Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]4[O:25][CH:24]=[N:23][C:22]=4[C:26]([O:28]C)=[O:27])=[CH:18][C:17]4[CH:30]=[C:31]([O:34][CH3:35])[CH:32]=[CH:33][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.P([O-])(O)(O)=O.[Na+].Cl>C1COCC1>[C:39]([O:38][C:36]([C:11]1[CH:10]=[CH:9][C:8]2[C:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:15]3[C:16]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:17]=4[CH:18]=[C:19]([C:21]4[O:25][CH:24]=[N:23][C:22]=4[C:26]([OH:28])=[O:27])[CH2:20][N:14]3[C:13]=2[CH:12]=1)=[O:37])([CH3:42])([CH3:40])[CH3:41]
Reactant: COC(=O)c1ncoc1C1=Cc2cc(OC)ccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC(C)(C)C)cc3n2C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=P([O-])(O)O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C=C(c1ocnc1C(=O)O)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)OC(C)(C)C)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
tert-Butyl 13-cyclohexyl-3-methoxy-6-(4-(methoxycarbonyl)-1,3-oxazol-5-yl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylate (205 mg, 0.360 mmol) was dissolved in THF (3.0 ml) and tetrabutylammonium hydroxide (1.1 mL, 1.100 mmol) (1.0M in methanol) was added to the reaction. The reaction was capped and stirred at room temperature for 2 hrs. A 0.1M aqueous solution of NaH2PO4 was added to the reaction followed by 0.1N aqueous hydrochloric acid. The product was extracted into ethyl acetate and the organic phase washed sequentially with 0.1N aqueous hydrochloric acid, 0.1M aqueous NaH2PO4, brine and dried over magnesium sulfate. The product solution was filtered, solvent removed and product dried in vacuuo to yield 191 mg of a yellow solid. 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 0.77-0.94 (m, 1H) 1.12-1.31 (m, 3H) 1.30-1.59 (m, 5H) 1.62 (s, 9H) 1.76 (d, J=11.29 Hz, 2H) 1.87-2.18 (m, 4H) 2.76-2.90 (m, 1H) 3.91 (s, 3H) 4.45 (d, J=14.04 Hz, 1H) 6.03 (d, J=12.21 Hz, 1H) 7.03 (d, J=2.44 Hz, 1H) 7.08 (dd, J=8.55, 2.75 Hz, 1H) 7.53 (d, J=8.85 Hz, 1H) 7.68 (d, J=8.24 Hz, 1H) 7.82 (d, J=8.55 Hz, 1H) 7.91 (s, 1H) 8.21 (d, J=5.80 Hz, 2H). LC-MS retention time 1.86 min; m/z 553 (MH−). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters Xterra MS 7u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:20]2[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]2=[O:30])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[CH:11][C:10]([CH:13]=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9]1.[BH4-].[Na+].[Cl-].[NH4+]>Cl[Cu].CO.C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([N:20]2[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]2=[O:30])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9]1
Reactant: CCOC(=O)C=Cc1ccn(-c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)c1
Agent: Cl[Cu]
Agent: [BH4-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)CCc1ccn(-c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
A solution of 150 mg (0.36 mmol) of the compound of Example 23 and 54 mg (0.54 mmol) of copper [I] chloride in 15 mL 1:1 Methanol-THF at 0° C. was treated with 136 mg (3.6 mmol) of sodium borohydride. The solution was stirred at 0° C. for 30 min and then warmed to ambient temperature for 1 h. The solution was treated with 2 mL saturated ammonium chloride solution, followed by filtration through celite. The filtrate was concentrated in vacuo and the residue was diluted with ethyl acetate and extracted with water (3×). Drying (Na2SO4) and concentration in vacuo afforded 150 mg (99%) of the title compound as a white solid. 1H NMR (CDCl3) δ 7.60, 7.34, 7.33, 6.91, 6.81, 6.21, 5.97, 4.81, 4.15, 4.08, 3.82, 3.72, 3.65, 2.87, 2.62, 2.04, 1.26.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=O.C([SiH](CC)CC)C>C(O)(C(F)(F)F)=O.CCOC(C)=O.C(=O)([O-])[O-].[Na+].[Na+]>[Cl:1][CH2:2][CH2:3][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1
Reactant: O=C(CCl)c1c[nH]c2ncccc12
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: ClCCc1c[nH]c2ncccc12
Reaction time: 16 h

Procedure:
A stirred solution of 2-chloro-1-(1H-pyrrolo[2,3-b]pyridin-3-yl)ethanone (12.5 g) in TFA at room temperature is treated with triethylsilane (72 mL, 7 eq.), stirred for 16 h, diluted with EtOAc and saturated sodium carbonate to pH 8. The phases are separated and the organic phase is dried over MgSO4 and concentrated in vacuo. The resultant residue is purified by flash chromatography (silica gel, 10% EtOAc in ether as eluent) to give the title pyrrolo[2,3-b]pyridine compound, identified by NMR and mass spectral analyses.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH:6]=[C:5]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])[CH:4]=[CH:3]1.[CH2:17]([NH:24][C:25]([C:27]1[S:31][C:30](Br)=[N:29][C:28]=1[CH3:33])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([NH:24][C:25]([C:27]1[S:31][C:30]([N:7]2[CH:6]=[C:5]([C:8](=[O:9])[NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:4]=[CH:3][C:2]2=[O:1])=[N:29][C:28]=1[CH3:33])=[O:26])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1nc(Br)sc1C(=O)NCc1ccccc1
Reactant: O=C(Nc1ccccc1)c1ccc(=O)[nH]c1
Product: Cc1nc(-n2cc(C(=O)Nc3ccccc3)ccc2=O)sc1C(=O)NCc1ccccc1
Yield: 31 %

Procedure:
Following the procedure as described in Example 3, making variations only as required to use 6-oxo-N-phenyl-1,6-dihydropyridine-3-carboxamide in place of 4-aminopyridin-2(1H)-one to react with N-benzyl-2-bromo-4-methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 31% yield: mp 223-225° C. (hexane/ethyl acetate); 1H-NMR (300 MHz, DMSO-d6) δ 10.39 (s, 1H), 9.40 (d, J=2.5 Hz, 1H), 8.89 (t, J=5.9 Hz, 1H), 8.14 (dd, J=9.6, 2.5 Hz, 1H), 7.70-7.68 (m, 2H), 7.36-7.28 (m, 6H), 7.26-7.18 (m, 1H), 7.11-7.07 (m, 1H), 6.86 (d, J=9.6 Hz, 1H), 4.41 (d, J=5.9 Hz, 2H), 2.61 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 162.4, 161.6, 160.1, 153.5, 150.5, 139.7, 139.3, 139.1, 134.0, 129.1, 128.7, 127.7, 127.3, 125.3, 124.4, 121.0, 120.2, 116.2, 43.2, 17.5; (ES+) m/z 445.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][NH:11][C:12]3[N:20]=[CH:19][N:18]=[C:17]4[C:13]=3[N:14]=[CH:15][N:16]4C3CCCCO3)[N:7]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:6]=2[CH:33]=1.Cl>CO.O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][NH:11][C:12]3[N:20]=[CH:19][N:18]=[C:17]4[C:13]=3[N:14]=[CH:15][NH:16]4)[N:7]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:6]=2[CH:33]=1
Reactant: Fc1ccc2nc(CNc3ncnc4c3ncn4C3CCCCO3)n(-c3ccccc3)c2c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Fc1ccc2nc(CNc3ncnc4[nH]cnc34)n(-c3ccccc3)c2c1
Yield: 85.5 %

Procedure:
(6-Fluoro-1-phenyl-1H-benzoimidazol-2-ylmethyl)[9-(tetrahydropyran-2-yl)-9H-purin-6-yl]amine (0.125 g, 0.28 mmol) in MeOH (2 mL) was treated with 4M HCl in dioxane (0.35 mL). After 15 min at 20° C. the reaction was poured onto a 10 g SCX cartridge which was eluted first with methanol then with 1:1 MeOH/2M NH3 in isopropanol. Product containing fractions were evaporated to a white solid. This was triturated with diethyl ether and dried to give 443 as a white solid, (86 mg, 85%). LCMS (Method C): RT 3.16 min [M+H]+ 360.02. NMR δ (ppm) (DMSO-d6): 12.9 (1H, s), 8.11 (2H, s), 7.92 (1H, s), 7.66-7.60 (6H, m), 7.09 (1H, td, J=9.31, 2.45 Hz), 6.93 (1H, dd, J=8.96, 2.50 Hz), 4.8 (2H, bs)
Reaction SMILES: [CH3:1][Mg+].[Br-].Cl[C:5]1[C:14]([F:15])=[CH:13][C:12]2[C:7](=[CH:8][C:9]([O:16][CH3:17])=[CH:10][CH:11]=2)[N:6]=1.[OH-].[NH4+]>C1COCC1.CCOCC>[F:15][C:14]1[C:5]([CH3:1])=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([O:16][CH3:17])[CH:8]=2
Reactant: COc1ccc2cc(F)c(Cl)nc2c1
Reactant: C[Mg+]
Agent: [Br-]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc2cc(F)c(C)nc2c1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 51.2 %

Procedure:
To a suspension of Cu(I)Br (1.49 g, 10.4 mmol) in THF (30 mL) was added 3M MeMgBr (6.93 ml, 20.8 mmol) in ether at −78° C. After stirring at −78° C. for 5 minutes, 2-chloro-3-fluoro-7-methoxyquinoline (0.55 g, 2.60 mmol) in THF (10 mL) was added. The reaction mixture was stirred at −78° C. for 1 hour, then allowed to warm to ambient temperature and stirred for 20 hours. Ammonium hydroxide (10 mL) was added slowly. The mixture was stirred at ambient temperature for 10 minutes, then passed through a pad of Celite® and washed with ether (50 mL). The filtrated was washed with brine (20 mL), dried (sodium sulfate), filtered and concentrated under reduced pressure. The crude residue was purified by flash chromatography 3:1 hexane/ethyl acetate to give 3-fluoro-7-methoxy-2-methylquinoline (0.255 g, 1.33 mmol, 51.3% yield) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[C:4]([CH2:13][N:14]2[CH2:19][CH2:18][N:17](S(C3C=CC=CC=3)(=O)=O)[C@@H:16]([CH2:29][CH3:30])[CH2:15]2)[CH:3]=1.[C:31]1([CH2:37][C:38](Cl)=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[C:4]([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([C:38](=[O:39])[CH2:37][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C@@H:16]([CH2:29][CH3:30])[CH2:15]2)[CH:3]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC[C@H]1CN(Cc2cc(Cl)ccc2OCC(=O)O)CCN1S(=O)(=O)c1ccccc1
Product: CC[C@H]1CN(Cc2cc(Cl)ccc2OCC(=O)O)CCN1C(=O)Cc1ccccc1

Procedure:
Prepared from the product from example 69 part f) and phenylacetyl chloride according to the procedure described in example 69 part g) to give the title compound as a white solid (30 mg).
Reaction SMILES: [O:1]([CH2:8][CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br.[OH-].[Na+]>O>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:10][CH2:9][CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCCCCCCBr
Reactant: OCCOc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: BrCCCCCCOCCOc1ccccc1
Yield: 83.1 %

Procedure:
2-Phenoxyethanol (2.76 g), 1,6-dibromohexane (14.6 g), TAB (1 g) and 50% sodium hydroxide (20 ml) were vigorously stirred for 21 h, added to water (100 ml) and extracted with diethyl ether (3×100 ml). The dried extract was evaporated and the residual colourless liquid (15 g) was purified by FCC eluting with cyclohexane followed by System A (1:1). Evaporation of the latter eluate gave the title compound (5.0 g) as a colourless liquid. T.l.c. (System A 1:1) Rf 0.6.
Reaction SMILES: [Br:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[O:8][C:9]([CH3:28])=[C:10]([CH3:27])[C:11]=2[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[C:16]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:15]=2)=[O:13])=[CH:4][CH:3]=1.B(Br)(Br)Br.C(Cl)Cl>C(Cl)Cl>[Br:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[O:8][C:9]([CH3:28])=[C:10]([CH3:27])[C:11]=2[C:12]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:15]=2)=[O:13])=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)c2c(Cc3ccc(Br)cc3)oc(C)c2C)cc1C1CCCC1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1oc(Cc2ccc(Br)cc2)c(C(=O)c2ccc(O)c(C3CCCC3)c2)c1C
Yield: 50.6 %

Procedure:
The title compound was prepared according to the procedure in Example 5, step 3 using [2-(4-bromo-benzyl)-4,5-dimethyl-furan-3-yl]-(3-cyclopentyl-4-methoxy-phenyl)-methanone (3.38 g, 7.23 mmol) and 1M boron tribromide/CH2Cl2 (15.2 mL) in CH2Cl2. Purification on Biotage KP-Sil eluting with 15% acetone/hexane gave 1.66 g (51%) of the title compound. 1H NMR (DMSO-d6) δ1.39-1.48 (m, 2H), 1.59-1.65 (m, 2H), 1.68-1.76 (m, 2H), 1.79 (s, 3H), 1.88-1.95 (m, 2H), 2.18 (s, 3H), 3.18 (quintet, 1H), 3.81 (s, 2H), 6.87 (d, 1H), 7.04 (d, 2H), 7.43-7.47 (m, 3H), 7.53 (s, 1H), 10.35 (s, 1H). IR (KBr) 3300, 2950, 1650, 1575 and 1280 cm−1. mass spectrum (+ESI) m/z 453 (M+H). Anal. Calcd. for C25H25BrO3: C, 66.23; H, 5.56; N, 0.00. Found: C, 66.12; H, 5.49; N, 0.03.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:27])([CH3:26])[CH2:10][C:11]([NH:13][C@@H:14]1[CH2:20][CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[NH:16][C:15]1=[O:25])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[NH:44][C:45]([O:47][CH3:48])=[O:46])=[CH:34][CH:33]=1.O>CN(C)C=O.C(OCC)(=O)C>[CH3:48][O:47][C:45]([NH:44][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=1[C:35]1[CH:34]=[CH:33][C:32]([CH2:31][N:16]2[C:17]3[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=3[CH2:19][CH2:20][C@@H:14]([NH:13][C:11](=[O:12])[CH2:10][C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])([CH3:27])[CH3:26])[C:15]2=[O:25])=[CH:37][CH:36]=1)=[O:46]
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2NC1=O)NC(=O)OC(C)(C)C
Reactant: COC(=O)Nc1ccccc1-c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Nc1ccccc1-c1ccc(CN2C(=O)[C@H](NC(=O)CC(C)(C)NC(=O)OC(C)(C)C)CCc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
A solution of 222 mg (0.594 mmol) of 3-t-butoxycarbonylamino-3-methyl- N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]butanamide (Step I) in 6 mL of dry dimethylformamide was treated with 30 mg of 60% sodium hydride oil dispersion (18 mg NaH, 0.75 mmol, 1.3 eq). The reaction mixture was stirred at room temperature for 30 minutes. To the solution was added 190 mg (0.594 mmol) of solid 4-bromomethyl-2'-(methoxycarbonyl)amino-1,1'-biphenyl. After stirring at room temperature for 1 hour, the reaction mixture was diluted with ethyl acetate followed by 50 mL of water. The organic layer was washed with water (4×), dried over magnesium sulfate, filtered and evaporated under vacuum. The residue was purified by preparative thin layer chromatography on silica gel, eluting with methylene chlorideethanol (100:3) to give 231 mg (0.376 mmol, 63%) of the product. 1H NMR (400 MHz, CDCl3): δ 1.23 (s, 3H), 1.33 (s, 3H), 1.39 (s, 9H), 1.85 (m, 1H), 2.40 (dd, 2H), 2.49 (m, 1H), 2.54 (m, 2H), 3.68 (s, 3H), 4.53 (m, 1H), 4.94 (d, 1H), 5.17 (d, 1H), 6.53 (br s, 1H), 6.66 (d, 1H), 7.2 (m, 12H), 8.09 (d, 1H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:15]([OH:17])=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[C:18]([O-:21])([O-])=[O:19].[K+].[K+].Cl>O>[C:6]([O:21][C:18]([N:12]1[CH2:11][CH2:10][C:9]([C:6]2[CH:7]=[CH:8][C:3]([Cl:2])=[CH:4][CH:5]=2)([C:15]([OH:17])=[O:16])[CH2:14][CH2:13]1)=[O:19])([CH3:9])([CH3:7])[CH3:5]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCNCC1
Agent: Cl
Agent: [K+]
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2ccc(Cl)cc2)CC1
Reaction time: 8 h

Procedure:
A sample of crude 4-(4-chloro-phenyl)-piperidine-4-carboxylic acid hydrochloride (5 mmol, 1 equiv) and 15 g of K2CO3 (113 mmol, 22.6 equiv) was diluted in 50 mL H2O. To the resultant solution was added a solution of 7.4 g BOC20 (34.1 mmol, ˜7 equiv) in 50 mLp-dioxane and the reaction mixture was stirred overnight under N2 atmosphere. The pH was adjusted to ˜4 with 1M HCl and allowed to stir for about 0.5 hour. The reaction mixture was concentrated under vacuum, and the remaining solution was extracted with 2×50 mL EtOAc. The combined organic extracts were dried under vacuum to yield 4-(4-chloro-phenyl)-piperidine-1,4-dicarboxylic acid mono-tert-butyl ester. The crude material was used without further purification for the next step: MS (ES) M−H expected=338.8, found=338.1.
Reaction SMILES: B.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][N+:14]([O-])=O)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]>O1CCCC1>[CH2:13]([NH2:14])[CH2:12][C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=1
Reactant: COc1ccc(C=C[N+](=O)[O-])cc1OC
Agent: B
Solvent: C1CCOC1
Product: COc1ccc(CCN)cc1OC
Temperature: 25 °C
Yield: 109.2 %

Procedure:
In a 3 L flask, containing an argon atmosphere, fitted with a dropping funnel and condenser, was placed 800 mL of a 1.0 M solution of borane in tetrahydrofuran. To the stirred solution was added a solution of 33.47 grams of 2-(3,4-dimethoxypheny)-nitroethene in 800 ml of tetrahydrofuran, at such a rate (~3 hours) that the temperature of the solution in the flask did not exceed 35° C. The mixture was heated to reflux for 20 hours and then allowed to cool to room temperature. The excess borane was quenched by careful addition of methanol (97 mL). The mixture was concentrated on a rotary evaporator. The residue was diluted with methanol (670 mL) and 2.0N HCl (670 mL). The mixture was heated to reflux for 1 hour. The methanol was removed on a rotary evaporator. The aqueous solution was extracted with diethyl ether (2×800 mL) to remove the neutral impurities. The pH of the aqueous solution was adjusted to 12-- 14 with sodium hydroxide pellets (66.88 g), then extracted with ether (3×800 mL). The organic layers were separately dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to provide 2.14 grams of neutral by-products and 31.65 grams of crude homoveratrylamine. Purification of the homoveratrylamine by bulb-to-bulb distillation (110° C. @ 0.6 mm Hg) provided 24.78 grams of the desired product, 85.5% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.O=S(Cl)[Cl:20]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:14]([C:15]([Cl:20])=[O:17])=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccnc1Nc1cccc(Cl)c1
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccnc1Nc1cccc(Cl)c1

Procedure:
Stirring 2-[(3-chloro-phenyl)amino]-3-pyridinecarboxylic acid (30.8 g, 124 mmol) with SOCl2 (50 mL, 680 mmol) and DMF (0.5 mL) at 25° C. for 1 hr gave a solution which deposited a precipitate. Excess thionyl chloride was evaporated, the residue was mixed with benzene, and the solvent was evaporated to give crude, solid 2-[(3-chlorophenyl)amino]-3-pyridinecarbonyl chloride which was used directly in the next step C. Collecting, washing with benzene and petroleum ether, and drying the precipitate gave 2-[(3-chlorophenyl)amino]-3-pyridinecarbonyl chloride (32 g, 96%) as a yellow solid, mp 112°-115° C.
Reaction SMILES: Cl[C:2]1[N:20]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[N:21]1([CH2:26][CH2:27][N:28]2[CH:32]=[C:31]([NH2:33])[CH:30]=[N:29]2)[CH2:25][CH2:24][CH2:23][CH2:22]1>>[N:21]1([CH2:26][CH2:27][N:28]2[CH:32]=[C:31]([NH:33][C:2]3[N:20]=[C:5]4[C:6]([C:10]5[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=5)=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)[CH:30]=[N:29]2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: FC(F)(F)c1ccc(-c2cccn3nc(Cl)nc23)cc1
Reactant: Nc1cnn(CCN2CCCC2)c1
Product: FC(F)(F)c1ccc(-c2cccn3nc(Nc4cnn(CCN5CCCC5)c4)nc23)cc1

Procedure:
[1-(2-Pyrrolidin-1-yl-ethyl)-1H-pyrazol-4-yl]-[8-(4-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine was prepared from 2-chloro-8-(4-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (0.100 g, 0.33 mmol) and 1-(2-pyrrolidin-1-yl-ethyl)-1H-pyrazol-4-ylamine (0.078 g, 0.43 mmol) in a manner analogous to Example 2d. Product was isolated as a tan solid (78 mg, 52%). MP=205-207° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.35 (s, 1H), 8.76 (d, J=6.44 Hz, 1H), 8.38 (d, J=8.00 Hz, 2H), 7.08-7.93 (m, 3H), 7.84 (s, 1H), 7.47 (s, 1H), 7.11 (t, J=7.08 Hz, 1H), 4.17 (t, J=6.37 Hz, 2H), 2.80 (t, J=6.24 Hz, 2H), 2.45 (s, 4H), 1.64 (s, 4H). MS=442 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][C:6]([Si](CC)(CC)CC)=[C:5]2[CH2:19][CH2:20][NH:21][C:22](=[O:37])[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=2)=[CH:25][CH:24]=1>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:19][CH2:20][NH:21][C:22](=[O:37])[C:23]1[CH:24]=[CH:25][C:26]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=2)=[CH:27][CH:28]=1
Reactant: CC[Si](CC)(CC)c1[nH]c2c(F)cc(Cl)cc2c1CCNC(=O)c1ccc(Cc2cccc(F)c2)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCCc1c[nH]c2c(F)cc(Cl)cc12)c1ccc(Cc2cccc(F)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 18.7 %

Procedure:
N-(2-(5-Chloro-7-fluoro-2-(triethylsilyl)-1H-indol-3-yl)ethyl)-4-(3-fluorobenzyl)benzamide (0.102 g; 0.189 mmol) was dissolved in trifluoroacetic acid (3 mL) and stirred at room temperature for 3 hours. The solution was concentrated under reduced pressure and the crude material was purified by flash chromatography on silica gel (eluent 20 to 100% ethyl acetate in heptane) to afford 0.015 g (19%) of the title compound as a white solid.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[CH2:15](O)[CH3:16].C(Cl)(Cl)Cl>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: O=C(O)CCCCCCCCCCBr
Reactant: CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)CCCCCCCCCCBr
Temperature: 25 °C
Yield: 72 %

Procedure:
1000 g of 90% pure 11-bromoundecanoic acid (equivalent to 3.39 mol), 304.0 g (6.60 mol) of ethanol and 20.0 g of p-toluenesulfonic acid were introduced into 400 ml of chloroform in an experimental apparatus with water trap (for entrainers with higher specific gravity than water). The mixture was heated under reflux until water no longer separated out (about 6 hours). After the solution had cooled to room temperature it was washed successively with 1 l of water, 500 ml of saturated NaHCO3 solution and 1 l of water. The solvent was removed in vacuo. Vacuum distillation (b.p. 131-133° C./1 mbar) resulted in 716.3 g (2.44 mol, 72%) of ethyl 11-bromoundecanoate.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[C:14][C:15]1[CH:22]=[CH:21][C:20](OC)=[CH:19][C:16]=1[CH:17]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:26][OH:27].C([O-])(=O)C.[Na+].C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[N+:26]([O-:27])=[CH:17][C:16]2[C:15]([CH:14]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: COc1ccc(C#CCCCCOCc2ccccc2)c(C=O)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: O
Product: [O-][n+]1cc2ccccc2cc1CCCCOCc1ccccc1
Yield: 80.7 %

Procedure:
2-[2-(4-Benzyloxybutyl)ethynyl]-5-methoxybenzaldehyde (2.60 g), hydroxylamine hydrochloride (0.63 g) and sodium acetate (0.78 g) were reacted in ethanol (30 ml) at 60° C. for 2 hr. Potassium carbonate (2.0 g) and water (5 ml) were added to the resulting reaction mixture, which was then heated under reflux for 12 hr. The reaction solution was evaporated, and the resulting residue was extracted with methylene chloride, washed with brine, and then dried. The solvent was removed and the resulting residue was purified by silica gel column chromatography (methylene chloride/methanol system), to give 2.0 g of the title compound as a brown amorphous.