Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=3)[C:11](=[O:19])[C:10]=2[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.BrC1C(=O)C2C(C=1C1C=CC=CC=1)=CC=C(O)C=2.O[CH2:45][CH2:46][N:47]1[CH2:52][CH2:51][S:50](=[O:54])(=[O:53])[CH2:49][CH2:48]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>>[O:53]=[S:50]1(=[O:54])[CH2:51][CH2:52][N:47]([CH2:46][CH2:45][O:18][C:14]2[CH:13]=[C:12]3[C:17]([C:9]([C:4]4[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=4)=[C:10]([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:11]3=[O:19])=[CH:16][CH:15]=2)[CH2:48][CH2:49]1
Reactant: O=C1C(c2cccnc2)=C(c2cc(F)cc(F)c2)c2ccc(O)cc21
Reactant: O=S1(=O)CCN(CCO)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(O)cc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C1C(c2cccnc2)=C(c2cc(F)cc(F)c2)c2ccc(OCCN3CCS(=O)(=O)CC3)cc21
Reaction time: 13 h

Procedure:
The procedure of Step 6 of Example 1 was repeated except for using 3-(3,5-difluorophenyl)-6-hydroxy-2-(pyridin-3-yl)-1H-inden-1-one obtained in Step 1 of Example 64 as a starting material instead of 2-bromo-6-hydroxy-3-phenyl-1H-inden-1-one, 4-(2-hydroxyethyl)thiomorpholine-1,1-dioxide (2.0 eq) instead of 4-(2-hydroxyethyl)morpholine, using 2 equivalents of PPh3 and DIAD, and being stirred for 13 h to provide 6-[2-(1,1-dioxothiomorpholin-4-yl)ethoxy]-3-(3,5-difluorophenyl)-2-(pyridin-3-yl)-1H-inden-1-one, which was treated with HCl/dioxane following the same procedure in Step 8 of Example 1 (40% for 2 steps).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([C:12]2[C:16]([CH3:17])=[CH:15][N:14]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[N:13]=2)[C:9]2[C:4](=[C:5]([OH:24])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl[CH2:26][C:27]1[C:28]([CH2:34][N:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[C:36]2=[O:45])=[N:29][CH:30]=[CH:31][C:32]=1[CH3:33].ClC1C=NC=C(Cl)C=1COC1C=CC=C2C=1N=C(C)C=C2N1C=CN=C1>>[CH3:33][C:32]1[CH:31]=[CH:30][N:29]=[C:28]([CH2:34][N:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[C:36]2=[O:45])[C:27]=1[CH2:26][O:24][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([CH3:1])[CH:11]=[C:10]2[C:12]1[C:16]([CH3:17])=[CH:15][N:14]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[N:13]=1
Reactant: Cc1cc(-c2nn(C3CCCCO3)cc2C)c2cccc(O)c2n1
Reactant: Cc1ccnc(Cn2cccc(C(F)(F)F)c2=O)c1CCl
Agent: Cc1cc(-n2ccnc2)c2cccc(OCc3c(Cl)cncc3Cl)c2n1
Product: Cc1cc(-c2nn(C3CCCCO3)cc2C)c2cccc(OCc3c(C)ccnc3Cn3cccc(C(F)(F)F)c3=O)c2n1

Procedure:
2-Methyl-4-[4-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-3-yl]-quinolin-8-ol and 1-(3-chloromethyl-4-methyl-pyridin-2-ylmethyl)-3-trifluoromethyl-1H-pyridin-2-one were coupled according to the procedure described for the synthesis of 8-(3,5-dichloro-pyridin-4-ylmethoxy)-4-imidazol-1-yl-2-methyl-quinoline to give the title compound which was used in the next step without purification.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14](Cl)[C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]1.CC([O-])(C)C.[Na+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([NH:23][CH:24]3[CH2:25][CH2:26][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:28][CH2:29]3)[C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc2c(cc(Cl)c3nnc(C)n32)n1Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cc2c(cc(NC3CCN(C(=O)OC(C)(C)C)CC3)c3nnc(C)n32)n1Cc1ccccc1
Temperature: 120 °C

Procedure:
A degassed mixture of 6-benzyl-4-chloro-1,7-dimethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (200. mg, 0.644 mmol, Example 228, Step 7), tert-butyl 4-aminopiperidine-1-carboxylate (520 mg, 2.6 mmol, Combi-Blocks), NaOtBu (180 mg, 1.9 mmol, Aldrich), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (93 mg, 0.16 mmol, Aldrich) and tris(dibenzylideneacetone)dipalladium(0) (71 mg, 0.077 mmol, Aldrich) in toluene (10. mL) was heated at 120° C. for 4 hours. Upon cooling, the reaction mixture was diluted with EtOAc and washed sequentially with water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. Flash chromatography, eluting with a gradient from 0-5% MeOH in DCM afforded product as a light yellow solid (0.15 g, 49%). A portion (11 mg) of this solid was purified via preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH). Yield: (7.1 mg, 65%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:71]=[CH:70][C:53]2[NH:54][C:55]([C@@H:57]([NH2:69])[CH2:58][C:59]3[CH:64]=[CH:63][C:62]([C:65]([F:68])([F:67])[F:66])=[CH:61][CH:60]=3)=[N:56][C:52]=2[CH:51]=1.ClCl>O1CCCC1.ClCCl.C(O)C>[Cl:49][C:50]1[CH:71]=[CH:70][C:53]2[NH:54][C:55]([C@@H:57]([NH:69][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([C:11]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:12])=[C:2]([CH3:1])[CH:3]=3)[CH2:58][C:59]3[CH:60]=[CH:61][C:62]([C:65]([F:67])([F:66])[F:68])=[CH:63][CH:64]=3)=[N:56][C:52]=2[CH:51]=1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Reactant: N[C@@H](Cc1ccc(C(F)(F)F)cc1)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N[C@@H](Cc2ccc(C(F)(F)F)cc2)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-2-(4-trifluoromethylphenyl)ethylamine in tetrahydrofuran. Yield: %; Rf value: 0.53 (silica gel: dichloromethane/ethanol=9:1); C29H26ClF3N4O2 (555.00); mass spectrum: (M+H)+=555/557 (chlorine isotope).
Reaction SMILES: C([Li])CCC.[CH2:6]([C:8]1[CH:9]=[C:10](Br)[CH:11]=[CH:12][CH:13]=1)[CH3:7].C[O:16][B:17](OC)[O:18]C.Cl>CCCCCC.O1CCCC1>[CH2:6]([C:8]1[CH:9]=[C:10]([B:17]([OH:18])[OH:16])[CH:11]=[CH:12][CH:13]=1)[CH3:7]
Reactant: COB(OC)OC
Reactant: CCc1cccc(Br)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCc1cccc(B(O)O)c1
Temperature: -70 °C
Reaction time: 1 h
Yield: 24 %

Procedure:
n-Butyllithium (11 ml of a 2.5M solution in hexane, 28 mmol) was added to a stirred solution of 3ethylbromobenzene (Chem. Pharm. Bull., 1968, 16, 2456; 4.6 g, 25 mmol) in anhydrous tetrahydrofuran (50 ml), whilst keeping the internal temperature below −60° C. The mixture was stirred at about −70° C. for 1 hour, then trimethylborate (4.4 ml, 38 mmol) added dropwise, again whilst keeping the internal temperature below −60° C. The reaction mixture was stirred at −70° C. for 30 minutes, then slowly allowed to warm to room temperature. 2M Hydrochloric acid was added, the mixture was extracted with dichloromethane (3×50 ml) and the combined extracts concentrated under reduced pressure The residue was dissolved in ether (50 ml), the solution extracted with 1M aqueous sodium hydroxide solution (2×30 ml) and the aqueous phase acidified with 2M hydrochloric acid, then extracted with ether (3×50 ml). The combined extracts were dried (MgSO4) and evaporated under reduced pressure to give the title compound as a white solid (0.9 g, 24%). δ(DMSOd6): 1.17 (t,3H), 2.57 (q,2H), 7.22 (t,2H), 7.57 (t,1H), 7.61 (s,1H), 7.93 (s,2H).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:9]=[C:8]2[C:3]=1[N:4]=[CH:5][C:6]([N:16]1[CH2:21][CH2:20][CH:19]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH2:18][CH2:17]1)=[N:7]2.[C:27]([O-:30])([O-])=O.[Na+].[Na+]>CO.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:12]([C:10]1[CH:9]=[C:8]2[C:3]([N:4]=[CH:5][C:6]([N:16]3[CH2:21][CH2:20][CH:19]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH2:18][CH2:17]3)=[N:7]2)=[C:2]([C:10]2[C:27](=[O:30])[NH:4][CH:3]=[CH:2][CH:11]=2)[CH:11]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)c1cc(Br)c2ncc(N3CCC(NS(C)(=O)=O)CC3)nc2c1
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)c1cc(-c2ccc[nH]c2=O)c2ncc(N3CCC(NS(C)(=O)=O)CC3)nc2c1

Procedure:
step 2—To a solution of 42 (0.040 g, 0.10 mmol) in MeOH and DCM (3 mL/1 mL), was added Na2CO3 (0.029 g, 0.27 mmol), 30 (0.012 g, 0.11 mmol) and Pd(PPh3)4 (0.010 g, 0.010 mmol). The reaction was irradiated in a microwave synthesizer at 115° C. for 30 min. The reaction was cooled, concentrated and partitioned between EtOAc/H2O (25 mL/25 mL). The aqueous layer was separated and washed EtOAc (2×25 mL). The combined organic extracts were washed with brine (25 mL), dried (Na2SO4), filtered and concentrated. The crude product was adsorbed onto SiO2 and purified by SiO2 chromatography eluting with 10% MeOH/DCM to afford 0.030 g (73%) of I-3.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH2:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Br[CH2:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)=[O:23]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:21][C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=1)=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: COc1ccc(COC(=O)CBr)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(COC(=O)CNCCCNC(=O)OC(C)(C)C)cc1
Reaction time: 2 h
Yield: 39.9 %

Procedure:
To a cold (0-5° C.) solution of 3-(t-butyloxycarbonylamino)-1-propylamine (4.00 g, 23 mmol) and triethylamine (2.8 mL, 20 mmol) in anhydrous CH2Cl2 (15 mL) was added slowly a solution of p-methoxybenzyl bromoacetate (5.18 g, 20 mmol) in anhydrous CH2Cl2 (10 mL) over a period of 2.5 h. The mixture was stirred at 0°-5° C. for 2 h, at which time TLC indicated that the reaction was complete. The mixture was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a dark residue. The crude material was purified by column chromatography on silica gel (elution with 50% ethyl acetate/hexane) to afford 2.81 g (40% yield) of p-methoxybenzyl [3-(t-butyloxycarbonylamino)-1-propylamino]acetate as an amber oil. 1H NMR (300 MHz, CDCl3 )δ1.41 (s, 9 H), 1.61 (quint, J=7 Hz, 2 H), 2.63 (t, J=7 Hz, 2 H), 3.17 (q, J=6 Hz, 2 H), 3.38 (s, 2 H), 3.78 (s, 3 H), 5.07 (s, 2 H), 6.86 (m, 2 H), and 7.26 (m, 2 H); IR (film), 1736, 1708 cm-1 ; MS (isobutane-DCI) MH+ =353. Anal. Calcd. for C18H28N2O5 : C, 61.35; H, 8.01; N, 7.95. Found: C, 60.87; H, 8.30; N, 7.89.
Reaction SMILES: [N:1]([C:4]1[CH:55]=[CH:54][C:7]([CH2:8][O:9][CH2:10][C@H:11]2[O:23][C@@H:15]([S:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@H:14]([O:24]CC3C=CC(OC)=CC=3)[C@@H:13]([O:34]CC3C=CC(OC)=CC=3)[C@@H:12]2[O:44]CC2C=CC(OC)=CC=2)=[CH:6][C:5]=1[Cl:56])=[N+:2]=[N-:3].O.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.O=C1O[C@H]([C@H](CO)O)C(O)=C1O>ClCCl>[N:1]([C:4]1[CH:55]=[CH:54][C:7]([CH2:8][O:9][CH2:10][C@H:11]2[O:23][C@@H:15]([S:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@H:14]([OH:24])[C@@H:13]([OH:34])[C@@H:12]2[OH:44])=[CH:6][C:5]=1[Cl:56])=[N+:2]=[N-:3]
Reactant: COc1ccc(CO[C@@H]2[C@@H](OCc3ccc(OC)cc3)[C@H](Sc3ccccc3)O[C@H](COCc3ccc(N=[N+]=[N-])c(Cl)c3)[C@H]2OCc2ccc(OC)cc2)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Solvent: O
Solvent: ClCCl
Product: [N-]=[N+]=Nc1ccc(COC[C@H]2O[C@@H](Sc3ccccc3)[C@H](O)[C@@H](O)[C@@H]2O)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
To a solution of phenyl 6-O-(4-azido-3-chlorobenzyl)-2,3,4-tri-O-(4-methoxybenzyl)-1-thio-β-D-glucopyranoside (9) (1.24 g, 1.55 mmol) in dichloromethane (10 ml) were added water (0.5 ml) and DDQ (1.41 g, 6.21 mmol), and the resulting mixture was stirred at room temperature for 3 hr. Thereto was added 5% aqueous L-ascorbic acid solution, and the mixture was stirred for a while, and extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue obtained was purified by silica gel column chromatography (eluent; dichloromethane:ethyl acetate=1:3) to give phenyl 6-O-(4-azido-3-chlorobenzyl)-1-thio-β-D-glucopyranoside (10) (584 mg, yield 86%) as yellow crystals.
Reaction SMILES: [C:1](Cl)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[NH:12]1[CH2:18][CH2:17][CH2:16][C@H:13]1[CH2:14][OH:15].C(=O)([O-])O.[Na+]>C(Cl)Cl.O>[C:1]([N:12]1[CH2:18][CH2:17][CH2:16][C@H:13]1[CH2:14][OH:15])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: OC[C@@H]1CCCN1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(OCc1ccccc1)N1CCC[C@H]1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
A solution of carbobenzoxychloride 7.87 g in methylene chloride 50 ml is dropped to a mixture of L-prolinol 4.9 g in methylene chloride 50 ml and sodium hydrogen carbonate 11.6 g in water 50 ml at 0° C. under vigorously agitation. The mixture is stirred for 1 hour at room temperature. The organic layer is separated, washed, dried and concentrated in vacuo to give N-carbobenzoxy-L-prolinol 10.25 g.
Reaction SMILES: C(OC(=O)[NH:10][C@H:11]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]2[C:26]3[CH:25]=[CH:24][N:23]=[CH:22][C:21]=3[CH:20]=[CH:19]2)[C:12]1=[O:27])C1C=CC=CC=1.C[OH:30]>CC(O)=O.[Pd]>[C:12]([OH:27])(=[O:30])[CH3:11].[NH2:10][C@H:11]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]2[C:26]3[CH:25]=[CH:24][N:23]=[CH:22][C:21]=3[CH:20]=[CH:19]2)[C:12]1=[O:27]
Reactant: CO
Reactant: O=C(N[C@H]1CCN(CCn2ccc3cnccc32)C1=O)OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: N[C@H]1CCN(CCn2ccc3cnccc32)C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-(S)-benzyloxycarbonylamino-4-(2-pyrrolo[3,2-c]pyridin-1-yl-acetylamino)-butyric acid methyl ester (0.51 g, 1.20 mmol) in THF (5 mL) is added diborane (5 mL, 0.500 mmol, 1 M solution in THF). The resulting mixture is stirred at room temperature for 4 hours and then concentrated in vacuo. The residue is suspended in EtOAc (10 mL), treated with 10 drops of H2O, 5 drops of 1 N NaOH and further quenched with saturated NH4Cl solution. The mixture is concentrated in vacuo to about ½ volume, partitioned between EtOAc and 10% Na2CO3 solution and the layers are separated. The aqueous layer is extracted with EtOAc. The combined organic phases are washed with saturated NaCl, dried over MgSO4, filtered and concentrated in vacuo. The crude product obtained is partially purified by column chromatography in a gradient of 2% MeOH/CH2Cl2 to 10% MeOH/CH2Cl2 to afford [2-oxo-1-(2-pyrrolo[3,2-c]pyridin-1-yl-ethyl)-pyrrolidin-3-(S)-yl]-carbamic acid benzyl ester. FAB MS, [M+H]+=379. To a solution of this crude [2-oxo-1-(2-pyrrolo[3,2-c]pyridin-1-yl-ethyl)-pyrrolidin-3-(S)-yl]-carbamic acid benzyl ester in MeOH (10 mL) and AcOH (3 mL) is added a catalytic amount of 10% palladium on activated carbon. The heterogenous mixture is stirred at room temperature under a balloon of H2 for 18 hours. The reaction mixture is filtered through a pad of Celite and washed with MeOH (3×). The crude product is concentrated in vacuo and then azeotroped with toluene to give 3-(S)-amino-1-(2-pyrrolo[3,2-c]pyridin-1-yl-ethyl)-pyrrolidin-2-one acetate as a residue (wet with excess HOAc). FAB MS, [M+H]+=245. The title compound is prepared in CH2Cl2 instead of CH3CN as described in EXAMPLE 1, Part K using the above 3-(S)-amino-1-(2-pyrrolo[3,2-c]pyridin-1-yl-ethyl)-pyrrolidin-2-one acetate in place of 7-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)-1-chloro-isoquinoline hydrochloride and 7-methoxynaphthalene-2-sulfonyl chloride as prepared in EXAMPLE 1, Part J. The crude product is partially purified by column chromatography eluting in a gradient of 3% MeOH/CH2Cl2 to 5% MeOH/CH2Cl2. The residue obtained is further purified by RP-HPLC eluting in a gradient of 10% CH3CN/H2O (0.1% TFA) to 80% CH3CN/H2O (0.1% TFA) and the appropriate product fractions are lyophilized to provide the title compound as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=1)[CH:8]=[O:9])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:26][C:27](=[O:30])[CH:28]=[CH2:29]>CCO.[Br-].C([N+]1C(C)=C(CCO)SC=1)C>[C:13]([C:11]1[CH:10]=[C:7]([C:8](=[O:9])[CH2:29][CH2:28][C:27](=[O:30])[CH3:26])[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:12]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: C=CC(C)=O
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1
Agent: CC[n+]1csc(CCO)c1C
Agent: [Br-]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)CCC(=O)c1cc(C(C)(C)C)cc(C(C)(C)C)c1
Temperature: 77.5 °C
Yield: 44.4 %

Procedure:
To a solution of 3,5-di-tert-butylbenzaldehyde (10.9 g, 50 mmol) in EtOH (200 mL) was added DIPEA (12.9 g, 100 mmol), but-3-en-2-one (3.5 g, 50 mmol) and 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide (2.5 g, 10 mmol). This mixture was heated to 75-80° C. overnight, evaporated, diluted with water (50 mL) and extracted with EA. The organic layer was washed with brine, dried, concentrated and purified by CC (EA/PE=1/100) to afford compound 5a (6.4 g, 44%) as colorless oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=2)[O:12][CH2:13][CH2:14][CH2:15][NH2:16])[CH2:4][CH2:3]1.Br[C:21]1[S:25][C:24]([NH2:26])=[N:23][N:22]=1>>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=2)[O:12][CH2:13][CH2:14][CH2:15][NH:16][C:21]2[S:25][C:24]([NH2:26])=[N:23][N:22]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(Cc2cccc(OCCCN)c2)CC1
Reactant: Nc1nnc(Br)s1
Product: CN1CCN(Cc2cccc(OCCCNc3nnc(N)s3)c2)CC1

Procedure:
The compound is prepared by a method analogous to that of Example 51 from 3-[3-[(4-methyl-1-piperazinyl) methyl]phenoxy]-1-propanamine and 5-bromo-1,3,4-thiadiazole-2-amine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[C:4]([F:12])[CH:3]=1.[F:13][C:14]([F:25])([F:24])[C:15]([C:18]1[CH:22]=[C:21]([NH2:23])[O:20][N:19]=1)([CH3:17])[CH3:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:23][C:21]2[O:20][N:19]=[C:18]([C:15]([CH3:17])([CH3:16])[C:14]([F:25])([F:24])[F:13])[CH:22]=2)=[O:11])=[C:4]([F:12])[CH:3]=1
Reactant: O=C(O)Cc1ccc(Br)cc1F
Reactant: CC(C)(c1cc(N)on1)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(c1cc(NC(=O)Cc2ccc(Br)cc2F)on1)C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 71.2 %

Procedure:
To a mixture of 2-(4-bromo-2-fluorophenyl)acetic acid (360 mg, 1.545 mmol) in DCM (50 mL) was added 3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-amine (300 mg, 1.545 mmol), HATU (881 mg, 2.317 mmol) and triethylamine (0.645 mL, 4.63 mmol). Then the mixture was stirred at 25° C. for 12 h. The mixture was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to yield a yellow oil of 2-(4-bromo-2-fluorophenyl)-N-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)acetamide (600 mg, 1.1 mmol, 71% yield): 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J=6.8 Hz, 1H), 7.34-7.29 (m, 1H), 7.21 (s, 1H), 6.64 (d, J=6.8 Hz, 1H), 6.43 (s, 1H), 3.75 (s, 2H), 1.52 (s, 6H); ES-LCMS m/z 409 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:18]=[CH:17][C:16]([C:19](O)=[O:20])=[CH:15][N:14]=2)[CH2:8]1)[CH3:2].[NH2:26][CH2:27][C:28]1[C:29]([CH3:39])=[N:30][CH:31]=[C:32]([CH:38]=1)[C:33]([O:35]CC)=[O:34].CCN=C=NCCCN(C)C.Cl.[Li+].[OH-]>>[CH2:1]([O:3][C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:18]=[CH:17][C:16]([C:19]([NH:26][CH2:27][C:28]3[C:29]([CH3:39])=[N:30][CH:31]=[C:32]([CH:38]=3)[C:33]([OH:35])=[O:34])=[O:20])=[CH:15][N:14]=2)[CH2:8]1)[CH3:2]
Reactant: CCOc1ccccc1O[C@@H]1CCCN(c2ncc(C(=O)O)cn2)C1
Reactant: CCOC(=O)c1cnc(C)c(CN)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Li+]
Product: CCOc1ccccc1O[C@@H]1CCCN(c2ncc(C(=O)NCc3cc(C(=O)O)cnc3C)cn2)C1

Procedure:
(R)-5-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)-6-methylnicotinic acid was prepared from (R)-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxylic acid and ethyl 5-(aminomethyl)-6-methylnicotinate using Amidation Method 2 (EDCl) and Ester Hydrolysis Method 1 (LiOH). 1H NMR (400 MHz, DMSO-d6) δ 9.17 (m, 1H), 8.95 (s, 1H), 8.80 (s, 2H), 8.45 (m, 1H), 7.03 (d, 1H), 6.90 (m, 3H), 4.58 (d, 2H), 4.35 (m, 1H), 4.12 (m, 1H), 3.90 (m, 5H), 2.79 (s, 3H), 2.03 (m, 1H), 1.87 (m, 2H), 1.52 (m, 1H), 1.21 (t, 3H). MS (ES+) 492.2 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][C:21]=1Cl)[C:7]([C:9]1[CH:14]=[CH:13][C:12](F)=[C:11]([N+:16]([O-])=O)[CH:10]=1)=[O:8])([O-])=O.C1C=CC=CC=1.[H][H].C(=O)([O-])[O-].[K+].[K+]>[Pd].[Cl-].C([N+](CCCCCCCC)(CCCCCCCC)C)CCCCCCC.Cl>[NH2:1][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:16])[CH:10]=1)=[O:8]
Reactant: O=C(c1ccc(F)c([N+](=O)[O-])c1)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: Cl
Solvent: c1ccccc1
Product: Nc1cccc(C(=O)c2cccc(N)c2)c1
Reaction time: 6 h
Yield: 104.3 %

Procedure:
To a closed glass vessel equipped with a thermometer and a stirrer, there are added 49 g (0.15 moles) of 3,3'-dinitro-4-chloro-4'-fluoro benzophenone, 1 g of palladium black catalyst and 300 ml of benzene. While the mixture being stirred at 65°-70° C., 20.2 l (0.9 moles) of hydrogen is absorbed therein during about 6 hours. Then, after there are added 180 g (0.45 moles) of 35% aqueous solution of potassium carbonate and 3 g of 90% aqueous solution of trioctylmethyl ammonium chloride (available from Tokyo-Kasei Co.), additional hydrogen, 7.4 l (0.33 moles), is introduced during about 5 hours while the mixture being stirred at 65°-70° C. The mixture at that temperature is filtered to remove the catalyst. Organic phase is separated from the filtrate, added with magnesium sulfate for removing water and then blown with dry hydrochloric gas to saturation. The precipitate thus obtained is filtered, washed with 50 ml of benzene and dried to obtain 33.2 g (yield 77.7%) of 3,3'-diamino benzophenone in the hydrochloric acid salt form. Recrystallization from 20% aqueous isopropyl alcohol gives pure compound, as slightly yellow needle-like crystals. M.P. 265°-267° C. (decomposed).