Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:21]#[C:22][CH2:23][OH:24])=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl.[CH3:34][N:35]([CH3:40])[CH2:36][CH2:37][CH2:38]Cl.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]#[C:22][CH2:23][OH:24])[CH:17]=3)[N:12]([CH2:38][CH2:37][CH2:36][N:35]([CH3:40])[CH3:34])[CH:11]=2)=[O:9])=[CH:25][CH:26]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(C#CCO)cc2c1O
Reactant: CN(C)CCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCO)ccc21
Temperature: 90 °C

Procedure:
A solution of N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxamide from Preparation No. 5 (0.458 g) is dissolved in DMF (10 mL), and K2CO3 (0.69 g) and 3-dimethylaminopropyl chloride hydrochloride (0.42 g) are added. The reaction mixture is heated to 90° C. for 6 h. Water is added and a dark solid formed, which is isolated by decanting the liquid. Column chromatography (elution with 1-20% MeOH/CHCl3) gave 0.103 g of a solid. Crystallization by dissolving in CH2Cl2 with a few drops of MeOH and adding to a 1:1 solution of pentane/Et2O gave 0.072 g of the title compound as a solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[CH3:18])[C:12]([NH2:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.O=P(Cl)(Cl)Cl>N1C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[CH3:18])[C:12]#[N:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(C(N)=O)cc1OCc1ccccc1
Agent: c1c[nH]cn1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc(C#N)cc1OCc1ccccc1
Reaction time: 0.5 h
Yield: 88.9 %

Procedure:
K2CO3 (18.1 g, 131.2 mmol) was added to a stirred solution of 3-hydroxy-4-methyl-benzoic acid (5 g, 33 mmol) in DMF (50 mL) followed by benzyl bromide (11.8 g, 69 mmol) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was filtered, the filterate was diluted with water and extracted with EtOAc. The organic layer was collected, dried over sodium sulfate and concentrated under reduced pressure to afford 11.3 g (crude) of 3-benzyloxy-4-methyl-benzoic acid benzyl ester which was such taken for the next step without purification. NaOH (4.0 g, 102 mmol) was added to a stirred solution of 3-benzyloxy-4-methyl-benzoic acid benzyl ester (11.3 g, 34 mmol) in a mixture of MeOH (50 mL) and H2O (50 mL), stirring was continued at ambient temperature for 2 hrs. The reaction mixture was concentrated under reduced pressure Cold water was then added and acidified it with 10% aqueous HCl, the precipitate was collected to afford 7.21 g (87.8% Yield) of 3-benzyloxy-4-methyl-benzoic acid. A mixture of 3-benzyloxy-4-methyl-benzoic acid (7.21 g, 29.7 mmol) in thionyl chloride (50 mL) was stirred at 79° C. for 4 hrs. The reaction mixture was concentrated under reduced pressure to afford 7.75 g (crude) of 3-benzyloxy-4-methyl-benzoyl chloride. A solution of 3-benzyloxy-4-methyl-benzoyl chloride (7.75 g) in THF (10 mL) was poured to cold aqueous solution of ammonia (50 mL) with stirring, The precipitate was collected to afford 6.7 g (94% Yield) of 3-benzyloxy-4-methyl-benzamide. A solution of 3-benzyloxy-4-methyl-benzamide (3.0 g, 12.4 mmol) in pyridine (4 mL) was cooled to −30° C. Imidazole (1.68 g, 24.8 mmol) followed by POCl3 (2.64 g, 49.6 mmol) were added to the cold solution with stirring and the reaction was continued at the same temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate. The organic layer was washed with water followed by 110% aqueous HCl solution. The organic layer separated was dried over sodium sulfate and concentrated under reduced pressure to afford 2.46 g (89% Yield) of 3-benzyloxy-4-methyl-benzonitrile. Pd/C (476 mg) was added to a stirred solution of 3-benzyloxy-4-methyl-benzonitrile (2.46 g, 11.0 mmol) in MeOH (25 mL) in an inert atmosphere and stirring was continued under H2 gas atmosphere at ambient temperature, overnight. The reaction mixture was filtered through celite. The filtrate collected was concentrated under reduced pressure to afford 1.367 g (93.6% Yield) of 3-hydroxy-4-methyl-benzonitrile.
Reaction SMILES: [CH2:1]([C:17]1[C:22](=[O:23])[CH:21]=[C:20]([CH3:24])[NH:19][C:18]=1[CH3:25])[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].[I:26]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[CH2:1]([C:17]1[C:22](=[O:23])[C:21]([I:26])=[C:20]([CH3:24])[NH:19][C:18]=1[CH3:25])[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]
Reactant: II
Reactant: CCCCCCCCCCCCCCCCc1c(C)[nH]c(C)cc1=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: CCCCCCCCCCCCCCCCc1c(C)[nH]c(C)c(I)c1=O
Temperature: 70 °C
Reaction time: 7 h

Procedure:
To a solution of 4 (100 mg, 4.52 mmol) in acetonitrile (25 mL) was added ceric ammonium nitrate (0.248 g, 0.45 mmol) followed by iodine (0.631 g, 4.97 mmol). The mixture was stirred at 70° C. under nitrogen for 7 h. After completion of the reaction, the mixture was cooled to room temperature and treated with an ice-cold aqueous solution of sodium thiosulfate with stirring. The mixture was extracted with portions of ethyl ether. The combined organic phase was dried over anhydrous MgSO4 and concentrated under diminished pressure to afford a crude residue. The residue was purified by chromatography on a silica gel column. Elution with hexane/ethyl acetate gave 3-hexadecyl-5-iodo-2,6-dimethylpyridin-4(1H)-one (6) as a light yellow solid: yield 93 mg (68%); silica gel TLC Rf 0.60 (1:1 hexane/ethyl acetate); 1H NMR (400 MHz, CDCl3) δ 0.86-0.89 (m, 3H), 1.24-1.28 (m, 28H), 2.20 (s, 3H), 2.26 (s, 3H) and 2.32-2.39 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:21][C:22]2[CH:23]=[C:24]([C:28]3[C:33]([CH3:34])=[CH:32][C:31]([O:35][CH2:36][C:37]4([OH:44])[CH2:42][CH2:41][S:40](=[O:43])[CH2:39][CH2:38]4)=[CH:30][C:29]=3[CH3:45])[CH:25]=[CH:26][CH:27]=2)S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)[CH:5]=[CH:4][C:3]=1[CH2:46][CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49].SCC(O)=O.O.[OH-].[Li+]>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:21][C:22]2[CH:23]=[C:24]([C:28]3[C:29]([CH3:45])=[CH:30][C:31]([O:35][CH2:36][C:37]4([OH:44])[CH2:42][CH2:41][S:40](=[O:43])[CH2:39][CH2:38]4)=[CH:32][C:33]=3[CH3:34])[CH:25]=[CH:26][CH:27]=2)[CH:5]=[CH:4][C:3]=1[CH2:46][CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49]
Reactant: CCOC(=O)CCc1ccc(N(Cc2cccc(-c3c(C)cc(OCC4(O)CCS(=O)CC4)cc3C)c2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1F
Agent: O=C(O)CS
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1ccc(NCc2cccc(-c3c(C)cc(OCC4(O)CCS(=O)CC4)cc3C)c2)cc1F
Temperature: 25 °C
Yield: 50.6 %

Procedure:
To a solution of ethyl 3-(2-fluoro-4-{({4′-[(4-hydroxytetrahydro-2H-thiopyran-4-yl)methoxy]-2′,6′-dimethylbiphenyl-3-yl}methyl) [(2-nitrophenyl)sulfonyl]amino}phenyl)propanoate (2.24 g, 3.04 mmol) in ethyl acetate (15 mL) was added m-chloroperbenzoic acid (70%, 0.46 g, 1.88 mmol) under stirring at 0° C., and the mixture was stirred at room temperature for 3 days. The reaction mixture was washed with 1 M aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1-ethyl acetate-ethyl acetate/methanol=17/3) to give ethyl 3-(2-fluoro-4-{({4′-[(4-hydroxy-1-oxidotetrahydro-2H-thiopyran-4-yl)methoxy]-2′,6′-dimethylbiphenyl-3-yl}methyl)[(2-nitrophenyl)sulfonyl]amino}phenyl)propanoate (1.36 g, yield 60%) as a colorless amorphous powder. To a solution of the obtained ethyl 3-(2-fluoro-4-{({4′-[(4-hydroxy-1-oxidotetrahydro-2H-thiopyran-4-yl)methoxy]-2′,6′-dimethylbiphenyl-3-yl}methyl)[(2-nitrophenyl)sulfonyl]amino}phenyl)propanoate (1.36 g, 1.81 mmol) and mercaptoacetic acid (0.38 mL, 5.43 mmol) in N,N-dimethylformamide (10 mL) was added lithium hydroxide monohydrate (0.46 g, 10.86 mmol) under stirring at room temperature, and the mixture was stirred at the same temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogencarbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1-ethyl acetate) to give the title compound (0.52 g, yield 50%) as a colorless oil.
Reaction SMILES: [O:1]=[C:2]1[CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:14][C:15]([OH:17])=O.Br.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[CH2:26][NH:25][CH2:24]2.C(N=C=NCCCN(C)C)C>ClCCl>[O:17]=[C:15]([N:25]1[CH2:24][C:23]2[C:27](=[CH:28][CH:29]=[C:21]([C:20]([F:19])([F:31])[F:30])[CH:22]=2)[CH2:26]1)[CH2:14][N:3]1[CH2:4][CH2:5][CH2:6][CH:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]1=[O:1]
Reactant: O=C(O)CN1CCCC(c2ccccc2)C1=O
Reactant: FC(F)(F)c1ccc2c(c1)CNC2
Agent: Br
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: O=C(CN1CCCC(c2ccccc2)C1=O)N1Cc2ccc(C(F)(F)F)cc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2-(2-oxo-3-phenylpiperidin-1-yl)acetic acid (0.137 g, 0.587 mmol; Example 91D) and 5-(trifluoromethyl)isoindoline hydrogen bromide (0.173 g, 0.646 mmol) in dichloromethane (0.5 mL) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (0.156 mL, 0.881 mmol) and the reaction was stirred at room temperature overnight. The reaction was loaded directly onto a SF15-12 column (Analogix®) and the product eluted using a gradient of 50% ethyl acetate/hexanes to 100% ethyl acetate over 15 minutes (Flow=30 mL/minute) to provide the title compound. 1H NMR (300 MHz, CDCl3) δ 7.66-7.11 (m, 8H), 4.96 (s, 2H), 4.89 (s, 2H), 4.44 (dd, J=2.6, 15.6, 1H), 4.08 (dt, J=2.3, 6.8, 1H), 3.80-3.65 (m, 2H), 3.59 (dt, J=4.0, 5.6, 1H), 2.39-2.16 (m, 1H), 2.16-1.78 (m, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])=[O:17])[C:5]2[C:6]([CH3:15])=[CH:7][N:8]([C@@H:11]([CH2:13][CH3:14])[CH3:12])[C:9]=2[CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:35][N:36]([CH:38]=O)[CH3:37].O>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>[CH3:35][N:36]([CH2:38][C:2]1[CH:10]=[C:9]([C:2]2[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]3[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=3[CH3:26])=[O:17])[C:5]3[C:6]([CH3:15])=[CH:7][N:8]([C@H:11]([CH3:12])[CH2:13][CH3:14])[C:9]=3[CH:10]=2)[CH:5]=[CH:4][CH:3]=1)[CH3:37]
Reactant: CC[C@@H](C)n1cc(C)c2c(C(=O)NCc3c(C)cc(C)[nH]c3=O)cc(Br)cc21
Reactant: CN(C)C=O
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: [Cs+]
Solvent: O
Product: CC[C@@H](C)n1cc(C)c2c(C(=O)NCc3c(C)cc(C)[nH]c3=O)cc(-c3cccc(CN(C)C)c3)cc21

Procedure:
(R)-6-bromo-1-(sec-butyl)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-methyl-1H-indole-4-carboxamide (100 mg, 0.23 mmol), N,N-dimethyl-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanamine, HCl (100 mg, 0.34 mmol) and Palladium Tetrakis (26 mg, 0.023 mmol) in DMF/water (3 mL:1 mL) were stirred for 10 min under nitrogen. Cesium carbonate (220 mg, 0.68 mmol) was added and the insoluble mixture was irradiated (microwave) at 150° C. for 15 min. The contents were evaporated, dissolved in DCM/MeOH (1:1), and pre-absorbed on silica gel and purified using silica gel chromatography (eluent: DCM/MeOH/NH4OH, gradient 0 to 80:20:2 in DCM). The isolated product was first treated with EtOAc along with some hexanes. The product was then dissolved in MeOH and purified by reversed-phase HPLC (30×100 Varian Polaris C18 column, eluent: 10-80% gradient of MeCN in water with 0.1% TFA). The product fractions were combined, most of the solvent was evaporated, and a sat. solution of NaHCO3 was added. Solids that crashed out were filtered, air-dried for 15 min, and dried in vacuum-oven overnight. The solid product was collected as 85 mg (75%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.48 (s, 1 H) 8.21 (t, J=5.05 Hz, 1 H) 7.77 (d, J=1.26 Hz, 1 H) 7.60-7.66 (m, 2 H) 7.41 (t, J=7.58 Hz, 1 H) 7.30 (s, 1 H) 7.25 (d, J=7.58 Hz, 1 H) 7.22 (d, J=1.52 Hz, 1 H) 5.87 (s, 1 H) 4.60-4.68 (m, 1 H) 4.36 (s, 1 H) 4.35 (s, 1 H) 3.49 (br. s., 2 H) 2.24 (s, 3 H) 2.19 (d, J=8.84 Hz, 9 H) 2.11 (s, 3 H) 1.77-1.88 (m, 2 H) 1.41 (d, J=6.57 Hz, 3 H) 0.74 (t, J=7.33 Hz, 3 H); LCMS: 499.4 (MH+).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][C:19]([CH3:26])([CH:23]([CH3:25])[CH3:24])[C:20]([NH2:22])=[O:21]>>[NH2:22][C:20](=[O:21])[C:19]([NH:18][C:15](=[O:17])[C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)([CH3:26])[CH:23]([CH3:25])[CH3:24]
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: CC(C)C(C)(N)C(N)=O
Product: CC(C)C(C)(NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42 a) and 2-amino-2,3-dimethyl-butanamide (CAN 40963-14-2) as starting materials, LC-MS (UV peak area/ESI) 96%, 346.2136 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH:7]=[CH:8][C:9]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:10])=[CH:5][CH:4]=1.[H][H]>C1COCC1.CO.[Pt](=O)=O>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][CH2:11][C:9](=[O:10])[CH2:8][CH2:7][C:6]2[CH:21]=[CH:22][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:18][CH:17]=1
Reactant: COc1ccc(C=CC(=O)C=Cc2ccc(OC)cc2)cc1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CCC(=O)CCc2ccc(OC)cc2)cc1
Yield: 59.5 %

Procedure:
To a solution of commercially available di(4-methoxybenzylidene) acetone (3.5 g, 12 mmol) in THF-MeOH (1:1,100 mL) was added platinum (IV) oxide (90 mg) and the resulting mixture was stirred at room temperature under 4 atmospheres of hydrogen for 19 hours. The catalyst was filtered and washed with THF, and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica gel (hexane-ethyl acetate 3:1) to provide 1,5-bis(4-methoxyphenyl)-3-pentanone (2.13 g) and the reduced side product 1,5-bis(4-methoxyphenyl)-3-pentanol (1.0 g).
Reaction SMILES: [C:1]([NH2:4])(=[S:3])[CH3:2].C(#N)C.Cl[CH:9]([C:15]([C:17]([F:20])([F:19])[F:18])=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11].C(N(CC)CC)C>>[CH3:2][C:1]1[S:3][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:15]([C:17]([F:18])([F:20])[F:19])[N:4]=1
Reactant: CCOC(=O)C(Cl)C(=O)C(F)(F)F
Reactant: CC(N)=S
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1sc(C)nc1C(F)(F)F
Temperature: 76 °C

Procedure:
A solution of thioacetamide in acetonitrile (6.66 mol), prepared as in Example 1, is placed in a flask. Ethyl 2-chloro-4,4,4-trifluoroacetoacetate (5.06 mol) is added and an exotherm is observed. Triethylamine (13.64 mol) is added and the mixture is heated to reflux (approx. 76° C.) for one hour. The resulting solution is cooled. Ethyl 2-methyl-4-(trifluoromethyl)-thiazole-5-carboxylate may be isolated by standard means.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH3:17]>C(Cl)(Cl)Cl>[F:9][C:10]1[CH:15]=[C:14]([C:5](=[O:7])[CH3:6])[CH:13]=[CH:12][C:11]=1[O:16][CH3:17]
Reactant: CC(=O)Cl
Reactant: COc1ccccc1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(C)=O)cc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
Aluminum chloride (80.0 g, 0.6 mol) and chloroform (750 mL) were placed in a 2 L three-necked round bottom flask fitted with a mechanical stirrer and cooled by means of an ice bath. To the stirred solution acetyl chloride (51.0 g, 0.65 mol) was added dropwise, maintaining the temperature between 5°-10° C. The mixture was stirred for 10 minutes at 5° C before the dropwise addition at 5°-10° C. of 2-fluoroanisole (62.6 g, 0.5 mol). The mixture was stirred at 0°-10° C. for 1 hour and poured into ice (1 L). The resultant layers were separated and the aqueous layer was extracted with dichloromethane (2×250 mL). The combined organic layers were washed with water (2×50 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo to a volume of 300 mL. Hexanes were added and a white solid formed which was isolated by filtration and air dried. This material was recrystallized from a mixture of dichloromethane and hexanes to afford (77.2 g, 92%) of material suitable for use in the next step: mp 92°-94° C.; 1H NMR (D6 -DMSO) 7.8 (m, 2H), 7.3 (t, 1H), 3.9 (s, 3H), 2.5 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.Cl.[Cl:11][CH2:12][CH2:13][CH2:14][NH2:15].C(N(CC)CC)C.[OH-].[Na+]>C(#N)C>[Cl:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:8][C:5]1[CH:4]=[N:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: NCCCCl
Reactant: ClCc1ccc(Cl)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: ClCCCNCc1ccc(Cl)nc1
Yield: 86.9 %

Procedure:
16.20 g (100 mmol) of 2-chloro-5-(chloromethyl)pyridine, 16.90 g (130 mmol) of 3-chloropropan-1-amine hydrochloride and 36.24 ml (260 mmol) of triethylamine in 200 ml acetonitrile stirred at 60° C. for 20 hours. After addition of 30.67 g (230 mmol) of 30 percent strength aqueous sodium hydroxide solution, the reaction mixture is concentrated under reduced pressure and the residue is extracted with chloroform. Concentration of the extract under reduced pressure gives 19.03 g (87% of theory) of 3-chloro-N-[(6-chloropyridin-3-yl)methyl]propan-1-amine which can be used without further purification for the next reaction (cf. Ex. II-2).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=O)[C:2]1=[O:11].[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[Cl:20])[NH2:16]>>[Cl:12][C:13]1[CH:14]=[C:15]([N:16]=[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]2=[O:11])[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: O=C1Nc2ccccc2C1=O
Reactant: Nc1ccc(Cl)c(Cl)c1
Product: O=C1Nc2ccccc2C1=Nc1ccc(Cl)c(Cl)c1
Temperature: 75 °C
Yield: 95.2 %

Procedure:
A mixture of 1H-indole-2,3-dione (10.3 g, 70 mmol), 3,4-dichloroaniline (17.0 g, 70 mmol) was heated at 75° C. for 2 hours in a tightly sealed round bottom flask under argon and cooled to room temperature. The solid was recrystallized from CH2Cl2, giving the desired product (19.4 g, 90%).
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH:19]([CH2:22][O:23][CH3:24])[CH2:20]O)[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].C(SCC(OC)C[NH2:45])CCCCCCCCCCCCCCC.C1(=O)NC(=O)C2=CC=CC=C12>>[CH2:1]([O:17][CH2:18][CH:19]([CH2:22][O:23][CH3:24])[CH2:20][NH2:45])[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]
Reactant: CCCCCCCCCCCCCCCCOCC(CO)COC
Reactant: CCCCCCCCCCCCCCCCSCC(CN)OC
Agent: O=C1NC(=O)c2ccccc21
Product: CCCCCCCCCCCCCCCCOCC(CN)COC

Procedure:
3-Hexadecyloxy-2-methoxymethylpropanol V k1 is allowed to react and worked up by the same procedure as described in (3). The phthalimide compound: m.p. 49°-51° C. The summary of the experimental condition and the physical data of the product are listed in Tables 5 and 6.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].COB(OC)[C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1.I[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[C:30]([S:31]([NH:34][C:35]3[C:40]([O:41][CH3:42])=[N:39][C:38]([CH3:43])=[CH:37][N:36]=3)(=[O:33])=[O:32])=[CH:29][CH:28]=[CH:27][N:26]=2)=[CH:21][CH:20]=1.C(O)C>O.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.C1(C)C=CC=CC=1>[CH3:42][O:41][C:40]1[C:35]([NH:34][S:31]([C:30]2[C:25]([C:22]3[CH:23]=[CH:24][C:19]([C:10]4[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=4)=[CH:20][CH:21]=3)=[N:26][CH:27]=[CH:28][CH:29]=2)(=[O:33])=[O:32])=[N:36][CH:37]=[C:38]([CH3:43])[N:39]=1
Reactant: COc1nc(C)cnc1NS(=O)(=O)c1cccnc1-c1ccc(I)cc1
Reactant: COB(OC)c1cccnc1
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: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1nc(C)cnc1NS(=O)(=O)c1cccnc1-c1ccc(-c2cccnc2)cc1
Temperature: 85 °C
Yield: 36.9 %

Procedure:
Tetrakis(triphenylphosphine)palladium (0) (25 mg) was added to a deoxygenated solution of sodium carbonate (223 mg), dimethoxy-(3-pyridyl)borane (116 mg) and 2-(4-iodophenyl)-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (828 mg) in a mixture of water (1.8 ml), ethanol (3 ml) and toluene (6 ml). The mixture was stirred and heated under argon at 85° C. for 17 hours and then allowed to cool to ambient temperature. Water was added and the reaction mixture was washed three times with ethyl acetate. The aqueous layer was acidified to pH 7 with 2M hydrochloric acid and extracted six times with ethyl acetate. These extracts were combined, washed with saturated sodium chloride solution then dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column, eluting with 0-8% methanol/dichloromethane to give N-(3-methoxy-5-methylpyrazin-2-yl)-2-(4-[3-pyridyl]phenyl)pyridine-3-sulphonamide (123 mg) as a solid; 1H NMR (CDCl3): 2.3 (s, 3H), 3.7 (s, 3H), 7.3-7.7 (m, 7H), 7.92 (m, 1H), 8.55-8.75 (m, 2H), 8.8 (dd, 1H), 8.9 (d, 1H); mass spectrum (+ve ESP): 434 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([N:23]3[CH2:28][CH2:27][C:26]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)([NH2:29])[CH2:25][CH2:24]3)=[O:22])[C:9]=2[CH3:36])=[CH:4][CH:3]=1.[C:37]([N:41]=[C:42]=[O:43])([CH3:40])([CH3:39])[CH3:38].C(N(CC)CC)C.O1CCCC1>ClCCl>[C:37]([NH:41][C:42](=[O:43])[NH:29][C:26]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:25][CH2:24][N:23]([C:21]([C:10]2[C:9]([CH3:36])=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=2)=[O:22])[CH2:28][CH2:27]1)([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(C)(C)N=C=O
Reactant: Cc1c(C(=O)N2CCC(N)(c3ccccc3)CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(C(=O)N2CCC(NC(=O)NC(C)(C)C)(c3ccccc3)CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: 40 °C
Reaction time: 16 h
Yield: 45 %

Procedure:
1-{[5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl]carbonyl}-4-phenylpiperidin-4-amine (1 eq, 39.3 mg, 0.073 mmol), tert-butyl isocyanate (1.5 eq, 0.013 mL, 0.109 mmol), and triethylamine (3.0 eq, 0.03 mL, 0.218 mmol) was stirred in dichloromethane (5 mL) for 16 h. Next, tetrahydrofuran (5 mL) and an additional 0.02 mL of tert-butyl isocyanate were added and the reaction was stirred for 16 h Finally, the reaction was heated to 40° C. for 16 h. The reaction was concentrated in vacuo. The crude reaction material was then purified by silica gel column chromatography using 0-100% ethyl acetate/hexane to yield pure 3-tert-butyl-1-(1-{[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl]carbonyl}-4-phenylpiperidin-4-yl)urea (21 mg, 45%). 1H NMR (300 MHz, CHLOROFORM-d) d ppm 1.15 (s, 9H) 1.93-2.17 (m, 4H) 2.20 (s, 3H) 2.42 (br. s., 1H) 3.13-3.35 (m, 1H) 3.58 (br. s., 1H) 4.25 (br. s., 1H) 4.44 (s, 1H) 4.52-4.69 (m, 1H) 5.13 (s, 1H) 7.03-7.10 (m, 2H) 7.13-7.37 (m, 7H) 7.38-7.46 (m, 3H).