Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]([CH3:25])[C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11]C(=O)OCC2C=CC=CC=2)[C@H:7]([CH2:22][O:23][CH3:24])[CH2:6]1)([CH3:3])[CH3:2].C(OCC)C>Br.C(O)(=O)C>[CH:1]([N:4]([CH3:25])[C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH2:11])[C@H:7]([CH2:22][O:23][CH3:24])[CH2:6]1)([CH3:3])[CH3:2]
Reactant: COC[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1NC(=O)OCc1ccccc1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: COC[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 337.2 %

Procedure:
Benzyl(1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(methoxymethyl)cyclohexylcarbamate (135 mg) was dissolved in 30% HBr in acetic acid (3 ml) and stirred at rt for 45 min. Diethyl ether was added and the resulting gum was isolated, washed with additional ether, stripped four times from benzene and dried under vacuum to provide the dihydrobromide salt of (1R,3R,4S)-N1-isopropyl-3-(methoxymethyl)-N1-methylcyclohexane-1,4-diamine (280 mg) as a gum, used without further purification. MS found: (M+H)+=215.2.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][CH:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:22]1>CCCCO>[Br:1][C:2]1[C:3]([N:21]2[CH2:26][CH2:25][CH2:24][CH:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[CH2:22]2)=[C:4]2[C:10]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)c1cccnc1
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Solvent: CCCCO
Product: CC(C)(C)OC(=O)NC1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)c4cccnc4)c23)C1
Temperature: 160 °C
Reaction time: 20 h
Yield: 32.5 %

Procedure:
A solution of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (120 mg, 0.358 mmol) in n-BuOH (5 mL) was treated with tert-butyl piperidin-3-ylcarbamate (359 mg, 1.79 mmol) and stirred at 160° C. for 20 hours in a sealed tube. The mixture was concentrated in vacuo, and the residue was purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column, 20-80% CH3CN/water gradient; 20 CV) to provide tert-butyl 1-(5-bromo-3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (60 mg, 32% yield) as a solid. 1H NMR (400 MHz, CDCl3) δ 10.10 (br s, 1H), 9.27 (m, 1H), 9.19 (d, 1H), 8.79 (d, 1H), 8.33-8.29 (m, 2H), 8.18 (br s, 1H), 7.51-7.47 (m, 1H), 4.54-4.78 (m, 1H), 3.84-3.69 (m, 1H), 3.64-3.41 (m, 3H), 3.08-2.95 (m, 1H), 2.09-1.96 (m, 1H), 1.92-1.50 (m, 2H), 1.42 (s, 9H); LCMS (APCI+) m/z 515.1, 517.1 (M+H)+, Retention time=2.83 minutes (Method 1).
Reaction SMILES: C(OC1C=CN([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][C:19]=2[CH3:26])=[O:17])C(=O)C=1)C1C=CC=CC=1.[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35][O:36][C:37]2[CH:42]=[CH:41][NH:40][C:39](=[O:43])[CH:38]=2)=[N:33][CH:34]=1>>[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35][O:36][C:37]2[CH:42]=[CH:41][N:40]([CH2:15][C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][C:19]=3[CH3:26])=[O:17])[C:39](=[O:43])[CH:38]=2)=[N:33][CH:34]=1
Reactant: Cc1cc(CO)ccc1C(=O)Cn1ccc(OCc2ccccc2)cc1=O
Reactant: O=c1cc(OCc2ccc(Cl)cn2)cc[nH]1
Product: Cc1cc(CO)ccc1C(=O)Cn1ccc(OCc2ccc(Cl)cn2)cc1=O
Yield: 99 %

Procedure:
4-(5-Chloro-pyridin-2-ylmethoxy)-1-[2-(4-hydroxymethyl-2-methyl-phenyl)-2-oxo-ethyl]-1H-pyridin-2-one is prepared following preparation 1c employing 4-(5-chloro-pyridin-2-ylmethoxy)-1H-pyridin-2-one (described in WO 09/103,478) instead of 4-benzyloxy-1H-pyridin-2-one.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=2[C:9]=1[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4].Cl[S:23]([C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[C:28]([OH:35])[CH:27]=1)(=[O:25])=[O:24]>>[CH2:1]([C:5]1[O:6][C:7]2[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=2[C:9]=1[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][S:23]([C:26]2[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[C:28]([OH:35])[CH:27]=2)(=[O:25])=[O:24])=[CH:15][CH:16]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Reactant: CCCCc1oc2ccccc2c1Cc1ccc(O)cc1
Product: CCCCc1oc2ccccc2c1Cc1ccc(OS(=O)(=O)c2ccc(C(=O)O)c(O)c2)cc1
Yield: 85.1 %

Procedure:
The title compound was prepared according to the procedure in Example 4 using 4-(2-butyl-benzofuran-3-ylmethyl)-phenol (0.500 g, 1.78 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.844 g, 3.56 mmol). Purification on 2% H3PO4/MeOH treated silica gel, eluting with EtOAc/hexane gave 0.728 g (86%) of the title compound as an orange solid, mp 135-138° C. 1H NMR (DMSO-d6) δ0.84 (t, 3H), 1.27 (sextet, 2H), 1.58 (quintet, 2H), 2.76 (t, 2H), 3.97 (s, 2H), 6.96 (d, 2H), 7.10 (dt, 1H), 7.17 (dt, 1H), 7.22-7.31 (m, 5H), 7.43 (d, 1H), 7.95 (d, 1H). IR (KBr) 3300, 2950, 1675, 1390 and 1175 cm−1. mass spectrum (−ESI) m/z 479 (M−H). Anal. Calcd. for C26H24O7S.0.2H2O: C, 64.50; H, 5.08; N, 0.00. Found: C, 64.50; H, 5.07; N, 0.06.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([CH2:31][N+:32]([O-])=O)([C:27]([F:30])([F:29])[F:28])[CH2:10][C:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([NH:19][CH:20]3[CH2:23][S:22][CH2:21]3)=[O:18])=[C:15]([CH3:26])[CH:14]=2)=O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:27]([F:30])([F:29])[F:28])[CH2:31][N:32]=[C:11]([C:13]3[CH:25]=[CH:24][C:16]([C:17]([NH:19][CH:20]4[CH2:23][S:22][CH2:21]4)=[O:18])=[C:15]([CH3:26])[CH:14]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1cc(C(=O)CC(C[N+](=O)[O-])(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)NC1CSC1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C2=NCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NC1CSC1
Temperature: 80 °C
Reaction time: 4 h
Yield: 16.9 %

Procedure:
To a solution of 4-[3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-3-nitromethyl-butyryl]-2-methyl-N-thietan-3-yl-benzamide (Example I21) (78 mg) in DMF (1.5 ml) zinc powder (48 mg) was added at ambient temperature. The reaction mixture was heated to 80° C. and concentrated hydrochloric acid (0.3 ml) was added drop-wise. The reaction mixture was stirred at 80° C. for 4 hours. Water was added and the mixture was extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by prep. HPLC to give give 4-[4-(3,5-dichloro-phenyl)-4-trifluoromethyl-4,5-dihydro-3H-pyrrol-2-yl]-2-methyl-N-thietan-3-yl-benzamide (12 mg). 1H-NMR (400 MHz, CDCl3): 7.75-7.25 (m, 6H), 6.35 (s, 1H), 5.45 (m, 1H), 4.90 (d, 1H), 4.45 (d, 1H), 3.82 (d, 1H), 3.55-3.38 (m, 5H), 2.48 (s, 3H) ppm.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:15]2=[O:25])[CH2:10][CH2:9]1)C1C=CC=CC=1.O.Cl.[H][H]>CO.[Pd]>[NH:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH2:18][CH2:17][N:16]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:15]2=[O:25])[CH2:12][CH2:13]1
Reactant: [H][H]
Reactant: O=C1N(c2ccccc2)CCN1C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: O=C1N(c2ccccc2)CCN1C1CCNCC1
Yield: 93.6 %

Procedure:
11.1 g of 1-(1-benzyl-4-piperidinyl)-3-phenyl-2-imidazolidinone are dissolved in 85 ml of methanol, 34 ml of water and 3.2 ml of hydrochloric acid (chemically pure), and, with the addition of 1.2 g of a 5% palladium on charcoal catalyst, hydrogenated at room temperature and under normal pressure. The calculated amount of hydrogen has been taken up after approx. 15 hours. The reaction mixture is filtered to remove the catalyst and concentrated in a water jet vacuum. The crystalline residue is treated with 2N sodium carbonate solution and extracted with chloroform. The combined chloroform extracts are dried over sodium sulphate and concentrated in a water jet vacuum to yield 7.6 g of 1-(4-piperidinyl)-3-phenyl-2-imidazolidinone as a colourless oil which crystallises on standing; melting point 123°-124° C.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([N:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[CH2:5][CH2:4]1.Cl[C:20]1[CH:25]=[C:24]([C:26]([N:28]2[C:36]3[C:31](=[CH:32][C:33]([F:37])=[CH:34][CH:35]=3)[CH2:30][CH2:29]2)=[O:27])[CH:23]=[C:22]([O:38][CH3:39])[N:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1>[F:37][C:33]1[CH:32]=[C:31]2[C:36](=[CH:35][CH:34]=1)[N:28]([C:26]([C:24]1[CH:23]=[C:22]([O:38][CH3:39])[N:21]=[C:20]([N:3]3[CH2:4][CH2:5][CH:6]([N:9]4[C:17]5[C:12](=[N:13][CH:14]=[CH:15][CH:16]=5)[NH:11][C:10]4=[O:18])[CH2:7][CH2:8]3)[CH:25]=1)=[O:27])[CH2:29][CH2:30]2
Reactant: COc1cc(C(=O)N2CCc3cc(F)ccc32)cc(Cl)n1
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1cc(C(=O)N2CCc3cc(F)ccc32)cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)n1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
A mixture of 0.361 g (1.24 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one dihydrochloride, 0.380 mg (1.24 mmol) (2-chloro-6-methoxypyridin-4-yl)-(5-fluoro-2,3-dihydroindol-1-yl)-methanone and 514 mg (3.72 mmol) potassium carbonate in 3.0 mL NMP was stirred for 8 h at 130° C. After cooling the reaction mixture to RT the precipitate formed was filtered off and purified by preparative HPLC. The fractions containing the product were combined and evaporated down i. vac.
Reaction SMILES: S(=O)(=O)(O)O.[OH:6][C@@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]([OH:15])=[O:14])[CH2:9][CH2:8]1.[CH3:16]O>>[OH:6][C@@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]([O:15][CH3:16])=[O:14])[CH2:9][CH2:8]1
Reactant: CO
Reactant: O=C(O)[C@H]1CC[C@@H](O)CC1
Agent: O=S(=O)(O)O
Product: COC(=O)[C@H]1CC[C@@H](O)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2.95 liters of methanol and 9.7 ml of conc. sulfuric acid are initially charged, and 175.0 g (1.21 mol) of cis-4-hydroxycyclohexanecarboxylic acid are added a little at a time at RT. The mixture is stirred at RT for 16 h. Almost all of the solvent is then removed on a rotary evaporator and the residue is taken up in 2 liters of a 1:1 mixture of saturated aqueous sodium bicarbonate solution and ethyl acetate. The phases are separated, and the organic phase is washed with 1 liter of 10% strength aqueous ammonium chloride solution and then dried over magnesium sulfate. After removal of the solvent on a rotary evaporator the residue is purified chromatographically on silica gel 60 (mobile phase: gradient ethyl acetate/petroleum ether 3:7→1:1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].S(=O)(=O)(O)O.[CH3:20]O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:20])=[O:7])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: CO
Reactant: O=C(O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
To a solution of 4-chloro-3-(trifluoromethyl)benzoic acid (10.37 g, 46.2 mmol) in methanol (100 mL) was added concentrated sulfuric acid (0.51 mL, 9.24 mmol). The mixture was heated under reflux overnight. The mixture was allowed to cool to room temperature and concentrated under reduced pressure to form a solid. The solid was filtered and washed with water. The solid was then stirred with saturated aqueous sodium bicarbonate solution to remove any residual sulfuric acid, filtered and dried under vacuum to give the title compound as a white solid (10.18 g). 1H NMR (400 MHz, CDCl3) δ ppm 3.96 (s, 3H), 7.60 (d, J=8.34 Hz, 1H), 8.14 (dd, J=8.34, 2.02 Hz, 1H), 8.37 (d, J=2.02 Hz, 1H).
Reaction SMILES: O1CCCCC1[O:7][CH:8]([CH2:20][N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[CH2:9][O:10][N:11]=[C:12]([Cl:19])[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.[CH2:27]([NH2:31])[CH2:28][CH2:29][CH3:30].Cl>C(O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)(C)C>[ClH:19].[OH:7][CH:8]([CH2:20][N:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1)[CH2:9][O:10][NH:11][C:12]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[N:31][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: ClC(=NOCC(CN1CCCCC1)OC1CCCCO1)c1cccnc1
Reactant: CCCCN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CC(C)O
Solvent: CCO
Product: CCCCN=C(NOCC(O)CN1CCCCC1)c1cccnc1
Temperature: 60 °C

Procedure:
A mixture of 3.7 g (9.68 mmol) of N-[2-[(2-tetrahydropyranyl)oxy]-3-(1-piperidinyl)propoxy]-3-pyridinecarboximidoyl chloride and 40 ml (0.41 mol) n-butylamine was refluxed for 3 hours. The excess of amine was evaporated in vacuum affording dark-brown oil, which was dissolved in 40 ml of ethanol containing 3.0 g of 4-toluenesulphonic acid and the mixture was heated at 60° C. for one hour. The solvent was removed under reduced pressure, the residue was made alkaline (pH 10) with 2 N of sodium hydroxide solution then extracted three times with chloroform. The organic solution was dried over sodium sulfate, filtered and the solvent was evaporated in vacuum. The dark oily residue was purified by chromatography to give the pure base, which was dissolved in 20 ml of ethanol and acidified with equivalent amount of dry hydrochloric acid dissolved in isopropyl alcohol to give the title compound as a pale-yellow crystalline solid.
Reaction SMILES: S(Cl)([Cl:3])=O.O[C@@H:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([OH:9])=[O:8].O>O1CCCC1.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:3][C@H:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([OH:9])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)[C@@H](O)Cc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@H](Cl)Cc1ccccc1
Temperature: 40 °C
Reaction time: 15 h
Yield: 90.1 %

Procedure:
Thionyl chloride (0.66 ml, 9.0 mmol) was added dropwise to a solution of (2S)-2-hydroxy-3-phenylpropionic acid (500 mg, 3.0 mmol, optical purity 100% ee (S)) in 5 ml of tetrahydrofuran at room temperature, and the mixture was stirred for 15 hours. To the reaction mixture was added 170 mg (0.60 mmol) of tetra-n-butylammonium chloride, and the mixture was heated at 40° C. for 4 hours. Water (5 ml) was added to the reaction mixture and, after 30 minutes of stirring, the mixture was extracted with 90 ml of ethyl acetate. The organic phase was washed with 10 ml of a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 499 mg (yield 90%) of the desired (2R)-chloro-3-phenylpropionic acid.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:44])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([C@@H:22]2[CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]2[OH:28])[CH:17]=[C:16]([C:29]([O:31]CC)=[O:30])[C:15]3=[O:34])=[C:8]([C:35]2[S:36][CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[N:39]=2)[CH:7]=1)[CH3:2].C1COCC1.[Li+].[OH-]>CO>[CH2:1]([NH:3][C:4](=[O:44])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([C@@H:22]2[CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]2[OH:28])[CH:17]=[C:16]([C:29]([OH:31])=[O:30])[C:15]3=[O:34])=[C:8]([C:35]2[S:36][CH:37]=[C:38]([C:40]([F:43])([F:41])[F:42])[N:39]=2)[CH:7]=1)[CH3:2]
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3[C@@H]2CCCC[C@@H]2O)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)O)cn3[C@@H]2CCCC[C@@H]2O)cn1
Temperature: 100 °C
Yield: 49.4 %

Procedure:
Ethyl 6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1-(cis-2-hydroxycyclohexyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (Example 253, 0.240 g, 0.38 mmol) was suspended in MeOH (6 mL) in a microwave vessel (CEM). THF (3.00 mL) was added. A 2.0 M aq solution of LiOH (0.381 mL, 0.76 mmol) was added. The microwave vessel was heated in the microwave at 100° C. for 15 min After cooling to room temperature, the solvent was removed in vacuo to give a residue which was purified by flash column chromatography on silica gel using (dichloromethane-methanol) to give 6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1-(cis-2-hydroxycyclohexyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (0.113 g, 49%).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1.[BH4-].[Na+]>O.CO>[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][NH:1][CH2:2][C:3]([OH:5])=[O:4])=[CH:11][CH:10]=1
Reactant: NCC(=O)O
Reactant: O=Cc1ccc(Br)cc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CNCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 30.7 %

Procedure:
i)—To a solution of glycine (15 g, 200 mmol) in water (80 ml) were added an aqueous solution of sodium hydroxide (20 ml, 10 M) and a solution of 4-bromobenzaldehyde (37 g, 200 mmol) in methanol (440 ml). After 10 minutes stirring at room temperature sodium borohydride (7.5 g, 200 mmol) was added in portions to this suspension. After 18 h stirring at room temperature the reaction mixture was concentrated under reduced pressure and washed with diethyl ether. The aqueous phase was neutralized with concentrated hydrochloric acid. The precipitate was collected by filtration, washed with water and diethyl ether. Drying the white solid afforded 2-(4-bromobenzylamino)acetic acid (14.98 g). The product was used in the following step without purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:35])=[C:4]([N:22]2[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]2)[CH:5]=[C:6]([N:8]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:9]([O:11][CH3:12])=[O:10])[CH:7]=1.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>C(Cl)CCl>[NH2:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[C:9](=[O:10])[O:11][CH3:12])[CH:5]=[C:4]([N:22]2[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]2)[C:3]=1[F:35].[C:38]([OH:40])([C:37]([F:42])([F:41])[F:36])=[O:39]
Reactant: COC(=O)N(Cc1ccc(OC)cc1)c1cc(N)c(F)c(N2CCN(C(=O)OC(C)(C)C)CC2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: COC(=O)N(Cc1ccc(OC)cc1)c1cc(N)c(F)c(N2CCNCC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-butyl 4-(3-amino-2-fluoro-5-((4-methoxybenzyl)(methoxycarbonyl)amino)phenyl)piperazine-1-carboxylate (317 mg, 0.474 mmol) was dissolved in ClCH2CH2Cl (4 ml). Trifluoroacetic acid (1 ml, 12.98 mmol) was added and the reaction mixture was stirred at room temperature for 2 hours, and then evaporated to dryness. 470.1 mg crude methyl (3-amino-4-fluoro-5-(piperazin-1-yl)phenyl)(4-methoxybenzyl)carbamate, TFA (470.1 mg) were isolated. The material was used for a next step
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][C@@H:8]([CH2:15][OH:16])[CH2:9][C@H:10]([CH3:14])[CH2:11][CH2:12][CH3:13])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[S:25](Cl)([C:28]1[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=1)(=[O:27])=[O:26].Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6](=[O:17])[CH2:7][C@@H:8]([CH2:15][O:16][S:25]([C:28]1[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=1)(=[O:27])=[O:26])[CH2:9][C@H:10]([CH3:14])[CH2:11][CH2:12][CH3:13])([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCC[C@@H](C)C[C@H](CO)CC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC[C@@H](C)C[C@H](COS(=O)(=O)c1ccc(C)cc1)CC(=O)OC(C)(C)C
Yield: 91.1 %

Procedure:
To alcohol 103 (1.98 g, 8.1 mmol) in CH2Cl2 (40 mL) at room temperature was added triethylamine (2.4 g, 0.024 mol), DMAP (20 mg) and tosyl chloride (2.3 g, 0.012 mol). After 14 hours 1N HCl was added and the two layers separated. The aqueous phase was extracted with ether and the combined organic phases dried (MgSO4) and concentrated. Flash chromatography (95% hexane/EtOAc) gave tosylate 104 as an oil (2.94 g, 91%). 13C NMR (100 MHz; CDCl3) 171.60, 144.92, 133.07, 130.02, 128.12, 80.80, 72.15, 39.73, 38.09, 37.89, 32.67, 29.71, 28.22, 21.83, 20.10, 19.54, 14.49.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][NH:7][C:8](=[O:22])[C@@H:9]([NH2:21])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)(=[O:3])[CH3:2].[F:23][C:24]([F:38])([F:37])[CH2:25][CH2:26][O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=1>>[C:1]([O:4][CH2:5][CH2:6][NH:7][C:8](=[O:22])[C@@H:9]([NH:21][C:32](=[O:33])[C:31]1[CH:35]=[CH:36][C:28]([O:27][CH2:26][CH2:25][C:24]([F:38])([F:37])[F:23])=[CH:29][CH:30]=1)[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:15][CH:16]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCNC(=O)[C@@H](N)Cc1ccc(C(F)(F)F)cc1
Reactant: O=C(O)c1ccc(OCCC(F)(F)F)cc1
Product: CC(=O)OCCNC(=O)[C@H](Cc1ccc(C(F)(F)F)cc1)NC(=O)c1ccc(OCCC(F)(F)F)cc1

Procedure:
A reaction similar to that described in Example 50 was conducted using 2-({(2S)-2-amino-3-[4-(trifluoromethyl)phenyl]propanoyl}amino)ethyl acetate and 4-(3,3,3-trifluoropropoxy)benzoic acid obtained in the preparation process of Example 33 (33a) to give the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[CH:2].Br[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:17]=1[CH3:23]>>[CH3:23][C:17]1[C:18]([CH3:22])=[CH:19][CH:20]=[CH:21][C:16]=1[C:2]#[C:1][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1
Reactant: C#Cc1ccc(CCC(=O)OC)cc1
Reactant: Cc1cccc(Br)c1C
Product: COC(=O)CCc1ccc(C#Cc2cccc(C)c2C)cc1

Procedure:
The title compound was prepared from methyl 3-(4-ethynylphenyl)propanoate (99 mg, 0.53 mmol) and 1-bromo-2,3-dimethylbenzene (0.08 mL, 0.59 mmol) according to the general procedure IC to give 22 mg (14%) of an orange oil after purification by flash chromatography (SiO2, EtOAc/hexanes, 1:5). Rf: 0.42 (EtOAc:hexanes, 2:5); 1HNMR (CDCl3) δ 7.47-7.44 (m, 2H), 7.37-7.34 (m, 1H), 7.19-7.17 (m, 2H), 7.12-7.03 (m, 2H), 3.67 (s, 3H), 2.99-2.94 (t, 2H, J=7.8 Hz), 2.66-2.61 (t, 2H, J=7.8 Hz), 2.45 (s, 3H), 2.29 (s, 3H); 13CNMR (CDCl3) δ 173.7, 142.7, 137.8, 132.2, 130.8, 130.5, 129.6, 126.4, 124.0, 122.1, 93.5, 89.2, 35.6, 31.4, 20.3, 17.6; ESI-MS m/z 315.1 (MNa+).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])=[O:7])=[CH:4][CH:3]=1.[N+](=[CH2:18])=[N-]>O1CCCC1>[CH3:18][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])=[O:7])=[CH:14][CH:15]=1
Reactant: C=[N+]=[N-]
Reactant: O=C1CCCN1C(=O)c1ccc(O)cc1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)N2CCCC2=O)cc1

Procedure:
150 mg. of 1-(p-hydroxybenzoyl)-2-pyrrolidinone are dissolved in 7 ml. of absolute tetrahydrofuran and then etheric diazomethane solution is added. The solvents are distilled off, the residue is triturated with diethyl ether and the mixture is filtered. There is obtained 1-(p-methoxybenzoyl)-2-pyrrolidinone which melts at 117.5°-119° C. after sublimation.
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Rh]>[CH:10]1([CH:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:8][NH2:9])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: NCC(c1ccccc1)c1ccccc1
Agent: [Rh]
Product: NCC(C1CCCCC1)C1CCCCC1

Procedure:
Most Boc-amino acids used in the peptide syntheses are commercially available. 2-methyltyrosine (Mmt) was prepared by catalytic hydrogenation (Pd/C) of 7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (7-OH-Tic) in AcOH under H2 pressure at 3 atm. 2',6'-dimethyltyrosine (Dmt) was prepared as described by J. H. Dygos et al. Synthesis, No. 8 (August) pp. 741-743 (1992). Most of the C-terminal amine substituents were also commercially available. 2-(2-bromophenyl)ethylamine, 2-(2-methylphenyl)ethylamine and 2,2-diphenylpropylamine were prepared by reduction of the corresponding nitriles with lithium aluminum hydride, as described by L. M. Amundsen and L. S. Nelson J. Am. Chem. Soc. 73, 242 (1951). 2-(2-biphenyl)ethylamine was synthesized as described by S. Goldschmidt and W. L. C. Veer Recueil 67, 489 (1948). Ethyl-α-phenyl-β-aminopropionate in racemic form was synthesized as described by E. Testa et al. Liebig's Ann. Chem. 614, 167 (1958). Acid hydrolysis of the latter product and subsequent amidation afforded racemic α-phenyl-β-aminopropionamide. 2,2-dicyclohexylethylamine was prepared from 2,2-diphenylethylamine by catalytic hydrogenation (Rh on carbon) at 6° C. under pressure (60 psi).