Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [2H][C:2]1[C:7]([2H])=[C:6]([NH2:9])[C:5]([NH2:10])=[C:4]([2H])[C:3]=1[2H].[Cl:13][C:14]([Cl:20])([Cl:19])[C:15](=N)OC>C(O)(=O)C>[Cl:13][C:14]([Cl:20])([Cl:19])[C:15]1[NH:10][C:5]2[CH:4]=[CH:3][CH:2]=[CH:7][C:6]=2[N:9]=1
Reactant: COC(=N)C(Cl)(Cl)Cl
Reactant: [2H]c1c([2H])c([2H])c(N)c(N)c1[2H]
Solvent: CC(=O)O
Product: ClC(Cl)(Cl)c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
O-Phenylenediamine (25 g) was dissolved in acetic acid (750 ml), and methyl 2,2,2-trichloroacetimidate (28.5 ml) was added dropwise over 15 min. After stirring at room temperature for 1 hr, the reaction mixture was concentrated to about 150 ml, and poured into water (1500 ml). The precipitated crystals were collected by filtration, washed with water (1000 ml) and suspended in toluene (500 ml). The solvent was evaporated under reduced pressure. The residue was again suspended in toluene (500 ml) and the solvent was evaporated under reduced pressure. The residue was dried under reduced pressure to give the object product (51.8 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([CH:10]=O)[CH:7]=[CH:6][C:5]=1[C:12]#[C:13][C:14]1([OH:22])[CH:19]2[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]2)[CH2:15]1)[CH3:2].[C:23]([CH:28]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:25][CH2:26][CH3:27])=[O:24]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([CH:10]=[CH:28][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:7]=[CH:6][C:5]=1[C:12]#[C:13][C:14]1([OH:22])[CH:19]2[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]2)[CH2:15]1)[CH3:2]
Reactant: CCOc1cc(C=O)ccc1C#CC1(O)CN2CCC1CC2
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C=Cc1ccc(C#CC2(O)CN3CCC2CC3)c(OCC)c1
Temperature: 100 °C
Yield: 44.4 %

Procedure:
A mixture of 3-[2-(2-ethoxy-4-formylphenyl)ethynyl]quinuclidin-3-ol (598 mg), carbethoxymethylenetriphenylphosphorane (1.04 g) in toluene (10 ml) was heated at 100° C. for 5 hours. The reaction mixture was cooled to ambient temperature and the toluene evaporated to give a solid which was crystallised from acetonitrile to give 3-[2-(2-ethoxy-4-(2-ethoxycarbonylethenyl)phenyl)ethynyl]quinuclidin-3-ol (328 mg) as a solid, m.p. 152-153° C.; microanalysis found: C, 71.5; H, 7.3; N, 3.7%; C22H27NO4 requires: C, 71.5: H, 7.37; N, 3.79%; NMR (CDCl3): 1.33(3H, t), 1.36-1.52(4H, m), 1.55-1.70(1H, m), 1.90-2.30(4H, m), 2.73-3.00(4H, m), 3.04(1H, d), 3.34(1H, dd), 4.09(2H, q), 4.26(2H, q), 6.33-6.45(1H, d), 6.93-7.03(1H, d,), 7.03(1H, dd), 7.35(1H, d), 7.60(1H, d); m/Z 370 (M+H).
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][C@H:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C@H:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:7]1)=O)C.C(O)C.[OH-].[Na+].[ClH:31]>CCOCC.C(OCC)(=O)C>[ClH:31].[F:19][C:16]1[CH:15]=[CH:14][C:13]([O:12][C@H:9]2[CH2:10][CH2:11][NH:6][CH2:7][C@H:8]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:18][CH:17]=1
Reactant: CCOC(=O)N1CC[C@H](Oc2ccc(F)cc2)[C@H](c2ccccc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CCO
Product: Fc1ccc(O[C@H]2CCNC[C@H]2c2ccccc2)cc1
Reaction time: 8 h

Procedure:
A mixture of 3.62 g of cis-1-ethoxycarbonyl-4-(4-fluorophenoxy)-3-phenylpiperidine, 52 ml of absolute ethanol and 28 ml of 20% sodium hydroxide solution is refluxed overnight under nitrogen. The ethanol is then removed in vacuo and the aqueous residue partitioned between water (50 ml) and ether (100 ml). The phases are separated and the aqueous phase extracted with 2×100 ml of ether. The combined ether extracts are washed with 100 ml of saturated sodium chloride solution and dried overnight over anhydrous sodium sulfate. Filtration and concentration in vacuo affords a cloudy yellow oil. The oil is dissolved in ether and treated dropwise with saturated etheral hydrogen chloride. The solvent is removed in vacuo and the resulting foam triturated with ether to afford a nearly colorless solid. The solid is dissolved in 70 ml of boiling ethyl acetate, filtered hot, and the filtrate concentrated to a volume of 30 ml. The solution is scratched, seeded and allowed to stand overnight at room temperature. Filtration followed by washing with ethyl acetate and ether and drying in vacuo affords the product as a colorless crystalline solid, mp 150°-152° C.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:27]=[CH:26][C:9]2[N:10]=[C:11]([NH:14][CH:15]3[C:19]4[C:20]([O:24][CH3:25])=[CH:21][CH:22]=[CH:23][C:18]=4[O:17][CH2:16]3)[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4].[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH3:25][O:24][C:20]1[C:19]2[CH:15]([NH:14][C:11]3[O:12][CH2:13][C:8]4[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:32]5[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]5)[CH:27]=[CH:26][C:9]=4[N:10]=3)[CH2:16][O:17][C:18]=2[CH:23]=[CH:22][CH:21]=1
Reactant: COc1cccc2c1C(NC1=Nc3ccc(NC(=O)CCl)cc3CO1)CO2
Reactant: CN1CCNCC1
Product: COc1cccc2c1C(NC1=Nc3ccc(NC(=O)CN4CCN(C)CC4)cc3CO1)CO2
Yield: 79.3 %

Procedure:
Prepared from rac-2-chloro-N-[2-(4-methoxy-2,3-dihydro-benzofuran-3-ylamino)-4H-benzo[d][1,3]oxazin-6-yl]-acetamide (Example 8) (370 mg, 0.95 mmol) and 1-methylpiperazine (2.12 ml, 19.08 mmol) according to the procedure described for Example 3 step B. Obtained the title compound as a white foam (340 mg, 79%), MS (ISP) m/e=452.3 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH:13]=O)[N:8]2[CH3:11])=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1.[CH:21]12[NH:28][CH:25]([CH2:26][CH2:27]1)[CH2:24][O:23][CH2:22]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH2:13][N:28]3[CH:21]4[CH2:27][CH2:26][CH:25]3[CH2:24][O:23][CH2:22]4)[N:8]2[CH3:11])=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1
Reactant: Cn1c(CC=O)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: C1CC2COCC1N2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cn1c(CCN2C3CCC2COC3)nc2c(N3CCOCC3)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.9 %

Procedure:
To a solution of (2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)acetaldehyde (117 mg, 0.40 mmol) in DCE (10 mL) was added 3-oxa-8-azabicyclo[3.2.1]octane (54 mg, 0.48 mmol) and powdered 4 Å molecular sieves. The reaction mixture was stirred at room temperature for 2 h, sodium triacetoxyborohydride (168 mg, 0.79 mmol) was added and the resulting mixture stirred for a further 16 h. The reaction mixture was filtered through Celite®, loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then the desired product eluted with 2 M NH3 in MeOH. The resulting residue was purified by column chromatography (Si—PCC, 0-10% MeOH in DCM) to give the title compound as a pale yellow oil (80 mg, 51%). LCMS (Method H): RT=2.34 min, [M+H]+ 393.5
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([S:13]([NH:16][C@H:17]([C:25]([N:27]3[CH2:32][CH2:31][S:30][CH2:29][CH:28]3[C:33]([O:35]CC)=[O:34])=[O:26])[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:24])[NH2:23])(=[O:15])=[O:14])=[CH:10]2)=[CH:5][CH:4]=1>CO.[OH-].[Na+]>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([S:13]([NH:16][C@H:17]([C:25]([N:27]3[CH2:32][CH2:31][S:30][CH2:29][CH:28]3[C:33]([OH:35])=[O:34])=[O:26])[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:23])[NH2:24])(=[O:14])=[O:15])=[CH:10]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)C1CSCCN1C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc2ccc(OC)cc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2ccc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)N3CCSCC3C(=O)O)cc2c1
Reaction time: 24 h
Yield: 68.5 %

Procedure:
A solution of 2 g of ethyl 4-[N2 -(7-methoxy-2-naphthalenesulfonyl)-L-arginyl]thiomorpholine-3-carboxylate in 15 ml of methanol and 4 ml of 2N sodium hydroxide solution was warmed to 50° C and held at that temperature for 24 hours. At the end of this period, the reaction mixture was concentrated and chromatographed on 200 ml of Daiaion® SK 102 ion exchange resin (200-300 mesh, H+ form, manufactured by Mitsubishi Chemical Industries Limited) packed in water, washed with ethanol-water (1:4) and eluted with ethanol-water-NH4OH (10:9:1). The main fraction was evaporated to dryness and washed with ether to give 1.3 g of 4-[N2 -(7-methoxy-2-naphthalenesulfonyl)-L-arginyl]thiomorpholine-3-carboxylic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])=[C:11]([C:23]#[N:24])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[C:11]([C:23]#[N:24])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)Cc1ccc(OCc2ccccc2)cc1C#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(OCc2ccccc2)ccc1CC(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl [4-(benzyloxy)-2-cyanophenyl]acetate (0.48 g, 1.48 mmol) in DCM (7 ml) was treated with TFA (3.43 ml, 44.5 mmol) and the mixture stirred at RT for 30 min. The volatiles were removed in vacuo to afford the title compound. LC/MS (m/z): 268 (M+H)+.
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:17]=[N:16][C:15]([C:18]3[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=3)[C:21]([O:23][CH3:24])=[O:22])=[N:14]2)=[CH:9][CH:8]=1.B>C1COCC1>[N:3]1([C:7]2[CH:8]=[CH:9][C:10]([N:13]3[CH:17]=[N:16][C:15]([C:18]4[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=4)[C:21]([O:23][CH3:24])=[O:22])=[N:14]3)=[CH:11][CH:12]=2)[CH2:2][CH2:6][CH2:5][CH2:4]1
Reactant: COC(=O)c1cccc(-c2ncn(-c3ccc(N4CCCC4=O)cc3)n2)c1
Agent: B
Solvent: C1CCOC1
Product: COC(=O)c1cccc(-c2ncn(-c3ccc(N4CCCC4)cc3)n2)c1
Reaction time: 16 h
Yield: 84.2 %

Procedure:
A solution of methyl 3-{1-[4-(2-oxo-pyrrolidin-1-yl)-phenyl]-1H-[1,2,4]triazol-3-yl}-benzoate (278 mg, 0.77 mmol) in THF (5 mL) is treated with borane.tetrahydrofuran complex (3.85 mmol) at ambient temperature. The resulting solution is stirred for 16 h, and quenched by the addition of 6N aq. HCl. After being allowed to stir for 30 min, the mixture is made basic with the addition of 1N aq. sodium hydroxide solution. The mixture is partially evaporated until a precipitate formed, which is collected by filtration, washed with water, and dried under vacuum to afford 226 mg (84%) of methyl 3-[1-(4-pyrrolidin-1-yl-phenyl)-1H-[1,2,4]triazol-3-yl]-benzoate.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]1[CH2:16][CH2:15][C@H:14]([NH2:17])[C@H:13]([O:18][CH3:19])[CH2:12]1.[H][H]>C(O)(=O)C>[CH3:19][O:18][C@H:13]1[C@@H:14]([NH2:17])[CH2:15][CH2:16][N:11]([CH2:10][C:2]2[NH:1][C:5]3[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=3[N:3]=2)[CH2:12]1
Reactant: [H][H]
Reactant: CO[C@@H]1CN(Cc2nc3ccccc3[nH]2)CC[C@@H]1N
Solvent: CC(=O)O
Product: CO[C@@H]1CN(Cc2nc3c([nH]2)CCCC3)CC[C@@H]1N

Procedure:
A mixture of 9 parts of cis-1-(1H-benzimidazol-2-ylmethyl)-3-methoxy-4-piperidinamine and 150 parts of acetic acid was hydrogenated at normal pressure and at room temperature with 2 parts of rhodium-on-charcoal catalyst 5%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) saturated with ammonia, as eluent. The second fraction was collected and the eluent was evaporated, yielding 5 parts of cis-3-methoxy-1-[(4,5,6,7-tetrahydro-1H-benzimidazol-2-yl)-methyl]-4-piperidinamine as a residue (intermediate 113).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[NH:11][CH2:12][CH2:13][N:7]3[C:6]=2[C:5]([CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:4][CH:3]=1.Br[C:20]1[C:25]([CH3:26])=[CH:24][C:23]([N+:27]([O-:29])=[O:28])=[CH:22][N:21]=1.N1C=CC=CC=1C1C=CC=CN=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O.C(OCC)(=O)C.[Cu]I>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:20]4[C:25]([CH3:26])=[CH:24][C:23]([N+:27]([O-:29])=[O:28])=[CH:22][N:21]=4)[CH2:12][CH2:13][N:7]3[C:6]=2[C:5]([CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:4][CH:3]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1Br
Reactant: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCN3
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCN3c1ncc([N+](=O)[O-])cc1C
Temperature: 150 °C
Reaction time: 5 h

Procedure:
A mixture of 8-chloro-5-(1-ethylpropyl)-2,3-dihydro-1H-imidazo[1,2-a]benzimidazole (30.6 mg, 0.116 mmol), 2-bromo-3-methyl-5-nitropyridine (50.4 mg, 0.232 mmol), copper(I) iodide (22.1 mg, 0.116 mmol), 2,2′-bipyridyl (36.2 mg, 0.232 mmol) and cesium carbonate (75.6 mg, 0.232 mmol) in 1-methyl-2-pyrrolidinone (1.0 mL) was stirred at 150° C. for 5 hrs. After cooling, the mixture was diluted with ethyl acetate, the precipitate was filtered through a pad of celite. The filtrate was extracted with ethyl acetate (×3). The combined organic layer was washed with 1N hydrochloric acid (×1) and brine (×1), dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-30% ethyl acetate/n-hexane gradient mixture to give the title compound as a yellow amorphous (13.5 mg, 0.0338 mmol, 29%).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[C:6](I)[C:5]([C:20]2[CH:21]=[C:22]([C:26]([NH:29][S:30]([CH2:33][C:34]([F:37])([F:36])[F:35])(=[O:32])=[O:31])([CH3:28])[CH3:27])[CH:23]=[CH:24][CH:25]=2)=[N:4]1)[CH3:2].[Cu][C:39]#[N:40]>CC(N(C)C)=O>[C:39]([C:6]1[C:5]([C:20]2[CH:21]=[C:22]([C:26]([NH:29][S:30]([CH2:33][C:34]([F:37])([F:36])[F:35])(=[O:32])=[O:31])([CH3:28])[CH3:27])[CH:23]=[CH:24][CH:25]=2)=[N:4][N:3]([CH2:1][CH3:2])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)#[N:40]
Reactant: N#C[Cu]
Reactant: CCn1nc(-c2cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c2)c(I)c1Oc1ccc(C(F)(F)F)cc1
Solvent: CC(=O)N(C)C
Product: CCn1nc(-c2cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c2)c(C#N)c1Oc1ccc(C(F)(F)F)cc1
Temperature: 150 °C
Yield: 32 %

Procedure:
A suspension of N-[2-(3-{1-ethyl-4-iodo-5-[4-(trifluoromethyl)phenoxy]-1H-pyrazol-3-yl}phenyl)propan-2-yl]-2,2,2-trifluoroethanesulfonamide (538 mg, 0.813 mmol), copper (I) cyanide (729 mg, 8.13 mmol) and DMA (0.813 mL) was heated to 150° C. for 16 h. The reaction was cooled, partitioned between EtOAc and sat aq NaHCO3, and filtered. The organic layer was washed with sat aq. NaHCO3 2×, dried (MgSO4) and concentrated to afford a light yellow purified twice via MPLC, 50 g silica, 10-50% EtOAc in heptanes to afford 146 mg of a white solid: MS: cal'd 561 (MH+), exp 561 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:10](=[O:21])[NH:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)[CH3:13])=[CH:8][CH:9]=1)=[O:4].[C:22]1([CH3:30])[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]=O)[CH:23]=1.C([BH3-])#N.[Na+].[Cl-].[NH4+]>O.C1COCC1.C(O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:10](=[O:21])[NH:11][CH:12]([C:14]2[CH:15]=[CH:16][C:17]([NH:20][CH2:30][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=3)=[CH:18][CH:19]=2)[CH3:13])=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1ccc(C(=O)NC(C)c2ccc(N)cc2)s1
Reactant: Cc1cccc(C=O)c1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(C(=O)NC(C)c2ccc(NCc3cccc(C)c3)cc2)s1
Yield: 43 %

Procedure:
A mixture of 304.0 mg (1.0 mmol) 5-[1-(4-amino-phenyl)-ethylcarbamoyl]-thiophene-2-carboxylic acid methyl ester, 120.0 mg (1.0 mmol) m-tolualdehyde and 2 ml ethanol was heated under reflux for 1 h. The solvent was evaporated and 3 ml THF and 315 mg (5.0 mmol) sodium cyanoborohydride were added to the residue. After 18 h 5 ml aqueous ammonium chloride solution and 10 ml water were added. The aqueous phase was extracted with dichloromethane, the combined organic phases were dried over magnesium sulfate, the solvent was evaporated and the residue subjected to silica gel chromatography (ethyl acetate/petrol ether 1:1) to yield 175 mg (0.43 mmol) 5-{1-[4-(3-Methyl-benzylamino)-phenyl]-ethylcarbamoyl}-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[BH4-].[Na+]>CO>[Br:1][C:2]1[C:3]([F:10])=[C:4]([CH2:5][OH:6])[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(Br)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cccc(Br)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.2 %

Procedure:
2.00 g of 3-bromo-2-fluorobenzaldehyde are dissolved in 98 ml of methanol; 560 mg of sodium borohydride are added portionwise thereto. The mixture is stirred at ambient temperature for 2 hours and then the solvent is evaporated under reduced pressure. The residue is taken up between water and ethyl acetate and the organic phase is separated, dried and concentrated under reduced pressure. The residue is purified by chromatography on silica gel, elution being carried out with a dichloromethane/methanol mixture. 1.56 g of compound are obtained.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH3:31])[CH2:10][NH:11][C:12]([CH3:30])([CH3:29])[CH2:13][C:14]([NH:16][C@@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[NH:19][C:18]1=[O:28])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32]([O:36][C:37]([NH:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[C:47]1[CH:52]=[CH:51][C:50]([CH2:53]O)=[CH:49][CH:48]=1)=[O:38])([CH3:35])([CH3:34])[CH3:33]>>[CH2:1]([O:8][C@H:9]([CH3:31])[CH2:10][NH:11][C:12]([CH3:30])([CH3:29])[CH2:13][C:14]([NH:16][C@@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH2:53][C:50]2[CH:49]=[CH:48][C:47]([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=3[CH2:40][NH:39][C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:38])=[CH:52][CH:51]=2)[C:18]1=[O:28])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](CNC(C)(C)CC(=O)N[C@@H]1CCc2ccccc2NC1=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCc1ccccc1-c1ccc(CO)cc1
Product: C[C@H](CNC(C)(C)CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3CNC(=O)OC(C)(C)C)cc2)C1=O)OCc1ccccc1

Procedure:
Prepared from 3-[2(R)-benzyloxypropyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R )-yl]butanamide (Example 1, Step C) and 2'-[(t-butoxycarbonylamino)methyl]-1,1'-biphenyl-4-methanol, methanesulfonate ester (Example 8, Step F) by the procedure described in Example 1, Step D. 1H NMR (200 MHz, CDCl3): δ1.14 (s, 3H), 1.19 (s, 3H), 1.23 (d, 6 Hz, 3H), 1.39 (s, 9H), 1.86 (m, 1H), 2.20-2.75 (m, 7H), 3.88 (m, 1H), 4.18 (d, 6 Hz, 2H), 4.48-4.66 (m, 3H), 4.92 (d, 15 Hz, 1H), 5.13 (d, 15 Hz, 1H), 7.10-7.43 (m, 20 H). CI-MS: calculated for C44H54N4O5 718; found 719 (M+H).
Reaction SMILES: [CH:1]1([C:5]2[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH2:15]C)[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.Br[C:18]1C=CC(C(OC)=O)=C(C)C=1.C1(C[Mg]Br)CCC1.C1([Mg]Br)CCC1>>[CH:4]1([CH2:1][C:5]2[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH3:15])[CH:6]=2)[CH2:3][CH2:2][CH2:18]1
Reactant: CCc1cc(C2CCC2)ccc1C(=O)OC
Reactant: COC(=O)c1ccc(Br)cc1C
Agent: Br[Mg]C1CCC1
Agent: Br[Mg]CC1CCC1
Product: COC(=O)c1ccc(CC2CCC2)cc1C
Yield: 84 %

Procedure:
The title compound (4.00 g, yellow oil, 84%) was prepared using a procedure similar to that used for the preparation of compound 181.3 using compound 152.1 (5.00 g) and cyclobutylmethylmagnesium bromide in place of compound 181.2 and cyclobutylmagnesium bromide respectively.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.I[CH:15]1[C:20](OC)([O:21]C)[CH2:19][CH2:18][O:17][CH2:16]1>>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([CH:15]2[C:20](=[O:21])[CH2:19][CH2:18][O:17][CH2:16]2)=[CH:5][CH:4]=1
Reactant: COC1(OC)CCOCC1I
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: O=C1CCOCC1c1ccc(C(F)(F)F)cc1

Procedure:
4-(trifluoromethyl)phenylboronic acid was reacted as described in Intermediate X(2) with 3-iodo-4,4-dimethoxytetrahydro-2H-pyran (Intermediate X(1)) to give 3-(4-(trifluoromethyl)phenyl)dihydro-2H-pyran-4(3H)-one (Intermediate Z(2)).
Reaction SMILES: C([O-])=O.[NH4+].[O:5]=[C:6]([N:31]1[CH2:36][CH2:35][N:34]([C:37](=[O:48])[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[C:44]([F:47])([F:46])[F:45])[CH2:33][CH2:32]1)[CH2:7][NH:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23]CC2C=CC=CC=2)=[CH:13][CH:12]=1)=[O:10]>CO.O.[Pd]>[O:5]=[C:6]([N:31]1[CH2:36][CH2:35][N:34]([C:37](=[O:48])[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[C:44]([F:46])([F:47])[F:45])[CH2:33][CH2:32]1)[CH2:7][NH:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[OH:23])=[CH:13][CH:12]=1)=[O:10]
Reactant: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc(-c2ccccc2OCc2ccccc2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc(-c2ccccc2O)cc1
Temperature: 25 °C
Yield: 47 %

Procedure:
Ammonium formate (350 mg, 5.5 mmol) was added to a stirred solution of 2′-Benzyloxy-biphenyl-4-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide (prepared by the method as described above) (156 mg, 0.26 mmol) in a mixture of MeOH (10 mL) and water (2 ml). 10% Pd/c (40 mg) was then added and the resulting mixture stirred at room temperature under an inert atmosphere. The reaction mixture was then stirred at reflux temperature for 3 hrs. The mixture was filtered over a bed of celite. The celite was washed with MeOH and the filtrate was concentrated. The residue was dissolved in EtOAc, washed with 5% aqueous NaOH solution, followed by saturated brine solution. The organic layer was dried over Na2SO4 and concentrated to get the residue. The residue was purified by preparative HPLC to afford 62 mg (47% yield) of 2′-Hydroxy-biphenyl-4-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LCMS Purity: 98.83%. 1H NMR (DMSO-d6): δ 9.6 (s, 1H), 8.64-8.5 (bs, 1H), 7.92-7.72 (m, 4H), 7.72-7.5 (m, 4H), 7.26-7.12 (d, 1H), 7.24-7.16 (t, 1H), 7.0-6.84 (m, 2H), 4.24-4.06 (bd, 2H), 3.82-3.52 (m, 4H), 3.52-3.42 (bs, 2H), 3.24-3.02 (bd, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][CH2:14][OH:15])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][Si](C=[N+]=[N-])(C)C>CO>[CH3:16][O:11][C:10](=[O:12])[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:13][CH2:14][OH:15]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)NC(CCO)C(=O)O
Solvent: CO
Product: COC(=O)C(CCO)NC(=O)OC(C)(C)C

Procedure:
2-tert-Butoxycarbonylamino-4-hydroxy-butyric acid (0.79 g, 3.6 mmol) was dissolved in 15 ml methanol at room temperature and (trimethylsilyl)diazomethane (2M solution in hexane) was added till solution become yellow. The mixture was concentrated down to afford crude 2-tert-butoxycarbonylamino-4-hydroxy-butyric acid methyl ester.
Reaction SMILES: C([C@@H]1CCCC[C@H]1N)C.[CH2:10]([CH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([CH2:18]C)[CH:13]1[NH2:20])C>>[CH3:10][CH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([CH3:18])[CH:13]1[NH2:20]
Reactant: CCC1CCCC(CC)C1N
Agent: CC[C@@H]1CCCC[C@H]1N
Product: CC1CCCC(C)C1N

Procedure:
trans-2-ethylcyclohexylamine, B.P. 77°-78° (23 mm.); 2,6-diethylcyclohexylamine, B.P. 96° C., (17 mm.);
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:22]=[C:21]([O:23]C)[CH:20]=[CH:19][C:18]=2[O:25]C)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.B(Br)(Br)Br>ClCCl>[OH:25][C:18]1[CH:19]=[CH:20][C:21]([OH:23])=[CH:22][C:17]=1[CH:14]1[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]1
Reactant: COc1ccc(OC)c(C2CCN(C(=O)OCc3ccccc3)CC2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(O)c(C2CCNCC2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 143.1 %

Procedure:
A solution of 1-benzyloxycarbonyl-4-(2,5-dimethoxyphenyl)piperidine (0.54 g), prepared as described in Example 21.b., in 10 mL of dichloromethane, was cooled to 0° C. and treated with a solution of boron tribromide in dichloromethane (1.0M, 9 mL). After stirring for 1 hour at 0° C., the reaction mixture was allowed to warm to room temperature. At the end of the period, the reaction mixture was cooled to 0° C. and quenched with methanol. The resulting solution was evaporated and then treated with additional amounts of methanol. After evaporation the product was obtained as a yellow solid (0.42 g); MS: 194; NMR: 1.6-1.9 (m, 4), 3.0 (m, 2), 3.3 (br, 2), 6.4-6.5 (m, 2), 6.6 (d, J=8, 1), 8.3-8.8 (m, 3).