Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[O:15][CH2:14][C@H:13]([CH2:16]OS(C4C=CC(Br)=CC=4)(=O)=O)[O:12][C:8]3=2)[N:3]=1.[NH:28]1[CH2:31][CH:30]([CH2:32][C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[NH:35][CH:34]=2)[CH2:29]1>>[NH:35]1[C:36]2[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:33]([CH2:32][CH:30]2[CH2:29][N:28]([CH2:16][CH:13]3[O:12][C:8]4=[C:9]5[C:4](=[CH:5][CH:6]=[C:7]4[O:15][CH2:14]3)[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]5)[CH2:31]2)=[CH:34]1
Reactant: c1ccc2c(CC3CNC3)c[nH]c2c1
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](COS(=O)(=O)c1ccc(Br)cc1)O3
Product: Cc1ccc2c3c(ccc2n1)OCC(CN1CC(Cc2c[nH]c4ccccc24)C1)O3

Procedure:
This compound was prepared as described for Example 1, using (2R)-4-bromobenzenesulfonic acid 8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl ester (0.26 g, 0.59 mmol), 3-azetidin-3-ylmethyl-1H-indole (0.11 g, 0.59 mmol), to afford 0.035 g of the (S)-enantiomer of the title compound as a light brown foam. 1H NMR (500 MHz, DMSO-D6): δ 2.74-2.82 (m, 3H), 2.90 (d, J=7.5 Hz, 2H), 2.96 (t, J=6.6 Hz, 2H), 3.03 (t, J=6.6 Hz, 2H), 3.51 (t, J=6.8 Hz, 2H), 3.42 (t, J=6.8 Hz, 2H), 4.08 (m, 1H), 4.30-4.32 (m, 1H), 4.37 (m, 1H), 6.94-6.97 (m, 1H), 7.04-7.08 (m, 2H), 7.30-7.36 (m, 3H), 7.42 (d, J=9.1Hz, 1H), 7.48 (d, J=7.9 Hz, 1H), 8.19 (d, J=8.5 Hz, 1H).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH:25]=[O:26])[CH2:23][CH2:22][C:21]([C:27]([NH:29][C:30]4[CH:35]=[CH:34][C:33]([C@@H:36]([OH:43])[C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=5)=[CH:32][CH:31]=4)=[O:28])=[CH:20][C:19]=3[CH:44]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:53])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH:25]=[O:26])[CH2:23][CH2:22][C:21]([C:27]([NH:29][C:30]4[CH:31]=[CH:32][C:33]([C@@H:36]([OH:43])[C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][N+:38]=5[O-:53])=[CH:34][CH:35]=4)=[O:28])=[CH:20][C:19]=3[CH:44]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc([C@@H](O)c4ccccn4)cc2)CCN3C=O)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc([C@@H](O)c4cccc[n+]4[O-])cc2)CCN3C=O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.1 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-formyl-N-[4-[(R)-hydroxy(2-pyridyl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (130 mg) in dichloromethane (20 ml) was added 3-chloroperbenzoic acid (70%, 65 mg) at 0° C., and the mixture was stirred at room temperature for 18 hours. To the-reaction solution was added sodium thiosulfate solution, and the mixture was stirred for several minutes, and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethanol:ethyl acetate 1:4) and recrystallized from ethyl acetate-diisopropylether to give 7-[4-(2-butoxyethoxy)phenyl]-1-formyl-N-[4-[(R)-hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 78) (68.2 mg) as pale yellow crystals.
Reaction SMILES: C(OCC)C.[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>O1CCCC1>[C:14]([O:16][CH2:17][CH3:18])(=[O:15])[CH:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[OH:13]
Reactant: CCOC(=O)C(=O)c1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)C(O)c1ccccc1

Procedure:
According to JP-A-11-193271, ethyl benzoylformate and cyclohexylmagnesium bromide are condensed to give ethyl 2-cyclohexyl-2-hydroxy-2-phenylacetate, which is hydrolyzed to give 2-cyclohexyl-2-hydroxy-2-phenylacetic acid. In this condensation reaction, diethyl ether having a boiling point of 35° C. is used in an amount of about 12-fold volume relative to ethyl benzoylformate, manipulation of dangerous reaction using the boiling point of diethyl ether is required and the yield is as low as 53.3%. In an attempt to improve this method into an industrially safe one, the present inventors used tetrahydrofuran instead of diethyl ether as a solvent and reproduced the reaction. As a result, there occurred reduction due to Grignard reagent to produce ethyl mandelate as a by-product, as well as addition of the Grignard reagent to ester bond. The proportion of the starting material that became a by-product was 42% and the yield of the objective product was as low as 58%. After hydrolysis of the obtained crude ethyl 2-cyclohexyl-2-hydroxy-2-phenylacetate, it was subjected to recrystallization and the like to increase the purity but the yield from ethyl benzoylformate of 2-cyclohexyl-2-hydroxy-2-phenylacetic acid did not exceed 43%.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([N:12]2[CH2:17][CH2:16][NH:15][C:14](=[O:18])[CH2:13]2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:9][CH:10]([N:12]2[CH2:17][CH2:16][NH:15][C:14](=[O:18])[CH2:13]2)[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CC(N2CCNC(=O)C2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CN(C2CNC2)CCN1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
A mixture of 3-(3-oxopiperazin-1-yl)azetidine-1-carboxylic acid tert-butyl ester (400 mg, 1.57 mmol) and TFA (3 mL) in DCM (6 mL) was stirred at room temperature for 2 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording 4-Azetidin-3-ylpiperazin-2-one as a white solid (227 mg, 93%). 1H NMR (CDCl3, 300 MHz): δ 6.08 (s, 1H); 3.63-3.56 (m, 3H); 3.42-3.35 (m, 3H); 3.31 (t, J=6.74 Hz, 1H); 3.03 (s, 2H); 2.59-2.51 (m, 2H).
Reaction SMILES: [CH2:1]([Sn:19](Cl)([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[N-:57]=[N+:58]=[N-:59].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([Sn:19]([N:57]=[N+:58]=[N-:59])([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC[Sn](Cl)(CCCCCCCCCCCCCCCCCC)CCCCCCCCCCCCCCCCCC
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCC[Sn](CCCCCCCCCCCCCCCCCC)(CCCCCCCCCCCCCCCCCC)N=[N+]=[N-]
Temperature: 120 °C
Reaction time: 6 h
Yield: 68.5 %

Procedure:
A mixture of 20.0 g of trioctadecyltin chloride, 3.0 g of sodium azide and 40 ml of toluene was stirred at 120° C. for 6 hours. After cooling, 100 ml of toluene was added to the reaction mixture. The toluene layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give 13.8 g of trioctadecyltin azide.
Reaction SMILES: [CH:1]([N:4]([CH:8]([CH3:10])[CH3:9])[C:5](Cl)=[S:6])([CH3:3])[CH3:2].[OH:11][N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22]>>[O:22]=[C:13]1[C:14]2[C:15](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16](=[O:17])[N:12]1[O:11][C:5](=[S:6])[N:4]([CH:8]([CH3:10])[CH3:9])[CH:1]([CH3:3])[CH3:2]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)N(C(=S)Cl)C(C)C
Product: CC(C)N(C(=S)ON1C(=O)c2ccccc2C1=O)C(C)C

Procedure:
This compound was prepared in analogy to example 8 starting from 32.35 g (0.18 mol) of diisopropyl-thiocarbamoyl chloride (prepared as described in (Chem. Ber., 101, (1968), 113) and N-hydroxyphthalimide. Yield 21.44 g of white crystals after recrystallization from hexane, mp. 73-75° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]N1C(=O)CCC1=O.O>C(Cl)Cl>[Br:32][CH2:11][CH2:10][CH2:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(CCCO)c1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: Cc1cccc(CCCBr)c1C
Yield: 83.8 %

Procedure:
Compound 49-2 (1.83 g) was dissolved in methylene chloride (40 ml), triphenylphosphine (3.25 g) and N-bromosuccinimide (2.18 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (2.12 g) as a colorless oil.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[CH:17]=[C:16]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([N:27]3[CH2:30][CH2:29][CH2:28]3)=[O:26])=[CH:21][CH:20]=2)[C:10]2[CH2:11][C:12]([CH3:15])([CH3:14])[O:13][C:9]=2[CH:8]=1)=[O:6]>CO>[N:27]1([C:25]([C:22]2[CH:21]=[CH:20][C:19]([O:18][C:16]3[C:10]4[CH2:11][C:12]([CH3:15])([CH3:14])[O:13][C:9]=4[CH:8]=[C:7]([C:5]([OH:6])=[O:4])[CH:17]=3)=[CH:24][CH:23]=2)=[O:26])[CH2:30][CH2:29][CH2:28]1
Reactant: COC(=O)c1cc(Oc2ccc(C(=O)N3CCC3)cc2)c2c(c1)OC(C)(C)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)Cc2c(Oc3ccc(C(=O)N4CCC4)cc3)cc(C(=O)O)cc2O1
Temperature: 60 °C
Yield: 77.5 %

Procedure:
Aqueous NaOH (3 N, 2.1 mL, 6.3 mmol) was added to a solution of 4-[4-(azetidine-1-carbonyl)-phenoxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (35b) (802 mg, 2.10 mmol) in 10 mL CH3OH. The mixture was heated to 60° C. for 3 hr, concentrated, diluted with H2O (60 mL) and acidified with 1N aqueous HCl to pH˜1. The aqueous phase was extracted with CH2Cl2 (60 mL), dried with MgSO4 and concentrated to give a white solid (598 mg, 74% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.99 (s, 1 H) 7.67 (d, J=7.33 Hz, 2 H) 7.02-7.10 (m, 3 H) 6.99 (s, 1 H) 4.32 (s, 2 H) 4.03 (s, 2 H) 2.89 (s, 2 H) 2.21-2.30 (m, 2 H) 1.42 (s, 6 H); LCMS for C21H21NO5 m/z 468.00 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[CH2:21][CH2:20][CH2:19][C@H:18]3[CH2:22][OH:23])[CH2:13][CH2:12]2)=[O:10])=[C:4]([CH3:24])[CH:3]=1.[F:25][C:26]([F:38])([F:37])[O:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>>[CH3:24][C:4]1[CH:3]=[C:2]([C:31]2[CH:30]=[CH:29][C:28]([O:27][C:26]([F:25])([F:37])[F:38])=[CH:33][CH:32]=2)[CH:7]=[C:6]([CH3:8])[C:5]=1[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH2:21][CH2:20][CH2:19][C@H:18]2[CH2:22][OH:23])[CH2:13][CH2:12]1)=[O:10]
Reactant: Cc1cc(Br)cc(C)c1C(=O)N1CCC(N2CCC[C@H]2CO)CC1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Product: Cc1cc(-c2ccc(OC(F)(F)F)cc2)cc(C)c1C(=O)N1CCC(N2CCC[C@H]2CO)CC1

Procedure:
In analogy to the procedure described for example 1, (4-bromo-2,6-dimethyl-phenyl)-[4-((S)-2-hydroxymethyl-pyrrolidin-1-yl)-piperidin-1-yl]-methanone (intermediate 4) was reacted with 4-trifluoromethoxy-phenyl boronic acid to give the title compound as light yellow solid. MS: 477.1 (MH+).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2([C:31]([OH:33])=O)[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[OH:34][NH:35]C(C1CCNCC1)=O>>[OH:34][NH:35][C:31]([C:15]1([S:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:7][CH:8]=2)(=[O:14])=[O:13])[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:17][CH2:16]1)=[O:33]
Reactant: O=C(NO)C1CCNCC1
Reactant: CCCCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(CCCOc3ccccc3)CC2)cc1
Product: CCCCOc1ccc(S(=O)(=O)C2(C(=O)NO)CCN(CCCOc3ccccc3)CC2)cc1

Procedure:
Starting from 4-(4-n-butoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)-piperidine-4-carboxylic acid (700 mg, 1.4 mmol) and following the procedure as outlined in example 83, 300 mg of 4-(4-n-butoxy-benzenesulfonyl)-1-3-phenoxy-propyl)-piperidine-4-carboxylic acid hydroxyamide was isolated as an off white solid. Yield 43%; mp 84° C.; MS: 491.5 (M+H)+; 1H NMR (300 MHz, DMSO-d6): δ0.9 (t, 3H), 1.5 (m, 2H), 1.8 (m, 2H), 2.18 (m, 2H), 2,3 (m, 2H), 2.58 (m, 2H), 2.6-2.73 (m, 2H), 3.2 (m, 2H), 3.40 (m 6H), 3.97 (t, 2H), 6.9-7.7 (m, 9H), 10.7 (bs, 1H), 11.28 (bs, 1H).
Reaction SMILES: C1CO[C:8]23OCC[O:12][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15](/[C:16](=[N:28]/[O:29][CH3:30])/[CH2:17][CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])O1.C=C1C2[C@](C)(CCC(=[O:50])C2)[C@@H]2[C@H]([C@H]3[C@@](CC2)(C)C(=O)CC3)C1>>[CH3:30][O:29]/[N:28]=[C:16]1/[C@@H:15]2[C@@H:25]([C@:23]3([CH3:24])[CH:18]([CH2:17]/1)[CH2:19][C:20](=[O:50])[CH2:21][CH2:22]3)[CH2:26][CH2:27][C@@:4]1([CH3:5])[C@H:6]2[CH2:7][CH2:8][C:3]1=[O:12]
Reactant: CO/N=C1\CC2CCCC[C@]2(C)[C@H]2CC[C@@]3(C)[C@@H](CC45OCCOC43OCCO5)[C@H]12
Reactant: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Product: CO/N=C1\CC2CC(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12
Yield: 55 %

Procedure:
The title compound II-au was prepared in 55% yield from 3,3:17,17-bis(ethylendioxy)-7-(E)-methoxyiminoandrostane by the procedure described above for the preparation of 6-methyleneandrostane-3,17-dione (II-ac, Prepn. 13). The crude product was purified by flash chromatography (SiO2, n-hexane/EtOAc 6/4). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS: δ 3.72 (3H, s), 2.89 (1H, m), 2.63-0.93 (19H, m), 1.12 (3H, s), 0.82 (3H, s).
Reaction SMILES: [N+](C1C=CC(COC(C2N3[C@H](SC=2)C([CH:20]([O:34]C(=O)C)[C:21]2[N:22]=[C:23]4[CH:32]=[N:31][C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[N:24]4[CH:33]=2)(Br)C3=O)=O)=CC=1)([O-])=O.P([O-])([O-])([O-])=O>[Pd].C1COCC1>[CH:33]1[N:24]2[C:25]3[C:30]([N:31]=[CH:32][C:23]2=[N:22][C:21]=1[CH:20]=[O:34])=[CH:29][CH:28]=[CH:27][CH:26]=3
Reactant: CC(=O)OC(c1cn2c(cnc3ccccc32)n1)C1(Br)C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CS[C@@H]21
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Product: O=Cc1cn2c(cnc3ccccc32)n1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
(5R, 6RS)-6-((RS)-Acetoxy imidazo[1,2-a]quinoxalin-2-ylmethyl)-6-bromo-7-oxo-4-thia-1-azabicyclo [3.2.0]hept-2-ene-2-carboxylic acid p-nitrobenzyl ester (951 mg) and 10% Pd—C (50% wet, 477 mg) were added to a mixture of THF (48 mL) and 0.5 mol/L phosphate buffer (pH 6.5, 48 mL). The mixture was hydrogenated at 400 kPa at room temperature for 4 h. The reaction solution was filtered and Pd—C was washed with water and n-butanol. The reaction mixture was cooled to 0° C. and 1 N NaOH was added to adjust the ph to 8.5. The aqueous layer was separated and then the organic layer was extracted with water. The combined aqueous layer was concentrated to 57 g and applied to Diaion HP-21 resin (60 mL, Mitsubishi Kasei Co. Ltd.) column chromatography. After adsorbing, the column was eluted with water and then 5, 10, 15 and 20% acetonitrile:water solution (each 60 mL). The combined fractions were concentrated under high vacuum at 35° C. and lyophilized to give the title compound as a yellow amorphous solid, yield 148 mg (26.1%), mp 300° C. (dec).
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[C@H:29]1[CH2:34][CH2:33][C@H:32]([O:35][CH2:36][C:37](=[O:39])[CH3:38])[CH2:31][CH2:30]1.[CH3:40][Mg]Br.O1CCCC1>O1CCCC1.[Cl-].[NH4+]>[OH:39][C:37]([CH3:40])([CH3:38])[CH2:36][O:35][C@H:32]1[CH2:31][CH2:30][C@H:29]([N:3]2[C:2](=[O:1])[C:7]([CH2:8][C:9]3[CH:14]=[CH:13][C:12]([C:15]4[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=4)=[CH:11][CH:10]=3)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]3[N:26]=[CH:27][N:28]=[C:4]23)[CH2:34][CH2:33]1
Reactant: C[Mg]Br
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)=O)CC2)c2ncnn12
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4′-({5-oxo-4-[trans-4-(2-oxopropoxy)cyclohexyl]-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (251 mg) in tetrahydrofuran (3 mL) was added 1 M methylmagnesium bromide-tetrahydrofuran solution (1 mL), and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with saturated aqueous ammonium chloride solution, 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, and the residue was purified by basic silica gel chromatography [eluent: hexane/ethyl acetate=70/30→40/60 (volume ratio)] to give the title compound as a colorless amorphous compound (237 mg, 91%).
Reaction SMILES: [C:1]1([CH3:25])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH:14]2[CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:17][NH:16][CH2:15]2)[CH2:9][CH2:8]1.CCN(C(C)C)C(C)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[C:50](O)(=[O:57])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>C(Cl)Cl>[C:50]([N:16]1[CH2:17][CH:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:14]([CH2:13][N:10]2[CH2:11][CH2:12][CH:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[CH3:25])[CH2:8][CH2:9]2)[CH2:15]1)(=[O:57])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: Cc1ccccc1C1CCN(CC2CNCC2c2ccccc2)CC1
Reactant: O=C(O)c1ccccc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccccc1C1CCN(CC2CN(C(=O)c3ccccc3)CC2c2ccccc2)CC1

Procedure:
The title compound was prepared from 3-(SR)-(4-(2-tolyl)-piperidin-1-ylmethyl)-4-(SR)-phenylpyrrolidine (Step A), 0.014 mL of DIEA, 12.5 mg of BOP-Cl and 5 mg of benzoic acid in 0.5 mL of CH2Cl2 using a procedure analogous to that described in Example 63 to provide the title compound. RF : 0.45 (5% MeOH in CH2Cl2). 1H NMR (300 MHz, CDCl3): δ 1.4-4.5 (m, 20H), 7.05-7.6 (m, 14H). Mass Spectrum (CI): 439.4 (M+H).
Reaction SMILES: O1C=CC=C1C[NH:7][C:8]1[C:9](=[CH:13][C:14]([S:25](=[O:28])(=[O:27])[NH2:26])=[C:15]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)[CH:16]=1)[C:10]([OH:12])=[O:11].[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([NH:36][NH:7][C:8]1[C:9](=[CH:13][C:14]([S:25](=[O:27])(=[O:28])[NH2:26])=[C:15]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)[CH:16]=1)[C:10]([OH:12])=[O:11])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: NCc1ccccc1
Reactant: NS(=O)(=O)c1cc(C(=O)O)c(NCc2ccco2)cc1Oc1cccc(Cl)c1
Product: NS(=O)(=O)c1cc(C(=O)O)c(NNCc2ccccc2)cc1Oc1cccc(Cl)c1

Procedure:
45.5 g of the carboxylic acid prepared in Example 9 (b) (0.1 mol) were reacted with 100 ml of benzylamine as in Example 9 (c), and the reaction product was purified by recrystallization from ethanol.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[CH:6]=[CH:5]2.[F:17][C:18]([F:30])([F:29])[O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[CH2:13]([CH:12]([CH2:15][CH3:16])[CH2:11][N:7]1[C:8]2[C:4](=[CH:3][C:2]([C:23]3[CH:22]=[CH:21][C:20]([O:19][C:18]([F:17])([F:29])[F:30])=[CH:25][CH:24]=3)=[CH:10][CH:9]=2)[CH:5]=[CH:6]1)[CH3:14]
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: CCC(CC)Cn1ccc2cc(Br)ccc21
Product: CCC(CC)Cn1ccc2cc(-c3ccc(OC(F)(F)F)cc3)ccc21

Procedure:
The title compound was prepared from 5-bromo-1-(2-ethylbutyl)-1H-indole and 4-(trifluoromethoxy)phenylboronic acid in substantially the same manner, as described in Step 2 of Example 25. The product was obtained as an oil. Mass spectrum (APCI, [M+H]+) m/z 362. 1HNMR (300 MHz, DMSO-d6): δ 7.82 (s, 1H), 7.77 (d, 2H, J=8.56 Hz), 7.51 (d, 1H, J=8.50 Hz), 7.44-7.39 (m, 4H), 6.49 (d, 1H, J=3.12 Hz), 4.07 (d, 2H, J=7.32 Hz), 1.80 (hep, 1H), 1.24 (p, 4H), and 0.85 ppm (t, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[C:7]1(=O)[O:12][C:10](=[O:11])[C:9]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:8]12.O>CN(C)C=O>[NH:4]1[CH:5]=[CH:6][C:2]([N:1]2[C:10](=[O:11])[C:9]3[C:8](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:7]2=[O:12])=[N:3]1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Nc1cc[nH]n1
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1c1cc[nH]n1
Temperature: 125 °C
Reaction time: 24 h
Yield: 72.9 %

Procedure:
To a stirred mixture of 3-aminopyrazole (5.00 g, 60.2 mmol) dissolved in N,N-dimethylformamide (75 mL) was added phthalic anhydride (8.91 g, 60.2 mmol). After addition was complete, the mixture was stirred at 125° C. for 24 h. Upon cooling to 25° C., water (100 mL) was added, which resulted in precipitation. The white suspension was cooled (−5° C.) and stirred for 30 min. Subsequent filtration, washing with water, and suction drying afforded 2-(1H-pyrazol-3-yl)-isoindole-1,3-dione (9.36 g, 73.0%) as a white solid: LR-ES-MS m/z calculated for C11H7N3O2 [M]+ 213, observed [M+H]+ 214.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].C(N(CC)CC)C.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>C(Cl)Cl>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([S:36]([NH:3][CH:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]([O:7][C@@H:8]2[CH:13]3[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]3)[CH2:9]2)=[O:6])(=[O:38])=[O:37])=[CH:32][CH:31]=1
Reactant: NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O[C@H]1CN2CCC1CC2)C(NS(=O)(=O)c1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.7 %

Procedure:
To a solution of (R)-quinuclidin-3-yl 2-amino-2-phenylacetate dihydrochloride (I25) (150 mg, 0.45 mmol) in DCM (5 ml) and triethylamine (190 ul, 1.35 mmol), was added 4-chlorobenzene-1-sulfonyl chloride (114 mg, 0.54 mmol). The reaction was stirred at RT for 3 hours, and then the solvent was evaporated. The crude was taken up with EtOAc and washed with water, brine and then with K2CO3. The organic phase was dried over Na2SO4, filtered and evaporated to dryness to obtain (R)-quinuclidin-3-yl 2-(4-chlorophenylsulfonamido)-2-phenylacetate (62 mg; 32% yield), which was used as such in the next step.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[NH2:14][NH2:15]>C(O)C>[C:9]([O:8][C:6](=[O:7])[NH:5][CH2:4][C:3]([NH:14][NH2:15])=[O:2])([CH3:12])([CH3:11])[CH3:10]
Reactant: COC(=O)CNC(=O)OC(C)(C)C
Reactant: NN
Solvent: CCO
Product: CC(C)(C)OC(=O)NCC(=O)NN
Temperature: 60 °C
Reaction time: 5.5 h
Yield: 75.9 %

Procedure:
The title compound was prepared essentially in accordance with the procedures of Tetrahedron Letters, Vol 36, No. 37 P6591-6594 as set forth herein. Under a nitrogen atmosphere in a round bottom flask, tert-butoxycarbonylamino-acetic acid methyl ester (2.0 mL, 13.5 mmol) is dissolved in absolute ethanol (50 mL) and anhydrous hydrazine (0.45 mL, 14.3 mmol) is added. The resulting mixture is heated in an oil bath at 60° C. for 3 hours then 80° C. for 5.5 hours. The reaction mixture is evaporated and the residue partitioned between water (50 mL) and dichloromethane (50 mL). The aqueous layer is extracted with dichloromethane (2×10 mL). The combined dichloromethane extracts are washed with water (2×30 mL). The dichloromethane layer is dried over magnesium sulfate and evaporated to give a solid that is triturated with diethyl ether to give hydrazinocarbonylmethyl-carbamic acid tert-butyl ester (1.94 g, 76% yield).