Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([F:12])=[C:8]([NH2:11])[CH:9]=2)[NH:4][N:3]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[CH2:25][C:24](=[O:26])[NH:23][C:22]([CH3:27])=[C:21]2[C:28](O)=[O:29])=[CH:16][CH:15]=1.C(Cl)CCl.CCN(CC)CC>CN(C=O)C.CCOC(C)=O.Cl>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([F:12])=[C:8]([NH:11][C:28]([C:21]3[CH:20]([C:17]4[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=4)[CH2:25][C:24](=[O:26])[NH:23][C:22]=3[CH3:27])=[O:29])[CH:9]=2)[NH:4][N:3]=1
Reactant: Nc1cc2c(Cl)n[nH]c2cc1F
Reactant: CC1=C(C(=O)O)C(c2ccc(Cl)cc2)CC(=O)N1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1=C(C(=O)Nc2cc3c(Cl)n[nH]c3cc2F)C(c2ccc(Cl)cc2)CC(=O)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 25.6 %

Procedure:
The product from Example 39, Step 2 (210 mg, 1.129 mmol, 1.0 equiv) was combined with the product from Example 4, Step 2 (300 mg, 1.129 mmol, 1.0 equiv), EDC (260 mg, 1.355 mmol, 1.2 equiv) and Et3N (189 μL, 1.355 mmol, 1.2 equiv) in DMF (3 mL) and stirred at room temperature for 18 hours. The reaction mixture was diluted with EtOAc and 1N HCl. The phases were separated, and the organic phase was washed twice with 1N HCl, once with satd. NaHCO3, and once with satd. NaCl. The organic phase was concentrated en vacuo. The residue was purified by flash chromatography (20-100% EtOAc in Hexanes) and further purified by reverse-phase HPLC (17-90% CH3CN/H2O, 0.1% TFA over 13 minutes, retention time 7.5 min) to provide 125 mg (26%) of the title compound as a white solid. MS (ES+) m/e 434 [M+H]+
Reaction SMILES: [CH:1]1([CH2:7][C@@H:8]([NH2:26])[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=[CH:18][N:17]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH:33]1([C:39](Cl)=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>ClCCl.O>[CH:1]1([CH2:7][C@@H:8]([NH:26][C:39]([CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)=[O:40])[CH2:9][N:10]2[CH2:11][CH2:12][N:13]([C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=[CH:18][N:17]=3)[CH2:14][CH2:15]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: N[C@H](CC1CCCCC1)CN1CCN(c2nccc3ccccc23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: O=C(N[C@H](CC1CCCCC1)CN1CCN(c2nccc3ccccc23)CC1)C1CCCCC1
Reaction time: 8 h

Procedure:
To a mixture of 0.25 g (0.64 mmol) of {(1R)-1-cyclohexylmethyl-2-[4-(isoquinolin-1-yl)-piperazin-1-yl]-ethyl}-amine and 0.145 g (1.05 mmol) of anhydrous potassium carbonate in 10 mL of dichloromethane and 1 mL of water at 0° C. was added dropwise 0.10 g (0.70 mmol) of cyclohexanecarboxylic acid chloride. The reaction mixture was allowed to stir under nitrogen overnight, during which time it came up to room temperature. The phases were separated and the aqueous phase was extracted with four additional 10 mL portions of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to yield the crude product, which was purified by flash chromatography on silica gel (dichloromethane/methanol) and converted to the hydrochloride salt of the title compound with isopropanolic HCl to yield 0.17 g (58%) as a white solid; mp=155-159° C.; MS (+) ESI m/z=463 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[CH:12]=[C:13]([CH:25]=[CH:26][CH:27]=2)[C:14]([NH:16][C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])=[O:15])=O)[CH:5]=[CH:4][N:3]=1.C1C(=O)N(Br)C(=O)C1.[F:36][C:37]([F:46])([F:45])[C:38]1[CH:43]=[CH:42][N:41]=[C:40]([NH2:44])[CH:39]=1.CCCCCC>C(Cl)Cl.CCOC(C)=O.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[N:41]3[CH:42]=[CH:43][C:38]([C:37]([F:45])([F:36])[F:46])=[CH:39][C:40]3=[N:44][C:9]=2[C:11]2[CH:12]=[C:13]([CH:25]=[CH:26][CH:27]=2)[C:14]([NH:16][C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])=[O:15])[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cc(C(F)(F)F)ccn1
Reactant: O=C(Cc1ccnc(Cl)n1)c1cccc(C(=O)Nc2c(F)cccc2F)c1
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3cc(C(F)(F)F)ccn3c2-c2ccnc(Cl)n2)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 45.6 %

Procedure:
To a stirred solution of 3-[(2-chloro-4-pyrimidinyl)acetyl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1, step B) (0.4 g, 1.03 mmol) in DCM (10 mL) at rt under N2 was added NBS (0.193 g, 1.09 mmol). The reaction was stirred approximately 30 min, then concentrated under vacuum to a foam like solid. The solid was dissolved in dioxane (10 mL) and 4-(trifluoromethyl)-2-pyridinamine (0.5 g, 3.10 mmol) was added. The reaction was stirred under nitrogen, heated to 80° C., and stirred for approximately 48 h, then cooled to rt. The reaction was diluted with EtOAc and half-saturated aqueous NaHCO3. The organic layer was separated and washed brine. The combined aqueous layers were extracted with EtOAc (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography to give a yellow solid. The solid was dissolved in minimal DCM and hexane was added until a precipitate formed. The slurry was filtered, washing the solids with cold hexane. The solids were dried under vacuum, however proton NMR indicates impurities so the solid was dissolved in minimal DCM and ether was added until a precipitate formed. The slurry was filtered, washing the solids with cold ether. The solids were dried under vacuum to give the title compound of step A (0.250 g, 0.47 mmol, 46%) as a white solid. MS (ESI): 530 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Li]CCCC.[CH2:15](Br)[CH:16]=[C:17]([CH3:19])[CH3:18]>C1COCC1>[CH2:15]([C:2]1[NH:1][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:16]=[C:17]([CH3:19])[CH3:18]
Reactant: c1ccc2[nH]ccc2c1
Reactant: CC(C)=CCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)=CCc1cc2ccccc2[nH]1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To silyl protected indole B (724 mmol, 1.52 mmol) in THF was added a few 4 Å molecular sieves and the mixture was cooled to −78° C. After n-BuLi (0.75 ml, 2.3M in hexanes) was added, the mixture was stirred for 20 min and prenyl bromide (420 mmol, 2.82 mmol) was added. The next day the reaction mixture was quenched by addition of NH4Cl (sat), and extracted with Et2O. The combined organic layers were washed with brine, dried (MgSO4), and filtered, and the filtrated was concentrated in vacuo. Final purification by flash column chromatography (5% EtOAc in hexanes) afforded prenyl indole C (560 mg, 68%) as well as recovered starting material (76 mg, 10%): 1H NMR δ 7.91 (d, J=0.8 Hz, 1H), 7.73 (d, J=8.4 Hz, 2H), 7.25, (d, J=8.5 Hz, 2H), 6.99 (s, 1H), 6.52 (d, J=0.8 Hz, 1H), 5.47 (m, 1H), 5.31 (s, 2H), 4.90 (s, 2H), 3.74 (d, J=7.2 Hz, 2H), 3.55 (s, 3H), 2.40 (s, 3H), 1.86 (s, 3H), 1.71 (s, 3H) 1.05 (s, 9H), 0.20 (s, 6H); 13C NMR δ 149.5, 144.5, 139.9, 138.7, 138.6, 136.5, 134.5, 129.7 (2C), 126.3 (2C), 119.8, 119.6, 106.5, 106.3, 105.3, 94.8, 65.5, 56.0, 27.9, 25.9 (3C), 25.7, 21.4, 18.3, 17.7, −5.2 (2C); HRMS (EI+) calcd for C29H41NO5SSi [M+] 543.2475. found 543.2476.
Reaction SMILES: Br[C:2]1[S:3][C:4]([Br:7])=[CH:5][N:6]=1.[CH3:8][NH:9][CH2:10][CH2:11][NH2:12].ClCCCl.CCO>C(O)(C)C.[Cu].[Cu]Cl>[Br:7][C:4]1[S:3][C:2]([N:9]([CH3:8])[CH2:10][CH2:11][NH2:12])=[N:6][CH:5]=1
Reactant: Brc1cnc(Br)s1
Reactant: CNCCN
Agent: Cl[Cu]
Agent: [Cu]
Solvent: CC(C)O
Solvent: CCO
Solvent: ClCCCl
Product: CN(CCN)c1ncc(Br)s1
Temperature: 70 °C
Yield: 36.6 %

Procedure:
15 mg (0.24 mmol) of copper and 68 mg (0.69 mmol) of copper(I) chloride were added to a solution of 1.0 g (4.1 mmol) of 2,5-dibromothiazole and 2.2 ml (24.7 mmol) of N-methylethylenediamine in isopropanol (2.3 ml). The mixture was then heated to 70° C. for 1 h. After cooling to RT, filtration through silica gel was carried out and the filtrate was evaporated under a vacuum. 348 mg (1.5 mmol, 36%) of N1-(5-bromothiazol-2-yl)-N1-methylethane-1,2-diamine were obtained by CC (DCE/EtOH/conc. aq. NH4—OH soln. 5:1:0.06) with the residue.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[N:9]=2)=[CH:6][C:5]([C@H:34]([N:36]2[CH2:41][CH2:40][N:39]([S:42]([CH3:45])(=[O:44])=[O:43])[CH2:38][CH2:37]2)[CH3:35])=[CH:4][N:3]=1.[F:46][C:47]1[CH:56]=[C:55]([NH2:57])[CH:54]=[C:53]2[C:48]=1[CH:49]=[CH:50][CH:51]=[N:52]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1.[NH4+].[Cl-]>[CH3:24][O:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][N:15]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[C:10]2[N:11]=[C:12]([CH3:14])[N:13]=[C:8]([C:7]3[C:2]([NH:57][C:55]4[CH:54]=[C:53]5[C:48]([CH:49]=[CH:50][CH:51]=[N:52]5)=[C:47]([F:46])[CH:56]=4)=[N:3][CH:4]=[C:5]([C@H:34]([N:36]4[CH2:41][CH2:40][N:39]([S:42]([CH3:45])(=[O:43])=[O:44])[CH2:38][CH2:37]4)[CH3:35])[CH:6]=3)[N:9]=2)=[CH:22][CH:21]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc([C@@H](C)N4CCN(S(C)(=O)=O)CC4)cnc3F)n2)cc1
Reactant: Nc1cc(F)c2cccnc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc([C@@H](C)N4CCN(S(C)(=O)=O)CC4)cnc3Nc3cc(F)c4cccnc4c3)n2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.4 %

Procedure:
A mixture of (R)-4-(2-fluoro-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (Example 146, Step 6) (140 mg, 0.220 mmol), 5-fluoroquinolin-7-amine (35.7 mg, 0.220 mmol) and lithium bis(trimethylsilyl)amide (1.0 M in THF; 0.661 mL, 0.661 mmol, Aldrich) in THF (3 mL) was stirred at 0° C. for 1 h. The reaction mixture was diluted with saturated NH4Cl (10 mL) and extracted with EtOAc (2×30 mL). The organic extract was washed with saturated NaCl (10 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as yellow oil. The crude product was purified by silica gel chromatography eluting with EtOAc to give (R)—N-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-2-yl)-5-fluoroquinolin-7-amine (122 mg, 0.157 mmol, 71.2% yield). 1H NMR (300 MHz, CDCl3) δ 1.40 (d, J=6.72 Hz, 3H) 2.57 (dd, J=11.91, 4.17 Hz, 4H) 2.65 (s, 3H) 2.67 (s, 3H) 3.07-3.24 (m, 4H) 3.81 (s, 3H) 4.76-4.98 (m, 4H) 6.86 (dd, J=12.28, 8.62 Hz, 4H) 7.11-7.25 (m, 9H) 7.38-7.52 (m, 1H) 7.82 (d, J=8.48 Hz, 1H) 8.42 (d, J=2.19 Hz, 1H) 8.77 (d, J=2.34 Hz, 1H) 8.91 (d, J=2.49 Hz, 1H) 9.14 (d, J=2.05 Hz, 1H) 12.57 (s, 1H). m/z (ESI, +ve ion) 778.1 (M+H)+.
Reaction SMILES: [H-].[Na+].Br[CH2:4][CH2:5][CH2:6]Br.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]#[N:17])=[C:11]([F:18])[CH:10]=1.[Cl-].[NH4+]>CS(C)=O.C(OCC)C.C(Cl)Cl>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([C:16]#[N:17])[CH2:6][CH2:5][CH2:4]2)=[C:11]([F:18])[CH:10]=1
Reactant: N#CCc1ccc(Br)cc1F
Reactant: BrCCCBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: CCOCC
Solvent: ClCCl
Product: N#CC1(c2ccc(Br)cc2F)CCC1
Reaction time: 2 h

Procedure:
To a slurry of NaH (1.64 g, 60% suspension in mineral oil, 41.1 mmol) in DMSO (19 mL) stirred at room temperature, was added a solution of 1,3-dibromopropane (2.1 mL, 20.6 mmol) and (4-Bromo-2-fluoro-phenyl)-acetonitrile (4.0 g, 18.7 mmol) in diethyl ether (10 mL) slowly keeping the temprature of the reaction between 25 degrees Celsius and 35 degrees Celsius. Stir for two hours after the addition is complete, and pour into saturated ammonium chloride (150 mL). Add 100 ml of CH2Cl2 and separate the layers. Extract the aqueous phase with 2×50 mL CH2Cl2 and combine the organics. After drying the organic liquid over MgSO4, the solids were removed by filtration, and the liquid was concentrated to an oil. The oil was purified by flash chromatography to yield the desired product. Yield: 1.43 g, 30%. MS (APCI) 254 (M+H), 256 (M+2+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18](O)=[O:19])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.Cl.[OH:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH2:25][CH2:26][NH:27][CH2:28]2>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:17]=[C:16]([C:18]([N:27]3[CH2:26][CH2:25][C:24]4[C:29](=[CH:30][CH:31]=[CH:32][C:23]=4[OH:22])[CH2:28]3)=[O:19])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1nc(-c2ccc(F)cc2)nc2ccccc12
Reactant: Oc1cccc2c1CCNC2
Agent: Cl
Product: O=C(c1nc(-c2ccc(F)cc2)nc2ccccc12)N1CCc2c(O)cccc2C1
Yield: 24.2 %

Procedure:
Reaction of 2-(4-fluorophenyl)quinazoline-4-carboxylic acid with 5-hydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 9 (24.2% yield): 1H NMR (300 MHz, DMSO-d6) δ 2.60 and 2.87 (2t, 2H), 3.51 and 4.07 (2t, 2H), 4.45 and 4.96 (2s, 2H), 6.32-6.79 (m, 2H), 6.88 and 7.08 (2t, 1H), 7.37-7.44 (m, 2H), 7.70-7.79 (m, 1H), 7.88-7.99 (2d, 1H), 8.07-8.18 (m, 2H), 8.53-8.62 (m, 2H), 9.50 and 9.55 (2s, 1H); 19F (282 MHz, DMSO-d6) δ −110.0; MS (ESI) m/z 400 ([M+H]+).
Reaction SMILES: F[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH3:20])[CH2:14][CH2:13]1.[C-:21]#[N:22].[Na+].C1OCCOCCOCCOCCOCCOC1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH2:18]([N:15]1[CH2:16][CH2:17][CH:12]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([F:11])([F:10])[F:9])[C:2]=2[C:21]#[N:22])[CH2:13][CH2:14]1)[CH2:19][CH3:20]
Reactant: CCCN1CCC(c2cccc(C(F)(F)F)c2F)CC1
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN1CCC(c2cccc(C(F)(F)F)c2C#N)CC1

Procedure:
To a solution of 4-[2-fluoro-3-(trifluoromethyl)phenyl]-1-propylpiperidine (1.57 g, 5.4 mmol) in N,N-dimethylformamide (35 ml) was added sodium cyanide (1.0 g, 20 mmol) and 18-crown-6-ether (50 mg). The mixture was heated at reflux for 15 h and then brought to ambient temperature. Aqueous sodium carbonate (10%, 50 ml) was added and the phases were separated. The aqueous phase was extracted with ethylacetate (2×50 ml) and the combined organic phases was dried (MgSO4) and evaporated under reduced pressure to give an oil. Purification by flash column chromatography (ethylacetate/methanol, 1:1) gave the title compound: 0.72 g (45%). The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 272-274° C. MS m/z (relative intensity, 70 eV) 296 (M+, 4), 268 (16), 267 (bp),204 (3), 184 (3).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]([O:20]CC2C=CC(OC)=CC=2)=[CH:8][N:7]=1)(=[O:3])[CH3:2].C([SiH](CC)CC)C.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>ClCCl>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:9]([OH:20])=[CH:8][N:7]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(COc2cnc(COC(C)=O)cc2OCc2ccccc2)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OCc1cc(OCc2ccccc2)c(O)cn1

Procedure:
A solution of {5-({[4-(methyloxy)phenyl]methyl}oxy)-4-[(phenylmethyl)oxy]-2-pyridinyl}methyl acetate (26.3 g, 67 mmol) in dichloromethane (700 ml) was treated with triethylsilane (10 ml, 62.6 mmol)and trifluoroacetic acid (35 ml). After 16 hours the mixture was evaporated and triturated with toluene/ethyl acetate (250 ml/5 ml) affording a white solid that was isolated by filtration and dried in vacuo (22.5 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[O:6][C@@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[N:9]2)[CH2:4][O:3]1.[H][H]>[Pd].C(O)C>[CH3:1][C:2]1([CH3:16])[O:6][C@@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH2:13])=[N:9]2)[CH2:4][O:3]1
Reactant: CC1(C)OC[C@H](Cn2ccc([N+](=O)[O-])n2)O1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC1(C)OC[C@H](Cn2ccc(N)n2)O1
Yield: 90.5 %

Procedure:
In a Parr shaker bottle was placed 1-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-3-nitro-1H-pyrazole (700 mg, 3.08 mmol), 10% palladium on carbon (500 mg) and ethanol (25 mL). The bottle was then placed on the Parr shaker at 50 psi of hydrogen pressure for 4 h. The reaction was then filtered through a pad of celite and washed with ethanol and concentrated in vacuo to afford 1-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (550 mg, 91%) as a yellow oil: LR-ES-MS m/z calculated for C9H15N3O2 [M]+ 197, observed 198 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([NH:20][C:21](=[O:26])[CH:22]=[CH:23][CH2:24]Br)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:31][O:32][CH2:33][CH2:34][NH:35][CH2:36][CH2:37][O:38][CH3:39]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([NH:20][C:21](=[O:26])[CH:22]=[CH:23][CH2:24][N:35]([CH2:36][CH2:37][O:38][CH3:39])[CH2:34][CH2:33][O:32][CH3:31])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCBr
Reactant: COCCNCCOC
Product: COCCN(CC=CC(=O)Nc1cc2c(Nc3ccc(F)c(Cl)c3)c(C#N)cnc2cc1OC)CCOC

Procedure:
In the mamner of Example 103, 4-bromo-but-2-enoic acid[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-methoxy-quinolin-6-yl]-amide and bis-(2-methoxy-ethyl)-amine was converted to 52.3 mg of the title compound as the bis-trifluoroacetate salt mass spectrum (electrospray, m/e): M+H 542.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]2[C:18]([NH2:20])=[O:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=1>>[C:29]([C:26]1[CH:25]=[CH:24][C:23]([CH2:22][N:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:9])=[O:10])[C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]2[C:18]([NH2:20])=[O:19])=[CH:28][CH:27]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: NC(=O)[C@H]1CCCC[C@H]1NS(=O)(=O)c1ccc(Cl)cc1
Product: CC(C)(C)c1ccc(CN([C@@H]2CCCC[C@@H]2C(N)=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Yield: 69 %

Procedure:
The titled compound was prepared in 69% yield from (1S,2R)-2-(4-chlorobenzenesulfonylamino)-cyclohexanecarboxylic acid amide (75 mg, 0.237 mmol) and 1-bromomethyl-4-tert-butyl-benzene (57 mg, 0.249 mmol) according to the procedure described for Example 3: 1H NMR (500 Mz, DMSO) δ 7.58 (d, 2 H, J=8.9), 7.48 (d, 2 H, J=8.6), 7.38 (br s, 1 H), 7.18 (d, 2 H, J=8.2), 7.09 (d, 2 H, J=8.2), 6.76 (br, s, 1 H), 4.53 (ABq, 2 H, Δv=39.4, Jab=16.2), 3. 95 (dt, 1 H, Jd=12.8, Jt=4.0), 2.80 (m, 1 H), 1.79 (m, 1 H), 1.72 (m, 1 H), 1.63 (m, 1 H), 1.48 (m, 2 H), 1.33 (m, 2 H), 1.25 (s, 9 H), 1.18 (m, 2 H); MS m/e 485.3 (M+Na)+.
Reaction SMILES: NC1[CH:3]=[C:4]([C:15](=[O:17])[CH3:16])[N:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[CH:6]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:24][N:25]([CH:27]=O)[CH3:26]>>[CH3:26][N:25]([CH3:24])[C:27]1[CH:3]=[C:4]([C:15](=[O:17])[CH3:16])[N:5]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([F:14])=[CH:12][CH:13]=2)[CH:6]=1
Reactant: CN(C)C=O
Reactant: CC(=O)c1cc(N)cn1Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(=O)c1cc(N(C)C)cn1Cc1ccc(F)cc1
Temperature: 25 °C

Procedure:
To a 100 mL round bottomed flask with a stirring bar and a nitrogen inlet was added 1-[4-amino-1-(4-fluorobenzyl)-1H-pyrrol-2-yl]ethanone AVI-2-1 (0.50 g, 2.15 mmol), dry DMF (20 mL), finely powdered Cs2CO3 (3.26 g, 10 mmol) and Mel (0.31 mL, 5.00 mmol). The resulting mixture was stirred lh at ambient temperature. The solids were removed by filtration and the solvent was removed in vacuo. The residue was dissolved in EtOAc and washed with water (3×) and brine. Drying (MgSO4), filtration and removal of the solvent in vacuo gave an oil. This material was chromatographed on silica gel using 50% EtOAc-hexanes as eluant to give 1-[4-dimethylamino-1-(4-fluorobenzyl)-1H-pyrrol-2-yl]ethanone AVI-3-1 as an oil. 1H NMR (CDCl3) δ 2.36 (3H, s), 2.70 (6H, s), 5.46 (2H, s), 6.36 (1H, d, j=2.0 Hz), 6.50 (1H, d, j=2.0 Hz), 6.98 (2H, m), 7.11 (2H, m).
Reaction SMILES: [CH:1]([N:3]([CH2:12][C@@H:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:14](O)=[O:15])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:2].C(OC(NC[C@@H](CCCCC)C(O)=O)=O)C1C=CC=CC=1.N1C=CC=CC=1.[F:49]C1N=C(F)N=C(F)N=1>ClCCl>[CH:1]([N:3]([CH2:12][C@@H:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:14]([F:49])=[O:15])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:2]
Reactant: CCCCC[C@H](CN(C=O)OCc1ccccc1)C(=O)O
Reactant: Fc1nc(F)nc(F)n1
Agent: CCCCC[C@H](CNC(=O)OCc1ccccc1)C(=O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCC[C@H](CN(C=O)OCc1ccccc1)C(=O)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
To a 250 mL round-bottomed flask was added (2R)-2-({formyl[(phenylmethyl)oxy]amino}methyl)heptanoic acid (WO 2003101442, also named (2R)-[(benzyloxyformylamino)methyl]heptanoic acid) (4.40 g, 15 mmol) in dichloromethane (60 mL), followed by pyridine (1.453 mL, 18.00 mmol) and 2,4,6-trifluoro-1,3,5-triazine (cyanuric fluoride) (2.168 g, 16.05 mmol). The reaction mixture was stirred at room temperature for 2 h, then was diluted with DCM, and washed with 5% Citric acid (150 mL) and sat. NaHCO3 (150 mL). The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography to provide (2R)-2-({formyl[(phenylmethyl)oxy]amino}methyl)heptanoyl fluoride as a colorless oil (1.88 g, 42%). LCMS: (M+H)+: 296.0.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>CN(C=O)C>[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([C:2]2[N:11]=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])[CH2:21][CH2:20]1
Reactant: COC(=O)c1cccnc1Cl
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccnc1N1CCN(C)CC1

Procedure:
3.4 g of methyl chloronicotinate, 5.5 g of potassium carbonate and 2.0 g of N-methylpiperazine were reacted in 50 ml of DMF analogously to Example 1a, 3.9 g (82%) of the product being obtained.
Reaction SMILES: [OH-].[Na+].O.[OH:4][CH2:5][P:6](=[O:15])([O:11][CH:12]([CH3:14])[CH3:13])[O:7][CH:8]([CH3:10])[CH3:9].[F:16][C:17]([F:30])([F:29])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=1[S:25](Cl)(=[O:27])=[O:26]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C1(C)C=CC=CC=1>[F:30][C:17]([F:16])([F:29])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=1[S:25]([O:4][CH2:5][P:6](=[O:15])([O:7][CH:8]([CH3:10])[CH3:9])[O:11][CH:12]([CH3:14])[CH3:13])(=[O:27])=[O:26]
Reactant: Cc1cccc(C(F)(F)F)c1S(=O)(=O)Cl
Reactant: CC(C)OP(=O)(CO)OC(C)C
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cccc(C(F)(F)F)c1S(=O)(=O)OCP(=O)(OC(C)C)OC(C)C
Yield: 94.8 %

Procedure:
A mixture of 100 mL of toluene, 11.6 g of 50% aqueous sodium hydroxide solution, and 10 mL of water was cooled in an ice bath and treated with 1.3 g of benzyltriethylammonium chloride and 12.0 g of diisopropyl P-(hydroxymethyl)phosphonate (prepared as in U.S. Pat. No. 5,272,128) and stirred vigorously. To this was added a solution of 15 g of the compound of Example 16 (2-trifluoromethyl-6-methylbenzenesulfonyl chloride) in 10 mL of toluene. The cooling bath was removed and the mixture stirred for one hour, then the layers were separated. The organic phase was washed with water (2×100 mL) and brine, then dried through calcium sulfate to yield 23 g of di-O-isopropyl P-[[(2-trifluoromethyl-6-methylphenyl)sulfonyloxy]methyl]phosphonate as a brown oil.