Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[C:13]1([CH3:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(OCC)C>[CH2:19]([O:1][N:2]1[C:7]([CH3:8])([CH3:9])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1ccccc1
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Solvent: CCOCC
Product: CC1(C)CC(O)CC(C)(C)N1OCc1ccccc1
Yield: 14.9 %

Procedure:
A mixture of 2.58 g (0.015 mol) of 1-oxyl-4-hydroxy-2,2,6,6-tetramethylpiperidine and 27.64 g (0.30 mol) of toluene under a nitrogen atmosphere is heated in a pressure vessel for 53 hours. The reaction mixture is diluted with diethyl ether and the resultant mixture is washed with 10 w/v % ascorbic acid (1×50 mL) and distilled water (2×50 mL). The organic phase is dried over anhydrous sodium sulfate and the volatiles are removed in vacuo. The residue is recrystallized from heptane to give 0.59 g (30% yield) of a white solid melting at 86-87° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[CH:7]2.S(OC)(O[CH3:21])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:21][O:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[CH:7]2
Reactant: COS(=O)(=O)OC
Reactant: CCOC(=O)c1ccc2cccc(O)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1ccc2cccc(OC)c2c1

Procedure:
A solution of 216 mg of ethyl 8-hydroxy-2-naphthylformate (from Preparation 9) in 15 ml of acetone containing six drops of dimethyl sulfate and 150 mg of potassium carbonate was stirred at 25° C. for twenty-four hours. The reaction solvent was removed and the product was dissolved in ethyl acetate, washed with 5% hydrochloric acid and with brine, dried and concentrated to give 200 mg of ethyl 8-methoxy-2-naphthylformate.
Reaction SMILES: [N+:1]([CH2:4][CH3:5])([O-:3])=[O:2].CO[CH:8]([O:14]C)[CH2:9][CH2:10][CH2:11][CH:12]=O>CCOC(C)=O.CCCCCC>[N+:1](/[C:4](/[CH3:5])=[CH:12]/[CH2:11][CH2:10][CH2:9][CH:8]=[O:14])([O-:3])=[O:2]
Reactant: COC(CCCC=O)OC
Reactant: CC[N+](=O)[O-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C/C(=C\CCCC=O)[N+](=O)[O-]
Yield: 62.8 %

Procedure:
Prepared according to the general procedure A from nitroethane 112b (80 mmol) and 5,5-dimethoxypentanal 131 (16 mmol) to provide the title compound as yellow oil (1.58 g, 63% yield) after silica gel chromatography (EtOAc/Hexane).
Reaction SMILES: [CH:1]1([N:4]2[C:9](=[O:10])[C:8]3[C:11](OS(C4C=CC(C)=CC=4)(=O)=O)=[CH:12][C:13](=[O:16])[N:14]([CH3:15])[C:7]=3[N:6]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[CH:29]=3)[C:5]2=[O:39])[CH2:3][CH2:2]1.[F:40][C:41]1[CH:47]=[C:46]([Br:48])[CH:45]=[CH:44][C:42]=1[NH2:43]>>[Br:48][C:46]1[CH:45]=[CH:44][C:42]([NH:43][C:11]2[C:8]3[C:9](=[O:10])[N:4]([CH:1]4[CH2:3][CH2:2]4)[C:5](=[O:39])[N:6]([C:28]4[CH:29]=[C:30]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[CH:31]=[CH:32][CH:33]=4)[C:7]=3[N:14]([CH3:15])[C:13](=[O:16])[CH:12]=2)=[C:41]([F:40])[CH:47]=1
Reactant: Nc1ccc(Br)cc1F
Reactant: Cc1ccc(S(=O)(=O)Oc2cc(=O)n(C)c3c2c(=O)n(C2CC2)c(=O)n3-c2cccc(NS(C)(=O)=O)c2)cc1
Product: Cn1c(=O)cc(Nc2ccc(Br)cc2F)c2c(=O)n(C3CC3)c(=O)n(-c3cccc(NS(C)(=O)=O)c3)c21
Temperature: 135 °C
Yield: 83.1 %

Procedure:
To toluene-4-sulfonic acid 3-cyclopropyl-1-(3-methanesulfonylaminophenyl)-8-methyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl ester 15 (3.5 g) obtained in Step 8 was added 2-fluoro-4-bromoaniline 16 (23 g), and the mixture was stirred under heating at 135° C. for 3 hrs. The reaction mixture was purified by column chromatography (chloroform:acetone=9:1) to give N-{3-[5-(4-bromo-2-fluoro-phenylamino)-3-cyclopropyl-8-methyl-2,4,7-trioxo-3,4,7,8-tetrahydro-2H-pyrido[2,3-d]pyrimidin-1-yl]phenyl}-methanesulfonamide 17 (3.0 g, 83%) as a white solid.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][Si:8]([CH3:13])([CH3:12])[CH2:9][CH2:10][OH:11].Cl[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][N:16]=1>CN(C=O)C>[N+:21]([C:18]1[CH:19]=[CH:20][C:15]([O:11][CH2:10][CH2:9][Si:8]([CH3:13])([CH3:12])[CH3:7])=[N:16][CH:17]=1)([O-:23])=[O:22]
Reactant: C[Si](C)(C)CCO
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOc1ccc([N+](=O)[O-])cn1
Temperature: 0 °C
Reaction time: 18 h
Yield: 82.8 %

Procedure:
Potassium t-butoxide (25.8 g) was added portionwise over 20 minutes to a solution of 2-(trimethylsilyl)ethanol (20.8 g) and 2-chloro-5-nitropyridine (27.8 g) in DMF (170 ml). The mixture was stirred for 18 hours and then poured into ice-water (900 ml). The mixture was extracted with ethyl acetate (3×300 ml) and the extracts were washed with water (200 ml), followed by saturated sodium chloride solution (200 ml) and dried (MgSO4). Volatile material was removed by evaporation to give 5-nitro-2-[2-(trimethylsilyl)ethoxy]pyridine (34.9 g) as an oil; NMR: 0.05(s,9H), 1.1-1.2(m,2H), 4.45-4.55(m,2H), 6.75(d,1H), 8.3(dd,1H), 9.05(d,1H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.O=S(Cl)[Cl:13]>>[Br:1][C:2]1[N:7]=[C:6]([C:8]([Cl:13])=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccc(Br)n1
Product: O=C(Cl)c1cccc(Br)n1
Temperature: 70 °C

Procedure:
A mixture of 6-bromo-2-pyridinecarboxylic acid (1 g, 5 mmol) in SOCl2 (10 ml, 140 mmol) was heated to 70° C. for 6 hours and concentrated to dryness to provide the title compound.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([C:9]([O:11][CH3:12])=[O:10])[CH2:4]1.CCN(CC)CC>CS(C)=O>[CH:2]([CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([C:9]([O:11][CH3:12])=[O:10])[CH2:4]1)=[O:1]
Reactant: COC(=O)C1CCCC(CO)C1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COC(=O)C1CCCC(C=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
To a cold (−78° C.) solution of 3-(methoxycarbonyl)cyclohexanecarboxylic acid (1.25 g, 6.71 mmol) in THF (20 mL) was added BH3.Me2S (0.7 mL, 7.38 mmol). The resulting mixture was stirred at −78° C. to room temperature overnight. The reaction mixture was quenched with a saturated aqueous NH4Cl solution and extracted with ethyl acetate. The organic phase was washed with brine, dried over Na2SO4, and evaporated. The residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=2/1) to give methyl 3-(hydroxymethyl)cyclo-hexanecarboxylate as a colorless oil (845 mg, yield; 73%). To a solution of methyl 3-(hydroxymethyl)cyclohexanecarboxylate (840 mg, 4.88 mmol) in Et3N (4.4 mL, 32 mmol) and DMSO (10 mL) was added sulfur trioxide-pyridine complex (2.56 g, 16.1 mmol). The mixture was stirred at room temperature for 1 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=2/1) to give methyl 3-formylcyclohexanecarboxylate as a pale yellow oil (795 mg, yield; 96%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]\[C:15]3[CH:16]=[C:17]([C:21]([OH:23])=O)[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[OH:25][CH2:26][CH:27]([NH2:29])[CH3:28]>>[OH:25][CH2:26][CH:27]([NH:29][C:21]([C:17]1[N:18]([CH3:20])[N:19]=[C:15](/[CH:14]=[CH:13]\[C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:9][O:10][C:11]=2[CH3:24])[CH:16]=1)=[O:23])[CH3:28]
Reactant: Cc1onc(-c2ccc(F)cc2)c1/C=C\c1cc(C(=O)O)n(C)n1
Reactant: CC(N)CO
Product: Cc1onc(-c2ccc(F)cc2)c1/C=C\c1cc(C(=O)NC(C)CO)n(C)n1
Yield: 3 %

Procedure:
As described for example 120 (step 4), 5-{(Z)-2-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-vinyl}-2-methyl-2H-pyrazole-3-carboxylic acid (0.3 mmol), was converted, using 2-hydroxy-1-methylethylamine instead of isopropylamine, to the title compound (2.9 mg, 3%) which was obtained as an off white solid. MS: m/e=385.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:13]=[C:12]([OH:14])[C:11]([OH:15])=[C:10]([N+:16]([O-:18])=[O:17])[C:4]=2[S:5][C:6]=1[C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[CH2:23](O)[CH3:24]>>[CH2:23]([O:8][C:7]([C:6]1[S:5][C:4]2[C:10]([N+:16]([O-:18])=[O:17])=[C:11]([OH:15])[C:12]([OH:14])=[CH:13][C:3]=2[C:2]=1[Cl:1])=[O:9])[CH3:24]
Reactant: CCO
Reactant: O=C(O)c1sc2c([N+](=O)[O-])c(O)c(O)cc2c1Cl
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1sc2c([N+](=O)[O-])c(O)c(O)cc2c1Cl

Procedure:
3-Chloro-5,6-dihydroxy-7-nitro-benzo[b]thiophene-2-carboxylic acid (70 mg) from Example 4, ethanol (2 ml) and thionyl chloride (0.16 ml) were refluxed for 4 hours. Ethanol was evaporated. The residue was heated with absolute ethanol and the hot mixture was filtered. The product was dried under vacuum.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].C(N(CC)CC)C.[CH:13]1[S:14][CH:15]=[C:16]2[C:22]=1[C:21](=[O:23])[NH:20][C:19]1[CH:24]=[CH:25][CH:26]=[CH:27][C:18]=1[NH:17]2>O1CCOCC1>[Cl:1][CH2:2][C:3]([N:17]1[C:18]2[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=2[NH:20][C:21](=[O:23])[C:22]2=[CH:13][S:14][CH:15]=[C:16]12)=[O:4]
Reactant: O=C1Nc2ccccc2Nc2cscc21
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C1Nc2ccccc2N(C(=O)CCl)c2cscc21
Reaction time: 3 h
Yield: 67.2 %

Procedure:
2.2 g of chloroacetyl chloride and 2 ml of triethylamine are simultaneously added dropwise to a boiling solution of 2.2 g of 9,10-dihydro-4H-thieno[3,4-b][1,5]benzodiazepin-10-one in 30 ml of absolute dioxane in the course of 40 minutes, and the mixture is stirred for a further 3 hours. It is then allowed to cool and is filtered; the filtrate is concentrated to dryness; the residue is chromatographed over a silica gel column by means of a mixture of petroleum ether/ethyl acetate (1:1), and the product is recrystallized from toluene to yield 2.0 g of 4-chloroacetyl-9,10-dihydro-4H-thieno[3,4-b][1,5]benzodiazepin-10-one (m. 220° C.).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]([CH3:22])[NH:17][C:18](=[O:21])[NH:19][N:20]=2)=[CH:11][CH:10]=1>C(O)=O>[CH:1]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]([CH3:22])[NH:17][C:18](=[O:21])[NH:19][N:20]=2)=[CH:13][CH:14]=1)=[O:3]
Reactant: CC(=O)OC(C)=O
Reactant: CC1NC(=O)NN=C1c1ccc(N)cc1
Solvent: O=CO
Product: CC1NC(=O)NN=C1c1ccc(NC=O)cc1
Temperature: 0 °C

Procedure:
With ice-cooling and stirring, acetic anhydride (1.4 ml) was added dropwise to formic acid (0.7 ml) and the mixture was stirred at 50° C. for 15 minutes. This solution was added to a solution of 6-(4-aminophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (2.28 g) in formic acid (6 ml) with ice-cooling and stirring, followed by further stirring with ice-cooling for 50 minutes. The reaction mixture was poured into ice water and the resulting precipitate was collected by filtration and washed with water. The solid was recrystallized from dimethyl sulfoxide to give 6-(4-formylaminophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (1.36 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([NH2:8])[CH:7]=1.[CH2:10]([N:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[CH3:19])[CH2:11][C:12]#[CH:13].C(N(CC)CC)C>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:13]#[C:12][CH2:11][CH2:10][N:14]2[CH2:18][CH2:17][CH2:16][C@H:15]2[CH3:19])=[C:6]([NH2:8])[CH:7]=1
Reactant: Nc1cc(Br)ccc1I
Reactant: C#CCCN1CCC[C@H]1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[C@@H]1CCCN1CCC#Cc1ccc(Br)cc1N
Temperature: 25 °C
Yield: 30 %

Procedure:
A solution of Example 168B (0.2 g, 0.67 mmol), 1-but-3-ynyl-(2R)-2-methyl-pyrrolidine (7.4 mL as a 0.1 M solution in acetonitrile, 0.74 mmol), and triethylamine (10 mL, 72.0 mmol) was degassed with nitrogen for 10 minutes while stirring at r.t. Next, Pd(PPh3)2Cl2 (0.010 g, 0.013 mmol) and CuI (0.003 g, 0.013 mmol) were added and the resulting mixture was degassed for an additional 10 minutes, sealed, and stirred at r.t. for 18 hours. Contents were then concentrated under reduced pressure and the residue was dissolved in 100 mL dichloromethane, washed twice with each: 50 mL sat. NaHCO3, 50 mL water, and 50 mL brine, dried with Na2SO4, and concentrated under reduced pressure. The crude material was purified by column chromatography (100% dichloromethane to 95:5 dichloromethane/methanol) to afford the product in 30% yield as a light yellow oil. 1H NMR (CD3OD, 300 MHz) δ 7.03 (d, J=9 Hz, 1H), 6.88 (d, J=3 Hz, 1H), 6.68 (dd, J=3, 9 Hz, 1H), 3.41-3.20 (m, 2H), 2.79-2.52 (m, 5H), 2.12-2.04 (m, 1H), 1.92-1.82 (m, 2H), 1.56-1.47 (m, 1H), 1.25 (d, J=6 Hz, 3H). MS (ESI) [M+H]+ at 308.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][N:14]=[C:13]3[CH:19]=O)[CH2:3][CH2:2]1.[CH3:21][O:22][C:23]1[CH:32]=[CH:31][C:26]2[C:27](=[O:30])[CH2:28][O:29][C:25]=2[C:24]=1[CH2:33][N:34]1[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]1.N1CCCCC1>CO>[CH3:21][O:22][C:23]1[CH:32]=[CH:31][C:26]2[C:27](=[O:30])/[C:28](=[CH:19]/[C:13]3[C:12]4[C:16](=[CH:17][CH:18]=[C:10]([O:9][CH2:8][CH2:7][N:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)[CH:11]=4)[NH:15][N:14]=3)/[O:29][C:25]=2[C:24]=1[CH2:33][N:34]1[CH2:35][CH2:36][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:38][CH2:39]1
Reactant: COc1ccc2c(c1CN1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Reactant: O=Cc1n[nH]c2ccc(OCCN3CCOCC3)cc12
Solvent: C1CCNCC1
Solvent: CO
Product: COc1ccc2c(c1CN1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccc(OCCN4CCOCC4)cc13)C2=O
Temperature: 60 °C
Reaction time: 3 h
Yield: 99.2 %

Procedure:
A solution of 5-(2-morpholinoethoxy)-1H-indazole-3-carboxaldehyde (0.0163 g, 0.0592 mmol) in methanol (0.5 mL) was added with tert-butyl 4-[(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.0172 g, 0.0493 mmol) and piperidine (0.00335 g, 0.0394 mmol), and the mixture was stirred at 60° C. for 3 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl (Z)-4-[(6-methoxy-2-{[5-(2-morpholinoethoxy)-1H-indazol-3-yl]methylene}-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.0303 g, 99%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([F:10])=[C:4]([NH:11][C:12]([CH3:15])([CH3:14])[CH3:13])[N:3]=1.C([O:18][CH:19]=[C:20]([C:26](=[O:37])[C:27]1[CH:32]=[C:31]([F:33])[C:30]([F:34])=[C:29]([Cl:35])[C:28]=1F)[C:21]([O:23][CH2:24][CH3:25])=[O:22])C>C(O)C>[C:12]([NH:11][C:4]1[N:3]=[C:2]([N:1]2[C:28]3[C:27](=[CH:32][C:31]([F:33])=[C:30]([F:34])[C:29]=3[Cl:35])[C:26](=[O:37])[CH:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:19]2=[O:18])[C:7]([C:8]#[N:9])=[CH:6][C:5]=1[F:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(Cl)c1F
Reactant: CC(C)(C)Nc1nc(N)c(C#N)cc1F
Solvent: CCO
Product: CCOC(=O)C1C(=O)c2cc(F)c(F)c(Cl)c2N(c2nc(NC(C)(C)C)c(F)cc2C#N)C1=O
Reaction time: 8 h
Yield: 45.4 %

Procedure:
A solution of 300 mg of unpurified 2-amino-6-t-butylamino-3-cyano-5-fluoropyridine in 2 ml ethanol was added dropwise to a solution of 420 mg of ethyl 3-ethoxy-2-(3-chloro-2,4,5-trifluorobenzoyl)acrylate in 2 ml ethanol at room temperature, and the mixture was stirred overnight. The solvent was distilled off the reaction solution, and to the residue were added 3 ml of N,N-dimethylformamide and 210 mg of potassium carbonate, and the mixture was stirred at room temperature for 90 minutes and 80° C. for 2 hours. The reaction solution was extracted by adding water and ethyl acetate, and the organic layer was collected and dried over magnesium sulfate. The solvent was distilled off, and the residue was collected by filtration using ethanol and washed with diethylether to obtain 280 mg of the title compound as a pale yellow powder.
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([C:14]2[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[C:16]([F:23])[C:15]=2[F:24])(=[O:13])=[O:12])=[CH:6][CH:5]=1)[CH3:3].[CH3:25][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI>C1COCC1>[CH3:3][N:2]([C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH3:25])[S:11]([C:14]2[C:15]([F:24])=[C:16]([F:23])[C:17]([F:22])=[C:18]([F:21])[C:19]=2[F:20])(=[O:13])=[O:12])=[CH:6][CH:5]=1)[CH3:1]
Reactant: CN(C)c1ccc(NS(=O)(=O)c2c(F)c(F)c(F)c(F)c2F)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CN(C)c1ccc(N(C)S(=O)(=O)c2c(F)c(F)c(F)c(F)c2F)cc1
Reaction time: 0.17 h
Yield: 60 %

Procedure:
4-(N,N-Dimethylamino)-1-(pentafluorophenylsulfonamido)benzene (100 mg, 0.273 mmol) was dissolved in dry THF (2.5 mL) and to the system was added under N2 at room temperature a 1M solution of lithium bis(trimethylsilyl)amide (0.274 mL). The reaction mixture was stirred for 10 min followed by addition of MeI (65 mg, 0.028 mL). The reaction mixture was stirred overnight, the solvent was evaporated under reduced pressure and the crude product purified by HPLC using silica as the stationary phase and eluting with 20%EtOAc/Hex (v/v) to afford the product as a white solid in 60% yield (62 mg). EI m/z: 380(35, M+), 149(100). 1H NMR (CD3OD) 7.05(d, J=8 Hz, 2H), 6.68(d, J=8 Hz, 2H), 3.33(s, 3H) 2.93(s, 6H). Anal. calcd. for C15H13F5SO2N2: C, 47.37, H, 3.45, N, 7.37. Found: C, 47.37, H, 3.49, N, 7.32.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([NH:12][C:13]2[N:18]=[C:17]([C:19]3[C:20]([C:28]4[CH:29]=[C:30]([NH:34]C(=O)C(F)(F)F)[CH:31]=[CH:32][CH:33]=4)=[N:21][N:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=34)[CH:16]=[CH:15][N:14]=2)[CH:9]=[CH:10][CH:11]=1.[Cl-].[NH:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1>>[NH2:34][C:30]1[CH:29]=[C:28]([C:20]2[C:19]([C:17]3[CH:16]=[CH:15][N:14]=[C:13]([NH:12][C:8]4[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:42]5[CH2:47][CH2:46][O:45][CH2:44][CH2:43]5)[CH:7]=4)[N:18]=3)=[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][N:22]3[N:21]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: C1COCCN1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(OCCCCl)c3)n2)c1)C(F)(F)F
Agent: [Cl-]
Product: Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(OCCCN4CCOCC4)c3)n2)c1
Yield: 71 %

Procedure:
The compound was synthesized from N-(3-{3-[2-({3-[(3-chloropropyl)oxy]-phenyl}amino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenyl)-2,2,2-trifluoroacetamide via chloride displacement with morpholine as described in Example 10, Step D to afford an orange solid in 71% yield. ES-LC/MS m/z 522 [M+H]+.
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[S:10])[CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[NH:6]1)[CH2:2][CH2:3][CH3:4].[C:15](=O)([O-])[O-].[K+].[K+].CI>C(#N)C>[CH2:1]([N:5]1[C:9]([S:10][CH3:15])=[CH:8][C:7]([C:11]([F:13])([F:12])[F:14])=[N:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1[nH]c(C(F)(F)F)cc1=S
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: CCCCn1nc(C(F)(F)F)cc1SC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 123.6 %

Procedure:
3.35 g of compound (8-6) and 4.07 g of potassium carbonate were suspended in 100 ml of acetonitrile. The suspension was stirred at room temperature for 15 minutes. A solution of 3.35 g of methyl iodide in 10 ml of acetonitrile was added dropwise. The mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure. After water was added to the residue, the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to produce 4.40 g of 1-butyl-5-methylthio-3-(trifluoromethyl)pyrazole (15).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][N:15]=3)[CH:10]=[C:9]([C:17](O)=[O:18])[C:8]2=[O:20])[CH:3]=1.C(Cl)(=O)C([Cl:24])=O.CN(C)C=O>ClCCl>[CH3:1][C:2]1[O:6][N:5]=[C:4]([N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][N:15]=3)[CH:10]=[C:9]([C:17]([Cl:24])=[O:18])[C:8]2=[O:20])[CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cc(-n2c(=O)c(C(=O)O)cc3cccnc32)no1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(-n2c(=O)c(C(=O)Cl)cc3cccnc32)no1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.7 g (6.3 mmol) of 1-(5-methyl-3-isoxazolyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylic acid was dissolved in dichloromethane (50 mL), and 3.0 mL (36 mmol) of oxalyl chloride was added thereto. One droplet of N,N-dimethylformamide was added to the above mixture, and the resulting mixture was stirred for one hour at room temperature. The reaction solution was concentrated under reduced pressure, and thus 1-(5-methyl-3-isoxazolyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylic acid chloride was obtained. The acid chloride thus obtained was dissolved in dichloromethane (50 mL), and 0.77 g (6.9 mmol) of 1,3-cyclohexanedione and 1.1 mL (7.5 mmol) of triethylamine were added to the above solution under ice cooling. The mixture was stirred for 30 minutes under ice cooling. 0.97 mL (6.9 mmol) of triethylamine and 0.59 g (6.9 mmol) of acetone cyanohydrin were added to the above mixture, and the resulting mixture was stirred for one hour at 40° C. The reaction mixture was poured into an aqueous solution of citric acid, and the mixture was extracted with dichloromethane. The organic phase was washed with water, dried, and concentrated. The residue was purified by column chromatography (ethyl acetate:n-hexane=1:1 to 9:1), and thus 0.27 g (yield: 12%) of the title compound was obtained as yellow crystals.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:6][CH:5]=1.[CH:23]#[C:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>CCCCCCC>[C:23]([C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:9][CH:8]=1)#[C:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: C#CCCCCC
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(OC(F)(F)F)cc2)cc1
Solvent: CCCCCCC
Product: CCCCCC#Cc1ccc(OC(F)(F)F)cc1

Procedure:
This product was prepared from toluene-4-sulfonic acid 4-trifluoromethoxy-phenyl ester and 1-heptyne following the general procedure for the Sonogashira cross-coupling process described above. Chromatography eluent: heptane; yield (100 mg, 78%); 1H NMR δ (CDCl3): 7.41 (d, J=8.55 Hz, 2H), 7.21 (d, J=8.56 Hz, 2H), 2.43 (t, J=7.21 Hz, 2H), 1.62 (p, J=7.16 Hz, 2H), 1.48-1.3 (m, 4H), 0.93 (t, J=7.22 Hz, 3H); LCMS m/z: 256.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[N:21]=[CH:22][N:23]([CH2:25][CH:26]=[CH2:27])[CH:24]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CON(C)[C:36](=[O:38])[CH3:37].[Cl-].[NH4+]>C1COCC1>[Si:1]([O:18][CH2:19][C:20]1[N:21]=[C:22]([C:36](=[O:38])[CH3:37])[N:23]([CH2:25][CH:26]=[CH2:27])[CH:24]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCn1cnc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Reactant: CON(C)C(C)=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCn1cc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)nc1C(C)=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
The compound (1.26 g) obtained in (1) was dissolved in THF (50 mL), and cooled to −78° C. while stirring under nitrogen stream. To the present solution was added dropwise n-butyl lithium (2.76 M hexane solution, 1.82 mL), followed by stirring at the same temperature for 30 minutes. Then, N-methoxy-N-methylacetamide (1.05 mL) was added, and stirring was continued for 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction solution to terminate the reaction, followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and subsequently the solvent was distilled off under reduced pressure. The resulting residue was purified by flash chromatography (ethyl acetate/hexane=5%→70%) using silica gel column (product name: Hi-Flash Column 3 L, manufactured by Yamazen Corporation) to afford the title compound (0.75 g).