Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].CCOP(OCC)([CH2:8][C:9]#[N:10])=O.[CH3:14][O:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][CH2:22][C:23]2=O)=[CH:18][CH:17]=1.O>O1CCCC1>[CH3:14][O:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][CH2:22][C:23]2=[CH:8][C:9]#[N:10])=[CH:18][CH:17]=1
Reactant: COc1ccc2c(c1)C(=O)CCC2
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(=CC#N)CCC2
Reaction time: 0.25 h
Yield: 98 %

Procedure:
To a solution of 60% sodium hydride (6.24 g, 156 mmol) in tetrahydrofuran (100 ml) was gradually added dropwise, under ice-cooling, diethyl cyanomethyl phosphonate (30.4 g, 172 mmol). The mixture was stirred for 15 minutes. To the reaction mixture was then added dropwise a solution of 7-methoxy-1-tetralone (25.2 g, 143 mmol) in THF (50 ml). The reaction mixture was heated for 3 hours under reflux. The reaction mixture was poured into water, and the organic layer was subjected to extraction with chloroform. The extract solution was washed with brine and water, which was dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by means of a silica gel column chromatography (hexane:ethyl acetate=9:1) to give the above-titled compound (a mixture of isomers) (28 g, yield 98%, oil). The above-titled compound (a mixture of isomers) was further purified by a silica gel column chromatography (hexane:ethyl acetate=98:2) to fractionally refine the respective isomers.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:14]([CH3:15])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][C@@H:8]([CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[O:9][C@H:10]2[CH2:16][NH:17][CH:18]=[O:19])([CH3:3])[CH3:2].[C:26]1([CH:32]([CH2:36][CH3:37])[C:33](Cl)=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C.Cl>ClCCl>[CH:1]([O:4][C:5]1[C:14]([CH3:15])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][C@@H:8]([CH:20]1[CH2:21][CH2:22][N:23]([C:33](=[O:34])[CH:32]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:36][CH3:37])[CH2:24][CH2:25]1)[O:9][C@H:10]2[CH2:16][NH:17][CH:18]=[O:19])([CH3:3])[CH3:2]
Reactant: Cc1ccc2c(c1OC(C)C)C[C@@H](C1CCNCC1)O[C@H]2CNC=O
Reactant: CCC(C(=O)Cl)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(C(=O)N1CCC([C@@H]2Cc3c(ccc(C)c3OC(C)C)[C@H](CNC=O)O2)CC1)c1ccccc1
Temperature: 10 °C

Procedure:
Stir a solution of N-((1R,3S)-5-isopropoxy-6-methyl-3-(4-piperidinyl)-1-isochromanyl-methyl)formamide (200 mg, 0.58 mmole) in dichloromethane (3 mL), cool to 10° C. and add 2-phenylbutyryl chloride (115 mg, 0.64 mmole) and triethylamine (88 mg, 0.87 mmole). Allow to warm to room temperature and pour into dilute HCl. Separate the layers an extract the aqueous layer two times with 4 mL of dichloromethane. Wash the combined organic extracts with water and dry over Na2SO4. Purify the crude product on a 10 g silica gel column (eluting with ethyl acetate:heptane 3:1). Collect the appropriate fractions and concentrate to obtain the title compound. It was used without further purification in the next step.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1)#[CH:2].Br[C:12]1[S:13][CH:14]=[CH:15][N:16]=1.C(N(CC)CC)C>C(#N)C.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.[Cu]I>[S:13]1[CH:14]=[CH:15][N:16]=[C:12]1[C:8]1[CH:7]=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[C:1]#[CH:2]
Reactant: C#Cc1ccc(OC)cc1
Reactant: Brc1nccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C#Cc1ccc(OC)cc1-c1nccs1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 70 %

Procedure:
The alkyne of the current example, 2-(2-thiazolyl)-4-methoxyphenylacetylene was prepared by adding to a degassed solution of 4 mmol of 4-ethynylanisole, 4 mmol of 2-bromothiazole, and 1 ml of triethylamine in 10 ml of acetonitrile, 140 mg (0.2 mmol) of PdCl2(PPh3)2 and 19 mg(0.1 mmol) of CuI. The mixture was degassed and stirred for 5 minutes at RT and heated to 90° C. for 12 hours. The reaction mixture was concentrated in vacuo and purified by silica column to afford 0.61 g of brown liquid in a 70% yield.
Reaction SMILES: [CH3:1][N:2]([S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([OH:14])=O)=[CH:8]2.[N:23]1(O)C2C=CC=CC=2N=N1.N.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.CN(C)C=O>[CH3:1][N:2]([S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([NH2:23])=[O:14])=[CH:8]2
Reactant: On1nnc2ccccc21
Reactant: CN(c1cccc2cc(C(=O)O)[nH]c12)S(=O)(=O)c1cccs1
Agent: N
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: CN(c1cccc2cc(C(N)=O)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 66.9 %

Procedure:
To a mixture of 7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (17.20 g), 1H-1,2,3-benzotriazol-1-ol (8.29 g) and N,N-dimethylformamide (150 ml) was added N-[3-(dimethylamino)propyl]-N,N-ethylcarbodiimide hydrochloride (11.8 g) at room temperature, and the mixture was stirred at 50° C. for 20 min. The mixture was allowed to cool to room temperature, and 28% aqueous ammonia (3.4 ml) was added. The reaction mixture was stirred at room temperature for 2 hr, and water was added. The mixture was acidified with 10% aqueous citric acid solution, and the resulting crystals were filtrated, washed with water, washed with cooled ethyl acetate, and dried to give the title compound (11.47 g, yield 67%) as colorless crystals. melting point 244-245° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:20][CH:21]([CH3:23])[CH3:22])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11].[F-].[K+].Br[CH2:27][C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1>C(#N)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:20][CH:21]([CH3:23])[CH3:22])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:27][C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(O)cc2)c(C)c1
Reactant: BrCc1ccncc1
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(OCc3ccncc3)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of N-(2,4-dimethylphenyl)-4-hydroxy-N-isobutylbenzenesulfonamide (33 mg, 0.099 mmol), and potassium fluoride, 40% by weight on alumina (40% KF.Al2O3 43.1 mg, 0.297 mmol) in acetonitrile (0.2 mL) were stirred for 5 mins, before addition of 4-(bromomethyl)pyridine (0.099 mmol) in acetonitrile (0.2 mL). The reaction mixture was capped and stirred at RT for 18 hours. Additional 40% KF.Al2O3 (43 mg) and more alkylating reagent (0.1 mmol) were added to the tube, which was capped and stirred for a further 18 hours. The reaction had additional potassium fluoride, 40% by weight on alumina (43 mg) and alkylating reagent (0.1 mmol), and then recapped and stirred for 2 days. The sample was filtered through cotton wool, and DMSO added to bring the total volume to 1 mL. The solutions were purified by mass directed autoprep on Sunfire C18 column using acetonitrile water with a formic acid modifier. The solvent was dried under a stream of nitrogen in the Radleys blowdown apparatus to give the required product.
Reaction SMILES: [CH3:1][Mg]I.Br[C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][N:9]=[CH:10]2.O>CCOCC.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][N:9]=[CH:10]2
Reactant: C[Mg]I
Reactant: Brc1cccc2cnccc12
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: O
Product: Cc1cccc2cnccc12

Procedure:
A 3M solution of methyl magnesium iodide in ether (50 ml, 0.15 mol) was added dropwise to a stirred, ice-cooled solution of 5-bromoisoquinoline (21 g, 0.10 mol), obtained by the method described in J. Org. Chem., 1964, 29, 329, and [1,3-bis(diphenylphosphino)propane]nickel(II) chloride (400 mg, 0.7 mmol) in anhydrous ether and the reaction mixture heated under reflux for 5 days, allowed to cool, then poured into water (500 ml). The organic phase was separated, combined with ether extracts of the aqueous phase, washed with saturated brine, dried (MgSO4) and evaporated under reduced pressure to yield an oil, chromatography of which on silica gel, using a 5-50% ether in hexane elution gradient, provided the required product (8.4 g). Rf 0.40 (SS 8), m/e 144 (M+H)+. Found: C,79.57; H,6.26; N,8.61. C10H9N; 0.27 C4H8O2 requires C,79.70; H,6.74; N,8.39%.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7]([C:9]1[C:17]2[N:16]=[C:15]([NH:18][C:19]([C:21]3[N:22]=[CH:23][C:24]4[C:29]([CH:30]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:20])[NH:14][C:13]=2[CH:12]=[C:11]([N+:31]([O-])=O)[CH:10]=1)=[O:8]>CN(C=O)C.C(O)(=O)C.[Pd]>[NH2:31][C:11]1[CH:10]=[C:9]([C:7](=[O:8])[NH:6][C:2]2[NH:3][CH:4]=[CH:5][N:1]=2)[C:17]2[N:16]=[C:15]([NH:18][C:19]([C:21]3[N:22]=[CH:23][C:24]4[C:29]([CH:30]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:20])[NH:14][C:13]=2[CH:12]=1
Reactant: O=C(Nc1nc2c(C(=O)Nc3ncc[nH]3)cc([N+](=O)[O-])cc2[nH]1)c1cc2ccccc2cn1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Nc1cc(C(=O)Nc2ncc[nH]2)c2nc(NC(=O)c3cc4ccccc4cn3)[nH]c2c1
Reaction time: 3 h
Yield: 103.1 %

Procedure:
0.1 g (0.2 mmol) of isoquinoline-3-carboxylic acid [4-(1H-imidazol-2-ylcarbamoyl)-6-nitro-1H-benzoimidazol-2-yl]-amide (Example 129) was suspended in a mixture of 2 mL of DMF and 5 mL of acetic acid. To this stirring solution, ˜20 mg of 10% Pd on carbon was added, and the resulting mixture was hydrogenated at 42 psi of H2 at room temperature for 3.0 h. The reaction mixture was filtered, and the solid was washed with 5 mL of DMF. The filtrate and washings were combined and evaporated to reduce the volume to 10 mL, then diluted with saturated NaHCO3 (10 mL), and extracted with ethyl acetate. The organic layer was washed with water and brine and evaporated to provide 85 mg (91%) of isoquinoline-3-carboxylic acid [6-amino-4-(1H-imidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide. LCMS: 413 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[NH:12][C:13]([C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([N+:25]([O-:27])=[O:26])[CH:23]=4)[NH:18][N:17]=3)=[CH:14][CH:15]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.[C:28]1(C)C=CC=CC=1>CNN.CN1CCCC1=O>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[NH:12][C:13]([C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([N+:25]([O-:27])=[O:26])[CH:23]=4)[N:18]([CH3:28])[N:17]=3)=[CH:14][CH:15]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccccc1
Reactant: O=C(Nc1cccc(F)c1)c1ccc(-c2n[nH]c3ccc([N+](=O)[O-])cc23)[nH]1
Agent: CNN
Solvent: CN1CCCC1=O
Product: Cn1nc(-c2ccc(C(=O)Nc3cccc(F)c3)[nH]2)c2cc([N+](=O)[O-])ccc21
Temperature: 120 °C

Procedure:
A mixture of 5-(2-chloro-5-nitro-benzoyl)-1H-pyrrole-2-carboxylic acid (3-fluoro-phenyl)-amide (250 mg, 0.6 mmol) (Example 47), methyl hydrazine (4 drops), toluene (0.6 mL) and 1-methyl-pyrrolin-2-one (0.2 mL) was heated at 120° C. for 2 hours. The reaction was concentrated, triturated with DCM and hexane to give 55 mg of the titled compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:20]=[CH:19][C:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:10][CH:9]=2)=[CH:4][N:3]=1.Cl[CH:22]([C:25]1([C:28]2[CH:29]=[C:30]3[C:35](=[CH:36][CH:37]=2)[N:34]=[CH:33][CH:32]=[CH:31]3)[CH2:27][CH2:26]1)[CH:23]=O.C(N(CC)CC)C>C(O)(C)C>[N:34]1[C:35]2[C:30](=[CH:29][C:28]([C:25]3([C:22]4[N:3]5[CH:4]=[C:5]([C:8]6[CH:9]=[CH:10][C:11]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])=[CH:19][CH:20]=6)[CH:6]=[N:7][C:2]5=[N:1][CH:23]=4)[CH2:27][CH2:26]3)=[CH:37][CH:36]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: O=CC(Cl)C1(c2ccc3ncccc3c2)CC1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2cnc(N)nc2)cc1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)cc1
Temperature: 90 °C
Yield: 50.9 %

Procedure:
A mixture of tert-butyl 4-(2-aminopyrimidin-5-yl)benzoate (0.144 g, 0.531 mmol) and chloro(1-quinolin-6-ylcyclopropyl)acetaldehyde (0.156 g, 0.637 mmol) in isopropyl alcohol (3 mL) was heated at 90° C. overnight. The mixture was adjusted to pH=9 using triethylamine, solvent was removed and the residue was purified by chromatography on silica gel using MeOH in methylene chloride (0-5%) to afford the desired product (125 mg, 50.9%). LCMS: (M+H)=463.1.
Reaction SMILES: Br[CH:2]([C:4]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=2[CH3:18])[C:8]2[N:19]=[C:20]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[S:21][C:7]=2[C:6](=[O:28])[N:5]=1)[CH3:3].[P:29]([O:36]CC)([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32]>>[Cl:17][C:13]1[C:12]([CH3:18])=[C:11]([CH2:10][N:9]2[C:8]3[N:19]=[C:20]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[S:21][C:7]=3[C:6](=[O:28])[N:5]=[C:4]2[CH:2]([P:29](=[O:36])([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])[CH3:3])[CH:16]=[CH:15][CH:14]=1
Reactant: Cc1c(Cl)cccc1Cn1c(C(C)Br)nc(=O)c2sc(N3CCOCC3)nc21
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(OCC)C(C)c1nc(=O)c2sc(N3CCOCC3)nc2n1Cc1cccc(Cl)c1C
Temperature: 25 °C
Reaction time: 14 h
Yield: 25.4 %

Procedure:
Added 5-(1-bromoethyl)-4-[(3-chloro-2-methylphenyl)methyl]-2-(4-morpholinyl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one (179 mg, 0.370 mmol) and triethyl phosphite (4 mL, 22.87 mmol) to a 20 mL screw capped vial and stirred overnight (14 hours) at room temperature. The next morning, starting material was still present, so the contents were transferred to a 25 mL round bottom flask and the contents were heated to 155° C. for 2 hours, whereupon LC/MS showed that the bromo starting material was consumed and a molecular ion corresponding to the desired product was present along with an impurity (believed to be the des-bromo compound by LC/MS). The yellow solution was distilled to remove the unreacted triethyl phosphite, then the residue was purified by column chromatography on silica gel eluted with 0-10% of a (2N solution of NH3 in methanol)/chloroform. The fractions containing product by TLC were combined, then concentrated to provide diethyl {1-[4-[(3-chloro-2-methylphenyl)methyl]-2-(4-morpholinyl)-7-oxo-4,7-dihydro[1,3]thiazolo[4,5-d]pyrimidin-5-yl]ethyl}phosphonate (51 mg, 0.094 mmol, 25.5% yield) as a light tan solid. LC/MS m/z MH+=541 (theoretical), found=541.1, 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.23-1.36 (m, 6H) 1.47 (dd, J=17.31, 6.95 Hz, 3H) 2.46 (s, 3H) 3.02-3.18 (m, 1H) 3.49-3.60 (m, 4H) 3.71-3.82 (m, 4H) 4.00-4.27 (m, 4H) 5.67 (d, J=−17.68 Hz, 1H) 5.90 (d, J=17.68 Hz, 1H) 6.41 (d, J=7.58 Hz, 1H) 7.05 (t, J=7.83 Hz, 1H) 7.32 (d, J=7.58 Hz, 1H)
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][C:6]([OH:12])([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].[Cl:19][C:20]1[CH:25]=[C:24](Cl)[C:23]([N+:27]([O-:29])=[O:28])=[CH:22][N:21]=1.Cl>O1CCOCC1.O>[Cl:19][C:20]1[CH:25]=[C:24]([NH:2][CH:3]2[CH2:8][CH2:7][C:6]([OH:12])([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]2)[C:23]([N+:27]([O-:29])=[O:28])=[CH:22][N:21]=1
Reactant: NC1CCC(O)(C(=O)O)CC1
Reactant: O=[N+]([O-])c1cnc(Cl)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)C1(O)CCC(Nc2cc(Cl)ncc2[N+](=O)[O-])CC1
Temperature: 60 °C
Reaction time: 24 h
Yield: 62 %

Procedure:
A 100 mL round bottom flask was charged with 4-amino-1-hydroxycyclohexanecarboxylic acid hydrochloride (0.28 g, 1.431 mmol), potassium carbonate (0.435 g, 3.15 mmol) and water (1.908 mL). To the mixture was added 2,4-dichloro-5-nitropyridine (0.276 g, 1.431 mmol) as a solution in dioxane (0.954 mL). After the resulting mixture was stirred at 60° C. for 24 hours, it was cooled to RT and treated with 2N aqueous HCl to bring the pH to about 4-5. The aqueous layer was extracted with DCM (3×40 mL). The combined organic portions were dried over sodium sulfate and concentrated to afford 4-(2-chloro-5-nitropyridin-4-ylamino)-1-hydroxycyclohexanecarboxylic acid as a yellow solid (0.28 g, 62.0% yield). MS m/z=316.2 [M+H]. Calc'd for C12H14ClN3O5: 315.1.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:5]=1[CH:6]=O)[CH3:2].C1(P(=[CH:35][C:36]([O:38][CH3:39])=[O:37])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[CH3:39][O:38][C:36](=[O:37])[CH:35]=[CH:6][C:5]1[CH:8]=[CH:9][C:10]([C:12]([F:15])([F:14])[F:13])=[CH:11][C:4]=1[O:3][CH2:1][CH3:2]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOc1cc(C(F)(F)F)ccc1C=O
Product: CCOc1cc(C(F)(F)F)ccc1C=CC(=O)OC
Yield: 52 %

Procedure:
2-Ethoxy-4-trifluoromethyl-benzaldehyde (729 mg, 3.34 mmol) was reacted with methyl (triphenylphosphoranylidene)acetate (1.45 g, 4.34 mmol) at 110° C. overnight as described above to yield title compound (476.5 mg, 52%).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[F:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[F:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][N:21]([CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)[CH2:20][CH2:19]1
Reactant: FCCN1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(N2CCN(CCF)CC2)CC1
Reaction time: 3 h
Yield: 82.9 %

Procedure:
1,1-Dimethylethyl 4-oxo-1-piperidinecarboxylate (15.7 g, 78.7 mmol) and 1-(2-fluoroethyl)piperazine (5.2 g, 39 mmol) were dissolved in 150 mL 1,2-DCE. HOAc (3.4 mL, 59 mmol) and TEA (5.5 mL, 39 mmol) were added followed by sodium triacetoxyborohydride (12.5 g, 59.0 mmol). The reaction was stirred for 3 h. TLC revealed the presence of starting material and so an additional 1.5 eq (12.5 g, 59.0 mmol) of sodium triacetoxyborohydride were added. Reaction was allowed to stir overnight. Saturated aqueous NaHCO3 solution was added carefully until the reaction stopped bubbling. Aqueous layer was then extracted with EtOAc (3×). Combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The resulting crude product was adsorbed onto silica gel and purified by flash chromatography to give title compound of step C (10.2 g, 82%). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.39-4.57 (m, 2H), 3.90 (d, J=12.46 Hz, 2H), 2.61-2.73 (m, 2H), 2.47-2.61 (m, 2H), 2.36-2.47 (m, 8H), 2.24-2.35 (m, 1H), 1.69 (d, J=12.46 Hz, 2H), 1.37 (s, 9H), 1.14-1.26 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:13]([O:14]C2CCCCO2)=[CH:12][C:5]2[CH:6]=[C:7]([C:9](=[O:11])[CH3:10])[O:8][C:4]=2[C:3]=1[CH3:21].[Br:22]Br>C(Cl)(Cl)Cl>[Br:22][C:6]1[C:5]2[CH:12]=[C:13]([OH:14])[C:2]([CH3:1])=[C:3]([CH3:21])[C:4]=2[O:8][C:7]=1[C:9](=[O:11])[CH3:10]
Reactant: BrBr
Reactant: CC(=O)c1cc2cc(OC3CCCCO3)c(C)c(C)c2o1
Solvent: ClC(Cl)Cl
Product: CC(=O)c1oc2c(C)c(C)c(O)cc2c1Br
Reaction time: 1 h

Procedure:
To a solution of 1-[6,7-dimethyl-5-(tetrahydro-pyran-2-yloxy)-benzofuran-2-yl]-ethanone (200 mg) in chloroform (20 mL) was added bromine (120 mg). After 1 h, the solution was washed with water and dried over MgSO4 and concentrated. The residue was purified by silica gel column eluting with 10% hexane in DCM to give 1-(3-Bromo-5-hydroxy-6,7-dimethyl-benzofuran-2-yl)-ethanone, as a yellow solid. 1H NMR (CDCl3, 300 MHz) δ: 7.38(s, 1H), 5.55 (s, 1H, OH), 2.60, 2.50, 2.31 (3 s, 9H) ppm. MS (m/z): 283, 285 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5](O)=[O:6].[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:6])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: C1CCNC1
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(C(=O)N2CCCC2)cc1Cl

Procedure:
75 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to pyrrolidine via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(pyrrolidine-1-carbonyl)benzamide. MS (Q1) 441 (M)+.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:12]1[CH:13]=[CH:14][C:15](=[O:21])[N:16]([CH:18]([CH3:20])[CH3:19])[N:17]=1)[C:4](=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O=C1CCC(=O)N1[O:29][C:30](=O)[CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36].C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH:18]([N:16]1[C:15](=[O:21])[CH:14]=[CH:13][C:12]([CH:3]([NH:2][C:30](=[O:29])[CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:37])[CH3:38])[C:4](=[O:11])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[N:17]1)([CH3:19])[CH3:20]
Reactant: CC(C)n1nc(C(N)C(=O)c2ccccc2)ccc1=O
Reactant: CC(C)(C)OC(=O)NCC(=O)ON1C(=O)CCC1=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)n1nc(C(NC(=O)CNC(=O)OC(C)(C)C)C(=O)c2ccccc2)ccc1=O
Temperature: 22.5 °C
Reaction time: 18 h
Yield: 81.2 %

Procedure:
Under ice-cooling, to a suspension of 6-(1-amino-2-oxo-2-phenylethyl)-2-isopropyl-3(2H)-pyridazinone hydrochloride (1.00 g) and tert-butyl {2-[(2,5-dioxo-1-pyrrolidinyl)oxy]-2-oxoethyl}carbamate (973 mg) in CH2Cl2 (10 ml) was added ethyl(diisopropyl)amine (0.651 ml) and stirred at the same temperature for 2 hours and at 20-25° C. for 18 hours. The mixture was washed with water, dried over MgSO4 and concentrated under reduced pressure to give syrup. The syrup was purified by column chromatography on silica gel (EtOAc only) to give tert-butyl (2-{[1-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-oxo-2-phenylethyl]amino}-2-oxoethyl)carbamate as an amorphous solid (1.13 g).
Reaction SMILES: [CH:1]1([N:4]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH2:28][C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=1>CN(C=O)C>[CH:1]1([N:4]([CH:14]2[CH2:19][CH2:18][N:17]([CH2:28][C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=3)[CH2:16][CH2:15]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: O=S(=O)(c1ccccc1)N(C1CCNCC1)C1CC1
Reactant: BrCc1ccc2ccccc2c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)N(C1CC1)C1CCN(Cc2ccc3ccccc3c2)CC1
Temperature: 80 °C
Reaction time: 12 h
Yield: 15.2 %

Procedure:
N-Cyclopropyl-N-piperidin-4-yl-benzenesulfonamide (56 mg, 0.2 mmol) was dissolved in DMF (2.5 ml) and triethylamine (75 μL, 54 mg, 0.54 mmol) added, followed by 2-bromomethyl-naphthalene (88 mg, 0.4 mmol). The reaction mixture was stirred for 12 hours at 80° C. and then the solvent was evaporated. The residue was purified by flash chromatography to give 12.8 mg of the desired product N-cyclopropyl-N-[1-(naphth-2-ylmethyl)-piperidin-4-yl]benzenesulfonamide (15). 1H NMR (CDCl3): δ 8.06-7.71 (m, 7H), 7.61-7.44 (m, 5H), 3.94-3.84 (m, 1H), 3.68 (S, 2H), 3.01-2.94 (m, 2H), 2.18-1.94 (m, 5H), 1.58-1.49 (m, 2H), 1.02-0.96 (m, 2H), 0.81-0.74 (m, 2H). MS (EI): m/z 421 (M+H+).
Reaction SMILES: [Br:1][C:2]1[C:9]([OH:10])=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:11])[CH:3]=1.[CH2:12](Cl)[O:13][CH3:14].[H-].[Na+].CCOCC>CN(C)C=O>[Br:1][C:2]1[C:9]([O:10][CH2:12][O:13][CH3:14])=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: COCCl
Reactant: O=Cc1cc(O)c(Br)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COCOc1cc(C=O)c(F)cc1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-Bromo-2-fluoro-5-hydroxy-benzaldehyde (750 mg, 3.41 mmol) and MOMCl (545 mg, 6.82 mmol) were dissolved in anhydrous N,N-dimethylformamide (5 mL) and cooled to 0° C. NaH (160 mg, 60% suspension in mineral oil, 4 mmol) is then added. The resulting mixture is allowed to stir at room temperature for 1 h. Ether is then added and washed with H2O (3×20 mL) and brine. After dried over Na2SO4, the ether is removed and the residue is purified through chromatography to afford the desired MOM ether (700 mg, 78%).