Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:35])[O:3][C:4]1[CH:5]=[C:6]([C@@H:14]([C:22]2[CH:27]=[CH:26][C:25]([NH:28][C:29](=[N:32][C:33]#[N:34])SC)=[CH:24][CH:23]=2)[CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12].[CH2:36]([NH2:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>O1CCCC1>[CH2:36]([NH:43][C:29]([NH:28][C:25]1[CH:26]=[CH:27][C:22]([C@H:14]([C:6]2[CH:7]=[CH:8][C:9]([O:10][CH:11]([F:13])[F:12])=[C:4]([O:3][CH:2]([F:35])[F:1])[CH:5]=2)[CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[CH:23][CH:24]=1)=[N:32][C:33]#[N:34])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: NCc1ccccc1
Reactant: CSC(=NC#N)Nc1ccc([C@@H](Cc2ccncc2)c2ccc(OC(F)F)c(OC(F)F)c2)cc1
Solvent: C1CCOC1
Product: N#CN=C(NCc1ccccc1)Nc1ccc([C@@H](Cc2ccncc2)c2ccc(OC(F)F)c(OC(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To the compound of Example 10 (400 mg, 0.79 mmol) in anhydrous tetrahydrofuran (10 ml) was added benzylamine (1 ml, excess). The mixture was stirred at room temperature for 72 h. The solvent and volatiles were removed in vacuo to yield the title compound as a white solid (300 mg). 1Hnmr (300 MHz, CDCl3) δ 3.28 (2H, d, J 7.99 Hz), 4.21 (1H, t, J 7.98 Hz), 4.47 (2H, d, J 5.69 Hz), 5.27 (1H, br), 6.43 (1H, t, J 73.58 Hz), 6.47 (1H, t, J 73.39 Hz), 6.89 (2H, d, J 6.03 Hz), 6.99-7.34 (12H, c) and 8.38 (2H, d, J 6.04 Hz). For C29H23N5O7F4 requires C, 63.94%; H, 4.47%; N, 12.43%; Found C, 63.87%; H, 4.48%; N, 12.52%.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=1)[O:11][C:12]1[C:17]([C:18]#N)=[CH:16][CH:15]=[CH:14][N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)=[O:24]>[Ni].O>[O:1]([C:8]1[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=1)[O:11][C:12]1[C:17]([CH:18]=[O:24])=[CH:16][CH:15]=[CH:14][N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CO
Reactant: N#Cc1cccnc1Oc1cccc(Oc2ccccc2)c1
Agent: [Ni]
Solvent: O
Product: O=Cc1cccnc1Oc1cccc(Oc2ccccc2)c1

Procedure:
Crude 2-(3-phenoxyphenoxy)-3-cyanopyridine (15 g) was stirred with Raney nickel alloy (15 g, 50:50) in refluxing 75% formic acid (200 ml) for 2 hours. The reaction mixture was diluted with water and then extracted repeatedly with ether. The combined ether extracts were dried, filtered and evaporated to give an orange oil. Filtration through a plug of silica (eluent hexane-ether, 1:1) afforded 2-(3-phenoxyphenoxy)-3-formylpyridine (3.03 g), infrared max. 1685 cm-1.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)[CH3:2].[Cl:8][C:9]1[CH:20]=[CH:19][C:12]([C:13](N(OC)C)=[O:14])=[CH:11][CH:10]=1.CN1C=CN=C1.FC1N=CC(C(N(OC)C)=O)=CC=1>>[Cl:8][C:9]1[CH:20]=[CH:19][C:12]([C:13]([C:7]2[N:3]([CH2:1][CH3:2])[CH:4]=[N:5][CH:6]=2)=[O:14])=[CH:11][CH:10]=1
Reactant: CON(C)C(=O)c1ccc(Cl)cc1
Reactant: CCn1ccnc1
Agent: CON(C)C(=O)c1ccc(F)nc1
Agent: Cn1ccnc1
Product: CCn1cncc1C(=O)c1ccc(Cl)cc1

Procedure:
The title compound was prepared using 1-ethyl-1H-imidazole and 4-chloro-N-methoxy-N-methylbenzamide (Intermediate 18, step a) in place of 1-methyl-1H-imidazole and 6-fluoro-N-methoxy-N-methylpyridine-3-carboxamide, respectively, according to the procedure described for Intermediate 21, step c.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Br:20])=[CH:4][N:3]=1.[CH3:21][N:22]([CH3:31])[C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1.C([O-])(=O)C.[NH4+]>C(O)C>[Br:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:27]([C:26]3[CH:29]=[CH:30][C:23]([N:22]([CH3:31])[CH3:21])=[CH:24][CH:25]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: CN(C)c1ccc(C=O)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Product: CN(C)c1ccc(-c2nc3c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)c(Br)cnc3[nH]2)cc1
Yield: 47.1 %

Procedure:
(1S,2S,3R,4R)-3-(2,3-Diamino-5-bromo-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (1.30 mg, 0.386 mmol), 4-(dimethylamino)benzaldehyde (63.3 mg, 0.424 mmol) and ammonium acetate (59.4 mg, 0.771 mmol) were heated in ethanol (5 mL) at 70° C. for 18 hours. The desired product precipitated from the reaction mixture. The mixture was diluted with ethyl ether (5 mL) and filtered. The remaining solid was dried under high vacuum to afford 85 mg (47%) of the title compound. mp: 264-265° C., 1H NMR (300 MHz, DMSO-d6): 12.73 (s, 1H), 7.96 (d, J=8 Hz, 2H), 7.84 (d, J=4 Hz, 1H), 7.65 (s, 1H), 7.15 (s, 1H), 6.81 (d, J=8 Hz, 2H), 6.70 (d, J=8 Hz, 1H), 6.37 (d, J=8 Hz, 1H), 6.32 (s, 2H), 3.89 (br s, 1H), 2.99 (s, 6H), 2.87 (s, 1H), 2.75 (s, 1H), 2.60 (d, J=7 Hz, 1H), 2.24 (d, J=8 Hz, 1H), 1.42 (d, J=8 Hz, 1H). MS: 467, 469 (M+H), HPLC: 2.43 min (G method).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=[O:13])[CH3:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH:14]([N-]C(C)C)([CH3:16])[CH3:15].[Li+].I[CH2:23][CH2:24][CH3:25].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O.C(OCC)(=O)C.CCCCCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=[O:13])[CH:12]([CH2:23][CH2:24][CH3:25])[CH2:15][CH2:14][CH3:16])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CC(C)[N-]C(C)C
Reactant: COc1ccc(C(C)=O)cc1OC
Reactant: CCCI
Agent: O=C([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: CCOC(C)=O
Product: CCCC(CCC)C(=O)c1ccc(OC)c(OC)c1
Temperature: 0 °C
Reaction time: 72 h

Procedure:
3′,4′-Dimethoxyacetophenone (9.91 grams, 55 mmol) was added over 20 minutes to a cooled (0° C.) stirred solution of lithium diisopropylamide (28.9 milliliters, 2M, 57.8 mmol). After an additional 5 minutes the solution was cooled to −78° C. and 1-iodopropane (10.73 milliliters, 110 mmol) was rapidly added. The solution was allowed to slowly warm to room temperature and stirring was continued for 3 days. Reaction progress was monitored by TLC (30% , ethyl acetate/hexane, UV) and an equilibrium had been reached after three days between starting material (Rf=0.15), monoalkylated product (Rf=0.32) and dialkylated product (Rf=0.42). The reaction was treated with water (60 milliliters), ethyl acetate (100 milliliters) and a saturated solution of sodium bicarbonate (100 milliliters). The organic layer was separated and washed successively with 5% hydrochloric acid (100 milliliters) and saturated aqueous sodium bicarbonate (100 milliliters). The organic layer was dried over magnesium sulfate and concentrated to afford 15.17 grams of crude product as an orange oily liquid. The crude product was purified by flash chromatography (silica gel, 20% ethyl acetate/hexane) to afford 3.68 (25%) of the dialkylated product (3′,4′-dimethoxy-2-propylvalerophenone) as a yellow solid and 1.01 grams (8%) of the monoalkylated product (3′,4′-dimethoxyvalerophenone) as a yellow oily liquid: 1H NMR (CDCl3) δ7.65-7.50 (m, 2H), 6.95-6.85(m, 1H), 3.95(s, 3 H), 3.94(s, 3 H), 2.99-2.88(m, 2 H), 1.81-1.64(m, 2 H), 1.52-1.34(m, 2 H), 1.04-0.91(m, 3 H). 13C NMR (CDCl3) δ199.1, 152.9, 148.8, 130.2, 122.5, 110.0, 109.8, 55.9, 55.8, 37.7, 26.7, 22.4, 13.8.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH2:9]([C:13]1[NH:14][C:15]([CH2:20][OH:21])=[C:16](CO)[N:17]=1)[CH2:10][CH2:11][CH3:12].C(O)C>O1CCOCC1>[CH2:9]([C:13]1[NH:14][C:15]([CH2:20][OH:21])=[C:16]([Cl:1])[N:17]=1)[CH2:10][CH2:11][CH3:12]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCCCc1nc(CO)c(CO)[nH]1
Solvent: C1COCCO1
Solvent: CCO
Product: CCCCc1nc(Cl)c(CO)[nH]1
Temperature: 25 °C

Procedure:
1.45 Grams (10.9 mmol) of an N-chlorosuccinimide was added to a solution consisting of 1.91 g (10.4 mmol) of a 2-butyl-4,5-bis(hydroxymethyl) imidazole, 100 ml of ethanol and 40 ml of 1,4-dioxane maintained at room temperature. The mixture was reacted for 18 hours with stirring and, then, the solvent was distilled off under reduced pressure. The resulting reaction product was washed with water and was recrystallized from acetonitrile to obtain a pale yellowish scale-like crystalline 2-butyl-4- chloro-5-(hydroxymethyl) imidazole in an amount of 1.00 g (yield, 51%). Recrystallization was further effected with acetonitrile to obtain the milk-white crystalline compound in pure form.
Reaction SMILES: Br[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]=1.[NH:19]1[CH2:26][CH2:25][CH2:24][NH:23][CH2:22][CH2:21][CH2:20]1>>[F:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][N:6]2[C:5]3[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=3[N:3]=[C:2]2[N:19]2[CH2:26][CH2:25][CH2:24][NH:23][CH2:22][CH2:21][CH2:20]2)=[CH:9][CH:10]=1
Reactant: C1CNCCCNC1
Reactant: Fc1ccc(Cn2c(Br)nc3ccccc32)cc1
Product: Fc1ccc(Cn2c(N3CCCNCCC3)nc3ccccc32)cc1
Temperature: 80 °C
Yield: 108.3 %

Procedure:
A mixture of 2-bromo-1-(4-fluorophenylmethyl)-1H-benzimidazole (10.07 g) and 1,5-diazacyclooctane (5.60 g) was heated at 80° C. for 1 hour. To the reaction mixture was added distilled water (300 ml), and the mixture was extracted with methylene chloride (300 ml). The extract was washed with water, and dried over anhydrous MgSO4. The solvent was removed under reduced pressure to give 1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-1,5-diazacyclooctane (12.1 g) as a colorless oily liquid.
Reaction SMILES: N(CCO)CCO.CCOCC.[C:13]([CH2:17][C:18]([OH:20])=[O:19])(=[O:16])[CH2:14][CH3:15].[N+]([O-])([O-])=O.[Ag+:25]>O>[C:13]([CH2:17][C:18]([O-:20])=[O:19])(=[O:16])[CH2:14][CH3:15].[Ag+:25]
Reactant: CCC(=O)CC(=O)O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: OCCNCCO
Solvent: CCOCC
Solvent: O
Product: CCC(=O)CC(=O)[O-]
Reaction time: 0.25 h
Yield: 423.5 %

Procedure:
Diethanolamine (0.22 g) was dissolved in water (0.5 mL), and to this was added an ether solution (3 mL) containing propionylacetic acid (0.25 g). Next, the mixture was stirred at 15° C. while an aqueous solution (1 mL) containing silver nitrate (0.34 g) was added dropwise, and this was further stirred for 15 minutes. The white precipitate that settled was filtered off to obtain silver propionylacetate (yield 1.89 g). FIG. 3 shows the infrared absorption spectrum (IR) of the silver propionylacetate that was obtained. IR:1714 cm−1, 1505 cm−1.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([S:11]([NH2:14])(=[O:13])=[O:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C(Cl)Cl>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([S:22][C:2]2[CH:3]=[C:4]([S:11]([NH2:14])(=[O:13])=[O:12])[CH:5]=[CH:6][C:7]=2[N+:8]([O-:10])=[O:9])=[CH:18][CH:17]=1
Reactant: NS(=O)(=O)c1ccc([N+](=O)[O-])c(Cl)c1
Reactant: Sc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: NS(=O)(=O)c1ccc([N+](=O)[O-])c(Sc2ccc(Cl)cc2)c1

Procedure:
3-Chloro-4-nitrobenzenesulphonamide (1.08 g; 4.53 mmol), 4-chlorothiophenol (0.66 g; 4.53 mmol) and K2CO3 (0.64 g; 4.60 mmol) were refluxed in dioxan (30 ml) for 3 hours. The mixture was then diluted with CH2Cl2, filtered and washed with water. The organic phase was dried over MgSO4 and evaporated down. The product was recrystallised from petroleum ether/ethyl acetate. Yield: 1.0 g=64% 13C (100 MHz, DMSO-d6) δ 148.57, 146.43, 138.07, 137.08, 135.76, 130.70, 128.74, 127.27, 125.43, 123.52
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].Cl.[C:6]1([CH3:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[CH2:12]1[C:10]2=[CH:11][C:6](=[CH:7][CH:8]=[CH:9]2)[CH2:12][C:10]2=[CH:11][C:6](=[CH:7][CH:8]=[CH:9]2)[CH2:12][C:8]2=[CH:9][CH:10]=[CH:11][C:6](=[CH:7]2)[CH2:12][C:8]2=[CH:9][CH:10]=[CH:11][C:6]1=[CH:7]2
Reactant: Cc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: c1cc2cc(c1)Cc1cccc(c1)Cc1cccc(c1)Cc1cccc(c1)C2
Reaction time: 2 h
Yield: 66 %

Procedure:
Calix (4) arene XXVI is prepared from 4-tert -butylcalix(4)arene (XXV; FIG. 13) as described (Gutsche, Levine, and Sujeeth, 1985). A hot solution of 5.0 g (6.75 mmol) of XXV in 250 ml of toluene is placed in a 500 ml three-necked round-bottom flask fitted with a mechanical stirrer and a gas inlet tube. The solution is cooled to 50°-55° C., treated with 5.0 g (37 mmol) of anhydrous AlCl3, and stirred for 2 h at 50°-55° C. in an inert atmosphere. The mixture is cooled in an ice bath and stirred with 125 ml of 1N HCl for 30 min, and the organic phase is separated and washed, dried, and evaporated to leave a yellow residue. This is triturated with 500 ml of ether, and the insoluble material is recrystallized from CHCl3 --CH3OH to yield 1.9 g (66%) of XXVI as off-white microcrystals. m.p. 313°-318° C.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[S-:15][C:16]#[N:17].[NH4+].[CH2:19]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC(C)=O.CN(C=O)C>[CH2:19]([N:26]([C:16]1[S:15][C:2]2[N:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4](=[O:6])[N:17]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: N#C[S-]
Reactant: O=C(O)c1cccnc1Cl
Reactant: c1ccc(CNc2ccccc2)cc1
Agent: [NH4+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: O=c1nc(N(Cc2ccccc2)c2ccccc2)sc2ncccc12
Yield: 73.4 %

Procedure:
The reaction procedure of Example 57 was followed except that 1.757 g (11.2 mmol) of 2-chloronicotinic acid, 15 ml of thionyl chloride, two droplets of DMF, 891 mg of ammonium thiocyanate, 15 ml of acetone, 2.15 g of N-benzylaniline and 10 ml of acetone were used. The product was then recrystallized from ethanol to obtain 2.84 g of 2-(N-benzyl-N-phenylamino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[CH2:19]([S:21](Cl)(=[O:23])=[O:22])[CH3:20]>C1COCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH:9][S:21]([CH2:19][CH3:20])(=[O:23])=[O:22])=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: NCc1ccc([N+](=O)[O-])cc1
Reactant: CCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCS(=O)(=O)NCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-nitro-benzylamine (47.2 mg, 0.25 mmol) in THF (250 μL) is added triethylamine (89 μL) and ethyl sulfonyl chloride (24 μL, 0.25 mmol). The reaction mixture is shaken at ambient temperature for 16 hours. The reaction mixture is then concentrated, methanol is added followed by Novabiochem AM resin to remove unreacted amine. This is then shaken for two hours, filtered, concentrated to yield ethanesulfonic acid 4-nitro-benzylamide, which is used as such for the subsequent reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl:20][S:21](O)(=[O:23])=[O:22].[OH-].[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:15]=[CH:16][C:17]([S:21]([Cl:20])(=[O:23])=[O:22])=[CH:18][CH:19]=1
Reactant: O=S(=O)(O)Cl
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccccc2)C1
Agent: [Na+]
Agent: [OH-]
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(S(=O)(=O)Cl)cc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
At 0° C., 1 mmol of 6,8-dichloro-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline (intermediate 4, example 2) was introduced into 1 ml of chlorosulfonic acid and stirred at room temperature for 3 hours. For workup, the reaction mixture was poured onto ice, adjusted to pH 7 to 8 with 1 N NaOH and extracted twice with ethyl acetate. The combined ethyl acetate phases were dried with Na2SO4 and concentrated in a rotary evaporator. The crude product obtained in this way was reacted further without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:20]([OH:22])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:25]=[CH:26][C:27]([CH:30]([CH3:32])[CH3:31])=[N:28][CH:29]=1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:20]([NH:23][C:24]1[CH:29]=[N:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1ccc(N)cn1
Reactant: Cc1ccc(OCc2ccccc2)c2c1C(C(=O)O)CCC2
Product: Cc1ccc(OCc2ccccc2)c2c1C(C(=O)Nc1ccc(C(C)C)nc1)CCC2
Yield: 93.4 %

Procedure:
By the reaction and treatment in the same manner as in Preparation Example 18 using 5-benzyloxy-8-methyl-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (1.34 g) and 5-amino-2-isopropylpyridine (0.62 g) as starting materials, 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-8-methyl-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.75 g) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[N:16]([CH3:24])[C:17](=O)OC(C)(C)C.[O:25]=[C:26]1[NH:30][C:29](=[O:31])[CH:28]([CH2:32][C:33]2[CH:43]=[CH:42][C:36]([O:37][CH2:38]C(O)=O)=[CH:35][CH:34]=2)[S:27]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[OH:15][C:12]1[CH:11]=[CH:10][C:9]([S:8][C:5]2[CH:6]=[CH:7][C:2]3[N:1]=[C:24]([CH2:38][O:37][C:36]4[CH:35]=[CH:34][C:33]([CH2:32][CH:28]5[S:27][C:26](=[O:25])[NH:30][C:29]5=[O:31])=[CH:43][CH:42]=4)[N:16]([CH3:17])[C:3]=3[CH:4]=2)=[CH:14][CH:13]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Sc2ccc(O)cc2)ccc1N
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Sc3ccc(O)cc3)cc21
Yield: 21.5 %

Procedure:
In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(4-hydroxyphenylthio)phenyl]-N-methylcarbamate (2.36 g), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (2.87 g), diethyl cyanophosphonate (1.67 g), triethylamine (1.03 g) and anhydrous tetrahydrofuran (60 ml) and the reaction mixture was purified. Then, in a similar manner to that described in Example (2-2a) a reaction was carried out using the above product and 4N hydrogen chloride/dioxane (20 ml) and the reaction mixture was purified to give the desired compound (0.72 g).
Reaction SMILES: [C:1]([N:4]1[CH2:12][CH2:11][CH:7]([C:8](Cl)=[O:9])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCN(CC)CC>C1COCC1.CCOC(C)=O>[C:1]([N:4]1[CH2:12][CH2:11][CH:7]([C:8]([O:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:9])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Reactant: Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)N1CCC(C(=O)Oc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 71.5 %

Procedure:
To a suspension of N-acetylisonipecotoyl chloride (3.70 g, 19.50 mmol) in THF (60 mL) were added phenol (2.70 g, 27 mmol) and Et3N (5.0 mL, 36 mmol). The resulting heterogeneous mixture was stirred at 25° C. for 20 h, diluted with EtOAc (50 mL) and was washed with a saturated solution of NH4Cl (50 mL). The crude compound was purified by filtration on silica gel using EtOAc/n-hexane as eluant to afford the title compound as a colorless solid (3.45 g, 80%): mp 96-98 C; 1H NMR (CDCl3) d 1.60-1.95 (m, 2H), 2.00-2.2 (m, 5H), 2.70-3.00 (m, 2H), 3.10-3.30 (m, 1H), 3.75-3.90 (m, 1H), 4.40-4.60 (m, 1H), 7.06 (d, J=7.5 Hz, 2H), 7.22 (d, J=7.5 Hz, 1H), 7.38 (t, J=7.5 Hz, 2H).
Reaction SMILES: [C:1]([C:4]1[C:5]([O:24][CH2:25][CH3:26])=[C:6]([CH:13]([OH:23])[CH2:14][NH:15][C:16](=O)[O:17]C(C)(C)C)[C:7]([C:11]#[N:12])=[C:8]([Cl:10])[CH:9]=1)(=[O:3])[CH3:2].Cl.C(N(CC)C(C)C)(C)C.C1N=CN(C(N2C=NC=C2)=O)C=1>O1CCOCC1>[C:1]([C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([C:11]#[N:12])=[C:6]([CH:13]2[O:23][C:16](=[O:17])[NH:15][CH2:14]2)[C:5]=1[O:24][CH2:25][CH3:26])(=[O:3])[CH3:2]
Reactant: CCOc1c(C(C)=O)cc(Cl)c(C#N)c1C(O)CNC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1c(C(C)=O)cc(Cl)c(C#N)c1C1CNC(=O)O1
Temperature: 70 °C

Procedure:
tert-Butyl [2-(3-acetyl-5-chloro-6-cyano-2-ethoxyphenyl)-2-hydroxyethyl]carbamate (290 mg, 0.76 mmol) (racemic mixture from step 2) was treated with 4.0 M hydrogen chloride in 1,4-dioxane (6.1 mL) for 15 minutes and the mixture was evaporated. The residue was dissolved in tetrahydrofuran (2.3 mL) and N,N-diisopropylethylamine (0.66 mL, 3.8 mmol). N,N-carbonyldiimidazole (250 mg, 1.5 mmol) was added and the reaction mixture was refluxed at 70° C. overnight. The reaction mixture was evaporated. Purification on silica gel using ethyl acetate in hexane (0-100%) gave the desired compound as a racemic mixture, 110 mg, 47%. LCMS calculated for C14H14ClN2O4(M+H)+: m/z=309.1; found: 309.1. 1H NMR (400 MHz, DMSO-d6): δ 8.00 (br s, 1 H), 7.93 (s, 1 H), 5.99 (m, 1 H), 3.89 (m, 1 H), 3.81 (m, 2 H), 3.52 (m, 1 H), 2.58 (s, 3 H), 1.23 (m, 3 H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[NH:10][CH:11]1[CH2:16][CH:15]([CH2:17][CH3:18])[NH:14][C:13]2[N:19]([CH3:23])[N:20]=[C:21]([CH3:22])[C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.C(=O)([O-])[O-].[K+].[K+].Cl[C:37]([O:39][CH2:40][CH3:41])=[O:38]>O>[CH2:40]([O:39][C:37]([N:14]1[CH:15]([CH2:17][CH3:18])[CH2:16][CH:11]([NH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:24])[C:12]2[C:21]([CH3:22])=[N:20][N:19]([CH3:23])[C:13]1=2)=[O:38])[CH3:41]
Reactant: CCC1CC(NC(=O)OCc2ccccc2)c2c(C)nn(C)c2N1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)N1c2c(c(C)nn2C)C(NC(=O)OCc2ccccc2)CC1CC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
(6-Ethyl-1,3-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b]pyridine-4-yl)-carbamic acid benzyl ester (0.35 g, 1.08 mmol) obtained in step (ii), dry THF (5 mL) and potassium carbonate (0.45 g, 3.2 mmol) were charged to a flask under a nitrogen atomsphere. This mixture was stirred at room temperature for about 0.5 h, after which time ethyl chloroformate (0.47 g, 3.2 mmol) was added drop-wise. This reaction mixture was then stirred for about 4 h, water was added to the mixture, and the aqueous layer was extracted with ethyl acetate (3×10 mL). The combined organic layer was washed with brine (1×20 mL), dried over sodium sulphate, and concentrated under vacuum to afford the title compound (0.375 g, 88%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[C:6]([C:8]([OH:10])=O)[N:5]([CH3:11])[N:4]=1.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[CH:25]=[C:26]([CH:43]=[CH:44][C:45]=1[Cl:46])[O:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([CH:34]=[C:35]([NH:37][C:38]([CH:40]3[CH2:42][CH2:41]3)=[O:39])[N:36]=2)[N:33]=1>CN(C)C(=O)C.O1CCCC1>[Cl:46][C:45]1[CH:44]=[CH:43][C:26]([O:27][C:28]2[CH:29]=[CH:30][C:31]3[N:32]([CH:34]=[C:35]([NH:37][C:38]([CH:40]4[CH2:42][CH2:41]4)=[O:39])[N:36]=3)[N:33]=2)=[CH:25][C:24]=1[NH:23][C:8]([C:6]1[N:5]([CH3:11])[N:4]=[C:3]([O:2][CH3:1])[CH:7]=1)=[O:10]
Reactant: COc1cc(C(=O)O)n(C)n1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: COc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2Cl)n(C)n1
Yield: 61.8 %

Procedure:
Using 3-methoxy-1-methyl-1H-pyrazole-5-carboxylic acid (191 mg, 1.22 mmol), tetrahydrofuran (4.5 mL), N,N-dimethylformamide (30 μL, 0.39 mmol), oxalyl chloride (107 μL, 1.22 mmol), N-[6-(3-amino-4-chlorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (300 mg, 0.87 mmol) and N,N-dimethylacetamide (6.0 mL), and in the same manner as in Example 238, the title compound (259 mg, 62%) was obtained as a white powder.