Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][C:11]=2[C:13]2[CH:14]=[N:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:6]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][C:24]=2[CH3:31])[N:5]=1)([CH3:3])[CH3:2].[OH-:32].[Na+].OO.O>CS(C)=O.C(O)C>[CH:1]([C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][C:11]=2[C:13]2[CH:14]=[N:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:6]([C:23]2[CH:30]=[CH:29][C:26]([C:27]([NH2:28])=[O:32])=[CH:25][C:24]=2[CH3:31])[N:5]=1)([CH3:3])[CH3:2]
Reactant: Cc1cc(C#N)ccc1-n1nc(C(C)C)c2c(-c3cnc4ccccc4c3)ccnc21
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CS(C)=O
Product: Cc1cc(C(N)=O)ccc1-n1nc(C(C)C)c2c(-c3cnc4ccccc4c3)ccnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
4-Fluoro-3-methylbenzonitrile (0.077 g) and cesium carbonate (0.203 g) were added to a solution of compound (6c) (0.150 g) in DMF (1.73 mL), followed by stirring at 80° C. for 18 hr. The reaction solution was distributed between ethyl acetate and water. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled away, and the residue was purified by neutral silica gel column chromatography (hexane/ethyl acetate) to obtain 4-{3-isopropyl-4-(quinolin-3-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}-3-methylbenzonitrile (0.154 g, 73%). This 4-{3-isopropyl-4-(quinolin-3-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}-3-methylbenzonitrile was dissolved in DMSO (5.0 mL) and ethanol (5.0 mL). A 4 N aqueous sodium hydroxide solution (0.195 mL) and a 30% hydrogen peroxide solution (0.088 mL) were added to the resulting solution, followed by stirring at room temperature for 30 min. Water was added to the reaction solution, and the precipitate was collected by filtration, washed with diethyl ether, and dried under reduced pressure to obtain compound (80) (0.135 g, 83%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([CH2:15]O)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].S(Cl)([Cl:19])=O>>[ClH:1].[Cl:19][CH2:15][C:13]1[CH:12]=[CH:11][N:10]=[C:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH:14]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccnc(-c2ccc(Cl)c(Cl)c2)c1
Product: Cl
Product: ClCc1ccnc(-c2ccc(Cl)c(Cl)c2)c1

Procedure:
The title compound, MS: m/e=271.0 (M+) was obtained as a light brown foam (100% yield) by the reaction of [2-(3,4-dichloro-phenyl)-pyridine-4-yl]-methanol with thionyl chloride at 20° C. for 1 h.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:34])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:14]=1)[N:11]([CH2:21][CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[C:10](=[O:27])[C:9]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[CH:8]2)=[O:4].[NH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH2:25]([CH:22]([CH2:23][CH3:24])[CH2:21][N:11]1[C:12]2[C:7](=[C:6]([OH:34])[C:5]([C:3]([NH:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:4])=[N:14][C:13]=2[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:8]=[C:9]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:10]1=[O:27])[CH3:26]
Reactant: NCCC(=O)O
Reactant: CCC(CC)Cn1c(=O)c(-c2ccccc2)cc2c(O)c(C(=O)OC)nc(-c3cccnc3)c21
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: CCC(CC)Cn1c(=O)c(-c2ccccc2)cc2c(O)c(C(=O)NCCC(=O)O)nc(-c3cccnc3)c21
Temperature: 25 °C
Yield: 38.3 %

Procedure:
A mixture of 1-(2-ethyl-butyl)-5-hydroxy-2-oxo-3-phenyl-8-pyridin-3-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (30 mg, 0.066 mmol), β-alanine (585 mg, 6.6 mmol) and NaOMe solution (10 mL, 4.9 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (5-90% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3, and the resulting precipitate was isolated by filtration to give 13 mg of the title compound as an off-white solid. MS: (+) m/z 515.36 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1.[CH3:12][C:13]([NH2:17])([CH2:15][CH3:16])[CH3:14].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:11][S:10][C:4]1[N:3]=[C:2]([NH:17][C:13]([CH2:15][CH3:16])([CH3:14])[CH3:12])[C:7]([C:8]#[N:9])=[CH:6][N:5]=1
Reactant: CSc1ncc(C#N)c(Cl)n1
Reactant: CCC(C)(C)N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC(C)(C)Nc1nc(SC)ncc1C#N
Temperature: 70 °C

Procedure:
4-Chloro-2-(methylthio)pyrimidine-5-carbonitrile (500 mg, 2.69 mmol) was dissolved in DMF (5 mL), 2-methylbutan-2-amine (0.378 mL, 3.24 mmol) and DIEA (1.411 mL, 8.08 mmol) were added and the reaction was heated at 70° C. overnight. LCMS showed the desired product mass as the dominant peak and no starting material remaining. The reaction was removed from heat and partitioned between ethyl acetate and water. The organic layer was washed once with brine before drying over magnesium sulfate, filtering, and condensing. The crude material was purified by silica gel chromatography (0-80% ethyl acetate in hexane over 1650 mL; 40 mL/min). Product fractions were combined, evaporated, and dried under high vacuum to afford 2-(methylthio)-4-(tert-pentylamino)pyrimidine-5-carbonitrile (359 mg, 1.519 mmol, 56.4% yield) as a white solid; MS (ESI) m/z 236.9 [M+1]+
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[C:19]([NH:22][CH2:23][C:24]1[S:28][C:27]([SH:29])=[N:26][N:25]=1)(=[O:21])[CH3:20].C(=O)(O)[O-].[Na+]>O>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:29][C:27]3[S:28][C:24]([CH2:23][NH:22][C:19](=[O:21])[CH3:20])=[N:25][N:26]=3)[CH2:15][S:14][C@H:9]12
Reactant: CC(=O)NCc1nnc(S)s1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(=O)NCc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)s1
Temperature: 60 °C
Reaction time: 5 h
Yield: 51.4 %

Procedure:
7-Aminocephalosporanic acid (1.36 g.), 5-acetamidomethyl-1,3,4-thiadiazole-2-thiol (1.04 g.) and sodium bicarbonate (885 mg.) were dissolved in water (70 ml.), and the solution was stirred at 60° C. for 5 hrs. After the reaction, the reaction mixture was adjusted to pH 5, and then allowed to stand overnight in a refrigerator. The precipitating crystals were collected by filtration to give 7-amino-3-(5-acetamidomethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (1.03 g.) m.p. 195°-197° C. (dec.).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:15]=[C:16]2[CH:22]=[CH:21][NH:20][C:17]2=[N:18][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].[I:25]I>CN(C=O)C>[I:25][C:22]1[C:16]2[C:17](=[N:18][CH:19]=[C:14]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:15]=2)[NH:20][CH:21]=1
Reactant: c1ccc(Oc2ccccc2-c2cnc3[nH]ccc3c2)cc1
Reactant: II
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Ic1c[nH]c2ncc(-c3ccccc3Oc3ccccc3)cc12
Reaction time: 0.5 h

Procedure:
To a solution of the azaindole 25 (18.30 g, 63.9 mmol) in DMF (100 mL) was added KOH (13.27 g, 236.5 mmol) in a single portion. After 0.5 h, iodine (16.18 g, 63.9 mmol) was added in portions over a 3 min. period. After a further 1 h the reaction was quenched by the addition of a solution of sodium thiosulfate (70 g) in H2O (400 mL). The semisolid was filtered off, dissolved in dichloromethane. The solution and washed with saturated brine (1×), dried (MgSO4), and concentrated to afford the iodide 26, which was used directly in the next step without further purification. 1H NMR (400 MHz; CDCl3) δ6.92-6.95 (m, 2H), 7.01 (tt, J=7.3, 1.0 Hz, 1H), 7.08 (dd, J=8.1, 1.3 Hz, 1H), 7.23-7.30 (m, 3H), 7.36 (dt, J=7.3, 1.8 Hz, 1H), 7.40 (s, H), 7.54 (dd, J=7.6, 1.8 Hz, 1H), 7.93 (d, J=2.0 Hz, 1H), 8.54 (d, J=2.0 Hz, 1H) and 11.06 (bs, 1H).
Reaction SMILES: [S:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=[CH:2]1.Br[CH2:11][CH2:12][OH:13].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.O.C(OCC)(=O)C>[OH:13][CH2:12][CH2:11][N:6]1[CH2:7][CH2:8][C:9]2[S:1][CH:2]=[CH:3][C:4]=2[CH2:5]1
Reactant: OCCBr
Reactant: c1cc2c(s1)CCNC2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: OCCN1CCc2sccc2C1
Temperature: 70 °C
Reaction time: 2 h
Yield: 54.8 %

Procedure:
A mixture of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine (0.86 g), 2-bromoethanol (0.66 g), potassium carbonate (2.58 g) and potassium iodide (3.10 g) in N,N-dimethylformamide (20 ml) was stirred at 70° C. for 2 hours. After cooling, ethyl acetate and water were added thereto. The organic layer was separated, washed with water twice, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixed solvent of methanol and dichloromethane (1:10) as an eluent. The fractions containing the objective compound were collected and evaporated under reduced pressure to give 5-(2-hydroxyethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (0.53 g) as an oil.
Reaction SMILES: C([CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15])[C:6](N)=[O:7])CCC.[OH-:16].[Na+].C(N)CCC.Cl>[Ni].O>[Cl:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:5][C:6]([OH:7])=[O:16]
Reactant: [OH-]
Reactant: CCCCC(C(N)=O)c1ccccc1Cl
Agent: [Ni]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCCCN
Product: O=C(O)Cc1ccccc1Cl
Yield: 95 %

Procedure:
225.5 g (1 mol) of N-t.-butyl-(2-chlorophenyl)-acetamide (melting point: 128°-130° C.) and 281 g of 15% strength NaOH (1.05 mols) are heated at 260° C., while stirring, for 3 hours in a 0.7 l nickel autoclave. The autoclave is cooled and the reaction mixture is run into a distillation apparatus. Distillation through a 30 cm column up to a head temperature of 100° C. gives 71.5 g of t.-butylamine of 97% purity, corresponding to a yield of 95% of the theoretical yield. 200 ml of water and 100 ml of 30% strength hydrochloric acid are added to the distillation bottom product. The acid which has been precipitated is filtered off with suction and dried in vacuo. 157.8 g of o-chlorophenylacetic acid of melting point 95° C. are obtained.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.Cl[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]1=O.N1C=CC=CC=1>COCCO.CCCCCC>[CH:8]1[CH:7]=[CH:6][C:5]2[CH2:4][CH2:3][CH2:2][N:1]3[C:10]=2[C:9]=1[C:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=13
Reactant: c1ccc2c(c1)CCCN2
Reactant: O=C1CCCCC1Cl
Solvent: c1ccncc1
Solvent: COCCO
Solvent: CCCCCC
Product: c1cc2c3c(c1)c1c(n3CCC2)CCCC1
Temperature: 120 °C

Procedure:
A mixture of 1,2,3,4-tetrahydroquinoline (4.0 mL, 32 mmol), 2-chlorocyclohexanone (3.6 mL, 32 mmol) and pyridine (3.0 mL, 38 mmol) in 2-methoxyethanol (80 mL) was heated to 120° C. for 48 h and was then concentrated. The black gummy residue was extracted into ethyl acetate and washed with 2 N HCl. The organic layer was dried (MgSO4) and concentrated. The material was purified by flash column chromatography (elution with 5% ethyl acetate-hexanes) to provide a clear oil which was dissolved in hexane. Upon cooling the solution to −78° C. a precipitate formed. The precipitate was collected to provide 5,6,8,9,10,11-hexahydro-4H-pyrido[3,2,1-jk]carbazole. MS (ES) m/z 212.1.
Reaction SMILES: [F:1][C:2]([F:14])([CH:11]([F:13])[F:12])[C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[BH4-].[Na+].Cl>C1(C)C=CC=CC=1>[F:1][C:2]([F:14])([CH:11]([F:12])[F:13])[CH:3]([OH:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(=O)C(F)(F)C(F)F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(O)C(F)(F)C(F)F
Temperature: 0 °C
Reaction time: 8 h
Yield: 88235.3 %

Procedure:
Ethyl 4,4,5,5-tetrafluoro-3-oxo-pentanoate (25.7 g, 0.119 mmol) was dissolved in toluene (260 ml) and cooled to 0° C. Sodium borohydride (5.4 g, 0.143 g) was added portionwise, and the mixture was allowed to reach room temperature overnight with stirring. The mixture was then cooled to 0° C. and acidified with 1 m HCl. The phases were separated, the aqueous phase was extracted two times with ethyl acetate, the combined organic phases were dried over magnesium sulfate and the solvent was removed under reduced pressure. The residue was dissolved in a minimum amount of methanol, the resulting solution was evaporated to dryness under reduced pressure to yield 22.9 g of a residue (0.105 mol, 88%) that were used directly in the next step.
Reaction SMILES: [C:1]([C:9]1[CH:25]=[CH:24][C:12]2[N:13]=[C:14]([C:16]3[CH:17]=[C:18]([C:21](O)=[O:22])[NH:19][CH:20]=3)[NH:15][C:11]=2[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O.N1C=CC=CC=1.O>[C:1]([C:9]1[CH:25]=[CH:24][C:12]2[N:13]=[C:14]([C:16]3[CH:17]=[C:18]([C:21]([N:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)=[O:22])[NH:19][CH:20]=3)[NH:15][C:11]=2[CH:10]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCNC1
Reactant: O=C(c1ccccc1)c1ccc2nc(-c3c[nH]c(C(=O)O)c3)[nH]c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(c1ccccc1)c1ccc2nc(-c3c[nH]c(C(=O)N4CCCC4)c3)[nH]c2c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 78.2 %

Procedure:
The 4-(5-benzoylbenzimidazol-2-yl)-pyrrole-2-carboxylic acid (130 mg) obtained in Example 5 was dissolved in N,N-dimethylformamide (2 ml) and pyridine (2 ml). Pyrrolidine (56 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (112 mg), and 1-hydroxybenzotriazole monohydrate (80 mg) were added and stirred overnight at 80° C. After the starting material was disappeared, the reaction mixture was allowed to cool to room temperature, and then added dropwise to water. The precipitate was collected by filtration, and dried in vacuo to afford ((4-(5-benzoylbenzimidazol-2-yl)-pyrrol-2-yl)-carbonyl)pyrrolidine (118 mg, 78%) as a red solid.
Reaction SMILES: [CH:1]([C:3]1[S:7][CH:6]=[C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][CH:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH:29](C)[CH3:30])(=[O:28])=[O:27])[CH2:22][CH2:21]2)[CH:4]=1)=O.[CH2:32]([S:34][CH2:35][CH2:36][NH2:37])[CH3:33].[C:38](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([BH3-])#N.[Na+].C=O>CS(C)=O.C(O)(=O)C>[CH2:29]([S:26]([N:23]1[CH2:22][CH2:21][CH:20]([C:11]2[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=[C:8]([C:5]4[CH:4]=[C:3]([CH2:1][N:37]([CH2:36][CH2:35][S:34][CH2:32][CH3:33])[CH3:38])[S:7][CH:6]=4)[CH:9]=3)[NH:13][CH:12]=2)[CH2:25][CH2:24]1)(=[O:27])=[O:28])[CH3:30]
Reactant: CC(C)S(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(C=O)c4)cc23)CC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CCSCCN
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CCSCCN(C)Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cs1
Reaction time: 8 h
Yield: 14.2 %

Procedure:
To a solution of 5-(5-formyl-3-thienyl)-3-{1-[(1-methylethyl)sulfonyl]-4-piperidinyl}-1H-indole-7-carboxamide (40 mg, 0.09 mmol) in DMSO (2 mL) was added [2-(ethylthio)ethyl]amine (105 mg, 1 mmol), acetic acid (50 μL), and sodium triacetoxyborohydride (212 mg, 1.0 mmol). The resulting mixture was stirred overnight. To the mixture was added sodium cyanoborohydride (80 mg, 1.2 mmol) and stirred overnight followed by addition of formaldehyde (100 μL, 1.2 mmol). The mixture was then stirred for an additional 3 h. It was then purified by Gilson Preparatory HPLC to give 7.0 mg of the title compound.
Reaction SMILES: [S:1]([Cl:5])(Cl)(=[O:3])=[O:2].[F:6][C:7]([F:27])([F:26])[O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][CH2:18][C:17]3([CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[C:16]2=[O:25])=[CH:11][CH:10]=1.CCN(CC)CC>C(Cl)(Cl)Cl>[O:25]=[C:16]1[C:17]2([CH2:24][CH2:23][N:22]([S:1]([Cl:5])(=[O:3])=[O:2])[CH2:21][CH2:20]2)[CH2:18][CH2:19][N:15]1[C:12]1[CH:11]=[CH:10][C:9]([O:8][C:7]([F:27])([F:6])[F:26])=[CH:14][CH:13]=1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Reactant: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)Cl)CC2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 405 mg (2.91 mmol) sulfuryl chloride in 15 mL anhydrous CHCl3 at 0° C. was slowly added a mixture of 915 mg (2.91 mmol) 2-(4-(trifluoromethoxy)phenyl)-2,8-diazaspiro[4.5]decan-1-one and 295 mg (2.91 mmol) NEt3 over a period of 30 min and stirred at 0° C. for 1 h. the mixture was allowed to warm to room temperature stirred for 1 h and 405 mg (2.91 mmol) sulfuryl chloride was added. The mixture was stirred for 5 h at room temperature, evaporated to dryness and used without further purification in the consecutive step. MS (ESI): 315.2 (M-SO2Cl)H+.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[S:18]1[CH:22]=[CH:21][C:20]2[CH:23]=[C:24]([CH:27]([OH:43])[CH2:28][O:29][CH2:30][CH2:31][O:32][S:33]([C:36]3[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH:25]=[CH:26][C:19]1=2.[O:44]1[CH:49]=[CH:48][CH2:47][CH2:46][CH2:45]1>C(Cl)Cl>[S:18]1[CH:22]=[CH:21][C:20]2[CH:23]=[C:24]([CH:27]([O:43][CH:45]3[CH2:46][CH2:47][CH2:48][CH2:49][O:44]3)[CH2:28][O:29][CH2:30][CH2:31][O:32][S:33]([C:36]3[CH:37]=[CH:38][C:39]([CH3:42])=[CH:40][CH:41]=3)(=[O:35])=[O:34])[CH:25]=[CH:26][C:19]1=2
Reactant: Cc1ccc(S(=O)(=O)OCCOCC(O)c2ccc3sccc3c2)cc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCOCC(OC2CCCCO2)c2ccc3sccc3c2)cc1
Reaction time: 0.5 h

Procedure:
0.97 g of pyridinium p-toluenesulfonate was added, at room temperature, to a solution of 7.6 g of 1-(benzo[b]thiophen-5-yl)-2-[2-(p-toluenesulfonyloxy)ethoxy]ethanol and 3.5 ml of 3,4-dihydro-2H-pyran dissolved in 40 ml of methylene chloride. The mixture was stirred at the same temperature for 20 minutes and further at 40°-45° for 30 minutes. The reaction mixture was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain 8.7 g of colorless, oily 1-(benzo[b]thiophen-5-yl)-1-(2-tetrahydropyranyloxy)-2-[2-(p-toluenesulfonyloxy)ethoxy]ethane.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](O)=O)([O-:3])=[O:2].[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.[OH:18][C:19]1C2N=NNC=2C=CC=1.CNC(N=C=NCC)CCNC.C(NC(C)C)(C)C>ClCCl>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:7][C:19]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:18])[CH:10]=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: C1CCNC1
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Reactant: Oc1cccc2[nH]nnc12
Agent: CCN=C=NC(CCNC)NC
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: O=C(Cc1cccc([N+](=O)[O-])c1)N1CCCC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 1.98 g of meta-nitrobenzoic acid in 50 mL of dichloromethane are successively added under argon, at 0° C., 0.81 mL of pyrrolidine, 0.13 g of hydroxybenzotriazole, 2.3 g of 1,3-dimethylaminopropyl-3-ethyl carbodiimide and 3.43 mL of diisopropylamine. The reaction mixture is then stirred at room temperature for 15 hours and washed with water. The organic phase is then washed with saturated sodium chloride solution, dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica, eluting with a mixture of ethyl acetate and cyclohexane (60/40 by volume) to give 1.92 g of 1-[(3-nitrophenyl)acetyl]pyrrolidine, the characteristics of which are as follows:
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([CH3:22])([O:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][O:17]3)[CH3:14])[C:7](=[O:23])[CH:6]3[CH2:24][O:25][CH2:26][CH2:27][N:5]3[C:4]=2[N:3]=1.IC.[CH3:30]C([O-])(C)C.[Na+]>CS(C)=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([CH3:14])([O:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][O:17]3)[CH3:22])[C:7](=[O:23])[C:6]3([CH3:30])[CH2:24][O:25][CH2:26][CH2:27][N:5]3[C:4]=2[N:3]=1
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(CN1C(=O)C2COCCN2c2nc(Cl)ncc21)OC1CCCCO1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CI
Product: CC(C)(CN1C(=O)C2(C)COCCN2c2nc(Cl)ncc21)OC1CCCCO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 133.1 %

Procedure:
To a mixture of 2-chloro-5-(2-methyl-2-(tetrahydro-2H-pyran-2-yloxy)propyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (96.2 mg, 0.242 mmol) and iodomethane (0.076 ml, 1.21 mmol) in DMSO (4 ml) at 0° C. was added sodium 2-methylpropan-2-olate (46.6 mg, 0.485 mmol). The ice-bath was removed and the reaction mixture was stirred at room temperature for 16 h, followed by being poured into water. Extraction with EtOAc, washing with water, drying and concentration in vacuo gave crude 2-chloro-6a-methyl-5-(2-methyl-2-(tetrahydro-2H-pyran-2-yloxy)propyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (133 mg, 0.322 mmol) as a red oil which was used without further purification. MS [M+H] found 411.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:26][CH2:25][CH2:24][CH:23]([OH:27])[CH2:22][CH2:21]2)=[CH:16][CH:15]=1)([O-:13])=[O:12].CCN(CC)CC>C(Cl)Cl>[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:26][CH2:25][CH2:24][C:23](=[O:27])[CH2:22][CH2:21]2)=[CH:16][CH:15]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc(N2CCCC(O)CC2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 84.1 %

Procedure:
To a dry round bottom flask was added 2M oxalyl chloride (1.392 mL, 2.78 mmol) and CH2Cl2 (10 mL). The resulting solution was cooled to −78° C. DMSO (0.395 mL, 5.57 mmol) was then slowly added to the solution over 10 min. The reaction was stirred at −78° C. for 20 mins. Then 1-(4-nitrophenyl)azepan-4-ol (470 mg, 1.989 mmol) dissolved in CH2Cl2 (5 ml) was added to the reaction and the reaction was stirred at −78° C. for 1.5 hr. After this time, Et3N (1.220 mL, 8.75 mmol) was added to the reaction mixture. The reaction mixture was then diluted with CH2Cl2 (30 ml). The reaction mixture was washed with water (20 ml) and saturated aqueous NaCl (20 ml). The organic layer was separated, dried over MgSO4, filtered and concentrated. The resulting residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-100% EtOAc/Hex to give the product, 1-(4-nitrophenyl)azepan-4-one (392 mg, 1.673 mmol, 84% yield) as a yellow solid. Anal. Calcd. for C12H14N2O3 m/z 234.2, found: 235.1 (M+H)+; 1H NMR (500 MHz, CDCl3) δ ppm 8.12 (d, J=9.35 Hz, 2H), 6.66 (d, J=9.35 Hz, 2H), 3.95-3.83 (m, 2H), 3.83-3.72 (m, 2H), 2.92-2.66 (m, 4H), 2.02-1.86 (m, 2H); 13C NMR (126 MHz, CDCl3) δ ppm 209.79, 151.25, 137.70, 126.52, 110.45, 51.82, 45.39, 42.64, 41.79, 23.88.