Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([C:13]3([CH2:26][C:27]#[N:28])[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)[CH:12]=2)[CH:5]=[CH:4][N:3]=1.Cl.C(N(CC)CC)C.[CH:37]1([S:40](Cl)(=[O:42])=[O:41])[CH2:39][CH2:38]1>O1CCOCC1.C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([C:13]3([CH2:26][C:27]#[N:28])[CH2:14][CH2:15][N:16]([S:40]([CH:37]4[CH2:39][CH2:38]4)(=[O:42])=[O:41])[CH2:17][CH2:18]3)[CH:12]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: CC(C)(C)OC(=O)N1CCC(CC#N)(n2cc(-c3ccnc(Cl)n3)cn2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: ClCCl
Product: N#CCC1(n2cc(-c3ccnc(Cl)n3)cn2)CCN(S(=O)(=O)C2CC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of tert-butyl 4-(4-(2-chloropyrimidin-4-yl)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate (0.487 g, 1.21 mmol) in 2 mL of dioxane was added 4 M HCl in dioxane (4.0 mL). The reaction was stirred at room temperature for 30 min, then evaporated to dryness. To the resulting crude HCl salt in methylene chloride (9.4 mL) was added triethylamine (0.505 mL, 3.62 mmol) followed by cyclopropanesulfonyl chloride (0.148 mL, 1.45 mmol). The mixture was stirred at room temperature for 30 min, washed with saturated sodium bicarbonate, dried, and evaporated to dryness. The residue was used directly in next step (402 mg, 82%). LCMS (M+H) 407.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[N:9][C:10]([O:12][Si](C)(C)C)=[CH2:11])[CH:5]=[CH:6][CH:7]=1.C(OC([N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([Cl:33])[CH:31]=2)/[C:26](=[CH:34]/[C:35]2[CH:40]=[C:39]([Br:41])[CH:38]=[CH:37][C:36]=2[O:42][CH:43]2[CH2:48][CH2:47][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:45][CH2:44]2)/[C:25]1=[O:56])=O)(C)(C)C>C1(C)C=CC=CC=1>[Br:41][C:39]1[CH:38]=[CH:37][C:36]([O:42][CH:43]2[CH2:44][CH2:45][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:47][CH2:48]2)=[C:35]([CH:34]2[CH2:12][C:10](=[O:11])[NH:9][CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:26]32[C:27]2[C:32](=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[NH:24][C:25]3=[O:56])[CH:40]=1
Reactant: C=C(N=Cc1cccc(Cl)c1)O[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Br)cc2/C=C2\C(=O)N(C(=O)OC(C)(C)C)c3cc(Cl)ccc32)CC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Br)cc2C2CC(=O)NC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)CC1

Procedure:
In a manner similar to the method described in Example 37d, 1-(3-chloro-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene in example 35d (43 mmol) in was reacted with E/Z-3-[5-bromo-2-(1-tert-butoxycarbonyl-piperidin-4-yloxy)-benzylidene]-6-chloro-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester in example 37c (10.8 g, 17 mmol) in toluene at 140° C. for 5 h to give the title compound as a yellow solid (Yield: 1.5 g).
Reaction SMILES: [CH3:1][C:2]1([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:7][CH2:6][CH2:5][N:4](C(OCC2C=CC=CC=2)=O)[CH2:3]1>C(OCC)(=O)C.CO.[Pd]>[CH3:1][C:2]1([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1
Reactant: CCOC(=O)C1(C)CCCN(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)C1(C)CCCNC1
Reaction time: 1.5 h
Yield: 90.9 %

Procedure:
A suspension of 1-benzyl 3-ethyl 3-methylpiperidine-1,3-dicarboxylate (3.945 g, 12.92 mmol) and 5% Pd/C (800 mg) in ethyl acetate (20 mL) and methanol (20.00 mL) was vigorously stirred under a hydrogen balloon for 1.5 hr. The reaction mixture was filtered to remove the catalyst and the filtrate was concentrated to dryness to give the desired crude product ethyl 3-methylpiperidine-3-carboxylate (2.010 g, 11.74 mmol, 91% yield) as a colorless oily residue. Anal. Calcd. for C9H17NO2 m/z 171.2, found: 172.2 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 4.25-4.06 (m, 2H), 3.31 (d, J=13.19 Hz, 1H), 2.93 (d, J=13.19 Hz, 1H), 2.59 (d, J=10.44 Hz, 1H), 2.41 (d, J=13.19 Hz, 1H), 2.23-2.11 (m, 1H), 1.68 (br. s., 1H), 1.52 (t, J=3.85 Hz, 1H), 1.46-1.31 (m, 2H), 1.27 (t, J=7.15 Hz, 3H), 1.10 (s, 3H).
Reaction SMILES: Br[Mg][CH:3]1[CH2:5][CH2:4]1.Br[C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([CH2:17][CH3:18])[CH:8]=1>O1CCCC1.[Zn+2].[Br-].[Br-].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:3]1([C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([CH2:17][CH3:18])[CH:8]=2)[CH2:5][CH2:4]1
Reactant: CCc1cc(Br)ccc1C(=O)OC
Reactant: Br[Mg]C1CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Br-]
Solvent: C1CCOC1
Product: CCc1cc(C2CC2)ccc1C(=O)OC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 89 %

Procedure:
To a stirred mixture of ZnBr2 (37.0 g, 164 mmol, 3.99 equiv) in tetrahydrofuran (150 mL) under nitrogen was added bromo(cyclopropyl)magnesium (3.28 M in THF, 50 mL, 4.00 equiv) dropwise at 0° C. After stirring at 15 minutes at 0° C., the temperature was lowered to −30° C. followed by the dropwise addition of a solution of Pd(dppf)Cl2 (2.00 g, 2.73 mmol, 0.07 equiv) in tetrahydrofuran (50 mL) and a solution of methyl 4-bromo-2-ethylbenzoate (compound 181.2, 10.0 g, 41.1 mmol, 1.00 equiv) in tetrahydrofuran (50 mL). The resulting solution was warmed slowly to 25° C. and stiffed for 15 h, then carefully quenched by slow addition of 100 mL of NH4Cl (aq.sat.). The mixture was extracted with 2×100 mL of ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:30) as eluent to yield 7.50 g (89%) of methyl 4-cyclopropyl-2-ethylbenzoate as a light yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[C:15](=[O:33])[N:16]([CH3:32])[C:17](=[O:31])[N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=4)[C:19]=3[CH3:20])=[C:12]([S:34](Cl)(=[O:36])=[O:35])[CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2].[C:38]1([C@@H:44]([CH2:46][OH:47])[NH2:45])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(N(C(C)C)CC)(C)C>C(Cl)(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[C:15](=[O:33])[N:16]([CH3:32])[C:17](=[O:31])[N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=4)[C:19]=3[CH3:20])=[C:12]([S:34]([NH:45][C@@H:44]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:46][OH:47])(=[O:36])=[O:35])[CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: Cc1c(-c2c(S(=O)(=O)Cl)cnn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: N[C@H](CO)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(-c2c(S(=O)(=O)N[C@H](CO)c3ccccc3)cnn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.5 %

Procedure:
To a suspension of 1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonic acid chloride (prepared in Example 204) (2.05 g) in chloroform (60 ml) were added (S)-2-phenylglycinol (767 mg) and diisopropylethylamine (0.99 ml) and the resulting mixture was stirred at room temperature for one hour. The reaction solution was concentrated under reduced pressure and thereto were added 1N hydrochloric acid (30 ml) and ethyl acetate (60 ml) such that the intended products were extracted into an organic layer. The organic layer was washed with 1N hydrochloric acid (30 ml) and saturated saline (30 ml), dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol) to afford (S)-1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrazole-4-sulfonamide (813 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@@H]2N1CCC2>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]([OH:10])[CH3:9]
Reactant: CC(=O)c1ccccc1F
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Product: C[C@H](O)c1ccccc1F

Procedure:
(S)-1-(2-Fluoro-phenyl)-ethanol was prepared according to the procedure described in Example 35, Step 1 using 2′-fluoroacetophenone and (R)-(+)-2-methyl-CBS-oxazaborolidine.
Reaction SMILES: Cl.Cl.[CH:3]1([NH:9][C:10]2[C:14]3([CH2:19][CH2:18][NH2+:17][CH2:16][CH2:15]3)[N:13]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)[C:12](=[O:27])[N:11]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH:28]([C:30]1[CH:31]=[C:32]([B:36]([OH:38])[OH:37])[CH:33]=[CH:34][CH:35]=1)=O.CCN(C(C)C)C(C)C.C([BH3-])#N>C1COCC1.CC(O)=O>[CH:3]1([NH:9][C:10]2[C:14]3([CH2:15][CH2:16][N:17]([CH2:28][C:30]4[CH:31]=[C:32]([B:36]([OH:38])[OH:37])[CH:33]=[CH:34][CH:35]=4)[CH2:18][CH2:19]3)[N:13]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)[C:12](=[O:27])[N:11]=2)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: O=C1N=C(NC2CCCCC2)C2(CC[NH2+]CC2)N1c1cccc(F)c1
Agent: Cl
Agent: [BH3-]C#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C1N=C(NC2CCCCC2)C2(CCN(Cc3cccc(B(O)O)c3)CC2)N1c1cccc(F)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 3.0 g (7.188 mmol) 4-(cyclohexylamino)-1-(3-fluorophenyl)-2-oxo-1,3-diaza-8-azoniaspiro[4.5]dec-3-ene dihydrochloride in 30 mL THF:AcOH (9:1) was added 1.8 g (12.005 mmol) 3-formylphenylboronic acid and 5.53 g (21.567 mmol) PS-DIEA resin and 5.97 g (14.388 mmol) MP-cyanoborohydride resin. The heterogeneous reaction mixture was stirred at rt for 24 hrs, then filtered, washed with 100 mL methanol, and concentrated. Purification by automated flash chromatography (8-30% CH3CN/H2O over 41 min, 0.05% added TFA reverse phase YMC ODSA 120 Å, 15-30 μM particle size,) afforded 3-{[4-(cyclohexylamino)-1-(3-fluorophenyl)-2-oxo-1,3,8-triazaspiro[4.5]dec-3-en-8-yl]methyl}phenylboronic acid as a solid. 1H NMR (CD3OD, 400 MHz) δ 7.44 (m, 1H), 7.38 (d, J=7.32 Hz, 1H), 7.29 (s, 1H), 7.18 (m, 1H), 7.09 (m, 3H) 6.93 (m, 1H), 3.75 (m, 1H), 3.31 (s, 2H), 2.78 (m, 2H), 2.12 (m, 4H), 1.97 (m, 4H), 1.78 (m, 2H), 1.65 (m, 1H), 1.35 (m, 5H). High resolution mass spec (FT/ICR) calc M+H=478.2661 found 478.2709.
Reaction SMILES: [Br:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([NH:11][C:12]2[N:17]=[C:16]([C:18]3[CH:19]=[N:20][N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=34)[CH:15]=[CH:14][N:13]=2)=[C:4]([O:27][CH3:28])[CH:3]=1.[NH4+].[Cl-].O>C(O)C.[Fe]>[Br:1][C:2]1[CH:3]=[C:4]([O:27][CH3:28])[C:5]([NH:11][C:12]2[N:17]=[C:16]([C:18]3[CH:19]=[N:20][N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=34)[CH:15]=[CH:14][N:13]=2)=[CH:6][C:7]=1[NH2:8]
Reactant: COc1cc(Br)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3c2CCCC3)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1cc(Br)c(N)cc1Nc1nccc(-c2cnn3c2CCCC3)n1
Yield: 92.5 %

Procedure:
N-(4-Bromo-2-methoxy-5-nitrophenyl)-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-amine (Intermediate 138, 944 mg, 2.12 mmol), iron (710 mg, 12.7 mmol) and NH4Cl (85 mg, 1.59 mmol) were heated in ethanol (40 mL) and water (13 mL) at reflux for 1.5 h. The mixture was then cooled and filtered. The residue was triturated in 10% CH3OH in CH2Cl2 (30 mL) for 15 minutes and then filtered. The residues were triturated again with 10% CH3OH in CH2Cl2 (30 mL) and filtered. The combined filtrates were washed with brine, dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 0-5% CH3OH in CH2Cl2 gave the title compound (814 mg, 92%) as a brown solid after trituration with diethyl ether; 1H NMR: 1.80-1.87 (2H, m), 1.96-2.03 (2H, m), 3.13 (2H, t), 3.77 (3H, s), 4.12 (2H, t), 4.82 (2H, s), 7.02 (1H, s), 7.05 (1H, d), 7.75 (1H, s), 7.77 (1H, s), 8.10 (1H, s), 8.34 (1H, d); m/z: ES+ MH+ 415/417.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:31])[NH:15][C:16]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH2:29][CH3:30])[N:19]=[CH:18][N:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>ClCCl.C(O)(C(F)(F)F)=O>[CH2:29]([O:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:20]1[N:19]=[CH:18][N:17]=[C:16]([NH:15][C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:31])[CH:21]=1)[CH3:30]
Reactant: CCOc1ccccc1-c1cc(NC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)ncn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1ccccc1-c1cc(NC(=O)C2CCNCC2)ncn1
Reaction time: 2.5 h
Yield: 49.8 %

Procedure:
To a stirred solution of 4-[6-(2-ethoxy-phenyl)-pyrimidin-4-ylcarbamoyl]-piperidine-1-carboxylic acid tert-butyl ester (IV), (0.500 g, 1.17 mmol) in dry dichloromethane (1.5 ml), TFA (1.5 ml) was added at 0° C. and the reaction mixture was stirred for 2-3 hours. After completion of the reaction (monitored by TLC) the solvent mixture was removed under reduced pressure and dichloromethane was added to the residue. Solid sodium carbonate was added and the mixture was stirred for 3-4 hours. Then it was filtered and washed with dichloromethane. The combined filtrate was concentrated under reduced pressure to obtain a solid which was washed with 10% ethyl acetate/hexane to remove nonpolar impurities, giving piperidine-4-carboxylic acid [6-(2-ethoxy-phenyl)-pyrimidin-4-yl]-amide (compound #1A) as pure white solid (0.19 g, 50%).
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[CH:36]=[CH:35][C:8]([CH2:9][N:10]([CH2:23][C:24]2[N:25]([S:29]([N:32]([CH3:34])[CH3:33])(=[O:31])=[O:30])[CH:26]=[CH:27][N:28]=2)[CH2:11][C:12]2[N:13]([S:17]([N:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])[CH:14]=[CH:15][N:16]=2)=[CH:7][CH:6]=1)C.Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[CH:4]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]([CH2:23][C:24]2[N:25]([S:29]([N:32]([CH3:34])[CH3:33])(=[O:31])=[O:30])[CH:26]=[CH:27][N:28]=2)[CH2:11][C:12]2[N:13]([S:17]([N:20]([CH3:22])[CH3:21])(=[O:18])=[O:19])[CH:14]=[CH:15][N:16]=2)=[CH:35][CH:36]=1)=[O:3]
Reactant: CCOC(OCC)c1ccc(CN(Cc2nccn2S(=O)(=O)N(C)C)Cc2nccn2S(=O)(=O)N(C)C)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CN(C)S(=O)(=O)n1ccnc1CN(Cc1ccc(C=O)cc1)Cc1nccn1S(=O)(=O)N(C)C
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 85.5 %

Procedure:
2,2′-[{[4-(diethoxymethyl)benzyl]imino}bis(methylene)]bis(N,N-dimethyl-1H-imidazole-1-sulfonamide) (International Publication WO 2007/058322 pamphlet, Example 27; 10.0 g), ethyl acetate (100 mL) and 2N hydrochloric acid (100 mL) were added, followed by stirring at room temperature for 3 minutes. The aqueous layer was neutralized with an aqueous saturated sodium carbonate solution, extracted with ethyl acetate and then washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain the title compound (7.46 g) having the following physical properties.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[C:28]([C:30]([N:32]2[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[CH2:36][CH2:35][CH2:34][CH2:33]2)=[O:31])[CH:27]=[CH:26][C:4]=1[C:5]([NH:7][C:8]1[C:16]2[N:15]=[C:14]([CH2:17][O:18][Si](C(C)(C)C)(C)C)[NH:13][C:12]=2[CH:11]=[CH:10][CH:9]=1)=[O:6].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:1][O:2][C:3]1[CH:29]=[C:28]([C:30]([N:32]2[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[CH2:36][CH2:35][CH2:34][CH2:33]2)=[O:31])[CH:27]=[CH:26][C:4]=1[C:5]([NH:7][C:8]1[C:16]2[N:15]=[C:14]([CH2:17][OH:18])[NH:13][C:12]=2[CH:11]=[CH:10][CH:9]=1)=[O:6]
Reactant: COc1cc(C(=O)N2CCCCc3ccccc32)ccc1C(=O)Nc1cccc2[nH]c(CO[Si](C)(C)C(C)(C)C)nc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1cc(C(=O)N2CCCCc3ccccc32)ccc1C(=O)Nc1cccc2[nH]c(CO)nc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 62.1 %

Procedure:
A mixture of 2-methoxy-N-(2-tert-butyldimethylsiloxymethyl-1H-benzimidazol-4-yl)-4-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonylbenzamide (250 mg) and tetrabutylammonium fluoride (1 mol solution in tetrahydrofuran 0.9 ml) in tetrahydrofuran (15 ml) was stirred at room temperature for 4 hours, and the solvent was removed by evaporation. The residue was purified by silica gel column chromatography (1% methanol in chloroform) to give 2-methoxy-N-(2-hydroxymethyl-1H-benzimidazol-4-yl)-4-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonylbenzamide (125 mg).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][N:6]=1)=[O:4].Cl[C:15]1[N:20]=[N:19][C:18]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]3[C:35]4[C:30](=[CH:31][CH:32]=[C:33]([F:36])[CH:34]=4)[CH2:29][CH2:28]3)[CH2:23][CH2:22]2)=[CH:17][CH:16]=1>>[F:36][C:33]1[CH:34]=[C:35]2[C:30]([CH2:29][CH2:28][N:27]2[CH:24]2[CH2:25][CH2:26][N:21]([C:18]3[N:19]=[N:20][C:15]([C:8]4[CH:9]=[CH:10][C:5]([C:3]([NH:2][CH3:1])=[O:4])=[N:6][CH:7]=4)=[CH:16][CH:17]=3)[CH2:22][CH2:23]2)=[CH:31][CH:32]=1
Reactant: CNC(=O)c1ccc(B(O)O)cn1
Reactant: Fc1ccc2c(c1)N(C1CCN(c3ccc(Cl)nn3)CC1)CC2
Product: CNC(=O)c1ccc(-c2ccc(N3CCC(N4CCc5ccc(F)cc54)CC3)nn2)cn1

Procedure:
The title compound was prepared following the procedure as described in Example 1, Method A, STEP 4, reacting 2-(N-methylaminocarbonyl)pyridine-5-boronic acid and 1-(1-(6-chloropyridazin-3-yl)piperidin-4-yl)-6-fluoroindoline.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1.S(=O)(=O)(O)O.[Br:19]([O-])(=O)=O.[K+]>O>[Br:19][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:4]=1[O:3][C:2]([F:12])([F:13])[F:1])[C:8]#[N:9]
Reactant: [O-][Br+2]([O-])[O-]
Reactant: N#Cc1ccc(OC(F)(F)F)cc1
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: N#Cc1ccc(OC(F)(F)F)c(Br)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 75.7 %

Procedure:
4-(Trifluoromethoxy)benzonitrile (5.57 g, 29.8 mmol) was added to 50% aqueous sulfuric acid (60 ml) and the mixture was warmed to 80° C. Potassium bromate (5.97 g, 35.7 mmol) was added in portions over 2 hours and the mixture was stirred at 80° C. for a further 2 hours. The mixture was cooled to room temperature and poured into water (200 ml). The mixture was extracted with ethyl acetate (3×200 ml) and the combined organic layers were dried (MgSO4) and evaporated under reduced pressure to give the title compound as an orange oil (6.0 g) which contained 4-trifluoromethoxy)benzonitrile (ca. 30%) as determined by 1H NMR. 1H NMR (250 MHz, CDCl3) δ 7.97 (1H, d, J=2.0 Hz), 7.68 (1H, dd, J=8.5, 2.0 Hz), and 7.42 (1H, dq, J=8.5, 1.5 Hz).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:26]=[C:27]=[O:28])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[CH2:29]([N:36]1[CH2:41][CH2:40][N:39]([C:42](=[O:52])[CH2:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[OH:51])[CH2:38][CH2:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl>[CH2:8]([NH:26][C:27](=[O:28])[O:51][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=1[CH2:44][CH2:43][C:42]([N:39]1[CH2:40][CH2:41][N:36]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:37][CH2:38]1)=[O:52])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Reactant: O=C(CCc1ccccc1O)N1CCN(Cc2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCNC(=O)Oc1ccccc1CCC(=O)N1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Triethylamine (0.84 ml) and octadecyl isocyanate (1.88 ml) were added to a solution containing 1-(4-benzylpiperazino)-3-(2-hydroxyphenyl)-1-propanone (1.76 g) in methylene chloride (18 ml) and stirred for 17 hours at room temperature. The insoluble matters were filtrated out and washed with chloroform. The filtrate and washings were combined and the mixture was washed with saturated sodium hydrogencarbonate aqueous solution and brine successively, dried over sodium sulfate anhydride, and concentrated. The residue was purified by silica gel column chromatography (silica gel 75 g, chloroform:methanol=60:1), thereby yielding the entitled compound (2.32 g) as white solid.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[Br:9][C:10]1[CH:11]=[CH:12][C:13]2[C:21]3[C:20](=O)[CH2:19][CH2:18][CH2:17][C:16]=3[N:15]([CH3:23])[C:14]=2[N:24]=1>CCO.O>[Br:9][C:10]1[CH:11]=[CH:12][C:13]2[C:21]3[C:20](=[N:2][OH:3])[CH2:19][CH2:18][CH2:17][C:16]=3[N:15]([CH3:23])[C:14]=2[N:24]=1
Reactant: Cn1c2c(c3ccc(Br)nc31)C(=O)CCC2
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cn1c2c(c3ccc(Br)nc31)C(=NO)CCC2
Temperature: 25 °C
Yield: 86 %

Procedure:
Hydroxylamine hydrochloride (0.54 g, 7.9 mmol) and sodium acetate (0.65 g, 7.9 mmol) were added to a suspension of 2-bromo-9-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-5-one (1.5 g, 5.3 mmol) in EtOH (13 mL) and H2O (5 mL), and the resulting suspension was heated at reflux for 4 h. The reaction was cooled to ambient temperature, and the solids were collected by filtration. The solids were washed with EtOH to provide the title compound (1.34 g, 87%) as an off-white powder: 1H NMR (500 MHz, DMSO-d6) δ 10.49 (s, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.31 (d, J=8.0 Hz, 1H), 3.68 (s, 3H), 2.86 (t, J=6.0 Hz, 2H), 2.68 (t, J=8.0 Hz, 2H), 1.96-1.84 (m, 2H).
Reaction SMILES: [CH3:1][N:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][C:4]([O:6]CC)=[O:5].[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[CH3:1][N:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)CN(C)c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(CC(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The product of step 1 (1.1 g, 5.6 mmol) was dissolved in methanol (50 mL) and 1M NaOH (17 mL) added. Allow reaction mixture to stir at ambient temperature over 18 hours. 10% Citric acid solution was added until a pH=4 was reached. Extract several times with EtOAc. The organic layer was washed several times with brine, dried (Na2SO4), filtered, and concentrated affording a quantitative yield of the title compound as a yellow oil. MS (ES+) m/z 166 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:24]=[CH:23][C:22]([OH:25])=[C:21]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C(=O)N([Br:41])C(=O)C1.O>CN(C=O)C>[CH2:1]([O:8][C:9]1[N:24]=[C:23]([Br:41])[C:22]([OH:25])=[C:21]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(OCc1ccccc1)c1c(OCc2ccccc2)ncc(O)c1OCc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(OCc1ccccc1)c1c(OCc2ccccc2)nc(Br)c(O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 67 %

Procedure:
A mixture of benzyl 2,4-bis(benzyloxy)-5-hydroxynicotinate (0.29 g, 0.66 mmol) and NBS (0.13 g, 0.72 mmol) in DMF (1.2 mL) was stirred at room temperature for 5 min then treated with water. The mixture was extracted with ethyl acetate. The organic layers were combined and washed with brine, dried over sodium sulfate, evaporated and purified by silica chromatography (0-30% ethyl acetate in hexanes) to give benzyl 2,4-bis(benzyloxy)-6-bromo-5-hydroxynicotinate (0.23 g, 68%).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C@H:7]2[CH2:12][CH2:11][CH2:10][N:8]2[CH3:9])[CH:4]=[CH:3][CH:2]=1.[H-].[Na+]>Cl>[CH3:9][N:8]1[CH:7]([C:5]2[CH:4]=[CH:3][CH:2]=[N:1][CH:6]=2)[CH2:12][CH2:11][CH2:10]1
Reactant: CN1CCC[C@@H]1c1cccnc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CN1CCCC1c1cccnc1
Temperature: 0 °C
Yield: 66.7 %

Procedure:
Sodium hydride (14.8 g, 0.616 mol of 60% dispersion in a mineral oil) was washed with toluene to remove the mineral oil and added to 100 ml of o-xylene. To this was added (R)-nicotine (10 g, 0.0617 mol). The reaction mixture was refluxed for 15 hrs, cooled to 0° C., the excess sodium hydride decomposed using dilute HCl (15%, 100 ml), the aqueous layer separated, the pH of the aqueous layer adjusted to >13 at 0° C. and extracted with dichloromethane. The solvent was then removed completely and the crude obtained was further purified by vacuum distillation at 0.1 mm Hg to get (R,S)-nicotine (6.68 g, 66.8% Y, 98.5% purity by GC, optical rotation: 0.8°)