Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)#[N:2].C(=O)([O-])[O-].[Cs+].[Cs+].[F-].[Cs+].Br[C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]=[C:26]([CH3:31])[CH:25]=[N:24]2>O.C1(C)C=CC=CC=1>[CH3:31][C:26]1[CH:25]=[N:24][C:23]2[C:28]([N:27]=1)=[CH:29][C:30]([C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)=[CH:21][CH:22]=2
Reactant: Cc1cnc2cc(Br)ccc2n1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [F-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cnc2ccc(-c3ccc(C#N)cc3)cc2n1
Temperature: 80 °C

Procedure:
4-Cyanophenylboronic acid (588 mg, 4.0 mmol), cesium carbonate (2.2 g, 7.0 mmol), and cesium fluoride (608 mg, 4.0 mmol) were combined in H2O (15 mL) and treated with the products from Example 61B (446 mg, 2.0 mmol) in toluene (10 mL) and heated at 80° C. for 3 hours. The reaction mixture was allowed to cool to room temperature and filtered through a pad of celite. The filtrate was partitioned between IPAc (60 mL) and H2O (50 mL). The organic layer was separated, washed with 20% brine, dried with Na2SO4, filtered, and the filtrate was concentrated under vacuum to provide the title compounds which were used in the next step without further purification. MS 246 (M+H)+; 1H NMR (400 MHz, CDCl3) δ 8.71 (s, 1H), 8.69 (s, 1H), 8.02-8.20 (m, 4H), 7.84-7.90 (m, 2H), 7.70-7.76 (m, 8H), 2.73 (s, 6H); 13C NMR (400 MHz, CDCl3) δ 154.34, 154.10, 146.47, 147.17, 143.80, 142.93, 141.74, 140.62, 140.39, 140.18, 139.16, 132.49, 130.16, 129.74, 129.25, 128.71, 128.63, 128.06, 127.77, 127.74, 127.66, 127.59, 127.22, 126.73, 118.39, 118.37, 111.61, 111.51, 22.96.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([OH:14])[CH:7]=1)[CH3:2].F[C:17]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:18]=1[CH:19]=[O:20].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:17]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:18]=2[CH:19]=[O:20])[CH:7]=1)[CH3:2]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1F
Reactant: CCOC(=O)Cc1ccc(OC)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc([N+](=O)[O-])cc2C=O)c1

Procedure:
To 3-hydroxy-4-methoxyphenylacetic acid (5.0 g, 27.4 mmol) in EtOH (100 mL) was added sulfuric acid (1 mL), and the mixture was stirred overnight at room temperature. Once no starting material was seen by analytical tlc, the solution was concentrated and dried under high vacuum to give (3-hydroxy-4-methoxy-phenyl)-acetic acid ethyl ester. A solution of (3-hydroxy-4-methoxy-phenyl)-acetic acid ethyl ester (1 equivalent), 2-fluoro-5-nitrobenzaldehyde (1 equivalent), and potassium carbonate (2 equivalents) in 1,4-dioxane was heated overnight at 70° C. The mixture was partitioned between EtOAc and H2O and acidified with 1N aqueous HCl to pH 1, and then extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was purified by silica gel chromatography (EtOAc in hexane gradient) to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][C:12]([NH2:15])=[N:13][CH:14]=2)=[CH:5][CH:4]=1.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>N1C=CC=CC=1>[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:15][C:12]2[N:11]=[CH:10][C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)=[CH:14][N:13]=2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: COc1ccc(-c2cnc(N)nc2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: COc1ccc(-c2cnc(NS(=O)(=O)c3ccc(C)cc3)nc2)cc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 27.6 %

Procedure:
To a solution of 5-(4-methoxyphenyl)pyrimidin-2-amine (302 mg, 1.5 mmol) in 10 mL of dry pyridine was added 4-methylbenzenesulfonyl chloride (320 mg, 1.68 mmol). The solution was stirred at room temperature under Argon. After 21 h, the pyridine was removed in vacuo and flashed off with toluene. The residue was partitioned between CH2Cl2 and 1M NaOH. The organic phase was washed with 1M NaOH until no turbidity was observed on rectification of a small sample. The alkaline phase was made acidic (˜pH 3) with 1M HCl and extracted with EtOAc. The crude solid product weighed 180 mg. The crude product was taken up in hot HOAc (4 mL) and diluted with 2 mL of water to initiate crystallization. The product was collected by filtration, washed with water and EtOH and dried in vacuo to give white needles (147 mg) with mp 220-223° C.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=O)[NH:16][N:15]=2)=[CH:10][CH:9]=1>O>[Cl:3][C:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14]([C:11]2[CH:12]=[CH:13][C:8]([O:7][CH3:6])=[CH:9][CH:10]=2)=[N:15][N:16]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(-c2n[nH]c(=O)c3ccccc23)cc1
Solvent: O
Product: COc1ccc(-c2nnc(Cl)c3ccccc23)cc1
Yield: 74 %

Procedure:
With cooling with ice, 25 ml of phosphorus oxychloride was added to 95.05 g (20 mmol) of the obtained 4-(4-methoxyphenyl)-2H-phthalazin-1-on, and the reaction liquid was stirred under reflux for 6 hours. Water was added to the reaction liquid, extracted with chloroform, and the organic layer was washed with saturated saline water. This was dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 4.00 g (yield: 74%) of 1-chloro-4-(4-methoxyphenyl)-phthalazine as a white solid.
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[C:9]([S:10](Cl)(=[O:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=12.O1CCCC1.[NH3:19].[OH-].[NH4+]>O>[N:1]1[O:2][N:3]=[C:4]2[C:9]([S:10]([NH2:19])(=[O:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: N
Reactant: O=S(=O)(Cl)c1cccc2nonc12
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NS(=O)(=O)c1cccc2nonc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 3.0 g of 2,1,3-benzoxadiazole-4-sulfonyl chloride and 200 mL of tetrahydrofuran at -30° C. was added 10 mL of ammonia under an inert atmosphere. The resulting suspension was stirred at ambient temperature for 3 hours. Concentrated ammonium hydroxide (20 mL) and water (20 mL) were added. The reaction was extracted with ethyl acetate and the organic extracts were combined, dried over magnesium sulfate, filtered, and stripped to give a crude solid. Recrystallization from chlorobutaneethanol afforded 1.82 g of the title compound as an orange-tan solid, m.p. 157°-159° C.
Reaction SMILES: CN([C:4]([O:8][N:9]1N=NC2C=CC=N[C:10]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([NH:28][C:29]1[N:34]=[C:33]([C:35]([OH:37])=O)[C:32]([Br:38])=[CH:31][CH:30]=1)(=[O:27])[CH3:26].C(N(CC)C(C)C)(C)C.Cl.CNOC>ClCCl>[C:25]([NH:28][C:29]1[N:34]=[C:33]([C:35]([N:9]([O:8][CH3:4])[CH3:10])=[O:37])[C:32]([Br:38])=[CH:31][CH:30]=1)(=[O:27])[CH3:26]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(=O)Nc1ccc(Br)c(C(=O)O)n1
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1nc(NC(C)=O)ccc1Br
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
HATU (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) (4.56 g, 12.0 mmol) was added to a solution of 6-acetamido-3-bromopicolinic acid (2.6 g, 10.0 mmol) and DIPEA (N,N-diisopropylethylamine)(5.2 ml, 30 mmol) in DCM (dichloromethane)(10 ml). After 10 minutes, N,O-dimethylhydroxylamine hydrochloride (1.5 g, 15.0 mmol) was added to the reaction. The reaction was stirred at room temperature for 5 min. The reaction mixture was partitioned between EtOAc (ethyl acetate) and saturated NH4Cl solution. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude material was used in the next step without further purification. MS (m/z) 302.1 [M+H]+. 1H NMR (400 MHz, cd3cl) δ 8.14 (s, 1H), 8.13 (d, J=8.4 Hz, 1H), 7.85 (d, J=8.4 Hz, 1H), 3.56 (s, 3H), 3.37 (s, 3H), 2.20 (s, 3H).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[C:5]1(=O)[O:11][C:9](=[O:10])[CH2:8][O:7][CH2:6]1>N1C=CC=CC=1>[OH:2][CH2:1][CH2:3][N:4]1[C:9](=[O:10])[CH2:8][O:7][CH2:6][C:5]1=[O:11]
Reactant: O=C1COCC(=O)O1
Reactant: NCCO
Solvent: c1ccncc1
Product: O=C1COCC(=O)N1CCO
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 12.6 %

Procedure:
Ethanolamine (2.44 g, 40 mmol) was added dropwise to a solution of diglycolic anhydride (2.32 g, 20 mmol) in pyridine (10 ml). The mixture was stirred for 5 minutes at ambient temperature and then heated at reflux for 2 hours. The volatiles were removed by evaporation and the residue was heated at 180° C. for 2 hours. The reaction mixture was allowed to cool and was purified by column chromatography eluting with methylene chloride/methanol (9/1) to give 4-(2-hydroxyethyl)3,5dioxomorpholine (400 mg, 12.5%)
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([O:11][CH2:12][CH2:13][OH:14])[CH:9]=[CH:10][C:4]=2[C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>>[CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([O:11][CH2:12][CH2:13][O:14][S:26]([CH3:25])(=[O:28])=[O:27])[CH:9]=[CH:10][C:4]=2[C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=1
Reactant: Cc1sc2cc(OCCO)ccc2c1-c1ccc(C(F)(F)F)cc1
Reactant: CS(=O)(=O)Cl
Product: Cc1sc2cc(OCCOS(C)(=O)=O)ccc2c1-c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to example 21.1, 2-[2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yloxy]-ethanol and methanesulfonic acid chloride were converted to yield Methanesulfonic acid 2-[2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yloxy]-ethyl ester as colorless solid, MS: 430 (M+).
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[C:14]([C:17](=[O:22])[C:18](=[CH2:21])[CH2:19][CH3:20])[CH:13]=[CH:12][C:3]=1[O:4][CH:5]([CH3:11])[C:6]([O:8]CC)=[O:7].C(=O)(O)[O-].[Na+]>C(O)C.O>[Cl:1][C:2]1[C:15]([Cl:16])=[C:14]([C:17](=[O:22])[C:18](=[CH2:21])[CH2:19][CH3:20])[CH:13]=[CH:12][C:3]=1[O:4][CH:5]([CH3:11])[C:6]([OH:8])=[O:7]
Reactant: C=C(CC)C(=O)c1ccc(OC(C)C(=O)OCC)c(Cl)c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C=C(CC)C(=O)c1ccc(OC(C)C(=O)O)c(Cl)c1Cl
Reaction time: 5 h

Procedure:
To a solution of 2,3-dichloro-4-(2-methylenebutyryl)-phenol (4.90 g., 0.02 mole) in dimethylformamide (20 ml.) is added potassium carbonate (6.08 g., 0.044 mole) and ethyl 2-bromopropionate (7.97 g., 0.044 mole). The reaction mixture is heated at 55°-60° C. for one hour with stirring. The reaction mixture is cooled. Water (50 ml.) is added and the resulting oil is extracted with ether (3 × 100 ml.). The combined ether extracts are dried over anhydrous magnesium sulfate, filtered and the ether is evaporated under reduced pressure to afford ethyl 2-[2,3-dichloro-4-(2-methylenebutyryl)phenoxy]propionate. The ester is dissolved in ethanol (75 ml.) and treated with a solution of sodium bicarbonate (5.04 g., 0.06 mole) in water (150 ml.). The mixture is heated on a steam bath with stirring for 5 hours and then concentrated under reduced pressure to a volume of 50 ml. Water (50 ml.) is added and the solution is acidified to a pH of 4 with hydrochloric acid (6N). The resulting oil is extracted with ether (3 × 100 ml.) and the combined extracts are dried over anhydrous magnesium sulfate. The ether is evaporated under reduced pressure to afford 6.34 g. (100%) of a white, waxy solid. Recrystallization from cyclohexane affords 5 g. (79%) of crude product, m.p. 115°-119° C. Further purification by recrystallization from butyl chloride affords substantially pure 2-[2,3-dichloro-4-(2-methylenebutyryl)phenoxy]propionic acid, m.p., 122.5°-123.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH:9]2[C:13](=[O:14])[CH2:12][CH2:11][C:10]2=[O:15])=[C:4]([CH3:16])[CH:3]=1.[C:17](=O)([O-])[O-].[K+].[K+].IC>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH3:16])[C:5]([C:9]2[C:13](=[O:14])[CH2:12][CH2:11][C:10]=2[O:15][CH3:17])=[C:6]([CH3:8])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(F)cc(C)c1C1C(=O)CCC1=O
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: COC1=C(c2c(C)cc(F)cc2C)C(=O)CC1
Temperature: 27.5 °C
Reaction time: 16 h
Yield: 64.2 %

Procedure:
To a solution of 2-(4-fluoro-2,6-dimethylphenyl)-cyclopentane-1,3-dione (2.9 g, 13.3 mmol) in tetrahydrofuran (290 ml) is added anhydrous potassium carbonate (22 g, 159 mmol) and iodomethane (22.6 g, 159 mmol. The resulting mixture is stirred at 25-30° C. for 16 hours. The organic layer is evaporated, reaction mixture is quenched with water (150 ml) and extracted with ethylacetate (3×100 ml). The combined organic extracts are combined, washed with water and brine, dried over anhydrous sodium sulphate, filtered and the filtrate is concentrated in vacuo. The residue is purified by column chromatography on silica gel to give 2-(4-fluoro-2,6-dimethylphenyl)-3-methoxy-cyclopent-2-enone (2 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([CH:10](N2C(C)=CC=C2C)[CH3:11])[C:5]=1[F:19])[CH3:2].Cl.[NH2:21]O.[OH-].[K+].C(O)C>O>[NH2:21][CH2:11][CH2:10][C:6]1[C:5]([F:19])=[C:4]([O:3][CH2:1][CH3:2])[CH:9]=[CH:8][N:7]=1
Reactant: NO
Reactant: CCOc1ccnc(C(C)n2c(C)ccc2C)c1F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOc1ccnc(CCN)c1F
Temperature: 25 °C

Procedure:
A mixture of 825 mg (3.15 mmole) of N-[(4-Ethoxy-3-fluoropyrid-2-yl)eth-2-yl]-2,5-dimethylpyrrole, 1.4 g (20.1 mmole) of hydroxylamine hydrochloride, 700 mg (12.5 mmole) of potassium hydroxide, 20 ml of ethanol, and 8 ml of water was refluxed for 3 days under nitrogen. The solution was cooled to room temperature, concentrated, and partitioned between 50 ml of 2N hydrochloric acid and ethyl acetate (3×). The aqueous layer was basified with 5N sodium hydroxide, extracted with ethyl acetate (3×), dried over sodium sulfate, and concentrated. The resulting red oil was found to be the titled compound with a small amount of 2,5-hexanedione dioxime also present. The oil was used as such for reaction without further purification: IR (KBr, cm−1) 2989, 1609, 1495, 1306, 1075; 1H NMR (300 MHz, DMSO-d6) δ 8.18 (d, 11H), 7.05 (t, 1H), 4.20 (q, 2H), 2.60-3.00 (m, 6H), 1.38 (t, 3H); MS (FD) m/e 185 (Mt).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1.[C:18](Cl)(=O)/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1>>[N+:15]([C:13]1[CH:12]=[CH:11][C:3]2[N:4]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=3)[C:18](/[CH:19]=[CH:20]/[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:1][C:2]=2[CH:14]=1)([O-:17])=[O:16]
Reactant: Nc1cc([N+](=O)[O-])ccc1Nc1ccccn1
Reactant: O=C(Cl)/C=C/c1ccccc1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Product: O=[N+]([O-])c1ccc2c(c1)nc(/C=C/c1ccccc1)n2-c1ccccn1

Procedure:
The titled compound was prepared from 2-(2-amino-4-nitroanilino)pyridine (Runti, C. Ann. Chim. (Rome), 1956, 46, 406) and (E)-cinnamoyl chloride according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). MW: 342.36; mp: 200.5-201.5° C.; 1H NMR (CDCl3) δ: 8.82 (1H, ddd, J=4.8, 1.8, 0.7 Hz), 8.72 (1H, d, J=2.2 Hz), 8.20 (1H, dd, J=8.8, 2.2 Hz), 8.81 (1H, d, J=16.0 Hz), 8.66 (1H, ddd, J=8.1, 7.7, 1.8 Hz), 7.58-7.47 (5H, m), 7.45-7.32 (3H, m), 7.07 d, J=16.0 Hz).
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[CH3:5][C:6]([C:9]1[CH:10]=[C:11]([O:15][C:16]2[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=2)[CH:12]=[CH:13][CH:14]=1)([CH3:8])[CH3:7].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.O>[CH3:8][C:6]([C:9]1[CH:10]=[C:11]([O:15][C:16]2[CH:17]=[C:18]([CH3:24])[C:19]([N:20]=[C:1]=[S:2])=[CH:21][C:22]=2[CH3:23])[CH:12]=[CH:13][CH:14]=1)([CH3:5])[CH3:7]
Reactant: Cc1cc(Oc2cccc(C(C)(C)C)c2)c(C)cc1N
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(Oc2cccc(C(C)(C)C)c2)c(C)cc1N=C=S
Reaction time: 2 h

Procedure:
Thiophosgene (0.38 ml) is added to a two-phase mixture at room temperature of 4-((3-(1,1-dimethyl-ethyl)phenyl)oxy)-2,5-dimethylaniline (1.35 g) in toluene (6 ml) and sodium bicarbonate (840 mg) in water (6 ml). The reaction mixture obtained is stirred for 2 h and the phases are then separated by settling. The aqueous phase is extracted with toluene and the combined organic phases are then washed with water, dried (magnesium sulphate) and then concentrated to give the title product.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].S(Cl)(Cl)=O.[CH2:10]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20](=[O:22])[CH3:21])[CH2:11][CH3:12]>>[C:20]([C:15]1[CH:16]=[C:17]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:18]=[CH:19][C:14]=1[O:13][CH2:10][CH2:11][CH3:12])(=[O:22])[CH3:21]
Reactant: O=S(=O)(O)Cl
Reactant: CCCOc1ccccc1C(C)=O
Solvent: O=S(Cl)Cl
Product: CCCOc1ccc(S(=O)(=O)Cl)cc1C(C)=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a mixture of chlorosulphonic acid (27 mL) and thionyl chloride (3.6 mL) at 0° C. was added portionwise 1-(2-propoxyphenyl)ethanone (5.0 g, 28.1 mmol). The resulting mixture was stirred at 0° C. for 20 min. and at room temperature overnight, poured cautiously into ice-water and extracted with methylene chloride. The organic solution was washed sequentially with water, aqueous sodium bicarbonate and brine, dried (MgSO4), and the solvent removed under reduced pressure to yield the title compound (6.3 g, 81%) as an off-white solid.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[NH:30]1[CH2:33][CH:32]([N:34]2[CH2:39][CH2:38][NH:37][C:36](=[O:40])[CH2:35]2)[CH2:31]1.ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][CH:33]4[NH:30][CH2:31][CH:32]4[N:34]4[CH2:39][CH2:38][NH:37][C:36](=[O:40])[CH2:35]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: O=C1CN(C2CNC2)CCN1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3NCC3N3CCNC(=O)C3)n(C)c2n1
Reaction time: 16 h

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (100 mg, 0.26 mmol), 4-azetidin-3-ylpiperazin-2-one (44 mg, 0.28 mmol) and 4 Å powdered molecular sieves (250 mg) in MeOH (2 mL) and DCE (5 mL) was stirred at room temperature for 2 h before the addition of sodium triacetoxyborohydride (108 mg, 0.51 mmol). The reaction mixture was stirred for 16 h then filtered through celite, washing with DCM. The organic phase was washed with brine (×1) and concentrated in vacuo. The organic phase was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-7%). The resulting oil was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording 514 as a yellow foam (42 mg, 31%). LCMS (Method I): RT 2.28 min [M+H]+ 531.2. 1H NMR (CDCl3, 400 MHz): δ 8.02-7.97 (m, 1 H); 7.79-7.74 (m, 1 H); 7.31-7.24 (m, 2 H); 5.93 (bs, 1 H); 4.35 (m, 4 H); 3.94 (s, 2 H); 3.94-3.80 (m, 7 H); 3.66 (bs, 2 H); 3.43-3.33 (m, 4 H); 3.21 (s, 3 H); 3.06 (s, 2 H); 2.58 (t, J=5.37 Hz, 2 H) and 1.45 (t, J=7.5 Hz, 3 H)
Reaction SMILES: C(=O)([S:3][CH2:4][C:5]([NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])([CH3:7])[CH3:6])C.[OH-].[Na+].C(OCC)(=O)C>CO>[SH:3][CH2:4][C:5]([NH:8][C:9](=[O:10])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:7])[CH3:6]
Reactant: CC(=O)SCC(C)(C)NC(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(CS)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of S-2-(Benzyloxycarbonylamino)-2-methylpropyl ethanethioate (4.75 g, 16.9 mmol) in methanol (35 mL) was mixed with a 5 N sodium hydroxide solution (3 equiv, 50 mL, 50.7 mmol) and stirred at RT for 15 min. TLC (20% ethyl acetate in hexanes) analysis of reaction mixture indicated all the starting material was consumed. The organic solvent was removed under reduced pressure and the resulting aqueous solution was made acidic (˜pH 3) with 6 N HCl (9 mL) while cooled in an ice bath. The aqueous suspension was extracted with ethyl acetate (3×100 mL) and the combined organic layer dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give benzyl 1-mercapto-2-methylpropan-2-ylcarbamate as a pale yellow oil, 4.6 g. This material was used without any further purification.
Reaction SMILES: CS(O)(=O)=O.CS(O)(=O)=O.[NH2:11][C@H:12]1[C:25](=[O:26])[N:24]([CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:23][C:15]2[C:16]3[CH:17]=[N:18][NH:19][C:20]=3[CH:21]=[CH:22][C:14]=2[CH2:13]1.[CH3:32][N:33]1[C:37]2([CH2:46][CH2:45][C:44]3[C:39](=[CH:40][CH:41]=[C:42]([C:47](O)=[O:48])[CH:43]=3)[CH2:38]2)[C:36](=[O:50])[NH:35][C:34]1=[O:51].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[CH3:29][C:28]([CH3:31])([CH3:30])[CH2:27][N:24]1[C:25](=[O:26])[C@H:12]([NH:11][C:47]([C:42]2[CH:43]=[C:44]3[C:39](=[CH:40][CH:41]=2)[CH2:38][C:37]2([C:36](=[O:50])[NH:35][C:34](=[O:51])[N:33]2[CH3:32])[CH2:46][CH2:45]3)=[O:48])[CH2:13][C:14]2[CH:22]=[CH:21][C:20]3[NH:19][N:18]=[CH:17][C:16]=3[C:15]=2[CH2:23]1
Reactant: CN1C(=O)NC(=O)C12CCc1cc(C(=O)O)ccc1C2
Reactant: CC(C)(C)CN1Cc2c(ccc3[nH]ncc23)C[C@@H](N)C1=O
Agent: CS(=O)(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CN1C(=O)NC(=O)C12CCc1cc(C(=O)N[C@@H]3Cc4ccc5[nH]ncc5c4CN(CC(C)(C)C)C3=O)ccc1C2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 7-(R)-amino-9-(2,2-dimethylpropyl)-6,7,9,10-tetrahydro-3H-2,3,9-triazacyclohepta[e]inden-8-one bis-methanesulfonate (110 mg, 0.23 mmol) [Chaturvedula et al. WO 2006/052378], (±)-3-methyl-2,5-dioxo-3′,4′-dihydro-1′H-spiro[imidazolidine-4,2′-naphthalene]-6′-carboxylic acid (77 mg, 0.28 mmol) [Bell et al. WO 2004/082605], HOBT (43 mg, 0.28 mmol), and EDC (54 mg, 0.28 mmol) in DMF (2 mL) is stirred at ambient temperature for 18 h. The reaction mixture is purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H-90:10:0.1 to 5:95:0.1. The pure, product-containing fractions are combined and made basic with saturated aqueous NaHCO3. The resulting mixture is extracted with EtOAc (2×20 mL), and the combined organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound.
Reaction SMILES: [C:1](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:2].[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[C:19]([NH2:27])[N:18]=1>ClCCl>[N:27]([C:19]1[N:18]=[CH:17][C:26]2[C:21]([CH:20]=1)=[CH:22][CH:23]=[CH:24][CH:25]=2)=[C:1]=[S:2]
Reactant: Nc1cc2ccccc2cn1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Solvent: ClCCl
Product: S=C=Nc1cc2ccccc2cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1,1′-thiocarbonyldipyridin-2(1H)-one (0.805 g, 3.47 mmol) in dichloromethane at room temperature was added isoquinolin-3-amine (0.5 g, 3.47 mmol). The reaction was stirred at room temperature for 18 hours. The LC/MS showed the desired product peak a major peak. The deep orange solution was concentrated and filtered. The filtrate was purified by silica gel chromatography (0-40% ethyl acetate-hexanes) to afford 4-isothioeyanato-6-(3-methoxyphenyl)pyrimidine (0.55 g, 2.96 mmol, 85% yield) a white solid. LCMS R.T.=2.47; [M+H]+=187.23.