Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH:28]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]([N:13]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:11][OH:12])=[O:4].[C:41](O)(=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[N:44][CH:43]=1.[OH-].[Na+]>>[NH2:27][C:24]1[CH:23]=[CH:22][C:21]([S:18]([N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[C@H:10]([CH2:11][OH:12])[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:3]([C@@H:2]([NH:1][C:41](=[O:48])[C:42]2[CH:47]=[CH:46][CH:45]=[N:44][CH:43]=2)[CH:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:4])(=[O:20])=[O:19])=[CH:26][CH:25]=1
Reactant: O=C(O)c1cccnc1
Reactant: CC(C)CN([C@H](CO)CCCCNC(=O)[C@@H](N)C(c1ccccc1)c1ccccc1)S(=O)(=O)c1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)CN([C@H](CO)CCCCNC(=O)[C@@H](NC(=O)c1cccnc1)C(c1ccccc1)c1ccccc1)S(=O)(=O)c1ccc(N)cc1

Procedure:
The title compound was then obtained in 65% yield using (2S,5S)-2-amino-N-{5-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-hydroxy-hexyl}-3,3-diphenyl-propionamide (product of example 72) and nicotinic acid with general procedure A. However, 1.0N NaOH was used instead of 1.0N hydrochloric acid for the preparation of the title compound.
Reaction SMILES: C(N1C=C(C(=O)C=C(O)C(OC)=O)C(=O)N(CC2C=CC=CC=2)C1=O)C1C=CC=CC=1.[F:32][C:33]1[CH:64]=[CH:63][CH:62]=[CH:61][C:34]=1[CH2:35][N:36]1[CH:41]=[C:40]([C:42](=[O:50])[CH:43]=[C:44]([OH:49])[C:45]([O:47]C)=[O:46])[C:39](=[O:51])[N:38]([CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=2[F:59])[C:37]1=[O:60]>>[F:32][C:33]1[CH:64]=[CH:63][CH:62]=[CH:61][C:34]=1[CH2:35][N:36]1[CH:41]=[C:40]([C:42](=[O:50])[CH:43]=[C:44]([OH:49])[C:45]([OH:47])=[O:46])[C:39](=[O:51])[N:38]([CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=2[F:59])[C:37]1=[O:60]
Reactant: COC(=O)C(O)=CC(=O)c1cn(Cc2ccccc2F)c(=O)n(Cc2ccccc2F)c1=O
Agent: COC(=O)C(O)=CC(=O)c1cn(Cc2ccccc2)c(=O)n(Cc2ccccc2)c1=O
Product: O=C(O)C(O)=CC(=O)c1cn(Cc2ccccc2F)c(=O)n(Cc2ccccc2F)c1=O
Yield: 56.5 %

Procedure:
The title compound was synthesized using a similar procedure to that described in Example 2, except that methyl 4-(1,3-dibenzyl-1,2,3,4-tetrahydro-2,4-dioxopyrimidin-5-yl)-2-hydroxy-4-oxobut-2-enoate was replaced with methyl 4-[1,3-bis(2-fluorobenzyl)-1,2,3,4-tetrahydro-2,4-dioxopyrimidin-5-yl]-2-hydroxy-4-oxobut-2-enoate (3b). The title compound was crystallized from hexane and ethyl acetate (2:1) to give an off-white solid. The yield was 56.5%. Mp. 178-179° C. 1H NMR (DMSO-d6): 15.00 (br, s, 1H), 14.02 (br, s, 1H), 8.90 (s, 1H), 7.55 (s, 1H), 7.08-7.40 (m, 8H), 5.23 (s, 2H), 5.05 (s, 2H). 13CNMR (DMSO-d6): 185.7, 169.2, 163.0, 160.2 (d, J=246.0 Hz), 159.8 (d, J=244.6 Hz), 159.7, 151.2, 149.9, 130.2, 129.0 (d, J=8.2 Hz), 128.4 (d, J=3.9 Hz), 124.5 (d, J=3.3 Hz), 124.3 (d, J=3.3 Hz), 123.1 (d, J=13.9 Hz), 122.3 (d, J=14.5 Hz), 115.4 (d, J=21.1 Hz), 115.1 (d, J=21.1 Hz), 107.6, 100.7, 47.8 (d, J=3.4 Hz), 38.2 (d, J=4.8 Hz).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[N:11]=[N:12][N:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][NH2:22])=[CH:17][CH:16]=3)[CH:14]=2)=[N:2]1.[C:23](Cl)(=[O:25])[CH3:24]>CN(C=O)C.C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[N:11]=[N:12][N:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])=[CH:17][CH:16]=3)[CH:14]=2)=[N:2]1
Reactant: NCc1ccc(-n2cc(-c3n[nH]c4ccccc34)nn2)cc1
Reactant: CC(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)NCc1ccc(-n2cc(-c3n[nH]c4ccccc34)nn2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]phenyl}methanamine (190 mg; 0.58 mmol; 1.0 eq.) and TEA (242 μl; 1.74 mmol; 3.0 eq.) in DMF (3.8 mL) was added acetyl chloride (46 μl; 0.70 mmol; 1.2 eq.) and the reaction mixture was stirred overnight at RT. Reaction mixture was diluted with DCM and washed with water and brine. The organic phase was dried over magnesium sulfate, filtered and concentrated. Purification by preparative HPLC afforded the title compound as a white solid. 1H NMR (300 Mz, DMSO) δ: 13.36 (brs, 1H), 8.29 (s, 1H), 8.47 (t, J=5.9 Hz, 1H), 8.36 (dt, J=8.0 Hz, J=1.0 Hz, 1H), 8.01 (d, J=8.6 Hz, 2H), 7.60 (dt, J=8.4 Hz, J=1.0 Hz, 1H), 7.49 (d, J=8.6 Hz, 2H), 7.47-7.41 (m, 1H), 7.28-7.23 (m, 1H), 4.34 (d, J=5.9 Hz, 2H), 1.90 (s, 3H). HPLC (Condition A): Rt 2.81 min (purity 97.7%). MS (ESI+): 333.2, MS (ESI−): 331.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:29])[NH:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][Si](C)(C)C.[CH2:30]([N:32]([CH2:46][CH3:47])[C:33](=[O:45])[NH:34][C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1)[CH3:31]>CCOC(C)=O.CCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:41]([C:38]1[CH:37]=[CH:36][C:35]([NH:34][C:33]([N:32]([CH2:46][CH3:47])[CH2:30][CH3:31])=[O:45])=[CH:40][CH:39]=1)(=[O:43])=[O:42])[C:6](=[O:11])[C:5]2([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:29])[NH:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][OH:18]
Reactant: CCN(CC)C(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[Si](C)(C)OCCOCCNC1(c2ccccc2Cl)C(=O)Nc2ccc(Cl)cc21
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCN(CC)C(=O)Nc1ccc(S(=O)(=O)N2C(=O)C(NCCOCCO)(c3ccccc3Cl)c3cc(Cl)ccc32)cc1
Yield: 47.6 %

Procedure:
This compound is prepared according to the procedure described in EXAMPLE 114 from 1.5 g of 5-chloro-3-(2-chlorophenyl)-1,3-dihydro-3-[[2-[2-(trimethylsilyloxy)ethoxy]ethyl]amino]indol-2-one and 1.03 g of 4-(N',N'-diethylureido)benzenesulfonyl chloride. Chromatography on silica using a DCM/AcOEt mixture (50/50; v/v) as the eluent gives 1 g of the expected product after crystallization from a DCM/iso ether mixture. M.p.=114°-118° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[S:5][C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1.O>CO.[Ni]>[CH3:1][O:2][CH2:3][C:4]1[S:5][C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([NH2:19])=[CH:17][CH:18]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1
Reactant: CCCc1nc(COC)sc1Cc1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Solvent: CO
Solvent: O
Product: CCCc1nc(COC)sc1Cc1ccc(N)cc1

Procedure:
0.9 of 2-methoxymethyl-4-propyl-5-(4-nitrobenzyl)thiazole in 50 ml of methanol is hydrogenated at normal pressure and room temperature in the presence of Raney nickel. After filtration of the catalyst and concentration of the filtrate, the brown oil obtained is taken up with acidified water. The aqueous phase is extracted with ether, rendered basic with dilute sodium hydroxide and extracted with ethyl acetate. The organic phase is dried and concentrated to give 0.5 g of 2-methoxymethyl-4-propyl-5-(4-aminobenzyl)thiazole in the form of an orange oil, which is used as such for the next step.
Reaction SMILES: Cl[C:2]1[CH:27]=[CH:26][C:5]([CH2:6][O:7][C:8]2[CH:16]=[CH:15][C:14]3[NH:13][C:12]4[CH:17]([CH2:20][C:21]([O:23]CC)=[O:22])[CH2:18][CH2:19][C:11]=4[C:10]=3[CH:9]=2)=[CH:4][C:3]=1[C:28]([F:31])([F:30])[F:29].[Br-].[CH:33]1([Zn+])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.O.O[Li].O>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.CO>[CH:33]1([C:2]2[CH:27]=[CH:26][C:5]([CH2:6][O:7][C:8]3[CH:16]=[CH:15][C:14]4[NH:13][C:12]5[CH:17]([CH2:20][C:21]([OH:23])=[O:22])[CH2:18][CH2:19][C:11]=5[C:10]=4[CH:9]=3)=[CH:4][C:3]=2[C:28]([F:29])([F:31])[F:30])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: [Zn+]C1CCCCC1
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(OCc3ccc(Cl)c(C(F)(F)F)c3)cc21
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Br-]
Agent: [Li]O
Solvent: CO
Solvent: O
Product: O=C(O)CC1CCc2c1[nH]c1ccc(OCc3ccc(C4CCCCC4)c(C(F)(F)F)c3)cc21
Yield: 27.5 %

Procedure:
A mixture of ethyl 2-(7-(4-chloro-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (50 mg, 0.111 mmol), 0.5 M cyclohexylzinc(II) bromide (0.5 M in THF, 3 mL, 1.5 mmol), and bis(tri-t-butylphosphine)palladium (3 mg, 5.87 μmol) were stirred under reflux for 18 h. The mixture was allowed to cool to room temperature before water (1 mL), MeOH (1 mL) and LiOH hydrate (70 mg, 1.668 mmol) were added. The mixture was stirred at room temperature for 2 h. The mixture was purified by HPLC. Fractions containing product were basified with 1 M NaHCO3 and partially concentrated. The residue was extracted with 0.5 M citric acid and CH2Cl2. The organics were dried over MgSO4, filtered and concentrated to give the title compound as a tanned sticky solid (14.4 mg). LCMS m/z=472.2 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.38-1.50 (m, 4H), 1.76-1.85 (m, 6H), 2.11-2.17 (m, 1H), 2.58-2.65 (m, 1H), 2.75-2.93 (m, 5H), 3.56-3.60 (m, 1H), 5.07 (s, 2H), 6.84 (dd, J=8.8, 2.5 Hz, 1H), 7.00 (d, J=2.4 Hz, 1H), 7.21 (d, J=8.8 Hz, 1H), 7.46 (d, J=8.1 Hz, 1H), 7.59 (d, J=8.1 Hz, 1H), 7.70 (d, J=1.2 Hz, 1H), 8.27 (s, 1H).
Reaction SMILES: [OH:1][C:2]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>CC(=O)CC>[CH2:24]([N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([OH:1])([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:3]1=[O:11])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C1Nc2ccccc2C1(O)c1ccccc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCC(C)=O
Solvent: O
Product: O=C1N(Cc2ccccc2)c2ccccc2C1(O)c1ccccc1
Yield: 64.7 %

Procedure:
Combine 3-hydroxy-3-phenyl-1,3-dihydro-indol-2-one (225 mg, 1 mmol) and cesium carbonate (977 mg, 3 mmol) in 2-butanone (5 mL). Add benzyl bromide (0.13 mL, 1 mmol) and heat at 60° C. for 3 h. with vigorous stirring. Dilute the reaction with water and wash with ethyl acetate (2×). Wash combined organic portions with brine and then dry (MgSO4), filter and concentrate in vacuo to give an oil. Purify with radial chromatography (gradient of 10% EtOAc/hexanes to 25% EtOAc/hexanes) to give 204 mg (65%) of the title compound as a white solid. MS (ES): m/z=298 (M+1−H2O); 1H NMR(DMSO-d6); δ7.37-7.27 (m, 11H), 7.18 (m, 1H), 7.05 (m, 1H), 6.98 (m, 1H), 6.87 (s, 1H), 4.92 (s, 2H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:11])=[CH:8][C:9]=1[OH:10])=[O:3].N1C[CH2:15][CH2:14][CH2:13]1.CC(C)=O>C1(C)C=CC=CC=1>[OH:11][C:7]1[CH:8]=[C:9]2[C:4]([C:2](=[O:3])[CH2:1][C:14]([CH3:15])([CH3:13])[O:10]2)=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(O)cc1O
Reactant: C1CCNC1
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: CC1(C)CC(=O)c2ccc(O)cc2O1
Yield: 33.8 %

Procedure:
To a solution of 2,4-dihydroxy acetophenone (6.00 g, 39.4 mmol) and pyrrolidine (15.0 mL, 181 mmol) in toluene (200 mL), acetone (22.9 g, 394 mmol) was added. After heated to reflux for 16 hrs, the solvents were removed and the residue was added HCl (2.0 N, 100 mL) and brine (200 mL) then the mixture was extracted with EtOAc (150×5 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by SGC (eluting with petroleum ether/ethyl acetate=6/1) to give target compound (2.56 g, 33%) as a brown yellow solid. LCMS (ESI) m/z: 191.1 [M−H]+; 1H-NMR (500 MHz, CDCl3): δ 7.79 (d, J=8.0 Hz, 1H), 6.49 (dd, J=8.5, 2.0 Hz, 1H), 6.36 (d, J=2.0 Hz, 1H), 2.68 (s, 2H), 1.45 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][NH:12][C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[F:17][C:18]([F:31])([F:30])[O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](O)=[O:28])=[CH:22][CH:21]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][N:12]([C:27](=[O:28])[CH2:26][C:23]4[CH:24]=[CH:25][C:20]([O:19][C:18]([F:30])([F:17])[F:31])=[CH:21][CH:22]=4)[C:11]=3[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Reactant: O=C(O)Cc1ccc(OC(F)(F)F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Cc1ccc(OC(F)(F)F)cc1)N1CCCc2c1cnn2-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
To a mixture of 1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine (0.023 g, 0.10 mmol), 4-(trifluoromethoxy)phenylacetic acid (0.025 g, 0.11 mmol) and Et3N (0.060 mL, 0.43 mmol) in DMF (0.6 mL) was added HATU (0.060 g, 0.15 mmol). The mixture was stirred at rt for 30 min. It was then quenched with water. The mixture was partitioned between EtOAc (50 mL) and sat. NaHCO3 (30 mL). The organic layer was separated, dried over Na2SO4, concentrated in vacuo, and purified by reverse phase HPLC to afford the desired product (0.040 g, 95%). 1H NMR (400 MHz, CDCl3) δ 8.51 (s, 1H), 7.43 (m, 2H), 7.30 (m, 2H), 7.18 (m, 4H), 3.91 (s, 2H), 3.76 (m, 2H), 2.79 (t, J=6.4 Hz, 2H), 2.00 (m, 2H); MS: (ES) m/z calculated for C21H17F4N3O2 [M+H]+ 420.1, found 420.1.
Reaction SMILES: CNS(C1C=C(C(=O)CC(CC2C=CC=CC=2)C(O)=O)C=CC=1)(=O)=O.[O:26]=[C:27]([C:40]1O[CH:42]=[C:43]2[CH:48]=[CH:47][CH:46]=C[C:44]=12)[CH2:28][CH:29]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:30]([OH:32])=[O:31]>>[CH3:42][C:43]1[CH:44]=[C:40]([C:27](=[O:26])[CH2:28][CH:29]([CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:30]([OH:32])=[O:31])[CH:46]=[CH:47][CH:48]=1
Reactant: O=C(CC(Cc1ccccc1)C(=O)O)c1occ2ccccc12
Agent: CNS(=O)(=O)c1cccc(C(=O)CC(Cc2ccccc2)C(=O)O)c1
Product: Cc1cccc(C(=O)CC(Cc2ccccc2)C(=O)O)c1

Procedure:
3-(methylaminosulfonyl)gamma-oxo-α-(phenylmethyl)benzenebutanoic acid, mp. 130°-133° C. gamma-oxo-alpha-(phenylmethyl)-2-benzofuranbutanoic acid, mp. 158°-161° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:3]=1.[CH3:16][C:17]1[C:18]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[N:19][CH:20]=[C:21]([CH3:23])[CH:22]=1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:27]2[CH2:28][CH2:29][N:24]([C:18]3[C:17]([CH3:16])=[CH:22][C:21]([CH3:23])=[CH:20][N:19]=3)[CH2:25][CH2:26]2)=[O:8])=[C:4]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:3]=1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: CS(=O)(=O)Nc1cc(Br)ccc1C(=O)O
Product: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3NS(C)(=O)=O)CC2)c(C)c1
Yield: 21 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 60 and using 4-bromo-2-methanesulfonylaminobenzoic acid (0.964 g) described in Preparation Example 122 and 1-(3,5-dimethylpyridin-2-yl)piperazine (0.629 g) described in Preparation Example 47, the title compound (0.321 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([N:8]([CH3:13])[CH2:9][C:10]([OH:12])=[O:11])=O)=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:17]>C1(C)C=CC=CC=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([N:8]([CH3:13])[CH2:9][C:10]([OH:12])=[O:11])=[S:17])=[CH:4][CH:3]=1
Reactant: CN(CC(=O)O)C(=O)c1ccc(Cl)cc1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: Cc1ccccc1
Product: CN(CC(=O)O)C(=S)c1ccc(Cl)cc1
Temperature: 90 °C
Yield: 67.7 %

Procedure:
To a slurry of 4.54 g of 4-chlorobenzoyl methyl glycine (20 mmol) in 60 ml of toluene under an atmosphere of nitrogen was added 0.89 g (20 mmol) of phosphorus pentasulfide. The reaction was heated to 90° C. for 3 hours. An additional 0.18 g of phosphorus pentasulfide was added, and the reaction was heated for an additional 1 hour, then cooled to room temperature. The product was filtered, the slurry was washed with ethyl acetate, and the combined filtrates were run through silica gel on Gelite, then stripped. The product was chromatographed on a silica gel column to give 3.3 g (68% yield) of 4-chlorothiobenzoyl methylglycine, melting point 72-73° C.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[C:8]([C:11]3[CH:12]=[C:13]([C:16]([NH2:18])=[O:17])[S:14][CH:15]=3)=[N:9][NH:10][C:6]=2[CH:5]=[CH:4][NH:3]1.[H-].[Na+].CC1C=CC(S(O[CH:32]([CH2:36][CH3:37])[CH2:33][O:34][CH3:35])(=O)=O)=CC=1>CN(C=O)C>[CH3:35][O:34][CH2:33][CH:32]([N:10]1[C:6]2[CH:5]=[CH:4][NH:3][C:2](=[O:1])[C:7]=2[C:8]([C:11]2[CH:12]=[C:13]([C:16]([NH2:18])=[O:17])[S:14][CH:15]=2)=[N:9]1)[CH2:36][CH3:37]
Reactant: NC(=O)c1cc(-c2n[nH]c3cc[nH]c(=O)c23)cs1
Reactant: CCC(COC)OS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(COC)n1nc(-c2csc(C(N)=O)c2)c2c(=O)[nH]ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.8 %

Procedure:
To a solution of 4-(4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)thiophene-2-carboxamide (50.0 mg) obtained in Step A of Example 141 in DMF (2 mL) was added sodium hydride (60% dispersion in mineral oil, 15.4 mg), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added 1-methoxybutan-2-yl 4-methylbenzenesulfonate (99.0 mg) obtained in Step A-1 of Example 17, and the mixture was stirred overnight at room temperature. The reaction mixture was extracted with water and ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (basic silica gel, ethyl acetate/methanol) to give the title compound (21.8 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=[O:19])[CH:12]=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[N-:20]=[N+:21]=[N-:22].[Na+].O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[C:11]([C:12]1[NH:22][N:21]=[N:20][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:19]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)C=CC(=O)c1ccc(OC)c(OC)c1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nn[nH]c1C(=O)c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 52.9 %

Procedure:
A solution (3.0 mL) of ethyl 4-(3,4-dimethoxyphenyl)-4-oxo-2-butenoate (104 mg, 0.39 mmol) in N,N-dimethylformamide was added to a solution (5.0 mL) of sodium azide (40 mg, 0.62 mmol) in N,N-dimethylformamide at 5° C. The temperature of the reaction solution was raised to room temperature before the reaction solution was stirred for 6 hr. After the completion of the reaction, iced water (10 mL) was added to the reaction solution, and the mixture was washed with ethyl acetate. The aqueous layer was then adjusted to pH 1.5 by the addition of 2 N hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was then removed by evaporation under the reduced pressure. The oil thus obtained was dried in vacuo to give ethyl 5-(3,4-dimethoxybenzoyl)-1H-1,2,3-triazole-4-carboxylate (63 mg, yield 52%).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10](OS(C)(=O)=O)[CH2:9][C@H:8]1[CH2:17][CH2:18][N:19]1[C:23]([CH2:24][OH:25])=[CH:22][N:21]=[CH:20]1)=[O:6])[CH:2]=[CH2:3].[C:26]([OH:29])(=[S:28])[CH3:27].CC(C)([O-])C.[K+]>>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:28][C:26](=[O:29])[CH3:27])[CH2:9][C@H:8]1[CH2:17][CH2:18][N:19]1[C:23]([CH2:24][OH:25])=[CH:22][N:21]=[CH:20]1)=[O:6])[CH:2]=[CH2:3]
Reactant: CC(O)=S
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CCn1cncc1CO
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1CCn1cncc1CO

Procedure:
(2R,4R)-1-Allyloxycarbonyl-2-[2-(5-hydroxymethyl-imidazol-1-yl) ethyl]-4-methanesulfonyloxypyrrolidine (1.63 g) was reacted with thioacetic acid (0.65 ml) and potassium t-butoxide (0.978 g) in substantially the same manner as that of Preparation 14-12) to give (2R,4S)-1-allyloxycarbonyl-4-acetylthio-2-[2-(5-hydroxymethyl-imidazol-1-yl)ethyl]pyrrolidine (884 mg) as an orange paste.
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]([C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[CH:21]=1)=[C:14]2[CH2:28][CH2:29][N:30]([CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH2:31][CH2:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=1)C1C=CC=CC=1.C1(OC)C=CC=CC=1.C(O)C1C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-]>[N+](C1C=CC=CC=1)([O-])=O>[CH2:44]([N:30]([CH2:31][CH2:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=1)[CH2:29][CH2:28][C:14]1[C:13]2[C:17](=[CH:18][CH:19]=[C:11]([NH2:10])[CH:12]=2)[NH:16][C:15]=1[C:20]1[CH:21]=[C:22]([CH3:27])[CH:23]=[C:24]([CH3:26])[CH:25]=1)[C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(NC(=O)OCc4ccccc4)cc3c2CCN(CCCCc2ccc([N+](=O)[O-])cc2)Cc2ccccc2)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: OCc1ccccc1
Solvent: COc1ccccc1
Solvent: O=[N+]([O-])c1ccccc1
Product: Cc1cc(C)cc(-c2[nH]c3ccc(N)cc3c2CCN(CCCCc2ccc([N+](=O)[O-])cc2)Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 11.5 h
Yield: 88.2 %

Procedure:
To a solution of [3-(2-{benzyl-[4-(4-nitrophenyl)butyl]amino}ethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]carbamic acid benzyl ester (500 mg in 25 mL dry methylene chloride) was added 0.50 mL anisole followed by 0.035 mL benzyl alcohol and the mixture stirred at room temperature. Then, 2.94 mL of a 1M solution of aluminum chloride in nitrobenzene was added dropwise. After 11.5 hours, the reaction was cooled to 0° C. and quenched by the addition of saturated aqueous sodium bicarbonate and partitioned between ethyl acetate and aqueous sodium potassium tartarate. The organic portion was washed with additional tartarate solution and dried over sodium sulfate. Purification of the concentrate by flash chromatography on silica gel (methylene chloride:methanol, 97:3) gave the title compound (354 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[I:9].[CH3:10][C:11]1[C:15]([C:16](O)=[O:17])=[C:14]([CH3:19])[O:13][N:12]=1.C(Cl)CCl>CN(C1C=CN=CC=1)C>[CH3:10][C:11]1[C:15]([C:16]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([I:9])[CH:4]=2)=[O:17])=[C:14]([CH3:19])[O:13][N:12]=1
Reactant: Cc1noc(C)c1C(=O)O
Reactant: Nc1ccc(Cl)c(I)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Product: Cc1noc(C)c1C(=O)Nc1ccc(Cl)c(I)c1

Procedure:
4-Chloro-3-iodoaniline (1.01 g, 4 mmol) was used in procedure E with 3,5-dimethyl-4-isoxazolecarboxylic acid (0.565 g, 4 mmol), EDC (1.32 g, 6.8 mmol), TEA (0.5 mL), DMAP (50 mg, 0.4 mmol) at 23° C. for overnight. The crude reaction was purified by silica gel chromatography (0-15% ethyl acetate/CH2Cl2) to yield 3,5-dimethyl-N-(4-chloro-3-iodophenyl)isoxazole-4-carboxamide as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[C:5]([Cl:10])=[CH:4][N:3]=1.[N:11]1([CH2:17][CH2:18][O:19][C:20]2[CH:28]=[CH:27][C:23]([C:24](O)=O)=[CH:22][CH:21]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>O=P(Cl)(Cl)Cl>[Cl:10][C:5]1[C:6]([Cl:9])=[C:7]2[N:8]=[C:24]([C:23]3[CH:27]=[CH:28][C:20]([O:19][CH2:18][CH2:17][N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)=[CH:21][CH:22]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: Nc1ncc(Cl)c(Cl)c1N
Reactant: O=C(O)c1ccc(OCCN2CCOCC2)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1cnc2[nH]c(-c3ccc(OCCN4CCOCC4)cc3)nc2c1Cl
Temperature: 100 °C

Procedure:
2,3-Diamino-4,5-dichloropyridine (Example 206a) (0.50 g, 2.5 mmol) and 4-(2-morpholin-4-ylethoxy)benzoic acid (Example 206c) (0.80 g, 2.5 mmol) were dissolved in POCl3 (10 ml) and heated to 100° C. for 10 h. The excess of POCl3 was evaporated off and the residue was dissolved in EtOAc and aqueous NaHCO3. The aqueous phase was basified with 10M NaOH and extracted three times with EtOAc. The combined organic phases were washed with brine, dried (Na2SO4) and evaporated in vacuo to afford the title product as a slightly yellow powder (0.74 g, 75%).