Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10](Cl)[N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:21]=[C:22]([O:26][CH3:27])[C:23]=1[O:24][CH3:25])[NH2:20].Cl>CC(C)=O.O>[C:1]1([NH:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:20][C:19]3[CH:21]=[C:22]([O:26][CH3:27])[C:23]([O:24][CH3:25])=[C:17]([O:16][CH3:15])[CH:18]=3)[N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: Clc1nccc(Nc2ccccc2)n1
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: COc1cc(Nc2nccc(Nc3ccccc3)n2)cc(OC)c1OC
Yield: 76.8 %

Procedure:
A solution of N-phenyl-2-chloro-4-pyrimidineamine (1.83 g, 8.91 mmol) and 3,4,5-trimethoxyaniline (1.83 g, 10.0 mmol) in acetone (10 ml) and water (15 ml) containing concentrated hydrochloric acid (0.2 ml) was heated at reflux for 10 h. On cooling the acetone was removed under reduced pressure, and the reaction taken to pH10 with 4N NaOH and extracted with ethyl acetate (2×75 ml). The combined organic layers were dried (MgSO4), concentrated under reduced pressure and the residue crystallised from ethyl acetate to give the title compound (2.41 g) as a colourless solid m.p. 191°. δH (CDCl3) 8.04 (1H, d, J 5.8 Hz), 7.37-7.34 (4H, m), 7.16-7.10 (1H, m), 7.05 (1H, br s), 6.85 (2H, s), 6.68 (1H, br s), 6.16 (1H, d, J 5.8 Hz), 3.82 (3H, s) and 3.81 (6H, s). MS m/z 353 (M+H)+. The pyrimidineamine used as starting material was prepared by heating a solution of 2,4-dichloropyrimidine (4.0 g, 26.8 mmol), aniline (2.46 ml, 27.0 mmol) and triethylamine (4.3ml, 30.0 mmol) in ethanol (50 ml) at reflux for 2 h. On cooling a white precipitate was collectd which was washed with cold ethanol (100 ml) and recrystallised from ethyl acetate to give the desired product (6.01 g) as a colourless solid m.p. 186°. MS/mz 206 (M+H)+.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=2[OH:17])[C:12]#[N:13])[C:4]1=[O:18].[Cl:19][C:20]1[C:28]2[CH:27]=[C:26]([S:29](Cl)(=[O:31])=[O:30])[S:25][C:24]=2[CH:23]=[C:22]([Cl:33])[CH:21]=1>N1C=CC=CC=1>[OH:17][C:16]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][C:9]=1[CH2:8][N:5]1[CH2:6][CH2:7][CH:3]([NH:2][S:29]([C:26]2[S:25][C:24]3[CH:23]=[C:22]([Cl:33])[CH:21]=[C:20]([Cl:19])[C:28]=3[CH:27]=2)(=[O:31])=[O:30])[C:4]1=[O:18]
Reactant: O=S(=O)(Cl)c1cc2c(Cl)cc(Cl)cc2s1
Reactant: N#Cc1ccc(O)c(CN2CCC(N)C2=O)c1
Agent: Cl
Solvent: c1ccncc1
Product: N#Cc1ccc(O)c(CN2CCC(NS(=O)(=O)c3cc4c(Cl)cc(Cl)cc4s3)C2=O)c1
Reaction time: 6 h

Procedure:
To a solution of 3-[(3-amino-2-oxo-pyrrolidin-1-yl)-methyl]-4-hydroxy-benzonitrile hydrochloride (0.20 g, 0.75 mmol) in 3 mL of pyridine at 0° C. is added 4,6-dichlorobenzo[b]thiophene-2-sulfonyl chloride. The solution is allowed to warm to ambient temperatures and is stirred for 6 hours. After this time, the solution is concentrated. The residue is dissolved in CH2Cl2. The organic solution is washed with 1 N HCl and saturated NaCl. The crude product is triturated with Et2O to give the title compound (0.22 g, 0.44 mmol) as a white solid.
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[F:18][C:19]([F:30])([F:29])[O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:3][CH:4]([C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:24][C:23]2[CH:26]=[CH:27][CH:28]=[C:21]([O:20][C:19]([F:18])([F:29])[F:30])[CH:22]=2)=[CH:15][CH:16]=1)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: OCc1cccc(OC(F)(F)F)c1
Reactant: CCOC(=O)CC(OCC)c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)CC(OCC)c1ccc(OCc2cccc(OC(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Ethyl 3-ethoxy-3-(4-hydroxyphenyl)propionate (100 mg, 0.420 mmol) produced in Example 1 (1C) and 3-trifluoromethoxybenzyl alcohol (123 mg, 0.640 mmol) were dissolved in tetrahydrofuran (2 mL), and triphenylphosphine (165 mg, 0.629 mmol) and a diethyl azodicarboxylate toluene solution (2.2 M, 290 μL, 0.638 mmol) were added thereto at room temperature, and then, the resulting mixture was stirred under a nitrogen atmosphere at room temperature for 4 hours. The solvent in the reaction solution was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 95:5 (v/v)), whereby the objective title compound was obtained as a colorless oily substance (124 mg, 72%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[CH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19](B4OC(C)(C)C(C)(C)O4)[CH:18]=3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:32]=1.CC(O)=[O:35].O.OO>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[CH:16][C:17]3[CH:18]=[C:19]([OH:35])[CH:20]=[CH:21][CH:22]=3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:32]=1
Reactant: CC1(C)OB(c2cccc(C=C3c4ccc(Cl)cc4CCc4cccnc43)c2)OC1(C)C
Reactant: CC(=O)O
Agent: OO
Solvent: O
Solvent: C1CCOC1
Product: Oc1cccc(C=C2c3ccc(Cl)cc3CCc3cccnc32)c1

Procedure:
Mix 8-chloro-11-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzylidene]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (300 mg, 0.68 mmol), HOAc (1 mL), water (1 mL), THF (5 mL) and 30% H2O2 (mL). Stir the reaction at RT for 4 h. Quench with aqueous Na2S2O3 and extract the product into EtOAc. Dry (MgSO4) and concentrate to give 250 mg crude product. Purify by column chromatography (15% ethyl acetate/hexane) to give 66 mg 3-(8-chloro-5,6-dihydro-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidenemethyl)-phenol, Z-isomer as a white solid, mp 221.2° C. MS (ES) 334 (M+1), 332 (M−1). HPLC shows 99% purity.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([N:10]([O:12][CH3:13])[CH3:11])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].[CH3:16]I.O>CN(C)C=O>[CH3:13][O:12][N:10]([CH3:11])[C:8]([C@H:5]1[CH2:6][CH2:7][C@H:2]([O:1][CH3:16])[CH2:3][CH2:4]1)=[O:9]
Reactant: CI
Reactant: CON(C)C(=O)[C@H]1CC[C@H](O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CON(C)C(=O)[C@H]1CC[C@H](OC)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
trans-4-Hydroxy-N-methoxy-N-methylcyclohexanecarboxamide (536 mg, 2.86 mmol) in N,N-dimethylformamide (5 mL) was mixed with sodium hydride (55 wt % dispersion in mineral oil, 150 mg, 3.44 mmol) and methyl iodide (214 μL, 3.44 mmol) under cooling with ice and stirred for 3 hours while the temperature was gradually raised to room temperature. After addition of water, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/2→1/1 (v/v)) to give the title compound as a colorless oil (556 mg, yield 97%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:10])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH3:11][N:12]([CH:14](N(C)C)OC(C)(C)C)[CH3:13]>CN(C)C=O>[CH3:11][N:12]([CH3:14])[CH:13]=[CH:1][C:2]1[NH:3][C:4](=[O:10])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: Cc1[nH]c(=O)ccc1C#N
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: CN(C)C=O
Product: CN(C)C=Cc1[nH]c(=O)ccc1C#N
Temperature: 110 °C
Reaction time: 3 h

Procedure:
To a stirred mixture containing 6.7 g of 1,6-dihydro-2-methyl-6-oxo-3-pyridinecarbonitrile in 100 ml of dimethylformamide was quickly added 11.5 ml of bis(dimethylamino)-t-butoxymethane and the reaction mixture was heated with stirring for 3 hours at 110° C. After a tlc analysis had shown some of the starting material still present, another 2.3 ml of bis(dimethylamino)-t-butoxymethane was added, the reaction mixture was heated with stirring to reflux for 90 minutes, and then allowed to cool to room temperature and stand overnight. The mixture was chilled and the separated product was collected, washed with chilled ethanol and dried in a vacuum oven at 90° C. to yield 8.2 g of 2-[2-(dimethylamino)ethenyl]-1,6-dihydro-6-oxo-3-pyridinecarbonitrile, m.p. 298°-300° C.
Reaction SMILES: [CH2:1]([S:8][CH2:9][C@H:10]([C:12]1[C:13]([CH3:24])=[N:14][O:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH2:32][CH2:31]1)=[O:29])[CH3:26]>>[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36]([C:20]3[CH:21]=[CH:22][C:17]([C:16]4[O:15][N:14]=[C:13]([CH3:24])[C:12]=4[C@H:10]([OH:11])[CH2:9][S:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:18][CH:19]=3)=[CH:35][CH:34]=2)[CH2:31][CH2:32]1)=[O:29])[CH3:26]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1[C@H](O)CSCc1ccccc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4[C@H](O)CSCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 2, using (S)-2-benzylsulfanyl-1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-ethanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([I:12])[CH:6]=1)=O.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][N:15]=1>C(#N)C>[OH:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:13]=[C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][N:15]3[CH:2]=2)=[CH:6][C:7]=1[I:12]
Reactant: COc1ccc(N)nc1
Reactant: O=C(CBr)c1ccc(O)c(I)c1
Solvent: CC#N
Product: COc1ccc2nc(-c3ccc(O)c(I)c3)cn2c1
Temperature: 110 °C
Yield: 51.9 %

Procedure:
1.46 g (corresponding to 4.28 mmol) of 2-bromo-4′-hydroxy-3′-iodoacetophenone and 584 mg (corresponding to 4.71 mmol) of 2-amino-5-methoxypyridine were dissolved in 30 mL of acetonitrile. The resulting solution was heated under reflux in an oil bath at 110° C. for 2.5 hours. After the completion of the reaction, the reaction solution was cooled down to room temperature, and precipitates were filtered and recovered. The precipitates were washed with acetonitrile and dried under reduced pressure. The resulting crude crystals were suspended in a mixed solution of 3.0 mL of water and 1.0 mL of methanol. Then, about 10 mL of a saturated sodium hydrogencarbonate solution was added thereto, and the mixture was sonicated for 5 minutes using an ultrasonic washing machine. Precipitates were filtered and recovered from the resulting mixture, sufficiently washed with water, and dried under reduced pressure, to obtain 812 mg (corresponding to 2.22 mmol) of 2-(4′-hydroxy-3′-iodophenyl)-6-methoxyimidazo[1,2-a]pyridine (FIG. 5, Step 1).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:23]=[C:22]([O:24][CH2:25][CH3:26])[N:21]=[C:20]([C:27]([OH:29])=O)[CH:19]=2)[CH2:14][CH2:13]1)=[O:10].Cl.[O:31]([NH2:33])[CH3:32]>>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:23]=[C:22]([O:24][CH2:25][CH3:26])[N:21]=[C:20]([C:27]([NH:33][O:31][CH3:32])=[O:29])[CH:19]=2)[CH2:14][CH2:13]1)=[O:10]
Reactant: CON
Reactant: CCOc1nc(C(=O)O)cc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)n1
Agent: Cl
Product: CCOc1nc(C(=O)NOC)cc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)n1

Procedure:
The title compound was synthesised by an analogous method to Example 8 starting from 6-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-2-ethoxypyrimidine-4-carboxylic acid (Example 312) and methoxylamine hydrochloride.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:17]1([CH2:22][CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=O)[NH:30][C:29]=2[CH3:36])=[O:27])[CH:21]=[CH:20][N:19]=[CH:18]1>>[N:17]1([CH2:22][CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=[C:11]3[C:10]4[C:14](=[CH:15][C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)=[CH:8][CH:9]=4)[NH:13][C:12]3=[O:16])[NH:30][C:29]=2[CH3:36])=[O:27])[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCCn1ccnc1
Reactant: O=C1Cc2ccc(-c3ccccc3)cc2N1
Product: Cc1[nH]c(C=C2C(=O)Nc3cc(-c4ccccc4)ccc32)c(C)c1C(=O)NCCCn1ccnc1
Yield: 43 %

Procedure:
6-Phenyl-1,3-dihydroindol-2-one (8 mg, 0.04 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (3-imidazol-1-ylpropyl)amide (10 mg) to give 7.3 mg (43%) of the title compound as an orange solid.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][C:7]1[C:8]([N+:18]([O-:20])=[O:19])=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[N+:12]([O-])[CH:11]=[CH:10]2>ClCCCl>[Cl:3][C:13]1[C:14]2[C:9](=[C:8]([N+:18]([O-:20])=[O:19])[C:7]([CH3:6])=[CH:16][CH:15]=2)[CH:10]=[CH:11][N:12]=1
Reactant: Cc1ccc2c[n+]([O-])ccc2c1[N+](=O)[O-]
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: Cc1ccc2c(Cl)nccc2c1[N+](=O)[O-]
Temperature: 70 °C
Yield: 85.9 %

Procedure:
Phosphorous oxychloride (2.15 mL, 23.0 mmol) was added dropwise to a solution of 6-methyl-5-nitroisoquinoline N-oxide (0.940 g, 4.60 mmol) in 1,2-dichloroethane (40.0 mL). The mixture was heated to 70° C. for 3 h to afford an off-white suspension. The mixture was concentrated and the residue was partitioned between dichloromethane and water. The aqueous phase was separated and extracted with dichloromethane. The combined organic phases were washed with saturated aqueous sodium bicarbonate solution, brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford 1-chloro-6-methyl-5-nitroisoquinoline (0.880 g, 86% yield) as an off-white solid. MS (ESI, pos. ion) m/z: 223.0 [M+H]+
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:7][C:6]=1[OH:32])(=O)C.[ClH:33]>C(O)C>[ClH:33].[NH2:4][C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:7][C:6]=1[OH:32]
Reactant: CCCCCCCCCCCCCCCCOc1cc(O)c(NC(C)=O)cc1C(C)(C)C
Agent: Cl
Solvent: CCO
Product: CCCCCCCCCCCCCCCCOc1cc(O)c(N)cc1C(C)(C)C
Reaction time: 5 h

Procedure:
A mixture of 23.0 g of 2-acetylamino-4-tert-butyl-5-hexadecyloxyphenol, 120 ml of ethanol and 96 ml of 35% hydrochloric acid was refluxed with stirring for 5 hours. The reaction solution was cooled to precipitate crystals. The crystals were collected by filtration. 23.2 g of 2-amino-4-tert-butyl-5-hexadecyloxyphenol hydrochloride was obtained.
Reaction SMILES: Cl[C:2]1[C:7]([C:8](OCC)=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]([Cl:14])[CH:3]=1.O.[NH2:16][NH2:17]>C(O)C.O>[Cl:14][C:4]1[N:5]=[C:6]([CH3:13])[C:7]2[C:8](=[O:9])[NH:16][NH:17][C:2]=2[CH:3]=1
Reactant: CCOC(=O)c1c(Cl)cc(Cl)nc1C
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1nc(Cl)cc2[nH][nH]c(=O)c12
Temperature: 80 °C
Reaction time: 17.5 h

Procedure:
A mixture of ethyl 4,6-dichloro-2-methylnicotinate (5.00 g, 21.36 mmol) and hydrazine monohydrate (2.1 mL, 43.3 mmol) in ethanol (22 mL) was heated to 80° C. and stirred for 17.5 h. The reaction was cooled to room temperature, diluted with water, filtered, rinsed with water, and dried under vacuum to provide 6-chloro-4-methyl-1H-pyrazolo[4,3-c]pyridin-3(2H)-one, which was carried onto the next step without further purification. MS ESI calc'd. for C7H6ClN3O [M+1]+ 184. found 184.
Reaction SMILES: [N:1]1([CH2:10][C:11]2[N:15]([CH2:16][CH2:17][C:18]([NH:20]O)=[NH:19])[C:14]3[CH:22]=[CH:23][CH:24]=[CH:25][C:13]=3[N:12]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[C:26]([O:29]C(=O)C)(=[O:28])[CH3:27].C(OCC)C>C(O)(=O)C.[Pd]>[C:26]([OH:29])(=[O:28])[CH3:27].[C:26]([OH:29])(=[O:28])[CH3:27].[N:1]1([CH2:10][C:11]2[N:15]([CH2:16][CH2:17][C:18]([NH2:20])=[NH:19])[C:14]3[CH:22]=[CH:23][CH:24]=[CH:25][C:13]=3[N:12]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: N=C(CCn1c(Cn2nnc3ccccc32)nc2ccccc21)NO
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOCC
Product: N=C(N)CCn1c(Cn2nnc3ccccc32)nc2ccccc21
Temperature: 25 °C
Reaction time: 0.12 h
Yield: 64 %

Procedure:
N-[3-(2-Benzotriazol-1-ylmethyl-benzimidazol-1-yl)-1-imino-propyl)-hydroxyamine (57 mg, 0.17 mmol) was dissolved in acetic acid (1 mL). Acetic anhydride was added and the solution was stirred at room temperature for 5-10 minutes. The solution was then added to 10% Pd/C (15 mg) in a Parr reaction vessel. The mixture was agitated under H2 (at 55 psi) for 4 hours. The catalyst was removed by filtration. Evaporation of the filtrate gave a yellow gum which was azeotroped with hexane several times. Trituration with diethyl ether gave 64 mg (64% yield) of the title compound as a tan solid.
Reaction SMILES: N1C=CC=CC=1.[C:7](OC(=O)C)(=[O:9])[CH3:8].[NH2:14][C:15]1[C:19]2[CH:20]=[C:21]3[C:34](=[C:35]([F:36])[C:18]=2[O:17][N:16]=1)[N:33]1[CH2:37][C@@H:38]([CH3:42])[O:39][C@@H:40]([CH3:41])[C@@H:32]1[C:23]1([C:28](=[O:29])[NH:27][C:26](=[O:30])[NH:25][C:24]1=[O:31])[CH2:22]3>C(Cl)CCl>[F:36][C:35]1[C:18]2[O:17][N:16]=[C:15]([NH:14][C:7](=[O:9])[CH3:8])[C:19]=2[CH:20]=[C:21]2[C:34]=1[N:33]1[CH2:37][C@@H:38]([CH3:42])[O:39][C@@H:40]([CH3:41])[C@@H:32]1[C:23]1([C:28](=[O:29])[NH:27][C:26](=[O:30])[NH:25][C:24]1=[O:31])[CH2:22]2
Reactant: CC(=O)OC(C)=O
Reactant: C[C@@H]1CN2c3c(cc4c(N)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CC(=O)Nc1noc2c(F)c3c(cc12)CC1(C(=O)NC(=O)NC1=O)[C@H]1[C@H](C)O[C@H](C)CN31
Temperature: 130 °C
Reaction time: 12 h

Procedure:
Pyridine (0.01 mL, 0.2 mmol) and acetic anhydride (0.10 mL, 0.14 mmol) were added sequentially to a solution of (2R,4S,4aS)-rel-8-amino-11-fluoro-2,4-dimethyl-1,2,4,4a-tetrahydro-2′H,6H-spiro[isoxazolo[4,5-g][1,4]oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione (Example 1, 54 mg, 0.13 mmol) in ethylene dichloride, and the mixture was stirred at 130° C. for 12 hours. After cooling to room temperature, solvent was removed, and the residue was purified over a silica gel flash column using a gradient of methanol in chloroform to give the title compound as a racemic mixture in the form of a yellow solid. Yield: 7.5 mg, (13%).
Reaction SMILES: [CH3:1][Si:2]([CH3:28])([CH3:27])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([CH:21]([CH2:25][CH3:26])[CH2:22][CH2:23][OH:24])[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1.N1C=CC=CC=1.Cl[C:36]([O:38][CH3:39])=[O:37]>O>[C:36](=[O:37])([O:24][CH2:23][CH2:22][CH:21]([N:19]1[CH:20]=[C:16]([C:15]2[C:10]3[CH:9]=[CH:8][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:27])([CH3:1])[CH3:28])[C:11]=3[N:12]=[CH:13][N:14]=2)[CH:17]=[N:18]1)[CH2:25][CH3:26])[O:38][CH3:39]
Reactant: CCC(CCO)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCC(CCOC(=O)OC)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Reaction time: 3 h

Procedure:
To a solution of [3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentan-1-01 (50 mg, 0.0001 mol) from Example 498 Step 2 in pyridine (1 mL, 0.01 mol), methyl chloroformate (30 μL, 0.0003 mol) was added. The reaction was stirred for 3 h, water was added and the product was extracted with ethyl acetate. The combined organic layers were washed 1N HCl, brine, dried over magnesium sulfate, filtered and concentrated to give methyl 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentyl carbonate as a semisolid residue (30 mg, 50%). LC/MS (M+H)+: m/z=460.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH2:19][NH2:20])=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[CH2:19][NH:20][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[CH3:1])=[CH:14][CH:13]=1
Reactant: Cc1ccccc1C(=O)O
Reactant: NCC(c1ccc(Cl)cc1)N1CCOCC1
Product: Cc1ccccc1C(=O)NCC(c1ccc(Cl)cc1)N1CCOCC1

Procedure:
From 2-methylbenzoic acid and 2-(4-chloro-phenyl)-2-morpholin-4-yl-ethylamine.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[NH:8][C:9]([C:12]3[C:21]([OH:22])=[C:20]4[C:15]([CH:16]=[CH:17][CH:18]=[N:19]4)=[C:14]([N:23]4[CH2:28][CH2:27]S[CH2:25][CH2:24]4)[N:13]=3)=[N:10][N:11]=2)=[CH:4][CH:3]=1.C(Cl)(Cl)Cl.O[O:36][S:37]([O-:39])=O.[K+]>CO>[O:36]=[S:37]1(=[O:39])[CH2:27][CH2:28][N:23]([C:14]2[N:13]=[C:12]([C:9]3[NH:8][C:7]([CH2:6][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:30][CH:29]=4)=[N:11][N:10]=3)[C:21]([OH:22])=[C:20]3[C:15]=2[CH:16]=[CH:17][CH:18]=[N:19]3)[CH2:24][CH2:25]1
Reactant: O=S([O-])OO
Reactant: Oc1c(-c2nnc(Cc3ccc(F)cc3)[nH]2)nc(N2CCSCC2)c2cccnc12
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=S1(=O)CCN(c2nc(-c3nnc(Cc4ccc(F)cc4)[nH]3)c(O)c3ncccc23)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 25.9 %

Procedure:
A 100 mL flask was charged with 7-[5-(4-fluorobenzyl)-4H-1,2,4-triazol-3-yl]-5-thiomorpholin-4-yl-1,6-naphthyridin-8-ol (26 mg, 0.062 mmol). Methanol (15 mL) and chloroform (˜3 mL to dissolve insoluble solids) were added, followed by a freshly prepared 0.16 M solution of Oxone (0.75 mL, 0.12 mmol) in methanol. The solution was stirred for 14 hours at room temperature. The reaction mixture was concentrated in vacuo, diluted with dichloromethane and extracted twice. The combined organics were concentrated in vacuo and purified by preparative HPLC. Thus, 5-(1,1-dioxidothiomorpholin-4-yl)-7-[5-(4-fluorobenzyl)-4H-1,2,4-triazol-3-yl]-1,6-naphthyridin-8-ol (7.3 mg, 26%) was prepared as a tan solid. 1H NMR (CD3OD/CDCl3): δ 8.99 (dd, J=4.4, 1.6 Hz, 1 H), 8.31 (dd, J=8.4, 1.6 Hz, 1 H), 7.52 (dd, J=8.4, 4.4 Hz, 1 H), 7.24 (m, 2 H), 6.91 (m, 2 H), 4.08 (s, 2 H), 3.85 (m, 4 H), 3.25 (m, 4 H); MS m/z 455 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:22]=[CH:21][C:12]([CH2:13][CH:14]3[S:18][C:17](=[O:19])[NH:16][C:15]3=[O:20])=[CH:11][C:10]=2[CH3:23])=[N:6][CH:7]=1.[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[C:25]1[C:33](O)=[O:34].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C>[O:19]=[C:17]1[NH:16][C:15](=[O:20])[CH:14]([CH2:13][C:12]2[CH:21]=[CH:22][C:9]([O:8][C:5]3[N:6]=[CH:7][C:2]([NH:1][C:33]([C:25]4[NH:24][C:32]5[C:27]([CH:26]=4)=[CH:28][CH:29]=[CH:30][CH:31]=5)=[O:34])=[CH:3][CH:4]=3)=[C:10]([CH3:23])[CH:11]=2)[S:18]1
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: Cc1cc(CC2SC(=O)NC2=O)ccc1Oc1ccc(N)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(CC2SC(=O)NC2=O)ccc1Oc1ccc(NC(=O)c2cc3ccccc3[nH]2)cn1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a solution of 5-[4-(5-aminopyridin-2-yloxy)-3-methylbenzyl]thiazolidine-2,4-dione (150 mg, 0.46 mmol) in DMF (5 mL) were added indole-2-carboxylic acid (74 mg, 0.46 mmol), 1-hydroxybenzotriazole monohydrate (70 mg, 0.46 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (110 mg, 0.57 mmol), and the resulting solution was stirred for 5 days at room temperature. This reaction solution was concentrated under reduced pressure. Water was added to the residue, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, evaporated, and the residue was then purified by silica gel column chromatography (chloroform:methanol=30:1). To the obtained powdery substance was added ethanol, the resulting solution was filtered and the filtrate was washed with ethanol, to thereby yield 100 mg of the title compound.