Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.[Br:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[C:12]([F:19])[CH:11]=1>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:2]2[N:3]=[CH:4][C:5]([OH:8])=[CH:6][CH:7]=2)=[C:12]([F:19])[CH:11]=1
Reactant: Oc1ccc(Br)nc1
Reactant: OB(O)c1ccc(Br)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: COCCOC
Product: Oc1ccc(-c2ccc(Br)cc2F)nc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 10.9 %

Procedure:
A mixture of Pd(PPh3)2Cl2 (0.42 g, 0.57 mmol) and 2-bromo-5-hydroxypyridine (1.0 g, 5.75 mmol) in DME (20 mL) was degassed with N2. 2M Na2CO3 (10 mL) was added, and the mixture was stirred at ambient temperature for 10 minutes. 4-Bromo-2-fluorobenzeneboronic acid (1.48 g, 6.61 mmol) was added. The reaction mixture was degassed again, purged with N2 and heated at 80° C. overnight, then cooled to ambient temperature, and partitioned between water and EtOAc. Concentrated HCl was added carefully to adjust aqueous pH to about 8, the mixture was filtered thought Celite®, and the EtOAc layer was separated and washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a dark brown oil. The crude product was purified by chromatography on a silica gel column eluted with 20% EtOAc/hexane to give 0.168 g of 6-(4-bromo-2-fluorophenyl)-3-pyridinol as an off-white solid. The impure fractions were combined, concentrated and further purified with 1:5 acetone/hexane to give additional 78 mg of 6-(4-bromo-2-fluorophenyl)-3-pyridinol (0.246 g overall, 16% yield). 1H NMR (400 MHz, CD3OD): δ 8.20 (d, 1H, J=2.7 Hz), 7.75-7.65 (m, 1H), 7.62 (dd, 1H, Ja=8.7 Hz, Jb=2.1 Hz), 7.50-7.40 (m, 2H), 7.28 (dd, 1H, Ja=8.5 Hz, Jb=2.9 Hz); LRMS (ESI), m/z 268/270 (M+H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[CH:4]C=1.C(C1C=CC(B(O)O)=CC=1F)#[N:39]>>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]2[N:24]=[C:20]([CH:17]3[CH2:18][CH2:19][N:14]([C:13]4[N:12]=[CH:11][N:10]=[C:9]([NH2:37])[C:8]=4[C:5]4[CH:4]=[N:39][CH:2]=[CH:7][CH:6]=4)[CH2:15][CH2:16]3)[N:21]([CH3:36])[CH:22]=2)=[CH:26][C:27]=1[C:32]([F:34])([F:33])[F:35]
Reactant: N#Cc1ccc(B(O)O)cc1F
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(F)cc2)CC1
Product: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2cccnc2)CC1

Procedure:
The title compound was prepared in an analogous manner as 5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine using 4-cyano-3-fluorophenylboronic acid instead of 4-fluorophenylboronic acid. LC-MS: (M+1=498, obsd.=498).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:11].[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH:21]=O)[CH:19]=2)[CH:14]=[N:13]1>>[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18](/[CH:21]=[C:4]3/[C:3](=[O:11])[N:2]([CH3:1])[C:10]4[C:5]/3=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:19]=2)[CH:14]=[N:13]1
Reactant: O=Cc1ccc2cn[nH]c2c1
Reactant: CN1C(=O)Cc2ccccc21
Product: CN1C(=O)/C(=C/c2ccc3cn[nH]c3c2)c2ccccc21
Yield: 17.5 %

Procedure:
The desired product was synthesized according to the method described for Example A11B, except substituting 1-methylindolin-2-one (37 mg, 0.249 mmol) and 1H-indazole-6-carbaldehyde (40 mg, 0.274 mmol) and then purified by preparatory HPLC to obtain the title compound (12 mg, 17%) as a yellow solid. 1H NMR (400 MHz, CD3OD) δ 8.13 (s, 1H), 7.96-7.86 (m, 3H), 7.67 (d, J=7.83 Hz, 1H), 7.46 (d, J=8.08 Hz, 1H), 7.33 (t, J=7.71 Hz, 1H), 7.02 (d, J=7.83 Hz, 1H), 6.93 (t, J=7.71 Hz, 1H), 3.31 (s, 3H); MS ESI 276.1 [M+H]+, calcd for [C17H13N3O+H]+ 276.11.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[CH3:17][CH2:18]O>>[F:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([O:6][CH2:17][CH3:18])=[O:5]
Reactant: CCO
Reactant: O=C(O)c1cc(I)ccc1F
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(I)ccc1F
Temperature: 100 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a solution of 2-fluoro-5-iodobenzoic acid (Oakwood, 0.99 g, 3.72 mmol) in EtOH (7.4 mL) was added H2SO4 (198 μL, 3.72 mmol). The resulting reaction mixture was stirred at 100° C. overnight and then concentrated in vacuo. The crude oil was purified using flash column chromatography (gradient from 0% to 10% EtOAc/hexanes) to give the title compound (916 mg, 84%) as a colorless oil. 1H NMR (CDCl3) δ 8.24 (dd, J=6.8, 2.4 Hz, 1H), 7.81 (ddd, J=8.8, 4.5, 2.4 Hz, 1H), 6.93 (dd, J=10.3, 8.6 Hz, 1H), 4.41 (q, J=7.0 Hz, 2H), 1.42 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])[CH3:3].C(N(CC)CC)C.[F:22][C:23]([F:29])([F:28])[S:24](Cl)(=[O:26])=[O:25].C(=O)(O)[O-].[Na+]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[F:22][C:23]([F:29])([F:28])[S:24]([N:12]1[CH2:11][CH2:10][CH:9]([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])[CH2:14][CH2:13]1)(=[O:26])=[O:25]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=S(=O)(Cl)C(F)(F)F
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)C(F)(F)F)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A 150 ml round-bottomed flask equipped with a magnetic stirrer is charged under argon with 2 g of 4-N-boc-aminopiperidine in 35 ml of DCM, 82 mg of 4-dimethylaminopyridine (DMAP) and 1.86 ml of triethylamine. After cooling to 0° C. using an ice bath, 1.6 ml of trifluoromethanesulphonyl chloride are added dropwise. The mixture is stirred at 0° C. for 30 min and then at RT for 1 h. It is poured into 100 ml of saturated aqueous sodium bicarbonate solution. It is extracted with AcOEt, washed with saturated aqueous NaCl solution, dried over MgSO4, filtered and concentrated to dryness under RP. Chromatography on silica gel (15-40 μm), eluting with a mixture of DCM and methanol (98/02 by vol.), gives 1.5 g of 1,1-dimethylethyl (1-trifluoromethanesulphonylpiperidin-4-yl)carbamate (cream solid). MS (E/I): m/z=232 (M+).
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[OH:14][C:15]1[C:16]([O:23][CH3:24])=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[O:19].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH:18]([C:17]1[C:16]([O:23][CH3:24])=[C:15]([CH:22]=[CH:21][CH:20]=1)[O:14][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])=[O:19]
Reactant: COc1c(O)cccc1C=O
Reactant: N#Cc1ccc(C(F)(F)F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(C=O)cccc1Oc1cc(C(F)(F)F)ccc1C#N
Yield: 91.1 %

Procedure:
2-Fluoro-4-trifluoromethyl-benzonitrile (0.56 mL, 0.76 g, 4 mmol), 3-hydroxy-2-methoxybenzaldehyde (0.61 g, 4 mmol) and cesium carbonate (1.3 g, 4 mmol) were heated with stirring in dry DMF (4 mL) at 50° C. for 18 h. The reaction mixture was cooled, poured into water and extracted with ethyl acetate. The ethyl acetate layer was separated, washed with water (2×), 10% sodium carbonate solution (2×), water (1×), brine (1×), and dried over MgSO4. After filtration, the solvent was removed in vacuo to yield 2-(3-formyl-2-methoxy-phenoxy)-4-trifluoromethyl-benzonitrile (1.17 g, 91%) as a brown solid.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][CH2:26][C:27]1[C:28]([F:44])=[C:29]([O:34][C:35]2[CH:36]=[C:37]([CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:38]#[N:39])[C:30]([Cl:33])=[CH:31][CH:32]=1.[C:45]([NH:48][C:49]1[CH:50]=[C:51]2[C:55](=[CH:56][CH:57]=1)[NH:54][C:53]([C:58](O)=[O:59])=[CH:52]2)(=[O:47])[CH3:46].CCN(C(C)C)C(C)C>CN(C=O)C>[C:45]([NH:48][C:49]1[CH:50]=[C:51]2[C:55](=[CH:56][CH:57]=1)[NH:54][C:53]([C:58]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([O:34][C:35]3[CH:36]=[C:37]([C:38]#[N:39])[CH:40]=[C:41]([Cl:43])[CH:42]=3)[C:28]=1[F:44])=[O:59])=[CH:52]2)(=[O:47])[CH3:46]
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: CC(=O)Nc1ccc2[nH]c(C(=O)O)cc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc2[nH]c(C(=O)NCc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4)c3F)cc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.9 %

Procedure:
HATU (0.023 g, 0.062 mmol) was added to a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.013 g, 0.041 mmol), 5-(acetylamino)-1H-indole-2-carboxylic acid (0.009 g, 0.041 mmol) and DIPEA (0.011 mL, 0.062 mmol) in DMF (0.5 mL). The reaction mixture was stirred at RT overnight and was extracted with ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was triturated with methanol to give the title compound (0.009 g, 43%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.50 (s, 1H), 9.74 (s, 1H), 8.95 (s, 1H), 7.91 (s, 1H), 7.78 (s, 1H), 7.40-7.49 (m, 3H), 7.32-7.40 (m, 1H), 7.28 (s, 1H), 7.15-7.24 (m, 1H), 7.06 (s, 1H), 4.53 (s, 2H), 1.98 (s, 3H). MS: m/z 511 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[CH2:10][CH2:11][OH:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][C:17]1[C:26]2[C:21](=[CH:22][C:23](O)=[CH:24][CH:25]=2)[CH:20]=[CH:19][N:18]=1>ClCCl.CO>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[CH2:10][CH2:11][O:12][C:23]1[CH:22]=[C:21]2[C:26](=[CH:25][CH:24]=1)[C:17]([NH2:16])=[N:18][CH:19]=[CH:20]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Nc1nccc2cc(O)ccc12
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CCO
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CCOc1ccc2c(N)nccc2c1

Procedure:
This compound was prepared from N-tert-butoxycarbonyl-L-β-homoprolinol [Leyendecker, F.; Jesser, F.; Laucher, D.; Tetrahedron Lett. 1983, 24, 3513-3516; 590 mg, 2.75 mmol] and 1-amino-6-hydroxy-isoquinoline (1e, 320 mg, 2.0 mmol) by the Mitsunobu procedure described in Example 1f. Yield: 650 mg (91%). ESI-MS: 358.0 (M+H)+. Rf (silica gel; dichloromethane/methanol, 9:1, v/v): 0.37.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1.[CH3:12][NH:13][CH3:14].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:12][N:13]([CH3:14])[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1
Reactant: CNC
Reactant: O=[N+]([O-])c1c(Cl)ncnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)c1ncnc(Cl)c1[N+](=O)[O-]
Temperature: -70 °C

Procedure:
Dissolve 50 g (0.26 mol) of 4,6-dichloro-5-nitropyrimidine in 500 mL of CH2Cl2 and cool to -70° C. Add a solution of 24 mL (0.28 mol) dimethylamine, 70 mL (0.40 mol) of diisopropylethylamine, and 100 mL of CH2Cl2 over 30 minutes. Warm to room temperature and wash the reaction mixture with 500 mL of 20% K2CO3. Dry the CH2Cl2 portion over MgSO4, treat with charcoal filter, and remove the filtrate under vacuum. Crystallize the residue with ether to provide 4-dimethylamino-6-chloro-5-nitropyrimidine.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:7]([N+]([O-])=O)[CH:6]=1)(=[O:4])=[O:3].[CH3:17][O-:18].[Na+].O>CO>[CH3:1][S:2]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:7]([O:18][CH3:17])[CH:6]=1)(=[O:4])=[O:3]
Reactant: C[O-]
Reactant: CS(=O)(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc([N+](=O)[O-])cc(S(C)(=O)=O)c1
Yield: 70.3 %

Procedure:
To a solution of 1-methylsulfonyl-3,5-dinitro-benzene (2.0 g; 8 mmol) in methanol (15 ml) a solution of sodium methoxide (0.5 g; 10 mmol) in methanol (5 ml) was added. The mixture was refluxed for 2 hours. Water was added and the precipitate washed with a diisopropylether/ethanol mixture. 1.3 g (5.62 mmol; 70% yield) of 1-methylsulfonyl-3-methoxy-5-nitro-benzene were obtained as a yellow solid.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([OH:14])=O)[CH:7]=2)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.ClC(OC)=O.[N:32]1([C:37]2[CH:38]=[C:39]([CH:41]=[CH:42][CH:43]=2)[NH2:40])[CH:36]=[N:35][CH:34]=[N:33]1>C(Cl)Cl>[CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:40][C:39]3[CH:41]=[CH:42][CH:43]=[C:37]([N:32]4[CH:36]=[N:35][CH:34]=[N:33]4)[CH:38]=3)=[O:14])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: CCCN(CC1CC1)c1cc(C(=O)O)ncn1
Reactant: Nc1cccc(-n2cncn2)c1
Agent: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2cccc(-n3cncn3)c2)ncn1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A cooled (0° C.) solution of 6-(cyclopropylmethyl(propyl)amino)pyrimidine-4-carboxylic acid (Intermediate 21, 112 mg; 0.45 mmol) in DCM was treated with diisopropylethylamine (78.4 mL; 0.52 mmol) and methyl chloroformate (36.2 mL; 0.47 mmol). After stirring at 0° C. for 15 minutes, 3-(1H-1,2,4-triazol-1-yl)aniline (Maybridge, 108 mg; 0.67 mmol) was added and the mixture stirred for 72 hours. The solvent was evaporated and the compound purified by preparative HPLC to give the title compound as a white solid.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11]/[C:10]/1=[CH:34]\[CH:35]=[O:36])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1(C)C=CC(S([CH2:46][N+:47]#[C-:48])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CO>[Si:1]([O:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:11]/[C:10]/1=[CH:34]\[C:35]1[O:36][CH:48]=[N:47][CH:46]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C/C1=C\C=O
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C/C1=C\c1cnco1
Yield: 33.1 %

Procedure:
To a solution of (E)-4-(t-butyldimethylsilyloxy)-3-(formylmethylidene)-1-(triphenylmethyl)piperidine (112 mg) in methanol (2.5 ml) were added successively p-toluenesulfonylmethyl isocyanide (45 mg) and potassium carbonate (32 mg), and the resulting mixture was refluxed for 3.5 hours. After refluxing, water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:19 to 1:3) as the eluent to afford the title compound (40 mg, yield: 32%) as a yellow oil.
Reaction SMILES: [S:1]([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([CH:20]=O)[CH:19]=[C:14]2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].Cl.[NH2:23][OH:24].N1C=CC=CC=1>CCO>[S:1]([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([CH:20]=[N:23][OH:24])[CH:19]=[C:14]2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3cc(C=O)cnc32)cc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2ccc3cc(C=NO)cnc32)cc1
Temperature: 70 °C
Yield: 98.6 %

Procedure:
To a solution of 1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (0.58 g, 1.93 mmol) in EtOH (5 mL) was added hydroxylamine hydrochloride (0.7 g, 9.6 mmol) and pyridine (0.5 mL). The reaction mixture was heated at 70° C. for 18 h and then the solvent was removed under reduced pressure to afford 0.6 g (98%) of 1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde oxime as white solid which was used in the next step without further purification. MS (ESI) m/z: 316.2 [M+1]+.
Reaction SMILES: [C:1](Cl)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:21]([OH:44])(=O)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]/[CH:33]=[CH:34]\[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]>C(OCC)(=O)C.CCCCCC>[CH2:21]([O:44][C:1](=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH:33]=[CH:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Cl
Reactant: CCCCCCCC/C=C\CCCCCCCCCCCC(=O)O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCCCCCC=CCCCCCCCCCCCCOC(=O)CCCCCCCC=CCCCCCCCC
Yield: 94.5 %

Procedure:
Compound D was prepared from Oleoyl chloride and Erucic acid following the general procedure discussed before and as shown in FIG. 9. Pure compound D was a colorless oil obtained by column chromatography with Ethyl acetate/Hexane=1:40. Reaction conditions for branched derivative compounds D2, D3, and D4 are also shown below.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][C:3]=1[N:12]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=1)[S:13]([C:16]1[CH:24]=[CH:23][C:19]([C:20]([O-:22])=O)=[CH:18][CH:17]=1)(=[O:15])=[O:14].[Na+].C(Cl)(=O)C(Cl)=O.Cl.[CH3:45][O:46][NH2:47].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:45][O:46][NH:47][C:20](=[O:22])[C:19]1[CH:23]=[CH:24][C:16]([S:13]([N:12]([C:3]2[N:4]=[CH:5][C:6]3[C:11]([C:2]=2[CH3:1])=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:34])[F:35])=[CH:28][CH:27]=2)(=[O:14])=[O:15])=[CH:17][CH:18]=1
Reactant: CON
Reactant: Cc1c(N(Cc2ccc(OC(F)(F)F)cc2)S(=O)(=O)c2ccc(C(=O)[O-])cc2)ncc2ccccc12
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CONC(=O)c1ccc(S(=O)(=O)N(Cc2ccc(OC(F)(F)F)cc2)c2ncc3ccccc3c2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.7 %

Procedure:
To a suspension of sodium 4-({(4-methylisoquinolin-3-yl)[4-(trifluoromethoxy)-benzyl]amino}sulfonyl)benzoate (107.7 mg, 0.200 mmol) prepared in Example 2 in chloroform (1 mL) was added oxalyl dichloride (21 μL, 0.240 mmol), and the mixture was stirred at room temperature for 2 hours. Then, thereto was added additional oxalyl dichloride (21 μL, 0.24 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure. Then, the resulting residue was suspended in chloroform (1 mL), and added dropwise to a suspension of O-methylhydroxylamine hydrochloride (50.1 mg, 0.600 mmol) and triethylamine (139 μL, 1.00 mmol) in chloroform (1 mL), and the mixture was stirred at room temperature for 1 hour. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1→0:10) to give N-methoxy-4-({(4-methylisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]amino}sulfonyl)-benzamide (88.1 mg, 81%) as a white powder.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][C:6]2[C:8]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[CH:9][CH:10]=[CH:11][C:5]=2[O:4][CH2:3]1.C(N(CC)CC)C.[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31](Cl)=[O:32]>C(Cl)Cl>[CH3:18][N:15]1[CH2:14][CH2:13][N:12]([C:8]2[C:6]3[CH2:7][C@H:2]([NH:1][C:31]([C:27]4[O:26][CH:30]=[CH:29][CH:28]=4)=[O:32])[CH2:3][O:4][C:5]=3[CH:11]=[CH:10][CH:9]=2)[CH2:17][CH2:16]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CO3)CC1
Reactant: O=C(Cl)c1ccco1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccco2)CO3)CC1
Temperature: 0 °C
Yield: 78.4 %

Procedure:
To an ice-cooled stirred solution of (S)-3-amino-5-(4-methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran (230 mg, 0.930 mmol) and triethylamine (194 μL, 1.39 mmol) in anhydrous methylene chloride (10 mL) was added 2-furoyl chloride (101 μL, 1.02 mmol) under nitrogen. The ice-bath was removed, and the reaction mixture was allowed to reach room temperature. The mixture was washed with a 2 M NH3 solution, dried (MgSO4), and the solvent was removed in vacuo. The remains was purified on a chromatotron (accelerated thin layer chromatography, eluent: chloroform/ethanol; 92:8+0.5% conc. NH3) affording 249 mg (79% yield) of the title compound as a white solid: mp sinters >50° C.; [α]21D−83° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 341 (52, M+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(C(C)C)C(C)C)C>C1COCC1>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: CN1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 42.8 %

Procedure:
A mixture of 1-chloro-4-nitro benzene (3 g, 19 mmol), 1-methyl piperazine (2.28 g, 22.8 mmol) and ethyl-diisopropylamine (2 ml) in THF (20 ml) was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure to give a residue, which was then partitioned between dichloromethane and water. The organic layer was separated and evaporated under reduced pressure to give crude compound, which was purified by column chromatography over silica gel, using ethyl acetate as eluent, to yield 1-methyl-4-(4-nitro-phenyl)-piperazine (1.8 g, 44%) as solid.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.C[Al](C)C.[N:13]1([CH2:22][C:23]2[CH:24]=[C:25]([CH:31]=[CH:32][CH:33]=2)[C:26]([O:28]CC)=O)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[CH:14]1>>[CH:3]1([N:2]([CH3:1])[C:26](=[O:28])[C:25]2[CH:31]=[CH:32][CH:33]=[C:23]([CH2:22][N:13]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[N:15]=[CH:14]3)[CH:24]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CNC1CCCCC1
Reactant: CCOC(=O)c1cccc(Cn2cnc3ccccc32)c1
Agent: C[Al](C)C
Product: CN(C(=O)c1cccc(Cn2cnc3ccccc32)c1)C1CCCCC1

Procedure:
N-Cyclohexyl-N-methyl 3-(1H-benzimidazylmethyl)benzamide was prepared by the method of Example 9 starting with N-methylcyclohexylamine and reacting with trimethylaluminium and ethyl 3-(1H-benzimidazylmethyl)benzoate.
Reaction SMILES: [N:1]1([CH:10]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([P:21](=[O:32])([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])([F:20])[F:19])=[CH:14][CH:13]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[Li]CCCC.[CH:44]([O:47][C:48]1[CH:60]=[C:59]([C:61]2[CH:66]=[CH:65][C:64]([CH2:67]Br)=[CH:63][CH:62]=2)[CH:58]=[CH:57][C:49]=1[C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])([CH3:46])[CH3:45]>CCCCCC.C1COCC1>[N:1]1([C:10]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]([P:21]([O:27][C:28]([CH3:31])([CH3:29])[CH3:30])([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:32])([F:19])[F:20])=[CH:16][CH:17]=2)[CH2:67][C:64]2[CH:63]=[CH:62][C:61]([C:59]3[CH:58]=[CH:57][C:49]([C:50]([O:52][C:53]([CH3:54])([CH3:56])[CH3:55])=[O:51])=[C:48]([O:47][CH:44]([CH3:46])[CH3:45])[CH:60]=3)=[CH:66][CH:65]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: CC(C)Oc1cc(-c2ccc(CBr)cc2)ccc1C(=O)OC(C)(C)C
Reactant: CC(C)(C)OP(=O)(OC(C)(C)C)C(F)(F)c1ccc(CC(c2ccccc2)n2nnc3ccccc32)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)Oc1cc(-c2ccc(CC(Cc3ccc(C(F)(F)P(=O)(OC(C)(C)C)OC(C)(C)C)cc3)(c3ccccc3)n3nnc4ccccc43)cc2)ccc1C(=O)OC(C)(C)C

Procedure:
To a solution of di(tert-butyl) {4-[2-(1H-1,2,3-benzotriazol-1-yl)-2-phenylethyl]phenyl}(difluoro)methylphosphonate (0.060 g, 0.110 mmol) in TRF (1.0 mL) were added n-BuLi 1.6 M in hexane (0.086 mL) and the bromide of Example 11, Step 1 (0.045 g, 0.111 mmol) in THF (1.0 mL). Then using the same protocol as described for Example 14 Step 1 the title compound was obtained.