Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11]([C@H:12]2[CH2:16][CH2:15][CH2:14][C@@H:13]2[OH:17])=[CH:10][CH:9]=[N:8]1.[H-].[Na+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C=O)C>[CH2:20]([O:17][C@H:13]1[CH2:14][CH2:15][CH2:16][C@@H:12]1[C:11]1[N:7]([CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[N:8]=[CH:9][CH:10]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O[C@H]1CCC[C@@H]1c1ccnn1C1CCCCO1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(CO[C@H]2CCC[C@@H]2c2ccnn2C2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 85.3 %

Procedure:
To a solution of the (1S*,2R*)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]cyclopentanol (975 mg, 4.13 mmol) prepared in Example 138a in DMF (20 mL), sodium hydride (63%; 236 mg, 6.19 mmol) and benzyl bromide (0.735 mL, 6.19 mmol) were added, and the reaction solution was stirred at room temperature for 7 hours. To the reaction solution, water (50 mL) was added, followed by extraction with ethyl acetate (50 mL). The thus obtained organic layer was washed twice with water (50 mL) and dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with silica gel chromatography (hexane/ethyl acetate=7:3) to yield the title compound (1.15 g, 57%) in the form of a diastereomeric mixture as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([CH:10]=O)[CH:7]=[CH:6][C:5]=1[C:12]#[C:13][C:14]1([OH:22])[CH:19]2[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]2)[CH2:15]1)[CH3:2].[C:23]([CH:28]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:25][CH2:26][CH3:27])=[O:24]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([CH:10]=[CH:28][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:7]=[CH:6][C:5]=1[C:12]#[C:13][C:14]1([OH:22])[CH:19]2[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]2)[CH2:15]1)[CH3:2]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOc1cc(C=O)ccc1C#CC1(O)CN2CCC1CC2
Solvent: Cc1ccccc1
Product: CCOC(=O)C=Cc1ccc(C#CC2(O)CN3CCC2CC3)c(OCC)c1
Temperature: 100 °C
Yield: 44.4 %

Procedure:
A mixture of 3-[2-(2-ethoxy-4-formylphenyl)ethynyl]quinuclidin-3-ol (598 mg), carbethoxymethylenetriphenylphosphorane (1.04 g) in toluene (10 ml) was heated at 100° C. for 5 hours. The reaction mixture was cooled to ambient temperature and the toluene evaporated to give a solid which was crystallised from acetonitrile to give 3-[2-(2-ethoxy-4-(2-ethoxycarbonylethenyl)phenyl)ethynyl]quinuclidin-3-ol (328 mg) as a solid, m.p. 152-153° C.; microanalysis found: C, 71.5; H, 7.3; N, 3.7%; C22H27NO4 requires: C, 71.5: H, 7.37; N, 3.79%; NMR (CDCl3): 1.33(3H, t), 1.36-1.52(4H, m), 1.55-1.70(1H, m), 1.90-2.30(4H, m), 2.73-3.00(4H, m), 3.04(1H, d), 3.34(1H, dd), 4.09(2H, q), 4.26(2H, q), 6.33-6.45(1H, d), 6.93-7.03(1H, d,), 7.03(1H, dd), 7.35(1H, d), 7.60(1H, d); m/Z 370 (M+H).
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[C:5]([O:19][CH3:20])=[C:6]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:7]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:9]=1.Cl[C:22]([O:24][CH2:25][C:26]([Cl:29])([Cl:28])[Cl:27])=[O:23]>>[Cl:27][C:26]([Cl:29])([Cl:28])[CH2:25][O:24][C:22](=[O:23])[NH:3][C:4]1[CH:9]=[C:8]([C:10]([CH3:12])([CH3:13])[CH3:11])[CH:7]=[C:6]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[C:5]=1[O:19][CH3:20]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: COc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Product: COc1c(NC(=O)OCC(Cl)(Cl)Cl)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75 %

Procedure:
NaOH (199 mg, 4.97 mmol) was added to an ice-bath cooled solution of N-[3-amino-5-(1,1-dimethylethyl)-2-methoxyphenyl]-methanesulfonamide (for reference procedure see for example WO2010026096, which is incorporated herein by reference in its entirety; 500 mg, 1.84 mmol). The ice bath was removed and complete dissolution of reagents occurred. 2,2,2-trichloroethyl chloroformate (380 μL, 2.76 mmol) was added and the reaction mixture was warmed to RT and stirred for 90 min. The reaction mixture was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 0-60% EtOAc in cyclohexane, to afford the title compound (620 mg, 75%) as a white solid. LCMS (Method 1): Rt 3.98 min, m/z 445, 447, 449 [MH+].
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][C@H:10]([C:15]([OH:17])=[O:16])[C:11]([SH:14])([CH3:13])[CH3:12]>C(O)C.O>[CH3:12][C:11]1([CH3:13])[S:14][CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[NH:9][CH:10]1[C:15]([OH:17])=[O:16]
Reactant: O=Cc1ccccc1
Reactant: CC(C)(S)[C@H](N)C(=O)O
Solvent: O
Solvent: CCO
Product: CC1(C)SC(c2ccccc2)NC1C(=O)O
Reaction time: 0.25 h

Procedure:
One mole of benzaldehyde was dissolved in 100 cc of 90% ethanol with continuous stirring. One mole of penicillamine was dissolved in water with continuous stirring. The two solutions were then mixed together while stirring was continued. The solution was left to stand at room temperature. Within 15 minutes, a white precipitate occurred. The white precipitate was washed with distilled water through sintered glass. The washed precipitate was then dryed at 100° C. to obtain crystals.
Reaction SMILES: Cl[Sn]Cl.Cl.S(=O)(=O)(O)[OH:6].[Br:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#N)=[CH:13][C:12]=1[F:19]>O.C(OCC)C>[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:6])=[CH:13][C:12]=1[F:19]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1ccc(Br)c(F)c1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCOCC
Solvent: O
Product: O=Cc1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 59 g (0.31 mol) of anhydrous SnCl2 and 320 cm3 of diethyl ether was placed on an ice water bath and saturated with hydrogen chloride gas generated by the drop-wise addition of concentrated sulfuric acid to concentrated hydrochloric acid until the SnCl2 assumed a liquid state and the mixture was dried with concentrated sulfuric acid. 31 g (0.16 mol) of 4-bromo-3-fluorobenzonitrile was added to the mixture and the resulting mixture was stirred at room temperature for 1 hour and allowed to stand overnight. 300 cm3 of water was added to the reaction product and the mixture was stirred over a hot water bath at 50° C. The diethyl ether was distilled off. The oily layer was separated out and the aqueous layer was extracted with ether. The two layers were combined, washed with water, and dried overnight with anhydrous Na2SO4. Diethyl ether was distilled off the resulting dried mixture. Diethyl ether was distilled off the distillation residue. The distillation residue was distilled under a vacuum (b.p. 122° C./25 mmHg) to yield 26 g (0.13 mol) of 4-bromo-3-fluorobenzaldehyde.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[CH:16]1[CH:21]=[CH:20][C:19]([CH:22]([NH2:26])[C:23]([OH:25])=[O:24])=[CH:18][CH:17]=1>>[C:23]([CH:22]([NH:26][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[C:19]1[CH:18]=[CH:17][CH:16]=[CH:21][CH:20]=1)([OH:25])=[O:24]
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: NC(C(=O)O)c1ccccc1
Product: O=C(O)c1cc2cc(Cl)ccc2nc1NC(C(=O)O)c1ccccc1
Yield: 33 %

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with DL-phenylglycine to provide the title compound in 33% yield as yellow needles (recrystallization from DMF/water).
Reaction SMILES: [Si:1]([CH:18]([OH:28])[C@H:19]1[O:25][C@@H:22]([O:23][CH3:24])[C@H:21]([OH:26])[C@@H:20]1[OH:27])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(Cl)Cl>C(Cl)Cl.N1C=CC=CC=1>[Si:1]([CH:18]([OH:28])[C@H:19]1[O:25][C@@H:22]([O:23][CH3:24])[C@:21]([C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([OH:26])[C@:20]1([C:29](=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[OH:27])([C:14]([CH3:17])([CH3:15])[CH3:16])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CO[C@@H]1O[C@H](C(O)[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](O)[C@H]1O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CO[C@@H]1O[C@H](C(O)[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@](O)(C(=O)c2ccccc2)[C@]1(O)C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 14.5 h

Procedure:
To a solution of 1-O-methyl 5-(t-butyldiphenylsilyl)-β-D-ribofuranoside (579 mg, 1.44 mmol) in methylene chloride-pyridine (4:1, 12.5 ml) was added dropwise benzoyl chloride (0.367 ml, 3.16 mmol) at 0° C. The reaction mixture was stirred for 2.5 h at 0° C. and for 14.5 h at room temperature. Ice was added to quench the reaction and the mixture was stirred for 1 h. Methylene chloride (100 ml) was added and two phases were separated. Organic layer was washed with water, saturated ammonium chloride, and brine, dried over anhydrous MgSO4, filtered, and concentrated to dryness to yield 1-O-methyl 5-(t-butyldiphenylsilyl)-2,3-dibenzoyl-β-D-ribofuranoside in crude form, which was then purified by silica gel column chromatography (Hx-EtOAc, 5:1→1:1) to yield 1-O-methyl 5-(t-butyldiphenylsilyl)-2,3-dibenzoyl-β-D-ribofuranoside in more pure form [Rf =0.75 (CHCl3 --MeOH, 10:1), 869 mg, 99%] as a thick syrup. 1H NMR (CDCl3) d 1.05 (s, 9H, t-Bu), 3.42 (s, 3H, --OCH3), 3.86 (dd, J=11.1 and 4.8 Hz, 1H, H-5a), 3.92 (dd, J=11.1 and 4.7 Hz, 1H, H-5b), 4.48 (dd, J=10.6 and 4.6 Hz, 1H), 5.15 (s, 1H), 5.63 (d, J=5.0 Hz, 1H), 5.82 (pseudo t, J=5.8 and 5.4 Hz, 1H), 7,29-8.18 (m, 20H, Ar). Anal. Calcd for C36H38O7Si1 : C, 70.79; H, 6.27; Found: C, 71.01; H, 6.20.
Reaction SMILES: C([O:4][C:5]1[C:6]2[C:11]([CH:12]=[C:13]([O:17][CH3:18])[C:14]=1[O:15][CH3:16])=[N:10][C:9](=[O:19])[C:8](=[O:20])[N:7]=2)(=O)C.[OH-].[Na+].Cl>O>[OH:4][C:5]1[C:6]2[C:11]([CH:12]=[C:13]([O:17][CH3:18])[C:14]=1[O:15][CH3:16])=[N:10][C:9](=[O:19])[C:8](=[O:20])[N:7]=2
Reactant: COc1cc2c(c(OC(C)=O)c1OC)=NC(=O)C(=O)N=2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc2c(c(O)c1OC)=NC(=O)C(=O)N=2
Yield: 91 %

Procedure:
5-Acetyloxy-6,7-dimethoxy-2,3-quinoxalinedione (47) (30 mg, 0.107 mmol) was added to a single-necked 15-mL flask. Sodium hydroxide aqueous solution (2 N, 1 mL) was added to the flask under nitrogen with stirring. The solution was then stirred at room temperature for 24 h. The solution was diluted with water (3 mL) and then acidified with HCl (4 N, 1 mL) to pH=2 to give a brown solid, which was collected by filtration and dried in vacuo, giving 23 mg (86%) of the title compound; mp 285-286° C. (dec); 1H NMR (DMSO-d6, 300 MHz) a 3.688 (s, 3H), 3.694 (s, 3H), 6.227 (s, 1H), 9.769 (s, 1H), 11.016 (s, 1H), 11.658 (s, 1H). EIMS m/e 238 (100, M+), HPLC purity >96%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4][NH2:5].[OH:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]=O>>[OH:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH2:10][NH:5][CH2:4][C:3]([O:2][CH3:1])=[O:6]
Reactant: COC(=O)CN
Reactant: O=Cc1ccccc1O
Product: COC(=O)CNCc1ccccc1O
Yield: 40 %

Procedure:
Prepared as in example 10-10a from glycine methyl ester and 2-hydroxybenzaldehyde. Yield 40%. MS M+H calculated 196.1; found 196.1
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([OH:10])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.O[CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>O1CCCC1>[O:15]1[CH2:16][CH2:17][CH:12]([O:10][C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][N:2]=[CH:3]3)[CH2:13][CH2:14]1
Reactant: OC1CCOCC1
Reactant: Oc1ccc2[nH]ncc2c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: c1cc2[nH]ncc2cc1OC1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 4.7 %

Procedure:
To a solution of the 1H-indazol-5-ol (150 mg, 1.12 mmol) obtained in Reference Example 4 in tetrahydrofuran (6 ml) were added 4-hydroxytetrahydropyran (0.107 ml, 1.12 mmol), triphenylphosphine (293 mg, 1.12 mmol) and a 40%-diethyl azodicarboxylate-toluene solution (0.517 ml, 1.14 mmol) at 0° C. After 30 minutes, the mixture thus obtained was heated to room temperature. After stirring overnight, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol) to obtain 5-(tetrahydro-2H-pyran-4-yloxy)-1H-indazole (11.4 mg, 47%).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][C:28]([C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:32]([CH3:39])[CH:31]=1)=[O:29]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:24][CH2:25][CH2:26][CH2:27][C:28]([C:30]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:32]([CH3:39])[CH:31]=3)=[O:29])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: Cn1cc(C(=O)CCCCBr)c2ccccc21
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCC(=O)c2cn(C)c3ccccc23)CC1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 5-bromo-1-(1-methyl-1 H-indol-3-yl)-1-pentanone were reacted and treated in the same manner as in Example 172 to give 4-amino-5-chloro-2-methoxy-N-((1-(5-(1 -methyl-1 H-indol-3-yl)-5-oxopentyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)[N:6]=[CH:5]2.[H-].[Na+].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].O>CN(C=O)C>[CH2:31]([O:30][C:28](=[O:29])[CH2:27][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)[N:6]=[CH:5]2)[CH3:32]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3cc(O)ccc32)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc2c(cnn2C2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.9 %

Procedure:
To a solution of tert-butyl 4-(5-hydroxy-1H-indazol-1-yl)piperidine-1-carboxylate (150 mg, 0.458 mmol) in DMF (10 mL) at 0° C. was added NaH (60% in mineral oil) (16.8 mg, 0.706 mmol) and ethyl 2-bromoacetate (119 mg, 0.706 mmol). The mixture was stirred at 25° C. for 3 h, poured into water, and the product extracted with ethyl acetate. The organic phase was washed with water, dried over Na2SO4, concentrated under reduced pressure and purified by TLC (Pet.Ether:EtOAc=1:1) to give tert-butyl 4-(5-(2-ethoxy-2-oxoethoxy)-1H-indazol-1-yl)piperidine-1-carboxylate (120 mg, yield 65%) as a colorless oil. LCMS (m/z): 404.2 [M+H]+
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Li]CCCC.[CH3:13][C:14]1([C:26]([O-:28])=[O:27])[CH2:18][CH2:17][CH2:16][N:15]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C([N-]C(C)C)(C)C.[Li+].CI>C1COCC1>[CH3:13][C:14]1([C:26]([O:28][CH3:1])=[O:27])[CH2:18][CH2:17][CH2:16][N:15]1[C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20]
Reactant: CC(C)NC(C)C
Reactant: CC(C)(C)OC(=O)N1CCCC1(C)C(=O)[O-]
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C1(C)CCCN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 63.2 %

Procedure:
To a solution of diisopropylamine (1.59 g, 15.7 mmol) in THF (10 mL) was added n-BuLi (7.54 mL, 2.5 M in n-hexane) dropwise at 0° C. Then the solution was stirred at the same temperature for 30 min. 1-tert-butyl 2-methylpyrrolidine-1,2-dicarboxylate (3.0 g, 13.0 mmol) was dissolved in 50 mL THF and cooled to −78° C. To the solution was added prepared lithium diisopropylamide (15.7 mmol) dropwise. After the reaction mixture was kept at −78° C. for 3 h, MeI (1.6 mL, 25.7 mmol) was added. The mixture was allowed to warm to 0° C. and stirred for 2 h. Then the reaction mixture was quenched with water (30 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were dried over Na2SO4 and concentrated under vacuum to give 2 g of the crude product. MS (ESI): 244 (MH+).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[H-].[Na+].[Cl:15][C:16]1[N:21]=[CH:20][C:19]([O:22][C:23]2[CH:30]=[CH:29][C:28]([CH2:31][OH:32])=[CH:27][C:24]=2[C:25]#[N:26])=[CH:18][CH:17]=1>CN(C=O)C>[Cl:15][C:16]1[N:21]=[CH:20][C:19]([O:22][C:23]2[CH:30]=[CH:29][C:28]([CH2:31][O:32][C:2]3[CH:3]=[C:4]4[N:11]([CH3:12])[CH2:10][CH2:9][N:5]4[C:6](=[O:8])[N:7]=3)=[CH:27][C:24]=2[C:25]#[N:26])=[CH:18][CH:17]=1
Reactant: N#Cc1cc(CO)ccc1Oc1ccc(Cl)nc1
Reactant: CN1CCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCn2c1cc(OCc1ccc(Oc3ccc(Cl)nc3)c(C#N)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (60 mg, 0.323 mmol), sodium hydride (25.9 mg, 0.647 mmol) and 2-((6-chloropyridin-3-yl)oxy)-5-(hydroxymethyl)benzonitrile (84 mg, 0.323 mmol) in DMF (2 mL).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2/[C:16](=[N:21]\[O:22][CH3:23])/[C:17]([NH:19][CH3:20])=[O:18])[CH:5]=[CH:4][CH:3]=1.[CH3:24][S-:25].[Na+].O>O1CCCC1>[CH3:24][S:25][C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2/[C:16](=[N:21]\[O:22][CH3:23])/[C:17]([NH:19][CH3:20])=[O:18])[CH:5]=[CH:4][CH:3]=1
Reactant: C[S-]
Reactant: CNC(=O)/C(=N/OC)c1ccccc1COc1cccc(Cl)n1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)/C(=N/OC)c1ccccc1COc1cccc(SC)n1
Reaction time: 5 h
Yield: 64.4 %

Procedure:
(E)-2-[2-(6-chloropyridin-2-yloxymethyl)phenyl]-2-methoxyimino-N-methylacetamide (1.2 g) was dissolved in tetrahydrofuran (10 ml), and sodium thiomethoxide (1 g) was added. The mixture was heated under reflux with stirring for 5 hours. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried, and the solvent was evaporated. The resulting oil was purified by column chromatography on silica gel to give the title compound (800 mg). mp. 130°-132° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=2)[CH2:13][CH2:12]1)=[O:10].[CH2:25]1[CH2:32][NH:31][S:28](=[O:30])(=[O:29])[CH2:27][CH2:26]1>>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[C:2]([N:31]2[CH2:32][CH2:25][CH2:26][CH2:27][S:28]2(=[O:30])=[O:29])[CH:7]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)cc3Br)CC2)c(C)c1
Reactant: O=S1(=O)CCCCN1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)cc3N3CCCCS3(=O)=O)CC2)c(C)c1
Yield: 28857.2 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 12 and using (2-bromo-4-chlorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (1.19 mg) described in Preparation Example 119 and 1,4-butanesultam (0.394 g), the title compound (0.389 g) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[CH2:16][C:17]([O-:19])=[O:18])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.CO.[OH-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[CH2:16][C:17]([OH:19])=[O:18])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: COc1cc(OC)cc(N2CCCC2CC(=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(OC)cc(N2CCCC2CC(=O)O)c1

Procedure:
A mixture of 53.6 g. (0.192 mole) methyl dl-2-[1-(3,5-dimethoxyphenyl)pyrrolidin-2-yl]acetate, 250 ml. methanol and 22.8 g. (0.57 mole) sodium hydroxide in 200 ml. water was stirred at room temperature for 2.5 hours. The methanol was evaporated and the aqueous residue cooled in ice. To this was added dropwise 48 ml. concentrated hydrochloric acid, the mixture extracted with 4×150 ml. methylene chloride, the extract washed with water, dried (MgSO4) and the solvent evaporated to afford 48.9 g. (96%) of product. 1H--NMR (CDCl3) ppm (delta): 3.80 (s, 6H, OCH3), 4.10 (m, 1H, N--CH), 5.82 (s, 3H, aromatic), 11.0 (s, 1H, COOH). Mass spectrum (m/e): 206 (base peak), 265 (M+).
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.CN(C=O)C.[H-].[Na+].Cl[C:15]1[N:20]=[C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:18]=[CH:17][N:16]=1>O>[Br:1][C:2]1[N:3]=[CH:4][N:5]([C:15]2[N:20]=[C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][N:16]=2)[CH:6]=1
Reactant: Brc1c[nH]cn1
Reactant: Clc1nccc(N2CCOCC2)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1cn(-c2nccc(N3CCOCC3)n2)cn1
Temperature: 120 °C
Yield: 94.3 %

Procedure:
To a cooled (0° C.) solution of 4-bromo-1-H-imidazole (0.8 g, 4.0 mmol) in anhydrous DMF (5.0 mmol) was added NaH (60% dispersion in mineral oil, 0.176 g, 4.4 mmol) in a portionwise fashion over 10 minutes. When gas evolution had ceased, 4-(2-Chloro-pyrimidin-4-yl)-morpholine (21)(0.79 g, 4.00 mmol) was added and the mixture heated under the influence of microwave radiation (120° C., 14 min, fixed hold time, pre-stirring 10 seconds, high absorption setting). Water (14 ml) was added to the reaction mixture which caused a precipitate to form. The precipitate was removed by filtration, washed with water (10 ml) and dried in a desiccator to give the title compound (1.17 g, 94.4%) in suitably clean form to be used without any further purification. m/z (LC-MS, ESP): 310 [M+H]+, R/T=3.79 mins
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:11]([CH3:15])[C:12]([OH:14])=O)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[S:22]1[CH:26]=[N:25][N:24]=[C:23]1[NH2:27]>>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:11]([CH3:15])[C:12]([NH:27][C:23]3[S:22][CH:26]=[N:25][N:24]=3)=[O:14])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: Nc1nncs1
Reactant: CC(C(=O)O)C(c1ccccc1)c1ccc2[nH]ncc2c1
Product: CC(C(=O)Nc1nncs1)C(c1ccccc1)c1ccc2[nH]ncc2c1
Yield: 42 %

Procedure:
Example 151 was prepared from 3-(1H-indazol-5-yl)-2-methyl-3-phenylpropanoic acid (40 mg, 0.26 mmol) and 1,3,4-thiadiazol-2-amine using General Coupling Method A to give 6 mg (42% yield). MS found: (M+H)+=364. 400 MHz 1H-NMR (CDCl3) δ 8.77 (s, 1H); 7.90 (s, 1H); 7.75 (s, 1H); 7.75 (s, 1H); 7.47 (m, 4H); 7.36 (app t, 2H); 7.25 (dd, 2H); 4.35 (d, 1H); 3.87 (m, 1H); 1.31 (d, 3H).