Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)C.[O:4]1[C:9]2[CH:10]=[CH:11][C:12]([CH2:14][NH:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]4[C:33]5[C:28](=[CH:29][CH:30]=[C:31]([O:34][CH3:35])[CH:32]=5)[C:27](/[CH:36]=[CH:37]/[C:38]([O:40]CC)=[O:39])=[CH:26][C:25]4=[O:43])[CH2:18][CH2:17]3)=[CH:13][C:8]=2[O:7][CH2:6][CH2:5]1.[OH-].[Na+]>O>[O:4]1[C:9]2[CH:10]=[CH:11][C:12]([CH2:14][NH:15][CH:16]3[CH2:17][CH2:18][N:19]([CH2:22][CH2:23][N:24]4[C:33]5[C:28](=[CH:29][CH:30]=[C:31]([O:34][CH3:35])[CH:32]=5)[C:27](/[CH:36]=[CH:37]/[C:38]([OH:40])=[O:39])=[CH:26][C:25]4=[O:43])[CH2:20][CH2:21]3)=[CH:13][C:8]=2[O:7][CH2:6][CH2:5]1
Reactant: CCOC(=O)/C=C/c1cc(=O)n(CCN2CCC(NCc3ccc4c(c3)OCCO4)CC2)c2cc(OC)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc2c(/C=C/C(=O)O)cc(=O)n(CCN3CCC(NCc4ccc5c(c4)OCCO5)CC3)c2c1
Reaction time: 1 h
Yield: 77.8 %

Procedure:
To 1 mL of an ethanol solution containing 65 mg of ethyl(2E)-3-(1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-2-oxo-1,2-dihydroquinolin-4-yl)acrylate, 0.2 mL of water and 0.11 mL of 5 mol/L aqueous sodium hydroxide solution were added and stirred for 1 hour. 2 mL of water was added, removed ethanol under reduced pressure, adjusted to pH 6.0 with 1 mol/L hydrochloric acid, and the resulting solid was filtered to afford 48 mg of (2E)-3-(1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-2-oxo-1,2-dihydroquinolin-4-yl)acrylic acid as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[N:15]([C:16]=1[C:17]1[CH:18]=[CH:19][C:20]3[N:21]([C:23]([C:26]([OH:29])([CH3:28])[CH3:27])=[N:24][N:25]=3)[N:22]=1)[CH:14]=[CH:13][O:12]2.[H-].[Na+].Br[CH2:33][CH2:34][O:35][CH3:36]>C1COCC1.CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[N:15]([C:16]=1[C:17]1[CH:18]=[CH:19][C:20]3[N:21]([C:23]([C:26]([O:29][CH2:33][CH2:34][O:35][CH3:36])([CH3:27])[CH3:28])=[N:24][N:25]=3)[N:22]=1)[CH:14]=[CH:13][O:12]2
Reactant: COCCBr
Reactant: CC(C)(O)c1nnc2ccc(-c3c(-c4ccc(F)cc4F)nc4occn34)nn12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COCCOC(C)(C)c1nnc2ccc(-c3c(-c4ccc(F)cc4F)nc4occn34)nn12
Temperature: 70 °C
Reaction time: 17 h
Yield: 10.5 %

Procedure:
In a 10 mL pear flask, 2-(6-(6-(2,4-difluorophenyl)imidazo[2,1-b]oxazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)propan-2-ol (0.100 g, 0.252 mmol, Example #37) and NaH (60% in mineral oil, 0.025 g, 0.631 mmol) in THF (5 mL) and DMF (1 mL) were added to give an off-white suspension. 1-Bromo-2-methoxyethane (0.140 g, 1.01 mmol) was then added and the suspension was stirred at about 70° C. for about 17 h. The mixture was concentrated under reduced pressure and was purified by flash chromatography on silica gel MeOH/DCM (gradient 1-5% over 14 min) and then further purified by RP-HPLC (Table 1, Method m) to afford the title compound (0.012 g, 11%) as a white fluffy solid: LC/MS (Table 1, Method g) Rt=2.02 min; MS m/z 455.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:20]([CH3:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=4[O:23][CH3:24])[C:12](=O)[CH2:13][N:7]3[C:6]=2[C:5]([CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:32])=O.N1C=CC=CC=1>>[Cl:32][C:12]1[N:11]([C:15]2[C:20]([CH3:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=2[O:23][CH3:24])[C:8]2[N:7]([CH:13]=1)[C:6]1[C:5]([CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:4][CH:3]=[C:2]([Cl:1])[C:10]=1[N:9]=2
Reactant: CCC(CC)c1ccc(Cl)c2nc3n(c12)CC(=O)N3c1c(C)cc(Cl)cc1OC
Reactant: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CCC(CC)c1ccc(Cl)c2nc3n(-c4c(C)cc(Cl)cc4OC)c(Cl)cn3c12
Temperature: 150 °C
Reaction time: 120 h

Procedure:
The mixture of 8-chloro-1-(4-chloro-2-methoxy-6-methylphenyl)-5-(1-ethylpropyl)-1H-imidazo[1,2-a]benzimidazol-2(3H)-one (31.8 mg, 0.0736 mmol) and phosphorus oxychloride (0.76 mL) and pyridine (11.9 μL, 0.147 mmol) was stirred at 150° C. for 5 days. After cooling, the mixture was concentrated in vacuo. The residue was neutralized with aqueous saturated sodium hydrogen carbonate and extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-15% ethyl acetate/n-hexane gradient mixture to give the title compound as an amorphous (8.7 mg, 0.0193 mmol, 26%).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][C:5]([C:17](O)=[O:18])([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1.S(Cl)(Cl)=O.[OH:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][C:5]([C:17]([N:28]4[CH2:29][CH2:30][CH:25]([OH:24])[CH2:26][CH2:27]4)=[O:18])([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1
Reactant: OC1CCNCC1
Reactant: O=C(O)C12CC(c3ccccc31)c1ccc(Cl)cc12
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(N1CCC(O)CC1)C12CC(c3ccccc31)c1ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.5 %

Procedure:
To a solution of 2-chloro-9,10-dihydro-9,10-methano-9-anthracenecarboxylic acid (described in example 1j) (6.51 g, 24.1 mmol) in toluene (70 mL) was added thionyl chloride (2.28 mL, 31.3 mmol, 1.3 eq). The reaction was heated to reflux monitoring gas evolution with a mineral oil bubbler. The system reached a steady state within 40 min at which time it was slightly cooled and 4-hydroxypiperidine (6.08 g, 60.3 mmol, 2.5 eq) was added portionwise. A significant amount of heat is evolved and the reaction becomes dark. The suspension was heated to reflux for 2 h, cooled to room temperature and stirred for 18 h. The reaction was diluted with ethyl acetate (200 mL) and washed with 3 N HCl (2×100 mL), 2.5 N NaOH (2×100 mL) and saturated brine (200 mL). The organic phase was dried over anhydrous magnesium sulfate, filtered, and reduced to an oil. The procedure yielded 6.95 g (82%) of the title compound as a viscous oil. No addition purification was required. 1H NMR (D6 -DMSO, 250 MHz) 7.63 (m, 1H), 7.21 (m, 6H), 4.41 (s, 1H), 4.18 (m, 1H), 3.65 (m, 2H), 3.25 (m, 2H), 2.76 (m, 2H), 1.90 (m, 2H), 1.38 (m, 2H) MS (CI, CH4) m/z 354 (M+1,100), 356 (36), 382 (M+29,19), 336 (27), 318 (9)
Reaction SMILES: [C:1]1([C:7]([C:9]2[NH:17][C:12]3=[CH:13][N:14]=[CH:15][CH:16]=[C:11]3[CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:18].[CH3:19][O:20][NH2:21]>>[ClH:18].[CH3:19][O:20][N:21]=[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:9]1[NH:17][C:12]2=[CH:13][N:14]=[CH:15][CH:16]=[C:11]2[CH:10]=1
Reactant: CON
Reactant: O=C(c1ccccc1)c1cc2ccncc2[nH]1
Agent: Cl
Product: CON=C(c1ccccc1)c1cc2ccncc2[nH]1

Procedure:
Phenyl (1H-pyrrolo[2,3-c]pyridin-2-yl)methanone O-methyloxime hydrochloride was prepared from phenyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (Example 35) and O-methylhydroxylamine hydrochloride following the procedure described for Example 104 (geometry of the oxime double bond undefined).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.Cl[C:32](Cl)([O:34]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:43][C:44]1[O:48][N:47]=[C:46]([CH3:49])[CH:45]=1>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:32]([NH:43][C:44]1[O:48][N:47]=[C:46]([CH3:49])[CH:45]=1)=[O:34]
Reactant: COc1cc2nccc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cc(N)on1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4cc(C)no4)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 38.5 %

Procedure:
2-Cloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (100 mg) was dissolved in chloroform (5 ml) and triethylamine (0.5 ml) to prepare a solution. A solution of triphosgene (100 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 15 min. Next, 5-amino-3-methylisoxazole (32 mg) was added thereto, and the mixture was further stirred at room temperature overnight. Distilled water was added to the reaction solution, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine and was dried over sodium sulfate. The organic layer was concentrated under the reduced pressure, and the residue was purified by HPLC using chloroform/acetone for development to give 53 mg of the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[Cl:11][C:12](Cl)([O:14]C(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1.O>C(Cl)Cl>[Cl:11][C:12]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:14]
Reactant: CCOC(=O)CCCCO
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)CCCCOC(=O)Cl
Temperature: 0 °C
Yield: 179.1 %

Procedure:
Ethyl 5-hydroxypentanoate (1.12 g, 7.66 mmol) was dissolved in 25 mL of methylene chloride, triphosgene (772 mg, 0.34 equivalent), and pyridine (0.743 mL, 1.2 equivalent) were sequentially added while stirred at 0° C., and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, water was added, and extraction operation (methylene chloride) was performed. The separated organic layer was washed using an aqueous saturated sodium chloride solution, and dried with magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the crude product. This was purified by column chromatography (ethyl acetate:n-hexane=1:10) to obtain the title compound (972 mg) having the following physical property values.
Reaction SMILES: C([O:3][C:4]1[N:9]=[CH:8][C:7]([C:10]2[CH:18]=[C:17]3[C:13]([CH:14]=[N:15][NH:16]3)=[C:12]([NH:19][C:20]([C:22]3[N:23]=[C:24]([CH3:27])[S:25][CH:26]=3)=[O:21])[CH:11]=2)=[CH:6][C:5]=1[NH:28][S:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:31])=[O:30])C.C(O)(=O)C.Cl>O>[OH:3][C:4]1[N:9]=[CH:8][C:7]([C:10]2[CH:18]=[C:17]3[C:13]([CH:14]=[N:15][NH:16]3)=[C:12]([NH:19][C:20]([C:22]3[N:23]=[C:24]([CH3:27])[S:25][CH:26]=3)=[O:21])[CH:11]=2)=[CH:6][C:5]=1[NH:28][S:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:30])=[O:31]
Reactant: CCOc1ncc(-c2cc(NC(=O)c3csc(C)n3)c3cn[nH]c3c2)cc1NS(=O)(=O)c1ccccc1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: Cc1nc(C(=O)Nc2cc(-c3cnc(O)c(NS(=O)(=O)c4ccccc4)c3)cc3[nH]ncc23)cs1
Temperature: 100 °C
Yield: 28.6 %

Procedure:
N-(6-{6-(Ethyloxy)-5-[(phenylsulfonyl)amino]-3-pyridinyl}-1H-indazol-4-yl)-2-methyl-1,3-thiazole-4-carboxamide (24 mg) was weighed to a microwave vial and acetic acid (0.25 ml) and concentrated HCl (0.25 ml) were added. The reaction was heated under microwave irradiation for 10 min at 100° C. The reaction was cooled to RT and then heated again under microwave irradiation for 10 min at 100° C. Water was added to the reaction and the resultant precipitate was collected by filtration. The precipitate was dissolved into MeOH:DCM then evaporated to dryness. The residue was then dissolved in DMSO:MeOH (0.8 ml, 1:1, v/v) and purified by MDAP (method F) to give the title compound (6.5 mg).
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:4])=[O:3].[NH2:18][C:19]1[N:24]=[C:23]([O:25][CH3:26])[N:22]=[C:21]([O:27][CH3:28])[N:20]=1.[O-:29][C:30]#[N:31].[Na+].N1C=CC=CC=1>ClCCl.C(#N)C>[CH3:26][O:25][C:23]1[N:22]=[C:21]([O:27][CH3:28])[N:20]=[C:19]([NH:18][C:30]([NH:31][S:2]([C:5]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:6]=2[C:7]([O:9][CH3:10])=[O:8])(=[O:4])=[O:3])=[O:29])[N:24]=1
Reactant: COC(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)Cl
Reactant: N#C[O-]
Reactant: COc1nc(N)nc(OC)n1
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CC#N
Solvent: ClCCl
Product: COC(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)NC(=O)Nc1nc(OC)nc(OC)n1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
At 55-60° C. and under argon, a solution of 5.0 g (17.9 mmol) of methyl 2-chlorosulfonyl-6-nitrobenzoate in 55 ml of dry dichloromethane is added dropwise over 2 h to a suspension of 2.79 g (17.9 mmol) of 2-amino-4,6-dimethoxy-1,3,5-triazine, 1.28 g (19.7 mmol) of sodium cyanate, 1.45 ml (17.9 mmol) of pyridine and 500 mg of freshly activated molecular sieve (pore size 3 Å) in 85 ml of dry acetonitrile. After 7 h of stirring at this temperature, the mixture is allowed to warm to room temperature. After a further 12 h, the reaction mixture is concentrated and the residue is suspended in 200 ml of water and adjusted to pH 10 using 2 N aqueous sodium hydroxide solution. The precipitated solid is filtered off with suction and the filtrate is extracted with ethyl acetate. The organic phase is separated off and the aqueous phase is adjusted to pH 1.5 using 3 N aqueous hydrochloric acid solution and stirred in an ice bath for 15 min. The precipitated solid is then filtered off with suction, washed first with water and then with methanol and dried under reduced pressure. This gives 2.88 g (36% of theory) of methyl 2-[([(4,6-dimethoxy-1,3,5-triazin-2-yl)amino]carbonylamino)sulfonyl]-6-nitrobenzoate of m.p. 185-195° C. (decomp.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].O[CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.O>[F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[O:10][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CSc1ccc(O)c(F)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CSc1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)c(F)c1
Yield: 64.9 %

Procedure:
A solution of 1.01 g 2-fluoro-4-methylsulfanyl phenol (compound in Production Example D088), 1.28 g t-butyl 4-hydroxy-1-piperidinecarboxylate, 2.5 g triphenylphosphine and 4.2 g diethyl azodicarboxylate (40% toluene solution) in anhydrous tetrahydrofuran (30 mL) was heated for 8 hours under reflux in a stream of nitrogen. Water was added thereto, the reaction mixture was extracted with ethyl acetate, and the extract was dried over sodium sulfate and purified by silica gel chromatography (hexane/ethyl acetate) to give 1.41 g t-butyl 4-(2-fluoro-4-methylsulfanylphenoxy)piperidine-1-carboxylate. 5 mL of 4 N hydrogen chloride in ethyl acetate was added to this product and left for 1 hour. The solvent was removed, and the precipitated crystals were washed with ethyl acetate-ether to give 780 mg of the title compound as colorless crystals.
Reaction SMILES: N1C2C(=CC=CN=2)C=C[CH:2]=1.[Cl:11][C:12]1[N:20]=[C:19]([Cl:21])[C:18]([F:22])=[CH:17][C:13]=1[C:14]([OH:16])=[O:15].C([N-]C(C)C)(C)C.[Li+]>C1COCC1>[Cl:11][C:12]1[N:20]=[C:19]([Cl:21])[C:18]([F:22])=[C:17]([CH3:2])[C:13]=1[C:14]([OH:16])=[O:15]
Reactant: O=C(O)c1cc(F)c(Cl)nc1Cl
Reactant: c1cnc2ncccc2c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(F)c(Cl)nc(Cl)c1C(=O)O

Procedure:
The introduction of the methyl group on the 1,8-naphthyridine substrate was accomplished by the formation of the di-anion of 2,6-dichloro-5-fluoronicotinic acid, preferably with lithium diisopropylamide in THF between -70° C. and -50° C. The di-anion was quenched with iodomethane and the target acid 2, 6-dichloro-5-fluoro-4-methylnicotinic acid is obtained after acidification. The remaining portion of the naphthyridine nucleus was elaborated using previously developed methodology.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([N:9]2[C:13]([CH3:14])=[C:12]([C:15]([OH:17])=O)[CH:11]=[N:10]2)[CH:6]=[CH:7][CH:8]=1.[NH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:29][CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[C:25]([CH:28]=1)[C:26]#[N:27].C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>O.CN(C)C=O>[C:26]([C:25]1[CH:28]=[C:21]([NH:20][C:15]([C:12]2[CH:11]=[N:10][N:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:19])[F:18])[CH:4]=3)[C:13]=2[CH3:14])=[O:17])[CH:22]=[CH:23][C:24]=1[O:29][CH2:30][C:31]([CH3:33])([CH3:32])[CH3:34])#[N:27]
Reactant: CC(C)(C)COc1ccc(N)cc1C#N
Reactant: Cc1c(C(=O)O)cnn1-c1cccc(C(F)(F)F)c1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1c(C(=O)Nc2ccc(OCC(C)(C)C)c(C#N)c2)cnn1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.4 %

Procedure:
1-(3-Trifluoromethylphenyl)-5-methylpyrazole-4-carboxylic acid (2 g), 5-amino-2-neopentyloxybenzonitrile (1.8 g), triethylamine (1.6 g) and diethyl cyanophosphate (1.4 g) were added to dimethylformamide (20 ml) and the mixture was stirred at room temperature for 1 h. The reaction mixture was added into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. n-Hexane was added to the residue to allow crystallization. The crystals were recrystallized from hydrous ethanol to give the title compound (1.4 g), melting point: 116–118° C.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)[C:7](O)=[O:8])(=[O:3])[CH3:2].CN(C=O)C.S(Cl)([Cl:30])=O>C1(C)C=CC=CC=1>[C:1]([S:4][CH2:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)[C:7]([Cl:30])=[O:8])(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)SCC(Cc1ccc(-c2ccccc2)cc1)C(=O)O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)SCC(Cc1ccc(-c2ccccc2)cc1)C(=O)Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 3-acetylthio-2-(4-phenylbenzyl)propionic acid (3.39 g, 10.8 mmole) in toluene (25 ml) add 1% DMF in toluene (2 drops) and thionyl chloride (1.2 ml, 1.65 g, 13.8 mmoles) and stir the resulting solution at room temperature for 18 hours. Concentrate the reaction mixture in vacuo, dissolve the residue in toluene (100 ml) and concentrate the solution in vacuo to give the title compound, a light brown oil (3.37 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[C:9](=[O:20])[N:10]([CH3:19])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([CH3:18])[CH:12]=3)[CH:7]=1.Cl[C:23]1[N:27]=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[S:25][N:24]=1.CC1C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[CH3:19][N:10]1[C:11]2[C:16](=[CH:15][N:14]=[C:13]([CH3:18])[CH:12]=2)[CH:17]=[C:8]([C:6]2[CH:7]=[C:2]([NH:1][C:23]3[N:27]=[C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[S:25][N:24]=3)[CH:3]=[CH:4][C:5]=2[CH3:21])[C:9]1=[O:20]
Reactant: Clc1nsc(-c2ccccc2)n1
Reactant: Cc1cc2c(cn1)cc(-c1cc(N)ccc1C)c(=O)n2C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Product: Cc1cc2c(cn1)cc(-c1cc(Nc3nsc(-c4ccccc4)n3)ccc1C)c(=O)n2C
Reaction time: 10 h

Procedure:
3-(5-Amino-2-methylphenyl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one 15 (30 mg, 0.107 mmol), 3-chloro-5-phenyl-1,2,4-thiadiazole (41 mg, 0.21 mmol) and TsOH (10 mg) were heated at 100° C. in dioxane (2 ml). After 10 h, the solution was cooled and filtered. The mixture was purified by preparative LC/MS to give 1,7-dimethyl-3-(2-methyl-5-(5-phenyl-1,2,4-thiadiazol-3-ylamino)phenyl)-1,6-naphthyridin-2(1H)-one (G1). MS m/z 440.5 (M+1).
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][C:5](=[NH:9])[O:6][CH2:7][CH3:8].N1C=CC=CC=1.Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18].CCOC(C)=O>C(Cl)Cl>[CH2:20]([O:19][C:17]([N:9]=[C:5]([O:6][CH2:7][CH3:8])[CH2:4][O:3][CH3:2])=[O:18])[CH3:21]
Reactant: CCOC(=N)COC
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)N=C(COC)OCC
Temperature: 0 °C
Reaction time: 12 h
Yield: 102.6 %

Procedure:
Ethyl 2-methoxyacetimidate hydrochloride (0.95 g, 6.18 mmol) was suspended in DCM (12.4 mL) and the mixture was cooled to 0° C. Pyridine (2.5 mL, 30.9 mmol) and ethyl chloroformate (1.2 mL, 12.4 mmol) were added sequentially and the solution was allowed to warm to RT and stirred for 12 h. EtOAc (100 mL) was added and solids were removed by filtration through a pad of diatomaceous earth. The filtrate was concentrated in vacuo to afford ethyl N-ethoxycarbonyl-2-methoxyacetimidate (1.2 g, 100%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 4.08-4.03 (m, 2H), 3.90 (q, J=7.0 Hz, 4H), 3.20 (s, 3H), 1.11 (t, J=6.9 Hz, 6H).
Reaction SMILES: Br[C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[C:6](C)[CH:7]=1.[ClH:10].ClCl.[C:13]([Cl:17])(Cl)([Cl:15])[Cl:14]>>[Cl:9][C:3]1[C:2]([Cl:10])=[CH:7][C:6]([C:13]([Cl:17])([Cl:15])[Cl:14])=[CH:5][N:4]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: Cl
Reactant: Cc1cnc(Cl)c(Br)c1
Agent: ClCl
Product: Clc1cc(C(Cl)(Cl)Cl)cnc1Cl

Procedure:
The product from (b) (64 g) in dry carbon tetrachloride (650 ml) was treated with dry hydrogen chloride. The precipitate was broken up and the suspension heated under reflux while dry chlorine was bubbled into the mixture, with illumination from an ultra-violet light source. After 41/2 hours, the mixture was cooled, filtered, and the filtrate evaporated to give the required 2,3-dichloro-5-trichloromethylpyridine. The mass spectrum was consistent with the structure assigned to this compound.
Reaction SMILES: [Cl-].O[NH3+].[C:4](=[O:7])([O-])[OH:5].[Na+].[CH2:9]([O:11][C:12]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[C:25]([C:30]#[N:31])=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:20][CH:19]=2)[C:15]2[S:32][C:33]([CH2:35][CH3:36])=[CH:34][C:14]=2[N:13]=1)[CH3:10].[N:37]12CCCN=C1CCCCC2>C(Cl)(Cl)Cl.C(Cl)Cl.CS(C)=O>[CH2:9]([O:11][C:12]1[N:16]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[NH:37][C:4](=[O:7])[O:5][N:31]=3)=[CH:22][CH:23]=2)[C:15]2[S:32][C:33]([CH2:35][CH3:36])=[CH:34][C:14]=2[N:13]=1)[CH3:10]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CCOc1nc2cc(CC)sc2n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [NH3+]O
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Product: CCOc1nc2cc(CC)sc2n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
A mixture of hydroxylammonium chloride (0.74 g), sodium hydrogencarbonate (1.07 g) and dimethyl sulfoxide (20 mL) was stirred at 40° C. for 30 min, 4′-[(2-ethoxy-5-ethyl-3H-thieno[2,3-d]imidazol-3-yl)methyl]biphenyl-2-carbonitrile (0.48 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with chloroform, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue obtained by silica gel column chromatography was dissolved in methylene chloride (20 mL), N,N′-carbonyldiimidazole (0.22 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.18 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with chloroform, washed successively with saturated aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as colorless crystals (0.33 g, 59%).
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[N+:17]([O-])([OH:19])=[O:18]>O>[N+:17]([C:8]1[C:7]2[C:6](=[O:16])[C:5]3[C:14](=[CH:1][CH:2]=[CH:3][CH:4]=3)[C:13](=[O:15])[C:12]=2[CH:11]=[CH:10][CH:9]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])O
Reactant: O=C1c2ccccc2C(=O)c2ccccc21
Solvent: O
Product: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Temperature: 35 °C
Reaction time: 0.23 h
Yield: 99.4 %

Procedure:
A mixture of 208 g of anthraquinone and 1,210 g of 99% strength nitric acid (molar ratio 1:19) is stirred for 14 minutes at 35°C and subsequently adjusted to an acid content of 78% with 319 ml of water. The product which precipitates is filtered off, washed until neutral and dried. The product is subjected to a fractional distillation at 5 mm Hg, and a head temperature of 262°C. 99.4% pure 1-nitroanthraquinone is obtained as the distillate, in 69% yield (176 g).