Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][CH2:2][C:3]1([CH2:6][C:7]([OH:9])=[O:8])[CH2:5][CH2:4]1.S(=O)(=O)(O)O.[CH2:15](O)[CH3:16]>>[CH2:15]([O:8][C:7](=[O:9])[CH2:6][C:3]1([CH2:2][SH:1])[CH2:5][CH2:4]1)[CH3:16]
Reactant: O=C(O)CC1(CS)CC1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)CC1(CS)CC1
Temperature: 20.5 °C
Reaction time: 3 h

Procedure:
To a 3 L flask, a solution of 1-(mercaptomethyl)cyclopropaneacetic acid (204.5 g) in ethanol (1000 ml) was charged. 96% sulfuric acid (22.73 g) was added, and the reaction mixture was stirred for 3 h at 19-22° C. The reaction mixture was concentrated to ¼ of its volume at 50° C. under reduced pressure, and the residue was partitioned between water (1000 ml) and ethyl acetate (200 ml). The organic phase was separated, washed with 10% NaHCO3 (400 ml), and dried for 2 h over anhydrous sodium sulfate. The mixture was filtered and evaporated at 50° C., under reduced pressure, to afford 197.9 g of the crude 1-(mercaptomethyl)cyclopropaneacetic acid ethyl ester, as a slightly colored liquid with a strong, unpleasant odor.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[C:14]3=[CH:15][N:16]([C:18]4[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=4[Cl:25])[N:17]=[C:13]3[CH:12]=[CH:11][N:10]=2)[CH:3]=1.[CH3:26][NH2:27]>CN1C(=O)CCC1>[Cl:24][C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:25])[C:18]=1[N:16]1[CH:15]=[C:14]2[C:9]([NH:8][C:4]3[CH:3]=[C:2]([NH:27][CH3:26])[N:7]=[CH:6][N:5]=3)=[N:10][CH:11]=[CH:12][C:13]2=[N:17]1
Reactant: CN
Reactant: Clc1cc(Nc2nccc3nn(-c4c(Cl)cccc4Cl)cc23)ncn1
Solvent: CN1CCCC1=O
Product: CNc1cc(Nc2nccc3nn(-c4c(Cl)cccc4Cl)cc23)ncn1
Yield: 45.3 %

Procedure:
A solution of (6-chloropyrimidin-4-yl)-[2-(2,6-dichlorophenyl)-2H-pyrazolo[4,3-c]pyridine-4-yl]amine (80 mg, 0.20 mmol) and methylamine (2M in THF, 300 μL, 0.60 mmol) in NMP (2.0 mL) was sealed in a microwave vial, purged with nitrogen and irradiated at 160° C. for 30 minutes in the microwave. Further methylamine (300 μL, 0.20 mmol) was added and the reaction mixture was irradiated at 170° C. for 30 minutes. The resultant mixture was cooled and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (4-5% methanol in DCM) to afford the title compound as a white solid (35.0 mg, 45% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.03 (br s, 1H), 9.14 (s, 1H), 8.21 (s, 1H), 7.91 (d, J=6.3 Hz, 1H), 7.80 (d, J=8.1 Hz, 2H), 7.70 (dd, J=9.0, 7.4 Hz, 1H), 7.23 (br s, 1H), 7.13 (d, J=6.4 Hz, 1H), 2.81 (d, J=4.7 Hz, 3H). LCMS (Method B): RT=2.99 min, m/z: 386 [M+H+].
Reaction SMILES: [O:1]=[C:2]([C@@H:23]([C:25]1[CH:26]=[C:27]([CH3:31])[CH:28]=[CH:29][CH:30]=1)[CH3:24])/[CH:3]=[CH:4]/[C@H:5]1[C@H:12]([O:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][C@H:10]2[C@@H:6]1[CH2:7][C:8](=[O:22])[O:9]2.B(Cl)([C@H]1[C@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1)[C@H]1[C@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1.CC(C)=O.C(=O)([O-])O.[Na+]>C1COCC1>[OH:1][C@@H:2]([C@@H:23]([C:25]1[CH:26]=[C:27]([CH3:31])[CH:28]=[CH:29][CH:30]=1)[CH3:24])/[CH:3]=[CH:4]/[C@H:5]1[C@H:12]([O:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][C@H:10]2[C@@H:6]1[CH2:7][C:8](=[O:22])[O:9]2
Reactant: Cc1cccc([C@@H](C)C(=O)/C=C/[C@@H]2[C@H]3CC(=O)O[C@H]3C[C@H]2OC(=O)c2ccccc2)c1
Agent: C[C@@H]1[C@H]2C[C@@H](C[C@H]1B(Cl)[C@@H]1C[C@@H]3C[C@H]([C@H]1C)C3(C)C)C2(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: Cc1cccc([C@@H](C)[C@H](O)/C=C/[C@@H]2[C@H]3CC(=O)O[C@H]3C[C@H]2OC(=O)c2ccccc2)c1
Yield: 440 %

Procedure:
A solution of enone{(1S,5R,6R,7R)-6-[(1E,4R)-3-oxo-4-(m-tolyl)-1-pentenyl]-7-benzoyloxy-2-oxabicyclo[3.3.0]octan-3-one} (147.0 g) synthesized in Example 3 in THF (1480 mL) was cooled to −40° C., (−)-B-chlorodiisopinocampheylborane (1.7 M hexane solution) (721 mL) was added, and the mixture was stirred under ice-cooling for 20 hr. Acetone (183 mL) was added and the mixture was stirred for 3 hr. Aqueous sodium hydrogen carbonate was added, and the mixture was extracted with t-butyl methyl ether. The extract was dried over magnesium sulfate, and concentrated under reduced pressure to give a crude title compound (649.9 g).
Reaction SMILES: C(N1C2C=CC=C(N)C=2C(C)=N1)C1C=CC=CC=1.[CH3:19][C:20]1[C:28]2[C:27]([NH2:29])=[CH:26][CH:25]=[CH:24][C:23]=2[N:22]([CH2:30][C:31]2[CH:32]=[N:33][C:34]([CH3:37])=[CH:35][CH:36]=2)[N:21]=1.[CH3:38][N:39]1[CH2:44][CH2:43][N:42]([CH2:45][CH2:46][O:47][C:48]2[CH:53]=[CH:52][N:51]3[C:54]([C:57]([O-])=[O:58])=[CH:55][N:56]=[C:50]3[CH:49]=2)[CH2:41][CH2:40]1.[Li+]>>[CH3:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[NH:29][C:57]([C:54]2[N:51]3[CH:52]=[CH:53][C:48]([O:47][CH2:46][CH2:45][N:42]4[CH2:43][CH2:44][N:39]([CH3:38])[CH2:40][CH2:41]4)=[CH:49][C:50]3=[N:56][CH:55]=2)=[O:58])[N:22]([CH2:30][C:31]2[CH:32]=[N:33][C:34]([CH3:37])=[CH:35][CH:36]=2)[N:21]=1
Reactant: CN1CCN(CCOc2ccn3c(C(=O)[O-])cnc3c2)CC1
Reactant: Cc1ccc(Cn2nc(C)c3c(N)cccc32)cn1
Agent: Cc1nn(Cc2ccccc2)c2cccc(N)c12
Agent: [Li+]
Product: Cc1ccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(OCCN6CCN(C)CC6)ccn45)cccc32)cn1

Procedure:
Prepared according to the method of Example 80, replacing 7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid and 1-benzyl-3-methyl-1H-indazol-4-amine with 3-methyl-1-((6-methylpyridin-3-yl)methyl)-1H-indazol-4-amine and lithium 7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate, respectively. MS (APCI) m/z=539 (M+H).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[CH2:7]([NH2:11])[CH2:8][CH2:9][CH3:10]>>[CH2:7]([N:11]([CH2:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])[CH2:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])[CH2:8][CH2:9][CH3:10]
Reactant: CCCCN
Reactant: C=CC(=O)OC
Product: CCCCN(CCC(=O)OC)CCC(=O)OC
Reaction time: 20 h
Yield: 99.6 %

Procedure:
At 20 to 30° C., 12.9 g of methyl acrylate was added to 5.00 g of n-butylamine. The resulting mixture was allowed to stand for 20 hours, followed by concentration under reduced pressure, whereby 16.7 g of N-butylbis[2-(methoxycarbonyl)ethyl]amine was obtained (at a quantitative yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH:9]([NH:12][CH2:13][CH2:14][OH:15])[CH2:8][CH2:7][C:6]=2[C:16]=1[O:17][CH3:18].Cl[C:20]1[N:25]=[C:24]([NH:26][C@@H:27]2[C@@H:32]3[CH2:33][C@@H:29]([CH:30]=[CH:31]3)[C@@H:28]2[C:34]([NH2:36])=[O:35])[C:23]([Cl:37])=[CH:22][N:21]=1>>[Cl:37][C:23]1[C:24]([NH:26][CH:27]2[CH:32]3[CH2:33][CH:29]([CH:30]=[CH:31]3)[CH:28]2[C:34]([NH2:36])=[O:35])=[N:25][C:20]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[CH2:11][CH2:10][CH:9]([NH:12][CH2:13][CH2:14][OH:15])[CH2:8][CH2:7][C:6]=3[C:16]=2[O:17][CH3:18])=[N:21][CH:22]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Reactant: COc1c(N)ccc2c1CCC(NCCO)CC2
Product: COc1c(Nc2ncc(Cl)c(NC3C4C=CC(C4)C3C(N)=O)n2)ccc2c1CCC(NCCO)CC2
Yield: 16.5 %

Procedure:
In an analogous manner to Experimental 691, part c, 2-(2-Amino-1-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-ylamino)-ethanol and (1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide were combined to yield 1S,2S,3R,4R)-3-{5-Chloro-2-[7-(2-hydroxy-ethylamino)-1-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino]-pyrimidin-4-ylamino}-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (32.98 mg, 16.5% yield) as a beige foam. HPLC purification separated the final product into its corresponding enantiomers. 1H-NMR (CDCl3) δ 8.18 (d, J=8.2 Hz, 1H), 7.89 (s, 1H), 7.40 (s, 1H), 6.96 (d, J=8.3 Hz, 1H), 6.86 (d, J=8.3 Hz, 1H), 6.37 (m, 1H), 6.31 (m, 1H), 5.63 (br s, 1H), 5.40 (br s, 1H), 4.36 (m, 1H), 3.72 (s, 3H), 3.63 (m, 2H), 3.23 (m, 1H), 3.06 (s, 1H), 2.94 (s, 1H), 2.85-2.52 (m, 5H). LC/MS (ESI+)=513 (M+H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=[O:59])[C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[C:28]4[C:23](=[CH:24][CH:25]=[C:26]([C:29]5[N:33]=[CH:32][N:31](C(C6C=CC=CC=6)(C6C=CC=CC=6)C6C=CC=CC=6)[N:30]=5)[CH:27]=4)[N:22](C4CCCCO4)[N:21]=3)[CH:15]=2)=[O:12])=[CH:2]1>Cl.O1CCOCC1>[NH:31]1[CH:32]=[N:33][C:29]([C:26]2[CH:27]=[C:28]3[C:23](=[CH:24][CH:25]=2)[NH:22][N:21]=[C:20]3[C:16]2[CH:15]=[C:14]([NH:13][C:11](=[O:12])[C:10]([C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][CH:2]=3)=[O:59])[CH:19]=[CH:18][CH:17]=2)=[N:30]1
Reactant: O=C(Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1)C(=O)c1c[nH]c2ccccc12
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Nc1cccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)c1)C(=O)c1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 16 %

Procedure:
2-Indol-3-yl-2-oxo-N-(3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)](1H-indazol-3-yl)}phenyl)acetamide was dissolved in 4 mL of 4.0 N HCl in 1,4-dioxane and the reaction was stirred at room temperature overnight. After neutralization with aqueous NaHCO3, the reaction mixture was evaporated to dryness and purified by preparative HPLC. (0.018 g, 16% yield over 2 steps): 1H NMR (CD3OD) δ 11.93 (s, 1H), 10.53 (s, 1H), 8.95 (s, 1H), 8.86 (s, 1H), 8.55 (s, 1H), 8.52 (s, 1H), 8.41 (dd, 1H), 8.14 (dd, 1H), 8.0 (d, 1H), 7.89 (d, 1H), 7.75 (d, 1H), 7.64–7.54 (m, 2H), 7.34–7.30 (m, 2H); ES-MS (m/z) 449.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-])=O)[N:4]([CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[N:3]=1.[Cl-].[NH4+]>C(O)C.[Fe]>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH2:11])[N:4]([CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[N:3]=1
Reactant: O=[N+]([O-])c1cccc2c1c(Cl)nn2CCN1CCCC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: Nc1cccc2c1c(Cl)nn2CCN1CCCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.9 %

Procedure:
A mixture of 3-Chloro-4-nitro-1-(2-pyrrolidin-1-yl-ethyl)-1H-indazole (0.40 g, 1.4 mmol), iron powder (0.76 g, 14 mmol), and ammonium chloride (37 mg, 0.68 mmol) in 80% Ethanol was heated to reflux for 3 hours, cooled to room temperature and concentrated under reduced pressure. The residue was stirred in triethylamine/ethyl acetate (1/4, 20 mL) for 15 minutes, filtered through a plug of silica gel which was rinsed with triethylamine/ethyl acetate (1/4), and concentrated to provide the title compound (0.30 g, 84%). 1H NMR (300 MHz, DMSO-d6) ppm 1.62 (m, 4H), 2.44 (m, 4H), 2.81 (t, 2H, J=6.78), 4.31 (t, 2H, J=6.78), 5.62 (s, 2H), 6.23 (d, 1H, J=7.46), 6.73 (d, 1H, J=8.48), 7.09 (m, 1H); MS (DCI/NH3) m/z 265 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CN(C=O)C.[NH2:19][C:20]1[N:24]([CH2:25][CH3:26])[N:23]=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+]>CC([O-])=O.CC([O-])=O.[Cu+2].C(O)(=O)C.O>[CH2:25]([N:24]1[C:20]([NH:19][C:2]2[C:3](=[CH:7][CH:8]=[C:9]([C:11]([OH:13])=[O:12])[CH:10]=2)[C:4]([OH:6])=[O:5])=[CH:21][CH:22]=[N:23]1)[CH3:26]
Reactant: CCn1nccc1N
Reactant: O=C(O)c1ccc(C(=O)O)c(Br)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: CCn1nccc1Nc1cc(C(=O)O)ccc1C(=O)O
Temperature: 135 °C
Yield: 45.4 %

Procedure:
A mixture of 2-bromoterephthalic acid (4.8 g, 0.02 mol), DMF (50 ml), Cu(OAc)2 (0.2 g), 5-amino-1-ethylpyrazole (2.22 g, 0.02 mol) and K2CO3 (2.71 g, 0.02 mol) was heated at 135° C. overnight, then at reflux overnight. The reaction mixture was poured into water, acidified with acetic acid and the precipitate which formed was collected by filtration and dried to afford 2.5 g of N-(1-ethylpyrazol-5-yl)-4-carboxyanthranilic acid.
Reaction SMILES: CCCC[CH:5]1[C:10](=[O:11])[N:9]([C:12]2[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=2)[N:8]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:6]1=[O:7].[C:25](Cl)(=[O:27])[CH3:26]>C(O)(=O)C>[C:19]1([N:8]2[C:6](=[O:7])[CH2:5][C:10](=[O:11])[N:9]2[C:12]2[CH:17]=[CH:16][C:15]([O:18][C:25](=[O:27])[CH3:26])=[CH:14][CH:13]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(=O)Cl
Reactant: CCCCC1C(=O)N(c2ccccc2)N(c2ccc(O)cc2)C1=O
Solvent: CC(=O)O
Product: CC(=O)Oc1ccc(N2C(=O)CC(=O)N2c2ccccc2)cc1

Procedure:
First, 1-Phenyl-2-(4'-acetyloxyphenyl)-3,5-pyrazolidinedione was prepared as follows. Oxyphenbutazone (1.00 g, 3.1 mmole) was suspended in 4 ml of glacial acetic acid and allowed to react with 2 ml of acetyl chloride at room temperature overnight. The solution was concentrated in vacuo at 86° C. to give a white residue (mp 126°-130° C.). The residue was crystallized from chloroformheptane (6:50) with cooling to give 0.81 g (mp 132°-134° C., 71% yield, lit., R. Pfester and F. Hafliger, Helvetica Chemica Acta, 40, 395 (1957) mp 135°-137° C. from methanol) of 1-phenyl-2-(4'acetyloxyphenyl)-3,5-pyrazolidinedione.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:39])=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]3([CH2:34][OH:35])[CH2:33][CH2:32]3)[NH:17][CH:16]2[C:36](O)=[O:37])[CH:12]=[CH:13][CH:14]=1.CC1(C)[O:45][C@@H:44]([CH2:46][CH2:47][NH2:48])[CH2:43][O:42]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.O1CCCC1>[OH:45][C@H:44]([CH2:43][OH:42])[CH2:46][CH2:47][NH:48][C:36]([CH:16]1[CH:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=2[F:39])[C:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]2([CH2:34][OH:35])[CH2:32][CH2:33]2)[NH:17]1)=[O:37]
Reactant: N#CC1(c2ccc(Cl)cc2F)C(CC2(CO)CC2)NC(C(=O)O)C1c1cccc(Cl)c1F
Reactant: CC1(C)OC[C@H](CCN)O1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: N#CC1(c2ccc(Cl)cc2F)C(CC2(CO)CC2)NC(C(=O)NCC[C@H](O)CO)C1c1cccc(Cl)c1F
Yield: 39.4 %

Procedure:
In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-hydroxymethyl-cyclopropylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 114c (0.4 g, 0.67 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.29 g, 2 mmol), HATU (0.46 g, 1.2 mmol) and iPr2NEt (0.58 mL, 3.4 mmol) in CH2Cl2 at room temperature for 20 h, then reacted with aqueous HCl solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-hydroxymethyl-cyclopropylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.15 g, 40%).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)[CH2:9]1)=O)(C)(C)C.[ClH:25].O1CCOCC1>>[ClH:25].[ClH:25].[C:19]1([CH:16]2[CH2:15][CH2:14][N:13]([CH:10]3[CH2:11][CH2:12][NH:8][CH2:9]3)[CH2:18][CH2:17]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC(c3ccccc3)CC2)C1
Agent: Cl
Solvent: C1COCCO1
Product: c1ccc(C2CCN(C3CCNC3)CC2)cc1
Yield: 61 %

Procedure:
A solution of 3-(4-phenyl-piperidin-1-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (preparation #5) (4.3 g, 13.1 mmol) in 4N HCl/dioxane (7 mL) was stirred at ambient temperature for about 16 h. The precipitate was collected by filtration, rinsed with Et2O (20 mL) and dried in vacuo to afford 4-phenyl-1-pyrrolidin-3-yl-piperidine dihydrochloride (2.4 g, 61%) as a hygroscopic beige solid that was used in subsequent reaction without further purification. RP-HPLC (Table 1, Method d) Rt 1.67 min; m/z: (M+H)+ 231.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:9]=NC(C)=N[CH:13]=2)[CH2:4][C@H:3]1[C:15]1[NH:16][C:17](=[O:30])[C:18]2[CH:23]=[N:22][N:21]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:19]=2[N:20]=1.C([BH3-])#N.[Na+].[CH3:35][O:36][C:37]1[CH:44]=CC(C=O)=C[CH:38]=1>>[CH3:35][O:36][C:37]1[CH:44]=[CH:13][C:8]([CH2:7][N:5]2[CH2:6][C@@H:2]([CH3:1])[C@H:3]([C:15]3[NH:16][C:17](=[O:30])[C:18]4[CH:23]=[N:22][N:21]([CH:24]5[CH2:29][CH2:28][O:27][CH2:26][CH2:25]5)[C:19]=4[N:20]=3)[CH2:4]2)=[CH:9][CH:38]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Cc1ncc(CN2C[C@@H](C)[C@H](c3nc4c(cnn4C4CCOCC4)c(=O)[nH]3)C2)cn1
Agent: [BH3-]C#N
Agent: [Na+]
Product: COc1ccc(CN2C[C@@H](C)[C@H](c3nc4c(cnn4C4CCOCC4)c(=O)[nH]3)C2)cc1

Procedure:
Following the procedure for the preparation of 6-{(3S,4S)-4-methyl-1-[(2-methylpyrimidin-5-yl)methyl]pyrrolidin-3-yl}-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting sodium cyanoborohydride and 4-methoxybenzaldehyde provided the title compound. 400 MHz 1H NMR (CDCl3) δ 8.01 (s, 1H), 7.29 (d, J=8.3 Hz, 2H), 6.87 (d, J=8.7 Hz, 2H), 4.82-4.08 (m, 1H), 4.13-4.08 (m, 2H), 3.84-3.75 (m, 4H), 3.61-3.51 (m, 3H), 3.35 (t, J=8.7 Hz, 1H), 2.97 (d, J=9.9 Hz, 1H), 2.82-2.80 (m, 1H), 2.53-2.49 (m, 1H), 2.42-2.30 (m, 3H), 1.95-1.82 (m, 3H), 1.18 (d, J=7.1 Hz, 3H).
Reaction SMILES: Cl.[N:2]1([CH2:8][CH2:9][N:10]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25][C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[C@@H:11]([C:13]([OH:15])=[O:14])[CH3:12])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.C(Cl)CCl.CN1CCOCC1.ON1C2C=CC=CC=2N=N1.[O:54]1[CH2:59][CH2:58][CH2:57][CH2:56][CH:55]1ON>CN(C=O)C>[N:2]1([CH2:8][CH2:9][N:10]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25][C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[C@@H:11]([C:13]([O:15][CH:55]2[CH2:56][CH2:57][CH2:58][CH2:59][O:54]2)=[O:14])[CH3:12])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1
Reactant: NOC1CCCCO1
Reactant: Cc1ccc(Sc2ccc(S(=O)(=O)N(CCN3CCOCC3)[C@H](C)C(=O)O)cc2)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1ccc(Sc2ccc(S(=O)(=O)N(CCN3CCOCC3)[C@H](C)C(=O)OC3CCCCO3)cc2)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 36.2 %

Procedure:
To the solution of N-[2-(4-morpholinyl)ethyl]-N-[[4-[(4-methylphenyl)thio]phenyl]sulfonyl]-D-alanine, monohydrochloride from Example 4d (3.61 g, 7.20 mmol) in dry DMF was added EDC (2.57 g, 13.4 mmol), 4-methylmorpholine (2.96 mL, 26.96 mmol), and N-hydroxybenzotriazole (1.81 g, 13.4 mmol) at zero degrees C. After stirring for 45 minutes at zero degrees C., O-tetrahydro-2H-pyran-2-yl-hydroxylamine (1.88 g, 16.0 mmol) was added and the solution was left stirring at room temperature overnight. The reaction was concentrated and partitioned between water and ethyl acetate. The combined ethyl acetate layers were washed with water and brine, dried with MgSO4, and concentrated to a white solid (2.4 g). Chromatographic purification (40% acetone in hexane) afforded N-[2-(4-morpholinyl)ethyl]-N-[[4-[(4-methylphenyl)thio]phenyl]sulfonyl]-D-alanine, tetrahydro-2H-pyran-2-yl ester, (1.43 g, 34.6% yield) as a white solid. The proton NMR and MIR were consistent for N-[2-(4-morpholinyl)ethyl]-N-[[4-[(4-methylphenyl)thio]phenyl]sulfonyl]-D-alanine, tetrahydro-2H-pyran-2-yl ester. Anal. calc'd for C27H37N3O6S2 : C, 57.53; H, 6.62; N, 7.45; S, 11.38. Found: C, 57.43; H, 6.80; N, 7.34; S,11.34.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[CH:3]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[O:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][CH:6]1[NH:15][S:16]([CH2:19][CH2:20][C:21]([O-:23])=[O:22])(=[O:18])=[O:17].[OH-].[Na+].Cl>CO>[F:31][C:2]([F:1])([F:30])[CH:3]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[O:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][CH:6]1[NH:15][S:16]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])(=[O:18])=[O:17]
Reactant: O=C([O-])CCS(=O)(=O)NC1C=Nc2ccccc2N1OC(c1cccnc1)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCS(=O)(=O)NC1C=Nc2ccccc2N1OC(c1cccnc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.8 %

Procedure:
Compound 295 (380 mg, 0.680 mmol) obtained in Example 289 was dissolved in methanol (3.00 mL). To this, a 2.00 mol/L aqueous sodium hydroxide solution (3.00 mL) was added and the mixture was stirred at room temperature for 1 hour. By addition of a 2.00 mol/L aqueous hydrochloric acid solution to neutralize the reaction mixture, the reaction was stopped. Then, extraction with ethyl acetate was performed, followed by washing with brine and drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=1/0 to 14/1) to give Compound 296 (308 mg, yield: 37%).
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6](=O)[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=3)=[CH:8][O:9][C:4]=2[C:3]=1[OH:20].C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C.O1CCOCC1.C(Cl)Cl.[Pd]>[OH:1][C:2]1[CH:19]=[CH:18][C:5]2[CH2:6][CH:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=3)[CH2:8][O:9][C:4]=2[C:3]=1[OH:20]
Reactant: Cc1cccc(-c2coc3c(O)c(O)ccc3c2=O)c1
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: Cc1cccc(C2COc3c(ccc(O)c3O)C2)c1

Procedure:
7,8-Dihydroxy-3-(3-methylphenyl)-4H-1-benzopyran-4-one (100 mg), dissolved in a mixture of ethanol/dioxan 2:1 (75 ml), is hydrogenated for 24 h at room temperature over palladium 10% on active charcoal (50 mg) in the presence of p-toluenesulphonic acid monohydrate (50 mg). After filtration of the catalyst, the filtrate is evaporated under vacuum to a minimum volume, then diluted with water (75 ml) and neutralized to pH 7 by addition of a saturated solution of NaHCO3. An oil is obtained which is extracted with ethyl acetate. The extract is dried over magnsium sulphate and evaporated under vacuum to yield an amorphous solid which is dissolved in methylene chloride and eluted on a silica gel column. After evaporation of the main fraction, one obtains 3,4-dihydro-7,8-dihydroxy-3-(3-methylphenyl)-2H-1-benzopyran, m.p. 95°-96°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](Cl)=[N:8][OH:9].[C:12]([C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1)#[CH:13].N>>[F:1][C:2]1[CH:11]=[C:6]([C:7]2[CH:13]=[C:12]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[O:9][N:8]=2)[CH:5]=[N:4][CH:3]=1
Reactant: ON=C(Cl)c1cncc(F)c1
Reactant: C#Cc1ccc(C#N)cc1
Agent: N
Product: N#Cc1ccc(-c2cc(-c3cncc(F)c3)no2)cc1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 28B (88 mg, 0.5 mmol) and 4-ethynylbenzonitrile (Aldrich, 64 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) 87.60 (s, 1H), 7.92 (dt, J=8.6, 1.7 Hz, 2H), 8.11 (dt, J=8.6, 1.7 Hz, 2H), 8.19 (ddd, J=9.2, 2.7, 1.7 Hz, 1H), 8.62 (d, J=2.7 Hz, 1H), 8.98 (t, J=1.4 Hz, 1H) ppm; MS (DCI/NH3) m/z 266 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[CH:26]=[CH:25][C:7]([CH2:8][C:9]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:10]=2[O:11][CH2:12][C:13](N2CC2C)=[O:14])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH2:27]([Mg]Br)[CH2:28][CH3:29].O>C1COCC1>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:10]=2[O:11][CH2:12][C:13](=[O:14])[CH2:27][CH2:28][CH3:29])=[CH:25][CH:26]=1)([CH3:2])[CH3:3]
Reactant: CCC[Mg]Br
Reactant: Cc1cc(C)c(Cc2ccc(C(C)C)cc2)c(OCC(=O)N2CC2C)c1
Solvent: C1CCOC1
Solvent: O
Product: CCCC(=O)COc1cc(C)cc(C)c1Cc1ccc(C(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a solution of 1-((2-(4-isopropylbenzyl)-3,5-dimethylphenoxy)acetyl)-2-methylaziridine obtained in Reference Example 166 (1.0 g, 2.85 mmol) in THF (20 mL) was added dropwise n-propylmagnesium bromide (a 2.0 M THF solution, 1.43 mL, 2.85 mmol) under argon atmosphere with ice-cooling, and the mixture was stirred for 30 minutes. The reaction solution was warmed to room temperature, water was added thereto, which was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4) to obtain 920 mg (yield 95%) of the title compound. Oily matter.