Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:11]([C:20]([O:22][CH3:23])=[O:21])=[CH:12][C:13]([C:16]([O:18]C)=[O:17])=[CH:14][CH:15]=1.C1COCC1.CO.[OH-].[K+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][C:11]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(C(=O)OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc(C(=O)O)ccc1-c1cc(OC)ccc1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 100 %

Procedure:
To a stirred solution of 66.13C (36.50 g, 115 mmol) in THF (70.0 mL, 854 mmol) and MeOH (70.0 mL, 1730 mmol) at 0° C. was added potassium hydroxide (63 mL, 126 mmol) slowly to maintain the temperature below 6° C. The reaction mixture was allowed to warm to room temperature and stirring was continued for 15 hours. The reaction mixture was concentrated in vacuo. 1N HCl was added to the aqueous phase and the resulting mixture was extracted with EtOAc. The organic layer was dried over MgSO4, and concentrated in vacuo to give 2′-fluoro-5′-(methyloxy)-2-((methyloxy)carbonyl)-1,1′-biphenyl-4-carboxylic acid 66.13D as a white solid (35.00 g, 100% yield). MS ESI (pos.) m/e: 322.1 (M+H2O)+, 305.0 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([N+:22]([O-])=O)=[C:13]([C:15](=[O:21])[C:16]#[C:17][CH2:18][CH2:19][CH3:20])[CH:14]=1)C1C=CC=CC=1>C(O)C.[Pd]>[NH2:22][C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][C:13]=1[C:15](=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCC#CC(=O)c1cc(OCc2ccccc2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCCCCC(=O)c1cc(O)ccc1N
Yield: 94.8 %

Procedure:
Analogously to the procedure of Example X, starting from 1.44 g (4.45 mmol) of 1-[5-(benzyloxy)-2-nitrophenyl]-2-hexin-1-one with 0.20 g of palladium/carbon (10%) in 50 ml of ethanol under hydrogen, after 3 h 874 mg (95%) of 1-(2-amino-5-hydroxyphenyl)-1-hexanone are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[CH2:20]([S:22](Cl)(=[O:24])=[O:23])[CH3:21].C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:22]([CH2:20][CH3:21])(=[O:24])=[O:23])[CH2:16][CH2:15]1
Reactant: CCS(=O)(=O)Cl
Reactant: NC(=O)c1cc(Br)cc2c(C3CCNCC3)c[nH]c12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
To 5-bromo-3-(4-piperidinyl)-1H-indole-7-carboxamide (900 mg, 2.8 mmol) in CH2Cl2 (100 mL) at 0° C., ethanesulfonyl chloride (0.8 mg, 8.4 mmol) and triethylamine (1.6 mL, 11.2 mmol) were added. The reaction mixture was stirred at 0° C. for 30 min., after which time the mixture was partitioned between CH2Cl2 and water. The aqueous phase was extracted with CH2Cl2 (50 mL×2) and the combined organic phase dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by solid phase extraction on a 500 mg aminopropyl column (International Sorbent Technologies) eluting with chloroform (30 mL×2) and ethyl acetate (50 mL) to give 800 mg of the title compound (69%).
Reaction SMILES: [CH3:1][C@@H:2]([NH2:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:11][CH2:12]O>ClCCl>[CH3:1][C@@H:2]1[C:3]2[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:12][CH2:11][NH:9]1
Reactant: C[C@@H](N)c1ccccc1
Reactant: OCCBr
Solvent: ClCCl
Product: C[C@H]1NCCc2ccccc21
Temperature: 51 °C
Reaction time: 50 h
Yield: 85303.6 %

Procedure:
51.45 g(0.43 mmole) of (R)-(+)-α-methylbenzylamine was dissolved in 52 ml of dichloromethane and 63.78 g(0.51 mmole) of 2-bromoethanol was added thereto. This mixture was stirred at 51° C. for 50 hours to complete the reaction. The reaction solution was concentrated under reduced pressure and the residue was subjected to fractional distillation to obtain 54 g of the title compound having pale yellow color.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C)C=O.F[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20]>O>[N+:19]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)([O-:21])=[O:20]
Reactant: C1CCNCC1
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccccc1N1CCCCC1
Reaction time: 2 h
Yield: 98.8 %

Procedure:
Piperidine (338 μl, 3.41 mmol, commercially available product) was added at room temperature to an N,N-dimethylformamide (DMF; 0.5 ml) solution of 2-fluoro-1-nitrobenzene (219 mg, 1.55 mmol, commercially available product). The resulting mixture was stirred for two hours. Water was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20 g, hexane/ethyl acetate=20/1). Thus, 1-(2-nitrophenyl)piperidine (315 mg, 98.8%) was yielded as a colorless oily material.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([NH:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:6]=[CH:5][CH:4]=1)#[N:2].[C:18](OC)(=[O:26])[C:19]1[C:20](=[CH:22][CH:23]=[CH:24][CH:25]=1)[SH:21].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:26]=[C:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[S:21][C:1]([C:3]2[N:8]=[C:7]([NH:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:6]=[CH:5][CH:4]=2)=[N:2]1
Reactant: CC(C)(C)OC(=O)CNc1nccc(C#N)n1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CNc1nccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 69 %

Procedure:
tert-Butyl [(6-cyano-2-pyrimidinyl)amino]acetate (1.00 g, 4.03 mmol) and methyl thiosalicylate (2.34 g, 13.9 mmol) were dissolved in toluene (50 ml), and triethylamine (1.95 ml, 13.9 mmol) was added thereto. The mixture was refluxed for 18 hrs. The solvent was evaporated, and the residue was recrystallized from ethanol to give the titled compound (1.03 g, 60%) as pale yellow crystals.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][N:34]([CH3:38])[C:35](Cl)=[O:36].C(N(CC)CC)C>ClCCl>[NH2:26][C:24]1[C:25]2=[C:17]([C:12]3[CH:13]=[CH:14][C:15]4[C:10]([CH:11]=3)=[N:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:16]=4)[CH:18]=[C:19]([CH:27]3[CH2:32][CH2:31][N:30]([C:35]([N:34]([CH3:38])[CH3:33])=[O:36])[CH2:29][CH2:28]3)[N:20]2[N:21]=[CH:22][N:23]=1
Reactant: CN(C)C(=O)Cl
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)N1CCC(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)CC1
Temperature: 40 °C
Reaction time: 17 h
Yield: 47.6 %

Procedure:
To a suspension of 5-(2-benzyl-2H-indazol-6-yl)-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (80 mg, 0.17 mmol) in dichloromethane (1 mL) was added N,N-dimethylcarbamoyl chloride (18 μL, 0.19 mmol) and triethylamine (73 μL, 0.52 mmol). The reaction was stirred at 40° C. for 17 h. The crude mixture was purified by preparative HPLC using a gradient elution from 15% to 50% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MeOH and the filtrate was concentrated to provide 40 mg (46%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.54 (d, 1 H), 7.87-7.97 (m, 1 H), 7.79 (dd, 1 H), 7.59 (d, 1 H), 7.28-7.39 (m, 5 H), 7.14 (dd, 1 H), 6.58-6.65 (m, 1 H), 5.65 (d, 2 H), 3.63 (s, 2 H), 3.32-3.40 (m, 1 H), 2.85 (s, 2 H), 2.74 (d, 6 H), 1.99 (s, 2 H), 1.66 (s, 2 H); ES-MS m/z 495.20 [M+H]+, HPLC RT (min) 2.69.
Reaction SMILES: O.O.O.O.O.O.O.O.O.[S-2:10].[Na+].[Na+].[C:13]1([C:19]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([CH2:27][CH2:28]OS(C)(=O)=O)[CH2:20][CH2:21]OS(C)(=O)=O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O.C(OCC)(=O)C>C(O)CCC.ClCCl>[C:13]1([C:19]2([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:20][CH2:21][S:10][CH2:28][CH2:27]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: [S-2]
Reactant: CS(=O)(=O)OCCC(CCOS(C)(=O)=O)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: c1ccc(C2(c3ccccc3)CCSCC2)cc1
Temperature: 20 °C
Yield: 87.5 %

Procedure:
100 g of sodium sulphide nonahydrate are added to a suspension of 140.8 g of 3,3-diphenyl-l,5-bis-(methanesulphonyl-oxy)pentane in 1400 cm3 of 1-butanol. The mixture is refluxed for 2 hours and then cooled to about 20° C. and then 1000 cm3 of water, 500 cm3 of ethyl acetate and 500 cm3 of dichloromethane are added. After stirring, the organic phase is separated, washed successively with 1000 cm3 of water, 500 cm3 of 1N hydrochloric acid, 500 cm3 of a saturated aqueous solution of sodium hydrogen carbonate and 1000 cm3 of water, and then dried over magnesium sulphate and concentrated to dryness at 60° C. under reduced pressure (2.7 kPa). The residue is crystallized from ethyl acetate, the crystals are washed with diisopropyl oxide, drained and dried. 76 g of 4,4-diphenyltetrahydrothiapyran are obtained in the form of white crystals; melting point 134° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:29])=[C:6]([C@:8]2([CH2:27]F)[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH:18][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:9]2)[CH:7]=1.Cl[C:31]1[O:32][C:33]2[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:34]=2[N:35]=1.NC1C=CC(F)=C([C@]2(C)C[C@@H](C(F)(F)F)OC(NC(=O)C3C=CC=CC=3)=N2)C=1.CN1C(=O)CCC1>O.CCOC(C)=O>[Cl:40][C:38]1[CH:37]=[CH:36][C:34]2[N:35]=[C:31]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([F:29])=[C:6]([C@:8]4([CH3:27])[CH2:13][C@@H:12]([C:14]([F:16])([F:15])[F:17])[O:11][C:10]([NH:18][C:19](=[O:26])[C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)=[N:9]4)[CH:7]=3)[O:32][C:33]=2[CH:39]=1
Reactant: Clc1ccc2nc(Cl)oc2c1
Reactant: Nc1ccc(F)c([C@]2(CF)C[C@@H](C(F)(F)F)OC(NC(=O)c3ccccc3)=N2)c1
Agent: C[C@@]1(c2cc(N)ccc2F)C[C@@H](C(F)(F)F)OC(NC(=O)c2ccccc2)=N1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: C[C@@]1(c2cc(Nc3nc4ccc(Cl)cc4o3)ccc2F)C[C@@H](C(F)(F)F)OC(NC(=O)c2ccccc2)=N1
Temperature: 120 °C
Reaction time: 4.5 h
Yield: 72.3 %

Procedure:
A mixture of N-((4S,6S)-4-(5-amino-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (0.200 g, 0.506 mmol, prepared as described in Example 1 Step 9 but using N-((4S,6S)-4-(5-bromo-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide 4g), 2,6-dichlorobenzoxazole (0.133 g, 0.708 mmol), potassium carbonate (4l, 0.126 g, 0.911 mmol) and NMP (2 mL) was stirred at 120° C. for 4.5 h, the mixture was diluted with water and EtOAc. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The crude was purified by silica gel chromatography: 40 g, 0-30% DCM-hexane in 15 min. The product was obtained as a white solid (0.200 g). MS m/z=547 [M+H]+. Calculated for C26H19ClF4N4O3: 546.9.
Reaction SMILES: [OH-].[Li+].C([O:5][C:6]([CH:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[O:25][C:26]([NH:29][C:30]4[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=4[F:38])=[N:27][N:28]=3)=[O:23])=[C:17]([F:39])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])C.C1COCC1.CO>O>[F:39][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[NH:21][C:22]([C:24]1[O:25][C:26]([NH:29][C:30]2[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=2[F:38])=[N:27][N:28]=1)=[O:23])[O:14][C@@H:11]1[CH2:10][CH2:9][C@H:8]([C:6]([OH:7])=[O:5])[CH2:13][CH2:12]1
Reactant: CCOC(=O)C1CCC(Oc2ccc(NC(=O)c3nnc(Nc4cc(F)c(F)cc4F)o3)c(F)c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1ccc(O[C@H]2CC[C@@H](C(=O)O)CC2)cc1F)c1nnc(Nc2cc(F)c(F)cc2F)o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.6 %

Procedure:
A solution of lithium hydroxide (965 mg, 23.0 mmol) in water (5 mL) was added in one portion to a solution of 4-(3-fluoro-4-{[5-(2,4,5-trifluoro-phenylamino)-[1,3,4]oxadiazole-2-carbonyl]-amino}-phenoxy)-cyclohexanecarboxylic acid ethyl ester (Intermediate 1, 1.2 g, 2.3 mmol) in a 1:1 mixture of THF and methanol (50 mL) and the mixture was stirred at ambient temperature for 4 h. The mixture was concentrated in vacuo, acidified with a 1M aqueous solution of citric acid and then filtered to leave a solid. The solid was washed with water, dried and recrystallised from ethanol (30 mL) to give the title compound as a white solid (700 mg, 64%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]1[C:16]([CH2:17][CH2:18][C:19]([OH:21])=O)=[CH:15][CH:14]=[C:13]([C:22]3[C:23]([N:42]([CH3:47])[S:43]([CH3:46])(=[O:45])=[O:44])=[CH:24][C:25]4[O:29][C:28]([C:30]5[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=5)=[C:27]([C:37](=[O:40])[NH:38][CH3:39])[C:26]=4[CH:41]=3)[N:12]=1)[NH:6]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:11]4[N:12]=[C:13]([C:22]5[C:23]([N:42]([CH3:47])[S:43]([CH3:46])(=[O:44])=[O:45])=[CH:24][C:25]6[O:29][C:28]([C:30]7[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=7)=[C:27]([C:37]([NH:38][CH3:39])=[O:40])[C:26]=6[CH:41]=5)[CH:14]=[CH:15][C:16]=4[CH2:17][CH2:18][C:19](=[O:21])[N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(CCC(=O)O)c(-c4cc5c(F)cccc5[nH]4)n3)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3C(=O)CC4)cc12

Procedure:
To a mixture of 3-(2-(4-fluoro-1H-indol-2-yl)-6-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)pyridin-3-yl)propanoic acid (88 mg, 0.133 mmol) and HATU (126 mg, 0.333 mmol) in DMF (6650 μl) was added DIEA (116 μl, 0.665 mmol). The resultant mixture was stirred for 1 h at ambient temperature then was diluted with EtOAc and washed successively with H2O (3×) and brine (1×). The organic layer was dried over MgSO4, filtered, concentrated in vacuo, and the residue purified by silica gel column chromatography using a gradient of 0-30% EtOAc/CH2Cl2 as eluent. 1H NMR δ (ppm) (CHCl3-d): 8.38 (1H, d, J=8.46 Hz), 8.12 (1H, s), 8.02 (2H, dd, J=8.55, 5.32 Hz), 7.69 (3H, d, J=9.74 Hz), 7.60 (1H, d, J=7.80 Hz), 7.36 (1H, td, J=8.24, 5.56 Hz), 7.25 (2H, t, J=8.60 Hz), 7.02 (1H, t, J=8.68 Hz), 5.95 (1H, br s), 3.35 (3H, s), 3.27˜3.22 (2H, m), 3.20˜3.15 (2H, m), 3.05 (3H, d, J=4.90 Hz), 2.85 (3H, s). MS (M+H)+: 641.
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:13]=[C:12]([Br:14])[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1.[OH-].[Na+]>CC(C)=O.O>[Br:14][C:12]1[CH:13]=[C:4]([CH:5]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:11]=1)[C:3]([OH:15])=[O:2]
Reactant: COC(=O)c1cc(Br)cc(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1cc(Br)cc(C(=O)O)c1
Reaction time: 4 h
Yield: 89.5 %

Procedure:
Dimethyl-5-bromoisophthalate (3 g, 11.0 mmol) was dissolved in acetone-H2O (2:1 v/v, 60 mL) and NaOH (0.40 g, 11.0 mmol) was added. The reaction mixture was allowed to stir for 4 h. Acetone was removed under reduced pressure and the aqueous layer was washed with EtOAc, acidified to pH ˜2-3 using 1.5N HCl, and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to yield 3-bromo-5-(methoxycarbonyl)benzoic acid (2.55 g, yield 89%): 1H NMR (300 MHz, DMSO-d6) δ 13.75 (br s, 1H), 8.40 (d, J=1.0 Hz, 1H), 8.26 (d, J=1.4 Hz, 1H), 8.23 (d, J=1.0 Hz, 1H), 3.89 (s, 3H). MS (ESI) m/z: Calculated for C9H7BrO4: 257.95. found: 258.0 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:49])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[C:36]([F:41])[CH:35]=3)[CH:25]=[C:26]([S:28]([CH2:31][CH2:32][CH3:33])(=[O:30])=[O:29])[CH:27]=2)[C:10]=1[CH2:42][CH2:43][C:44]([O:46]CC)=[O:45])C.[OH-].[Na+]>>[C:44]([CH2:43][CH2:42][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[C:36]([F:41])[CH:35]=3)[CH:25]=[C:26]([S:28]([CH2:31][CH2:32][CH3:33])(=[O:29])=[O:30])[CH:27]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:49])=[O:3])([OH:46])=[O:45]
Reactant: CCCS(=O)(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)OCC)c2CCC(=O)OCC)cc(-c2ccc(F)c(F)c2)c1
Agent: [Na+]
Agent: [OH-]
Product: CCCS(=O)(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc(F)c(F)c2)c1
Yield: 44.8 %

Procedure:
A similar procedure as described in Example 40, step 8 was used, starting from 4-[2-(2-ethoxycarbonyl-ethyl)-3-[6-(5-(propane-1-sulfonyl)-3′,4′-difluoro-biphenyl-3-yloxy)-hexyl]-phenoxy]-butyric acid ethyl ester (130 mg, 0.19 mmol) and 1.0 N aqueous sodium hydroxide (1.9 mL) to afford 4-[2-(2-carboxy-ethyl)-3-[6-(5-(propane-1-sulfonyl)-3′,4′-difluoro-biphenyl-3-yloxy)-hexyl]-phenoxy]-butyric acid (55 mg, 46%) as an amorphous white solid: ES(+)-HRMS m/e calcd for C34H40F2O8S (M+Na)+ 669.2304, found 669.2299.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[O:14][CH:15]=[C:16]([CH3:18])[CH:17]=2)[N:3]=1.[NH2:19][CH2:20][C:21]1[C:26]([Cl:27])=[CH:25][C:24]([C:28]([F:31])([F:30])[F:29])=[CH:23][N:22]=1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([NH:19][CH2:20][C:21]2[C:26]([Cl:27])=[CH:25][C:24]([C:28]([F:31])([F:30])[F:29])=[CH:23][N:22]=2)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[O:14][CH:15]=[C:16]([CH3:18])[CH:17]=2)[N:3]=1
Reactant: Cc1coc(-c2nc(N)nc(S(C)=O)c2C#N)c1
Reactant: NCc1ncc(C(F)(F)F)cc1Cl
Solvent: COCCOC
Product: Cc1coc(-c2nc(N)nc(NCc3ncc(C(F)(F)F)cc3Cl)c2C#N)c1

Procedure:
From 2-amino-4-methanesulfinyl-6-(4-methyl-furan-2-yl)-pyrimidine-5-carbonitrile and 2-aminomethyl-3-chloro-5-(trifluoromethyl)pyridine in DME. ES-MS m/e (%): 411 (M{37Cl}+H+, 35), 409 (M{35Cl}+H+, 100).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[N:8]=[C:7]([N:9]2[CH2:13][C@@H:12]3[C@@H:14]([NH2:17])[CH2:15][CH2:16][C@@H:11]3[CH2:10]2)[CH:6]=[CH:5][CH:4]=1.C(O[C:25]([N:27](C)[C@@H:28]([CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34])[C:29](O)=[O:30])=O)(C)(C)C.O.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.Cl.O1CCOCC1>ClCCl>[CH3:25][NH:27][C@H:28]([C:29]([NH:17][C@@H:14]1[C@@H:12]2[C@@H:11]([CH2:10][N:9]([C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:18])[F:19])[N:8]=3)[CH2:13]2)[CH2:16][CH2:15]1)=[O:30])[CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34]
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](CC(C)(C)C)C(=O)O
Reactant: N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CN[C@@H](CC(C)(C)C)C(=O)N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
(3aR,4S,6aS)-2-(6-(Trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-amine from Example 264 Step A (95.7 mg, 0.353 mmol) was combined with (S)-2-(tert-butoxycarbonyl(methyl)amino)-4,4-dimethylpentanoic acid (101 mg, 0.388 mmol) and 1-hydroxybenzotriazole hydrate (59.4 mg, 0.388 mmol) in dichloromethane (1 mL). After 20 minutes, N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (0.068 mL, 0.388 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with water and extracted with 2×2 mL of dichloromethane. The combined extracts were applied directly to a 12 g silica gel cartridge and purified with a gradient of 1-10% methanol in (2 N ammonia)/dichloromethane. The resulting oil was treated with 4 N hydrogen chloride in 1,4-dioxane (1 mL, 4 mmol) for 3 hours at room temperature. The solvent was removed under a stream of nitrogen and the residue basified with aqueous sodium bicarbonate and extracted with 2×2 mL of dichloromethane. The combined extracts were applied directly to a 12 g silica gel cartridge and purified with a gradient of 1-10% methanol in (2 N ammonia)/dichloromethane to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.36 (d, J=7.3, 1H), 7.51 (t, J=7.9, 1H), 6.98 (d, J=7.2, 1H), 6.52 (d, J=8.6, 1H), 4.45-4.35 (m, 1H), 3.74 (dd, J=10.9, 2.8, 1H), 3.62 (dd, J=10.8, 7.5, 1H), 3.52 (dd, J=10.7, 7.8, 1H), 3.29 (dd, J=10.8, 3.4, 1H), 3.24-3.18 (m, 1H), 2.79-2.64 (m, 2H), 2.42 (s, 3H), 2.14 (td, J=12.5, 7.0, 1H), 2.01-1.79 (m, 3H), 1.69 (dq, J=12.8, 8.0, 1H), 1.51 (dd, J=14.1, 6.6, 1H), 1.44-1.33 (m, 1H), 1.00 (s, 9H); MS (ESI+) m/z 413 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)=[C:6]([C@H:15]([O:29][CH2:30][CH2:31][OH:32])[C@@H:16]2[O:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]2)[CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:40][S:41](Cl)(=[O:43])=[O:42].O>C(Cl)Cl>[F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)=[C:6]([C@H:15]([O:29][CH2:30][CH2:31][O:32][S:41]([CH3:40])(=[O:43])=[O:42])[C@@H:16]2[O:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:17]2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(-c2c(F)cccc2[C@H](OCCO)[C@H]2CN(C(=O)OC(C)(C)C)CCO2)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1cccc(-c2c(F)cccc2[C@H](OCCOS(C)(=O)=O)[C@H]2CN(C(=O)OC(C)(C)C)CCO2)c1
Temperature: 25 °C
Yield: 94.5 %

Procedure:
To a solution of (R)-tert-butyl 2-((S)-(6-fluoro-3′-methylbiphenyl-2-yl)(2-hydroxyethoxy)methyl)morpholine-4-carboxylate (498 mg, 1.12 mmol) in dry CH2Cl2 (15 mL) was added Et3N (472 mg, 4.68 mmol) at ˜0 to −5° C. A solution of MsCl (267 mg, 2.34 mmol) in dry CH2Cl2 (10 mL) was added dropwise at the same temperature. The mixture was allowed to warm to rt gradually. Tlc showed the stating material had disappeared. Water (10 mL) was added and the aqueous layer was extracted with CH2Cl2 (3×20 mL). The combined organic layers were washed with 10% aq citric acid, satd aq NaHCO3 and brine, dried over Na2SO4, filtered and concentrated to afford crude (R)-tert-butyl 2-((S)-(6-fluoro-3′-methylbiphenyl-2-yl)(2-(methylsulfonyloxy)ethoxy)methyl)morpholine-4-carboxylate (554 mg, 95%). which was used in the next step without further purification. MS (E/Z): 524 (M+H+)
Reaction SMILES: C[O:2][C:3](=[O:44])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][C@@H:12]([NH:14][CH2:15][C@@H:16]([C:25]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[C:31]3[C:26]=2[CH:27]=[CH:28][C:29](=[O:43])[NH:30]3)[O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH3:13])[CH:6]=1.[OH-].[Li+].Cl>C1COCC1.CO.O>[CH2:36]([O:35][C:32]1[CH:33]=[CH:34][C:25]([C@@H:16]([O:17][Si:18]([C:21]([CH3:22])([CH3:24])[CH3:23])([CH3:20])[CH3:19])[CH2:15][NH:14][C@@H:12]([CH3:13])[CH2:11][C:7]2[CH:6]=[C:5]([CH2:4][C:3]([OH:44])=[O:2])[CH:10]=[CH:9][CH:8]=2)=[C:26]2[C:31]=1[NH:30][C:29](=[O:43])[CH:28]=[CH:27]2)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: COC(=O)Cc1cccc(C[C@H](C)NC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(OCc3ccccc3)c3[nH]c(=O)ccc23)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](Cc1cccc(CC(=O)O)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.3 %

Procedure:
To a solution of (3-{(S)-2-[(R)-2-(8-benzyloxy-2-oxo-1,2-dihydroquinolin-5-yl)-2-(tert-butyldimethylsilanyloxy)ethylamino]propyl}phenyl)acetic acid methyl ester (810 mg, 1.3 mmol) in a 3:2:1 mixture of THF/MeOH/water (4 mL) was added lithium hydroxide (158 mg, 6.59 mmol). The resulting mixture was stirred at room temperature for 3 hours and then acidified to pH 6 with concentrated aqueous hydrochloric acid. This mixture was concentrated under reduced pressure to give a yellow solid (307 mg, 39% yield), which was used in the next reaction without further purification.