Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:10][CH2:11][CH3:12])(=O)C.O.O1[CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH2:11]([OH:10])/[CH:12]=[CH:15]/[CH2:16][CH2:17][CH2:18][CH2:15][CH2:16][CH2:17][CH2:18][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCOC(C)=O
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Product: CCCCCCCCCCC/C=C/CO
Reaction time: 1 h

Procedure:
To dodecyl aldehyde (5.0 g) dissolved in methylene chloride was added (carbomethoxymethylene)triphenylphosphorane (9.1 g), and the mixture was stirred for 2 hours. The reaction mixture was concentrated and subjected to chromatography on a silica gel column with eluent systems of n-hexane-ethyl acetate (from 100:1 to 20:1) to give the methyl ester of trans-2-tetradecenoic acid (5.2 g). To the methyl ester dissolved in tetrahydrofuran was added lithium aluminium hydride (0.9 g) under ice-cooling, and the mixture was stirred for 1 hour. The reaction mixture was distributed into ethyl acetate and water, and the ethyl acetate layer was dried, concentrated and subjected to chromatography on a silica gel column with an eluent system of n-hexane-ethyl acetate (50:1) to give trans-2-tetradecenol (3.2 g). To the solution of the trans-2-tridecenol in methylene chloride were added pyridinium chlorochromate (3.5 g) and Celite (5.0 g), and the mixture was stirred. The reaction mixture was filtered and concentrated to give trans-2-tetradecenal (2.3 g).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[N:18]=[C:19](/[CH:22]=[CH:23]/[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:20][CH:21]=2)=[CH:11][CH:10]=1)(=O)=O.[N:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[NH:32][CH:31]=1>>[C:24]1(/[CH:23]=[CH:22]/[C:19]2[O:20][CH:21]=[C:17]([CH2:16][O:15][C:12]3[CH:11]=[CH:10][C:9]([CH2:8][CH2:7][CH2:6][N:30]4[C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=5[N:32]=[CH:31]4)=[CH:14][CH:13]=3)[N:18]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: c1ccc2[nH]cnc2c1
Reactant: CS(=O)(=O)OCCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Product: C(=C/c1nc(COc2ccc(CCCn3cnc4ccccc43)cc2)co1)\c1ccccc1
Yield: 49 %

Procedure:
In substantially the same manner as in Working Example 25, 3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl methanesulfonate was allowed to react with benzimidazole to give 1-[3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl]benzimidazole. The yield was 49%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 115-117° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]([C@@H:13]([CH2:17][CH3:18])[C:14]([OH:16])=O)[C:9]2=[O:12])=[CH:4][CH:3]=1.C([O:23][C:24](=[O:42])[CH2:25][C@H:26]([NH2:41])[CH:27]([OH:40])[CH2:28][O:29][C:30]1[C:35]([F:36])=[C:34]([F:37])[CH:33]=[C:32]([F:38])[C:31]=1[F:39])(C)(C)C>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]([C@@H:13]([CH2:17][CH3:18])[C:14]([NH:41][C@H:26]([C:27](=[O:40])[CH2:28][O:29][C:30]3[C:35]([F:36])=[C:34]([F:37])[CH:33]=[C:32]([F:38])[C:31]=3[F:39])[CH2:25][C:24]([OH:42])=[O:23])=[O:16])[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: CC[C@@H](C(=O)O)n1ccc2ccc(Cl)cc2c1=O
Reactant: CC(C)(C)OC(=O)C[C@H](N)C(O)COc1c(F)c(F)cc(F)c1F
Product: CC[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)COc1c(F)c(F)cc(F)c1F)n1ccc2ccc(Cl)cc2c1=O

Procedure:
This compound was prepared using (S)-2-(7-chloro-1-oxo-1H-isoquinolin-2-yl)-butyric acid (prepared as described in methods A-E) and (3S)-3-amino-4-hydroxy-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic acid tert-butyl ester (prepared as described in methods N-P) using procedures similar to those described in methods F, G and E. The product was isolated as a white solid (94% last step). IR (solid) 1639.3, 1618.8, 1593.2, 1516.4, 1485.6, 1219.4, 1168.1, 1106.7, 932.6, 830.2 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 0.80 (3H, t), 1.94-2.12 (2H, m), 2.55-2.61 (1H, m), 2.74-2.80 (1H, m), 4.58-4.63 (1H, m), 5.12-5.76 (3H, m), 6.70 (1H, d), 7.51-7.78 (4H, m), 8.11-8.12 (1H, m), 8.60-8.95 (1H, 2×d) ppm; 13C NMR (100 MHz, d6-DMSO) δ 23.8, 24.5, 32.9, 34.6, 47.8, 52.8, 55.2, 58.2, 58.9, 74.4, 75.6, 100.1, 100.3, 100.5, 101.0, 101.2, 104.6, 126.5, 136.6, 131.3, 131.4, 133.0, 135.6, 135.6, 139.0, 139.1, 141.4, 141.6, 144.6, 144.8, 144.9, 147.1, 147.1, 160.7, 170.4, 172.0, 173.0, 202.2; 19F NMR (376 MHz, d6-DMSO) (proton decoupled) δ −140.57, −140.60, −140.64, −140.66, −141.00, −141.03, −141.06, −141.09, −156.78, −156.80, −156.84, −156.86, −156.96, −156.98, 157.02, −157.04; MS ES(+) 543.20 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([OH:14])[C:11]([CH3:15])=[C:10]([CH3:16])[N:9]=2)=[N:6][CH:7]=1.C(N(CC)CC)C.[Cl:24][CH2:25][C:26](Cl)=[O:27]>C1COCC1>[Cl:24][CH2:25][C:26]([NH:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[N:13]=[C:12]([OH:14])[C:11]([CH3:15])=[C:10]([CH3:16])[N:9]=2)=[CH:4][CH:3]=1)=[O:27]
Reactant: O=C(Cl)CCl
Reactant: Cc1nc(-c2ccc(N)cn2)nc(O)c1C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nc(-c2ccc(NC(=O)CCl)cn2)nc(O)c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of compound of example 48 (0.04 g, 0.185 mmol) in THF (4 mL), at 0° C. was added triethylamine (0.028 g, 0.277 mmol) and chloroacetylchloride (0.0313 g, 0.277 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. THF was removed under reduced pressure, and reaction mixture was quenched with water and extracted with ethyl acetate (3×10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography using silica gel and 1% methanol in chloroform as an eluent to obtain the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=[N:22]O)[C:16]=2[F:24])[N:12]([S:25]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)(=[O:27])=[O:26])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O.O>O1CCCC1>[C:1]([O:5][C:6](=[O:34])[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[N:22])[C:16]=2[F:24])[N:12]([S:25]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)(=[O:26])=[O:27])[CH:11]=1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(Cc1cc(-c2cccc(C=NO)c2F)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CN(Cc1cc(-c2cccc(C#N)c2F)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 8 h
Yield: 73.4 %

Procedure:
To a solution (5 mL) of tert-butyl{[5-{2-fluoro-3-[(hydroxyimino)methyl]phenyl}-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (150 mg) in tetrahydrofuran were added triethylamine (93 mg) and methanesulfonyl chloride (84 mg) at room temperature. The reaction mixture was stirred at 70° C. for 8 hr, and cooled to room temperature. Water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=8:1→3:1) to give the title compound as a pale-yellow oil (yield 106 mg, 73%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16](Br)=[CH:17][CH:18]=3)[N:13]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:12]=2[CH3:28])[CH:5]=1.[N:30]1[CH:35]=[CH:34][CH:33]=[C:32](B(O)O)[CH:31]=1>>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([C:32]4[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=4)=[CH:17][CH:18]=3)[N:13]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:12]=2[CH3:28])[CH:5]=1
Reactant: COC(=O)c1cccc(Sc2c(C)n(Cc3ccccc3)c3cc(Br)ccc23)c1
Reactant: OB(O)c1cccnc1
Product: COC(=O)c1cccc(Sc2c(C)n(Cc3ccccc3)c3cc(-c4cccnc4)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 11, Step 1, using the following starting materials: 3-(1-benzyl-6-bromo-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester and 3-pyridineboronic acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5](=[CH:11][C:12]([O:14][CH3:15])=[O:13])[CH2:6][C:7]([O:9][CH3:10])=[O:8].O>CO.[Pd]>[CH3:10][O:9][C:7](=[O:8])[CH2:6][CH:5]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH2:4][C:3]([O:2][CH3:1])=[O:16]
Reactant: COC(=O)C=C(CC(=O)OC)CC(=O)OC
Agent: [Pd]
Solvent: O
Solvent: CO
Product: COC(=O)CC(CC(=O)OC)CC(=O)OC

Procedure:
3-(methoxycarbonylmethylene)glutaric acid dimethylester (89 g, 267 mmol) in methanol (200 ml) was shaken with (10% palladium on charcoal: 50% water) (9 g) under an atmosphere of hydrogen gas (3.5 bar) for (30 h). The solution was filtered through kieselguhr and concentrated in vacuo to give 3-(methoxycarbonylmethyl)glutaric acid dimethylester as an oil, yield (84.9 g, 94%).
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8]3[NH:9][CH:10]([C:16]4[N:17]=[C:18]([NH:21][C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])[S:19][CH:20]=4)[CH2:11][C:12](=[O:15])[C:13]=3[O:14][C:6]=2[CH:5]=[CH:4][C:3]=1[O:27][CH3:28]>C1COCC1.O=[Mn]=O>[OH:15][C:12]1[CH:11]=[C:10]([C:16]2[N:17]=[C:18]([NH:21][C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])[S:19][CH:20]=2)[N:9]=[C:8]2[C:7]3[C:2]([Br:1])=[C:3]([O:27][CH3:28])[CH:4]=[CH:5][C:6]=3[O:14][C:13]=12
Reactant: COc1ccc2oc3c(c2c1Br)NC(c1csc(NC(=O)C(C)C)n1)CC3=O
Agent: O=[Mn]=O
Solvent: C1CCOC1
Product: COc1ccc2oc3c(O)cc(-c4csc(NC(=O)C(C)C)n4)nc3c2c1Br
Temperature: 110 °C
Yield: 65.8 %

Procedure:
A mixture of 16B (1.1 g, 2.3 mmol) and MnO2 (6 g) in THF (20 mL) was heated to 110° C. and reacted overnight. TLC monitored the reaction. After the reaction completed, the reaction mixture was filtered and the filtrate was concentrated to give 16C (0.7 g, 63.9% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][C:23]([OH:25])=O)[N:21]=1)=[CH:5]2.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][C:23]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:25])[N:21]=1)=[CH:5]2
Reactant: O=C(O)C[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)=N1
Reactant: C1COCCN1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(C[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)=N1)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.9 %

Procedure:
The compound (50 mg, 0.13 mmol) prepared in Example 27 was dissolved in N,N-dimethylformamide (2 ml). Morpholine (17 mg, 0.20 mmol), EDC (43 mg, 0.23 mmol) and HOBT (36 mg, 0.26 mmol) were added thereto, and the mixture was stirred for 8 h at room temperature. After completion of the reaction, saturated sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and concentrated. The residue was purified by column chromatography to give the title compound (22 mg, Yield 37%).
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([CH3:11])=[CH:6][C:5]=1[NH:12]C(=O)C>CO>[Br:3][C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([CH3:11])=[CH:6][C:5]=1[NH2:12]
Reactant: CC(=O)Nc1cc(C)c(C)cc1Br
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(N)c(Br)cc1C
Temperature: 80 °C
Reaction time: 18 h

Procedure:
Potassium hydroxide (15.9 g, 284 mmol) was added to a stirred solution of N-2-bromo-4,5-dimethylphenyl)acetamide (1-7) (17.2 g, 71.0 mmol) in methanol (350 mL) at ambient temperature. After stirring at approximately 80° C. for 18 h, the reaction mixture was cooled and the organic volatiles removed in vacuo. The remaining aqueous phase was diluted with additional water (65 mL) and the resultant solid product was filtered, washed with water and dried in vacuo to afford 1-8 as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][CH:12]([C:16]([OH:18])=O)[CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C.[F:34][C:35]([F:39])([F:38])[CH2:36][NH2:37]>ClCCl.C(#N)C.CN(C=O)C>[F:34][C:35]([F:39])([F:38])[CH2:36][NH:37][C:16]([CH:12]1[CH2:11][CH:10]2[CH:14]([CH2:15][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]2)[CH2:13]1)=[O:18]
Reactant: CC(C)(C)OC(=O)N1CC2CC(C(=O)O)CC2C1
Reactant: NCC(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC2CC(C(=O)NCC(F)(F)F)CC2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 275.3 %

Procedure:
To a solution of 3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]octane-7-carboxylic acid (0.100 g, 0.392 mmol) in dichloromethane (5 mL) were added oxalyl chloride (0.250 g, 1.96 mmol) and a drop of DMF, and the mixture was stirred at ambient temperature for 2 h. The solvent was evaporated and the residue (acid chloride) was vacuum dried. To the acid chloride in acetonitrile (5 mL) were added DIPEA (0.200 mL, 1.15 mmol) and 2,2,2-trifluoroethylamine (0.080 g, 0.081 mmol), and the mixture was stirred overnight at ambient temperature. The solvent was evaporated, and the crude amide was purified by silica gel column chromatography, eluting with an ethyl acetate in hexane gradient, to obtain 0.075 g of N-(2,2,2-trifluoroethyl)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]octane-7-carboxamide (mixture of cis and trans isomers) as an oil. The majority of this sample (0.065 g, 0.19 mmol) was dissolved in dichloromethane (3 mL), combined with TFA (2 mL), and stirred at ambient temperature for 1 h. The solvent was evaporated, and the residue was purified by HPLC, using acetonitrile and 0.05% aqueous TFA as the mobile phase, to obtain 0.050 g of N-(2,2,2-trifluoroethyl)-3-azabicyclo[3.3.0]octane-7-carboxamide trifluoroacetate (as a mixture of cis and trans isomers), as an oil (1H NMR (CD3OD, 300 MHz): δ 3.93 (q, J=9.28 Hz, 2H), 3.38-3.21 (m, 4H), 3.02-2.80 (m, 3H), 2.32-2.22 (m, 2H), 1.74-1.62 (m, 2H); MS (m/z): 238 (M+1)). This material exhibited a Ki value at human α4β2 of 261 nM and did not pass HIS for α7.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][C:10](=[O:16])[NH:11]2.[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[N:27]1[CH2:34][C@H:33]2[NH:35][CH2:36][C@@H:28]1[CH2:29][CH:30]=[CH:31][CH2:32]2.C(O)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[OH:1][CH:2]([CH2:3][N:35]1[CH2:36][CH:28]2[N:27]([C:18]3[CH:19]=[CH:20][C:21]4[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:17]=3)[CH2:34][CH:33]1[CH2:32][CH:31]=[CH:30][CH2:29]2)[CH2:4][O:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][C:10](=[O:16])[NH:11]2
Reactant: O=C1CCc2c(cccc2OC[C@@H]2CO2)N1
Reactant: C1=CC[C@H]2CN[C@@H](C1)CN2c1ccc2ccccc2c1
Agent: C1=C\C[C@H]2CN[C@@H](C/1)CN2c1ccc2ccccc2c1
Solvent: CCO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCc2c(cccc2OCC(O)CN2CC3CC=CCC2CN3c2ccc3ccccc3c2)N1
Temperature: 95 °C

Procedure:
(S)-5-Oxiranylmethoxy-3,4-dihydro-1H-quinolin-2-one (25 mg, 0.114 mmol) and Z-(1S,6S)-7-naphthalen-2-yl-7,9-diaza-bicyclo[4.2.2]dec-3-ene (30 mg, 0.114 mmol) were placed in a μW tube with ethanol (2 ml), CH2Cl2 (2 mL), DIPEA (100 μL, 0.576 mmol) and heated to 95° C. for 900 sec. The solvent was evaporated from the reaction mixture and the residue was purified via flash chromatography (gradient 10% to 100% Ethyl acetate/heptane) to yield the title compound as a residue.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:15][CH:14]3[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:11]([CH2:12][CH2:13]3)[CH:10]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:5][CH:4]=1.[CH2:36](Br)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[CH2:36]([O:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:15][CH:14]3[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:11]([CH2:12][CH2:13]3)[CH:10]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:5][CH:4]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC(C)(C)OC(=O)N1C2CCC1C(OCc1ccc3ccccc3c1)C(c1ccc(CO)cc1)C2
Reactant: BrCc1ccccc1
Product: CC(C)(C)OC(=O)N1C2CCC1C(OCc1ccc3ccccc3c1)C(c1ccc(COCc3ccccc3)cc1)C2

Procedure:
In an analogous manner to that described in Example 1(g), by alkylating tert-butyl (1RS,2RS,3RS,5SR)-3-(4-hydroxymethyl-phenyl)-2-(naphthalen-2-ylmethoxy)-8-aza-bicyclo[3.2.1]octane-8-carboxylate [Example 86(eee)] with benzyl bromide there was obtained tert-butyl (1RS,2RS,3RS,5SR)-3-(4-benzyloxymethyl-phenyl)-2-(naphthalen-2-ylmethoxy)-8-aza-bicyclo[3.2.1 ]octane-8-carboxylate, which was used as the crude product in the reaction for BOC cleavage.
Reaction SMILES: F[C:2]1[C:7](F)=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15]([CH2:32]CS(C)(=O)=O)C(=O)C2C=C(C(F)(F)F)N=C(C(F)(F)F)C=2)=[C:4]([O:38][CH3:39])[CH:3]=1.[CH:40]1(OC2C=CC=CC=2B(O)O)C[CH2:41]1>>[CH:39]1([O:38][C:4]2[CH:3]=[CH:2][CH:7]=[CH:6][C:5]=2[C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[NH:15][CH3:32])[CH2:41][CH2:40]1
Reactant: OB(O)c1ccccc1OC1CC1
Reactant: COc1cc(F)c(F)cc1-c1ccncc1N(CCS(C)(=O)=O)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Product: CNc1cnccc1-c1ccccc1OC1CC1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
The title compound was prepared in analogy to example 72, from (4-iodo-pyridin-3-yl)-methyl-amine (example 36, intermediate b) and 2-cyclopropoxyphenylboronic acid after stirring at 90° C. for 18 hours. The compound was purified by silica gel chromatography on a 20 g column using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Light yellow oil (94%). MS (ESI): m/z=241.134 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25]4[CH:29]=[CH:28][N:27]([CH2:30][C:31]([O:33]C)=[O:32])[N:26]=4)[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:35]=[C:36]([C:39]([F:42])([F:41])[F:40])[CH:37]=[CH:38][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>C(#N)C.O.[Cl-].[Na+].O.Cl.CCOC(C)=O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25]4[CH:29]=[CH:28][N:27]([CH2:30][C:31]([OH:33])=[O:32])[N:26]=4)[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:35]=[C:36]([C:39]([F:42])([F:40])[F:41])[CH:37]=[CH:38][C:16]=3[CH2:15]2)(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)Cn1ccc(-c2ccc3c(c2)N(S(=O)(=O)c2ccc(C(C)(C)C)cc2)Cc2ccc(C(F)(F)F)nc2N3)n1
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(-c4ccn(CC(=O)O)n4)cc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To methyl-{3-[6-[(4-tert-butylphenyl)sulfonyl]-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-8-yl]-1H-pyrazol-1-yl}acetate (Example 433, 3.5 mg, 0.006 mmol) in acetonitrile (0.5 mL) and water (0.5 mL) was added LiOH (2 mg, 0.005 mmol). After stirring overnight at rt, the reaction was diluted with 2 mL of brine, 0.5 mL of 2N HCl, and 20 mL of EtOAc. The organic layer was separated, washed with water and brine, dried with Na2SO4, and concentrated to give the title compound. 1H NMR (500 MHz, (CD3OD): δ 8.05 (brd s, 1H), 7.91 (brd s, 1H), 7.63 (s, 1H), 7.61 (d, 1H), 7.44 (d, 1H), 7.18 (d, 2H), 7.06 (d, 1H), 7.02 (d, 1H), 6.96 (d, 2H), 5.02 (s, 2H), 1.23 (s, 9H). LCMS: m/e 586.2 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:9]=[N:10][CH:11]=1)=O)C.[BH4-].[Na+]>C(O)C>[N:10]1[CH:11]=[C:6]([CH2:4][OH:3])[CH:7]=[C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:9]=1
Reactant: CCOC(=O)c1cncc(-c2cccnc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1cncc(-c2cccnc2)c1
Temperature: 50 °C
Yield: 34 %

Procedure:
To a solution of [3,3′]bipyridinyl-5-carboxylic acid ethyl ester (1 eq) in ethanol was added sodium borohydride (2 eq) at room temperature. The reaction mixture was heated in a 50° C. oil bath for 60 minutes and then quenched by addition of H2O. Once the reaction solvent was removed in vacuo, a solution of the residue in dichloromethane was washed with NaCl(sat), dried over sodium sulfate, filtered and concentrated. The crude solid was purified by flash chromatography using a solvent gradient of 95% DCM, 5% MeOH and 0.1% TEA to yield [3,3′]bipyridinyl-5-yl-methanol (34%). MH+(187).
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10]Br)([CH3:4])([CH3:3])[CH3:2].[CH3:13][NH2:14].C1COCC1>>[C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10][NH:14][CH3:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: CN
Solvent: C1CCOC1
Product: CNCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 86 %

Procedure:
(3-Bromo-propyl)-carbamic acid tert-butyl ester (11.2 g, 47.0 mmol) was combined with 2.0 M Methylamine in THF (100 mL, 200 mmol) and was stirred at room temperature for 4 h. After this period, a precipitate formed in the solution. The solution was filtered and concentrated under reduced pressure to yield 7.58 g (86%) of (3-methylamino-propyl)-carbamic acid tert-butyl ester as a clear oil. [M+H]+ 188.94.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][N:5]=2)[CH2:3][CH2:2]1.[O-:12][CH2:13][CH3:14].[Na+].C(OCC)C.[Cl-].[NH4+]>C(O)C>[CH:1]1([C:4]2[N:9]=[C:8]([C:10](=[NH:11])[O:12][CH2:13][CH3:14])[CH:7]=[CH:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: N#Cc1ccnc(C2CC2)n1
Reactant: CC[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=N)c1ccnc(C2CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-cyclopropylpyrimidine-4-carbonitrile (20.97 g, 144.5 mmol) in ethanol (100 mL) was added sodium ethoxide (1.8 g, 78.9 mmol of sodium metal in 30 mL of ethanol). The reaction mixture was stirred at room temperature for 30 minutes. Diethyl ether (300 mL) was added to the reaction mixture followed by a saturated aqueous solution of ammonium chloride (50 mL). The mixture was extracted with diethyl ether (100 mL×3). The combined organics were washed with brine (50 mL×2), dried over magnesium sulfate, filtered, concentrated under reduced pressure and dried under high vacuum to afford the title compound. The material was used without further purification. 1H NMR (500 MHz, CDCl3) δ 1.10-1.15 (m, 2H), 1.16-1.22 (m, 2H), 1.43 (t, 3H), 2.32 (tt, 1H), 4.44 (q, 2H), 7.50 (d, 1H), 8.72 (d, 1H).
Reaction SMILES: [C:1]12([C:11]3[C:12]([OH:22])=[CH:13][C:14]4[C:19]([CH:20]=3)=[CH:18][C:17]([Br:21])=[CH:16][CH:15]=4)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>>[C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([Br:21])=[CH:18]4)=[CH:13][C:12]=3[O:22][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: Oc1cc2ccc(Br)cc2cc1C12CC3CC(CC(C3)C1)C2
Reactant: CCCCCCCBr
Product: CCCCCCCOc1cc2ccc(Br)cc2cc1C12CC3CC(CC(C3)C1)C2
Yield: 78.6 %

Procedure:
Following the procedure of Example 8(b), but reacting 3.4 g (9.5 mmol) of 3-(1-adamantyl)-6-bromo-2-naphthol with 2.05 g (11.4 mmol) of 1-bromoheptane, 3.4 g (79%) of 7-(1-adamantyl)-6-heptyloxy-2-bromonaphthalene were obtained.