Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>C1(C)C=CC=CC=1>[N:12]1([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: C1CNCCN1
Reactant: Clc1ccnc2ccccc12
Solvent: Cc1ccccc1
Product: c1ccc2c(N3CCNCC3)ccnc2c1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of 4-chloroquinoline (2.0 g, 12.2 mmol) in toluene (100 mL) was added piperazine (7.98 g, 92.7 mmol). The reaction mixture was heated to reflux and stirred for 96 hours, after which it was cooled to room temperature and then further cooled to 0° C. The resulting mixture was filtered to remove the hydrochloride salts that had precipitated. After washing the salts with toluene, the combined filtrate was washed with 10% aqueous acetic acid (2×25 mL). The combined aqueous extracts were washed with diethyl ether (25 mL) and then basified to pH 8-10 by adding 1M NaOH. The resulting aqueous mixture was extracted with dichloromethane (3×25 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation. The crude residue, 4-Piperazinylquinoline, was obtained as a yellow solid (2.54 g, 97%) and used without further purification. 1H NMR was consistent with that reported in the literature (Abel, M. D., et al., Journal of Heterocyclic Chemistry (1996), 33(2), 415-420).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.Cl.[CH3:33][C:34]1[CH:39]=[CH:38][C:37]([NH:40]N)=[CH:36][CH:35]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:40][C:37]3[C:38]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:39][C:34]([CH3:33])=[CH:35][CH:36]=3)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(Cl)cc3)CC2)c1
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Product: Cc1ccc2[nH]c(-c3ccc(Cl)cc3)c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c2c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(4-chlorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-methylphenylhydrazine hydrochloride: ESMS m/e: 528.2 (M+H)+.
Reaction SMILES: B(F)(F)F.CCOCC.[CH3:10][O:11]/[CH:12]=[CH:13]/[C:14]([O:16][Si](C)(C)C)=[CH2:15].[C:21]1([CH:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)C=O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CCOCC>[CH:27]([CH:10]1[CH2:15][C:14](=[O:16])[CH:13]=[CH:12][O:11]1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=CC(c1ccccc1)c1ccccc1
Reactant: C=C(/C=C/OC)O[Si](C)(C)C
Agent: FB(F)F
Solvent: CCOCC
Product: O=C1C=COC(C(c2ccccc2)c2ccccc2)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 80.4 %

Procedure:
A solution of boron trifluoride diethyl etherate (7.8 g, 55 mmol) in dry ether (50 ml) was added to a stirred mixture of E-1-methoxy-3-trimethylsilyloxybuta-1,3-diene (8.3 g, 48 mmol), diphenylacetaldehyde 1 (11.4 g, 58 mmol) and dry ether (300 ml) cooled to −78° C. After one hour, the mixture was allowed to reach 0° C. for three hours. The deep red reaction mixture was quenched with saturated aqueous NaHCO3, and the mixture was allowed to come to room temperature. The organic phase was separated and the aqueous phase was extracted with ether (3×70 ml). The combined organic phases were washed with brine, and dried over anhydrous Na2SO4. Evaporation of solvent under reduced pressure and purification of the crude product by chromatography (hexane/ethyl acetate 8:2) gave 2-diphenylmethyl-2,3-dihydro-4H-pyran-4-one 2 (10.2 g, 80.2%, yield) as a yellow solid.
Reaction SMILES: [C:1]([NH:4][N:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[NH:3])[NH2:2].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[C:18](=O)[CH2:19]Br>C(O)C>[NH2:3][C:1]1[N:4]([N:5]=[CH:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:19]=[C:18]([C:17]2[CH:22]=[CH:23][CH:24]=[C:15]([O:14][CH3:13])[CH:16]=2)[N:2]=1
Reactant: COc1cccc(C(=O)CBr)c1
Reactant: N=C(N)NN=Cc1ccccc1
Solvent: CCO
Product: COc1cccc(-c2cn(N=Cc3ccccc3)c(N)n2)c1

Procedure:
A solution of 16.2 g (0.1 mol) of benzaldehyde guanylhydrazone and 11.8 g (0.050 mol) of 3-methoxyphenacyl bromide (Aldrich, Buchs, Switzerland; 98 %, Cat. no. 11,567-3) in 50 ml of ethanol is stirred at 20° C. for 3 hours. The product that has crystallized out is filtered off with suction and dried. In that manner there is obtained the title compound, m.p. 170°-171° C., 1H-NMR (DMSO): δ=8.56 (s, 1H); 8.03 (s, 1H); 7.92 (m, 2H); 7.5 (m, 3H); 7.26 (m, 3H); 6.76 (m, 1H); 6.2 (s, 2H); 3.8 (s, 3H).
Reaction SMILES: [C:1]([N:9]([CH2:11][C:12](O)=O)[CH3:10])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C.[C:22]1(=[O:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25](=[O:32])[CH:24]=C1>C1(C)C=CC=CC=1>[CH3:10][N:9]1[C:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:24]2[C:12]([C:22](=[O:33])[C:31]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:25]2=[O:32])=[CH:11]1
Reactant: O=C1C=CC(=O)c2ccccc21
Reactant: CN(CC(=O)O)C(=O)c1ccccc1
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: Cn1cc2c(c1-c1ccccc1)C(=O)c1ccccc1C2=O
Reaction time: 0.25 h
Yield: 19.7 %

Procedure:
N-Benzoylsarcosine (3.86 g, 0.020 mol) was dissolved in 7 mL (0.070 mol) of acetic anhydride and heated until a yellow color was observed. Forty milliliters of toluene was added to the reaction flask after the color change was observed. After stirring for 15 minutes, 3.16 g (0.020 mol) of 1,4-naphthoquinone was added. The resulting black mixture was heated for 1.5 hours, then stirred at room temperature overnight. The mixture was filtered to yield 1.13 g (19%) of yellow-brown solid. The solid was recrystallized several times from toluene to give bright yellow crystals: mp 268°-271° C.; IR 1655 and 1645 (C=0) cm-1 ; H-1 NMR (CDCl3) δ 3.60 (s, 3, NCH3), 7.10-7.75 (complex m and s, 8, ArH and pyrrole H), 7.95-8.30 (m, 2, ArH); MS m/e 287 M+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([CH:17]=1)[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1)=[O:8].[H-].[Na+].F[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N+:28]([O-:30])=[O:29]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([CH:17]=1)[C:7]([N:9]([CH:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N+:28]([O-:30])=[O:29])=[O:8]
Reactant: CN1CCC(NC(=O)c2cc(Cl)ccc2F)CC1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCC(N(C(=O)c2cc(Cl)ccc2F)c2ccccc2[N+](=O)[O-])CC1
Reaction time: 0.67 h

Procedure:
A mixture of 31.3 g 5-chloro-2-fluoro-N-(1-methyl-4-piperidinyl)-benzamide, 5.6 g of 55% sodium hydride/oil dispersion and 250 ml dimethylformamide are stirred at 45° for 40 minutes. Thereafter 29.7 g 2-fluoro-nitrobenzene are added and stirring is continued at 50° for 80 hours. The solvent is evaporated in vacuo and the residue partitioned between 2 N hydrochloric acid and toluene. The acid phase is made alkaline with 2 N sodium hydroxide and extracted with methylene chloride. The organic phase is dried and evaporated in vacuo to give the heading compound, which recrystallised from ether has a m.p. 164°-166°.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12](CC3C=CC(CCC(O)=O)=CC=3)[C:11]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:10]=3[N:9]=2)=[C:4](OCC2CCCC2)[CH:3]=1.FC1C=C(N)C(N)=CC=1F.[Br:48]C1C=CC=CC=1C(O)=O>>[Br:48][C:4]1[CH:3]=[CH:2][CH:7]=[CH:6][C:5]=1[C:8]1[NH:12][C:11]2[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:10]=2[N:9]=1
Reactant: O=C(O)c1ccccc1Br
Reactant: O=C(O)CCc1ccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)cc1
Agent: Nc1cc(F)c(F)cc1N
Product: Fc1cc2nc(-c3ccccc3Br)[nH]c2cc1F

Procedure:
The title compound was prepared in analogy to Example 19, intermediate b, from 4,5-difluoro-benzene-1,2-diamine (CAS Reg. No. 76179-40-3) and 2-bromo-benzoic acid (CAS Reg. No. 88-65-3). Colorless powder (75%). MS (Turbo Spray): m/z=309.2 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C:9]1[C:10]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][N:28]([CH:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:23][CH:22]=3)[CH:17]=2)=[N:11][C:12](Br)=[CH:13][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH3:55][C:56]([C:60]1[CH:65]=[C:64](B2OC(C)(C)C(C)(C)O2)[CH:63]=[CH:62][N:61]=1)([CH3:59])[C:57]#[N:58]>C1(C)C=CC=CC=1.O>[C:1]([O:5][C:6]([N:8]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C:9]1[C:10]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][N:28]([CH:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:23][CH:22]=3)[CH:17]=2)=[N:11][C:12]([C:64]2[CH:63]=[CH:62][N:61]=[C:60]([C:56]([C:57]#[N:58])([CH3:59])[CH3:55])[CH:65]=2)=[CH:13][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C#N)c1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)nc1-c1cc(-c2ccc(CN(C(=O)OC(C)(C)C)C3CCOCC3)cc2)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(-c2ccnc(C(C)(C)C#N)c2)nc1-c1cc(-c2ccc(CN(C(=O)OC(C)(C)C)C3CCOCC3)cc2)no1
Temperature: 70 °C
Yield: 68.1 %

Procedure:
A mixture of tert-butyl N-[[4-[5-[3-[bis(tert-butoxycarbonyl)amino]-6-bromo-pyrazin-2-yl]isoxazol-3-yl]phenyl]methyl]-N-tetrahydropyran-4-yl-carbamate (110.0 g, 151 mmol), K2CO3 (41.6 g, 301 mmol), and 2-methyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]propanenitrile (41.0 g, 151 mmol) in toluene (770 mL) and water (220 mL) is stirred and degassed with N2 for 30 min. at 20° C. The catalyst Pd(dtbpf)Cl2 (1.96 g, 3.01 mmol) is added and the mixture is degassed for an additional 10 min. The mixture is heated at 70° C. until the reaction is complete. The mixture is cooled to ambient temperature, diluted with water (220 mL), and filtered through a bed of Celite. The organic phase is concentrated to remove most of the solvent. The concentrate is diluted with i-PrOH (550 mL). The resultant suspension is stirred for at least 1 h and then the solid is collected by filtration to afford a tan powder. The solid is dissolved in toluene (990 mL) and stirred with Biotage MP-TMT resin (18.6 g) for 2 h at ambient temperature. The resin is removed by filtration. The filtrate is concentrated then diluted with i-PrOH (550 mL) and then re-concentrated. Add i-PrOH (550 mL) and stir for 1 h at ambient temperature. Cool the suspension to 5° C. and collect the solid by filtration then dry to afford tert-butyl N-[[4-[5-[3-[bis(tert-butoxycarbonyl)amino]-6-[2-(1-cyano-1-methyl-ethyl)-4-pyridyl]pyrazin-2-yl]isoxazol-3-yl]phenyl]methyl]-N-tetrahydropyran-4-yl-carbamate (Compound I-1) (81.9 g; 68%, yield, 98.7 area % purity by HPLC) as a cream-colored powder.
Reaction SMILES: [C:1]12([NH:11][C:12](=[O:20])[NH:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:21]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[CH3:21][O:18][C:17](=[O:19])[CH2:16][CH2:15][CH2:14][NH:13][C:12]([NH:11][C:1]12[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2)=[O:20]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)CCCNC(=O)NC12CC3CC(CC(C3)C1)C2
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)CCCNC(=O)NC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 20 h
Yield: 94.4 %

Procedure:
A mixture of 4-(3-adamantan-1-yl-ureido)butyric acid 822 (0.15 g, 0.54 mmol), K2CO3 (0.09 g, 0.64 mmol), and iodomethane (0.04 mL, 0.59 mmol) in DMF (20 mL) was stirred at room temperature for 20 h. Then the product was extracted with ether (20 mL), and the ether was washed with 1 N NaOH aqueous solution (20 mL) and brine (20 mL), dried over Na2SO4, and evaporated to afford 0.15 g (95%) of 883: 1H NMR (CDCl3) 1.66-1.68 (6H, m), 1.81 (2H, quint, J=6.9 Hz), 1.94-1.97 (6H, m), 2.05-2.07 (3H, m), 2.37 (2H, t, J=6.9 Hz), 3.16 (2H, q, J=6.9 Hz), 3.68 (3H, s), 4.09 (1H, s), 4.25 (1H, s); LC-MS (ESI) m/z calcd for C16H26N2O3 [M+H]+ 295.19. found [M+H]+ 295.24; mp 114 C. Anal. (C16H26N2O3) C, H, N.
Reaction SMILES: [F:1][C:2]1[N:3]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][C:6]=1[CH2:7][OH:8].C[N+]1([O-])CCOCC1>C(#N)C.C(OCC)(=O)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[F:1][C:2]1[N:3]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:4]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][C:6]=1[CH:7]=[O:8]
Reactant: O=S(=O)(c1ccccc1)n1c(-c2ccccc2)cc(CO)c1F
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=Cc1cc(-c2ccccc2)n(S(=O)(=O)c2ccccc2)c1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 33.5 %

Procedure:
To a solution (20 mL) of [2-fluoro-5-phenyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methanol (330 mg) in acetonitrile were added tetra-n-propylammonium perruthenate (53 mg), N-methylmorpholine N-oxide (270 mg) and molecular sieves 4A powder (500 mg), and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was diluted with ethyl acetate, filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→4:1) to give the title compound as a colorless oil (yield 110 mg, 34%).
Reaction SMILES: C(O)(=O)C.[BrH:5].C(O)(=O)C.C(O[C@@H:14]1[O:31][CH2:30][C@@H:25]([O:26][C:27](=[O:29])[CH3:28])[C@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:15]1[O:16][C:17](=[O:19])[CH3:18])(=O)C>C(Cl)(Cl)Cl>[C:17]([O:16][C@@H:15]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:25]([O:26][C:27](=[O:29])[CH3:28])[CH2:30][O:31][C@@H:14]1[Br:5])(=[O:19])[CH3:18]
Reactant: Br
Reactant: CC(=O)O[C@@H]1OC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CO[C@@H]1Br
Temperature: 25 °C

Procedure:
Acetic acid (6 mL) and a 30% hydrobromic acid-acetic acid solution (25 mL) were put in a 100 mL round bottom flask containing 1,2,3,4-tetra-O-acetyl β-D-xylose (5.0 g, 15.7 mmol) and stirred at room temperature for an hour. Chloroform (100 mL) was poured into the reaction mixture. The resulting mixture was washed with water (100 mL×2) and with a saturated aqueous solution of sodium hydrogen carbonate (100 mL×1), and dried over calcium chloride for 10 minutes. The resulting mixture was concentrated to 20 mL. To the resulting mixture, diethyl ether (8 mL) was added, followed by stirring. Petroleum ether (5 mL) was quietly added to the resulting mixture, which was cooled in the freezer for crystallization. The crystals are filtered by suction, washed with cold ether and dried to give the title compound. White acicular crystals. Yield 4.6 g, 87%. The product was unstable at room temperature, and stored in the freezer.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[NH:10][C:11](=[O:17])[CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14].C(N(CC)C(C)C)(C)C.Br[CH2:28][CH2:29][O:30][CH2:31][CH2:32]Br.C(=O)(O)[O-].[Na+]>CN(C)C=O>[Br:8][C:6]1[CH:7]=[C:2]([N:1]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[C:3]([NH:10][C:11](=[O:17])[CH2:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[C:4]([CH3:9])[CH:5]=1
Reactant: BrCCOCCBr
Reactant: Cc1cc(Br)cc(N)c1NC(=O)CC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(Br)cc(N2CCOCC2)c1NC(=O)CC(C)(C)C
Temperature: 180 °C
Yield: 60 %

Procedure:
N-(2-Amino-4-bromo-6-methyl-phenyl)-3,3-dimethyl-butyramide (1v, 1.01 g), N,N-diisopropyl-ethylamine (1.80 mL) and bis(2-bromoethyl)ether (0.50 mL) were dissolved in dry N,N-dimethylformamide (5 mL) and heated to 180° C. for 50 minutes in a sealed microwave process vial. Saturated aqueous sodium bicarbonate (20 mL) was added and the mixture was extracted with ethyl acetate (3×20 mL), the combined organic phases were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography to furnish 0.740 g (60% yield) of the title compound as a white solid. LC-MS (m/z) 370 (MH+); tR=3.05, (UV, ELSD) 95%, 99%. 1H NMR (500 MHz, DMSO-d6): 1.05 (s, 9H), 2.09 (s, 3H), 2.23 (s, 2H), 2.80 (t, 4H), 3.69 (t, 4H), 7.03 (d, 1H), 7.15 (d, 1H), 8.99 (s, 1H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][CH:3]=1.[C:10](=[O:13])([O-])[O-].[K+].[K+]>[Cu]I.O1CCOCC1>[OH:9][CH2:8][C:6]1[N:7]=[C:2]([N:7]2[CH2:6][CH2:5][CH2:4][C:10]2=[O:13])[CH:3]=[CH:4][CH:5]=1
Reactant: OCc1cccc(Br)n1
Reactant: O=C([O-])[O-]
Agent: [Cu]I
Agent: [K+]
Solvent: C1COCCO1
Product: O=C1CCCN1c1cccc(CO)n1
Yield: 204.3 %

Procedure:
A mixture of (6-bromopyridine-2-methanol (9.76 g, 51.9 mmol), copper(I) iodide (0.99 g, 5.19 mmol) N,N′-dimethylethane-1,2-diamine (1.12 mL, 10.38 mmol), 1,4-dioxane (400 mL) and potassium carbonate (14.35 g, 103.84 mmol) was heated at reflux for 8 h, cooled, concentrated in vacuo and partitioned between EtOAc and water. The organic phase was separated, the aqueous phase re-extracted with EtOAc and the combined organic extracts were dried (MgSO4) and concentrated in vacuo to give the title compound (10.19 g, quantitative) as a pale-yellow solid; NMR δH (400 MHz, CDCl3) 8.32 (1H, d, J 8.5 Hz), 7.69 (1H, dd, J 8.5, 7.5 Hz), 6.96 (1H, dd, J 7.5, 1.5 Hz), 4.71 (2H, d, J 5.0 Hz), 4.17-4.13 (2H, m), 3.50 (1H, t, J 5.0 Hz), 2.70-2.66 (2H, m), 2.19-2.11 (2H, m); (M+H)+ 193; LC-MS Retention time 1.46 min.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][NH:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:9]1)=O)(C)(C)C.[ClH:26].O1CCOCC1>C(OCC)(=O)C>[ClH:26].[CH2:19]([O:18][C:16]([NH:15][CH2:14][CH:10]1[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]1)=[O:17])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(CNC(=O)OCc2ccccc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(NCC1CCCNC1)OCc1ccccc1
Reaction time: 1.33 h
Yield: 84 %

Procedure:
A solution of 3-(benzyloxycarbonylaminomethyl)-piperidine-1-carboxylic acid tert-butyl ester (594 mg, 1.7 mmol) in ethyl acetate (10 mL) was stirred on an ice bath and treated with a solution of hydrogen chloride in dioxane (4.0 N, 10 mL, 40 mmol). The mixture was stirred for 80 minutes, then was concentrated under vacuum. The gummy residue was triturated repeatedly in ether to provide a white powder (408 mg, 84%)which was extremely hygroscopic and was used without further purification. 1H NMR (300 MHz, CD3OD) δ7.34 (m, 5H), 5.07 (s, 2H), 3.34 (m, 2H), 3.09 (m, 2H), 2.88 (m, 1H), 2.66 (m, 1H), 1.90 (m, 3H), 1.70 (m, 1H), 1.30 (m, 1H).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].[NH2:31][C:32]1[CH:47]=[CH:46][C:35]([O:36][CH2:37][CH:38]([OH:45])[CH2:39][N:40]([CH2:43][CH3:44])[CH2:41][CH3:42])=[CH:34][CH:33]=1>C1COCC1>[CH2:43]([N:40]([CH2:41][CH3:42])[CH2:39][CH:38]([OH:45])[CH2:37][O:36][C:35]1[CH:34]=[CH:33][C:32]([NH:31][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:15]=[C:16]([NH:20][C:21]([C:23]5[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=5)=[O:22])[CH:17]=[CH:18][CH:19]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:30])=[CH:47][CH:46]=1)[CH3:44]
Reactant: CCN(CC)CC(O)COc1ccc(N)cc1
Reactant: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)n(C)n1
Solvent: C1CCOC1
Product: CCN(CC)CC(O)COc1ccc(NC=C2C(=O)Nc3cc(C(=O)c4cccc(NC(=O)c5cc(C)nn5C)c4)ccc32)cc1
Temperature: 65 °C
Reaction time: 24 h
Yield: 35 %

Procedure:
A small screw cap test tube was charged with 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 60, 132.3 mg, 0.3288 mmol) and THF (2 mL). To the resulting solution was added 1-(4-Amino-phenoxy)-3-diethylamino-propan-2-ol (prepared below; 95.7 mg, 0.4015 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. The room temperature reaction mixture was concentrated in vacuo. The solid residue was recrystallized from EtOAc (5 mL) and Hexanes (2 mL) yielding the title compound in 35% yield (0.072 g, 0.1156 mmol).
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].F[C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17]>C1COCC1>[CH:1]1([CH2:4][O:5][C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[N+:16]([O-:18])=[O:17])[CH2:3][CH2:2]1
Reactant: OCC1CC1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)cc1OCC1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.7 %

Procedure:
Cyclopropyl methanol (15 g, 207 mmol) was added to a stirred suspension of NaH (60% in mineral oil, 8.37 g) in 200 mL THF over a period of 15 min at 0° C. under an atmosphere of nitrogen. The reaction mixture was allowed to warm to room temperature and stirred for 1 h at RT. The mixture was cooled to 0° C. and a solution of 2,4-difluoro-1-nitrobenzene (30 g, 187 mmol) in 200 mL THF was added in a drop wise manner. The reaction mixture was stirred at 0° C. for 2 h and then poured onto ice water. The mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over MgSO4 and concentrated under reduced pressure to give 22.0 g of 2-(cyclopropylmethoxy)-4-fluoro-1-nitrobenzene as an orange oil (86%).
Reaction SMILES: I[C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[C:16]([C:18]12[CH2:25][CH2:24][CH2:23][N:22]1[CH2:21][CH2:20][CH2:19]2)#[CH:17].Cl>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:19]1[C:18]2([C:16]3[O:8][C:7]4[C:2](=[N:3][CH:4]=[CH:5][CH:6]=4)[CH:17]=3)[N:22]([CH2:23][CH2:24][CH2:25]2)[CH2:21][CH2:20]1
Reactant: Oc1cccnc1I
Reactant: C#CC12CCCN1CCC2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: c1cnc2cc(C34CCCN3CCC4)oc2c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
2-Iodo-3-pyridinol (902 mg, 4.1 mmol), copper(I) iodide (116 mg, 0.61 mmol), bis(triphenylphosphine)palladium(II) chloride (119 mg, 0.17 mmol) and triethylamine (570 mL, 4.1 mmol) were combined in DMF (4.5 mL) and stirred for one hour. 7a-Ethynyl-hexahydro-1H-pyrrolizine(460 mg, 3.4 mmol) in DMF (1.2 mL) was added dropwise and the mixture was heated at 60° C. for 18 h. The reaction mixture was allowed to cool to ambient temperature and 2 N aqueous HCl was added. The heterogeneous mixture was washed with Et2O (2×), basified with 15% NaOH solution and extracted with CH2Cl2 (2×). The CH2Cl2 extracts were combined, dried (MgSO4) concentrated and chromatographed (silica gel; CHCl3 /MeOH, 96:4) to afford an amber oil which solidified upon storage at -20° C. (405 mg, 52%): mp 39-41° C.; 1H NMR (CDCl3, 300 MHz) δ 1.86-1.97 (m, 6H), 2.24-2.34 (m, 2H), 2.68-2.76 (m, 2H), 3.21-3.28 (m, 2H), 6.77 (s, 1H), 7.12 (dd, J=8.5, 5 Hz, 1H), 7.65 (d, J=8.5 Hz, 1H), 8.46 (d, J=5 Hz, 1H); MS (CI/NH3) m/z: 229 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([O:17][CH:18]([CH3:20])[CH3:19])[C:12]([O:14]CC)=[O:13])=[CH:6][C:5]=1[CH2:21][CH2:22][OH:23])[CH3:2].[C:24]1([N:30]=[C:31]=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([O:17][CH:18]([CH3:19])[CH3:20])[C:12]([OH:14])=[O:13])=[CH:6][C:5]=1[CH2:21][CH2:22][O:23][C:31](=[O:32])[NH:30][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(OCC)c(CCO)c1)OC(C)C
Reactant: O=C=Nc1ccccc1
Product: CCOc1ccc(CC(OC(C)C)C(=O)O)cc1CCOC(=O)Nc1ccccc1

Procedure:
Using ethyl 3-[4-ethoxy-3-(2-hydroxyethyl)phenyl]-2-isopropoxypropanoate and phenylisocyanate, the title compound was obtained in the same manner as described in Example 148.