Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][C:6]([N+:12]([O-])=O)=[C:5]([NH:15][CH3:16])[N:4]=1.CS(O)(=O)=O.[H][H]>[Pd].C.CO>[NH2:9][C:8]1[C:3]([NH:2][CH3:1])=[N:4][C:5]([NH:15][CH3:16])=[C:6]([NH2:12])[CH:7]=1
Reactant: CNc1nc(NC)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Agent: CS(=O)(=O)O
Solvent: CO
Product: CNc1nc(NC)c(N)cc1N

Procedure:
A 250 ml Parr bottle was charged with 2,6-di(methylamino)-3,5-dinitropyridine (20.0 g, 0.088 mole), 30 ml methanesulfonic acid, 200 ml methanol and 1.0 g 5% Pd/charcoal catalyst. The mixture was subjected to hydrogenation at ambient temperature with an initial hydrogen pressure of 65 psig. When no further uptake of hydrogen was observed, the mixture was treated with anhydrous silica gel (25 g), filtered free of catalyst and drying agent under a nitrogen atmosphere, and methanol removed under vacuum. The trimethanesulfonate salt of 3,5-diamino-2,6-di(methylamino)pyridine was obtained under nitrogen by addition of cold i-butanol-benzene to the concentrate, followed by vacuum drying (40°-50°C) over P2O5.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH2:14]([OH:26])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>N1C=CC=CC=1>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:26][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CCCCCCCCCCCCO
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Product: CCCCCCCCCCCCOC(=O)c1ccc(OC(C)=O)cc1
Yield: 68.4 %

Procedure:
In 10 ml of pyridine was dissolved 2.0 g of 4-acetoxybenzoic acid chloride, and 2.4 g of dodecyl alcohol was added to the solution. Reaction was carried out at room temperature with stirring. The reaction mixture was treated by customary procedures to obtain 2.4 g of dodecyl 4-acetoxybenzoate. In the same manner as described in Referential Example 13, the acetoxy group was selectively isolated to quantitatively obtain dodecyl 4-hydroxybenzoate. This ester was dissolved in 20 ml of pyridine and a solution of 2.2 g of 3-chloro-4-benzyloxybenzoic acid chloride in 20 ml of pyridine was added to the above solution. The mixture was reacted at room temperature with stirring overnight and the reaction mixture was treated by customary procedures to obtain 3.3 g of 4'-dodecyloxycarbonylphenyl 3-chloro-4-benzyloxybenzoate. In the same manner as described in Referential Example 10, this ester was catalytically reduced to obtain 2.7 g of 4'-dodecyloxycarbonylphenyl 3-chloro-4-hydroxybenzoate.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[C:6]([Cl:18])[C:7]([CH3:17])=[C:8]([O:11][CH2:12][C:13]([O:15]C)=[O:14])[CH:9]=2)[C:4](=[O:19])[C:3]21[CH2:23][CH2:22][CH2:21][CH2:20]2.[OH-].[K+].CO.Cl>O>[O:1]=[C:2]1[C:10]2[C:5](=[C:6]([Cl:18])[C:7]([CH3:17])=[C:8]([O:11][CH2:12][C:13]([OH:15])=[O:14])[CH:9]=2)[C:4](=[O:19])[C:3]21[CH2:23][CH2:22][CH2:21][CH2:20]2
Reactant: COC(=O)COc1cc2c(c(Cl)c1C)C(=O)C1(CCCC1)C2=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1c(OCC(=O)O)cc2c(c1Cl)C(=O)C1(CCCC1)C2=O

Procedure:
A mixture of methyl [1' ,3'-dioxo-4'-chloro-5'-methylspiro(cyclopentane-1,2'-indan)-6'-yloxy]acetate (3.5 g., 0.0104 mole) potassium hydroxide (0.67 g., 0.012 mole) and methanol (200 ml.) is refluxed for 1/2 hour, diluted with water (800 ml.) and acidified with hydrochloric acid affording 3.1 g. of [1' ,3'-dioxo-4'-chloro-5'-methylspiro(cyclopentane-1,2'-indan)-6'-yloxy]acetic acid which melts at 204°-5°C. after recrystallization from acetic acid-water.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([O:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=O)[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].[NH2:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][C:50](O)=[O:51]>>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([O:28][CH2:29][CH2:30][CH2:31][C:32]([CH:50]([OH:51])[CH2:49][CH2:48][O:47][CH2:46][CH2:45][O:44][CH2:43][CH2:42][O:41][CH2:40][CH2:39][O:38][CH2:37][CH2:36][NH2:35])=[O:34])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:1]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCC(=O)O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: NCCOCCOCCOCCOCCC(=O)O
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCC(=O)C(O)CCOCCOCCOCCOCCN)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 16 h
Yield: 155.1 %

Procedure:
The mixture of pentafluorophenyl ester of 4-(Cholest-5-en-3β-yloxy)butanoic acid (121 mg, 0.19 mmol) and 15-amino-4,7,10,13-tetraoxapentadecanoic acid (104 mg, 0.39 mmol) was dried in an apparatus equipped with septum for 4 h at room temperature and 0.1 Pa. The apparatus was flushed with argon (2×) and then dry N,N-dimethylformamide (4 ml) and N-ethyldiisopropylamine (1 ml) were added through the septum and the mixture was stirred at room temperature for 16 h. Flash chromatography of the crude reaction mixture on silica gel column (100 ml) in toluene-ethyl acetate (gradient: 0-40% ethyl acetate, 10 ml/min, 160 min) gave [4-(Cholest-5-en-3β-yloxy)butanoyl]-15-amino-4,7,10,13-tetraoxapentadecanol acid (general formula X, where n3=3 and n4=3; 208 mg, 88%). 1H NMR (400 MHz, Acetone) δ ppm: 3.71 t, J=6.32 Hz, 2H (CH2-3); 3.55-3.60 m, 14H (7×CH2—O); 3.51 t, J=5.60 Hz, 2H (CH2-14); 3.45 t, J=6.32 Hz, 2H (CH2-4′); 3.34 q, J=5.73 Hz, 1H (CH-3″); 2.53 t, J=6.32 Hz, 2H (CH2-2); 2.34 ddd, J=13.20, 4.70, 2.10 Hz, 1H (H-4a″); 2.24 t, J=7.45 Hz, 2H (CH2-2′); 1.82-2.17 m, 5H (cholesteryl); 1.76-1.82 m, 2H (CH2-3′); 1.01 s, 3H (CH3-19″); 0.94 d, J=6.57 Hz, 3H (CH3-21″); 0.87 d, J=1.26 Hz, 3H (CH3-26″); 0.86 d, J=1.52 Hz, 3H (CH3-27″); 0.81-1.66 m, 34H (cholesteryl); 0.71 s, 3H (CH3-18″); for C42H73NO8—H HR-MS, calculated m/z: 720.5409. found m/z: 720.5407.
Reaction SMILES: [CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:21]([C:31]([OH:33])=O)[C:20]([CH2:34][CH3:35])=[CH:19]1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3].C(O[N:40]([C@H]1CN(C(OC(C)(C)C)=O)[C@H](C(=O)N)C=C1C)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)C=C>>[CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:21]([C:31](=[O:33])[NH2:40])[C:20]([CH2:34][CH3:35])=[CH:19]1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3]
Reactant: C=CCON([C@@H]1C=C(CC)[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](C(N)=O)C=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Product: C=CCON([C@@H]1C=C(CC)[C@@H](C(N)=O)N(C(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Yield: 77 %

Procedure:
The title compound was prepared from (2S,5R)-5-(N-(allyloxy)-2-nitrophenylsulfonamido)-1-(tert-butoxycarbonyl)-3-ethyl-1,2,5,6-tetrahydropyridine-2-carboxylic acid (Intermediate 211, 1.89 g, 3.69 mmol) following the procedure described for Intermediate 20. Silica gel chromatography (0%-80% ethyl acetate/hexanes) afforded the title compound (1.445 g, 77%) as a beige foam.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[C:11](=[O:17])[NH:10][CH2:9][CH2:8]2.Br[CH2:19][CH2:20][CH2:21][Cl:22]>CN(C)C=O>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[C:11](=[O:17])[N:10]([CH2:19][CH2:20][CH2:21][Cl:22])[CH2:9][CH2:8]2
Reactant: COc1cc2c(cc1OC)C(=O)NCC2
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)C(=O)N(CCCCl)CC2
Temperature: 80 °C

Procedure:
2.1 gm (44 millimols) of sodium hydride were added to a solution of 8.0 gm (41 millimols) of 6,7-dimethoxy-3,4-dihydro-2H-isoquinolin-1-one in 100 ml of dimethyl formamide, and the mixture was heated at 80° C. for 30 minutes. Then, 20 ml of 1-bromo-3-chloro-propane were added dropwise, and the mixture was heated at 100° C. for 3 hours. The solvent was then removed in vacuo, the solid residue was digested in water, and the aqueous mixture was extracted with chloroform several times. The combined organic extracts were dried over sodium sulfate and evaporated to dryness, and the evaporation residue was purified by chromatography on silica gel (chloroform/methanol = 150/l), yielding 3.2 gm of 1-(6,7-dimethoxy-3,4-dihydro-2H-isoquinolin-1-one-2-yl)-3-chloro-propane as a viscous oil having an Rf -value of 0.8 (ethyl acetate).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:57]=[CH:56][C:9]([O:10][CH2:11][CH2:12][CH2:13][C:14]3[S:18][C:17]([N:19]4[CH2:28][CH2:27][C:26]5[C:21](=[C:22]([C:29](=[O:48])[N:30]([C:39]6[S:40][C:41]7[CH:47]=[CH:46][CH:45]=[CH:44][C:42]=7[N:43]=6)COCC[Si](C)(C)C)[CH:23]=[CH:24][CH:25]=5)[CH2:20]4)=[N:16][C:15]=3[C:49]([O:51]C(C)(C)C)=[O:50])=[CH:8][CH:7]=2)[CH:3]=[N:2]1.Cl>C(Cl)Cl.CCOCC>[NH:1]1[CH:5]=[C:4]([C:6]2[CH:57]=[CH:56][C:9]([O:10][CH2:11][CH2:12][CH2:13][C:14]3[S:18][C:17]([N:19]4[CH2:28][CH2:27][C:26]5[C:21](=[C:22]([C:29](=[O:48])[NH:30][C:39]6[S:40][C:41]7[CH:47]=[CH:46][CH:45]=[CH:44][C:42]=7[N:43]=6)[CH:23]=[CH:24][CH:25]=5)[CH2:20]4)=[N:16][C:15]=3[C:49]([OH:51])=[O:50])=[CH:8][CH:7]=2)[CH:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1CCCOc1ccc(-c2cn[nH]c2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(Nc1nc2ccccc2s1)c1cccc2c1CN(c1nc(C(=O)O)c(CCCOc3ccc(-c4cn[nH]c4)cc3)s1)CC2

Procedure:
Compound 73A (30 mg) in DCM (1 ml) was treated with HCl 2 N in ether (5 ml) for 2 days. The precipitate was collected and dried to give the title compound 73: 1H NMR (400 MHz, DMSO-D6) δ ppm 8.09 (2H, s), 8.02 (1H, d), 7.79 (1H, d), 7.68 (1H, d), 7.51 (2H, d), 7.44-7.48 (2H, m), 7.33-7.42 (2H, m), 6.91 (2H, d), 4.87 (2H, s), 3.99 (2H, t), 3.75 (2H, t), 3.19 (2H, t), 3.04 (2H, t); LCMS (APCI) m/e 637 (M+H).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([C:9]2[O:13][N:12]=[C:11]([CH2:14][N:15]3[CH:19]=[C:18]([C:20]([O:22]CC)=[O:21])[CH:17]=[N:16]3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1.[OH-].[Li+]>C(O)C.O>[F:26][C:2]([F:1])([F:25])[C:3]1[CH:4]=[C:5]([C:9]2[O:13][N:12]=[C:11]([CH2:14][N:15]3[CH:19]=[C:18]([C:20]([OH:22])=[O:21])[CH:17]=[N:16]3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1cnn(Cc2noc(-c3cccc(C(F)(F)F)c3)n2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cnn(Cc2noc(-c3cccc(C(F)(F)F)c3)n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28 %

Procedure:
The compound (0.85 g) obtained in Example 114b was dissolved in ethanol (8 mL) and water (2 ml), and lithium hydroxide (0.42 g) was added. The reaction mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was diluted with water and adjusted to pH 5-6 with 1N hydrochloric acid. The resulting precipitate was collected by filtration and the obtained solid was recrystallized from ethyl acetate-petroleum ether to give the title compound (0.22 g) as a colorless solid.
Reaction SMILES: [CH2:1]([C:8]1[NH:9][C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>>[CH2:1]([C:8]1[N:12]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCCCCCCBr
Reactant: c1ccc(Cc2nc(-c3ccccc3)c(-c3ccccc3)[nH]2)cc1
Product: CCOC(=O)CCCCCCCn1c(Cc2ccccc2)nc(-c2ccccc2)c1-c1ccccc1
Yield: 52.6 %

Procedure:
2-Benzyl-4,5-diphenylimidazole (3.3 g) (Weiss, M, J. ,Am. Chem. Soc., 1952, 74, 5193-5) was reacted with ethyl 8-bromooctanoate as in Example 9. Colnmn chromatography on silica gel eluted with a dichloromethane:ethanol gradient followed by distillation at 200° C./0.1 torr to remove volatile impurities gave a yellow oil. Recrystallisation from hexane gave 2-benzyl-1-(7-ethoxycarbonylheptyl)-4,5-diphenylimidazole (2.69 g, 52.6%) as a white solid, m.p. 82°-3°. Found: C, 80.35; H, 7.58; N, 6.08%; C32H36N2O2 requires: C, 79.96; H, 7.55; N. 5.83%.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6](C(C)C)[C:5]=1[O:13][CH2:14][C:15]1C=CC=[CH:17][CH:16]=1)([CH3:3])[CH3:2]>C(O)C.C(O)(=O)C.[Pd]>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:13][CH2:14][CH:15]=[CH:16][CH3:17])([CH3:3])[CH3:2]
Reactant: CC(C)c1cccc(C(C)C)c1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CC=CCOc1ccccc1C(C)C

Procedure:
Benzyl (2,6-diisopropylphenyl) ether 60 mg was dissolved in 20 ml of anhydrous ethanol solution of 5% acetic acid. After adding 30 mg of active carbon in 10% palladium thereinto, it was dissolved under hydrogen gas for 15 hours. Thus-obtained mixture Was washed with water and saturated sodium chloride aqueous solution. The resultant was dried with anhydrous magnesium sulfate and then concentrated.
Reaction SMILES: [CH3:1][Si:2]([CH3:15])([CH3:14])[C:3]1[CH:13]=[CH:12][C:6]([O:7][Si](C)(C)C)=[CH:5][CH:4]=1.O>C(O)C.Cl>[CH3:1][Si:2]([CH3:15])([CH3:14])[C:3]1[CH:13]=[CH:12][C:6]([OH:7])=[CH:5][CH:4]=1
Reactant: C[Si](C)(C)Oc1ccc([Si](C)(C)C)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: C[Si](C)(C)c1ccc(O)cc1
Reaction time: 0.08 h
Yield: 93.4 %

Procedure:
28.7 g p-trimethylsilylphenoxytrimethylsilane was dissolved in 9 ml 95 percent ethyl alcohol. One drop of concentrated hydrochloric acid and 4 ml water were added, and the mixture was shaked for 5 minutes. After standing for another 15 minutes, the mixture was washed two times with 30 ml water and separated. The organic phase was poured into a crystallizing dish; p-trimethylsilylphenol crystallized out as white needles. After drying overnight in vacuo, 18.7 g of product was obtained (mp 76 degrees Celsius).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15](=[O:17])[CH3:16])[CH:6]=[C:7]([S:9]([F:14])([F:13])([F:12])([F:11])[F:10])[CH:8]=1.[Br-:18].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.O.C(=O)([O-])O.[Na+]>C1COCC1>[Br:18][CH2:16][C:15]([C:5]1[CH:6]=[C:7]([S:9]([F:10])([F:11])([F:12])([F:13])[F:14])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:17]
Reactant: COc1cc(C(C)=O)cc(S(F)(F)(F)(F)F)c1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C(=O)CBr)cc(S(F)(F)(F)(F)F)c1
Yield: 105.4 %

Procedure:
1-[3-Methoxy-5-(pentafluorosulfanyl)phenyl]ethanone (O2.007; 1.63 g) was dissolved in THF (150 ml), and phenyltrimethylammonium tribromide (2.2 g) was added at RT while stirring. After stirring at RT for 2 h, the mixture was admixed with water, neutralized with sodium hydrogencarbonate solution and extracted three times with EA. The alkaline water phase was extracted 3× with EA. The combined organic phases were dried over magnesium sulfate and, after the desiccant had been filtered off, dried under reduced pressure. The residue was purified by means of preparative HPLC (met. A). The product fractions, each of them clean, were combined, freed of the acetonitrile under reduced pressure, neutralized with sodium hydrogencarbonate and extracted three times with EA. The combined organic phases were dried over magnesium sulfate and, after the desiccant had been filtered off, dried under reduced pressure. 1.27 g of the title compound were isolated. LC-MS rt: 1.65 min [M+H]+: 354.9 (met. b)
Reaction SMILES: C[O:2][C:3]([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[C:8]([O:18][CH2:19][CH:20]2[CH2:22][CH2:21]2)=[CH:7][N:6]=1)=[O:4].[OH-].[Li+].Cl>O1CCCC1.O>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([C:9]2[C:8]([O:18][CH2:19][CH:20]3[CH2:21][CH2:22]3)=[CH:7][N:6]=[C:5]([C:3]([OH:4])=[O:2])[N:10]=2)=[CH:16][CH:15]=1
Reactant: COC(=O)c1ncc(OCC2CC2)c(-c2ccc(Cl)cc2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ncc(OCC2CC2)c(-c2ccc(Cl)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.4 %

Procedure:
To a solution of 2.655 g 4-(4-chloro-phenyl)-5-cyclopropylmethoxy-pyrimidine-2-carboxylic acid methyl ester in 27 mL tetrahydrofuran was added 11 mL of a 1M solution of lithium hydroxide in water and the mixture was stirred at room temperature for 1 h. The reaction mixture was acidified by addition of 1M hydrochloric acid. The precipitate was collected by filtration washed with water and dried to constant weight under high vacuum to yield 2.473 g of the title compound as white solid, MS 305.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(Cl)(=O)[C:16](Cl)=[O:17]>C(Cl)CCl>[F:1][C:2]1[CH:10]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:8]=[CH:7][C:3]=1[C:4]([N:6]=[C:16]=[O:17])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: NC(=O)c1ccc(C(F)(F)F)cc1F
Solvent: ClCCCl
Product: O=C=NC(=O)c1ccc(C(F)(F)F)cc1F

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-8 by using 2-fluoro-4-(trifluoromethyl)benzamide (0.200 g, 0.96 mmol), EDC (10 mL) and oxalyl chloride (0.1 mL, 1.15 mmol) to afford 0.200 g of the product.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][N:6]1[C:10]([S:11][C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[CH:13]=2)=[C:9]([CH2:20]O)[N:8]=[C:7]1[CH3:22]>>[Cl:3][CH2:20][C:9]1[N:8]=[C:7]([CH3:22])[N:6]([CH3:5])[C:10]=1[S:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[CH:13]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(C)cc(Sc2c(CO)nc(C)n2C)c1
Product: Cc1cc(C)cc(Sc2c(CCl)nc(C)n2C)c1
Temperature: 70 °C

Procedure:
To 19 ml of thionyl chloride was added 370 mg (1.4 mmol) of [1,2-dimethyl-5-(3,5-dimethylphenylthio)-1H-imidazol-4-yl]methanol (42b), and the mixture was heated at 70° C. for 3 hours. The reaction mixture was concentrated under reduced pressure. Ice-water and then a saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture to neutralize, and extracted with diethyl ether. The organic layer was washed with water and dried over sodium sulfate, and the solvent was concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate)to give 288 mg of 4-chloromethyl-1,2-dimethyl-5-(3,5-dimethylphenylthio)imidazole (42c)as oil (yield 73%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:32])=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=4)[C:26]([OH:28])=O)=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.Cl.[N:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2([NH2:43])[CH2:42][CH2:41]2)[N:35]=1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:29]=[C:25]([C:26](=[O:28])[NH:43][C:40]5([C:36]6[N:35]=[N:34][CH:39]=[CH:38][CH:37]=6)[CH2:42][CH2:41]5)[C:24]([O:30][CH3:31])=[CH:23][C:22]=4[CH3:32])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)cc12
Reactant: NC1(c2cccnn2)CC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5cccnn5)CC4)c(OC)cc3C)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.04 g, 0.092 mmol, 1 eq), 1-(pyridazin-3-yl)cyclopropanamine HCl salt (0.017 g, 0.092 mmol, 1 eq) and Py-Bop (0.062 g, 0.12 mmol, 1.3 eq) in DMF at ambient temperature under nitrogen was added triethylamine (0.028 g, 0.3 mmol, 3 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was purified by flash column chromatography using 4% MeOH/CHCl3 as eluant. Yield: 0.032 g (63%). 1H NMR (400 MHz, CD3OD): δ 9.15 (s, 1H), 9.00 (d, J=3.8 Hz, 1H), 8.53-8.40 (m, 1H), 8.02-7.95 (m, 2H), 7.84 (dd, J=1.5, 8.5 Hz, 1H), 7.79 (s, 1H), 7.70-7.62 (m, 2H), 7.59 (d, J=1.5 Hz, 1H), 7.34 (dd, J=1.8, 8.5 Hz, 1H), 7.31-7.26 (m, 2H), 7.16 (s, 1H), 4.09 (s, 3H), 2.98-2.95 (m, 3H), 2.38 (s, 3H), 1.89-1.87 (m, 2H), 1.57-1.52 (m, 2H). 19F NMR (376.57 MHz, CD3OD): δ−112.66 LCMS: (ES+) m/z=551.2 (M+H)+
Reaction SMILES: [I-].[K+].C[Si](C)(C)Cl.[CH2:8]([C:10]1[CH:11]=[C:12]([C:19]2[O:23][C:22]([C:24]([N:26]3[CH2:31][CH2:30][N:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH2:28][CH2:27]3)=[O:25])=[CH:21][CH:20]=2)[C:13]([CH3:18])=[N:14][C:15]=1[O:16]C)[CH3:9]>C(#N)C.O>[CH2:8]([C:10]1[C:15](=[O:16])[NH:14][C:13]([CH3:18])=[C:12]([C:19]2[O:23][C:22]([C:24]([N:26]3[CH2:31][CH2:30][N:29]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH2:28][CH2:27]3)=[O:25])=[CH:21][CH:20]=2)[CH:11]=1)[CH3:9]
Reactant: CCc1cc(-c2ccc(C(=O)N3CCN(c4ccccc4)CC3)o2)c(C)nc1OC
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCc1cc(-c2ccc(C(=O)N3CCN(c4ccccc4)CC3)o2)c(C)[nH]c1=O
Temperature: 70 °C

Procedure:
Two equivalents of potassium iodide and two equivalents of trimethylchlorosilane are added to a solution of one equivalent of [5-(5-ethyl-6-methoxy-2-methylpyridin-3-yl)-furan-2-yl]-(4-phenylpiperazin-1-yl)-methanone in anhydrous acetonitrile (3-5 ml/mmol) under argon, the latter being prepared in accordance with the procedure set out in PREPARATION 6, and the cloudy mixture is heated at 60-80° C. for 1-3 h. The mixture is then cooled to rt and diluted with water. The precipitated product is filtered off with suction, washed with water and dried in a vacuum oven at 40° C. The filtrate is extracted with ethyl acetate and, after concentration, occasionally affords further product, which is purified by chromatography on silica gel. MS: m/e=392 (M+H). 1H NMR (D6-DMSO, δ ppm): 11.79 (s, 1H); 7.53 (s, 1H); 7.27 (m, 2H); 7.13 (d, 1H); 6.99 (m, 2H); 6.85 (m, 1H); 6.69 (d, 1H); 3.85 (br s, 4H); 3.23 (m, 4H); 2.50 (m, 5H); 1.12 (t, 3H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:8])[CH2:5][NH:6][CH3:7].C(N(CC)CC)C.[C:16]1([CH:26]=[C:27]2[CH2:32][C:31](=[O:33])[O:30][C:28]2=[O:29])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1>ClCCl>[C:16]1([CH:26]=[C:27]([CH2:32][C:31](=[O:33])[N:6]([CH3:7])[CH2:5][C:4]([O:3][CH3:2])=[O:8])[C:28]([OH:30])=[O:29])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: CNCC(=O)OC
Reactant: O=C1CC(=Cc2cccc3ccccc23)C(=O)O1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CN(C)C(=O)CC(=Cc1cccc2ccccc12)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
To a solution of 1.40 g of sarcosine methyl ester hydrochloride in 50 ml of dichloromethane were added 1.54 ml of triethylamine and 1.70 g of the 2-(1-naphthylmethylene)succinic anhydride obtained, and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was washed successively, with diluted hydrochloric acid, and a saturated sodium chloride aqueous solution, dried over anhydrous magnesium, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: chloroform) to obtain 2.37 g of 2-(1-naphthylmethylene)-3-(N-methyl-N-methoxycarbonylmethylcarbamoyl)propionic acid as a white powder.