Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O>[CH2:15]([O:8][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[N:7]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: ClCc1ccccc1
Reactant: Oc1cccc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1cccc(OCc2ccccc2)n1
Yield: 93.2 %

Procedure:
To a flask were added 5.0 g 6-chloro-2-hydroxypyridine, 5.3 g potassium carbonate and 75 ml N,N-dimethylformamide. After cooling to 5 C under nitrogen, 5.9 g of benzyl chloride were added drop wise and the reaction mixture was warmed to 60 C for 3 hours. After cooling to 10 C, the reaction mixture was quenched with 75 ml of water and the product was extracted with ethyl acetate and washed with water. Following solvent removal, the product was purified by silica gel chromatography using 5% ethyl acetate in hexane to give a clear colorless oil 7.9 g.
Reaction SMILES: Cl.Cl.[NH2:3][C@@H:4]([C@H:20]([O:22][CH3:23])[CH3:21])[CH2:5][S:6]([CH2:9][C:10]1[CH:11]=[N:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:8])=[O:7].Br[CH2:25][C:26]#[N:27].C(N(C(C)C)C(C)C)C>C(#N)C>[C:26]([CH2:25][NH:3][C@@H:4]([C@H:20]([O:22][CH3:23])[CH3:21])[CH2:5][S:6]([CH2:9][C:10]1[CH:11]=[N:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:7])=[O:8])#[N:27]
Reactant: N#CCBr
Reactant: CO[C@H](C)[C@H](N)CS(=O)(=O)Cc1cnc2ccccc2c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CO[C@H](C)[C@@H](CS(=O)(=O)Cc1cnc2ccccc2c1)NCC#N

Procedure:
A mixture of (2S,3R)-2-amino-3-methoxy-1-(3-quinolylmethanesulfonyl)butane dihydrochloride (0.93 g), bromoacetonitrile (0.41 ml) and N-ethyldiisopropylamine (1.7 ml) in acetonitrile (15 ml) was refluxed for 16 h, cooled and evaporated. The residue was partitioned between MDC (15 ml) and saturated sodium hydrogen carbonate solution (15 ml). The organic phase was collected and the aqueous re-extracted with MDC (15 ml). The combined MDC phases were dried (MgSO4) and evaporated. The residue was flash chromatographed (silica gel, step gradient: 70–100% EtOAc/hexane) to give the subtitle compound (0.59 g). MS (APCI+ve ion) 348(MH+); 1H NMR δ(CDCl3): 8.91 (1H, m), 8.3 (1H, d, J=2 Hz), 8.14 (1H, d, J=8 Hz), 7.78 (1H, d, J=8 Hz), 7.78 (1H, t, J=8 Hz), 7.60 (1H, t, J=8 Hz), 4.55 (2H, s), 3.4–3.88 (4H, m), 3.33 (3H, s), 2.93–3.28 (2H, m), 2.18 (1H, m), 0.93 (3H, d, J=6.3 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](/[CH:14]=[C:15]3/[C:16](=[O:22])[N:17]=[C:18](SC)[S:19]/3)[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:23]#[N:24])[CH3:2].[CH3:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][NH2:32].CCN(C(C)C)C(C)C>>[CH3:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][NH:32][C:18]1[S:19]/[C:15](=[CH:14]\[C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]=[CH:6][C:5]([C:23]#[N:24])=[C:4]3[O:3][CH2:1][CH3:2])/[C:16](=[O:22])[N:17]=1
Reactant: COCCOCCN
Reactant: CCOc1c(C#N)cnc2ccc(/C=C3\SC(SC)=NC3=O)cc12
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1c(C#N)cnc2ccc(/C=C3\SC(NCCOCCOC)=NC3=O)cc12

Procedure:
Similar procedure as described in example 14h was used, starting from 4-ethoxy-6-[2-methylsulfanyl-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-quinoline-3-carbonitrile (example 14g), 2-(2-methoxy-ethoxy)-ethylamine and DIEA to give 6-[2-[2-(2-methoxy-ethoxy)-ethylamino]-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-ethoxy-quinoline-3-carbonitrile. LC-MS m/e 427 (MH+).
Reaction SMILES: [NH:1]([CH:3]([C:5]1[CH:18]=[CH:17][C:16]2[O:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[S:8][C:7]=2[CH:6]=1)[CH3:4])[OH:2].C[Si]([N:23]=[C:24]=[O:25])(C)C.O>O1CCCC1>[CH:6]1[C:7]2[S:8][C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[O:15][C:16]=2[CH:17]=[CH:18][C:5]=1[CH:3]([N:1]([OH:2])[C:24]([NH2:23])=[O:25])[CH3:4]
Reactant: CC(NO)c1ccc2c(c1)Sc1ccccc1O2
Reactant: C[Si](C)(C)N=C=O
Solvent: C1CCOC1
Solvent: O
Product: CC(c1ccc2c(c1)Sc1ccccc1O2)N(O)C(N)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the product from Step 2 (250 mg, 0.965 mmol) in tetrahydrofuran (THF, 4 mL) there was added 85% trimethylsilyl isocyanate (196 mg, 1.45 mmol) and the solution was stirred at room temperature for 1 hour. Water (4 mL) was added, stirring was continued for 10 minutes, then the THF was evaporated; the residue was extracted twice with ether and the crude product obtained from evaporation of the extracts was crystallized from ether to afford the title compound as white crystals, m.p.: dec 155° C. with gassing.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][NH:10][C:11]([CH:13]2[CH2:17][C:16]3([CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH2:15][N:14]2[C:23](=[O:33])[C@@H:24]([NH:28][C:29](=[O:32])[O:30][CH3:31])[CH:25]([CH3:27])[CH3:26])=O)=[CH:4][CH:3]=1.O1CCOCC1.C([O-])(=O)C.[NH4+:45]>CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:45][C:11]([CH:13]3[CH2:17][C:16]4([CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[CH2:15][N:14]3[C:23](=[O:33])[C@@H:24]([NH:28][C:29](=[O:32])[O:30][CH3:31])[CH:25]([CH3:27])[CH3:26])=[N:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)N[C@H](C(=O)N1CC2(CCOCC2)CC1C(=O)NCC(=O)c1ccc(Br)cc1)C(C)C
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)N[C@H](C(=O)N1CC2(CCOCC2)CC1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Temperature: 110 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
In a 10 ml seal tube, methyl (2S)-1-(3-(2-(4-bromophenyl)-2-oxoethylcarbamoyl)-8-oxa-2-azaspiro[4.5]decan-2-yl)-3-methyl-1-oxobutan-2-ylcarbamate (200 mg, 371 μmol) was combined with dioxane (6 ml) to give a colorless solution. Ammonium acetate (286 mg, 3.71 mmol) was added and it was stirred at 110° C. overnight. It was cooled and diluted with EtOAc (10 ml). The mixture was filtered and concentrated in vacuo to afford methyl (2S)-1-(3-(5-(4-bromophenyl)-1H-imidazol-2-yl)-8-oxa-2-azaspiro[4.5]decan-2-yl)-3-methyl-1-oxobutan-2-ylcarbamate as a yellow solid (170 mg, 88.1%). ESI-LRMS m/e calcd for C24H31BrN4O4 [M+] 519. found 520 [M+H+].
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5](=[O:11])[N:4]([CH3:12])[C:3]1=[O:13]>CO.[Pd]>[NH2:8][C:6]1[C:5](=[O:11])[N:4]([CH3:12])[C:3](=[O:13])[N:2]([CH3:1])[CH:7]=1
Reactant: Cn1cc([N+](=O)[O-])c(=O)n(C)c1=O
Agent: [Pd]
Solvent: CO
Product: Cn1cc(N)c(=O)n(C)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.5 %

Procedure:
To a stirred solution of 1,3-dimethyl-5-nitropyrimidine-2,4(1H,3H)-dione (2.0 g, 10.802 mmol) in methanol (200 mL), 10% Pd—C (0.500 g) was added under hydrogen atmosphere and the reaction mixture was stirred at room temperature for 2 h. Reaction mixture was filtered through a celite bed and washed with methanol. The filtrate was collected and concentrated under reduced pressure to give 1.5 g of the product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[H-].[Na+].Br[C:15]1[CH:16]=[N:17][CH:18]=[C:19]([Br:21])[CH:20]=1>CN(C)C=O>[Br:21][C:19]1[CH:18]=[N:17][CH:16]=[C:15]([O:11][C:5]2[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:20]=1
Reactant: Brc1cncc(Br)c1
Reactant: COc1cc(O)cc(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(OC)cc(Oc2cncc(Br)c2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 98.9 %

Procedure:
Under an argon atmosphere, a solution of 3,5-dimethoxyphenol (6.94 g, 45 mmol) in dimethylformamide (30 mL) was added slowly to a stirred suspension of sodium hydride (1.44 g of a 75% suspension in mineral oil, 0.045 mol) in dimethylformamide (30 mL) at 0–5° C. The icebath was removed and the resulting mixture was stirred for 2.5 h at room temperature. 3,5-Dibromopyridine (7.11 g, 0.03 mol) was added to the mixture, which was then heated to 100° C. for 72 h, then the mixture was cooled to room temperature and successively washed with water (100 mL) and 5 N NaOH solution (10 mL). The mixture was extracted with diethyl ether (3×50 mL). The combined organic phases were dried (MgSO4), filtered and concentrated by rotary evaporation to give 9.2 g of a white solid, which was purified by column chromatography, eluting with cyclohexane/ethyl acetate (90/10, v/v). Selected fractions containing the product were concentrated via rotary evaporation to give 2.5 g (29%) of a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[C:13]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]([F:12])([F:10])[F:11])(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(F)cc1C(F)(F)F
Product: CC(=O)Nc1ccc(F)cc1C(F)(F)F
Yield: 98 %

Procedure:
A solution of 2-amino-5-fluorobenzotrifluoride (2.025 g, 11.31 mmol, Aldrich) in acetic anhydride (10 mL) was stirred at room temperature for 12 h, and then most of the acetic anhydride was removed. The white needle crystals were collected by filtration, affording 2.445 g (98%) of 2-acetamido-5-fluorobenzotrifluoride. 1H NMR (CDCl3): δ2.205 (s, 3H); 7.229-7.335 (m, 3H); 8.055 (dd, 1H, J1 =4.8 Hz, J2 =8.4 Hz).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.Br[CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20]>>[CH3:18][C:19]([CH3:22])([CH3:21])[CH2:20][N:3]1[C:4]2[C:9](=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2)[CH:10]=[C:2]1[CH3:1]
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: CC(C)(C)CBr
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(C)(C)C

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile and 1-bromo-2,2-dimethylpropane: 1H NMR (400 MHz, CDCl3) δ 7.51 (d, J=8.5 Hz, 1H), 7.45 (d, J=8.5 Hz, 1H), 6.59 (s, 1H), 3.94 (s, 2H), 2.49 (s, 3H), 1.01 (s, 9H); MS (ES) m/z 295 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]4[N:19]([CH:20]([CH3:22])[CH3:21])[N:18]=[CH:17][N:16]=4)=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:23]=1.ClCCl.[I-].C(OC([N:35]1[CH2:38][CH:37]([Zn+])[CH2:36]1)=O)(C)(C)C.Cl>CN(C)C(=O)C.[Cu]I>[NH:35]1[CH2:38][CH:37]([C:2]2[CH:3]=[CH:4][C:5]3[C:11]4[S:12][C:13]([C:15]5[N:19]([CH:20]([CH3:21])[CH3:22])[N:18]=[CH:17][N:16]=5)=[CH:14][C:10]=4[CH2:9][CH2:8][O:7][C:6]=3[CH:23]=2)[CH2:36]1
Reactant: CC(C)n1ncnc1-c1cc2c(s1)-c1ccc(Br)cc1OCC2
Reactant: CC(C)(C)OC(=O)N1CC([Zn+])C1
Agent: [Cu]I
Agent: Cl
Agent: [I-]
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CC(C)n1ncnc1-c1cc2c(s1)-c1ccc(C3CNC3)cc1OCC2
Temperature: 80 °C
Reaction time: 2 h
Yield: 11.4 %

Procedure:
Following the procedure for 419, 5-(8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-2-yl)-1-isopropyl-1H-1,2,4-triazole (313.4 mg, 0.803 mmol) was dissolved in N,N-dimethyacetamide and purged with nitrogen. Added [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (32.8 mg, 0.04 mmol) and copper(I) iodide (15.3 mg, 0.08 mmol). Bubbled in nitrogen for 10 minutes. Added (1-(tert-butoxycarbonyl)azetidin-3-yl)zinc(II) iodide (279.8 mg, 0.80 mmol) in 2.8 mL DMA. Heated at 80° C. overnight. Complete reaction was confirmed by LCMS. Diluted reaction mixture with 1 M HCl and extracted tert-butyl 3-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)azetidine-1-carboxylate with ethyl acetate. Dried over magnesium sulfate and concentrated in vacuo. Purified by flash chromatography (0 to 50% ethyl acetate in hexanes). Concentrated in vacuo and re-dissolved the residue in 10 mL 1,4-dioxane. Added 5 mL 4 N HCl in dioxane and let stir for 2 hours. Complete deprotection was confirmed by LCMS. Concentrated in vacuo purified by HPLC to give 370 (33.3 mg, 11% yield, M=1 367.1)
Reaction SMILES: [N:1]1([CH2:6][CH:7]([CH2:17][O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](O)=[O:15])[CH:5]=[CH:4][N:3]=[CH:2]1.C([N:30](CC)CC)C.ClC(OCC)=O.N>ClCCl>[N:1]1([CH2:6][CH:7]([CH2:17][O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH2:30])=[O:15])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCN(CC)CC
Reactant: COc1ccc(COCC(Cn2ccnc2)OCCCCCC(=O)O)cc1
Agent: CCOC(=O)Cl
Agent: N
Solvent: ClCCl
Product: COc1ccc(COCC(Cn2ccnc2)OCCCCCC(N)=O)cc1
Temperature: 0 °C

Procedure:
A stirred solution of 6-[2-(1H-imidazol-1-yl)-1-[[(4-methoxyphenyl)methoxy]methyl]ethoxy]hexanoic acid (Example 1; 10 g, 0.027M) and triethylamine (3.0 g, 0.030 mol) in dry dichloromethane (100 ml) at -50° C. was treated dropwise with ethyl chloroformate (3.2 g, 0.029 mol). The solution was allowed to warm up to 0° C. over 0.5 hours, cooled back to -78° C. and treated with gaseous ammonia. The solution was allowed to warm up to room temperature over 6 hours and washed with an aqueous saturated solution of sodium hydrogen carbonate and dried (Na2CO3). The solvent was evaporated off under reduced pressure to give a residue which was purified by column chromatography (silica gel, ethyl acetate to 10% methanol in ethyl acetate) to give 6-[2-(1H-imidazol-1-yl)-1-[[(4-methoxyphenyl)methoxy]methyl]-ethoxy]hexanamide as a pale yellow oil.
Reaction SMILES: [CH2:1]([SH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH:14](=[O:18])/[CH:15]=[CH:16]/[CH3:17]>C(OCC)C>[CH2:1]([S:13][CH:15]([CH2:16][CH3:17])[CH:14]=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCS
Reactant: C/C=C/C=O
Solvent: CCOCC
Product: CCCCCCCCCCCCSC(C=O)CC
Temperature: 25 °C

Procedure:
Lauryl mercaptan (1 mole) was stirred with diethyl ether (150 ml) at 10° C and to this was added dropwise crotonaldehyde (1 mole) over a period of 2 hours. After the completion of the addition, the reaction mixture was warmed to room temperature and reacted for a further 22 hours. The reaction mixture was then distilled to give a laurylmercaptobutyraldehyde product fraction (0.90 moles) of boiling range 147°-150° C at 1.5 mm Hg. The reaction mixture was maintained under nitrogen at all times.
Reaction SMILES: CC1(C)[O:6][CH:5]([CH2:7][O:8][C:9]2[CH:21]=[C:20]3[C:12]([C:13]4[C:14]([C:25]5[CH:30]=[CH:29][CH:28]=[C:27]([N:31]6[CH2:39][C:38]7[C:33](=[CH:34][C:35]([CH3:40])=[CH:36][CH:37]=7)[C:32]6=[O:41])[C:26]=5[CH3:42])=[CH:15][CH:16]=[C:17]([C:22]([NH2:24])=[O:23])[C:18]=4[NH:19]3)=[CH:11][CH:10]=2)[CH2:4][O:3]1.C(O)(C(F)(F)F)=O>CO.CS(C)=O>[OH:6][CH:5]([CH2:4][OH:3])[CH2:7][O:8][C:9]1[CH:21]=[C:20]2[C:12]([C:13]3[C:14]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([N:31]5[CH2:39][C:38]6[C:33](=[CH:34][C:35]([CH3:40])=[CH:36][CH:37]=6)[C:32]5=[O:41])[C:26]=4[CH3:42])=[CH:15][CH:16]=[C:17]([C:22]([NH2:24])=[O:23])[C:18]=3[NH:19]2)=[CH:11][CH:10]=1
Reactant: Cc1ccc2c(c1)C(=O)N(c1cccc(-c3ccc(C(N)=O)c4[nH]c5cc(OCC6COC(C)(C)O6)ccc5c34)c1C)C2
Solvent: CS(C)=O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(c1)C(=O)N(c1cccc(-c3ccc(C(N)=O)c4[nH]c5cc(OCC(O)CO)ccc5c34)c1C)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.8 %

Procedure:
A solution of racemic 7-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-(2-methyl-3-(6-methyl-1-oxoisoindolin-2-yl)phenyl)-9H-carbazole-1-carboxamide (Example 44-4, 30 mg, 0.052 mmol) in methanol-DMSO was treated with TFA (0.5 mL) and the solution was stirred overnight at rt. The mixture was concentrated and purified by preparative HPLC to provide 7-(2,3-dihydroxypropoxy)-4-(2-methyl-3-(6-methyl-1-oxoisoindolin-2-yl)phenyl)-9H-carbazole-1-carboxamide as a white solid (9.4 mg, 32%). 1H NMR (400 MHz, DMSO-d6) δ 11.39 (1 H, s), 8.16 (1 H, br. s.), 7.94 (1 H, d, J=7.7 Hz), 7.54-7.65 (3 H, m), 7.49 (3 H, t, J=7.9 Hz), 7.25-7.38 (2 H, m), 6.99 (1 H, d, J=7.7 Hz), 6.92 (1 H, d, J=8.8 Hz), 6.60 (1 H, d, J=1.3 Hz), 4.82-5.01 (3 H, m), 4.60-4.71 (1 H, m), 3.96-4.08 (1 H, m), 3.76-3.96 (2 H, m), 3.48 (2H, t, J=5.6 Hz), 2.44 (3 H, s), 1.77-1.88 (3 H, m). Mass spectrum m/z 536.1 (M+H)+.
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:6]=[C:7]([C:11]2([NH2:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[OH-].[Na+].[CH2:20]([O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C@H:35]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[C@H:36]2[CH2:38][O:37]2)=[CH:30][C:29]=1[F:47])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(OCC)(=O)C>[F:47][C:29]1[CH:30]=[C:31]([CH:32]=[CH:33][C:28]=1[O:27][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:34][C@H:35]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:43])[CH3:44])[C@H:36]([OH:37])[CH2:38][NH:17][C:11]1([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([CH:2]([CH3:4])[CH3:3])[CH:6]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC(C)c1cccc(C2(N)CCCCC2)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)c(F)c1)[C@H]1CO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)c1cccc(C2(NC[C@@H](O)[C@H](Cc3ccc(OCc4ccccc4)c(F)c3)NC(=O)OC(C)(C)C)CCCCC2)c1
Reaction time: 72 h
Yield: 53.4 %

Procedure:
The free base (270 mg, 1.24 mmol) of 1-(3-isopropylphenyl)cyclohexanamine hydrochloride 3 is obtained as a colorless oil by neutralization of the salt with 1N NaOH, extraction into ethyl acetate, drying over Na2SO4, and concentration. This is dissolved in 10 mL of CH2Cl2, and to it is added compound 17 (280 mg, 0.73 mmol) and 1.25 g of silica gel. The solvent is removed in vacuo and the reactants on silica are allowed to stand at ambient temperature for three days. The product mixture is eluted from the silica with 10% methanol in CH2Cl2, concentrated, and chromatographed on silica gel, eluting with 4% methanol (containing 2% NH4OH) in CH2Cl2, to afford compound 18 (238 mg, 0.39 mmol, 54%) as a colorless oil: 1H NMR (CDCl3) δ 7.43–7.26 (m, 8H), 7.12 (m, 1H), 6.94–6.84 (m, 3H), 5.09 (s, 2H), 4.64 (d, J=9 Hz, 1H), 3.80 (br, 1H), 3.31 (br, 1H), 2.92–2.83 (m, 2H), 2.7 (m, 1H), 2.37 (m, 2H), 2.0–1.95 (m, 4H), 1.67–1.50 (m, 5H), 1.35 (s+m, 10H), 1.25 (d, J=7 Hz, 6H).
Reaction SMILES: [Si](O[C@@H:9]1[CH2:13][C:12](=[O:14])[C@H:11]([CH2:15][CH2:16][C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=2)[C@H:10]1/[CH:27]=[CH:28]/[CH:29]([O:41][Si](C(C)(C)C)(C)C)[CH2:30][C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=1)(C(C)(C)C)(C)C.C1(C)C=CC=CC=1>CC(O)=O.O.C1COCC1>[OH:41][CH:29]([CH2:30][C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=1)/[CH:28]=[CH:27]/[C@H:10]1[CH:9]=[CH:13][C:12](=[O:14])[C@@H:11]1[CH2:15][CH2:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccc(CC[C@H]2C(=O)C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]2/C=C/C(Cc2ccc3ccccc3c2)O[Si](C)(C)C(C)(C)C)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1ccc(CC[C@H]2C(=O)C=C[C@@H]2/C=C/C(O)Cc2ccc3ccccc3c2)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 77.3 %

Procedure:
A mixture of methyl 4-(2-((1R,2R,3R)-3-((tert-butyldimethylsilyl)oxy)-2-((E)-3-((tert-butyldimethylsilyl)oxy)-4-(naphthalen-2-yl)but-1-en-1-yl)-5-oxocyclopentyl)ethyl)benzoate (1 g, 1.46 mmol) in HOAc/H2O/THF (32 mL, 2:1:1) was stirred at 70° C. overnight and then was co-evaporated with toluene. Purification of the residue by flash chromatography (ethyl acetate/hexanes) gave methyl 4-(2-((1R,2S)-2-((E)-3-hydroxy-4-(naphthalen-2-yl)but-1-en-1-yl)-5-oxocyclopent-3-en-1-yl)ethyl)benzoate (497 mg, 77%).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:11]=2[O:18][CH3:19])[N:3]=1.COC1C(OC)=CC=CC=1CO.[NH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C([O-])([O-])=O.[K+].[K+]>>[CH3:19][O:18][C:11]1[C:12]([O:16][CH3:17])=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][O:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[N:3]=1
Reactant: C1CNCCN1
Reactant: COc1cccc(COc2cncc(Cl)n2)c1OC
Agent: COc1cccc(CO)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cccc(COc2cncc(N3CCNCC3)n2)c1OC

Procedure:
The title compound was prepared according to the procedure of example 50, step 2, starting from 2-chloro-6-[(2,3-dimethoxybenzyl)oxy]pyrazine (2.51 g, 8.93 mmol; obtained according to the procedure of example 50, step 1, starting from 2,3-dimethoxybenzyl alcohol), piperazine (2.38 g, 27.7 mmol) and K2CO3 (1.23 g, 8.9 mmol). The yield of the title compound was 1.66 g (56%) which was obtained as an oil. Purity 100% (HPLC). MS m/z 331 (M+H)+. HRMS m/z calcd for C17H22N4O3 (M)+ 330.1692, found 330.1690.
Reaction SMILES: [CH3:1][C:2]([N:9]1[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[N:10]1)([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4]>C(O)C.[C].[Pd]>[NH2:14][C:12]1[CH:11]=[N:10][N:9]([C:2]([CH3:1])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:13]=1
Reactant: CCOC(=O)C(C)(C)n1cc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(C)(C)n1cc(N)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.9 %

Procedure:
To a solution of ethyl 2-methyl-2-(4-nitro-1H-pyrazol-1-yl)propanoate (20 g) obtained in Step F of Example 103 in ethanol (200 mL) was added 10% palladium-carbon (3.0 g), and the mixture was stirred overnight at room temperature under hydrogen atmosphere (at normal pressures). The palladium carbon was removed by filtration through Celite, and the solvent was evaporated under reduced pressure to give the title compound (17 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[C:9]([CH3:17])=[N:10][N:11]2[CH:15]=[C:14]([CH3:16])[S:13][C:12]=12)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[Br:24]C(F)(F)C(F)(F)Br.[Cl-].[NH4+]>O1CCCC1>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[C:9]([CH3:17])=[N:10][N:11]2[C:15]([Br:24])=[C:14]([CH3:16])[S:13][C:12]=12)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cn2nc(C)c(NC(=O)OC(C)(C)C)c2s1
Reactant: FC(F)(Br)C(F)(F)Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1nn2c(Br)c(C)sc2c1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58.9 %

Procedure:
A tetrahydrofuran (10 mL) solution of tert-butyl(2,6-dimethylpyrazolo[5,1-b][1,3]thiazol-7-yl)carbamate (266 mg, 0.995 mmol) was cooled to −78° C., and n-butyllithium (2.64M, 0.829 mL, 2.19 mmol) was added dropwise and the mixture was stirred for 10 minutes. Then, 1,2-dibromotetrafluoroethane (0.142 ml, 1.19 mmol) was added to the mixture, and the reaction mixture was warmed to room temperature and stirred at room temperature over one day and night. To the reaction mixture, a saturated aqueous solution of ammonium chloride was added, and a substance of interest was extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by medium pressure silica gel column chromatography (n-heptane/ethyl acetate: 3/1 then 2/1) to obtain the title compound (203 mg, 0.586 mmol).
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[C:6]([CH3:12])=[N:7][C:8]([CH3:11])=[CH:9][CH:10]=1>C(O)C.[Pd]>[CH3:12][C:6]1[C:5]([O:4][C:3]2[CH:13]=[CH:14][C:15]([NH2:17])=[CH:16][C:2]=2[F:1])=[CH:10][CH:9]=[C:8]([CH3:11])[N:7]=1
Reactant: Cc1ccc(Oc2ccc([N+](=O)[O-])cc2F)c(C)n1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(Oc2ccc(N)cc2F)c(C)n1
Yield: 99.8 %

Procedure:
A solution of intermediate 9 (5.88 g, 22.44 mmol) in ethanol (200 ml) was hydrogenated at room temperature in the presence of palladium 10% on activated carbon (0.58 g) for 3 hours. The solids were filtered off and the filtrate was evaporated till dryness to yield intermediate 10 (5.20 g, >99%) that was used without further purification.