h

Procedure:
4-(4-Hydroxyphenyl)-7-methoxy-3-phenyl-3-chromene (77.7 g) was dissolved in ethanol (1500 ml) at 50° C. Palladium on carbon, 10%, 50% wet (6 g) was added to the solution and the mixture was hydrogenated at 55° C. and 1 atmosphere for 8 hours.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([Cl:9])[CH:3]=1.[Mg].[C:11]([N:18]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>O1CCCC1>[Cl:9][C:4]1[CH:3]=[C:2]([C:20]2([OH:23])[CH2:21][CH2:22][N:18]([C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])[CH2:19]2)[CH:7]=[CH:6][C:5]=1[F:8]
Reactant: Fc1ccc(Br)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(F)c(Cl)c2)C1

Procedure:
Preparation according to Preparation 5: 4-bromo-2-chloro-1-fluorobenzene (4.0 g, 19.1 mmol), dry tetrahydrofuran (50 mL), magnesium turnings (0.5 g, 21.0 mmol) and 1-N-boc-3-pyrrolidinone (3.89 g, 21.0 mmol). Yield: 1.65 g. MS m/z (rel. intensity, 70 eV) 315 (M+, 1), 259 (50), 214 (63), 157 (44), 57 (bp).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[N:10]([C@@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17](=[O:39])[CH2:18][C@H:19]([NH:31]C(=O)OC(C)(C)C)[CH2:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=3)[CH2:12]2)[C:9]2[CH:40]=[CH:41][CH:42]=[CH:43][C:8]=2[N:7]=1.[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47]>>[NH2:31][C@H:19]([CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=1)[CH2:18][C:17]([N:13]1[CH2:14][CH2:15][CH2:16][C@@H:11]([N:10]2[C:9]3[CH:40]=[CH:41][CH:42]=[CH:43][C:8]=3[N:7]=[C:6]2[CH2:5][CH2:4][CH2:3][O:2][CH3:1])[CH2:12]1)=[O:39].[C:46]([OH:48])([C:45]([F:50])([F:49])[F:44])=[O:47]
Reactant: COCCCc1nc2ccccc2n1[C@@H]1CCCN(C(=O)C[C@@H](Cc2ccc3ccccc3c2)NC(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Product: COCCCc1nc2ccccc2n1[C@@H]1CCCN(C(=O)C[C@H](N)Cc2ccc3ccccc3c2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
134F was dissolved in 25% trifluoroacetic acid and stirred at room temperature for 3 hr. Solvent was removed under vacuum and purified by preparatory LC/MS (20-25% CH3CN in H2O) to give (R)-3-amino-1((R)-3-(2-(3-methoxypropyl)-1H-benzo[d]imidazol-1-yl)piperidin-1-yl)-4-(naphthalen-2-yl)butan-1-one (243) as a TFA salt (97 mg, 24%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.62 (m, 1H) 1.86 (br. s., 1H) 1.97-2.15 (m, 3H) 2.53-2.91 (m, 3H) 2.94-3.26 (m, 7H) 3.40 (m, 3H) 3.75-4.10 (m, 3H) 4.42-4.71 (m, 2H) 7.50 (m, 5H) 7.72-7.96 (m, 5H) 8.21 (m, 1H). ESI-MS:m/z 485.5 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[Na+].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)CCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S([O-])c1ccc(Cl)cc1
Reactant: BrCc1ccccc1
Agent: [Na+]
Solvent: CCCCO
Product: O=S(=O)(Cc1ccccc1)c1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 5 h
Yield: 72.8 %

Procedure:
Sodium 4-chlorobenzenesulfinate (306 mg, 1.54 mmol) and benzyl bromide (0.18 ml, 1.54 mmol) were added to n-butanol (15 ml). The resulting mixture was stirred at 70° C. for 5 hours. After cooling to room temperature, the solvent was concentrated under reduced pressure. To the residue were added ethyl acetate. The resulting mixture was washed successively with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to chromatography on a silica gel column, whereby from the fraction eluted with hexane:ethyl acetate (=8:1), the title compound (299 mg, 73%) was obtained as a white solid.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20](O)=[O:21])=[CH:11][CH:10]=2)=[C:4]([O:26][CH3:27])[CH:3]=1.C1(C)C=CC=CC=1.O=S(Cl)[Cl:37]>CN(C=O)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([Cl:37])=[O:21])=[CH:11][CH:10]=2)=[C:4]([O:26][CH3:27])[CH:3]=1
Reactant: COc1cc(F)c(F)cc1-c1ccc(OCc2cccc(C(=O)O)c2)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc(F)c(F)cc1-c1ccc(OCc2cccc(C(=O)Cl)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.5 %

Procedure:
A mixture of 3-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-benzoic acid (16.44 g, 44.39 mmol), toluene (180 mL), SOCl2 (19.4 mL, 265.8 mmol), and anhydrous DMF (1 mL) was heated to reflux overnight, cooled to room temperature, and evaporated to dryness. The residue was co-evaporated twice with toluene followed by high vacuum at 70° C. for 4 h to give 3-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-benzoyl chloride as a solid (17 g).
Reaction SMILES: S(=O)(=O)(O)O.N[C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH3:21])[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:9][CH:8]=1.N([O-])=[O:23].[Na+]>O.S([O-])([O-])(=O)=O.[Cu+2]>[OH:23][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH3:21])[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:9][CH:8]=1
Reactant: O=N[O-]
Reactant: CCOC(=O)CCC(C)c1ccc(N)cc1
Agent: [Cu+2]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: CCOC(=O)CCC(C)c1ccc(O)cc1
Temperature: 25 °C
Yield: 52.4 %

Procedure:
To a solution of 350 g of concentrated sulfuric acid and 350 ml of water cooled to 0° C., 40 g of ethyl 4-(4-aminophenyl)pentanoate was added dropwise, maintaining the temperature at 0°-2° C. The mixture was then treated dropwise with 13.66 g of sodium nitrite in 25 ml of water at such a rate that the temperature did not exceed 2° C. The resultant solution was added dropwise to a refluxing solution of 387 g of copper sulfate in 600 ml of water over a period of approximately 30 minutes. The mixture was refluxed an additional 10 minutes, cooled to room temperature, and 800 ml of water was added. The mixture was extracted thrice with dichloromethane (additional water was needed to dissolve the salts). The organic phase was washed with water, dried over anhydrous sodium sulfate, filtered and evaporated to give an oil. The oil was distilled at 0.6 mm to give 21.05 g (53%) of product, b.p. 129° C., which crystallized on cooling, m.p. 32°-34° C.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[C:9]1(=[O:14])[CH2:13][CH2:12][CH2:11][CH2:10]1.[CH2:15]([O:17][C:18](=[O:37])[CH:19]([CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[C:20](N1C2C=CC=CC=2N=N1)=[O:21])[CH3:16]>C1COCC1>[CH2:15]([O:17][C:18](=[O:37])[CH:19]([CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[C:20](=[O:21])[CH:10]1[CH2:11][CH2:12][CH2:13][C:9]1=[O:14])[CH3:16]
Reactant: CCOC(=O)C(C(=O)n1nnc2ccccc21)C1CCCCC1
Reactant: O=C1CCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)C1CCCC1=O)C1CCCCC1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a −78° C. cold solution of LDA (2 M solution in heptane/ethylbenzene/THF, 15.7 ml, 31 mmol) in THF (96 ml) under an argon atmosphere was added a solution of cyclopentanone (2.78 ml, 31 mmol; CAS Reg. No. 120-92-3) in THF (72 ml) within 25 min. The mixture was stirred for 2 h at −78° C. A solution of 3-benzotriazol-1-yl-2-cyclohexyl-3-oxo-propionic acid ethyl ester (9 g, 29 mmol) in THF (63 ml) was added and the solution was stirred at ambient temperature for 14 h. Ice water was added, the mixture was poured onto ice water/brine 1/1 and extracted two times with TBME. The combined extracts were washed with ice water/brine 1/1 and dried over Na2SO4. After filtration the solvent was removed under reduced pressure to give the title compound (8.8 g; quant.) which was used in the next step without further purification.
Reaction SMILES: Cl.[O:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]3[CH:20]=[CH:19][C:15]([CH:16]=[N:17][OH:18])=[CH:14][CH:13]=3)[CH2:8][CH2:7]2)[O:5][CH2:4][CH2:3]1.C([BH3-])#N.[Na+].[OH-].[Na+]>CN(C1C=CC(N=NC2C=CC(S(O)(=O)=O)=CC=2)=CC=1)C.O.CO>[OH:18][NH:17][CH2:16][C:15]1[CH:19]=[CH:20][C:12]([N:9]2[CH2:8][CH2:7][C:6]3([O:5][CH2:4][CH2:3][O:2]3)[CH2:11][CH2:10]2)=[CH:13][CH:14]=1
Reactant: ON=Cc1ccc(N2CCC3(CC2)OCCO3)cc1
Agent: CN(C)c1ccc(N=Nc2ccc(S(=O)(=O)O)cc2)cc1
Agent: Cl
Agent: [BH3-]C#N
Solvent: O
Solvent: CO
Product: ONCc1ccc(N2CCC3(CC2)OCCO3)cc1
Reaction time: 1 h
Yield: 78.5 %

Procedure:
Hydrochloric acid (4N, in dioxane) was added dropwise into a mixture of 4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)benzaldehyde oxime (5.3 g, 20.24 mmol) (which was obtained in Example 51), sodium cyanoborohydride (6.3 g, 101.2 mmol), methyl alcohol(200 mL), and methyl orange (10 mg), until an acidic solution (pH about 4) was achieved. The mixture was then stirred for 1 hour, poured into water, neutralized with NaOH (2N) and extracted with ethyl acetate. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography (hexanes/ethyl acetate/methyl alcohol 10/5/1) gave a white solid (4.2 g, 78% yield); mp 107-109° C,; 1H NMR (400 MHz, DMSO-d6) δ 1.64 (m, 4H), 3.20 (m, 4H), 3.74 (s, 2H), 3.90 (s, 4H), 5.84 (brs, 1H), 6.86 (m, 2H), 7.14 (m, 2H), 7.19 (brs, 1H); MS (ES) m/z: 265 (MH+).