Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]2[C:11]3([CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]3)[CH2:10][N:9]([C:23]([O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])=[O:24])[C:6]2=[CH:7][CH:8]=1.C(Br)(Br)(Br)[Br:33].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:33][CH2:2][C:3]1[CH:4]=[C:5]2[C:11]3([CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]3)[CH2:10][N:9]([C:23]([O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])=[O:24])[C:6]2=[CH:7][CH:8]=1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)N1CCC2(C1)CN(C(=O)OCC[Si](C)(C)C)c1ccc(CO)cc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(C1)CN(C(=O)OCC[Si](C)(C)C)c1ccc(CBr)cc12
Reaction time: 2.5 h
Yield: 77.8 %

Procedure:
1-(2-(Trimethylsilyl)ethyl) 1′-tert-butyl 5-(hydroxymethyl)spiro[indoline-3,3′-pyrrolidine]-1,1′-dicarboxylate (441 mg, 0.98 mmol) was dissolved in methylene chloride (10 mL). Thereafter, carbon tetrabromide (359 mg, 1.08 mmol) and triphenylphosphine (310 mg, 1.18 mmol) were added to the above obtained solution under cooling on ice, and the thus obtained mixture was then stirred at the same temperature as above for 2.5 hours. Thereafter, the reaction solution was concentrated in vacuo, and the obtained residue was then purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain 1-(2-(trimethylsilyl)ethyl) 1′-tert-butyl 5-(bromomethyl)spiro[indoline-3,3′-pyrrolidine]-1,1′-dicarboxylate (390 mg, 77%) in the form of a colorless amorphous product.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][N:16]=3)=[CH:10][C:9]=2[CH3:22])=[O:7])=[CH:4][CH:3]=1.CC1C=C(CC(O)=O)N(C)C=1C(C1C=CC(Cl)=CC=1)=O.CC1C=CC(C(C2N(C)C(CC(O)=O)=CC=2)=O)=CC=1.[CH3:64][N:65]([CH3:69])[C:66](Cl)=[O:67]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:66]([N:65]([CH3:69])[CH3:64])=[O:67])=[CH:17][N:16]=3)=[CH:10][C:9]=2[CH3:22])=[O:7])=[CH:23][CH:24]=1
Reactant: Cc1cc(Cc2ccc(N)cn2)n(C)c1C(=O)c1ccc(Cl)cc1
Reactant: CN(C)C(=O)Cl
Agent: Cc1cc(CC(=O)O)n(C)c1C(=O)c1ccc(Cl)cc1
Agent: Cc1ccc(C(=O)c2ccc(CC(=O)O)n2C)cc1
Solvent: c1ccncc1
Product: Cc1cc(Cc2ccc(NC(=O)N(C)C)cn2)n(C)c1C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 57 %

Procedure:
{2-[5-(4-Chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2-ylmethyl]pyridin-5-yl}amine [prepared by the method described in Example 5, but substituting the methyl ester of zomepirac for the methyl ester of tolmetin in Step (a)] (0.45 g, 1.32 mmol) and dimethylcarbamoyl chloride (0.13 ml, 1.46 mmol) were dissolved in pyridine (6.6 ml), and the mixture was stirred at room temperature for 96 h. The solvents were removed in vacuo and the residue was crystallized from chloroform-hexane mixture to give 1-{2-[5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2-ylmethyl]pyridin-5-yl}-3,3-dimethylurea (0.31 g, 57%) as a solid, mp 227.2-230.0° C.
Reaction SMILES: [CH:1]1([C:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]([CH2:16][CH2:17][CH3:18])[C:8](=[O:19])[CH:7]([NH:20]C(OCC3C=CC=CC=3)=O)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.Br.C(OCC)C>C(O)(=O)C>[NH2:20][CH:7]1[N:6]=[C:5]([CH:1]2[CH2:2][CH2:3][CH2:4]2)[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([CH2:16][CH2:17][CH3:18])[C:8]1=[O:19]
Reactant: CCCN1C(=O)C(NC(=O)OCc2ccccc2)N=C(C2CCC2)c2ccccc21
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCCN1C(=O)C(N)N=C(C2CCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
5-Cyclobutyl-1,3-dihydro-3(R,S)-[(benzyloxycarbonyl)amino]-1-propyl-2H-1,4-benzodiazepin-2-one (1.5 g, 3.7 mmol) was treated with a solution of 30% hydrogen bromide in acetic acid (5 ml), and stirred for 20 min at room temperature. The mixture was then added dropwise onto cold (0° C.) diethyl ether (50 ml). A white solid was precipitated and filtered off. The solid was treated with 10% sodium hydroxide solution (50 ml), then extracted with ethyl acetate (80 ml). The organic layer was separated, dried (Na2SO4) and evaporated to give a colourless oil. This material was then used without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[N:23][C:24]=4[NH:34][NH2:35])[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:37](N1C=CN=C1)(N1C=CN=C1)=[O:38].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>O1CCOCC1>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:27]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:26][C:25]4[C:24]5=[N:34][N:35]=[C:37]([OH:38])[N:23]5[CH:22]=[CH:21][C:20]=4[N:19]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccnc(NN)c4cc3-c3ccccc3)cc2)CCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccn5c(O)nnc5c4cc3-c3ccccc3)cc2)CCC1
Temperature: 95 °C

Procedure:
To a round bottom flask was added tert-butyl{1-[4-(5-hydrazino-3-phenyl-1,6-naphthyridin-2-yl)phenyl]cyclobutyl}carbamate (1-6) (2.77 g, 5.75 mmol), and 1,1′-carbonylbis(1H-imidazole) (4.10 g, 4.40 mmol), in 1,4Dioxane (30 mL). The sealed reaction mixture was then heated at 95° C. under an atmosphere of nitrogen. To the crude reaction mixture was added a saturated solution of sodium bicarbonate (100 mL) and ethyl acetate. The organic layer was washed with a saturated solution of sodium bicarbonate, followed by water, then brine, dried over sodium sulfate, filtered, and concentrated. The resulting residue was then purified by silica gel chromatography eluting with 0-10% IPA/DCM. The appropriate fractions were then combined and the solvent was removed in vacuo to give tert-butyl{1-[4-(3-hydroxy-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]cyclobutyl}carbamate (1-6a) as a tan solid. MS (M+H)+: observed=508.1, calculated=508.6.
Reaction SMILES: C([O:8][CH2:9][C@H:10]1[C@H:15]([O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[CH2:14][CH2:13][CH2:12][O:11]1)C1C=CC=CC=1.[H][H]>O1CCCC1.[Pd]>[O:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH:17]1[O:16][C@@H:15]1[CH2:14][CH2:13][CH2:12][O:11][C@H:10]1[CH2:9][OH:8]
Reactant: c1ccc(COC[C@@H]2OCCC[C@H]2OC2CCCCO2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: OC[C@@H]1OCCC[C@H]1OC1CCCCO1

Procedure:
2.93 g of dl-trans-2-benzyloxymethyl-3-(tetrahydropyran-2-yloxy)tetrahydropyran (prepared as described in Preparation 35) were dissolved in 130 ml of tetrahydrofuran and were then hydrogenated at room temperature for 8 hours in the presence of 1.30 g of a 10% w/w palladium on activated carbon catalyst and of hydrogen at an initial pressure of 4 atmospheres (about 4 bars). The catalyst was removed by filtration, and then the solvent was distilled off. The resulting residue was purified by column chromatography through 50 g of silica gel. Those fractions eluted with mixtures of hexane and diethyl ether ranging from 2:1 to 1:1 by volume were worked up to give 1.87 g of the title compound as a colorless oil.
Reaction SMILES: Cl.[CH:2]1[C:12]2[CH:11]=[CH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:7](=[C:17]3[CH2:22][CH2:21][N:20]([C:23](=[O:26])[CH2:24][NH2:25])[CH2:19][CH2:18]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:34][C:35]([CH3:41])([CH3:40])[CH2:36][C:37](Cl)=[O:38]>ClCCl>[CH:13]1[C:9]2[CH:10]=[CH:11][C:12]3[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=3[C:7](=[C:17]3[CH2:18][CH2:19][N:20]([C:23](=[O:26])[CH2:24][NH:25][C:37](=[O:38])[CH2:36][C:35]([CH3:41])([CH3:40])[CH3:34])[CH2:21][CH2:22]3)[C:8]=2[CH:16]=[CH:15][CH:14]=1
Reactant: NCC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Reactant: CC(C)(C)CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)CC(=O)NCC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Reaction time: 0.5 h

Procedure:
80.0 mg (0.217 mmol) of 2-[4-(5H-dibenzo[a,d][7]annulen-5-ylidene)-1-piperidinyl]-2-oxoethanamine hydrochloride was dissolved in 1 ml of dichloromethane. 75.9 mg (0.750 mmol) of triethylamine was added to the obtained solution. Then a solution of 35.1 mg (0.260 mmol) of 3,3-dimethylbutanoyl chloride in 0.5 ml of dichloromethane was slowly added to the obtained mixture. After stirring for 30 minutes, the product was purified by the silica gel chromatography (hexane:ethyl acetate=93:7 to 3:1) to obtain the title compound.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:11]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1.C([Li])CCC.[Br:25]C(Cl)(Cl)C(Br)(Cl)Cl.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[Br:25][C:10]1[N:5]2[N:4]=[C:3]([S:2][CH3:1])[C:11]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[C:6]2[CH:7]=[CH:8][CH:9]=1
Reactant: CSc1nn2ccccc2c1NC(=O)OC(C)(C)C
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CSc1nn2c(Br)cccc2c1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
After dissolving tert-butyl N-[2-methylthiopyrazolo[1,5-a]pyridin-3-yl]carbamate (220 mg) in tetrahydrofuran (3 mL), a solution of n-butyllithium in hexane (1.6 M; 1.51 mL) was added dropwise at −78° C. under a nitrogen stream, and the mixture was stirred for 30 minutes. A solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (384 mg) in tetrahydrofuran (2 mL) was added to the reaction mixture, and stirring was continued for 30 minutes. Saturated aqueous ammonium chloride was added to the reaction mixture, the temperature was raised to room temperature, extraction was performed with ethyl acetate and the extract was washed with water and brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and tert-butyl N-[7-bromo-2-methylthiopyrazolo[1,5-a]pyridin-3-yl]carbamate was obtained from the n-hexane:ethyl acetate (10:1) fraction as yellow crystals. After dissolving this in 1,2-dimethoxyethane (6 mL) and water (1 mL), 2,4-dichlorophenylboric acid (191 mg), tetrakis(triphenylphosphine)palladium (0) complex (116 mg) and barium hydroxide octahydrate (315 mg) were added and the mixture was heated and stirred at 80° C. for 4 hours under a nitrogen stream. Water was added to the reaction mixture, extraction was performed with ethyl acetate and the extract was washed with brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (160 mg) was obtained from the n-hexane:ethyl acetate (20:1) fraction as a yellow oil.
Reaction SMILES: CC1CCCO1.[C:7](=[N:10][OH:11])([NH2:9])[CH3:8].C[O-].[Na+].[C:15]12([C:28](OCC)=O)[CH2:20][CH:19]1[CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]2>O>[CH3:8][C:7]1[N:9]=[C:28]([C:15]23[CH2:20][CH:19]2[CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]3)[O:11][N:10]=1
Reactant: CC(N)=NO
Reactant: CCOC(=O)C12CC1CN(C(=O)OC(C)(C)C)C2
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CC1CCCO1
Product: Cc1noc(C23CC2CN(C(=O)OC(C)(C)C)C3)n1
Yield: 53.6 %

Procedure:
2-Methyltetrahydrofuran (15 mL), acetamide oxime (2.54 g, 34.3 mmol) and sodium methoxide (3.70 g, 68.6 mmol) were added to 3-tert-butyl 1-ethyl 3-azabicyclo[3.1.0]hexane-1,3-dicarboxylate (103) (3.5 g, 13.72 mmol) and the mixture was heated to reflux for 20 minutes. Upon cooling the suspension was treated with 60 mL of water and extracted with ethyl acetate (2×50 mL). The combined organics were washed with saturated sodium chloride and dried over magnesium sulfate. The mixture was concentrated and the residue was chromatographed over 20 g of silica gel with hexanes/ethyl acetate; obtained 1.95 g of 104 as a white solid. MS (ESI) m/z 304.0 [M+K]+. 1H NMR (CDCl3) δ: 1.17 (m, 1H), 1.46 (s, 9H), 1.74 (m, 1H), 2.18 (s, 2H), 2.22 (m, 1H), 2.36 (s, 3H), 3.50 (m, 1H), 3.70 (m, 1H).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH:6]=[CH:7][C:8]2[S:12][C:11]([C:13](Cl)=[O:14])=[CH:10][CH:9]=2)[C:3]2[CH:16]=[CH:17][CH:18]=[CH:19][C:2]1=2.N1C=CC=C(C[OH:27])C=1>N1C=CC=CC=1>[S:1]1[CH:5]=[C:4]([CH:6]=[CH:7][C:8]2[S:12][C:11]([C:13]([OH:27])=[O:14])=[CH:10][CH:9]=2)[C:3]2[CH:16]=[CH:17][CH:18]=[CH:19][C:2]1=2
Reactant: O=C(Cl)c1ccc(C=Cc2csc3ccccc23)s1
Reactant: OCc1cccnc1
Solvent: c1ccncc1
Product: O=C(O)c1ccc(C=Cc2csc3ccccc23)s1

Procedure:
The acid chloride of 5-[2-(benzo[b]thiophen-3-yl)ethenyl]thiophene-2-carboxylic acid was prepared as described in Example 9. To a suspension of 5-[2-(benzo[b]thiophen-3-yl)ethenyl]thiophene2-carboxylic acid chloride (5.00 g) and pyridine (50 ml) was added 3-pyridylcarbinol (1.79 g). After refluxing overnight, the mixture was evaporated, and the residue was dissolved in ether, filtered, and concentrated. The residue was purified by high performance liquid chromatography (silica gel, eluted with 2:1 ethyl acetate:hexane). The appropriate fractions were combined and evaporated. The residue was recrystallized from toluene/hexane to afford 1.4 g (23%) of the product, mp 97°-98° C.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:6]=[C:5]([O:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:4]=1)[NH2:2].[CH3:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[C:28]2=O>C(O)(=O)C.C(O)C>[CH3:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[C:28]2=[N:2][NH:1][C:3]1[CH:8]=[C:7]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[N:6]=[C:5]([O:15][CH2:16][CH2:17][N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[N:4]=1
Reactant: NNc1cc(N2CCOCC2)nc(OCCN2CCOCC2)n1
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1ccc2c(c1)C(=NNc1cc(N3CCOCC3)nc(OCCN3CCOCC3)n1)C(=O)N2
Temperature: 60 °C
Reaction time: 8 h

Procedure:
4-[2-(4-Hydrazino-6-(morpholin-4-yl)-pyrimidin-2-yloxy)-ethyl]-morpholine (80 mg; ¼ mmol) was added to a flask along with 5-methylisatin (53 mg; ⅓ mmol) and ethanol (4 mL). One drop of acetic acid was added, and the reaction was stirred overnight at 60° C. The mixture was then filtered and the precipitate was washed with ethanol (1 mL) and dried to give 5-methyl-3-{[6-morpholin-4-yl-2-(2-morpholin-4-yl-ethoxy)-pyrimidin-4-yl]-hydrazono}-1,3-dihydro-indol-2-one.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8].Cl[CH2:10][C:11]([NH:13][C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:21])=[O:12].O>C1(C)C=CC=CC=1>[CH3:20][C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:21])[C:14]=1[NH:13][C:11](=[O:12])[CH2:10][N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8]
Reactant: Cc1cccc(C)c1NC(=O)CCl
Reactant: O=C1CCCN1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cccc(C)c1NC(=O)CN1CCCC1=O
Reaction time: 2 h
Yield: 90.4 %

Procedure:
In 300 ml of toluene was suspended 9.2 g of 60% sodium hydride in a nitrogen stream, and 21.3 g of 2pyrrolidinone was slowly added dropwise to the suspension at an inner temperature controlled at 40° C. or lower. After stirring the mixture for 2 hours, 19.7 g of 2-chloro-N(2,6-dimethylphenyl)acetamide was added thereto, and the mixture was allowed to react at 60° to 70° C. for 2 hours. To the reaction mixture was added 50 ml of hot water of about 70° to 85° C., followed by allowing to cool with stirring. The precipitated crystals in the aqueous layer were collected by filtration and dried under reduced pressure to obtain 22.2 g (90%) of the titled compound.
Reaction SMILES: [CH:1]([NH:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15])(=[O:7])=[O:6])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:20][CH2:21][CH2:22][N:23]1[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]2[C:24]1=[O:33]>CN1CCCC1=O.C(OCC)(=O)C>[O:33]=[C:24]1[C:25]2[C:26](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27](=[O:28])[N:23]1[CH2:22][CH2:21][CH2:20][N:4]([CH:1]([CH3:3])[CH3:2])[S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15])(=[O:7])=[O:6]
Reactant: CC(C)NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(C)N(CCCN1C(=O)c2ccccc2C1=O)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Yield: 73 %

Procedure:
The compound (6.29 g, 25.75 mmol) obtained in step A was dissolved in N-methylpyrrolidone (100 ml), and the mixture was stirred under ice-cooling. Thereto was added 60% sodium hydride (1.21 g, 30 mmol) and the mixture was stirred at room temperature for 20 min. After stirring, N-(3-bromopropyl)phthalimide (8.31 g, 31.0 mmol) was added and the mixture was stirred at 70° C. for 90 min. The reaction mixture was diluted with ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure. The obtained solid was washed with diethyl ether-hexane mixed solvent, and dried under reduced pressure to give the title compound (8.11 g, yield 73%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13].ClC1C=CC=C(Cl)C=1NC1C=CC=CC=1C(=O)C(OC)=O>>[Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]([OH:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(=O)c1ccccc1Nc1c(Cl)cccc1Cl
Agent: COC(=O)C(=O)c1ccccc1Nc1c(Cl)cccc1Cl
Product: CCOC(=O)C(O)c1ccccc1Nc1c(Cl)cccc1Cl
Yield: 84.3 %

Procedure:
The same procedures as in the Step 3 of Example 1 were repeated except that 3.42 g of ethyl 2-(2,6-dichloroanilino)-phenylglyoxylate were employed instead of 3.24 g of methyl 2-(2,6-dichloroanilino)phenylglyoxylate, thereby yielding 2.9 g of ethyl 2-(2,6-dichloroanilino)phenylglycolate m.p. 154.5°-156.0° C. Yield: 86% of theoretical amount
Reaction SMILES: [CH3:1][CH:2]([CH2:6][C:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3](O)=[O:4].O.[NH2:16][NH2:17]>C(O)C>[CH3:1][CH:2]1[CH2:6][C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:17][NH:16][C:3]1=[O:4]
Reactant: CC(CC(=O)c1ccccc1)C(=O)O
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC1CC(c2ccccc2)=NNC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
7.7 g (40 mmole) of 2-methyl-4-oxo-4-phenylbutanoic acid was added to a 100 ml single-necked round bottom flask followed by 3.0 ml (60 mmole) of hydrazine monohydrate and then 20 ml of reagent grade ethanol (100%, 95% of ethanol should be fine also). The flask was fitted with a reflux condenser and the reaction mixture was heated to reflux in an oil bath at 110 C (temperature of oil bath) and stirred for 2 h. The flask was then removed from the oil bath and the reaction mixture cooled to ambient temperature. The stir bar was removed and the solvent was evaporated in vacuo in a water bath at 45° C. The residue was then treated with 50 ml of Milli-Q water and stirred for 10 minutes to give a suspension. The precipitate was collected by filtering, washed with 100 ml of 2N NaHCO3, then washed with 60 ml Milli-Q water three times, and dried over a medium frit sintered glass funnel in vacuo to give 7.15 g of white crystals (Syn. ID, WH-8-004). Yield, 95%, confirmed by ESI-MS. ESI-MS: m/z 189.2 (M+H+).
Reaction SMILES: N[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:11][C@H:12]([C:14]2[N:15]=[C:16]3[S:30][CH:29]=[C:28]([CH3:31])[N:17]3[C:18](=[O:27])[C:19]=2[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)[CH3:13])[N:3]=1.N([O-])=[O:33].[Na+]>C(O)(=O)C.O>[F:26][C:22]1[CH:21]=[C:20]([C:19]2[C:18](=[O:27])[N:17]3[C:28]([CH3:31])=[CH:29][S:30][C:16]3=[N:15][C:14]=2[C@@H:12]([NH:11][C:4]2[N:3]=[C:2]([OH:33])[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][NH:8]3)[CH3:13])[CH:25]=[CH:24][CH:23]=1
Reactant: O=N[O-]
Reactant: Cc1csc2nc([C@H](C)Nc3nc(N)nc4[nH]cnc34)c(-c3cccc(F)c3)c(=O)n12
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1csc2nc([C@H](C)Nc3nc(O)nc4[nH]cnc34)c(-c3cccc(F)c3)c(=O)n12
Temperature: 20 °C
Reaction time: 16 h
Yield: 25.8 %

Procedure:
A solution of 7-{(1S)-1-[(2-amino-9H-purin-6-yl)amino]ethyl}-6-(3-fluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (27 mg, 62 μmol) in acetic acid (0.41 mL) and water (84 μL) at 0° C. was treated with a solution of sodium nitrite (13 mg, 0.19 mmol) in water (0.15 mL) dropwise and stirred at 0° C. for 30 minutes and at 20° C. for 16 hours. The reaction mixture was concentrated and purified by RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (7 mg, 20%) as a white solid. LCMS for C20H17FN7O2S (M+H)+: m/z=437.8. 1H NMR (300 MHz, DMSO-d6): δ 7.79 (br s, 1H), 7.68-7.61 (m, 1H), 7.50-7.38 (m, 3H), 7.23-7.14 (m, 2H), 7.06 (br s, 1H), 5.02-4.92 (m, 1H), 2.64 (s, 3H), 1.26 (d, J=6.7 Hz, 3H).
Reaction SMILES: [H-].[Na+].C(NC([N:10]1[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11]1)=O)(C)(C)C.[CH2:16]([O:20][C:21]1[C:25](S(C)(=O)=O)=[N:24][S:23][N:22]=1)[CH2:17][CH2:18][CH3:19]>C1COCC1>[CH2:16]([O:20][C:21]1[C:25]([O:15][CH:12]2[CH2:13][CH2:14][NH:10][CH2:11]2)=[N:24][S:23][N:22]=1)[CH2:17][CH2:18][CH3:19]
Reactant: CC(C)(C)NC(=O)N1CCC(O)C1
Reactant: CCCCOc1nsnc1S(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCOc1nsnc1OC1CCNC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A suspension of NaH (0.066 g, 0.0028 mol) in THF (25 mL) was treated with 1-t-butylcarbamoyl-3-hydroxypyrrolidine (Ref. Syn. Commun. 15, 587) (0.5 g, 0.0027 mol) and the reaction warmed to 50° C. for 30 min. After cooling to ambient temperature, 3-butyloxy-4-methanesulfonyl-1,2,5-thiadiazole (0.55 g, 0.0027 mol) in THF (5 mL) was added and the reaction heated to reflux for 2.5 h. The solvent was evaporated, the residue treated with ice-water, and the mixture extracted with ether. The extracts were washed with brine, dried, and the solvent evaporated. The residue was dissolved in ether (50 mL) and treated with a slow stream of HCl for 5 min. After stirring overnight, the reaction was extracted with cold water. The aqueous was washed with ether, made basic, and extracted with EtOAc. The extracts were washed with brine, dried, and the solvent evaporated to give a clear oil. The HCl salt (0.42 g) crystallized from EtOAc, m.p. 127°-128° C. (Compound 27).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[N:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=1[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19].[CH:22]1([CH:25]([C:32]2[CH:37]=[C:36]([CH2:38]O)[N:35]=[CH:34][N:33]=2)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:24][CH2:23]1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C1COCC1>[CH:22]1([CH:25]([C:32]2[CH:37]=[C:36]([CH2:38][O:16][C:13]3[CH:14]=[N:15][C:10]([C:3]4[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=4[F:1])=[C:11]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=3)[N:35]=[CH:34][N:33]=2)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:24][CH2:23]1
Reactant: COc1ccc(F)c(-c2ncc(O)cc2CC(C)(C)C)c1
Reactant: CCOC(=O)CC(c1cc(CO)ncn1)C1CC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)CC(c1cc(COc2cnc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)ncn1)C1CC1
Reaction time: 2 h
Yield: 67.1 %

Procedure:
Under a nitrogen atmosphere, to a solution of 6-(2-fluoro-5-methoxyphenyl)-5-neopentylpyridin-3-ol (300 mg) and ethyl 3-cyclopropyl-3-(6-(hydroxymethyl)pyrimidin-4-yl)propanoate (259 mg) in THF (8.0 mL) were added 1,1′-(azodicarbonyl)dipiperidine (419 mg) and tributylphosphine (409 μL) at room temperature, and the mixture was stirred for 2 hr. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (362 mg) as a colorless oil.