Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[C:12]([C:13](=O)[CH:14]([CH3:16])[CH3:15])=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2].Cl.[NH2:19][OH:20].[OH-].[Na+].Cl>CCO.O>[CH:1]([C:4]1[C:12]([C:13](=[N:19][OH:20])[CH:14]([CH3:16])[CH3:15])=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2]
Reactant: NO
Reactant: CC(C)C(=O)c1c(C(C)C)nn2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)C(=NO)c1c(C(C)C)nn2ccccc12
Temperature: 0 °C
Yield: 48.9 %

Procedure:
To a solution of 2.3 g (10 mmol) of 1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one in 32 ml of anhydrous EtOH was added hydroxylamine hydrochloride 1.5 g (20 mmol), followed by dropwise addition of 2.4 g NaOH in 6 ml of water. The mixture was stirred and refluxed over night. After cooling, the solution was poured into a solution of 8.3 ml of 6N HCl and 380 ml ice water with stirring for 30 minutes. The precipitate was filtered and washed with ethyl ether-hexane to furnish 1.2 g (74.5%) of 1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one oxime (as a mixture of cis- and trans-isomers), which was separated on an aluminum oxide column with hexane-dichloromethane-ethyl acetate as eluant to yield 0.3 g (cis-) and 0.325 g (trans-) isomers of 1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one oxime. Compound 1012.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16]([NH:20][CH:21]([CH3:23])[CH3:22])([C:18]#[N:19])[CH2:15]1)([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.[OH:24]S(O)(=O)=O>C(Cl)Cl>[CH:1]([N:14]1[CH2:17][C:16]([NH:20][CH:21]([CH3:23])[CH3:22])([C:18]([NH2:19])=[O:24])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)NC1(C#N)CN(C(c2ccccc2)c2ccccc2)C1
Reactant: O=S(=O)(O)O
Solvent: ClCCl
Product: CC(C)NC1(C(N)=O)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-benzhydryl-3-isopropylaminoazetidine-3-carbonitrile (I-(7A-106)a; 3.40 g, 11.1 mmol) in methylene chloride (25 ml) cooled in an ice bath was treated with H2SO4 (5.95 ml, 111 mmol), dropwise. After the reaction mixture was allowed to warm to room temperature and stir overnight, it was cooled in an ice bath and then carefully quenched with concentrated NH4OH to pH 11. The mixture was extracted with methylene chloride, the combined organic layers were dried (Na2SO4) and then concentrated, in vacuo, to afford a crude foam (3.3 g) that was then purified on a Biotage™ Flash 40M column using 0–2% methanol in methylene chloride as eluant to afford the title compound I-(7A-106)b (2.32 g, 64%) as a brown solid: +ESI MS (M+1) 324.4; 1H NMR (400 MHz, CD3OD) δ 7.40 (d, J=7.5 Hz, 4H), 7.24 (t, J=7.5 Hz, 4H), 7.15 (t, J=7.1 Hz, 2H), 4.46 (s, 1H), 3.53 (d, J=8.7 Hz, 2H), 3.06 (d, J=8.7 Hz, 2H), 2.90 (septuplet, J=6.4 Hz, 1H), 0.97 (d, J=6.6 Hz, 6H).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH2:7]([C:11]1[N:12]([CH3:23])[C:13]2[C:18](C=1C(O)=O)=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:9][CH3:10]>C(Cl)Cl>[CH2:7]([C:11]1[N:12]([CH3:23])[C:13]2[C:14]([C:1]=1[C:2]([Cl:4])=[O:3])=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:8][CH2:9][CH3:10]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCc1c(C(=O)O)c2ccccc2n1C
Solvent: ClCCl
Product: CCCCc1c(C(=O)Cl)c2ccccc2n1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Oxalyl chloride (5.89 mL, 66.1 mmol) was added under nitrogen to a solution of 2-butyl-1-methyl-1H-indole-3-carboxylic acid (3.06 g, 13.2 mmol), prepared in the previous step, in 100 mL of methylene chloride at room temperature. There was an immediate evolution of gas. After the addition the reaction was stirred at room temperature for 2 h. The solvent was removed under reduced pressure. To remove excess oxalyl chloride the residue was dissolved in benzene and the solvent removed under reduced pressure to give 2-butyl-1-methyl-1H-indole-3-carbonyl chloride as a brown oil. The material was immediately used without additional purification.
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)#[C:2][CH2:3][CH2:4][CH3:5].[N+:12]([CH:15](C(OC)=O)[C:16]([O:18][CH3:19])=[O:17])([O-])=[O:13].F[P-](F)(F)(F)(F)F.C([N+]1C=CN(C)C=1)CCC>C1(C)C=CC=CC=1>[CH2:3]([C:2]1[C:15]([C:16]([O:18][CH3:19])=[O:17])=[N:12][O:13][C:1]=1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)[CH2:4][CH3:5]
Reactant: CCCC#Cc1ccccn1
Reactant: COC(=O)C(C(=O)OC)[N+](=O)[O-]
Agent: CCCC[n+]1ccn(C)c1
Agent: F[P-](F)(F)(F)(F)F
Solvent: Cc1ccccc1
Product: CCCc1c(C(=O)OC)noc1-c1ccccn1
Yield: 5 %

Procedure:
A solution of 2-(pent-1-ynyl)pyridine (150 mg, 1.03 mmol), dimethyl nitromalonate (0.35 mL, 2.58 mmol), and 1-butyl-3-methylimidazolium hexafluorophosphate (0.021 mL, 0.103 mmol) in toluene (3 mL) was heated to 170° C. for 120 minutes under microwave. The reaction mixture was concentrated to yield a crude product which was purified by silica gel chromatography with hexanes/ethyl acetate (10/1) to afford methyl 4-propyl-5-(pyridine-2-yl)isoxazole-3-carboxylate (14.3 mg, 0.052 mmol). The compound had an HPLC retention time=3.05 min.—Column: YMC S5 COMBISCREEN® 4.6×50 mm; Gradient time: 4 min; Flow rate=4 ml/min; Solvent A=10% MeOH—90% Water—0.2% H3PO4; Solvent B=90% MeOH—10% water—0.2% H3PO4; Start % B=0; Final % B=100. LC-MS: M+1=247.1. 1H NMR (500 MHz, CDCl3) δ ppm 0.97 (t, 3H), 1.66 (sxt, J=7.48 Hz, 2H), 3.15-3.20 (m, 2H), 4.01 (s, 3H), 7.33 (ddd, J=7.56, 4.81, 1.10 Hz, 1H), 7.83 (td, J=7.77, 1.79 Hz, 1H), 7.91 (d, J=7.97 Hz, 1H), and 8.72 (d, J=4.12 Hz, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]3[CH:29]=[C:30]([NH:37][C:38]4[N:43]=[CH:42][C:41]([CH:44]5[CH2:49][CH2:48][N:47]([CH3:50])[CH2:46][CH2:45]5)=[CH:40][CH:39]=4)[C:31]4[N:32]([CH:34]=[CH:35][N:36]=4)[CH:33]=3)[C:18]=1[CH2:19][O:20]C(=O)C)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+]>CO>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]3[CH:29]=[C:30]([NH:37][C:38]4[N:43]=[CH:42][C:41]([CH:44]5[CH2:49][CH2:48][N:47]([CH3:50])[CH2:46][CH2:45]5)=[CH:40][CH:39]=4)[C:31]4[N:32]([CH:34]=[CH:35][N:36]=4)[CH:33]=3)[C:18]=1[CH2:19][OH:20])[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(C4CCN(C)CC4)cn3)c3nccn3c2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CN1CCC(c2ccc(Nc3cc(-c4cccc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4CO)cn4ccnc34)nc2)CC1
Yield: 78.9 %

Procedure:
A solution of acetic acid 2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-[8-(1′-methyl-1′,2′,3′,4′,5′,6′-hexahydro-[3,4′]bipyridinyl-6-ylamino)-imidazo[1,2-a]pyridin-6-yl]-benzyl ester (270 mg, 0.4012 mmol) and K2CO3 (166 mg, 1.2036 mmol) in CH3OH (15 mL) was stirred at room temperature for 3 h. TLC showed a complete reaction. The solution was poured onto water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give the desired product (200 mg) with high purity.
Reaction SMILES: [ClH:1].[CH2:2]([N:6]([C:37]([NH:39][C:40]1[CH:45]=[CH:44][C:43]([F:46])=[CH:42][C:41]=1[F:47])=[O:38])[CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:36]=[CH:35][C:17]([O:18][C:19]3[CH:24]=[CH:23][C:22]([N:25]([S:31]([CH3:34])(=[O:33])=[O:32])[CH2:26][C:27]([O:29]C)=[O:28])=[CH:21][CH:20]=3)=[CH:16][CH:15]=2)[CH2:9][CH2:8]1)[CH2:3][CH2:4][CH3:5].[OH-].[Na+].Cl>CO>[ClH:1].[CH2:2]([N:6]([C:37]([NH:39][C:40]1[CH:45]=[CH:44][C:43]([F:46])=[CH:42][C:41]=1[F:47])=[O:38])[CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:36]=[CH:35][C:17]([O:18][C:19]3[CH:20]=[CH:21][C:22]([N:25]([CH2:26][C:27]([OH:29])=[O:28])[S:31]([CH3:34])(=[O:33])=[O:32])=[CH:23][CH:24]=3)=[CH:16][CH:15]=2)[CH2:9][CH2:8]1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCN(C(=O)Nc1ccc(F)cc1F)C1CCN(Cc2ccc(Oc3ccc(N(CC(=O)OC)S(C)(=O)=O)cc3)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCN(C(=O)Nc1ccc(F)cc1F)C1CCN(Cc2ccc(Oc3ccc(N(CC(=O)O)S(C)(=O)=O)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 81.6 %

Procedure:
To a solution of the compound prepared in Example 3(106) (80 mg) in methanol (1 ml) was added 2N aqueous solution of sodium hydroxide (0.5 ml). The reaction mixture was stirred for 2.5 hours at room temperature. To the reaction mixture on ice bath was added 1N hydrochloric acid until the pH of the solution was below 5, then it was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, concentrated. The obtained residue was purified by column chromatography on silica gel (dichloromethane:methanol=9:1). To a solution of the obtained compound in ethyl acetate was added 4N hydrogen chloride in ethyl acetate solution. The reaction mixture was concentrated to give the title compound (64 mg) having the following physical data.
Reaction SMILES: S([O:6][CH3:7])(OC)(=O)=O.[NH2:8][C:9]1[C:10](=O)[NH:11][C:12]([CH3:15])=[CH:13][N:14]=1.[OH-].[Na+]>>[NH2:8][C:9]1[C:7](=[O:6])[N:11]([CH3:10])[C:12]([CH3:15])=[CH:13][N:14]=1
Reactant: Cc1cnc(N)c(=O)[nH]1
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Product: Cc1cnc(N)c(=O)n1C
Reaction time: 15 h
Yield: 18.8 %

Procedure:
8.87 g of dimethyl sulfate are added dropwise to a mixture of 8.13 g of 3-amino-6-methylpyrazin-2-one and 72 ml of 1N sodium hydroxide solution at room temperature. After the mixture has been stirred at 20°-25° C. for 15 hours, the precipitate is filtered off, the filtrate is concentrated to one quarter of the volume and the concentrate is extracted with ethyl acetate. 1.7 g of 3-amino-1,6-dimethylpyrazin-2-one with a melting point of 217°-219° C. are obtained by washing with saturated sodium chloride solution, drying with sodium sulfate and concentrating the organic phase.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[C:21]1([N:31]=[C:32]=[O:33])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1>O1CCCC1>[CH3:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][CH:2]([NH:1][C:32]([NH:31][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][CH:22]=2)=[O:33])[C:3]1=[O:20]
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Reactant: O=C=Nc1cccc2ccccc12
Solvent: C1CCOC1
Product: CN1C(=O)C(NC(=O)Nc2cccc3ccccc23)N=C(c2ccccc2)c2ccccc21
Reaction time: 8 h

Procedure:
Equimolar amounts of 3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 1-naphthylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: m.p. 234°-235° C.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][S:15][CH3:16])[C:8]([C:17]([N:19]([CH2:42][CH:43]([CH3:45])[CH3:44])[C@H:20]2[CH2:25][C@@H:24]([NH:26][C:27]([O:29][CH2:30][C:31](Cl)(Cl)Cl)=[O:28])[CH2:23][N:22]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:21]2)=[O:18])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C.O>[C:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][S:15][CH3:16])[C:8]([C:17]([N:19]([CH2:42][CH:43]([CH3:44])[CH3:45])[C@H:20]2[CH2:25][C@@H:24]([NH:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:23][N:22]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:21]2)=[O:18])=[CH:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CSCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](NC(=O)OCC(Cl)(Cl)Cl)CN(C(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)N[C@@H]1C[C@H](N(CC(C)C)C(=O)c2cnc(C(C)(C)C)nc2NCCCSC)CN(C(=O)OC(C)(C)C)C1
Temperature: 80 °C
Reaction time: 12 h
Yield: 12.4 %

Procedure:
To a solution of tert-butyl (3S,5R)-3-{[(2-tert-butyl-4-{[3-(methylsulfanyl)propyl]amino}pyrimidin-5-yl)carbonyl](2-methylpropyl)amino}-5-{[(2,2,2-trichloroethoxy)carbonyl]amino}piperidine-1-carboxylate (1.12 g) in ethanol (10 ml) was added 4 M aqueous sodium hydroxide solution (10 ml), and the mixture was stirred at 80° C. for 12 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with ethyl acetate-hexane (10:90-85:15) and concentrated under reduced pressure to give the object compound (119 mg).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[C:9]([F:28])[C:10]([CH3:27])=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:22][C:23](OC)=[O:24])[N:17]=[CH:16]4)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[CH:1]1([NH:4][C:5](=[O:6])[C:7]2[CH:12]=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:22][C:23]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[O:24])[N:17]=[CH:16]4)[C:10]([CH3:27])=[C:9]([F:28])[CH:8]=2)[CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: COC(=O)Cn1ncc2cc(-c3cc(C(=O)NC4CC4)cc(F)c3C)ccc21
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(cnn2CC(=O)N2CCOCC2)c1

Procedure:
Example 138 was prepared by General Method D using methyl (5-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-1H-indazol-1-yl)acetate (Example 123) and morpholine to give the title compound (0.001 g).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:9][CH2:10][NH2:11])[CH:5]=[C:6]([I:8])[N:7]=1)[CH3:2].[F:12][C:13]([F:26])([F:25])[O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH:23]=O)=[CH:17][CH:16]=1>>[CH2:1]([C:3]1[N:4]2[CH2:9][CH2:10][NH:11][CH:23]([CH2:22][CH2:21][C:18]3[CH:17]=[CH:16][C:15]([O:14][C:13]([F:12])([F:25])[F:26])=[CH:20][CH:19]=3)[C:5]2=[C:6]([I:8])[N:7]=1)[CH3:2]
Reactant: O=CCCc1ccc(OC(F)(F)F)cc1
Reactant: CCc1nc(I)cn1CCN
Product: CCc1nc(I)c2n1CCNC2CCc1ccc(OC(F)(F)F)cc1

Procedure:
According to the general procedure (GP10), microwave-assisted Pictet-Spengler reaction (60 W; 140° C.; 6.5 bars; 10 min.) between 2-(2-ethyl-4-iodo-imidazol-1-yl)-ethylamine (5.621 mmol) and 3-(4-trifluoromethoxy-phenyl)-propionaldehyde (1.206 g; 5.528 mmol) afforded 3-ethyl-1-iodo-8-[2-(4-trifluoromethoxy-phenyl)-ethyl]-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine. LC-MS: tR=0.78 min.; [M+H]+=465.87 g/mol.
Reaction SMILES: [I:1][C:2]1[N:3]=[N:4][C:5](I)=[CH:6][CH:7]=1.[F:9][C:10]([F:24])([F:23])[C:11]1[CH:12]=[C:13]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C(=O)C>[I:1][C:2]1[N:3]=[N:4][C:5]([N:20]2[CH2:19][CH2:18][N:17]([C:13]3[CH:14]=[CH:15][CH:16]=[C:11]([C:10]([F:23])([F:24])[F:9])[CH:12]=3)[CH2:22][CH2:21]2)=[CH:6][CH:7]=1
Reactant: Ic1ccc(I)nn1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: FC(F)(F)c1cccc(N2CCN(c3ccc(I)nn3)CC2)c1
Temperature: 70 °C
Yield: 48 %

Procedure:
A mixture of 5.2 parts of 3,6-diiodopyridazine, 3.5 parts of 1-[3-(trifluoromethyl)phenyl]piperazine, 3.2 parts of sodium carbonate and 90 parts of N,N-dimethylacetamide was stirred and heated overnight at 70° C. The reaction mixture was poured onto water. The precipitated product was filtered off and crystallized from 2-propanol, yielding 3.2 parts (48%) of 3-iodo-6-[4-[3-(trifluoromethyl)phenyl]-1-piperazinyl]pyridazine; mp. 144.6° C. (compound 202).
Reaction SMILES: C[O:2][C:3](=[O:24])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9](=[O:23])[C@H:10]([CH2:19][CH:20]([CH3:22])[CH3:21])[NH:11][C:12]1[S:16][N:15]=[C:14]([O:17][CH3:18])[N:13]=1.[OH-].[Na+]>CO>[CH3:18][O:17][C:14]1[N:13]=[C:12]([NH:11][C@H:10]([C:9]([N:5]2[CH2:6][CH2:7][CH2:8][C@H:4]2[C:3]([OH:24])=[O:2])=[O:23])[CH2:19][CH:20]([CH3:22])[CH3:21])[S:16][N:15]=1
Reactant: COC(=O)[C@@H]1CCCN1C(=O)[C@H](CC(C)C)Nc1nc(OC)ns1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1nsc(N[C@@H](CC(C)C)C(=O)N2CCC[C@H]2C(=O)O)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 88.7 %

Procedure:
To an ice-cooled solution of N-(3-methoxy-[1,2,4]thiadiazol-5-yl)-L-leucyl-L-proline methyl ester (0.68 g, 1.91 mmol) in methanol (10 mL) was added a solution of 1N sodium hydroxide (2.4 mL, 2.4 mmol). The resulting mixture was stirred in ice for 3 h, then at room temperature for 16 h. Volatile materials were removed in vacuo and the residue was dissolved in water (10 mL) and washed with ethyl acetate. The aqueous layer was collected and acidified with 1N HCl solution (pH ca. 5.6) as a voluminous white precipitate separated. The mixture was extracted into ethyl acetate (6×25 mL), and the combined organic layers was dried (sodium sulfate), filtered and concentrated to a light yellow foam. Trituration with diethyl ether gave N-(3-methoxy-[1,2,4]thiadiazol-5-yl)-L-leucyl-L-proline as a white solid (0.58 g, 89%). M.p. foamed at 78° C. and melted at 89.0-92.0C.; 1H-NMR (CDCl3) δ7.65 (br. s, 1H, NHCH), 4.70 (br. t, 1H, NHCH), 4.49 (t, J=5.3 Hz, 1H, CHCO2), 3.97 (s, 3H, OMe), 3.56-3.58 (m, 2H), 2.03-2.21 (m, 3H), 1.60-1.76 (m, 3H), 0.76-0.99 (m, 1H), 0.99 (d, J=6.5 Hz, 3H, Me), 0.96 (d, J=6.2 Hz, 3H, Me); MS (m/z) 343 (M+ +1), 228, 200, 102, 83.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:31]=[CH:30][C:8]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([C:23](OCCCC)=O)[CH2:19][CH2:18]3)=[CH:13][N:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH2:32]([C:35]1[CH:36]=[N:37]C(Br)=[N:39][CH:40]=1)[CH2:33][CH3:34]>>[CH3:1][S:2]([C:5]1[CH:31]=[CH:30][C:8]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([C:23]4[N:39]=[CH:40][C:35]([CH2:32][CH2:33][CH3:34])=[CH:36][N:37]=4)[CH2:19][CH2:18]3)=[CH:13][N:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CCCc1cnc(Br)nc1
Reactant: CCCCOC(=O)N1CCC(c2ccc(COc3ccc(S(C)(=O)=O)cc3)nc2)CC1
Product: CCCc1cnc(N2CCC(c3ccc(COc4ccc(S(C)(=O)=O)cc4)nc3)CC2)nc1

Procedure:
The title compound was prepared from tort-butyl 4-[2-(4-methanesulfonylphenoxymethyl)pyridin-5-yl]piperidine-1-carboxylate (Example 1) (50 mg, 0.11 mmol) and 5-propyl-2-bromopyrimidine (26 μL, 0.22 mmol) following a procedure analogous to that in Example 48 as a white crystal (31 mg, yield 60%).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([OH:9])=[O:8])[C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2.[N:21]12[CH2:28][CH2:27][CH:24]([CH2:25][CH2:26]1)[C@@H:23](O)[CH2:22]2.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[S:1]1[CH:5]=[C:4]([CH:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([O:9][C@@H:23]2[CH:24]3[CH2:27][CH2:28][N:21]([CH2:26][CH2:25]3)[CH2:22]2)=[O:8])[C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2
Reactant: O[C@H]1CN2CCC1CC2
Reactant: O=C(O)C(Nc1ccccc1)c1csc2ccccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(Nc1ccccc1)c1csc2ccccc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 44.1 %

Procedure:
2-(Benzo[b]thiophen-3-yl)-2-(phenylamino)acetic acid (I42) (295 mg, 1.04 mmol), (R)-quinuclidin-3-ol (159 mg, 1.25 mmol), HOBt (191 mg, 1.25 mmol), and DCC (258 mg, 1.25 mmol) were dissolved in dry THF and stirred at room temperature for 15 hours. THF was evaporated, and the crude product was dissolved in EtOAc and washed sequentially with NaHCO3, water and brine. The organic phase was dried over Na2SO4, filtered and evaporated. The crude was purified by flash chromatography (DCM/MeOH=9/1) to obtain (R)-quinuclidin-3-yl 2-(benzo[b]thiophen-3-yl)-2-(phenylamino)acetate (180 mg, 44% yield, mixture of diastereomers).
Reaction SMILES: N([O-])=O.[Na+].[CH2:5]([O:12][C:13]1[CH:14]=[CH:15][C:16]([O:20][CH:21]([CH3:23])[CH3:22])=[C:17](N)[CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[I-:24].[K+]>O.S(=O)(=O)(O)O>[CH2:5]([O:12][C:13]1[CH:14]=[CH:15][C:16]([O:20][CH:21]([CH3:23])[CH3:22])=[C:17]([I:24])[CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)Oc1ccc(OCc2ccccc2)cc1N
Reactant: [I-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: CC(C)Oc1ccc(OCc2ccccc2)cc1I
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48.2 %

Procedure:
Sodium nitrite (589 mg, 8.5 mmol) in water (2.5 mL) was added dropwise to a stirred, cooled (0° C.) suspension of 5-benzyloxy-2-isopropoxybenzeneamine (Description 109, 2.05 g, 8.4 mmol) in aqueous sulfuric acid (2M, 14 mL). The mixture was stirred at 0° C. for 30 min., then added dropwise to a stirred, cooled (0° C.) solution of potassium iodide (2.50 g, 15.1 mmol) in water (10 mL). The mixture was stirred at room temperature for 90 min., then water (50 mL) was added. The mixture was extracted with ethyl acetate (3×50 mL). The combined organic fractions were washed with aqueous sodium thiosulfate (10%, 2×50 mL), hydrochloric acid (2M, 2×50 mL), saturated aqueous sodium hydrogen carbonate (2×50 mL), and brine (50 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/CH2Cl2 (80:20), to give the title compound as a cream solid (1.49 g, 48%). 1H NMR (360 MHz, CDCl3) δ 7.42-7.30 (6H, m), 6.90 (1H, dd, J 9.0, 2.9 Hz), 6.77 (1H, d, J 9.0 Hz), 4.98 (2H, s), 4.41 (1H, hept, J 6.1 Hz), and 1.35 (6H, d, J 6.1 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:16])=[C:5]([CH:9]=[CH:10][C:11]=1[S:12]([CH3:15])(=[O:14])=[O:13])[C:6]([OH:8])=O.Cl.[OH:18][C:19]1[N:23]([CH3:24])[N:22]=[CH:21][CH:20]=1.C1(N=C=NC2CCCCC2)CCCCC1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([CH3:16])=[C:5]([C:6]([C:20]2[CH:21]=[N:22][N:23]([CH3:24])[C:19]=2[OH:18])=[O:8])[CH:9]=[CH:10][C:11]=1[S:12]([CH3:15])(=[O:14])=[O:13]
Reactant: Cn1nccc1O
Reactant: COc1c(S(C)(=O)=O)ccc(C(=O)O)c1C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(S(C)(=O)=O)ccc(C(=O)c2cnn(C)c2O)c1C
Reaction time: 2 h
Yield: 25.5 %

Procedure:
To a stirred mixture of 3-methoxy-2-methyl-4-(methylsulfonyl)benzoic acid (340 mg, 1.39 mmol) and 5-hydroxy-1-methylpyrazole hydrochloride (230 mg) in anhydrous methylene chloride (10 mL) were added DCC (dicyclohexylcarbodiimide) (315 mg) and triethylamine (260 mg) at room temperature, followed by stirring for 2 hours. The reaction mixture was subjected to filtration through Celite, the filtrate was concentrated, and the obtained residue was dissolved in 10 mL of anhydrous acetonitrile. Triethylamine (260 mg) and acetone cyanohydrin in a catalytic amount were added thereto, and the reaction solution was stirred overnight at room temperature. 150 mL of ethyl acetate was added to the reaction mixture, and the solution was washed once with a 1N hydrochloric acid aqueous solution and washed once with a saturated brine. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:methanol=9:1) to obtain 5-hydroxy-1-methylpyrazol-4-yl 3-methoxy-2-methyl-4-(methylsulfonyl)phenyl ketone (115 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[S:15][C:14]([NH:16]C(C(F)(F)F)=O)=[C:13]([C:23]([OH:25])=[O:24])[C:12]=1[CH3:26])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].Cl>C1COCC1.CCOCC>[CH2:1]([O:8][C:9]([C:11]1[S:15][C:14]([NH2:16])=[C:13]([C:23]([OH:25])=[O:24])[C:12]=1[CH3:26])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(C(=O)OCc2ccccc2)sc(NC(=O)C(F)(F)F)c1C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1c(C(=O)OCc2ccccc2)sc(N)c1C(=O)O
Reaction time: 24 h
Yield: 96 %

Procedure:
The compound prepared in Example 6 was dissolved in THF (1 ml) and Et2O (1 ml). 10% Na2CO3 (2 ml) was added and the reaction was stirred vigorously. After 24 h, the reaction was acidified with 1M HCl and extracted with CHC13 (2×). The combined organic layers were dried over MgSO4, filtered and concentrated to yield 40 mg of a white solid (96%). 1H-NMR (CDCl3) 2.83 (s, 3H), 5.34 (s, 2H), 7.40 (m, 5H); 13C-NMR. (d6-DMSO) 15.7 (CH3), 65.1 (CH2), 105.3 (C), 107.0 (C), 127.7 (CH), 128.0 (CH), 128.6 (CH), 136.6 (C), 148.7 (C), 161.9 (C), 166.7 (C), 167.2 (C);