Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:11]([CH3:37])[C@H:12]([C:16]([N:18]([CH3:36])[C@H:19]([C:32]([O:34]C)=[O:33])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:22]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].Cl>O1CCOCC1.[OH-].[Na+]>[C:1]([N:11]([CH3:37])[C@H:12]([C:16]([N:18]([CH3:36])[C@H:19]([C:32]([OH:34])=[O:33])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([C:28]([CH3:30])([CH3:31])[CH3:29])[CH:22]=1)=[O:17])[CH:13]([CH3:14])[CH3:15])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: COC(=O)[C@H](Cc1ccc(O)c(C(C)(C)C)c1)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)[C@@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(=O)O)N(C)C(=O)OCc1ccccc1
Reaction time: 2 h

Procedure:
To a solution of 1.96 g of Z-N-Me-Val-N-Me-Tyr(3-tBu)-OMe in 1,4-dioxane (40 ml), 2 N NaOH (5 ml) was added at room temperature and the mixture was stirred for 2 hours. The reaction mixture was adjusted to pH 3 with dilute hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine and the organic layer was dried with sodium sulfate. The solvent was distilled off under reduced pressure to give Z-N-Me-Val-N-Me-Tyr(3-tBu)-OH. To a solution of this Z-N-Me-Val-N-Me-Tyr(3-tBu)-OH in THF (20 ml), ethyl chloroformate (0.40 ml) and NMM (0.46 ml) were added under cooling with ice and the mixture was stirred for 15 minutes. Subsequently, ammonia gas was bubbled into the reaction mixture for 5 minutes. The solvent was distilled off under reduced pressure and the precipitating salt was filtered off and washed with ethyl acetate. The solvent was distilled off under reduced pressure and the resulting residue was subjected to silica gel column chromatography (eluting solvent; n-hexane:ethyl acetate=2:3) to give Z-N-Me-Val-N-Me-Tyr(3-tBu)-NH2 in the amount of 1.17 g (61%).
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:41][CH:42]([CH3:44])[CH3:43])[C:22]([NH:24][N:25]([CH2:37][CH:38]([CH3:40])[CH3:39])[S:26]([CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1)(=[O:28])=[O:27])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10].[ClH:45]>CO.O1CCOCC1>[ClH:45].[OH:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:41][CH:42]([CH3:44])[CH3:43])[C:22]([NH:24][N:25]([CH2:37][CH:38]([CH3:39])[CH3:40])[S:26]([CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1)(=[O:27])=[O:28])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:10]
Reactant: CC(C)C[C@@H](C(=O)NN(CC(C)C)S(=O)(=O)CCc1ccccn1)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)S(=O)(=O)CCc1ccccn1)[C@H](C/C=C/c1ccccc1)C(=O)NO
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 0.547 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methyl-2′-[2-(2-pyridyl)ethanesulphonyl]-valerohydrazide in 5 ml of methanol was treated with 4 ml of a 1 M solution of hydrogen chloride in dioxan. The mixture was stirred at room temperature for 3 hours and evaporated. The residue was triturated with diethyl ether to give 0.463 g of (E)-2(R)-[1(S)-(hydroxycarbamoyl)-4-phenyl-3-butenyl]-2′-isobutyl-4-methyl-2′-[2-(2-pyridyl)ethanesulphonyl]valerohydrazide hydrochloride in the form of a white solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:12][C:13]3[N:14]=[C:15]([N:22]4[CH2:27][CH2:26][CH:25]([CH2:28][C:29]([OH:31])=O)[CH2:24][CH2:23]4)[C:16]4[CH:21]=[CH:20][NH:19][C:17]=4[N:18]=3)[CH:8]=2)[NH:3]1.C1C=CC2N(O)N=[N:38]C=2C=1.C(Cl)CCl.N>CN(C=O)C>[O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:12][C:13]3[N:14]=[C:15]([N:22]4[CH2:27][CH2:26][CH:25]([CH2:28][C:29]([NH2:38])=[O:31])[CH2:24][CH2:23]4)[C:16]4[CH:21]=[CH:20][NH:19][C:17]=4[N:18]=3)[CH:8]=2)[NH:3]1
Reactant: O=C(O)CC1CCN(c2nc(Nc3ccc4c(c3)CCC(=O)N4)nc3[nH]ccc23)CC1
Reactant: On1nnc2ccccc21
Agent: N
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: NC(=O)CC1CCN(c2nc(Nc3ccc4c(c3)CCC(=O)N4)nc3[nH]ccc23)CC1
Reaction time: 0.67 h
Yield: 76.9 %

Procedure:
To a solution of 2-(1-(2-(2-oxo-1,2,3,4-tetrahydroquinolin-6-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-yl)acetic acid (26 mg, 0.062 mmol) and HOBt (35 mg, 0.23 mmol) in DMF (2 mL), EDC (40 mg, 0.21 mmol) was added. After being stirred for 40 min, NH3 (0.5 M in dioxane, 1.00 mL, 0.500 mmol) was added. The mixture was stirred for 20 h. It was then purified by HPLC to give the titled compound (20 mg). MS 420.3 (M+H); UV 201.8, 279.8 nm.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[O:7][CH:8]([CH3:9])[C:4]=2[CH:3]=1.[Cl-].[Li+].[CH2:15]([Sn](CCCC)(CCCC)CCCC)[CH:16]=[CH2:17]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:9][CH:8]1[C:4]2[CH:3]=[C:2]([CH2:17][CH:16]=[CH2:15])[CH:12]=[CH:11][C:5]=2[C:6](=[O:10])[O:7]1
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: CC1OC(=O)c2ccc(Br)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: C=CCc1ccc2c(c1)C(C)OC2=O

Procedure:
5-Bromo-3-methyl-2-benzofuran-1(3H)-one (1.00 g, 4.40 mmol) was dissolved in toluene (30 mL) treated with lithium chloride (0.560 g, 13.2 mmol), Pd(Ph3P)4 (0.254 g, 0.220 mmol), and allyl tributylstannane (1.75 g, 5.29 mmol). The reaction mixture was degassed and stirred at reflux under N2 for 3 h. The reaction mixture was poured into water and extracted with ethyl acetate; the organic layer was washed wtih brine 1×, dried and purified by MPLC eluting with 0-10% ethyl acetate/hexanes. to afford the title compound. 1H NMR (500 MHz, D-DMSO, δ in ppm): 7.75 (d, J=8 Hz, 1H), 7.50 (s, 1H), 7.42 (d, J=8 Hz, 1H), 6.00 (m, 1H), 5.66 (q, J=6.5 Hz, 1H), 5.13 (m, 2H), 3.53 (d, J=6.5 Hz, 2H), 1.54 (d, J=7 Hz, 3H).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].C([O-])(O)=O.[Na+].[CH2:15]([N:19]([CH2:34][CH2:35][CH2:36][CH3:37])[C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][CH:24]=[C:25]2[S:30](Cl)(=[O:32])=[O:31])[CH2:16][CH2:17][CH3:18]>O.CC(C)=O>[CH2:15]([N:19]([CH2:34][CH2:35][CH2:36][CH3:37])[C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][CH:24]=[C:25]2[S:30]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5])(=[O:32])=[O:31])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCN(CCCC)c1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: N[C@@H](CC(=O)O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCCCN(CCCC)c1cccc2c(S(=O)(=O)N[C@@H](CC(=O)O)C(=O)O)cccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Two mmoles of aspartic acid and 4 mmoles of NaHCO3 were dissolved in 5 ml of water. A solution containing 1 mmol of 5-dibutylamino-naphthalene-1-sulfonyl chloride (Bansyl chloride, Purchased from TCI) in acetone was slowly added. More acetone was added until the solution was clear. The mixture was stirred overnight at room temperature and protected from light. Acetone was removed by flash evaporation and the remaining water solution was acidified to a of pH=4.5 to 5 by adding 2M citric acid. Then, NaCl was added until saturation and the solution was extracted with three portions of ethyl acetate (20 ml each). Extracts were combined, dried over MgSO4 and the solution was filtered. The solvent was removed and the residue was purified by liquid chromatography on a silica gel. A gradient of 0 to 5% methanol in dichloromethane was used as eluent. Fractions containing the desired product were combined and solvents removed. The residue was triturated in 1:1 ether: petroleum ether. The precipitate was filtered out and dried in vacuum overnight thus affording 5-dibutylamino-naphthalene-1-sulfonyl)-L-aspartic acid (NST705).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[N:15]1[C:19]2=[N:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N:27]([CH2:30][CH3:31])[CH2:28][CH3:29])[C:22]=3[N:18]2[CH2:17][CH:16]1[CH2:32][C:33](OC)=[O:34].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[N:15]1[C:19]2=[N:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N:27]([CH2:30][CH3:31])[CH2:28][CH3:29])[C:22]=3[N:18]2[CH2:17][CH:16]1[CH2:32][CH2:33][OH:34]
Reactant: CCN(CC)c1cccc2nc3n(c12)CC(CC(=O)OC)N3c1ccc(Cl)cc1Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CCN(CC)c1cccc2nc3n(c12)CC(CCO)N3c1ccc(Cl)cc1Cl
Yield: 76.9 %

Procedure:
To a suspension of lithium aluminum hydride (20 mg, 0.54 mmol) in tetrahydrofuran (1.5 mL) was added a solution of methyl [1-(2,4-dichlorophenyl)-5-(diethylamino)-2,3-dihydro-1H-imidazo[1,2-a]benzimidazol-2-yl]acetate (Example 72, 60.0 mg, 0.134 mmol) in tetrahydrofuran (1.5 mL) at 0° C. and the resultant mixture was stirred at 0° C. for 10 min. After sodium sulfate decahydrate (600 mg) was added at 0° C., the resultant mixture was filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 30-60% ethyl acetate/n-hexane gradient mixture to give the title compound as a solid (43.1 mg, 0.103 mmol, 77%). Analytically pure material was obtained by recrystallization from ethyl acetate/n-hexane.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][O:41][C:42]1[CH:43]=[C:44]([CH:60]=[CH:61][CH:62]=1)[CH2:45][N:46]1[CH2:50][CH2:49][N:48]([C@@H:51]([C:55]([CH3:58])([CH3:57])[CH3:56])[C:52](O)=[O:53])[C:47]1=[O:59].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[OH:32][C@H:3]([C@@H:2]([NH:1][C:52](=[O:53])[C@@H:51]([N:48]1[CH2:49][CH2:50][N:46]([CH2:45][C:44]2[CH:60]=[CH:61][CH:62]=[C:42]([O:41][CH3:40])[CH:43]=2)[C:47]1=[O:59])[C:55]([CH3:58])([CH3:57])[CH3:56])[CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1
Reactant: COc1cccc(CN2CCN([C@H](C(=O)O)C(C)(C)C)C2=O)c1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2cccc(OC)c2)C1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.2 %

Procedure:
A solution containing the product from Example 2C (0.025 g, 0.047 mmol) in THF (0.5 mL) was treated with the product from Example 71A (0.020 g, 0.062 mmol), DEPBT (0.021 g, 0.071 mmol), and N,N-diisopropylethylamine (0.041 mL, 0.235 mmol), stirred at 25° C. for 16 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was purified by reversed phase chromatography on a C18 column eluting with a gradient starting with 5-100% acetonitrile in water (0.1% TFA). The product was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic phase was washed brine, dried over MgSO4, filtered and concentrated to give the title compound (0.024 g, 59% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.83 (s, 9 H), 0.89 (s, 9 H), 1.55 (m, 2 H), 2.32 (m, 1 H), 2.80 (m, 6 H), 3.18 (m, 1 H), 3.50 (s, 3 H), 3.65 (m, 1 H), 3.74 (s, 3 H), 3.85 (d, J=9.93 Hz, 1 H), 4.20 (m, 5 H), 4.54 (d, J=7.72 Hz, 1 H), 6.63 (d, J=9.93 Hz, 1 H), 6.85 (m, 3 H), 7.08 (m, 5 H), 7.28 (m, 4 H), 7.48 (d, J=9.56 Hz, 1 H), 7.86 (m, 5 H), 8.63 (d, J=4.78 Hz, 1 H).
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[N:22][CH:21]=[CH:20][N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.[Li+].[OH-].Cl>CO.O>[OH:11][B:9]1[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[N:22][CH:21]=[CH:20][N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]=2[CH:6]([CH2:5][C:4]([OH:24])=[O:3])[O:10]1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3cnccn3)cc(C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(Oc2cnccn2)cc2c1C(CC(=O)O)OB2O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of [1-hydroxy-4-methyl-6-(pyrazin-2-yloxy)-1,3-dihydro-benzo[c][1,2]-oxaborol-3-yl]-acetic acid ethyl ester (0.250 g, 0.762 mmol) in methanol (5 mL) was added a solution of LiOH (0.091 g, 3.81 mmol) in water (4 mL) at 0° C. The resulting mixture was stirred at 0° C. for 3 hours. The reaction mixture was acidified to pH 2 using 6M HCl and extracted with EtOAc. The organic extracts were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (DCM/MeOH/AcOH=20:1:trace) to give pure product as a white powder after lyophilization (0.150 g, 65.6%). mp 156-157° C. 1HNMR (400 MHz, DMSO-d6 δ 9.20 (s, 1H), 8.53 (d, J=1.17 Hz, 1H), 8.35 (d, J=2.64 Hz, 1H), 8.19 (dd, J=2.63, 1.46 Hz, 1H), 7.25 (d, J=2.05 Hz, 1H), 7.10 (d, J=1.46 Hz, 1H), 5.51 (dd, J=9.51, 2.20 Hz, 1H), 3.07 (dd, J=15.52, 2.63 Hz, 1H), 2.28 (s, 3H), 2.13 (dd, 1H). MS (ESI) m/z=301 [M+H]+.
Reaction SMILES: [OH:1][CH:2]([CH:6]([NH:14][C:15](=[O:33])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[N:22]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:23]1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([OH:5])=O.[CH:34]1([NH2:37])[CH2:36][CH2:35]1>>[CH:34]1([NH:37][C:3](=[O:5])[CH:2]([OH:1])[CH:6]([NH:14][C:15](=[O:33])[C:16]2[CH:21]=[CH:20][CH:19]=[N:18][C:17]=2[N:22]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:23]2)[CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:36][CH2:35]1
Reactant: NC1CC1
Reactant: O=C(NC(Cc1ccccc1)C(O)C(=O)O)c1cccnc1-n1ccc(-c2ccccc2)n1
Product: O=C(NC(Cc1ccccc1)C(O)C(=O)NC1CC1)c1cccnc1-n1ccc(-c2ccccc2)n1

Procedure:
The reaction was carried out in analogy to reaction step 1.3 by reacting 2-hydroxy-4-phenyl-3-(2-(3-phenyl-1H-pyrazol-1-yl)nicotinamido)butanoic acid with cyclopropylamine; ESI-MS [M+H]+: 482.2
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH3:12])[C:3]=1[C@H:13]([OH:16])[CH2:14][OH:15].N1C=CC=CC=1.[C:23](Cl)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH3:12])[C:3]=1[C@H:13]([OH:16])[CH2:14][O:15][C:23]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1cc2ccccc2c(Cl)c1[C@H](O)CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc2ccccc2c(Cl)c1[C@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 24 h

Procedure:
A suspension of (S)-1-(1-chloro-3-methylnaphthalen-2-yl)ethane-1,2-diol (6.70 grams, 28.2 mmol) and CH2Cl2 (67 mL) was treated with pyridine (4.78 mL, 59.2 mmol) at 23° C. Trityl chloride (8.28 g, 29.6 mmol) was added and the reaction was stirred for 24 h. The reaction was washed with 1.0 M aq CuSO4 monohydrate (3×50 mL), H2O (2×50 mL), and brine (50 mL). The final organic layer was dried over Na2SO4, filtered, and concentrated. The residue was treated with benzene and purified by flash column chromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to give (S)-1-(1-chloro-3-methylnaphthalen-2-yl)-2-(trityloxy)ethanol. 1H NMR (400 MHz, CDCl3) δ 8.22 (d, J=8.2 Hz, 1H), 7.69 (d, J=8.2 Hz, 1H), 7.53-7.44 (m, 2H), 7.51 (s, 1H), 7.43-7.40 (m, 6H), 7.30-7.20 (m, 9H), 5.93-5.77 (m, broad, 1H), 3.59 (dd, J=9.4, 9.0 Hz, 1H), 3.52 (dd, J=9.4, 5.0 Hz, 1H), 2.85 (d, broad, J=4.3 Hz, 1H), 2.52 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH:3]([NH2:14])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.[C:17]1([S:27](Cl)(=[O:29])=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1>N1C=CC=CC=1.CCOCC>[F:16][C:2]([F:1])([F:15])[CH:3]([NH:14][S:27]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)(=[O:29])=[O:28])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1
Reactant: NC(Cc1c[nH]c2ccccc12)C(F)(F)F
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Solvent: c1ccncc1
Solvent: CCOCC
Product: O=S(=O)(NC(Cc1c[nH]c2ccccc12)C(F)(F)F)c1cccc2ccccc12
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A mixture of 100 mg (0.44 mmol) of 2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethylamine and 99 mg (0.44 mmol) of 1-naphthylsulfonyl chloride in 4 mL of pyridine was warmed at 70° C. After 3 hours, the mixture was cooled and concentrated to afford a thick oily residue. The residue was diluted with ether and washed twice with 10% aqueous acetic acid and brine, dried over sodium sulfate, decanted and concentrated in vacuo. The crude material was crystallized from ether-hexanes to afford 102 mg (55%) as off white needles, MS: m/z 419.3 (M+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH:8]2[CH:13]([OH:14])[CH:12]3[CH2:15][CH2:16][N:9]2[CH2:10][CH2:11]3)[CH:2]=1.[H-].[Na+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:20]1([CH2:19][O:14][CH:13]2[CH:12]3[CH2:11][CH2:10][N:9]([CH2:16][CH2:15]3)[CH:8]2[CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OC1C2CCN(CC2)C1Cc1cccnc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: c1ccc(COC2C3CCN(CC3)C2Cc2cccnc2)cc1

Procedure:
The manner in which 3-(phenylmethoxy and 2-phenylethoxy)-2-(3-pyridylmethyl)-1-azabicyclo[2.2.2]octanes of the present invention are synthesized can vary. For example, pyridine-3-carboxaldehyde and quinuclidin-3-one hydrochloride (commercially available from Aldrich) are reacted together in the presence of methanolic potassium hydroxide as described in Neilsen and Houlihan, Org. React. 16: 1-438 (1968). This aldol condensation product, 2-(3-pyridylmethylene)-1-azabicyclo[2.2.2]octan-3one, is then dissolved in methanol and hydrogenated in the presence of Raney nickel catalyst to afford 2-(3-pyridylmethyl)-1-azabicyclo[2.2.2]octan-3-ol. Treatment of the alcohol with sodium hydride followed by benzyl bromide in a suitable solvent affords the desired product, 3-(phenylmethoxy)-2-(3-pyridylmethyl)-azabicyclo[2.2.2]octane. 3-(2-Phenylethoxy)2-(3-pyridylmethyl)-1-azabicyclo[2.2.2]octane can be synthesized by substituting benzyl bromide with 2-bromoethylbenzene.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.[Br:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:29]=1[C:23]1([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[NH:22][C:21]2=[O:30]>>[Br:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:29]=1[C:23]1([CH2:24][CH2:25][N:26]([C:10](=[O:12])[CH2:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:2]([F:1])([F:14])[F:13])[CH2:27][CH2:28]1)[NH:22][C:21]2=[O:30]
Reactant: O=C(O)Cc1ccccc1C(F)(F)F
Reactant: O=C1NC2(CCNCC2)c2c(Br)cccc21
Product: O=C1NC2(CCN(C(=O)Cc3ccccc3C(F)(F)F)CC2)c2c(Br)cccc21

Procedure:
The title compound was prepared following a procedure analogous to that described in Example 31 using 2-(2-(trifluoromethyl)phenyl)acetic acid and 7-bromospiro[isoindoline-1,4′-piperidin]-3-one. LC-MS Method 2 tR=2.092, min, m/z=469; 1H NMR (CDCl3) 1.35 (d, 1H), 1.43 (d, 1H), 2.72 (m, 1H), 2.90 (m, 2H), 3.40 (t, 1H), 3.80-4.05 (m, 3H), 4.88 (d, 1H), 7.31 (t, 2H), 7.38 (d, 1H), 7.48 (t, 1H), 7.61 (d, 1H), 7.68 (d, 1H), 7.78 (d, 1H), 9.17 (s, 1H).
Reaction SMILES: [O:1]1CCCC1.[CH3:6][C:7]1[CH:12]=[C:11]([NH:13][C:14]2[N:19]=[CH:18][N:17]=[C:16]([NH:20]C(C3CC3)=O)[CH:15]=2)[C:10](=[O:26])[N:9]2[C:27]3([CH2:35][CH2:34][CH2:33][C:32](=O)[CH2:31]3)[NH:28][C:29](=[O:30])[C:8]=12.[OH-].[K+].[BH4-].[Na+]>C(O)C>[NH2:20][C:16]1[N:17]=[CH:18][N:19]=[C:14]([NH:13][C:11]2[C:10](=[O:26])[N:9]3[C:27]4([CH2:31][CH2:32][CH:33]([OH:1])[CH2:34][CH2:35]4)[NH:28][C:29](=[O:30])[C:8]3=[C:7]([CH3:6])[CH:12]=2)[CH:15]=1
Reactant: Cc1cc(Nc2cc(NC(=O)C3CC3)ncn2)c(=O)n2c1C(=O)NC21CCCC(=O)C1
Reactant: C1CCOC1
Agent: [BH4-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(Nc2cc(N)ncn2)c(=O)n2c1C(=O)NC21CCC(O)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A flask containing tetrahydrofuran and ethanol (1:1, 20 mL) was charged with N-(6-((8′-methyl-1′,3,5′-trioxo-1′,5′-dihydro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridin]-6′-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide (5, 0.4 g, 0.9 mmol) and 3 M potassium hydroxide solution (8.0 mL) was added to the above reaction. The reaction was stirred at room temperature for 18 h. After complete hydrolysis, sodium borohydride (0.18 g, 0.4 mmol) was added to the above reaction at room temperature. The reaction mass was stirred for 2 h when TLC showed completion of starting material. The solvents were removed under reduced pressure and crude was dissolved in 10% methanol in dichloromethane and neutralized with 10% citric acid. The organic layer was separated and dried over sodium sulfate, filtered and concentrated to obtain solid. The solid was filtered and washed with methanol (5 mL) and pentane (20 mL) and dried under high vacuum to afford 6′-((6-aminopyrimidin-4-yl)amino)-4-hydroxy-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (Cpd. No. 205) as yellow solid as a mixture of diastereomers. Yield: 0.045 g, 13%; MS (ESI) m/z 357.19 [M+1]+; 1H NMR: (400 MHz, DMSO-d6) δ 9.89 & 8.48 (2 s, 1H each, isomer A & B), 8.59 & 8.57 (2 s, 1H each, isomer A & B), 8.42 (brs, 1H), 8.16 (brs, 1H), 6.52 (brs, 2H), 6.16 (brs, 1H), 5.16 & 4.85 (2 s, 1H each, isomer A & B), 4.22 and 3.73 (2 m, 1H each, isomer A & B), 2.99 & 2.88 (2 m, 2H each, isomer A & B), 2.42 (s, 3H), 1.98-1.11 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]([CH2:25][NH:26][CH3:27])[CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C:19]3=[O:24])[CH2:14][CH2:13]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[F:28][C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31](Cl)=[O:32]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:10][CH2:11][N:12]2[CH2:13][CH2:14][CH:15]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C:19]3=[O:24])[CH2:16][CH2:17]2)[CH2:25][N:26]([CH3:27])[C:31](=[O:32])[C:30]2[CH:34]=[CH:35][CH:36]=[CH:37][C:29]=2[F:28])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(Cl)c1ccccc1F
Reactant: CNC[C@@H](CCN1CCC(N2CCCCC2=O)CC1)c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Product: CN(C[C@@H](CCN1CCC(N2CCCCC2=O)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1F
Reaction time: 0.75 h

Procedure:
To solution of (S)-1′-[3-(3,4-dichloro-phenyl)-4-methylamino-butyl]-[1,4′]bipiperidinyl-2-one (0.3 g) in dichloromethane (7 mL) at 0° C. was added 2-fluorobenzoyl chloride neat. After 45 minutes at ambient temperature, the solution was washed with aqueous sodium bicarbonate, dried and evacuated to an oil which was purified with chromatography, eluting with methanol:dichloromethane (gradient 3:97, 6:94). Concentration to a viscous oil under high vacuum provided the title compound (0.3 g). MS: m/z=534(M+1).