Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:39])[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[CH3:36])=[O:28])=[C:22]([O:37][CH3:38])[CH:21]=3)=[CH:13][CH:12]=2)[CH2:9][N:8]([CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:7]1)=[O:5])C.[OH-].[Na+]>C(#N)C.C(O)C>[CH2:40]([N:8]1[CH2:9][CH:10]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:39])[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[CH3:36])=[O:28])=[C:22]([O:37][CH3:38])[CH:21]=3)=[CH:13][CH:12]=2)[CH:6]([C:4]([OH:5])=[O:3])[CH2:7]1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CC1c1ccc(NC(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCO
Product: COc1cc(CC(=O)Nc2ccc(C3CN(Cc4ccccc4)CC3C(=O)O)cc2)ccc1NC(=O)Nc1ccccc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.2 %

Procedure:
A stirred solution of 1-benzyl-4-(4-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-phenyl)-pyrrolidine-3-carboxylic acid ethyl ester (2.95 g, Reference Example 16) in a mixture of acetonitrile (150 mL) and ethanol (125 mL), at 50° C., was treated slowly with aqueous sodium hydroxide solution (0.46 mL, 30%). After stirring for 8 hours at room temperature and then gentle stirring for a week, the mixture was filtered. The solid was washed with dichloromethane (30 mL), then dried under reduced pressure (2.7 kPa) and then treated with water (200 mL). The mixture was acidified by addition of hydrochloric acid (3.5 mL, 1 M), then allowed to stand at room temperature for 15 hours, then treated with ethyl acetate (400 mL) and then filtered to give the title compound (1.16 g) as a white powder, m.p. 255° C. 1H-NMR [400 MHz, (CD3)2SO]: δ 2.27 (s, 3H); 2.45 to 2.60 (m, 1H); 2.80 to 3.00 (m, 4H); 3.49 (m, 1H); 3.57 (s, 2H); 3.58 and 3.68 (2 d, J=14 Hz, 2H); 3.90 (s, 3H); 6.85 (bd, J=8 Hz, 1H); 6.95 (bt, J=7 Hz, 1H); 7.02 (bs, 1H); 7.05 to 7.20 (m, 2H); 7.20 to 7.30 (m, 3H); 7.30 to 7.40 (m, 4H); 7.52 (bd, J=8 Hz, 2H); 7.82 (bd, J=8 Hz, 1H); 8.04 (d, J=8 Hz, 1H); 8.48 (bs, 1H); 8.59 (bs, 1H); 10.07 (bs, 1H). MS(LSIMS): 593[M+HI]+.
Reaction SMILES: [C:1]([C:4]1[O:8][N:7]=[C:6]([CH3:9])[CH:5]=1)(=[O:3])[CH3:2].Cl.[N:11](OCCCCC)=[O:12]>CCOCC>[CH3:9][C:6]1[CH:5]=[C:4]([C:1]([CH:2]=[N:11][OH:12])=[O:3])[O:8][N:7]=1
Reactant: CC(=O)c1cc(C)no1
Reactant: CCCCCON=O
Agent: Cl
Solvent: CCOCC
Product: Cc1cc(C(=O)C=NO)on1
Yield: 32.5 %

Procedure:
In 30 ml of ether was dissolved 2.5 g of 5-acetyl-3-methylisoxazole. While gaseous hydrogen chloride was passed through the resultant solution with stirring, a solution of 4.5 g of amyl nitrite in 10 ml of ether was dropped thereinto. After a further one hour stirring at room temperature after completion of said dropwise addition, the resulting precipitate was isolated by filtration. Recrystallization from chloroform gave 1.0 g of (3-methylisoxazole-5-yl)glyoxal-2-oxim having m.p. of 179° C.-180° C. Yield, 27%.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:21][C:20](=[O:22])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[S:18]2(=[O:30])=[O:29])=[C:13]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:12]=1)(C)(C)C.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]>C(Cl)Cl>[OH:44][C:42]([C:41]([F:46])([F:45])[F:40])=[O:43].[NH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[S:18](=[O:30])(=[O:29])[N:19]([CH2:23][CH2:24][Si:25]([CH3:26])([CH3:27])[CH3:28])[C:20](=[O:22])[CH2:21]2)=[C:13]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:12]=1
Reactant: CC(C)(C)OC(=O)NCCCc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(CCCN)cc2OCc2ccccc2)S1(=O)=O
Reaction time: 1 h

Procedure:
To a solution of (3-{3-benzyloxy-4-[1,1,4-trioxo-5-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-2-yl]-phenyl}-propyl)-carbamic acid tert-butyl ester (6.0 g, 10.4 mmol) (from Example 57, step B) in 20 mL of CH2Cl2 is added trifluoroacetic acid (5.0 mL). The mixture stirred for 1 h and then the solvent is removed under reduced pressure to afford the title compound as an orange oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([O:35][CH2:36][CH3:37])[C:7]2[N:8]([C:10]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4([NH:23]C(=O)OCC)[CH2:22][CH2:21][CH2:20]4)=[CH:15][CH:14]=3)[N:12]=2)[N:9]=1)[CH3:2].[OH-].[K+].[CH2:40](O)[CH2:41]CC>>[CH2:36]([O:35][C:6]1[C:7]2[N:8]([C:10]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([C:19]4([NH2:23])[CH2:20][CH2:21][CH2:22]4)=[CH:17][CH:18]=3)[N:12]=2)[N:9]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)[CH2:37][CH2:40][CH3:41]
Reactant: CCOC(=O)NC1(c2ccc(-c3nc4c(OCC)cc(OCC)nn4c3-c3ccccc3)cc2)CCC1
Reactant: CCCCO
Agent: [K+]
Agent: [OH-]
Product: CCCCOc1cc(OCC)nn2c(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc12
Temperature: 25 °C
Yield: 9 %

Procedure:
A mixture of ethyl {1-[4-(6,8-diethoxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate (0.12 g, 0.24 mmol) and potassium hydroxide (powder, 0.077 g, 1.17 mmol, 5.0 equiv) in n-butanol (2.5 mL) was heated at the reflux temperature for 24 h. The resulting mixture was cooled to room temperature and separated between a 4:1 DCM/isopropanol solution (50 mL) and water 50 mL). The organic phase was washed with a saturated aqueous NaCl solution (25 mL), dried (Na2SO4 anh.) and concentrated under reduced pressure. The resulting material was purified using MPLC (Biotage Isolera; SNAP 10 g cartridge: 100% DCM 4.0 min., gradient to 95% DCM/5% MeOH 1 min., 95% DCM/5% MeOH 3.5 min., gradient to 90% DCM/10% MeOH 1 min., 90% DCM/10% MeOH 3.5 min., gradient to 80% DCM/20% MeOH 6 min., 80% DCM/20% MeOH 4.7 min.) to give 1-[4-(8-butoxy-6-ethoxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutanamine (0.013 g, 9%):
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([CH2:13][NH:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[C:20]([F:26])[CH:19]=3)=[O:16])=[CH:11][C:10]([C:27]([F:30])([F:29])[F:28])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([CH2:13][NH:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH:24]=[O:25])=[C:20]([F:26])[CH:19]=3)=[O:16])=[CH:11][C:10]([C:27]([F:30])([F:28])[F:29])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1)Nc1ccc(CO)c(F)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=Cc1ccc(NC(=O)NCc2cc(C(F)(F)F)nn2-c2cccc(Cl)c2)cc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 50.4 %

Procedure:
To a stirred solution of 1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(3-fluoro-4-(hydroxymethyl)phenyl)urea (240 mg, 0.54 mmol, 1.0 eq) in DCM (10 mL) and cooled to 0° C. was added Dess-Martin periodinane (345 mg, 0.813 mmol, 1.5 eq) slowly portion wise at 0° C. and stirred for 1 h at 0° C., and then stirred for 30 min. at RT. DCM was evaporated and EtOAC (50 mL) was added. The mixture was washed with water (20 mL), brine (20 mL), dried over anhydrous Na2SO4 and evaporated under vacuum. The crude product was purified by CC using EtOAc/PE (2:3) to yield compound 1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(3-fluoro-4-formylphenyl)urea (120 mg; 48%) as an yellow solid (TLC: EtOAc/PE (1:1); Rf: 0.5).
Reaction SMILES: [CH3:1][O:2][P:3]([C:7]([OH:20])([CH:14]1CCCCC1)[P:8](=[O:13])([O:11][CH3:12])[O:9][CH3:10])(=[O:6])[O:4][CH3:5].C1(C(P(=O)(OC)OC)=O)CCCCC1.COP([O-])OC>>[CH3:10][O:9][P:8]([C:7]([P:3](=[O:6])([O:2][CH3:1])[O:4][CH3:5])([OH:20])[CH3:14])(=[O:13])[O:11][CH3:12]
Reactant: COP(=O)(OC)C(O)(C1CCCCC1)P(=O)(OC)OC
Agent: COP(=O)(OC)C(=O)C1CCCCC1
Agent: COP([O-])OC
Product: COP(=O)(OC)C(C)(O)P(=O)(OC)OC

Procedure:
[Hydroxy(cyclohexyl)methylidene]bisphosphonic acid tetramethyl ester from dimethyl cyclohexanoylphosphonate and dimethylphosphite (31-P NMR 23.13 ppm; CDCl3).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([N:10]3[CH2:14][CH2:13][C:12]4([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[C:11]3=[O:20])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.C(O)(=O)C.[Na].[C:26]1([CH2:32][CH2:33][CH:34]=O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1.O>[CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([N:10]3[CH2:14][CH2:13][C:12]4([CH2:19][CH2:18][N:17]([CH2:34][CH2:33][CH2:32][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[CH2:16][CH2:15]4)[C:11]3=[O:20])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: O=CCCc1ccccc1
Reactant: O=C1N(c2ccc(C3CC3)cc2)CCC12CCNCC2
Agent: [Na]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: O=C1N(c2ccc(C3CC3)cc2)CCC12CCN(CCCc1ccccc1)CC2
Temperature: 25 °C
Yield: 25 %

Procedure:
A mixture of 20 mg (0.074 mmol) 2-(4-Cyclopropyl-phenyl)-2,8-diaza-spiro[4.5]decan-1-one, 42 uL acetic acid, 44 mg (0.148 mmol) sodium triacetyoxyborohydride and excess 3-phenyl-propionaldehyde in 2 mL THF was stirred for at room temperature over night. Water was added, the mixture was extracted with ethyl acetate and the combined organic layers were evaporated to dryness. The residue was taken up in methanol and subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3. The product containing fractions were evaporated to yield 7.1 mg (25%) of the title compound. MS m/e: 389.4 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([OH:12])[CH:3]=1.C(OC(=O)C)(=O)C.ClCCl.[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1>N1C=CC=CC=1>[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH:30][C:6](=[O:8])[C:5]2[CH:9]=[C:10]([F:11])[C:2]([F:1])=[CH:3][C:4]=2[OH:12])=[CH:27][CH:26]=1
Reactant: O=C(O)c1cc(F)c(F)cc1O
Reactant: COc1ccc(CN)cc1
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1ccc(CNC(=O)c2cc(F)c(F)cc2O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.2 %

Procedure:
To a solution 4,5-difluoro-2-hydroxybenzoic acid (1 g, 6 mmol, US0061666246) in pyridine (2 mL) was added acetic anhydride (0.8 mL, 7 mol) and the mixture was stirred at room temperature for 2 hr. To this added 10% HCl (10 mL) and extracted the acetate intermediate with ethyl acetate. The ethyl acetate was evaporated and the residue taken up in dichloromethane (10 mL). To this solution added oxalyl chloride (1 mL) and few drops of dimethylformamide and stirred for 1 hr. The solvent was removed and the acid chloride was re-dissolved in dichloromethane (10 mL) and added slowly to dichloromethane solution (10 mL) of p-methoxybenzylamine (0.855 mL, 6.5 mmol). The reaction mixture after 2 hr showed new peak by HPLC and complete disappearance of the starting material. The dichloromethane was removed and the residue dissolved in methanol and to it added 10% aqueous NaOH solution (3 mL) and mixture stirred for 1 hr. The methanol was removed and the residue acidified and extracted with ethyl acetate. The ethyl acetate layer was dried, filtered and evaporated to yield 1.5 g (85%) of N-(4-methoxybenzyl)-4,5-difluoro-2-hydroxybenzamide as a white solid. RP-HPLC: 2.70 min; ES-MS (M+H)+=294; 1H-NMR (CD3OD) δ (ppm) 7.8 (dd, 1), 7.4 (d, 2), 6.8 (d, 2), 6.6 (dd, 1), 4.6 (s, 2), 3.8 (s, 3).
Reaction SMILES: [C:1]([CH2:4][NH:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:28])[CH:19]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)[CH3:20])=[CH:13][CH:12]=2)[CH2:7]1)(=[O:3])[CH3:2].Br[CH2:30][CH:31]1[CH2:34][CH2:33][CH2:32]1>>[C:1]([CH2:4][NH:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:18](=[O:28])[CH:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:30][CH:31]4[CH2:34][CH2:33][CH2:32]4)=[CH:23][CH:22]=3)[CH3:20])=[CH:15][CH:16]=2)[CH2:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)CNC1CCN(c2ccc(NC(=O)C(C)c3ccc(O)cc3)cc2)C1
Reactant: BrCC1CCC1
Product: CC(=O)CNC1CCN(c2ccc(NC(=O)C(C)c3ccc(OCC4CCC4)cc3)cc2)C1

Procedure:
N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-2-(4-hydroxyphenyl)propionamide was reacted with bromomethylcyclobutane by method H. This resulted in a product with the molecular weight 449.60 (C27H35N3O3); MS (ESI): 450 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[CH3:18][C:19]1[NH:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][C:22]=2[O:28][CH2:29][C@@H:30]1[CH2:32][O:31]1>C(O)C>[F:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH:10]3[CH2:11][CH2:12][N:13]([CH2:32][C@H:30]([OH:31])[CH2:29][O:28][C:22]4[CH:23]=[CH:24][CH:25]=[C:26]5[C:21]=4[NH:20][C:19]([CH3:18])=[CH:27]5)[CH2:14][CH2:15]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1
Reactant: Cc1cc2cccc(OC[C@@H]3CO3)c2[nH]1
Reactant: O=c1[nH]c2cc(F)ccc2n1C1CCNCC1
Solvent: CCO
Product: Cc1cc2cccc(OC[C@@H](O)CN3CCC(n4c(=O)[nH]c5cc(F)ccc54)CC3)c2[nH]1
Temperature: 80 °C
Reaction time: 5 h
Yield: 70.8 %

Procedure:
A mixture of 5-fluoro-1-(4-piperidinyl)-1,3-dihydro-2H-benzimidazol-2-one (13.7 mg, 0.058 mmol), 2-methyl-7-[(2S)-oxiranylmethoxy]-1H-indole (12 mg, 0.058 mmol) in ethanol (2 mL) was kept on stirring at 80° C. for 5 h. The volatiles were removed in vacuo and residue purified by silica gel flash chromatography to give titled compound (18 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH2:35][CH3:36])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH2:37]([C:39]1[C:40]([N:49]2[CH2:54][CH2:53][CH:52]([CH2:55][CH2:56][S:57]([CH3:60])(=[O:59])=[O:58])[CH2:51][CH2:50]2)=[CH:41][C:42]([O:46][CH2:47][CH3:48])=[C:43]([CH:45]=1)[NH2:44])[CH3:38].Cl.O1CCOCC1.N>CO>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:44][C:43]3[CH:45]=[C:39]([CH2:37][CH3:38])[C:40]([N:49]4[CH2:50][CH2:51][CH:52]([CH2:55][CH2:56][S:57]([CH3:60])(=[O:59])=[O:58])[CH2:53][CH2:54]4)=[CH:41][C:42]=3[O:46][CH2:47][CH3:48])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH2:35][CH3:36]
Reactant: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Reactant: CCOc1cc(N2CCC(CCS(C)(=O)=O)CC2)c(CC)cc1N
Agent: Cl
Agent: N
Solvent: CO
Solvent: C1COCCO1
Product: CCOc1cc(N2CCC(CCS(C)(=O)=O)CC2)c(CC)cc1Nc1nccc(-c2c(-c3ccc(OCC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 180 °C
Yield: 58 %

Procedure:
In a microwave vial with septum cap, 5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(ethyloxy)benzamide (Intermediate Example 6) (0.148 g, 0.293 mmol) and 5-ethyl-2-(ethyloxy)-4-{4-[2-(methylsulfonyl)ethyl]-1-piperidinyl}aniline (0.104 g, 0.293 mmol) were taken up in 1,1,1-trifluoroethanol (1.5 mL) and 4M HCl in dioxane (0.147 mL, 0.587 mmol) was added. The vial was sealed and heated in the microwave at 180° C. for 40 min. Reaction was complete by MS, it was cooled to rt, neutralized with 7N ammonia in MeOH, and concentrated in vacuo onto silica gel and flash chromatographed. The desired fractions were combined and concentrated and the resulting solid was triturated with diethyl ether, filtered and air dried to give the title compound (0.14 g, 0.17 mmol, 58%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.70 (s, 1H), 9.29 (d, J=6.8 Hz, 1H), 8.34 (s, 1H), 8.23 (d, J=5.2 Hz, 1H), 8.03 (s, 1H), 7.61-7.79 (m, 2H), 7.55 (s, 1H), 7.29-7.48 (m, 2H), 7.08-7.28 (m, 3H), 6.89 (t, J=6.8 Hz, 1H), 6.76 (s, 1H), 6.56 (d, J=5.1 Hz, 1H), 4.23 (q, J=6.7 Hz, 2H), 4.03 (q, J=6.9 Hz, 2H), 3.07-3.20 (m, 2H), 2.84-3.04 (m, 5H), 2.60 (t, J=10.9 Hz, 2H), 2.51 (q, J=7.5 Hz, 2H), 1.75 (d, J=11.2 Hz, 2H), 1.60-1.70 (m, 2H), 1.35-1.55 (m, 4H), 1.15-1.36 (m, 5H), 1.05 (td, J=7.2, 1.9 Hz, 3H). MS (M+H, ES+) 824.
Reaction SMILES: C([O:3][C:4](=[O:22])[C@@H:5]([O:20][CH3:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([C:17]([OH:19])=O)([CH3:16])[CH3:15])=[CH:9][CH:8]=1)C.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=1[CH2:33][CH2:34][NH2:35].C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=1[CH2:33][CH2:34][NH:35][C:17]([C:14]([CH3:15])([O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:20][CH3:21])[C:4]([OH:3])=[O:22])=[CH:12][CH:11]=1)[CH3:16])=[O:19]
Reactant: CCOC(=O)[C@H](Cc1ccc(OC(C)(C)C(=O)O)cc1)OC
Reactant: COc1ccc(OC)c(CCN)c1
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: COc1ccc(OC)c(CCNC(=O)C(C)(C)Oc2ccc(C[C@H](OC)C(=O)O)cc2)c1

Procedure:
The title compound was prepared from (2S)-3-[4-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (PREPARATION 5, step 2) and 2-(2,5-dimethoxy-phenyl)-ethylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C24H31NO7 [M−H]−: 445.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]=[O:10])[CH:5]=[CH:6][CH:7]=1.O.[NH2:12][NH2:13]>C1(C)C=CC=CC=1.O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:10])[NH:12][NH2:13])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C=Nc1cccc(F)c1
Reactant: NN
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: NNC(=O)Nc1cccc(F)c1
Reaction time: 2 h

Procedure:
A solution of 3-fluorophenyl isocyanate (5.0 g, 36.0 mmol) in 20 ml of toluene is added to hydrazine hydrate (2.1 g, 42.0 mmol) in 70 ml of dioxane, maintaining the temperature of the reaction at less than 12°. After 2 hours, the reaction is filtered and the solvent is removed from the filtrate by rotoevaporation to give the white solid, 4-(3-fluorophenyl)-semicarbazide.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]#[N:15])=[CH:4][CH:3]=1.[Br:16]([O-])(=O)=O.[Na+].BrBr>N(C(C)(CC)C#N)=NC(C)(CC)C#N.ClC1C=CC=CC=1>[Br:16][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]#[N:15])=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [O-][Br+2]([O-])[O-]
Agent: BrBr
Agent: CCC(C)(C#N)N=NC(C)(C#N)CC
Agent: [Na+]
Solvent: Clc1ccccc1
Product: N#Cc1ccccc1-c1ccc(CBr)cc1
Temperature: 5 °C
Yield: 493.9 %

Procedure:
4′-Methyl-2-cyanobiphenyl (105 g, 0.54 mol) and sodium bromate (12.3 g, 0.082 mol) were added to monochlorobenzene (300 g) and the internal temperature was set for 65° C. 2,2′-Azobis(2-methylbutyronitrile) (2.0 g, 0.010 mol) was added, bromine (45.6 g, 0.29 mol) was added dropwise over 5 hr and the reaction mixture was maintained at this temperature for 1 hr. The resulting inorganic salt was filtered off and the reaction mixture was cooled to 5° C. The precipitated crystals were collected by filtration to give 4′-bromomethyl-2-cyanobiphenyl (110 g, 0.405 mol). The yield was 75%.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:2]1.Br[CH2:14][CH2:15][N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[O:26]=[C:17]1[C:18]2[C:19](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20](=[O:21])[N:16]1[CH2:15][CH2:14][N:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:2]1
Reactant: CC(C)(C)OC(=O)c1cc[nH]c1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)c1ccn(CCN2C(=O)c3ccccc3C2=O)c1
Reaction time: 12 h
Yield: 12.6 %

Procedure:
To a solution of 2.62 g of tert-butyl 1H-pyrrole-3-carboxylate and 7.96 g of N-(2-bromoethyl)phthalimide in DMF (100 ml) was added 10.2 g of cesium carbonate at room temperature, followed by stirring for 12 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The extract was washed with saturated brine and then dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography using hexane/chloroform as an eluent solvent, and washed with diethyl ether to obtain 670 mg of tert-butyl 1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1H-pyrrole-3-carboxylate as a colorless solid.
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9]1[CH:10]=[C:11]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[OH:27])[C:20](=[O:28])[NH:19][CH:18]=2)[CH:12]=[CH:13][C:14]=1[O:15]C)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].B(Br)(Br)Br.ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH2:1]([N:4]([CH2:8][C:9]1[CH:10]=[C:11]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[OH:27])[C:20](=[O:28])[NH:19][CH:18]=2)[CH:12]=[CH:13][C:14]=1[OH:15])[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3]
Reactant: CCCN(CCC)Cc1cc(-c2c[nH]c(=O)c3cccc(O)c23)ccc1OC
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCCN(CCC)Cc1cc(-c2c[nH]c(=O)c3cccc(O)c23)ccc1O
Temperature: 0 °C
Yield: 85.8 %

Procedure:
To a solution of the compound of Example 63 (84.6 mg, 222 μmol) in dichloromethane (5 mL) was added 1 mol/L boron tribromide-dichloromethane solution (1.11 mL, 1.11 mmol), and the mixture was refluxed for 24 hours. After cooling, the reaction mixture was poured in ice water and the solution was brought to pH 8 with sodium carbonate. This was extracted using dichloromethane, dried over anhydrous sodium sulfate, and then solvent was distilled off. The residue obtained was purified by Chromatolex NH column chromatography [ethyl acetate-methanol=20:1], thereby affording 69.8 mg of the title compound as colorless powder. Yield 86%.
Reaction SMILES: C[O:2][C:3](=[O:22])[CH:4]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1.[OH-].[K+]>C(O)C.O>[CH3:21][S:18]([C:15]1[CH:16]=[CH:17][C:12]([CH:4]([CH2:5][CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][O:7]2)[C:3]([OH:22])=[O:2])=[CH:13][CH:14]=1)(=[O:20])=[O:19]
Reactant: COC(=O)C(CC1CCCCO1)c1ccc(S(C)(=O)=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)c1ccc(C(CC2CCCCO2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.5 %

Procedure:
A solution of 2-(4-methanesulfonyl-phenyl)-3-(tetrahydro-pyran-2-yl)-propionic acid methyl ester (prepared as in Example 8, 75 mg, 0.23 mmol) in ethanol (5 mL) was treated with a solution of potassium hydroxide (32 mg, 0.58 mmol) in water (1 mL). The reaction was stirred for 3 h at 25° C. The reaction was then concentrated in vacuo to remove the ethanol and then acidified to pH=2 with a 1N aqueous hydrochloric acid solution. This solution was then extracted with methylene chloride (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, hexanes to 60/40 hexanes/ethyl acetate plus 1% acetic acid) afforded 2-(4-methanesulfonyl-phenyl)-3-(tetrahydro-pyran-2-yl)-propionic acid (60 mg, 85%) as a white solid: FAB-HRMS m/e calcd for C15H20O5S (M+H)+ 313.1109, found 313.1111.