Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][N:10]=2)=[CH:5][C:3]=1[NH2:4].[C:17]([O:21][C:22]([NH:24][C:25]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=S)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(N(C(C)C)CC)(C)C.[I-].C[N+]1C=CC=CC=1Cl>ClCCl>[C:31]([O:30][C:28]([NH:27][C:25]([NH:24][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])=[N:4][C:3]1[CH:5]=[C:6]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=[CH:8][C:2]=1[Cl:1])=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: COc1ccnc(-c2ccc(Cl)c(N)c2)c1
Reactant: CC(C)(C)OC(=O)NC(=S)NC(=O)OC(C)(C)C
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccnc(-c2ccc(Cl)c(N=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c2)c1
Reaction time: 16 h
Yield: 42.9 %

Procedure:
To a suspension of 2-chloro-5-(4-methoxypyridin-2-yl)aniline (165 mg), N,N′-bis(tert-butoxycarbonyl)thiourea (233 mg) and diisopropylethylamine (0.28 ml) in dichloromethane (7 ml) was added 1-methyl-2-chloropyridinium iodide (232 mg), and the mixture was stirred for 16 hours. The mixture was diluted with dichloromethane, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 30 g, n-hexane:ethyl acetate=2:1) to give N,N′-bis(tert-butoxycarbonyl)-N″-(2-chloro-5-(4-methoxypyridin-2-yl)phenyl)guanidine (144 mg).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH2:35][CH2:36][Cl:37])=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][N:23]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.C(OCC)(=O)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:22]3[C:31]4[C:26](=[CH:27][C:28]([O:34][CH2:35][CH2:36][Cl:37])=[C:29]([O:32][CH3:33])[CH:30]=4)[N:25]=[CH:24][N:23]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCl
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(O)c2)no1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCl
Temperature: 50 °C
Yield: 93 %

Procedure:
To a solution of (1-(5-tert-butyl-isoxazol-3-yl)-3-(3-hydroxy-phenyl)-urea, 300.13 mg, 1.098 mmol) from Example 1A and (4-chloro-7-(2-chloro-ethoxy)-6-methoxy-quinazoline from the previous step (300 mg, 1.098 mmol) in THF was added Cs2CO3 (532.7 mg, 1.64 mmol), and the mixture was heated at 50° C. for 12 h. Completion of the reaction was monitored by LCMS. The reaction mixture was diluted with ethyl acetate and the solution was washed with water and brine successively. The organic layer was dried (Na2SO4) and concentrated to dryness to afford the pure compound 1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(2-chloro-ethoxy)-6-methoxy-quinazolin-4-yloxy]-phenyl}-urea (525 mg, 93%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.58 (s, 1H), 9.00 (s, 1H), 8.55 (s, 1H), 7.57 (s, 2H), 7.40 (m, 2H), 7.22 (d, 1H), 6.95 (d, 1H), 6.45 (s, 1H), 4.50 (m, 2H), 4.00 (m, 5H), 1.28 (s, 9H); LC-MS (ESI) m/z 512 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:10]([CH3:14])[C:11]([OH:13])=[O:12])[CH:5]=[C:6]([I:9])[C:7]=1[OH:8].[I:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19]Br.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C=O)C>[I:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][O:12][C:11](=[O:13])[CH:10]([C:4]1[CH:3]=[C:2]([I:1])[C:7]([O:8][CH2:10][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([I:1])[CH:3]=2)=[C:6]([I:9])[CH:5]=1)[CH3:14]
Reactant: CC(C(=O)O)c1cc(I)c(O)c(I)c1
Reactant: BrCc1cccc(I)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C(=O)OCc1cccc(I)c1)c1cc(I)c(OCc2cccc(I)c2)c(I)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 183.5 %

Procedure:
A suspension of 3,5-diiodo-4-hydroxyphenypropionic acid (209 mg, 0.5 mmol), 3-iodobenzyl bromide (371 mg, 1.25 mmol), and cesium carbonate (490 mg, 1.5 mmol) in 5 mL DMF was stirred for 15 h at room temperature. After that time, 1 M HCl (15 mL) was added and an oil formed. The oil was extracted with ether and methanol was added. Crystals formed in the solution upon cooling, yielding the title compound as white crystals (390 mg, 92%); 1H NMR (CDCl3) δ 8.00 (S, 1H), 7.71-7.60 (m, 6H), 7.29-7.26 (m, 1H), 7.16 (appar. t, J=7.8 Hz, 1H), 7.11 (appar. t, J=7.8 Hz, 1H), 5.05 (s, 2H), 4.91 (s, 2H), 2.87 (t, J=7.6 Hz, 2H), 2.67 (t, J=7.6 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[N:16]=[C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[C:14]([N+:23]([O-])=O)=[C:13]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[N:12]=2)=[CH:5][CH:4]=1.[Cl-].[Ca+2].[Cl-]>C(#N)C.O.[Zn]>[NH2:23][C:14]1[C:13]([N:26]2[CH2:27][CH2:28][O:29][CH2:30][CH2:31]2)=[N:12][C:11]([CH:10]=[CH:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[N:16][C:15]=1[N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: COc1ccc(C=Cc2nc(N3CCOCC3)c([N+](=O)[O-])c(N3CCOCC3)n2)cc1
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Zn]
Solvent: CC#N
Solvent: O
Product: COc1ccc(C=Cc2nc(N3CCOCC3)c(N)c(N3CCOCC3)n2)cc1
Yield: 74.8 %

Procedure:
The synthesis method shall be explained concretely, and in order, below. A mixed solution of 2-[2-(4-methoxyphenyl)vinyl]-4,6-dimorpholino-5-nitropyrimidine (1.35 g, 3.16 mmol), zinc dust (6.19 g, 94.8 mmol), and calcium chloride (224 mg, 2.02 mmol) in acetonitrile (80 ml) and water (20 ml) was refluxed under heating for 1 hour. The undissolved matter was separated out by celite filtering, the filtrate was distilled away under reduced pressure, water was added to the residue, the precipitated crystals were taken out by filtering, and 5-amino-2-[2-(4-methoxyphenyl)vinyl]-4,6-dimorpholinopyrimidine (940 mg, yield 75%) was obtained. The melting point measurement result, the MS measurement result, and the NMR data for the obtained Compound 131 are shown below.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][S:14]([CH2:17][C:18](NC1N=NN(CCCCCCCCCCCC)N=1)=[O:19])(=[O:16])=[O:15])([CH3:3])[CH3:2].[CH2:38]([OH:52])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51]>>[CH2:38]([O:52][C:18](=[O:19])[CH2:17][S:14](=[O:16])(=[O:15])[NH:13][C:5]1[C:6]([CH:10]([CH3:11])[CH3:12])=[CH:7][CH:8]=[CH:9][C:4]=1[CH:1]([CH3:3])[CH3:2])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51]
Reactant: CCCCCCCCCCCCn1nnc(NC(=O)CS(=O)(=O)Nc2c(C(C)C)cccc2C(C)C)n1
Reactant: CCCCCCCCCCCCCCO
Product: CCCCCCCCCCCCCCOC(=O)CS(=O)(=O)Nc1c(C(C)C)cccc1C(C)C

Procedure:
This compound was prepared in the same manner as for the title compound of Example 2, except that 2-DAT was replaced with tetradecanol, mp 53°-55° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH:19]=O)=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:21]=1.[CH3:23][O:24][CH2:25][CH2:26][NH2:27]>>[Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[CH:11]3[CH2:10][CH:9]([CH2:12]3)[N:8]3[C:13]([CH2:19][NH:27][CH2:26][CH2:25][O:24][CH3:23])=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:21]=1
Reactant: NC(=O)c1nc2n(c1C=O)C1CC(C1)c1cc(F)c(Br)cc1-2
Reactant: COCCN
Product: COCCNCc1c(C(N)=O)nc2n1C1CC(C1)c1cc(F)c(Br)cc1-2

Procedure:
10-bromo-9-fluoro-3-formyl-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide (75 mg) was reacted with 2-methoxyethylamine similarly to as in the synthesis of 9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-3-[(4-methylpiperazin-1-yl)methyl]-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide to afford 10-bromo-9-fluoro-3-(((2-methoxyethyl)amino)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide which was directly reacted with 2-Methyl-3-butyne-ol via General Procedure E to afford 14 mg (16%) of 9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-3-[(2-methoxyethylamino)methyl]-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide. M+1=427.
Reaction SMILES: C[O:2][C:3](=[O:22])/[CH:4]=[CH:5]/[CH:6]=[C:7](\[CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)/[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.[OH-].[Na+]>CO>[CH:16]1(/[C:7](/[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:6]\[CH:5]=[CH:4]\[C:3]([OH:22])=[O:2])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COC(=O)/C=C/C=C(/c1ccc(OC)cc1)C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(/C(=C/C=C/C(=O)O)C2CCCCC2)cc1
Reaction time: 2 h

Procedure:
As described in Example 99, (E,E)-5-cyclohexyl-5-(4-methoxyphenyl)-2,4-pentadienoic acid methyl ester (5.9) was saponified in a refluxing mixture of methanol (20 mL) and 2N NaOH (20 mL). After 2 hours the reaction was worked up in the normal manner, and the crude was crystallized from cyclohexane-hexane to give 3.37 g of (E,E)-5-cyclohexyl-5-(4-methoxyphenyl)-2,4-pentadienoic acid, mp 130.5°-131.5° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[CH:29]2[C:24]([CH2:25][NH:26][CH2:27][CH2:28]2)=[C:5]2[C:6]([OH:23])([OH:22])[CH:7]=[C:8]([CH:10]([CH3:21])[CH2:11][CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:9]=[C:4]2[O:3]1.[Cl:31][CH2:32][CH:33]=[C:34](Cl)C>CN(C)C=O>[CH3:30][C:2]1([CH3:1])[CH:29]2[C:24]([CH2:25][N:26]([CH2:34][CH:33]=[CH:32][Cl:31])[CH2:27][CH2:28]2)=[C:5]2[C:6]([OH:22])([OH:23])[CH:7]=[C:8]([CH:10]([CH3:21])[CH2:11][CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:9]=[C:4]2[O:3]1
Reactant: CC(CCCc1ccc(F)cc1)C1=CC(O)(O)C2=C3CNCCC3C(C)(C)OC2=C1
Reactant: CC(Cl)=CCCl
Solvent: CN(C)C=O
Product: CC(CCCc1ccc(F)cc1)C1=CC(O)(O)C2=C3CN(CC=CCl)CCC3C(C)(C)OC2=C1

Procedure:
5,5-Dimethyl-8-(4-p-fluorophenyl-1-methylbutyl)-10-hydroxy-1,2,3,4-tetrahydro-5H[1]benzopyrano[4,3-c]pyridin-10-ol (1 mole) and 1,3-dichloro-2-butene (0.5 mole) were reacted in dimethylformamide as described in Example 7 to give the desired product.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][C@H:18]1[NH:23][C@@H:22]([CH3:24])[CH2:21][N:20]([C:25]([C:27]2[C:28]([CH3:34])=[C:29]([CH:32]=O)[NH:30][CH:31]=2)=[O:26])[CH2:19]1>C(O)C.N1CCCCC1>[CH3:24][C@H:22]1[NH:23][C@@H:18]([CH3:17])[CH2:19][N:20]([C:25]([C:27]2[C:28]([CH3:34])=[C:29]([CH:32]=[C:9]3[C:8]4[C:12](=[CH:13][CH:14]=[CH:15][C:7]=4[C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[NH:11][C:10]3=[O:16])[NH:30][CH:31]=2)=[O:26])[CH2:21]1
Reactant: O=C1Cc2c(cccc2-c2ccccc2)N1
Reactant: Cc1c(C(=O)N2C[C@@H](C)N[C@@H](C)C2)c[nH]c1C=O
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(C(=O)N2C[C@@H](C)N[C@@H](C)C2)c[nH]c1C=C1C(=O)Nc2cccc(-c3ccccc3)c21
Temperature: 25 °C
Reaction time: 72 h
Yield: 19.5 %

Procedure:
To a solution of 4-phenyl-1,3-dihydro-indol-2-one (52.3 mg, 0.25 mmol) and 4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-[4-((cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrol-2-ylmethylene]-4-phenyl-1,3-dihydro-indol-2-one as a yellow solid (21.5 mg, 20%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:14][CH3:15])[CH:13]=1)[CH:6]=[CH:7][N+:8]([O-:10])=[O:9].[CH2:16]=[CH:17][CH:18]=[CH2:19].C1(C=CC(O)=CC=1)O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]2[CH:7]([N+:8]([O-:10])=[O:9])[CH2:19][CH:18]=[CH:17][CH2:16]2)[CH:11]=[C:12]([O:14][CH3:15])[CH:13]=1
Reactant: C=CC=C
Reactant: COc1cc(C=C[N+](=O)[O-])cc(OC)c1
Agent: Oc1ccc(O)cc1
Solvent: Cc1ccccc1
Product: COc1cc(OC)cc(C2CC=CCC2[N+](=O)[O-])c1
Temperature: -78 °C

Procedure:
A stainless steel pressure vessel was charged with 28.6 g. (0.137 mole) 3,5-dimethoxy-beta-nitrostyrene, 20 g. (0.378 mole) butadiene, 40 ml. toluene and a few crystals of hydroquinone. The vessel was cooled to -78° C. under a nitrogen atmosphere and sealed. The sealed vessel was heated at 100° C. for 48 hours, cooled and the reaction mixture concentrated under nitrogen. The residual solid was crystallized from methanol to afford 29.8 g. of title compound, M.P. 80.5°-82° C. J. Org. Chem., 27, 376 (1962) reported M.P. 73°-75° C. 1H-NMR (CDCl3) ppm (delta): 3.75 (s, 6H, OCH3), 4.95 (m, 1H, CHNO2), 5.75 (s, 2H, olefin), 6.40 (s, 3H, aromatic).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C[Al](C)C.[CH3:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:16][C:17]1[CH:24]=[CH:23][C:20]([C:21](=[NH:22])[NH:9][C:8]2[CH:10]=[CH:11][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)=[CH:19][CH:18]=1
Reactant: Cc1ccc(C#N)cc1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(C(=N)Nc2ccc(S(C)(=O)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a suspension of 4-(methylsulfonyl)aniline (10 mmol) in toluene (100 mL), trimethylaluminum (2M solution in toluene, 15 mmol) is added over 15 minutes. The reaction mixture is warmed to room temperature and stirred for 2.5 hours. A solution of 4-methylbenzonitrile (20 mmol) in toluene (50 mL) is added over 10 minutes and the reaction mixture is heated to 80°-85° C. After 20 hours, the reaction mixture is cooled to room temperature and poured over a slurry of silica gel in chloroform. After filtration, the residue is washed with a mixture of methylene chloride/methanol (2/1). The combined filtrates are concentrated in vacuo and the resulting yellowish solid is stirred with a mixture of hexane/ether (2/1, 1000 mL). The intermediate is filtered and washed with more of hexane/ether (2/1). The pale yellow solid 4-methyl-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide is used in the next reaction without further purification.
Reaction SMILES: [CH3:1][C:2]([NH:5][S:6]([C:9]1[CH:13]=[CH:12][N:11]([CH3:14])[CH:10]=1)(=[O:8])=[O:7])([CH3:4])[CH3:3].C([Li])CCC.[CH3:20][S:21]SC.Cl>C1COCC1>[CH3:4][C:2]([NH:5][S:6]([C:9]1[CH:13]=[CH:12][N:11]([CH3:14])[C:10]=1[S:21][CH3:20])(=[O:8])=[O:7])([CH3:1])[CH3:3]
Reactant: CSSC
Reactant: Cn1ccc(S(=O)(=O)NC(C)(C)C)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1c(S(=O)(=O)NC(C)(C)C)ccn1C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 58.8 %

Procedure:
To a solution of 6.48 g (30 mmol) of N-(1,1-dimethylethyl)-1-methyl-1H-pyrrole-3-sulfonamide in 150 mL THF under nitrogen atmosphere cooled to -78° C. was added dropwise at such a rate as to keep the temperature below -65° C. 25.52 mL (61.5 mmol) 2.41M n-butyllithium in hexanes. The reaction was stirred at -78° C. for ca. 30 minutes. To the reaction mixture was added 2.97 mL (33 mmol) of dimethyldisulfide in one portion and the resulting reaction mixture was allowed to warm to room temperature and stir for ca. 1.5 hours. The reaction mixture was cooled to 0° C. and acidified with 1N HCl. The THF phase was separated washed with brine, dried (MgSO4) and concentrated in vacuo. The crude residue was chromatographed on silica (20% ethyl acetate/80% hexanes) affording 4.63 g of the title compound as an off white solid, m.p. 116°-119° C. 1H NMR (CDCl3, 200 MHz.) δ: 6.72(d,1H), 6.58(d,1H), 4.96(bs,1H), 3.74(s,3H), 2.35(s,3H), 1.23(s,9H).
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[C:22](=[O:23])[N:21]2[CH:17]([CH2:18][CH:19]([O:24][C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27][N:26]=3)[CH2:20]2)[C:16](=[O:35])[NH:15][C:14]2([C:36]([NH:38][S:39]([CH:42]3[CH2:44][CH2:43]3)(=[O:41])=[O:40])=[O:37])[CH:12]([CH2:13]2)[CH:11]=[CH:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.CCN(C(C)C)C(C)C.Cl[C:55]([O:57][CH:58]([CH3:60])[CH3:59])=[O:56]>C1(C)C=CC=CC=1>[CH:58]([O:57][C:55](=[O:56])[NH:3][CH:4]1[C:22](=[O:23])[N:21]2[CH:17]([CH2:18][CH:19]([O:24][C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27][N:26]=3)[CH2:20]2)[C:16](=[O:35])[NH:15][C:14]2([C:36]([NH:38][S:39]([CH:42]3[CH2:43][CH2:44]3)(=[O:40])=[O:41])=[O:37])[CH:12]([CH2:13]2)[CH:11]=[CH:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)([CH3:60])[CH3:59]
Reactant: NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(Oc3nccc4ccccc34)CN2C1=O
Reactant: CC(C)OC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(Oc3nccc4ccccc34)CN2C1=O
Yield: 78.2 %

Procedure:
Prepared from cyclopropanesulfonic acid [14-amino-18-(isoquinolin-1-yloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-ene-4-carbonyl)-amide bis hydrochloride (50 mg, 0.075 mmol), 44 mL (0.25 mmol) of DIPEA and 0.10 mL (0.1 mmol) of 1 M isopropyl chloroformate in toluene (Aldrich) as described in the procedure above to give 40 mg (78%) of a white solid. Preparative HPLC condition: YMC XTERRA, S5, 30×50 mm, gradient: 50% B to 100% B. 15 min. hold 2 min. flow rate 40 mL/min) NMR (300 MHz, CD3OD) δ. LC-MS (Method A, retention time: 3.32 min), MS m/z 682 (M++1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24](=[O:42])[NH:25][C@H:26]([C:35]3[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=3)[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:19]2)=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[C:49]1([CH3:72])[CH:54]=[CH:53][C:52]([S:55]([O:58][CH2:59][CH2:60]OS(C2C=CC(C)=CC=2)(=O)=O)(=[O:57])=[O:56])=[CH:51][CH:50]=1>CN(C)C=O>[C:31]([O:30][C:28](=[O:29])[CH2:27][C@H:26]([NH:25][C:24]([C@@H:20]1[CH2:21][CH2:22][CH2:23][N:18]([C:16](=[O:17])[CH2:15][CH2:14][CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)[CH2:19]1)=[O:42])[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:60][CH2:59][O:58][S:55]([C:52]2[CH:53]=[CH:54][C:49]([CH3:72])=[CH:50][CH:51]=2)(=[O:57])=[O:56])=[CH:37][CH:36]=1)([CH3:32])([CH3:33])[CH3:34]
Reactant: Cc1ccc(S(=O)(=O)OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)OCCOc2ccc([C@H](CC(=O)OC(C)(C)C)NC(=O)[C@@H]3CCCN(C(=O)CCC4CCN(C(=O)OC(C)(C)C)CC4)C3)cc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 62.8 %

Procedure:
270.0 mg (0.46 mmol) 4-(3-{(R)-3-[(S)-2-tert-butoxycarbonyl-1-(4-hydroxy-phenyl)-ethylcarbamoyl]-piperidin-1-yl}-3-oxo-propyl)-piperidine-1-carboxylic acid tert-butyl ester were dissolved in 17.7 ml N,N-dimethylformamide. 449 mg (1.38 mmol) cesium carbonate and 255.3 mg (0.69 mmol) ethylene glycol bis-p-toluenesulfonate were added. The mixture was stirred at room temperature for 20 hours and concentrated. The remainder was taken up with saturated ammonium chloride solution and ethyl acetate. The aqueous phase was extracted with 3×20 ml ethyl acetate. The extracts were dried over sodium sulfate and concentrated. Chromatography over 10 g silica gel (dichloromethane/ethanol 100/0-90/10) gave 227 mg (63%) tert-butyl 4-{3-[(3R)-3-({(1S)-3-tert-butoxy-1-[4-(2-{[(4-methylphenyl)sulfonyl]oxy}ethoxy)phenyl]-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate which were purified by HPLC:
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]([F:10])([F:9])[F:8])[N:4]([C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)[N:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[CH2:27][C:28]#[N:29].[OH-].[K+]>C(O)C>[F:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[C:27](=[CH:15][C:14]1[CH:17]=[CH:18][C:11]([N:4]2[C:5]([C:7]([F:10])([F:9])[F:8])=[CH:6][C:2]([CH3:1])=[N:3]2)=[CH:12][CH:13]=1)[C:28]#[N:29]
Reactant: Cc1cc(C(F)(F)F)n(-c2ccc(C=O)cc2)n1
Reactant: N#CCc1cc(F)ccc1F
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(C(F)(F)F)n(-c2ccc(C=C(C#N)c3cc(F)ccc3F)cc2)n1
Reaction time: 2 h
Yield: 87.3 %

Procedure:
To a stirred mixture of 4-(3-methyl-5-trifluoromethyl-pyrazol-1-yl)-benzaldehyde (127 mg, 0.50 mmol) and 2,5-difluoro-phenylacetonitrile (77 mg, 0.50 mmol) in ethanol (4 mL) was added 0.5 mL of aqueous 6N KOH at room temperature. The mixture was stirred for 2 hours and the resulting precipitate was collected by filtration to give 2-(2,5-difluoro-phenyl)-3-[4-(3-methyl-5-trifluoromethyl-pyrazol-1-yl)-phenyl]-acrylonitrile (170 mg, 87% yield) as a white solid: 1H-NMR (CDCl3) δ 2.45 (s, 3H), 6.51 (s, 1H), 7.1 (m, 2H), 7.3 (m, 1H), 7.6 (d, 2H, J=9), 7.67 (s, 1H), 8.0 (d, 2H, J=9) ppm. ESMS calculated for C20H12F5N3: 389.1; Found: 390.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([SH:12])[N:7]=1)=[O:5])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:20]1[CH2:23][CH2:22][CH2:21]1>CC#N>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][CH:20]2[CH2:23][CH2:22][CH2:21]2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cccc(S)n1
Reactant: BrC1CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)c1cccc(SC2CCC2)n1
Temperature: 50 °C
Reaction time: 18 h
Yield: 93 %

Procedure:
After 6-mercapto-pyridine-2-carboxylic acid ethyl ester (0.40 g, 2.18 mmol) was dissolved in CH3CN (9 mL), Cs2CO3(2.667 g, 6.54 mmol) and bromo cyclobutane (0.385 mL, 3.27 mmol) were added thereto, and the mixture was stirred at 50° C. for 18 hours. After the termination of the reaction, the reactant was filtered, concentrated under reduced pressure, and purified by column chromatography (eluent, EtOAc/Hex=1/5) to obtain the title compound (0.481 g, 92%).
Reaction SMILES: N(OCCC(C)C)=O.N[C:10]1[C:11]([CH:32]([CH3:34])[CH3:33])=[C:12]([NH:19][C:20](=[O:31])[CH2:21][N:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][OH:30])[CH2:24][CH2:23]2)[C:13]([CH:16]([CH3:18])[CH3:17])=[CH:14][CH:15]=1.[CH3:35][S:36]SC>>[CH:32]([C:11]1[C:10]([S:36][CH3:35])=[CH:15][CH:14]=[C:13]([CH:16]([CH3:17])[CH3:18])[C:12]=1[NH:19][C:20](=[O:31])[CH2:21][N:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][OH:30])[CH2:24][CH2:23]1)([CH3:34])[CH3:33]
Reactant: CSSC
Reactant: CC(C)c1ccc(N)c(C(C)C)c1NC(=O)CN1CCN(CCO)CC1
Agent: CC(C)CCON=O
Product: CSc1ccc(C(C)C)c(NC(=O)CN2CCN(CCO)CC2)c1C(C)C
Temperature: 110 °C
Yield: 68 %

Procedure:
Isoamyl nitrite (1 ml) was slowly dropped into a solution of N-[3-amino-2,6-diisopropylphenyl]-2-[4-(2-hydroxyethyl)piperazin-1-yl]acetamide (500 mg) in dimethyl disulfide (10 ml) with heating and stirring at 110° C. followed by stirring at the same temperature for 20 minutes. The reaction solution was allowed to cool and concentrated. The resulting residue was purified by a silica gel column chromatography (developing solvent, chloroform:methanol=20:1) to provide 370 mg (yield 68%) of N-[2,6-diisopropyl-3-(methylthio)phenyl]-2-[4-(2-hydroxyethyl)piperazin-1-yl]acetamide.