Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([CH2:12][C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:14])[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.OC(C(F)(F)F)=O.[NH2:28][CH:29]([CH2:41][CH3:42])[CH:30]([C:32]1[O:33][C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1)[OH:31].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CN1CCOCC1>C(Cl)Cl>[O:33]1[C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=[C:32]1[CH:30]([OH:31])[CH:29]([NH:28][C:9](=[O:11])[CH:8]([CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[CH2:12][C:13]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH2:41][CH3:42]
Reactant: O=C(O)C(CC(=O)N1CCOCC1)CC1CCCCC1
Reactant: CCC(N)C(O)c1nc2ccccc2o1
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Solvent: ClCCl
Product: CCC(NC(=O)C(CC(=O)N1CCOCC1)CC1CCCCC1)C(O)c1nc2ccccc2o1
Reaction time: 14 h
Yield: 106 %

Procedure:
To a stirred mixture of 2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyric acid (84.9 mg, 0.3 mmol), 2-amino-1-benzooxazol-2-yl-butan-1-ol TFA salt (96.9 mg), prepared as in reference 21, and HOBt (55.1 mg, 0.36 mmol) in MeCl2 (5 ml), was added EDC (86.4 mg, 0.45 mmol) and N-methylmorpholine (0.25 ml) at room temperature. After stirring for 14 hours, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated NaHCO3, brine, dried with MgSO4 and concentrated to yield 150 mg of N-[1-(benzooxazol-2-yl-hydroxy-methyl)-propyl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide; MS: 470.5(M−1), 472.4(M+1).
Reaction SMILES: [N:1]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([C:10]#[N:11])[N:9]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[NH2:1][CH2:4][C:5]1[S:6][CH:7]=[C:8]([C:10]#[N:11])[N:9]=1
Reactant: N#Cc1csc(CN=[N+]=[N-])n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1csc(CN)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.1 %

Procedure:
To a magnetically stirred solution of 2-azidomethyl-thiazole-4-carbonitrile (1.3 g, 7.8 mmol) in a mixture of THF (40 mL) and water (4 mL) was added triphenylphosphine (3.10 g, 11.8 mmol) portionwise with ice-bath cooling. After the addition was complete, the mixture was stirred for an additional 18 h at room temperature and extracted with 3% hydrochloric acid (10 mL). The resultant aqueous solution was extracted with ether, basified to pH=12 with 3N NaOH, extracted into ethyl acetate (3×), and the combined organic layers were washed with 100 mL of brine, dried with anhydrous magnesium sulfate and concentrated in vacuo to yield 1.0 g (91%) of the title compound as an oil which was used in next step with out further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:33]3[CH:38]=[CH:37][C:36]([CH:39]=O)=[CH:35][CH:34]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=4[F:29])=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12.[NH2:41][CH2:42][CH2:43][CH2:44][CH2:45][OH:46].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C.C(O)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:33]3[CH:34]=[CH:35][C:36]([CH2:39][NH:41][CH2:42][CH2:43][CH2:44][CH2:45][OH:46])=[CH:37][CH:38]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:27])([F:26])[F:28])=[CH:21][C:20]=4[F:29])=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12
Reactant: NCCCCO
Reactant: COc1cc(-c2nn(-c3ccc(C=O)cc3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COc1cc(-c2nn(-c3ccc(CNCCCCO)cc3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Reaction time: 72 h

Procedure:
A mixture of N1-{4-[4-amino-1-(4-formylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-2-fluoro-4-(trifluoromethyl)benzamide (Intermediate 2) (0.075 g, 0.14 mmol), 4-amino-1-butanol (0.024 g, 0.27 mmol), and sodium triacetoxyborohydride (0.087 g, 0.41 mmol) in dichloroethane (1.4 mL) was shaken for 3 days. Additional portions of 4-amino-1-butanol (0.1 mL) and sodium triacetoxyborohydride (0.089 g, 0.42 mmol) were added and the reaction mixture was shaken for 3 days. Acetic acid (0.1 mL) was added and the reaction mixture was shaken for 7 days. An additional portion of sodium triacetoxyborohydride (0.098 g, 0.46 mmol) was added and the reaction mixture was shaken for 16 h. 1N NaOH (1 mL) was added and the reaction mixture was concentrated, dissolved in DMF (2 mL), filtered through a syringe-tip Acrodisc filter, and purified by preparative RP-HPLC (Rainin C18, 8 μm, 300 Å, 25 cm; 20-80% acetonitrile-0.05 M ammonium acetate over 25 min, 21 mL/min); the fraction eluting from 12.5-14.8 min was collected, concentrated, and lyopholized to N1-{4-[4-amino-1-(4-{[(4-hydroxybutyl)amino]methyl}phenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-2-fluoro-4-(trifluoromethyl)benzamide as a white solid. (0.030 g, 0.048 mmol): 1H NMR (d6-DMSO, 400 MHz): δH 9.94 (1H, d, J=4.4 Hz), 8.35-8.40 (2H, m), 8.17 (2H, d, J=8.0 Hz), 8.00 (1H, t, J=7.4 Hz), 7.90 (1H, d, J=10.4 Hz), 7.75 (1H, d, J=7.2 Hz), 7.53-7.57 (2H, m), 7.45 (1H, s), 7.40 (1H, d, J=8.8 Hz), 3.96 (3H, s), 3.83 (2H, s), 3.39 (2H, t, J=6.2 Hz), 2.45-2.50 (2H, m), and 1.45-1.51 (4H, m); RP-HPLC (Hypersil C18, 5 μm, 100 Å, 15 cm; 5%-100% acetonitrile-0.1 M ammonium acetate over 15 min, 1 mL/min). Rt 9.93 min. MS: MH+ 624.3.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[F:27])=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:28][CH3:29])C1C=CC=CC=1>C(O)(C(F)(F)F)=O.C1(C)C=CC=CC=1>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([O:19][C:13]2[C:12]3[C:17](=[CH:18][C:9]([OH:8])=[C:10]([O:28][CH3:29])[CH:11]=3)[N:16]=[CH:15][N:14]=2)=[C:21]([F:27])[CH:22]=1
Reactant: COc1cc2c(Oc3ccc(Cl)cc3F)ncnc2cc1OCc1ccccc1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Oc3ccc(Cl)cc3F)ncnc2cc1O
Yield: 90.7 %

Procedure:
A solution of 7-benzyloxy-4-(4-chloro-2-fluorophenoxy)-6-methoxyquinazoline (451 mg, 1.1 mmol) in TFA (4.5 ml) was heated at reflux for 3 hours. The mixture was diluted with toluene and the volatiles removed by evaporation. The residue was triturated with methylene chloride, collected by filtration, washed with ether and dried under vacuum to give 4-(4-chloro-2-fluorophenoxy)-7-hydroxy-6-methoxyquinazoline (320 mg, 90%).
Reaction SMILES: [CH3:1][NH2:2].Cl[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][N:5]=1>>[CH3:1][NH:2][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: CN
Reactant: O=[N+]([O-])c1cccnc1Cl
Product: CNc1ncccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
Methylamine (33% in EtOH) (110 mL, 883 mmol) was placed in a 500 mL three necked round bottom flask. It was cooled to 0° C. using ice bath. 2-chloro-3-nitropyridine (20 g, 126 mmol) was added to the above solution in portions as this is an exothermic reaction. After the addition was complete the reaction mixture was stirred for 2 h at 0° C. and later 1 h at room temperature. Solvent was concentrated and residue was taken in 500 mL of water and extracted with EtOAc 3×150 mL. Combine organic layer was dried over Na2SO4, filtered and concentrated to give a bright orangish yellow solid (19 g, 98.5%).
Reaction SMILES: [CH3:1][C:2]1[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([N:10]1[C:19]2[C:14](=[C:15](C3C=CC(CO)=CC=3)[CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1)=[O:9].OCC1C=CC(B(O)O)=CC=1.[CH3:44][S:45][C:46]1[N:51]=[C:50]([CH2:52][N:53]2[CH:57]=[C:56](B3OC(C)(C)C(C)(C)O3)[CH:55]=[N:54]2)[CH:49]=[CH:48][N:47]=1>>[CH3:1][C:2]1[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([N:10]1[C:19]2[C:14](=[C:15]([C:56]3[CH:55]=[N:54][N:53]([CH2:52][C:50]4[CH:49]=[CH:48][N:47]=[C:46]([S:45][CH3:44])[N:51]=4)[CH:57]=3)[CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1)=[O:9]
Reactant: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4ccc(CO)cc4)cccc32)c1C
Reactant: CSc1nccc(Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)n1
Agent: OCc1ccc(B(O)O)cc1
Product: CSc1nccc(Cn2cc(-c3cccc4c3CCCN4C(=O)CCCOc3cccc(C)c3C)cn2)n1

Procedure:
The title compound was prepared using a procedure analogous to 4-(2,3-dimethylphenoxy)-1-(5-(4-(hydroxymethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)butan-1-one except that 4-(hydroxymethyl)phenylboronic acid was replaced with 2-(methylthio)-4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)pyrimidine. LCMS, [M+H]+=528.4. 1H NMR (400 MHz, CDCl3) δ 8.51 (d, J=5.3 Hz, 1H), 7.62 (s, 1H), 7.46 (s, 1H), 7.16-7.25 (m, 3H), 7.02 (t, J=7.8 Hz, 1H), 6.74 (d, J=7.5 Hz, 1H), 6.69 (d, J=5.1 Hz, 1H), 6.65 (d, J=8.4 Hz, 1H), 5.40 (s, 2H), 3.94 (t, J=5.5 Hz, 2H), 3.81 (t, J=6.8 Hz, 2H), 2.79 (t, J=7.2 Hz, 2H), 2.54-2.63 (m, 5H), 2.11-2.26 (m, 5H), 1.82-1.97 (m, 5H).
Reaction SMILES: C[C:2]([C:4]1[S:5][C:6]([CH2:9][CH:10]([N:12]=[N+:13]=[N-:14])[CH3:11])=[CH:7][CH:8]=1)=[O:3].BrBr.[OH-:17].[Na+]>>[N:12]([CH:10]([CH3:11])[CH2:9][C:6]1[S:5][C:4]([C:2]([OH:3])=[O:17])=[CH:8][CH:7]=1)=[N+:13]=[N-:14]
Reactant: [OH-]
Reactant: CC(=O)c1ccc(CC(C)N=[N+]=[N-])s1
Agent: BrBr
Agent: [Na+]
Product: CC(Cc1ccc(C(=O)O)s1)N=[N+]=[N-]

Procedure:
For the preparation of the amine starting material of Example 10f, α-methyl-2-thiophenethanol, acetyl chloride and aluminum chloride were reacted in methylene chloride to give (RS)-2-(5-acetyl-2-thienyl)-1-methylethyl acetate. The resulting acetate was saponified with sodium hydroxide in methanol to give 5-[(RS)-2-hydroxypropyl]-2-thienyl methyl ketone which was subsequently reacted with p-toluenesulfonyl chloride to give (RS)-2-(5-acetyl-2-thienyl)-1-methylethyl-p-toluenesulfonate, m.p. 101°-103°. With sodium azide in dimethylsulfoxide there was obtained therefrom 5-[(RS)-2-azidopropyl]-2-thienyl methyl ketone which was oxidized with bromine in sodium hydroxide solution to give 5-[(RS)-2-azidopropyl]-2-thiophenecarboxylic acid. With thionyl chloride, there was obtained therefrom the corresponding acid chloride and from this there was prepared with ammonia 5-[(RS)-2-azidopropyl]-2-thiophenecarboxamide, m.p. 79°-80° C., from diethyl ether. Treatment with triphenylphosphine and hydrolysis gave 5-[(RS)-2-aminopropyl]-2-thiophenecarboxamide, m.p. 91°-92° from acetonitrile.
Reaction SMILES: C1(O)C=CC=CC=1.[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2(C3C=CC(O)=CC=3)[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1>>[C:9]1([OH:8])[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[CH:13][CH:14]=1
Reactant: Oc1ccc(C2(c3ccc(O)cc3)CCC(O)CC2)cc1
Solvent: Oc1ccccc1
Product: Oc1ccc(-c2ccc(O)cc2)cc1

Procedure:
The same reaction and post-treatment as described in Example 1 were carried out, except that 75.7 g (0.20 mole) of the phenol adduct of 4,4-bis(4-hydroxyphenyl)cyclohexanol was used in place of 56.9 g (0.20 mole) of 4,4-bis(4-hydroxyphenyl)cyclohexanol. 4,4'-Biphenol was obtained as white crystals in a yield of 33.8 g. The product had a purity of 98.1% based on liquid chromatography and a p-phenylphenol content of 1.2%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[NH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[N:21]1([CH2:20][CH2:19][O:18][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:27]=[CH:28][CH:29]=[C:2]([N:36]4[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]4)[CH:3]=3)=[CH:9][CH:10]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1cccc(Br)c1
Reactant: C1CCNCC1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1cccc(N2CCCCC2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 3-bromo-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-benzamide (200 μmol, 1 eq.), cesium carbonate (300 μmol, 1.5 eq), and piperidine (300 μmol, 1.5 eq.) is suspended in anhydrous dioxane (2 ml) in a 2-dram vial. To the heterogeneous mixture is added bis(tri-t-butylphosphine)palladium(0) (5 mg, 5 mol %). The mixture is heated and agitated for 12 hours. The mixture is cooled to room temperature, filtered and concentrated. The residue is purified using reverse phase conditions (5:95; AcCN:H2O) to give N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-3-piperidin-1-yl-benzamide. Mp: 147-148° C. 1H NMR (300 MHz, DMSO-d6) δ 10.16 (s, 1H), 8.22 (m, 1H), 7.87 (m, 1H), 7.60 (s, 1H), 7.55 (m, 2H), 7.47 (m, 3H), 7.17 (d, 1H), 7.04 (d, 1H, J=8.7), 4.33 (t, 2H, J=5.7), 3.62 (t, 4H, J=4.5), 3.32 (m, 4H), 2.90 (t, 2H, J=5.7), 2.58 (m, 4H), 1.65 (m, 4H), 1.57 (m, 2H). MS: 460.2 (M+1).
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[C:25]([C:26]4([OH:30])[CH2:29][O:28][CH2:27]4)=[CH:24][C:16]([C:17]([O:19]C(C)(C)C)=[O:18])=[C:15]([F:31])[CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.FC(F)(F)C(O)=O>ClCCl>[C:1]12([CH2:11][O:12][C:13]3[C:25]([C:26]4([OH:30])[CH2:27][O:28][CH2:29]4)=[CH:24][C:16]([C:17]([OH:19])=[O:18])=[C:15]([F:31])[CH:14]=3)[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: CC(C)(C)OC(=O)c1cc(C2(O)COC2)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1cc(C2(O)COC2)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-(adamantan-1-ylmethoxy)-2-fluoro-5-(3-hydroxyoxetan-3-yl)benzoate ((330 mg, 0.76 mmol) in dichloromethane (4 mL) was added trifluoroacetic acid (1 mL) and the reaction mixture was stirred for 2 hour at ambient temperature. Removal of all volatiles in vacuo gave 4-(adamantan-1-ylmethoxy)-2-fluoro-5-(3-hydroxyoxetan-3-yl)benzoic acid as an oily residue (0.29 g, quant.).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[F:25][C:26]1([F:33])[CH2:28][CH:27]1[CH2:29][C:30](Cl)=[O:31]>O1CCCC1.O>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:30](=[O:31])[CH2:29][CH:27]2[CH2:28][C:26]2([F:33])[F:25])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=C(Cl)CC1CC1(F)F
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: O=C(CC1CC1(F)F)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
15.3 g (120 mmol) 4-Chloroaniline, 18.4 ml (132 mmol) triethylamine and 50 mg dimethylaminopyridine dissolved in 150 ml tetrahydrofuran was treated, under ice-cooling, with 18.6 g (120 mmol) 2-(2,2-difluorocyclopropyl)acetyl chloride. The mixture was stirred for 2 hours at room temperature and poured into 1000 ml water. The precipitated crystals were separated, washed with a small amount of hydrochloric acid and dried in vacuo (200 mbar). A sample was analysed by thin layer chromatography (dichloromethane:methanol=95:5) (Rf=0.62).
Reaction SMILES: B(Br)(Br)Br.C([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]=[CH:15][S:16]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26]([NH2:29])(=[O:28])=[O:27])(=[O:18])=[O:17])C.CO>ClCCl>[OH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]=[CH:15][S:16]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26]([NH2:29])(=[O:28])=[O:27])(=[O:17])=[O:18]
Reactant: CCOc1ccccc1C=CS(=O)(=O)Nc1ccccc1S(N)(=O)=O
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: NS(=O)(=O)c1ccccc1NS(=O)(=O)C=Cc1ccccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.2 %

Procedure:
Boron tribromide (1 M in dichloromethane, 5.4 mL, 5.44 mmol) was added dropwise over 5 min to a suspension of 2-[2-(2-ethoxy-phenyl)-ethenesulfonylamino]-benzenesulfonamide (example 222) (0.21 g, 0.54 mmol) in dichloromethane (10 mL) at −78° C. The reaction mixture was allowed to warm to room temperature and stirred overnight. Cooled to −20° C. and methanol (5 mL) was added slowly. The resulting solution was warmed up to room temperature and heated at 50° C. for 1 hour. The volatiles were removed under reduced pressure and the residue was taken up in methanol (5 mL). The mixture was concentrated in vacuo and the process was repeated once more. The residue was taken up in water (5 mL) and ethyl acetate (15 mL). The organic phase was separated, dried over magnesium sulfate and concentrated in vacuo. Purification by preparative HPLC gave 31 mg (16% yield) of the title compound.
Reaction SMILES: Cl.C(OC(=O)[NH:8][C@@H:9]([C:11](=[O:22])[NH:12][C:13]1[CH:18]=[C:17]([Cl:19])[C:16]([F:20])=[C:15]([Cl:21])[CH:14]=1)[CH3:10])(C)(C)C.C(Cl)Cl>O.CO>[NH2:8][C@H:9]([CH3:10])[C:11]([NH:12][C:13]1[CH:14]=[C:15]([Cl:21])[C:16]([F:20])=[C:17]([Cl:19])[CH:18]=1)=[O:22]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1cc(Cl)c(F)c(Cl)c1
Agent: Cl
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: C[C@@H](N)C(=O)Nc1cc(Cl)c(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 106.1 %

Procedure:
To a solution of hydrochloric acid (12 M, 266 mL, 3.19 mol) in water (272 mL) and MeOH (135 mL) was added a solution of crude [(R)-1-(3,5-dichloro-4-fluoro-phenylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester (208.6 g, max. 594 mmol) in MeOH (600 mL) via an addition funnel over 30 min CH2Cl2 (300 mL) was then added and the reaction mixture was stirred at room temperature overnight. An additional portion of HCl (12M, 100 mL) was added and stirring was continued for another 20 h. The volatile solvents were removed in vacuo and the remaining aqueous mixture was cooled to −15 to −20° C. Toluene (400 mL) was added followed by the addition of NaOH solution (50% aqueous, 300 mL), which was added at a rate to keep the internal temperature below 25° C. The layers were separated and the aqueous layer was extracted with toluene (2×1 L). The combined organic layers were dried with Na2SO4 and concentrated to give 158.3 g of the title compound as a dark brown oil that solidified slowly in the freezer, m/z 251.1 [M+H]+. This crude material was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([CH2:17][NH:18][C:19]2[C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][N:22]=[C:21]([Cl:30])[N:20]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-].O.Cl>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([CH2:17][NH:18][C:19]2[C:24]([C:25]([OH:27])=[O:26])=[CH:23][N:22]=[C:21]([Cl:30])[N:20]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnc(Cl)nc1NCC1CCCN(C(=O)OCc2ccccc2)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cnc(Cl)nc1NCC1CCCN(C(=O)OCc2ccccc2)C1
Reaction time: 20 h
Yield: 98.2 %

Procedure:
To a solution of ethyl 4-((1-(benzyloxycarbonyl)piperidin-3-yl)methylamino)-2-chloropyrimidine-5-carboxylate (0.382 g, 0.88 mmol) in THF (5 mL), aq. 1N LiOH (1.00 mL, 1.00 mmol) was added. After being stirred for 20 h, water (10 mL) was added. The solution was acidified with 1N HCl (2 mL) to pH 1-2. The product was extracted with EtOAc. The EtOAc solution was washed with brine, dried over Na2SO4, concentrated in vacuo to give 4-((1-(benzyloxycarbonyl)piperidin-3-yl)methylamino)-2-chloropyrimidine-5-carboxylic acid (0.350 g).
Reaction SMILES: [CH2:1]([OH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH2:18]1[CH:22]([CH2:23][CH2:24][CH2:25][CH2:26][C:27](N)=[O:28])SS[CH2:19]1>CCCCCC>[C:27]([O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:18][CH2:19][CH2:1]/[CH:2]=[CH:3]\[CH2:4][CH2:5][CH3:6]
Reactant: NC(=O)CCCCC1CCSS1
Reactant: CCCCCCCCCCCCCCCCO
Solvent: CCCCCC
Product: CCC/C=C\CCCCCCCCC(=O)OCCCCCCCCCCCCCCCC
Yield: 88 %

Procedure:
Preparation of hexadecyl cis-10-tetradecenoate, 8 was carried out according to the Scheme 2. Methyl undecenoate, 5 (10.21 g, 0.0515 mol) in dichloromethane (150 ml) was cooled to −78° C. and ozone gas was bubbled into the reaction mixture for 1 hr. The reaction was quenched by adding dimethyl sulphide (DMS, 5 ml) and was stirred for 6 hr at 25° C. The solvents were removed under vacuum and the residue 6 thus obtained was used directly further preparation of cis-10-myristoleate, 7. n-Butyl-triphenyl phosphonium bromide salt (10.0 g, 0.0251 mol) was taken in dry THF (50 ml) and cooled to 0° C. To this slurry, n-Butyl lithium (17.0 ml, 1.6 M in hexane) was added and stirred for 0.5 hr. 1-Al-methyl deaconate containing crude product 6 (5.01 g, 0.025 mol) dissolved in dry THF (50 ml) was added slowly to the above contents and allowed the reaction mixture to warm to roam temperature and then heated to reflux temperature to reflux for 4 hr. THF was removed from the reaction product under reduced pressure, and to the residue distilled water (25 ml) was added and extracted with ether (25 ml×3 times). The combined ether layer was dried over anhydrous sodium sulphate and solvent was evaporated and dried under vacuum to get the product and was further purified by column chromatography using hexane and ethyl acetate (98:2) as eluent to obtain cis-10-myristoleate, 7 (3.35 g, 0.014 mol) in 56% yield with 97% purity by GC. cis-10-Myristoleate, 7 (3.35 g, 0.014 mol) was enzymatically transesterified with cetyl alcohol (4.07 g, 0.0168 mol) in the presence of Lipozyme TL IM (0.745 g, 10 wt % of the total substrate), at 65° C. for 8 hr. The reaction was monitored by TLC and after completion of reaction, hexane (50 ml) was added and the lipase, was separated by filtration and the solvent was evaporated to get the crude product and was purified by column chromatography to obtain hexadecyl cis-10-tetradecenoate, 8 (5.55 g, 0.0123) in 88% yield with 95% purity by GC. The structure of hexadecyl cis-10-tetradecenoate, 8 was confirmed by 1H NMR, IR, and GC-MS.
Reaction SMILES: Cl.[NH2:2][OH:3].[CH2:4]([C:7]1[C:14]([OH:15])=[CH:13][C:12]([CH2:16][CH:17]=[CH2:18])=[C:11]([OH:19])[C:8]=1[CH:9]=O)[CH:5]=[CH2:6].C(O)C>O>[CH2:4]([C:7]1[C:14]([OH:15])=[CH:13][C:12]([CH2:16][CH:17]=[CH2:18])=[C:11]([OH:19])[C:8]=1[CH:9]=[N:2][OH:3])[CH:5]=[CH2:6]
Reactant: C=CCc1cc(O)c(CC=C)c(C=O)c1O
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CCO
Product: C=CCc1cc(O)c(CC=C)c(C=NO)c1O

Procedure:
Hydroxylamine hydrochloride (2 g) was dissolved in 20 ml of water and added to 2,5-diallyl-3,6-dihydroxybenzaldehyde (2 g). Enough ethanol was added to completely solubilise the aldehyde. The mixture was heated on a steam bath for ten minutes until TLC showed the reaction to be complete. The water and ethanol were evaporated and the solid recrystallised from ethanol/water, to give a beige solid, m.p. 241°-243° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[F:19][C:20]([F:35])([F:34])[C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:23]3[CH:24]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:26]=[C:21]([C:20]([F:19])([F:35])[F:34])[CH:22]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Product: CCCNC(=O)c1nnc2c(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cccc2c1N
Yield: 93.2 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (150 mg, 0.485 mmol) and 3,5-bis(trifluromethyl)phenylboronic acid (258 mg, 1.000 mmol) were reacted to afford the title compound 200 mg, 94% yield as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 8.50 (br, 1H), 8.13 (s, 2H), 7.99-7.93 (m, 2H), 7.84-7.73 (m, 2H), 3.47 (apparent quartet, J=7.0 Hz, 2H), 1.68 (apparent sextet, J=7.0 Hz, 2H), 1.01 (t, J=7.0 Hz, 3H). MS APCI, m/z=443 (M+H). HPLC 2.85 min.