Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[CH:9][C:10]([N+:15]([O-:17])=[O:16])=[C:11]([CH:14]=2)[CH:12]=[O:13])[CH2:3][CH2:2]1.[BH4-].[Na+]>O1CCCC1.C(O)C>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[CH:9][C:10]([N+:15]([O-:17])=[O:16])=[C:11]([CH2:12][OH:13])[CH:14]=2)[CH2:3][CH2:2]1
Reactant: O=Cc1cc(N2CCOCC2)ccc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: O=[N+]([O-])c1ccc(N2CCOCC2)cc1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.3 %

Procedure:
To a suspension of the crude 5-morpholino-2-nitrobenzaldehyde in a mixture of tetrahydrofuran and ethanol (100 mL/100 mL) was slowly added sodium borohydride (4.0 g). The mixture was stirred at room temperature for 1 hour, and then was partitioned between ether and saturated ammonium chloride. The aqueous phase was extracted with ether, and the organic phases were combined, washed by brine, dried over anhydrous sodium sulfate, evaporated and purified by silica gel chromatography to afford the product (5-morpholino-2-nitrophenyl)methanol (8.5 g, yield 62.3%, two steps).
Reaction SMILES: CN(C=O)C.C(Cl)(=O)C([Cl:9])=O.O[C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:27][CH3:28])=[C:20]([O:23][C:24](=[O:26])[CH3:25])[CH:21]=2)[N:16]=[CH:15][N:14]=1>ClCCCl>[Cl:9][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:27][CH3:28])=[C:20]([O:23][C:24](=[O:26])[CH3:25])[CH:21]=2)[N:16]=[CH:15][N:14]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc2ncnc(O)c2cc1OC(C)=O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Cl)c2cc1OC(C)=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 80.4 %

Procedure:
To a stirred solution of anhydrous DMF (4.5 mL) in DCE (20 mL), cooled in an ice-water bath, is added dropwise under nitrogen a solution of oxalyl chloride (7.9 ml, 90 mmol) in DCE (40 mL). A white precipitate forms during the addition. After the end of addition the cold bath is removed and the reaction mixture is stirred at room temperature for 5 min. Acetic acid 4-hydroxy-7-methoxy-quinazolin-6-yl ester (6.5 g, 27.8 mmol) is added in portions via scoopula under nitrogen flow and the mixture is heated immediately to reflux. Heating is continued for 3 hours, followed by cooling to room temperature. The reaction mixture is poured into excess ice:water mixture (100 mL) and extracted with DCM (500 mL). The aqueous layer is further extracted with DCM (2×50 mL). The combined organic extracts are dried (Na2SO4) and concentrated under reduced pressure to yield 5.63 g (22.34 mmol, 80%) of desired product as a tan solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[N+:9]([O-])([OH:11])=[O:10]>S(=O)(=O)(O)O>[NH2:1][C:2]1[C:7]([N+:9]([O-:11])=[O:10])=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])O
Reactant: Nc1ccc(Cl)cn1
Agent: O=S(=O)(O)O
Product: Nc1ncc(Cl)cc1[N+](=O)[O-]

Procedure:
A procedure similar to that described in Preparation 56 was repeated, except that 25.0 g of 2-amino-5-chloro-pyridine, 100 ml of concentrated sulfuric acid and 12.5 ml of concentrated nitric acid were used, to give 18.5 g of the title compound, melting at 138° 139° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]([OH:20])=O)[CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C>C(Cl)Cl>[CH2:21]([NH:28][C:18]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:17]2)=[O:20])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1Cc2ccc(C(=O)O)cc2C1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1Cc2ccc(C(=O)NCc3ccccc3)cc2C1
Yield: 86.8 %

Procedure:
Using 2-(tert-butoxycarbonylamino)-5-carboxyindan (400 mg, 1.44 mmol), benzylamine (0.24 ml, 2.2 mmol), triethylamine (1.4 ml, 10 mmol), propanephosphonic acid anhydride (2.1 ml), dimethylaminopyridine (a catalytic amount) and methylene chloride (12 ml), a similar procedure to a) in Production Example 218 was carried out. The product obtained was purified by silica gel chromatography (methylene chloride:methanol=95:5) to obtain N-benzyl-2-(tert-butoxycarbonylamino)-5-indan carboxamide (460 mg, 1.25 mmol) having the following physical properties:
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[CH:14]=[CH:13][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][C:10]=3[N:9]3[CH2:20][C:21](=O)[N:22]([CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])[CH2:23][C:24]4[CH:28]=[CH:27][O:26][C:25]=4[C:8]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(C)C>C1COCC1>[CH:1]1([C:7]2[C:15]3[CH:14]=[CH:13][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][C:10]=3[N:9]3[CH2:20][CH2:21][N:22]([CH2:29][CH2:30][N:31]([CH3:32])[CH3:33])[CH2:23][C:24]4[CH:28]=[CH:27][O:26][C:25]=4[C:8]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(=O)N(CCN(C)C)Cc1ccoc1-3
Solvent: CSC
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCN(CCN(C)C)Cc1ccoc1-3
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 13-cyclohexyl-5-[2-(dimethylamino)ethyl]-6-oxo-4,5,6,7-tetra hydrofuro[3′,2′:6,7][1,4]diazocino[1,8-a]indole-10-carboxylate in THF (0.08 M), 10 eq of BH3.Me2S (2 M sol. in THF) were added and the mixture was stirred at RT for 2 h. The solution was carefully quenched by adding 1.25 M HCl in MeOH until effervescence subsided. Then the volatiles were driven off by boiling the mixture to dryness. The crude residue was used directly in the next step; MS (ES+) m/z 450 (M+H)+.
Reaction SMILES: Cl.[C:2]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]([OH:14])=O)[CH2:7][CH2:6]1)(=[O:4])[CH3:3].[CH2:15]([C@H:22]1[CH2:26][NH:25][C@H:24]([C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)=[CH:32][CH:31]=2)=[O:28])[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:2]([N:5]1[CH2:6][CH2:7][N:8]([CH2:11][C:12]([N:25]2[CH2:26][C@H:22]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:23][C@H:24]2[C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)=[CH:32][CH:31]=2)=[O:28])=[O:14])[CH2:9][CH2:10]1)(=[O:4])[CH3:3]
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Reactant: CC(=O)N1CCN(CC(=O)O)CC1
Agent: Cl
Product: CC(=O)N1CCN(CC(=O)N2C[C@H](Cc3ccccc3)C[C@H]2C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)CC1
Yield: 24.9 %

Procedure:
Proceeding as in Example 1, but substituting 2-(4-acetylpiperazin-1-yl)acetic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 115, (2S,4R)-1-(2-(4-acetylpiperazin-1-yl)acetyl)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (9.5 mg, 24.9%); Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 9.96 (s, 1H), 7.96 (s, 1H), 7.53-7.60 (m, 2H), 7.25-7.30 (m, 2H), 7.14-7.22 (m, 5H), 6.92-6.99 (m, 4H), 4.67-4.71 (m, 1H), 3.70-3.75 (m, 1H), 3.45-3.50 (m, 1H), 3.23-3.30 (m, 2H), 3.10-3.27 (m, 4H), 2.53-2.62 (m, 3H), 2.37-2.45 (m, 2H), 2.14-2.30 (m, 2H), 1.85-1.99 (m, 2H). MS (EI) for C31H33FN4O4. found 545.6 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH2:11][NH:12][C:13]1[CH:23]=[CH:22][C:16]([C:17]([O:19]CC)=[O:18])=[CH:15][CH:14]=1.[OH-].[K+].C(O)C.O.Cl>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH2:11][NH:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[CH:22][CH:23]=1
Reactant: CCOC(=O)c1ccc(NCCCc2ccccc2OC)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccccc1CCCNc1ccc(C(=O)O)cc1

Procedure:
A mixture of 7.0 g. of ethyl p-[3-(o-methoxyphenyl)propyl]aminobenzoate (prepared as described in Example 41), 7.0 g. of potassium hydroxide and 100 ml. of ethanol-water (9:1) is refluxed for 3.5 hours, acidified while hot with concentrated hydrochloric acid, diluted with water and chilled. The mixture is filtered and the solid washed with water to give off-white crystals, m.p. 155°-157° C. Recrystallization from ethanol gives off-white crystals, m.p. 156°-158° C.
Reaction SMILES: Cl[CH2:2]/[CH:3]=[C:4]1/[C:5]2[CH:18]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[CH:16]=[CH:15][C:6]=2[O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]/1=2.[N:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[NH:25][CH:24]=1>>[CH3:22][O:21][C:19]([C:29]1[CH:30]=[CH:31][C:26]2[N:25]=[CH:24][N:23]([CH2:2]/[CH:3]=[C:4]3/[C:5]4[CH:18]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[CH:16]=[CH:15][C:6]=4[O:7][CH2:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]/3=4)[C:27]=2[CH:28]=1)=[O:20]
Reactant: c1ccc2[nH]cnc2c1
Reactant: COC(=O)c1ccc2c(c1)/C(=C/CCl)c1ccccc1CO2
Product: COC(=O)c1ccc2c(c1)/C(=C/Cn1cnc3ccc(C(=O)OC)cc31)c1ccccc1CO2

Procedure:
In Examples 27 through 32, the products were prepared using Compound h and corresponding benzimidazole derivatives in a manner similar to Example 26.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH2:5][NH:6][C:7](=[O:9])[CH3:8].[Cl:13][S:14](O)(=[O:16])=[O:15]>>[C:7]([NH:6][CH2:5][C:4]1[CH:3]=[C:2]([F:1])[CH:12]=[CH:11][C:10]=1[S:14]([Cl:13])(=[O:16])=[O:15])(=[O:9])[CH3:8]
Reactant: CC(=O)NCc1cccc(F)c1
Reactant: O=S(=O)(O)Cl
Product: CC(=O)NCc1cc(F)ccc1S(=O)(=O)Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(Step 1) To chlorosulfonic acid (50 ml) was added N-(3-fluorobenzyl)acetamide (11.8 g) by small portions under ice-cooling. The mixture was allowed to warm to room temperature, and stirred at 70° C. for 3 hr. The reaction mixture was poured into ice water to quench the reaction, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure to give 2-[(acetylamino)methyl]-4-fluorobenzenesulfonyl chloride (14.1 g) as a white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.N1CCCC1>>[Cl:11][C:12]1[CH:19]=[CH:18][C:15](/[CH:16]=[C:3]2\[C:2](=[O:10])[NH:1][C:9]3[C:4]\2=[CH:5][CH:6]=[CH:7][CH:8]=3)=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: O=C1Cc2ccccc2N1
Solvent: C1CCNC1
Product: O=C1Nc2ccccc2/C1=C/c1ccc(Cl)cc1
Yield: 93.9 %

Procedure:
Oxindole (0.13 g, 1 mmol), 4-chlorobenzaldehyde (0.17 g, 1.2 mmol) were mixed in alcohol; then pyrrolidine (0.17 ml, 2 mmol) was added. The mixture was refluxed for 3 hours. The formed precipitates was collected by filtration and washed with alcohol twice to give the title compound as yellow powder (0.24 g, 92%). LC/MS m/e calcd. for C15H10ClNO 255, observed (M+H)+: 256.1.
Reaction SMILES: [CH3:1][O-].[Na+].CS([O:8][CH2:9][CH2:10][CH:11]1[CH2:16][N:15]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[C:19]([O:26][CH:27]([CH3:29])[CH3:28])[CH:18]=2)[CH2:14][CH2:13][N:12]1[CH3:30])(=O)=O>CO>[CH3:1][O:8][CH2:9][CH2:10][CH:11]1[CH2:16][N:15]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[C:19]([O:26][CH:27]([CH3:29])[CH3:28])[CH:18]=2)[CH2:14][CH2:13][N:12]1[CH3:30]
Reactant: C[O-]
Reactant: CC(C)Oc1cc(N2CCN(C)C(CCOS(C)(=O)=O)C2)ccc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CO
Product: COCCC1CN(c2ccc([N+](=O)[O-])c(OC(C)C)c2)CCN1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
51.1 mg of sodium methoxide are added to a solution of 2-{1-methyl-4-[4-nitro-3-(propan-2-yloxy)phenyl]piperazin-2-yl}ethyl methanesulfonate in 3 ml of methanol. The reaction medium is stirred for 10 minutes at ambient temperature and then 30 minutes at 90° C. in a microwave (CEM). The reaction medium is concentrated to dryness under reduced pressure, and taken up with water and ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and evaporated. Purification is carried out by flash chromatography on silica gel (40-63 microns), elution being carried out with a mixture of dichloromethane and methanol (100/0) to (80/20). 100 mg of 2-(2-methoxyethyl)-1-methyl-4-[4-nitro-3-(propan-2-yloxy)phenyl]piperazine are obtained in the form of a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:11]3[CH2:14][CH2:13][CH2:12]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.C1C(=O)N([I:22])C(=O)C1>CN(C)C=O.C(Cl)Cl>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:11]3[CH2:14][CH2:13][CH2:12]3)=[N:9][C:10]=2[I:22])[CH:5]=[CH:6][N:7]=1
Reactant: Clc1nccn2c(C3CCC3)ncc12
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Clc1nccn2c(C3CCC3)nc(I)c12

Procedure:
8-Chloro-3-cyclobutylimidazo[1,5-a]pyrazine (1058 mg, 5.1 mmol) and NIS (1146 mg, 5.1 mmol) in anh DMF (10 mL) were stirred at 60° C. under Ar for 6 h. The reaction was diluted with DCM (˜400 mL), washed (H2O, brine), dried (Na2SO4) and concentrated under reduced pressure. Purification of the crude material by flash chromatography on silica gel (50 g cartridge, 10:1-8:1-7:1-6:1 hexanes:EtOAc) afforded the title compound as a pale yellow solid; 1H NMR (400 MHz, CDCl3) δ 7.51 (d, J=4.8 Hz, 1H), 7.26 (d, J=4.8 Hz, 1H), 3.75 (quintetd, J=1.2 Hz, 8.4 Hz, 1H), 2.62-2.42 (m, 4H), 2.32-1.98 (m, 2H); MS (ES+): m/z 334.0 (100) [MH+]; HPLC: tR=3.38 min (OpenLynx, polar—5 min).
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1)[OH:4].[C:23]1([CH2:29][CH2:30][C:31](Cl)=[O:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:11][C:7]1[CH:6]=[C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:31](=[O:32])[CH2:30][CH2:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:17][CH:18]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1cccc(F)c1
Reactant: O=C(Cl)CCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(CCc1ccccc1)NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(3-fluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (450 mg, 1.44 mmol) in ethyl acetate (20 ml) were added 3-phenylpropionyl chloride (320 ml, 2.15 mmol) and saturated aqueous sodium hydrogen carbonate (20 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (528 mg, 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=4)[N:14]=[CH:15][C:10]=3[CH2:9][C:8](=[O:27])[N:7]([CH2:28][CH2:29][CH2:30][N:31]3C(=O)C4C(=CC=CC=4)C3=O)[C:6]=2[CH:42]=1.CN>C(O)C.ClCCl>[NH2:31][CH2:30][CH2:29][CH2:28][N:7]1[C:8](=[O:27])[CH2:9][C:10]2[CH:15]=[N:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=3)=[N:12][C:11]=2[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:42][C:6]1=2
Reactant: COc1ccc(Nc2ncc3c(n2)-c2ccc(Cl)cc2N(CCCN2C(=O)c4ccccc4C2=O)C(=O)C3)cc1OC
Agent: CN
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc(Nc2ncc3c(n2)-c2ccc(Cl)cc2N(CCCN)C(=O)C3)cc1OC
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a stirring solution of 2-{3-[9-chloro-2-(3,4-dimethoxy-phenylamino)-6-oxo-5,6-dihydrobenzo[b]pyrimido[4,5-d]azepin-7-yl]-propyl}-isoindole-1,3-dione (I-40-c) (51 mg, 0.09 mmol) in ethanol (1.5 mL) was added methylamine (40% by wt in H2O, 0.5 mL). After stirring for 2.5 h at room temperature, the solution was diluted with dichloromethane and washed with water. The organics were dried over magnesium sulfate and concentrated. Preparative HPLC gave I-40: MS Rt=1.32 min. m/z=454 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3](=[O:18])[C@H:4]([O:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[C:9](=O)[NH:10][CH:11]=[N:12]2)[CH3:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.[S:44]1[CH:48]=[C:47]([CH2:49][N:50]2[C:58]3[C:53](=[CH:54][C:55]([NH2:59])=[CH:56][CH:57]=3)[CH:52]=[N:51]2)[N:46]=[CH:45]1>ClCCCl>[CH3:1][N:2]([CH3:19])[C:3](=[O:18])[C@H:4]([O:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[C:9]([NH:59][C:55]1[CH:54]=[C:53]3[C:58](=[CH:57][CH:56]=1)[N:50]([CH2:49][C:47]1[N:46]=[CH:45][S:44][CH:48]=1)[N:51]=[CH:52]3)=[N:10][CH:11]=[N:12]2)[CH3:5]
Reactant: Nc1ccc2c(cnn2Cc2cscn2)c1
Reactant: C[C@@H](Oc1cccc2nc[nH]c(=O)c12)C(=O)N(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCCl
Product: C[C@@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cscn4)c3)c12)C(=O)N(C)C
Temperature: 45 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
A mixture of (2R)—N,N-dimethyl-2-[(4-oxo-3,4-dihydroquinazolin-5-yl)oxy]propanamide (200 mg, 0.77 mmol), triphenylphosphine (603 mg, 2.3 mmol) and carbon tetrachloride (2.2 ml, 23 mmol) in 1,2-dichloroethane (5 ml) was stirred at 45° C. for 2 hours. 1-(1,3-Thiazol-4-ylmethyl)-1H-indazol-5-amine (184 mg, 0.8 mmol) was added and the solvents were evaporated under vacuum. Acetonitrile (5 ml) was added. The mixture was stirred at 75° C. for 2 hours. After cooling, the solvents were evaporated under vacuum. The residue was diluted in 6N methanolic ammonia and the solvents were evaporated under vacuum. The residue was purified by chromatography on silica gel (eluant: 3% to 5% methanol in DCM) to give the title compound as a beige foam (215 mg, 60%); NMR Spectrum (CDCl3) 1.73 (d, 3H), 3.06 (s, 3H), 3.14 (s, 3H), 5.43 (q, 1H), 5.80 (s, 2H), 6.81 (d, 1H), 6.93 (s, 1H), 7.48 (m, 2H), 7.60 (t, 1H), 7.84 (dd, 1H), 8.08 (s, 1H), 8.43 (s, 1H), 8.62 (s, 1H), 8.78 (s, 1H); Mass spectrum 474.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:13][C@@H:14]([C@@H:16]2[CH2:20][C:19](=[O:21])[N:18]([C@@H:22]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[CH3:23])[CH2:17]2)[CH3:15])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2[CH:11]=O)[CH:7]=1.Cl.[NH2:33][OH:34].C(=O)(O)[O-].[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:13][C@@H:14]([C@@H:16]2[CH2:20][C:19](=[O:21])[N:18]([C@@H:22]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[CH3:23])[CH2:17]2)[CH3:15])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2/[CH:11]=[N:33]/[OH:34])[CH:7]=1
Reactant: NO
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(Br)cn4ncc(C=O)c34)CC2=O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(Br)cn4ncc(/C=N/O)c34)CC2=O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 100 mL round bottom flask was charged with 6-bromo-4-((R)-1-((R)-1-((R)-1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbaldehyde (466 mg, 0.958 mmol), hydroxylamine hydrochloride (79.9 mg, 1.15 mmol), sodium bicarbonate (96.6 mg, 1.15 mmol) and ethanol (8.0 mL). The mixture was stirred at room temperature for 3 h. The reaction was concentrated under reduced pressure to afford (E)-6-bromo-4-((R)-1-((R)-1-((R)-1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbaldehyde oxime without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Cl[C:12]1[CH:13]=[C:14]([CH:20]=[CH:21][N:22]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[CH:13]=[C:14]([CH:20]=[CH:21][N:22]=2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCOC(=O)c1ccnc(Cl)c1
Product: CCOC(=O)c1ccnc(-c2ccc(Cl)cc2)c1

Procedure:
4-Chlorophenylboronic acid (185 mg) and ethyl 2-chloroisonicotinate (200 mg) were reacted in the same manner as in Preparation Example 1 to obtain the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[CH:8]=O.[NH2:14][C:15]1[N:20]=[CH:19][C:18]([C:21]2[CH:22]=[C:23]([NH2:32])[C:24]([NH:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:25][CH:26]=2)=[CH:17][N:16]=1.O.C([O-])(O)=O.[Na+]>C(O)(=O)C>[C:28]([N:27]1[C:24]2[CH:25]=[CH:26][C:21]([C:18]3[CH:17]=[N:16][C:15]([NH2:14])=[N:20][CH:19]=3)=[CH:22][C:23]=2[N:32]=[C:8]1[C:7]1[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=1[C:2]1[S:1][CH:5]=[CH:4][N:3]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)Nc1ccc(-c2cnc(N)nc2)cc1N
Reactant: O=Cc1ccccc1-c1nccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)n1c(-c2ccccc2-c2nccs2)nc2cc(-c3cnc(N)nc3)ccc21
Temperature: 25 °C
Reaction time: 60 h
Yield: 15.6 %

Procedure:
A solution of 2-thiazol-2-yl-benzaldehyde (100 mg, 0.53 mmol) and 4-(2-amino-pyrimidin-5-yl)-N1-tert-butyl-benzene-1,2-diamine (120 mg, 0.45 mmol) in acetic acid (5 mL) is warmed to 50° C. for 12 hours and then at 80° C. for 60 hours. After this time the reaction is cooled to room temperature and pour into water and NaHCO3 (sat.). The product is extracted into EtOAc (3×) and the combined organics are dried (MgSO4), filtered and concentrated. Purification via flash chromatography (12 g silica gel, 0-5% MeOH/CH2Cl2) affords the title compound (30 mg, 16%). LCMS (ESMS): m/z 427.20 (M++1)
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][OH:16])[CH2:11][CH2:10]2)[O:6][N:5]=1)[CH3:3].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[CH3:24][S:25]([O:16][CH2:15][CH:12]1[CH2:13][CH2:14][N:9]([C:7]2[O:6][N:5]=[C:4]([CH:2]([CH3:1])[CH3:3])[N:8]=2)[CH2:10][CH2:11]1)(=[O:27])=[O:26]
Reactant: CC(C)c1noc(N2CCC(CO)CC2)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1noc(N2CCC(COS(C)(=O)=O)CC2)n1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
A solution of {1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methanol (prepared as in Step 3, 174 g, 0.77 mol) and triethylamine (140 mL, 1.0 mol) in dichloromethane (1 L) at 5° C. was treated with a solution of methanesulfonyl chloride (69 mL, 0.89 mol) in dichloromethane (150 mL) over a 1 h period. The mixture was stirred at 5° C. for 30 min, and then was quenched by the addition of water (400 mL). The mixture was stirred for 30 min, and then the organic extract was washed with water (2×400 mL), dried (MgSO4) and concentrated. The residue was treated with heptane (1 L), stirred for 3 h, and the resulting solid was collected by filtration (heptane wash) and air-dried to afford {1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl methanesulfonate (219.7 g, 94%) as an off-white solid. 1NMR (400 MHz, CDCl3): δ 4.21-4.15 (m, 2H), 4.08 (d, 2H, J=6.6 Hz), 3.04 (m, 2H), 3.01 (s, 3H), 2.86 (septet, 1H, J=6.9 Hz), 2.05-1.93 (m, 1H), 1.88-1.81 (m, 2H), 1.43-1.31 (m, 2H), 1.26 (d, 6H, J=6.8 Hz); LRMS (ESI), m/z 304 (M+H).
Reaction SMILES: CO[C:3](=[O:21])[C:4]([OH:20])=[CH:5][C:6](=[O:19])[N:7]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([CH3:18])[CH:12]=1)[O:8][CH3:9].C=O.CN.ClC1C=C(C=CC=1Cl)[CH2:30][N:31](C)[C:32](C1CN(C)C(=O)C=1O)=O>>[F:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:7]([O:8][CH3:9])[C:6]([C:5]2[CH2:30][N:31]([CH3:32])[C:3](=[O:21])[C:4]=2[OH:20])=[O:19])=[CH:12][C:13]=1[CH3:18]
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Reactant: COC(=O)C(O)=CC(=O)N(Cc1ccc(F)c(C)c1)OC
Agent: C=O
Agent: CN
Product: CON(Cc1ccc(F)c(C)c1)C(=O)C1=C(O)C(=O)N(C)C1
Yield: 76 %

Procedure:
3-[(4-Fluoro-3-methylbenzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 64-A) was treated with paraformaldehyde and methylamine as described in the preparation of Compound 12 to give the title compound as white crystals (76% yield); mp 160–164° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 2.27 (3H, s, CH3), 3.10 (3H, s, NCH3), 3.73 (3H, s, OCH3), 4.15 (2H, s, NCH2), 4.81 (2H, s, NCH2), 6.97 (1H, m, aromatic), 7.12 (2H, m, aromatics). Anal. calcd for C15H17FN2O4: C, 58.44; H, 5.56; N, 9.09. Found: C, 58.41; H, 5.61; N, 8.90.