Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[CH:18]=[N:19][N:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:21]=3[C:22]([F:25])([F:24])[F:23])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].Cl.[CH2:33]([NH2:35])[CH3:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[CH2:33]([NH:35][C:3](=[O:4])[CH:2]([OH:1])[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[CH:18]=[N:19][N:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:21]=3[C:22]([F:23])([F:25])[F:24])[O:14][N:13]=2)=[CH:8][CH:7]=1)[CH3:34]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3cnn(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCNC(=O)C(O)c1ccc(-c2noc(-c3cnn(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 77.8 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-VII, 35 mg, 0.081 mmol), ethanamine-HCl (9.95 mg, 0.122 mmol), HATU (40.2 mg, 0.106 mmol), and 4-methylmorpholine (32.9 mg, 0.325 mmol) were added to DMF (1 mL). It was stirred for 1 h and then was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 12 min, 20 mL/min, 220 nM, product retention=13.3 min) to provide (R/S)-N-ethyl-2-hydroxy-2-(4-(5-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (30 mg, 0.063 mmol, 77% yield): LCMS=458.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.46 (1 H, s), 8.11 (2 H, d, J=8.58 Hz), 7.51-7.72 (7 H, m), 5.09 (1 H, s), 3.24-3.30 (2 H, m), 1.14 (3 H, t, J=7.15 Hz); HPLC peak RT=7.9 min (Method A).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:25]([CH3:38])=[C:26]([CH3:37])[C:27]4[O:31][C:30]([CH3:33])([CH3:32])[C:29](=[O:34])[C:28]=4[C:35]=3[CH3:36])[CH2:20][CH2:19]2)=[CH:14][CH:13]=1>CCCCCC>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:29]2([OH:34])[C:28]3[C:35]([CH3:36])=[C:24]([N:21]4[CH2:22][CH2:23][N:18]([C:15]5[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=5)[CH2:19][CH2:20]4)[C:25]([CH3:38])=[C:26]([CH3:37])[C:27]=3[O:31][C:30]2([CH3:32])[CH3:33])=[CH:3][CH:4]=1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(=O)C(C)(C)O4)CC2)cc1
Reactant: COc1ccc(Br)cc1
Solvent: CCCCCC
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(O)(c3ccc(OC)cc3)C(C)(C)O4)CC2)cc1
Yield: 95 %

Procedure:
Using 4-bromoanisole and 4-(4-methoxyphenyl)-1-(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-on-5-yl)piperazine obtained in Reference Example 13, the title compound was synthesized in the same manner as in Example 33. Yield 95%. mp. 157–159° C. (hexane).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH3:9])[CH:3]=1.[CH3:10][N:11]([CH3:19])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH2:18])[CH:13]=1>>[CH3:10][N:11]([CH3:19])[C:12]1[CH:13]=[C:14]([NH:18][C:2]2[CH:3]=[C:4]([NH:8][CH3:9])[N:5]=[CH:6][N:7]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: CN(C)c1cccc(N)c1
Reactant: CNc1cc(Cl)ncn1
Product: CNc1cc(Nc2cccc(N(C)C)c2)ncn1

Procedure:
The title compound is prepared analogously as described in Example 105A from (6-chloro-pyrimidin-4-yl)-methylamine and N,N-dimethyl-m-phenylenediamine. The crude product obtained after evaporation of the ethyl acetate layer is purified by flash chromatography (CH2Cl2/CH3OH).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:41]([CH:45]6[CH2:47][CH2:46]6)[CH:42]=[N:43][CH:44]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:57])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:41]([CH:45]6[CH2:46][CH2:47]6)[CH:42]=[N:43][CH:44]=5)=[O:57])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cncn4C4CC4)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cncn4C4CC4)cc2)CCN3CC(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 71.6 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(3-cyclopropylimidazol-4-yl)methylthio]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.3 g) was dissolved in dichloromethane (10 ml), and the mixture was cooled to −78° C. 3-chloroperbenzoic acid (0.17 g) in dichloromethane solution (5 ml) was added dropwise to the solution. The mixture was stirred for 1 hour at −78° C., and then, sodium thiosulfate solution was added to the mixture. The mixture was concentrated, and extracted with ethyl acetate. The organic layer was washed with aqueous sodium bicarbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: triethylamine/methanol/ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(3-cyclopropylimidazol-4-yl)methylsulfinyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 74) (0.22 g) as yellow amorphous.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=[O:14])[C:11]([CH:15]([NH:17][C:18](=O)[CH3:19])[CH3:16])=[N:10][N:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>ClCCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=[O:14])[C:11]3=[C:15]([CH3:16])[N:17]=[C:18]([CH3:19])[N:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)NC(C)c1nnc(-c2ccc(Br)cc2)[nH]c1=O
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc(C)n2nc(-c3ccc(Br)cc3)[nH]c(=O)c12
Reaction time: 0.5 h

Procedure:
A solution of 10.0 g (29.66 mmol) of N-{1-[3-(4-bromophenyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]ethyl} from example 7A in 340 ml of 1,2-dichloroethane is treated with 13.64 g (8.30 ml, 88.98 mmol) of phosphoryl chloride. The mixture is boiled under reflux for 15 h. After cooling, the solvent is removed. The residue is stirred with diethyl ether and filtered off with suction. The crystals are stirred for 1 h with 150 ml of saturated aqueous sodium hydrogencarbonate solution, and subsequently diluted with 100 ml of water. After 30 min, the solid is filtered off with suction, washed well with water and rewashed with petroleum ether.
Reaction SMILES: C([N:6]1[CH2:11][CH2:10][N:9]([CH:12]2[C:18]3[CH:19]=[C:20]([S:23][CH3:24])[CH:21]=[CH:22][C:17]=3[S:16][C:15]3[CH:25]=[C:26]([O:29][CH3:30])[CH:27]=[CH:28][C:14]=3[CH2:13]2)[CH2:8][CH2:7]1)(OCC)=O.C(O)CO.[OH-].[K+]>O>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:14]2[CH2:13][CH:12]([N:9]3[CH2:8][CH2:7][NH:6][CH2:11][CH2:10]3)[C:18]3[CH:19]=[C:20]([S:23][CH3:24])[CH:21]=[CH:22][C:17]=3[S:16][C:15]=2[CH:25]=1
Reactant: CCOC(=O)N1CCN(C2Cc3ccc(OC)cc3Sc3ccc(SC)cc32)CC1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: COc1ccc2c(c1)Sc1ccc(SC)cc1C(N1CCNCC1)C2

Procedure:
61 G. of 1-carbethoxy-4-(10,11-dihydro-3-methoxy-8-methylthio-dibenzo[b,f]thiepin-10-yl)-piperazine, 600 ml. of ethylene glycol, 25 g. of potassium hydroxide and 2.7 ml. of water are heated at 160°C. for a period of 2 hours. Then, the mixture is poured on to water and extracted with benzene. The organic phase is washed with water, dried over magnesium sulfate and evaporated under reduced pressure, whereby there is obtained 1-(10,11-dihydro-3-methoxy-8-methylthio-dibenzo[b,f]thiepin-10-yl)-piperazine.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH:5]=[CH:6][C:7]([OH:9])=[O:8].[N+:13]([O-])([O-:15])=[O:14].[Na+].S(=O)(=O)(O)O.N([O-])=O.[Na+]>C(Cl)Cl>[N+:13]([C:12]1[CH:11]=[CH:10][C:4]([CH:5]=[CH:6][C:7]([OH:9])=[O:8])=[CH:3][C:2]=1[OH:1])([O-:15])=[O:14]
Reactant: O=[N+]([O-])[O-]
Reactant: O=C(O)C=Cc1cccc(O)c1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(O)C=Cc1ccc([N+](=O)[O-])c(O)c1
Reaction time: 24 h
Yield: 26.1 %

Procedure:
3-Hydroxycinnamic acid (3.00 g, 18.3 mmol) was dissolved in methylene chloride(40 mL) followed by the addition of sodium nitrate (1.70 g, 26.1 mmol). The addition of sulfuric acid (25 mL/3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/CH2Cl2) gave the desired product(1.0 g, 26%). 1H NMR (CD3COCD3): δ 8.07 (d, 1H), 7.69 (d, 1H), 7.51 (s, 1H), 7.46 (d, 2H), 6.75 (d,1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]1[CH:20]=O.N1CCCCC1>C(O)C>[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]1[CH:20]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]1=[O:10]
Reactant: O=Cc1cc2ccccc2[nH]1
Reactant: O=C1Cc2ccccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1Nc2ccccc2C1=Cc1cc2ccccc2[nH]1
Temperature: 95 °C

Procedure:
A mixture of 2-oxindole (133 mg), indole-2-carbaldehyde (174 mg) (prepared according to Synthetic Communications, 1993, 23, 3109) and piperidine (10 mg) in ethanol was heated in a sealed tube at 95° C. for 4 hours. The mixture was cooled to room temperature. The solid was collected by vacuum filtration, washed with cold ethanol and dried in vacuum oven for overnight to give 3-(1H-indol-2-ylmethylene)-1,3-dihydro-indol-2-one.
Reaction SMILES: C([O:5][C:6]([N:8]1[C:13]2[CH:14]=[C:15]([NH:18][C:19]3[N:24]=[C:23]([NH:25][C:26]4[CH:27]=[C:28]([NH:32][C:33](=[O:36])[CH:34]=[CH2:35])[CH:29]=[CH:30][CH:31]=4)[C:22]([F:37])=[CH:21][N:20]=3)[CH:16]=[CH:17][C:12]=2[O:11][CH2:10][CH2:9]1)=O)(C)(C)C.[C:38](OC(=O)C)(=O)C.N1C=CC=CC=1>C(Cl)Cl>[C:6]([N:8]1[C:13]2[CH:14]=[C:15]([NH:18][C:19]3[N:24]=[C:23]([NH:25][C:26]4[CH:27]=[C:28]([NH:32][C:33](=[O:36])[CH:34]=[CH2:35])[CH:29]=[CH:30][CH:31]=4)[C:22]([F:37])=[CH:21][N:20]=3)[CH:16]=[CH:17][C:12]=2[O:11][CH2:10][CH2:9]1)(=[O:5])[CH3:38]
Reactant: CC(=O)OC(C)=O
Reactant: C=CC(=O)Nc1cccc(Nc2nc(Nc3ccc4c(c3)N(C(=O)OC(C)(C)C)CCO4)ncc2F)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CC(=O)Nc1cccc(Nc2nc(Nc3ccc4c(c3)N(C(C)=O)CCO4)ncc2F)c1

Procedure:
The title compound was prepared by treating the product of Example 85 with acetic anhydride and pyridine in CH2Cl2 at rt for 1 hr, followed by washing with 1N HCl, then with aqueous NaHCO3, drying over Na2SO4 and removal of solvents in vacuo. MS m/z: 449.1 (M+H+).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][S:17][C:18]1[CH:23]=[CH:22][C:21]([C:24](=[O:26])[CH3:25])=[CH:20][C:19]=1B1OC(C)(C)C(C)(C)O1>>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:23]2[CH:22]=[C:21]([C:24](=[O:26])[CH3:25])[CH:20]=[CH:19][C:18]=2[S:17][CH3:16])[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: CSc1ccc(C(C)=O)cc1B1OC(C)(C)C(C)(C)O1
Product: CSc1ccc(C(C)=O)cc1-c1nc2cc(F)cc(F)c2c(Cl)c1C

Procedure:
Essentially prepared according to Procedure F using 2,4-dichloro-5,7-difluoro-3-methylquinoline (150 mg, 0.59 mmol) and 1-(4-(methylthio)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethanone to give 1-(3-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)-4-(methylthio)phenyl)ethanone. Mass Spectrum (ESI) m/e=378.1 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cl:21][C:22]1[S:23][C:24]([CH2:27]Cl)=[CH:25][CH:26]=1>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:27][C:24]3[S:23][C:22]([Cl:21])=[CH:26][CH:25]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: ClCc1ccc(Cl)s1
Reactant: CCOC(=O)N1CCC(c2c[nH]c3ccccc23)CC1
Product: CCOC(=O)N1CCC(c2cn(Cc3ccc(Cl)s3)c3ccccc23)CC1
Reaction time: 15 h

Procedure:
This compound was prepared following the procedure described in example 13 (part B) at room temperature for 15 hours, starting with 3.5 g (13 mmol) of 4-(1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester and 1.9 mL (16 mmol) of 2-chloro-5-chloromethyl-thiophene. After standard work-up, 5.2 g (99% of yield) of the expected product was obtained.
Reaction SMILES: C1(P(C2C=CC=CC=2)(S)=[S:8])C=CC=CC=1.[CH2:16]([O:18][C:19](=[O:24])[CH:20]([C:22]#[N:23])[CH3:21])[CH3:17].CCOC(C)=O>C(O)(C)C>[NH2:23][C:22](=[S:8])[CH:20]([CH3:21])[C:19]([O:18][CH2:16][CH3:17])=[O:24]
Reactant: CCOC(=O)C(C)C#N
Reactant: S=P(S)(c1ccccc1)c1ccccc1
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)C(N)=S
Yield: 54.8 %

Procedure:
A mixture of diphenylphosphinodithioic acid (ALFAAESAR, 37.4 g, 149 mmol) and 2-cyanopropionic acid ethyl ester (ABCR, 9.90 mL, 74.7 mmol) in isopropanol (350 mL) was heated under reflux for 5 h. TLC (Hex:EtOAc 7:3) showed reaction had gone to completion. Reaction mixture was allowed to cool and was placed in the fridge overnight. Reaction mixture was filtered off and washed with isopropanol. Residue was partitioned between ethyl acetate (250 mL) and 1N NaOH (250 mL). Phases were separated and organic phase was washed with water (300 mL), brine (300 mL), dried over sodium sulfate and concentrated to dryness. Crude was purified by chromatography on silica gel using a hexane/EtOAc gradient. Appropriate fractions were combined and evaporated to yield title compound as a white solid (6.6 g, 40.9 mmol, 54.8% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm: 9.60 (s, 1H), 9.40 (s, 1H), 4.05 (q, 2H), 3.74 (q, 1H), 1.29 (d, 3H), 1.15 (t, 3H). [ES+MS] m/z 162 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[CH3:10][NH:11][CH3:12].C(=O)([O-])[O-].[K+].[K+].O>C(O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][N:11]([CH3:12])[CH3:10])=[CH:6][CH:7]=1
Reactant: CNC
Reactant: ClCc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CN(C)Cc1ccc(Cl)nc1

Procedure:
2-Chloro-5-(chloromethyl)pyridine (500 mg) was dissolved in ethanol (7.0 ml). dimethylamine (0.83 ml, 33% in ethanol) and potassium carbonate (641 mg) were added and the resulting mixture was refluxed for 1.5 hours. After evaboration of ethanol, water was added and the aqueous mixture was extracted with ethyl acetate. 1H NMR (400 MHz, d6-DMSO) δ: 8.31 (d, 1H, J 2.3 Hz), 7.77 (dd, 1H, J 8.2, 2.3 Hz), 7.47 (d, 1H, J 8.2 Hz), 3.41 (s, 2H), 2.14 (s, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[CH:9]([CH3:15])[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1.[Br:17][CH2:18][CH2:19][CH2:20]Br.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[Br:17][CH2:18][CH2:19][CH2:20][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:16])[CH:9]([CH3:15])[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:7]=1
Reactant: BrCCCBr
Reactant: COC(=O)CC(C)C(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)CC(C)C(=O)c1ccc(OCCCBr)cc1

Procedure:
The mixture of the phenol from Step A (4.0 g) 1,3-dibromopropane (18.2 ml), potassium carbonate (7.5 g) and methyl ethyl ketone (100 ml) was refluxed for 1 hour. The mixture was filtered, concentrated in vacuo and the residue was purified by chromatography on silica gel to provide the title compound as an oil.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[C:7]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[N:6]1.[Cl:26][C:27]1[CH:43]=[CH:42][C:30]2[N:31]([CH3:41])[C:32](=[O:40])[N:33]([CH:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[C:29]=2[CH:28]=1.C(N(CC)CC)C>CCO>[Cl:26][C:27]1[CH:43]=[CH:42][C:30]2[N:31]([CH3:41])[C:32](=[O:40])[N:33]([CH:34]3[CH2:39][CH2:38][N:37]([CH2:3][CH:2]([OH:1])[CH2:4][N:5]4[CH:9]=[C:8]([C:10]5[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=5)[C:7]([C:16]5[CH:17]=[CH:18][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=5)=[N:6]4)[CH2:36][CH2:35]3)[C:29]=2[CH:28]=1
Reactant: Cn1c(=O)n(C2CCNCC2)c2cc(Cl)ccc21
Reactant: FC(F)(F)c1ccc(-c2nn(CC3CO3)cc2-c2ccncc2)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cn1c(=O)n(C2CCN(CC(O)Cn3cc(-c4ccncc4)c(-c4ccc(C(F)(F)F)cc4)n3)CC2)c2cc(Cl)ccc21
Temperature: 80 °C
Yield: 21.6 %

Procedure:
To a solution of 4-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1H-pyrazol-4-yl]-pyridine (68 mg, 0.197 mmol) and 5-chloro-1-methyl-3-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one (0.055 g, 0.207 mmol) in EtOH (1 mL) was added triethylamine (0.027 mL, 0.197 mmol). The reaction mixture was heated at 80° C. overnight, concentrated, and purified by column chromatography (silica, 2-10% MeOH/CH2Cl2) to afford the title compound (0.026 g, 22%). MS (electrospray): exact mass calculated for C31H30ClF3N6O2, 611.2 [M+H]+, m/z found, 611.2. 1H NMR (400 MHz, CDCl3): 8.59 (br s, 2H), 8.20 (s, 1H), 7.67 (d, J=8.2 Hz, 2H), 7.61 (d, J=5.9 Hz, 2H), 7.55 (d, J=8.2 Hz, 2H), 7.35 (br s, 1H), 7.09 (dd, J=8.2,1.8 Hz, 1H), 6.89 (d, J=8.2 Hz, 1H), 4.55-4.60 (m, 2H), 4.39 (d, J=14.2, 4.1 Hz, 1H), 4.31 (d, J=14.2, 6.1 Hz, 1H), 3.80-3.90 (m, 2H), 3.37 (s, 3H), 3.18-3.33 (m, 2H), 3.02-3.17 (m, 2H), 2.77-2.95 (m, 2H), 1.99 (t, J=12.4 Hz, 2H).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[C:28]1([S:34](Cl)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][S:34]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)(=[O:36])=[O:35])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Product: O=S(=O)(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1)c1ccccc1

Procedure:
The title compound, white solid (106 mg, 90%), MS (ISP) m/z=471.4 [(M+H)+], mp 122.5° C., was prepared in accordance with the general method of example 26 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and benzenesulfonyl chloride.
Reaction SMILES: [F:1][C:2]1[C:3](Br)=[N:4][C:5]([Br:10])=[C:6]([F:9])[C:7]=1[Br:8].[F:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCCC1>[Br:10][C:5]1[C:6]([F:9])=[C:7]([Br:8])[C:2]([F:1])=[C:3]([C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[F:12])[N:4]=1
Reactant: CC1(C)OB(c2cc([N+](=O)[O-])ccc2F)OC1(C)C
Reactant: Fc1c(Br)nc(Br)c(F)c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)c(-c2nc(Br)c(F)c(Br)c2F)c1
Temperature: 55 °C
Reaction time: 48 h
Yield: 28.2 %

Procedure:
To a degassed mixture of 3,5-difluoro-2,4,6-tribromopyridine (4.26 g, 12.1 mmol), 2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (2.80 g, 10.4 mmol), aqueous sodium carbonate (10 ml of a 2M solution) and tetrahydrofuran (40 ml) was added tetrakis(triphenylphosphine)palladium(0) (0.67 g). The mixture was then stirred at 55° C. for 48 h under an atmosphere of nitrogen. The reaction mixture was then partitioned between water and ethyl acetate. The organic layer was separated and evaporated and the residue chromatographed on silica gel eluting with isohexane on a gradient of dichloromethane (20-40%) to afford 2,4-dibromo-3,5-difluoro-6-(2-fluoro-5-nitrophenyl)pyridine as a solid (1.21 g): δH (400 MHz, CDCl3) 7.37 (1H, t, J 9), 8.38 (1H, m), 8.55 (1H, dd, J 6 and 3).
Reaction SMILES: [CH2:1]([O:13][C:14]1[CH:30]=[CH:29][C:17]([C:18]([O:20][C:21]2[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=2)=[O:19])=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[OH2:31]>C(O)(=O)C.[O-2].[O-2].[O-2].[Cr+6]>[CH2:1]([O:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([O:20][C:21]2[CH:28]=[CH:27][C:24]([C:25]([OH:31])=[O:26])=[CH:23][CH:22]=2)=[O:19])=[CH:29][CH:30]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCOc1ccc(C(=O)Oc2ccc(C=O)cc2)cc1
Reactant: O
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)O
Product: CCCCCCCCCCCCOc1ccc(C(=O)Oc2ccc(C(=O)O)cc2)cc1
Reaction time: 20 h
Yield: 83 %

Procedure:
The 4-(4-n-dodecoxybenzoyloxy)-benzaldehyde produced in step A4 (17.4 g) was dissolved in acetic acid (60 ml) and treated with a solution of chromium trioxide (12.7 g) dissolved in 50% acetic acid added dropwise over 20 minutes at 40° C. After stirring at 45°-50° for 20 hours, water (150 ml) was added and the mixture stirred for 3 hours. The product separated and was recrystallised from acetic acid (55 ml) to give 4-(4-n-dodecoxybenzoyloxy)-benzoic acid (15 g, 83% theory).
Reaction SMILES: [CH2:1]([N:4]([CH3:24])[C:5](=[O:23])[C:6]1[C:18]([I:19])=[C:17]([NH2:20])[C:16]([I:21])=[C:8]([C:9]([N:11]([CH2:13][CH:14]=[CH2:15])[CH3:12])=[O:10])[C:7]=1[I:22])[CH:2]=[CH2:3].[C:25](Cl)(Cl)=[O:26].C1(C)C=CC=CC=1>O1CCOCC1>[CH2:1]([N:4]([CH3:24])[C:5](=[O:23])[C:6]1[C:18]([I:19])=[C:17]([N:20]=[C:25]=[O:26])[C:16]([I:21])=[C:8]([C:9]([N:11]([CH2:13][CH:14]=[CH2:15])[CH3:12])=[O:10])[C:7]=1[I:22])[CH:2]=[CH2:3]
Reactant: C=CCN(C)C(=O)c1c(I)c(N)c(I)c(C(=O)N(C)CC=C)c1I
Reactant: O=C(Cl)Cl
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: C=CCN(C)C(=O)c1c(I)c(N=C=O)c(I)c(C(=O)N(C)CC=C)c1I
Temperature: 60 °C

Procedure:
To a solution of N,N′-diallyl-5-amino-2,4,6-triiodo-N,N′-dimethyl-isophthalamide (5 g, 7.5 mmol) in 1,4-dioxane (10 mL) was added ˜11 equivalents of 20% phosgene solution in toluene (35 mL, 70 mmol) at ambient temperature, the solution was heated at 60° C. for 15 hours. The reaction was allowed to cool to ambient temperature and then concentrated at reduced pressure to yield an off white, semi-crystalline solid. Dioxane (50 mL×2) was added and removed slowly at reduced pressure to give an off white, semi-crystalline solid which was placed on a vacuum line to remove any residual solvent. The material was used without further purification.
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][N:2]=1.[NH2-:11].[Na+].[OH-].[Na+]>CN(C=O)C>[C:1]1([NH2:11])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][N:2]=1
Reactant: [NH2-]
Reactant: c1cc2c(cn1)CCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Nc1nccc2c1CCCC2
Temperature: 170 °C
Yield: 46.7 %

Procedure:
To a solution of 5,6,7,8-tetrahydroisoquinoline (5.0 g, 37.6 mmol) in DMF (8 mL) was added sodium amide (2.55 g, 63.9 mmol). The resulting mixture was heated to 170° C. for 16 h and cooled to room temperature. To the mixture was added aqueous 2 N NaOH (50 mL). The mixture was extracted with DCM (100 mL×3), and the combined organic phase was dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluting with DCM/MeOH v/v 10:1) to give 5,6,7,8-tetrahydroisoquinolin-1-amine as a yellow solid (2.6 g, yield 46%). ESI MS: m/z 149 [M+H]+. 1H NMR (400 MHz, CDCl3): δ 7.80 (d, J=5.2 Hz, 1H), 6.44 (d, J=5.2 Hz, 1H), 4.34 (br, 2H), 2.67 (t, J=12 Hz, 2H), 2.39 (t, J=12 Hz, 2H), 1.88 (m, 2H), 1.78 (m, 2H).