Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13]([F:15])[F:14])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.[CH3:35][O:36][CH2:37][C:38](Cl)=[O:39]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13]([F:14])[F:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([C:38](=[O:39])[CH2:37][O:36][CH3:35])[CH2:33][CH2:34]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1
Reactant: COCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)NC1CCNCC1
Agent: Cl
Product: COCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f60) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: O.[C:2]([OH:6])(=[O:5])[CH:3]=O.[C:7]([C:10]1[C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:12][N:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=12)(=[O:9])[CH3:8]>C(Cl)Cl>[O:9]=[C:7]([C:10]1[C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:12][N:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=12)/[CH:8]=[CH:3]/[C:2]([OH:6])=[O:5]
Reactant: CC(=O)c1c(-c2ccccc2)nn2ccccc12
Reactant: O=CC(=O)O
Solvent: ClCCl
Solvent: O
Product: O=C(O)/C=C/C(=O)c1c(-c2ccccc2)nn2ccccc12
Temperature: 100 °C
Yield: 7.4 %

Procedure:
A mixture of glyoxylic acid monohydrate (3.50 g) and 3-acetyl-2-phenylpyrazolo[1,5-a]pyridine (5.00 g) was stirred and heated at 100° C. for 4 hours. The warm reaction mixture was dissolved in methylene chloride (50 ml), and then extracted with 1N aqueous solution of sodium hydroxide (50 ml). The aqueous layer was washed with methylene chloride (total 200 ml) and then with ethyl acetate (total 200 ml). The aqueous solution was adjusted to pH 4~5 with 10% hydrochloric acid. The isolated oil was extracted with chloroform. The extract was evaporated in vacuo and crystallized from methylene chloride to give 4-oxo-4-(2phenylpyrazolo[1,5-a]pyridin-3-yl)crotonic acid (0.46 g).
Reaction SMILES: [CH3:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Cl[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][N:13]=1.C([O-])([O-])=O.[K+].[K+]>>[CH:4]([C:3]1[C:2]([CH3:1])=[C:9]([CH:8]=[CH:7][CH:6]=1)[O:10][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][N:13]=1)=[O:5]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: Cc1c(O)cccc1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1c(C=O)cccc1Oc1ccc(C#N)cn1
Yield: 91.5 %

Procedure:
Using a method similar to Example 221, Step 1, using 2-methyl-3-hydroxy-benzaldehyde (see European Patent 0807621 A1) (965 mg, 6.42 mmol), 6-chloronicotinonitrile (890 mg, 6.42 mmol) and K2CO3 (1.33 g, 9.63 mmol) gives 6-(3-formyl-2-methyl-phenoxy)-nicotinonitrile (1.40 g) as a white solid. 1HNMR (CDCl3): 10.30 (s, 1H), 8.41 (s, 1H), 7.96 (d, 1H), 7.78 (d, 1H), 7.45 (t, 1H), 7.30 (d, 1H), 7.10 (d, 1H), 2.45 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9](O)[C:8]([O:12][CH2:13][CH3:14])=[C:7]([O:15][CH2:16][CH3:17])[CH:6]=1)[CH3:2].[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[CH2:27][CH2:28][OH:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:6]=[C:7]([O:15][CH2:16][CH3:17])[C:8]([O:12][CH2:13][CH3:14])=[C:9]([O:29][CH2:28][CH2:27][C:21]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:20]=2[Cl:19])[CH:10]=1)[CH3:2]
Reactant: OCCc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)c1cc(O)c(OCC)c(OCC)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(OCC)c(OCC)c(OCCc2ccc(Cl)cc2Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
g (3.93 mmol) of 3,4-Diethoxy-5-hydroxy-benzoic acid ethyl ester was dissolved in 20 ml of anhydrous tetrahydrofuran. To this solution was added 0.83 g (4.33 mmol) of 2-(2,4-Dichlorophenyl)-ethanol, 3.93 g (equivalent to 11.8 mmol PPh3) of triphenylphosphine derivatized polystyrene and 2.05 g (11.8 mmol) of DEAD. The solution was shaken for 16 h at RT. The polymer was filtered off and washed with ethyl acetate. The solvent was removed under reduced pressure. The residue was taken-up in ethyl acetate and the solution was washed three times with water and twice with saturated aqueous sodium chloride. The organic phase was dried with magnesium sulphate, filtered and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel eluting with ethyl acetate/n-heptane (1/5).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][CH:7]=1.C1C(=O)N([Br:21])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:21][CH2:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][CH:7]=1
Reactant: Cc1cnc(-c2ccccc2)nc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cnc(-c2ccccc2)nc1

Procedure:
Synthesized using compound 64b (205 mg, 1.20 mmol), NBS (236 mg, 1.32 mmol) and DBPO (14.6 mg, 0.06 mmol) in carbon tetrachloride according to Method A. Crude product was purified by flash chromatography on silica-gel using hexane/ethyl acetate (10:1) as eluent. Product was used directly in the next step without further characterization. White solid. Yield: 89 mg, 30%. (ESI): m/z=250.68 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[Cl:13][C:14]([Cl:19])([Cl:18])[C:15](Cl)=[O:16]>CCOC(C)=O>[Cl:13][C:14]([Cl:19])([Cl:18])[C:15]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:16]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: O=C(N1CCOCC1)C(Cl)(Cl)Cl
Reaction time: 0.33 h

Procedure:
Morpholine (4.0 mL, 45 mmol) is dissolved in EtOAc (50 mL) and saturated K2CO3 (40 mL) added. The mixture is cooled in an ice bath and trichloroacetyl chloride (5.0 mL, 45 mmol) added drop-wise. The reaction is stirred for 20 min then diluted with EtOAc (200 mL) and washed with aq. K2CO3 (20 mL), water (2×50 mL) and brine (30 mL). The organic layer is dried over MgSO4. Rotary evaporation gives trichloroacetylmorpholine.
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:18]=[CH:17][C:16]([C:19]([OH:21])=O)=[CH:15][N:14]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].S(Cl)(Cl)=O.C(C1C=CC(C2N=CC(C(Cl)=O)=C[N:39]=2)=CC=1)CCCCC.N>O1CCOCC1>[CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:18]=[CH:17][C:16]([C:19]([NH2:39])=[O:21])=[CH:15][N:14]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1ccc(-c2ncc(C(=O)Cl)cn2)cc1
Reactant: CCCCCCc1ccc(-c2ncc(C(=O)O)cn2)cc1
Agent: N
Solvent: O=S(Cl)Cl
Solvent: C1COCCO1
Product: CCCCCCc1ccc(-c2ncc(C(N)=O)cn2)cc1

Procedure:
12.0 G. of 2-(p-n-hexylphenyl)-5-pyrimidinecarboxylic acid are reacted with 80 ml. of thionyl chloride with the exclusion of moisture and worked up in a manner analogous to that described in Example 7. The remaining 2-(p-n-hexylphenyl)-5-pyrimidinecarboxylic acid chloride is dissolved in 120 ml. of abslute dioxane while warming and added with stirring to a solution of 200 ml. of absolute dioxane saturated with ammonia at room temperature and treated further in a manner analogous to that described in Example 7. A sample of the obtained crude 2-(p-n-hexylphenyl)-5-pyrimidinecarboxamide is sublimed at 180° C. in a high vacuum for purification; melting point 250.2°-258.3° C.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:16][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC>C1COCC1>[Si:1]([O:8][CH:9]1[CH2:14][CH2:13][C:12](=[O:15])[CH:11]([CH3:16])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(=O)CC1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1CC(O[Si](C)(C)C(C)(C)C)CCC1=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 85.7 %

Procedure:
To a 5.0 L round bottom flask containing 4-(tert-butyldimethylsilyloxy)cyclohexanone (7.03 g, 30.8 mmol) (Aldrich) was added THF (100 mL) and the reaction was cooled to −78° C. To the reaction mixture was added lithium bis(trimethylsilyl)amide (33.9 ml, 33.9 mmol) (Aldrich) and the reaction mixture was stirred for 30 minutes followed by the addition of iodomethane (2.309 ml, 36.9 mmol). The reaction mixture was stirred for 30 minutes at −78° C. and 2 hours at room temperature, quenched with saturated NH4Cl, extracted with EtOAc (200 mL), dried (NaSO4), filtered, and concentrated in vacuo. The residue was purified on SiO2 and eluted with 0-20% ethyl acetate/hexane to give a white solid (6.40 g) in 86% yield. 1H NMR (300 MHz, CDCl3) δ ppm 4.19-4.07 (m, 1H), 2.98-2.72 (m, 1H), 2.50-1.99 (m, 2H), 1.91-1.64 (m, 2H), 1.62-1.44 (m, 1H), 1.15 (dt, J=4.4, 6.8, 1H), 1.07-0.99 (m, 3H), 0.95-0.85 (m, 9H), 0.11 (d, J=1.6, 6H). MS (DCI+) M/Z 243.
Reaction SMILES: [H-].[Na+].[CH2:3]1[CH2:7]OC[CH2:4]1.[CH2:8]([OH:20])[CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][OH:19]>O>[CH2:7]([O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][OH:20])[CH:3]=[CH2:4]
Reactant: OCCOCCOCCOCCO
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: C=CCOCCOCCOCCOCCO
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 32 %

Procedure:
Under nitrogen atmosphere, NaH (1.2 g, 50 mmol) was charged into a flask, and then dry THF (15 mL) was added thereto and stirred at 0° C. for 15 minutes. Tetraethyleneglycol (10.7 g, 55 mmol) was added to the NaH mixture at 0° C. The mixture was stirred at room temperature for 1 hour. Next, the mixture was diluted with water (20 mL) and an organic material was extracted with methylene chloride (3×10 mL). The resulting organic layer was collected, dried on MgSO4 and concentrated to obtain a crude product as yellow liquid. The crude product was purified with a column chromatography (Hex:EA=1:2 (10% MeOH)) to obtain the target product (3.8 g, 32%) in a colorless oily phase. The NMR analysis result of the obtained product is as follows.
Reaction SMILES: [C:1]([C:4]([CH:17]1[CH2:21][CH2:20][NH:19][CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2].[CH2:22]1[O:32][C:31]2[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][C:24]=2[O:23]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:4]([CH:17]1[CH2:21][CH2:20][N:19]([CH2:27][C:26]2[CH:29]=[CH:30][C:31]3[O:32][CH2:22][O:23][C:24]=3[CH:25]=2)[CH2:18]1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2]
Reactant: ClCc1ccc2c(c1)OCO2
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCN(Cc2ccc3c(c2)OCO3)C1

Procedure:
A mixture containing 3-(R,S)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine (0.75 g--see Preparation 8), 3,4-methylenedioxybenzyl chloride (0.51 g--commercially available), anhydrous potassium carbonate (0.75 g) and acetonitrile (30 ml) was stirred at room temperature for 30 minutes. The mixture was partitioned between 10% aqueous potassium carbonate (20 ml) and dichloromethane (50 ml), the layers were separated and the aqueous layer extracted with dichloromethane (3×50 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a foam which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 10%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a foam, yield 0.5 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][N:12]([CH3:14])[N:13]=2)=[CH:5][C:4]=1[CH2:15]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:36]N1C(=O)CCC1=O>C(Cl)Cl>[Br:36][CH2:15][C:4]1[CH:5]=[C:6]([C:9]2[N:10]=[N:11][N:12]([CH3:14])[N:13]=2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(-c2nnn(C)n2)cc1CO
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(-c2nnn(C)n2)cc1CBr
Temperature: 0 °C
Reaction time: 16 h
Yield: 62.8 %

Procedure:
(2-Methoxy-5-(2-methyl-2H-tetrazol-5-yl)phenyl)methanol (100 mg, 0.45 mmol) and triphenylphosphine (238 mg, 0.9 mmol) were combined in methylene chloride (3 mL) and cooled to 0° C. N-Bromosuccinimide (170 mg, 0.95 mmol) was introduced in portions and the reaction allowed to warm to room temperature. After 16 h, the reaction mixture was diluted with methylene chloride and washed with concentrated sodium bicarbonate (2×), brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (30% ethyl acetate/hexanes) gave 80 mg (63%) of the desired material. LC/MS (HPLC method 3): tR=2.69 min, 285.02 (MH)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[O:13][N:12]=[C:11]([CH3:14])[CH:10]=1.[Na].[N+:16]([C:19]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=1[OH:27])([O-:18])=[O:17]>>[CH3:14][C:11]1[CH:10]=[C:9]([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:27][C:20]2[CH:21]=[CH:22][C:23]([O:25][CH3:26])=[CH:24][C:19]=2[N+:16]([O-:18])=[O:17])[O:13][N:12]=1
Reactant: Cc1cc(CCCCCCCBr)on1
Reactant: COc1ccc(O)c([N+](=O)[O-])c1
Agent: [Na]
Product: COc1ccc(OCCCCCCCc2cc(C)no2)c([N+](=O)[O-])c1

Procedure:
[I; R is CH3, n is 7, X is O, Ar is 2--O2N--4--CH3OC6H3 ] was prepared from 4.0 g of 5-(7-bromoheptyl)-3-methylisoxazole (Example 37a) and 2.94 g of the sodium salt of 2-nitro-4-methoxyphenol according to the procedure of Example 37, part (b), and was obtained in the form of a yellow solid (4.0 g), m.p. 51° C. when recrystallized from an ether-hexane mixture; MIC vs. rhinovirus Type 2 in vitro=0.3 μg/ml; and vs. polio-2 virus=0.17 μg/ml.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:14][CH2:15][CH3:16])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][CH3:13])=[CH:7][CH:6]=1)[CH3:2].C(N(CC)CC)C.[C:24](Cl)(=[O:33])[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl>[CH2:15]([O:14][CH:4]([O:3][CH2:1][CH3:2])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]([CH3:13])[C:24](=[O:33])[O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:7][CH:6]=1)[CH3:16]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(OCC)c1ccc(CNC)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(OCC)c1ccc(CN(C)C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
To a stirred solution of 1-(4-(diethoxymethyl)phenyl)-N-methylmethanamine (1.1 g, 4.9 mmol) and triethylamine (0.75 g, 7.35 mmol) in anhydrous dichloromethane (10 mL) was added benzyl carbonochloridate (1.0 g, 5.88 mmol) at 0° C. After the addition, the mixture was allowed to stir at room temperature overnight. The mixture was diluted with dichloromethane (50 mL), washed with water (50 mL×3), brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to give crude product which was purified by chromatography (silica gel, petroleum ether/ethyl acetate=100:1 to 20:1) to give benzyl 4-(diethoxymethyl)benzyl(methyl)carbamate (1.0 g, yield 57% for two steps) as a light yellow oil. 1H-NMR (400 MHz, CDCl3) δ: 3.82 (s, br 1H), 5.19 (s, 3H), 6.91-6.95 (m, 1H), 7.32-7.36 (m, 2H); LC-MS (ESI) m/z: 358 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:23])[CH:11]=2)[CH:6]=1.[C:25]1([S:31](Cl)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(C(C)C)CC)(C)C>C1COCC1>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][S:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:33])=[O:32])=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:23])[CH:11]=2)[CH:6]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(N)cc2)c1C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(NS(=O)(=O)c3ccccc3)cc2)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.2 %

Procedure:
To a solution of [4-(4-amino-phenyl)-6-fluoro-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (55 mg, 0.17 mmol) and benzenesulfonyl chloride (61 mg, 0.34 mmol) in THF (3 mL) was added diisopropylethylamine (62 mg, 0.49 mmol) at 0° C. under nitrogen. The reaction mixture was warmed to room temperature and stirred for 3 hours. The solvent was removed under vacuum and the residue was diluted with water (10 mL). The mixture was extracted with ethyl acetate (2×20 mL). The combined organic extracts were washed with brine solution (50 mL) and dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent under vacuum gave the crude residue which was purified using an ISCO (12 g) column, eluting with 2-25% ethyl acetate in hexanes, to afford [4-(4-benzenesulfonylamino-phenyl)-6-fluoro-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (38 mg, 48%) as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 7.84 (d, J=7.5 Hz, 2 H), 7.77 (dd, J=9.1, 6.0 Hz, 1 H), 7.70 (s, 1 H), 7.59 (t, J=7.5 Hz, 1 H), 7.49 (t, J=7.5 Hz, 2 H), 7.15-7.22 (m, 3 H), 7.10 (d, J=8.2 Hz, 2 H), 6.80 (s, 1 H), 6.71 (dd, J=11.3, 2.3 Hz, 1 H), 3.78-3.90 (m, 2 H), 3.73 (s, 3 H), 2.09 (s, 3 H). HRMS calcd. for C26H21FNO4S [(M−H)−] 462.1181, obsd. 462.1179.
Reaction SMILES: COC1[CH:4]=[C:5]([C:14](C)(C)C(O)=O)[CH:6]=CC=1NS(C)(=O)=O.[CH3:20][C:21]1[CH:22]=[C:23]([CH2:28][CH2:29][CH2:30][NH:31][C:32](=[O:49])[C:33]([C:36]2[CH:41]=[CH:40][C:39]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])=[C:38](OC)[CH:37]=2)([CH3:35])[CH3:34])C=CC=1C>>[C:5]([C:22]1[CH:21]=[CH:20][C:29]([CH2:30][NH:31][C:32](=[O:49])[C:33]([C:36]2[CH:41]=[CH:40][C:39]([NH:42][S:43]([CH3:46])(=[O:44])=[O:45])=[CH:38][CH:37]=2)([CH3:35])[CH3:34])=[CH:28][CH:23]=1)([CH3:14])([CH3:6])[CH3:4]
Reactant: COc1cc(C(C)(C)C(=O)NCCCc2ccc(C)c(C)c2)ccc1NS(C)(=O)=O
Reactant: COc1cc(C(C)(C)C(=O)O)ccc1NS(C)(=O)=O
Product: CC(C)(C)c1ccc(CNC(=O)C(C)(C)c2ccc(NS(C)(=O)=O)cc2)cc1

Procedure:
Through similar procedure to that in Example 1-5 excepting using 2-(3-methoxy-4-(methylsulfonylamino)phenyl)-2-methylpropionic acid (8-12), N-[3-(3,4-Dimethylphenyl)propyl]-2-[3-methoxy-4-(methylsulfonylamino)phenyl]-2-methylpropionamide (9-6, CHK-600) having following physicochemical properties was synthesized:
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[C:5]([CH3:7])[N:6]=1.C([N:23]=[C:24]=[S:25])(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O>[CH3:1][C:2]1[O:3][C:4]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:24]([NH2:23])=[S:25])=[CH:10][CH:9]=2)=[C:5]([CH3:7])[N:6]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Cc1nc(C)c(-c2ccc(N)cc2)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(C)c(-c2ccc(NC(N)=S)cc2)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.9 %

Procedure:
To a solution of 4-(2,4-dimethyl-oxazol-5-yl)-phenylamine (470 mg, 2.5 mmol, CAS 100060-02-41) in tetrahydrofurane (20 mL) was added benzoyl isothiocyanate (449 mg, 2.8 mmol). The reaction was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and the residue was suspended in methanol (30 mL). Potassium carbonate (1036 mg, 7.5 mmol) dissolved in water (15 mL) was added drop wise to the suspension. The reaction was stirred at room temperature over night. The resulting solution was evaporated and the residue was stirred with water. The precipitate was filtered off, washed twice with water and twice with diethyl ether. The residue was dissolved in tetrahydrofurane and the solvent was removed under reduced pressure to yield the title compound as an off-white solid (420 mg, 68%). MS ISP (m/e): 248.1 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=9.80 (s, 1H, NH), 7.55 (d, 2H), 7.50 (d, 2H), 2.41 (s, 3H), 2.29 (s, 3H).
Reaction SMILES: [C:1]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH:25]1[C:30]([N+:31]([O-:33])=[O:32])=[CH:29][CH:28]=[C:27](O)[CH:26]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C.CN(C)C=O>[N+:31]([C:30]1[CH:25]=[CH:26][C:27]([O:23][C:22](=[O:24])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:1]([O:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:2])=[CH:28][CH:29]=1)([O-:33])=[O:32]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=C(O)CCCCCCCCCCNC(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(CCCCCCCCCCNC(=O)OCc1ccccc1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 55.7 %

Procedure:
In a solvent mixture (120 ml) of ethyl acetate and N,N-dimethylformamide (5:1) was dissolved N-carbobenzoxy-11-aminoundecanoic acid (10.1 g, 30 m mols) and p-nitrophenol (4.59 g, 33 m mols), followed by addition of N,N'-dicyclohexylcarbodiimide (6.80 g, 33 m mols). The mixture was stirred at room temperature for 15 hours, after which the precipitate was filtered off. The solvent was distilled off and the residue was crystallized in petroleum ether, recovered by filtration and recrystallized from ethyl acetate-petroleum ether. By the above procedure there was obtained 7.65 g of N-carbobenzoxy-11-aminoundecanoic acid p-nitrophenyl ester. m.p. 72°-73° C.; Rf1 =0.94.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([O:10][CH2:11][O:12][CH3:13])[CH2:6][CH2:5]1.[C:14]1(=O)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH:14]1([NH:1][CH2:2][CH2:3][N:4]2[CH2:5][CH2:6][CH:7]([O:10][CH2:11][O:12][CH3:13])[CH2:8][CH2:9]2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COCOC1CCN(CCN)CC1
Reactant: O=C1CCCCCCC1
Product: COCOC1CCN(CCNC2CCCCCCC2)CC1
Yield: 90.9 %

Procedure:
Using 3 g of 1-(2-aminoethyl)-4-methoxymethoxy-piperidine and 2 g of cyclooctanone, 4.3 g of 1-(2-cyclooctylaminoethyl)-4-methoxymethoxypiperidine was obtained in the same manner as in Reference Example 1.
Reaction SMILES: [Cl:1][C:2]1[N:6]2[N:7]=[C:8]([CH:20]([CH3:22])[CH3:21])[C:9]([CH:18]=O)=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:5]2=[CH:4][CH:3]=1.[NH2:23][CH2:24][CH2:25][OH:26].C([BH3-])#N.[Na+]>C(O)C.C(O)(=O)C>[Cl:1][C:2]1[N:6]2[N:7]=[C:8]([CH:20]([CH3:21])[CH3:22])[C:9]([CH2:18][NH:23][CH2:24][CH2:25][OH:26])=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:5]2=[CH:4][CH:3]=1
Reactant: NCCO
Reactant: CC(C)c1nn2c(Cl)ccc2c(-c2ccc(F)cc2)c1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)c1nn2c(Cl)ccc2c(-c2ccc(F)cc2)c1CNCCO
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46 %

Procedure:
To a suspension of 7-chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazine-3-carbaldehyde (40 mg) in ethanol (1 mL) was added 2-aminoethanol (11.8 mg), sodium cyanoborohydride (12.1 mg), and acetic acid (1 drop) in an ice-water bath. After 10 minutes, the mixture was stirred at ambient temperature. After 2 hours, sodium cyanoborohydride (11.8 mg) was added and the reaction mixture was acidified to pH4 with acetic acid (5 drops). After stirring overnight, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated sodium bicarbonate, water, and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by p-TLC (chloroform-methanol=10-1) to give 2-({[7-chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]methyl}amino)ethanol as pale yellow oil (21 mg).