Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6]([CH2:7][CH2:8][C:9]([OH:11])=O)=[CH:5][CH:4]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH3:47][C:48]1[S:52][C:51]([CH2:53][CH2:54][NH2:55])=[CH:50][CH:49]=1>CN(C=O)C>[CH3:47][C:48]1[S:52][C:51]([CH2:53][CH2:54][NH:55][C:9](=[O:11])[CH2:8][CH2:7][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:14])=[CH:13][CH:12]=2)=[CH:50][CH:49]=1
Reactant: Cc1ccc(CCN)s1
Reactant: O=C(O)CCc1ccc(C(F)(F)F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(CCNC(=O)CCc2ccc(C(F)(F)F)cc2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
To a solution of 3 g (13 mmol) 4-(trifluoromethyl)hydrocinnamic acid (commercially available) in 30 mL DMF under argon were added 4.7 g (14.37 mmol) TBTU and 11.2 mL (65.3 mmol) N-ethyldiisopropylamine. A solution of 1.85 g (13 mmol) 2-(5-methyl-thiophen-2-yl)-ethylamine in 5 mL DMF was added drop wise over a period of 2 minutes. The mixture was stirred at room temperature for 1 h. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate. The solution was washed with water and with a sat. NaHCO3 solution, dried over Na2SO4, filtered and concentrated in vacuo. The solid was stirred in 30 mL ether, filtered and dried. The mother liquor was concentrated in vacuo and purified on silica eluting with a gradient formed from heptane and ethyl acetate. The product containing fractions were evaporated. 3.75 g (84%) of the title compound was yielded as white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33](=[O:46])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[CH:45]=[N:44][CH:43]=[CH:42][N:41]=2)[CH:35]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[C:11]([C:20]([F:22])([F:23])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33](=[O:46])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[CH:45]=[N:44][CH:43]=[CH:42][N:41]=2)[CH:35]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cnccn2)c1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N
Product: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2cnccn2)c1

Procedure:
The title compound was prepared from [2-amino-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) (281 mg, 0.75 mmol) and 3-oxo-3-(3-pyrazin-2-yl-phenyl)-propionic acid tert-butyl ester (Example K14) (224 mg, 0.75 mmol) according to the general procedure M. Obtained as an orange foam (370 mg, 82%).
Reaction SMILES: OC(C(F)(F)F)=O.[CH3:8][N:9]1[C:17]2[CH:16]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[C:20]([C:33]([F:36])([F:35])[F:34])[CH:19]=3)[N:14]=[C:13]([C:37]#[N:38])[C:12]=2[N:11]=[N:10]1.F[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=1>CS(C)=O>[CH3:8][N:9]1[C:17]2[CH:16]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH:27]4[CH2:28][CH2:29][N:30]([C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=5)[CH2:31][CH2:32]4)=[C:20]([C:33]([F:36])([F:35])[F:34])[CH:19]=3)[N:14]=[C:13]([C:37]#[N:38])[C:12]=2[N:11]=[N:10]1
Reactant: Fc1ccccn1
Reactant: Cn1nnc2c(C#N)nc(-c3ccc(OCCC4CCNCC4)c(C(F)(F)F)c3)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: Cn1nnc2c(C#N)nc(-c3ccc(OCCC4CCN(c5ccccn5)CC4)c(C(F)(F)F)c3)cc21
Temperature: 200 °C

Procedure:
To 1-methyl-6-(4-(2-(piperidin-4-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile TFA salt (170 mg) in DMSO (2 ml) was added 2-fluoropyridine (121 mg) and TEA (0.22 ml). The mixture was heated at 200° C. for 40 minutes, then purified by basic HPLC to give 1-methyl-6-(4-(2-(1-(pyridin-2-yl)piperidin-4-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile which was then converted to HCl salt by lypholising with 1M hydrochloric acid (1 ml) (50 mg).
Reaction SMILES: [Cl:1][C:2]1[C:8]([Cl:9])=[CH:7][CH:6]=[C:5]([N+:10]([O-:12])=[O:11])[C:3]=1N.N([O-])=O.[Na+].O.[BrH:18]>C(O)(=O)C.S(=O)(=O)(O)O>[Br:18][C:3]1[C:2]([Cl:1])=[C:8]([Cl:9])[CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11]
Reactant: Br
Reactant: Nc1c([N+](=O)[O-])ccc(Cl)c1Cl
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(Cl)c(Cl)c1Br
Temperature: 15 °C
Reaction time: 0.25 h

Procedure:
Substituted nitrobenzenes, not hitherto described in the chemical literature, used in the preparation of substituted anilines as hereinbefore described in Reference Example 2, were prepared as follows: (a) 2,3-Dichloro-6-nitroaniline [29 g; prepared by a modification (reaction at 125° C.) of the procedure described by Beilstein and Kurbatow, Ann., 192, 235 (1878)] was dissolved with stirring at 55°-60° C. in glacial acetic acid (350 ml). A solution of sodium nitrite (11 g) in concentrated sulphuric acid (80 ml) was then added to the solution thus obtained with stirring over 15 minutes at a temperature of 55°-60° C. maintained by intermittent cooling with water. The red solution obtained was cooled to 15° C. and poured, with stirring, into a solution of cuprous bromide (20 g) in concentrated hydrobromic acid (200 ml) and ice (500 g). The mixture was allowed to attain laboratory temperature, heated for one hour at 60° C. and then steam-distilled. The distillate obtained was extracted with diethyl ether (6×500 ml). The combined ethereal extracts were washed successively with aqueous sodium hydroxide solution (2N; 3×750 ml and water (2×500 ml), dried over anhydrous sodium sulphate and filtered. The filtrate was evaporated to dryness to give a yellow powder, which was then crystallised from hexane (125 ml) to give 2-bromo-3,4-dichloronitrobenzene (26.7 g), m.p. 73° C., in the form of yellow crystals.
Reaction SMILES: [CH3:1][N:2]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH:3]1[CH2:7][CH:6]([CH2:8][S:9][C:10]2[S:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)[O:5][C:4]1=[O:19].[OH-:37].[Li+]>O.C1COCC1>[CH3:1][N:2]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH:3]([CH2:7][CH:6]([OH:5])[CH2:8][S:9][C:10]1[S:11][C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1)[C:4]([OH:19])=[O:37]
Reactant: [OH-]
Reactant: COc1ccc(-c2ccc(S(=O)(=O)N(C)C3CC(CSc4nc5ccccc5s4)OC3=O)cc2)cc1
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(S(=O)(=O)N(C)C(CC(O)CSc3nc4ccccc4s3)C(=O)O)cc2)cc1
Reaction time: 4 h

Procedure:
To a solution of N-methyl 3-[(4′-Methoxy[1,1′-biphenyl]-4-yl)sulfonyl]amino-2-oxo-5-[[(2-benzothiazolyl)thio]methyl]-tetrahydrofuran 62c (1.00 g, 2.05 mmol) in water (5 mL) and THF (5 mL) is slowly added lithium hydroxide (0.49 g, 20.5 mmol). The reaction is stirred for 4 hr, then concentrated to dryness. The reaction mixture is diluted with water and then the mixture is extracted with ethy ether (2×25 mL) The ethyl ether layer is discarded and the aqueous layer is slowly acidified with 1N HCl to pH 5, and then extracted 3 times with ethyl acetate. The combined ethyl acetate layers are washed with water and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The white solid is then recrystallized with ethyl acetate/hexanes to give the desired product as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7]Br)([CH3:4])([CH3:3])[CH3:2].[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[CH2:16][OH:17].C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:9])[CH2:7][N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[CH2:16][OH:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: OCC1CCCCN1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CN1CCCCC1CO
Temperature: 50 °C
Reaction time: 16 h

Procedure:
Bromo-acetic acid tert-butyl ester (0.39 g, 2 mmol) was dissolved in DMF (1 mL). A solution of piperidin-2-yl-methanol (0.25 g, 2.2 mmol) in DMF (1 mL) and diisopropylethylamine (0.38 mL, 2.2 mmol) was added. The reaction mixture was stirred at 50° C. for 16 h. The solvent was removed in vacuo. EtOAc (20 mL) and water (7 mL) was added. The two phases were separated. The aqueous phase was extracted twice with EtOAc (20 mL). The combined EtOAc phases were dried over magnesium sulfate, filtered and the filtrate was evaporated in vacuo. The product was isolated as an oil. Yield: 0.37 g, 80%.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.[CH2:13]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[CH3:14]>>[CH2:13]([N:15]1[CH2:20][CH2:19][N:18]([C:2]2[N:7]=[CH:6][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=2)[CH2:17][CH2:16]1)[CH3:14]
Reactant: CCN1CCNCC1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Product: CCOC(=O)c1ccc(N2CCN(CC)CC2)nc1
Temperature: 96 °C
Reaction time: 0.08 h

Procedure:
To 55.69 g of ethyl 6-chloropyridine-3-carboxylate was added 115 ml of 1-ethylpiperazine and the mixture was heated with stirring (55-137° C.) for 5 minutes. After completion of the reaction, the 1-ethylpiperazine was distilled off under reduced pressure, the residue was crystallized from water-metanol. The crystal was washed with water and then dried under reduced pressure to afford 71.89 g of the title compound as a colorless crystal.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])=[CH:13][CH:12]=2)[N:8]=[C:7]([C:25]([O:27]CC)=[O:26])[CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O>CO>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])=[CH:15][CH:16]=2)[N:8]=[C:7]([C:25]([OH:27])=[O:26])[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc(C(=O)OCC)nn1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCc1cc(C(=O)O)nn1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 2 h
Yield: 80.6 %

Procedure:
To a solution of ethyl 5-butyl-1-[(2'-cyanobiphenyl-4-yl)methyl]pyrazole-3-carboxylate (5.75 g) in methanol (100 ml) was added 2N-NaOH (15 ml) and the mixture was allowed to stand at room temperature for 2 hours. Water (10 ml) was added and methanol was evaporated under reduced pressure. The mixture was made acidic by addition of 2N-HCl, followed by extraction with ether. The organic layer was washed with water (20 ml×2), dried, and concentrated under reduced pressure, to give a colorless syrup. The syrup was recrystallized from chloroform to give colorless crystals (4.3 g, 81%).
Reaction SMILES: [OH:1][NH:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([N:11]2[CH2:14][CH:13]([NH:15][C:16]([CH2:18][NH:19][C:20](=[O:31])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)=[O:17])[CH2:12]2)[CH2:7][CH2:6]1)=[NH:4].[C:32](N1C=CN=C1)(N1C=CN=C1)=[O:33].C1CCN2C(=NCCC2)CC1>CC#N>[O:33]=[C:32]1[O:1][N:2]=[C:3]([CH:5]2[CH2:10][CH2:9][CH:8]([N:11]3[CH2:12][CH:13]([NH:15][C:16]([CH2:18][NH:19][C:20](=[O:31])[C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=4)=[O:17])[CH2:14]3)[CH2:7][CH2:6]2)[NH:4]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: N=C(NO)C1CCC(N2CC(NC(=O)CNC(=O)c3cccc(C(F)(F)F)c3)C2)CC1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(c3noc(=O)[nH]3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of the above intermediate from Step B (0.044 g, 0.1 mmol), 1,1′-carbonyldiimidazole (Aldrich, 0.0178 g, 0.11 mmol), DBU (Acros, 0.06 mL, 0.4 mmol) in CH3CN (1 mL) was stirred at rt overnight. The crude product was purified by HPLC to give a TFA salt as a yellowish solid.
Reaction SMILES: C([C@H:3]([S:7]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[N:9][C:10]([C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]#[C:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=2)[CH:17]=1)=[O:11])=[O:8])[C:4]([O-])=[O:5])C.[CH2:33]([CH2:35][NH2:36])[OH:34]>>[OH:34][CH2:33][CH2:35][NH:36][C:4](=[O:5])[CH2:3][S:7](=[O:8])([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[N:9][C:10](=[O:11])[C:12]1[CH:17]=[C:16]([C:18]#[C:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=2)[CH:15]=[N:14][CH:13]=1
Reactant: CC[C@@H](C(=O)[O-])S(=O)(=NC(=O)c1cncc(C#Cc2cccc(O)c2)c1)c1ccccc1
Reactant: NCCO
Product: O=C(CS(=O)(=NC(=O)c1cncc(C#Cc2cccc(O)c2)c1)c1ccccc1)NCCO

Procedure:
In a manner similar to that described for Example 471, (S)-Ethyl[N-({5-[(3-hydroxyphenyl)ethynyl]pyridin-3-yl}carbonyl)-S-phenylsulfonimidoyl]acetate (75 mg, 0.17 mmol) and ethanolamine (0.05 mL, 0.84 mmol) were reacted to give the title compound as colorless oil (63 mg, 81
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9](OCO)[CH:8]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[S:7][C:6]=2[C:18]=1[Cl:19].B(F)(F)F.C[CH2:25][O:26]CC.[OH-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[C:3]([O:26][CH3:25])=[CH:4][C:5]2[CH:9]=[C:8]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17]3)[S:7][C:6]=2[C:18]=1[Cl:19]
Reactant: CCOCC
Reactant: OCOC1c2ccc(Cl)c(Cl)c2SC1C1CCCC1
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1cc2cc(C3CCCC3)sc2c(Cl)c1Cl
Reaction time: 8 h

Procedure:
A mixture of 2.5 g of 6,7-dichloro-2-cyclopentyl-2,3-dihydro-3-hydroxymethoxybenzo[b]thiophene and 10 ml of glacial acetic acid containing 5 ml of boron trifluoride etherate is warmed on a steam bath for 15 minutes and allowed to stand overnight. The mixture is poured into a chilled solution of dilute sodium hydroxide and the organic material is extracted into ether. Washing with water, followed by drying over anhydrous magnesium sulfate and evaporation in vacuo, gives 2.0 g of wax-like crystals. Recrystallization from ether-hexane gives 1.8 g of 6,7-dichloro-2-cyclopentyl-5-methoxybenzo-[b]thiophene as fine needles, mp 59.5°-60°.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([NH:17]C(=O)C)=[N:13][NH:14]3)=[CH:10][CH:9]=2)[CH:5]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:3]=1.[ClH:27]>CO>[ClH:27].[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([NH2:17])=[N:13][NH:14]3)=[CH:10][CH:9]=2)[CH:5]=[C:4]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[N:3]=1
Reactant: CC(=O)Nc1n[nH]c2cc(-c3cc(N4CCOCC4)nc(N)n3)ccc12
Agent: Cl
Solvent: CO
Product: Nc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2CCOCC2)n1
Temperature: 60 °C
Reaction time: 4 h
Yield: 92.7 %

Procedure:
In a 100 mL flask under argon was dissolved N-{6-[2-amino-6-(4-morpholinyl)-4-pyrimidinyl]-1H-indazol-3-yl}acetamide (0.15 g, 0.26 mmol) in CH3OH (10 mL). HCl (0.69 mL, 8.3 mmol, 12 M) was added and the reaction mixture was stirred at 60° C. for 4 hours. The mixture was cooled to room temperature and filtered. The solid was washed with hexanes to afford a HCl salt of the title compound (75 mg) as a light yellow solid. LC-MS (ES) m/z=312 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 3.73 (m, 4H), 3.89 (m, 4H), 6.98 (s, 1H), 7.66 (d, J=8.6 Hz, 1H), 8.08 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]([N:16]3[CH2:21][CH2:20][N:19]([S:22]([CH:25]=[CH:26][CH2:27][CH2:28][CH2:29][C:30]4[N:35]=[CH:34][CH:33]=[CH:32][N:31]=4)(=[O:24])=[O:23])[CH2:18][CH2:17]3)=[N:14][CH:15]=2)=[CH:4][CH:3]=1.[NH2:36][OH:37]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]([N:16]3[CH2:17][CH2:18][N:19]([S:22]([CH2:25][CH:26]([NH:36][OH:37])[CH2:27][CH2:28][CH2:29][C:30]4[N:35]=[CH:34][CH:33]=[CH:32][N:31]=4)(=[O:24])=[O:23])[CH2:20][CH2:21]3)=[N:14][CH:15]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=S(=O)(C=CCCCc1ncccn1)N1CCN(c2ccc(C#Cc3ccc(F)cc3)cn2)CC1
Solvent: C1CCOC1
Product: O=S(=O)(CC(CCCc1ncccn1)NO)N1CCN(c2ccc(C#Cc3ccc(F)cc3)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
To a solution of 2-{(4EZ)-5-[(4-{5-[(4-fluorophenyl)ethynyl]pyridin-2-yl}piperazin-1-yl)sulfonyl]pent-4-enyl}pyrimidine (760 mg, 1.55 mmol) in THF (10 mL) was added a solution of hydroxylamine (2 mL, 50% aqueous solution in water). The reaction was stirred for 2 hours at RT before being quenched with saturated aqueous ammonium chloride solution (5 mL). The layers were separated and the aqueous phase extracted with ethyl acetate (3×20 mL). The combined organic extracts were then dried, (MgSO4), filtered and concentrated in vacuo. The residue was then purified by bond elut (silica, EtOAc to 10% MeOH in ethyl acetate) to give 2-[5-[(4-{5-[(4-fluorophenyl)ethynyl]pyridin-2-yl}piperazin-1-yl)sulfonyl]-4-(hydroxyamino)pentyl]pyrimidine (518 mg, 0.99 mmol, 64%).
Reaction SMILES: I[C:2]1[CH:26]=[CH:25][C:5]([O:6][CH:7]2[CH2:12][CH2:11][CH:10]([C:13]([N:15]3[CH2:20][CH2:19][N:18]([CH:21]4[CH2:24][CH2:23][CH2:22]4)[CH2:17][CH2:16]3)=[O:14])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[NH:27]1[CH2:32][CH2:31][CH2:30]C[C:28]1=[O:33].C(=O)([O-])[O-].[K+].[K+]>CCOC(C)=O.[Cu]>[CH:21]1([N:18]2[CH2:19][CH2:20][N:15]([C:13]([C@H:10]3[CH2:11][CH2:12][C@H:7]([O:6][C:5]4[CH:25]=[CH:26][C:2]([N:27]5[CH2:32][CH2:31][CH2:30][C:28]5=[O:33])=[CH:3][CH:4]=4)[CH2:8][CH2:9]3)=[O:14])[CH2:16][CH2:17]2)[CH2:24][CH2:23][CH2:22]1
Reactant: O=C(C1CCC(Oc2ccc(I)cc2)CC1)N1CCN(C2CCC2)CC1
Reactant: O=C1CCCCN1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: O=C1CCCN1c1ccc(O[C@H]2CC[C@H](C(=O)N3CCN(C4CCC4)CC3)CC2)cc1

Procedure:
To a mixture of 0.87 g (3.27 mmol) of cis-(4-cyclobutyl-piperazin-1-yl)-(4-hydroxy-cyclohexyl)-methanone, 0.80 g (3.64 mmol) of 4-iodephenol, 1.05 g (4.00 mmol) of triphenylphisphine in 20 ml THF, 0.92 g (4.00 mmol) of di-tert-butyl azodicarboxylate was added at 0° C., and stirred for 12 h at room temperature. After evaporation, the residue was purified by column chromatography on silica gel eluting with cyclohexane and ethyl acetate=from 100:0 to 2:1. The combined product fractions were evaporated to dryness to yield 0.54 g (21% yields, about 65% purity) of [4-(4-iodo-phenoxy)-cyclohexyl]-(4-cyclobutyl-piperazin-1-yl)-methanone. A mixture 100 mg of [4-(4-iodo-phenoxy)-cyclohexyl]-(4-cyclobutyl-piperazin-1-yl)-methanone, 142 mg (1.67 mmol) of 2-piperidone, 77 mg (0.56 mmol) of potassium carbonate and 37 mg (1.12 mmol) of copper was stirred at 175 degree for 6 hr. The mixture was diluted with AcOEt, filtered through celite. The filtrate was evaporated. The mixture was purified with preparative HPLC (CH3CN: 0.05% HCOOH-water, Zorbax Comb Ht 20*50 mm, 5 micron). The combined product fractions were evaporated. The residue was solved with saturated NaHCO3, extracted with AcOEt, washed with brine, dried over MgSO4, and evaporated to dryness to yield 31 mg (52%) of the title compound. MS (m/e): 426.2 (MH+).
Reaction SMILES: [C:1]([O:5]/[N:6]=[C:7](\[OH:24])/[C:8]1[CH:13]=[CH:12][CH:11]=[N:10][C:9]=1[C:14](=[O:23])[C:15]1[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][C:16]=1[OH:22])([CH3:4])([CH3:3])[CH3:2].CN(C=O)C.[C:30](Cl)(=O)[C:31](Cl)=O>C1COCC1>[C:1]([O:5]/[N:6]=[C:7](\[O:24][CH2:30][CH3:31])/[C:8]1[CH:13]=[CH:12][CH:11]=[N:10][C:9]=1[C:14](=[O:23])[C:15]1[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][C:16]=1[OH:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)O/N=C(\O)c1cccnc1C(=O)c1cc(Br)ccc1O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCO/C(=N\OC(C)(C)C)c1cccnc1C(=O)c1cc(Br)ccc1O
Reaction time: 2 h

Procedure:
To a solution of (Z)-2-(5-bromo-2-hydroxybenzoyl)nicotinic acid O-t-butyloxime (540 mg) and DMF (0.02 ml) in THF (6 ml) was added, at room temperature, oxalyl chloride (0.33 ml). The mixture was stirred for 2 hours at the same temperature and then concentrated, which was dissolved in THF (2 ml). To the solution was added ethanol (8 ml) at room temperature. The mixture was stirred for 1.5 hour at the same temperature and concentrated. To the concentrate was added water, followed by extraction with ethyl acetate. The extract solution was washed with a saturated aqueous saline solution, dried (anhydrous sodium sulfate), and concentrated. The concentrate was purified by means of a silica gel column chromatography (eluent: ethyl acetate/hexane) to give ethyl(Z)-2-(5-bromo-2-hydroxybenzoyl)nicotinate O-t-butyloxime (403 mg) (Compound 139).
Reaction SMILES: COC1C=CC(C([NH:24][C:25]2[CH2:26][O:27][CH2:28][C@:29]([C:32]3[CH:37]=[C:36]([NH:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH:35]=[CH:34][C:33]=3[F:43])([CH3:31])[N:30]=2)(C2C=CC(OC)=CC=2)C2C=CC=CC=2)=CC=1.FC(F)(F)C(O)=O>ClCCl>[CH2:39]([NH:38][C:36]1[CH:35]=[CH:34][C:33]([F:43])=[C:32]([C@:29]2([CH3:31])[CH2:28][O:27][CH2:26][C:25]([NH2:24])=[N:30]2)[CH:37]=1)[CH2:40][CH2:41][CH3:42]
Reactant: CCCCNc1ccc(F)c([C@]2(C)COCC(NC(c3ccccc3)(c3ccc(OC)cc3)c3ccc(OC)cc3)=N2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCNc1ccc(F)c([C@]2(C)COCC(N)=N2)c1

Procedure:
A solution of [bis-(4-methoxy-phenyl)-phenyl-methyl]-[(R)-5-(5-butylamino-2-fluoro-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-amine (26 mg, 44.7 mol) in dichloromethane 2.5 ml) was treated at room temperature with trifluoroacetic acid (17.1 1, 223 mol) for 20 hours. The reaction mixture was evaporated at reduced pressure and the crude product purified by flash chromatography on silica gel using a gradient of dichloromethane/methanol=100/0 to 90/10 as the eluent. The title compound was obtained as a light yellow oil (58%); (calculated) C15H22FN3O [279.350]; (found) [M+H]+=280.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5](/[CH:6]=[CH:7]/[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[CH2:13](O)[CH3:14]>S(=O)(=O)(O)O>[CH2:13]([O:9][C:8](=[O:10])/[CH:7]=[CH:6]/[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:12][CH:11]=1)[CH3:14]
Reactant: O=C(O)/C=C/c1ccc(Cl)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)/C=C/c1ccc(Cl)cc1
Temperature: 70 °C

Procedure:
To a solution of trans-4-chlorocinnamic acid (10 g, 55 mmol) in ethanol (60 mL) was added a catalytic amount of concentrated sulfuric acid (2-3 drops), and the mixture was heated (70° C.) until a majority of the starting material was consumed as evidenced by LCMS. The reaction mixture was concentrated and the contents were redissolved in ethyl acetate. The organic phase was extracted with an aqueous solution of sodium bicarbonate (5%, 3×) followed by a brine wash. The organic phase was dried (MgSO4), filtered and concentrated to afford trans-4-chlorocinnamic acid ethyl ester as a colorless oil. MS (ESI) m/z 211.1 ([M+H]+).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]([CH2:23][CH2:24][CH2:25][C:26]1[S:27][CH:28]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:30]=1)=[N+]=[N-]>C1COCC1.O>[C:31]1([C:29]2[N:30]=[C:26]([CH2:25][CH2:24][CH2:23][NH2:20])[S:27][CH:28]=2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: [N-]=[N+]=NCCCc1nc(-c2ccccc2)cs1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCCCc1nc(-c2ccccc2)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.4 %

Procedure:
Triphenylphosphine (485 mg, 1.85 mmol) was added to a solution of 2-(3-azidopropyl)-4-phenylthiazole (0.3 g, 1.23 mmol) in THF—H2O (10 mL, 8:2 v/v) at 0° C. The reaction mixture was allowed to warm up to room temperature, stirred for 8 h and then concentrated under reduced pressure. The residue was diluted with 1.5N HCl and the aqueous layer was washed with CH2Cl2. The pH of the aqueous layer was adjusted to ˜8-9 using 10% NaOH solution and the organic product was extracted with CH2Cl2. The combined extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford 3-(4-phenylthiazol-2-yl)propan-1-amine (240 mg, yield 89%) as a pale yellow liquid, which was carried through without further purification. MS (ESI) m/z: Calculated for C12H14N2S: 218.09. found: 219.2 (M+H)+.