Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[C:5]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH:16]=2)[NH:4][N:3]=1.[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=1[S:37](Cl)(=[O:39])=[O:38].O>N1C=CC=CC=1>[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=1[S:37]([NH:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[C:5]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[CH:16]=2)[NH:4][N:3]=1)(=[O:39])=[O:38]
Reactant: O=S(=O)(Cl)c1c(Cl)cccc1Cl
Reactant: Nc1n[nH]c(SCc2cccc(Oc3ccc(F)cc3)c2)c1-c1ccccn1
Solvent: c1ccncc1
Solvent: O
Product: O=S(=O)(Nc1n[nH]c(SCc2cccc(Oc3ccc(F)cc3)c2)c1-c1ccccn1)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.7 %

Procedure:
3-Amino-4-(2-pyridyl)-5-(3-(4-fluorophenoxy)benzylthio)-(1H)-pyrazole (0.39 g, 0.99 mmol) was dissolved in 5 ml of pyridine. Commercial 2,6-dichlorobenzenesulfonyl chloride (0.26 g, 1.04 mmol) was added and the red solution was stirred overnight at room temperature. The reaction mixture was poured into 50 ml of water and was extracted twice with 100 ml portions of ethyl acetate. The organic layers were washed with water and brine, combined, dried over MgSO4 and concentrated. The crude product was slurried in cold ethyl acetate and the solid was filtered off and washed with small portions of cold ethyl acetate and cold diethyl ether and dried under vacuum to afford 0.32 g (53% yield) of the final compound.
Reaction SMILES: CN1CCOCC1.C(N=C=NCCCN(C)C)C.[CH3:19][CH:20]([CH3:43])[C@H:21]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:22][NH:23][C@H:24]([C:32]([OH:34])=O)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl.[CH3:45][O:46][C:47](=[O:54])[C@H:48]([CH2:50][CH2:51][S:52][CH3:53])[NH2:49].O.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:45][O:46][C:47](=[O:54])[C@H:48]([CH2:50][CH2:51][S:52][CH3:53])[NH:49][C:32](=[O:34])[C@H:24]([CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[NH:23][CH2:22][C@@H:21]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH:20]([CH3:19])[CH3:43]
Reactant: CC(C)[C@@H](CN[C@@H](Cc1ccccc1)C(=O)O)NC(=O)OC(C)(C)C
Reactant: COC(=O)[C@@H](N)CCSC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CCSC)NC(=O)[C@H](Cc1ccccc1)NC[C@@H](NC(=O)OC(C)(C)C)C(C)C
Temperature: 25 °C
Yield: 79.5 %

Procedure:
N-Methyl morpholine (4.0 ml) and 1-ethyl-3-(3-dimethylaminopropyl) carbodimide (EDC) hydrochloride (0.96 g, 0.005 mole) were added to a solution of the product of Step B (1.76 g, 0.005 mole), methionine methyl ester hydrochloride (1.0 g, 0.005 mole) and 1-hydroxybenzotriazole hydrate (HOBT,0.677 g, 0.005 mole) in dimethylformamide (DMF, 30 ml) the reaction mixture was stirred at room temperature over the weekend, concentrated in vacuo and taken up in ice, water, and ethyl acetate. After addition of 10% aqueous citric acid, the ethyl acetate solution was separated, washed with water (2×), aqueous NaHCO3 and brine, and dried over sodium sulfate. Filtration and evaporation of the ethyl acetate solution gave a pale yellow residue, which was purified by column chromatography (silica gel) using 35% ethyl acetate-hexane. The title compound (1.97 g) was obtained as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)[C:5]([C:15]#[N:16])=[C:4]([S:17]([CH3:19])=O)[N:3]=1.SC[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)[C:5]([C:15]#[N:16])=[C:4]([S:17][CH2:19][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2cccc(F)c2)c1C#N
Reactant: SCCc1ccccn1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(SCCc2ccccn2)nc(N)nc1-c1cccc(F)c1

Procedure:
From 2-amino-4-(3-fluoro-phenyl)-6-methanesulfinyl-pyrimidine-5-carbonitrile, 2-mercaptoethylpyridine and DBU in DME. ES-MS m/e (%): 352 (M+H+, 100).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:18][CH2:19][CH2:20][CH:21]=[O:22])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4].[CH3:23][Mg]Br>C1(C)C=CC=CC=1.C1COCC1>[CH2:1]([C:5]1[N:6]([CH2:18][CH2:19][CH2:20][CH:21]([OH:22])[CH3:23])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cnc3ccccc3c2n1CCCC=O
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCCCc1nc2cnc3ccccc3c2n1CCCC(C)O

Procedure:
The general method described in Step 7 of Example 1 was used to react 4-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyraldehyde (8.5 g, 28.8 mmol) with methylmagnesium bromide (20.6 mL of a 1.4 M solution in toluene/THF, 28.8 mmol) to provide 5-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-ol (3.54 g) as an off-white solid after chromatography on silica gel (elution with 5% methanol in dichloromethane).
Reaction SMILES: [C:1]([Si:5]([CH3:18])([CH3:17])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)C>[NH2:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][O:6][Si:5]([C:1]([CH3:2])([CH3:3])[CH3:4])([CH3:17])[CH3:18])=[CH:9][CH:10]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc([N+](=O)[O-])cc1
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OCc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 7.5 h
Yield: 94.2 %

Procedure:
In ethanol (80 ml) was dissolved tert-butyldimethyl-4-nitrobenzyloxysilane (16.5 g), and to the mixture was added dried 5% palladium on carbon (0.83 g). Under hydrogen atmosphere, the mixture was stirred at room temperature under atmospheric pressure for 7.5hours. The palladium was filtered off, and the filtrate was concentrated. The residue was separated and purified with column chromatography (ethyl acetate/hexane=1/4) to give 4-aminobenzyloxy-tert-butyldimethylsilane (13.8 g) as colorless oil.
Reaction SMILES: [CH3:1]N(C)C1C=CN=C2C=1C=CN2.[C:13]1([C:18]2[NH:29][C:21]3=N[CH:23]=[CH:24][C:25](N(C)C)=[C:20]3[CH:19]=2)[CH2:17][CH2:16][CH2:15]C=1.C1(=O)NC(=O)C=C1.[Br-].[Yb+3].[Br-].[Br-]>C1(C)C=CC=CC=1>[CH2:1]1[C:21]2[NH:29][C:18]3[C:19](=[CH:15][CH:16]=[CH:17][CH:13]=3)[C:20]=2[CH2:25][CH2:24][CH2:23]1
Reactant: CN(C)c1ccnc2[nH]c(C3=CCCC3)cc12
Reactant: CN(C)c1ccnc2[nH]ccc12
Agent: O=C1C=CC(=O)N1
Agent: [Br-]
Agent: [Yb+3]
Solvent: Cc1ccccc1
Product: c1ccc2c3c([nH]c2c1)CCCC3
Yield: 88 %

Procedure:
This compound was prepared using the same general procedure as outlined for la starting with 4-dimethylamino-7-azaindole. To a 25 mL round-bottomed flask containing a magnetic stirring bar equipped with a reflux condenser and a three-way stopcock connected to an argon balloon was charged with (2-cyclopent-1-enyl-1H-pyrrolo[2,3-b]pyridine-4-yl)-dimethylamine (12 mg, 0.05 mmol) followed by toluene (2 mL), maleimide (157 mg, 0.79 mmol) and ytterbium(III) bromide (19 mg, 0.04 mmol). The reaction mixture was refluxed for 1 h and the toluene evaporated under vacuum. The crude material was triturated with methanol (10 mL) filtered and washed with methanol. The filtrate was concentrated and purified by silica gel column chromatography to obtain tetrahydrocarbazole (15 mg, 88% yield). An oven dried, 25 mL round-bottomed flask containing a magnetic stirring bar was charged with 7-dimethylamino-1,2,3,3a,3b,6a,11,11b-octahydro-5,10,11-triaza-benzo[a]trindene-4,6-dione (15 mg, 0.04 mmol) followed by acetonitrile (4 mL). DDQ (35 mg, 0.15 mmol) was added at 15° C. and then stirred at rt for 1 h and at reflux for 6 h. Acetonitrile was evaporated under vacuum and dissolved in ethyl acetate then washed with saturated sodium bicarbonate, brine, dried (MgSO4) and concentrated to give a crude material. The crude material was purified by silica gel column chromatography to give Sac (2.3 mg, 15% yield). MS (m/z): 321 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][C:3]=1[CH3:10].[CH3:11][NH2:12]>C(O)C>[CH3:10][C:3]1[CH:4]=[CH:5][C:6]([CH2:8][OH:9])=[N:7][C:2]=1[NH:12][CH3:11]
Reactant: CN
Reactant: Cc1ccc(CO)nc1Cl
Solvent: CCO
Product: CNc1nc(CO)ccc1C
Yield: 37 %

Procedure:
0.96 g of (6-chloro-5-methylpyridin-2-yl)-methanol (6.09 mmol) and 7 ml of methylamine at 33% in ethanol are heated at 120° C in a bomb for 96 hours. 2 ml of methylamine at 33% in ethanol are added every 24 hours. The reaction mixture is concentrated under vacuum and the title compound isolated by chromatography on a silica column (eluent: cyclohexane/ethyl acetate; 40:60).
Reaction SMILES: [O-:1]Cl=O.[Na+].[Cl:5][C:6]1[N:7]=[C:8]([S:21]([NH:24][CH3:25])(=[O:23])=[O:22])[N:9]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:10]=1[CH:11]=[O:12].CC(=CC)C>O.C1COCC1.CC(O)(C)C>[Cl:5][C:6]1[N:7]=[C:8]([S:21]([NH:24][CH3:25])(=[O:23])=[O:22])[N:9]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:18])[CH3:19])[C:10]=1[C:11]([OH:1])=[O:12]
Reactant: [O-][Cl+][O-]
Reactant: CNS(=O)(=O)c1nc(Cl)c(C=O)n1COCC[Si](C)(C)C
Agent: CC=C(C)C
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1nc(Cl)c(C(=O)O)n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of NaClO2 (0.21 g, 2.34 mmol) and NaH2PO4.H2O (0.19 g, 1.41 mmol) in H2O (0.5 mL) was added to a solution of 4-chloro-5-formyl-N-methyl-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-2-sulfonamide (0.083 g, 0.23 mmol) and 2-methyl-2-butene (1.41 mL of a 2M solution in THF, 2.81 mmol) in THF (0.70 mL) and t-BuOH (0.16 mL). The reaction mixture was stirred at RT for 1 h and extracted with EtOAc. The organic layer was dried (Na2SO4), filtered and dried to provide 4-chloro-2-[(methylamino)sulfonyl]-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid as a clear oil that was assumed to be quantitative and used without further purification.
Reaction SMILES: [C:1]1([C:7](=O)[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[CH3:10][O:11][NH2:12]>C(O)(=O)C>[CH3:10][O:11][N:12]=[C:7]([C:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1)[CH3:8]
Reactant: CC(=O)C1=CCCCC1
Reactant: CON
Solvent: CC(=O)O
Product: CON=C(C)C1=CCCCC1
Temperature: 24 °C
Reaction time: 48 h

Procedure:
To a stirred solution of a cyclohexenyl-ethanone (0.06 mmol), in acetic acid (500 μl) was added methoxyamine (4.7 mg). The reaction mixture was stirred at 24° C. for 48 h under nitrogen to obtain the cyclohexenyl-ethanone O-methyl-oxime.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:11][N:10](CC2C=CC=CC=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(NC(C)C)(C)C.C(OC(Cl)C)=O>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:28])[NH:7][CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Agent: CC(Cl)OC=O
Solvent: Cc1ccccc1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)NC1CNCC1c1ccc(Cl)c(Cl)c1
Reaction time: 24 h
Yield: 153 %

Procedure:
To a solution of rac-(3S,4R)-[1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (5.59 g, 0.013 mol) and N,N-diisopropylamine (6.81 mL, 0.017 mol) in toluene (60 mL) was added at ambient temperature 1-chloroethyl formate (1.88 mL, 0.017 mol) and the reaction mixture was stirred for 24 h. It was concentrated and the resulting residue was diluted in methanol (60 mL) and stirred for 3 h at ambient temperature. Concentration afforded the crude title compound (6.59 g, 67% purity) as a light brown solid which was directly used without further purification.
Reaction SMILES: [CH:1]([N:14]1[C:18]2=[N:19][C:20]([CH3:24])=[CH:21][C:22]([CH3:23])=[C:17]2[C:16]([C:25]#[N:26])=[C:15]1/[CH:27]=[CH:28]/[C:29]([O:31]CC)=[O:30])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O.Cl>C(O)C.C1COCC1>[CH:1]([N:14]1[C:18]2=[N:19][C:20]([CH3:24])=[CH:21][C:22]([CH3:23])=[C:17]2[C:16]([C:25]#[N:26])=[C:15]1/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C=C/c1c(C#N)c2c(C)cc(C)nc2n1C(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: Cc1cc(C)c2c(C#N)c(/C=C/C(=O)O)n(C(c3ccccc3)c3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a solution of ethyl (2E)-3-(1-benzhydryl-3-cyano-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-yl)propenoate (1.52 g, 3.59 mmol) in ethanol (14 ml) and THF (10 ml) was added a 1 N aqueous sodium hydroxide solution (7.2 ml) and the mixture was stirred at room temperature for 7 hours. The reaction solution was poured into water, neutralized with 1 N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to give the objective product as a solid material.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[C:9]([C:11]1[CH:12]=[C:13]([NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH:14]=[CH:15][CH:16]=1)#[CH:10]>C1COCC1.C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[N:7]=[C:6]([CH:10]=[CH:9][C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:23])[C:19]([F:20])([F:21])[F:22])[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: C#Cc1cccc(NC(=O)C(F)(F)F)c1
Reactant: Clc1ccnc(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(Nc1cccc(C=Cc2ccnc(Cl)n2)c1)C(F)(F)F
Temperature: 50 °C

Procedure:
To a mixture of 2,4-dichloropyrimidine (14.5 g, 97.5 mmol), dichlorobis(triphenyl-phosphine)palladium(II) (1.3 g, 2.6 mmol), and copper(I) iodide (25 mg, 0.13 mmol) in degassed THF was added TEA (34 mL, 263 mmol), and the mixture was heated to 50° C. A solution of N-(3-ethynyl-phenyl)-2,2,2-trifluoro-acetamide (14 g, 65 mmol) in THF was added to the mixture over 45 minutes. After several h, the reaction was cooled to rt and diluted with DCM. The organic mixture was washed with water and brine, dried over MgSO4 and concentrated. The crude material was purified through silica to give the title compound as an off-white solid. 1H NMR (400 MHz, d6-DMSO): δ 11.43 (s, 1H), 8.83 (d, J=4.8 Hz, 1H), 8.00 (s, 1H), 7.80 (d, J=4.8 Hz, 1H), 7.76 (m, 1H), 7.54-7.52 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:29])[C:13]2[CH:18]=[C:17]([OH:19])[CH:16]=[C:15]([O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=3)[CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:30]([O:32][C:33](=[O:42])[C:34]1[CH:39]=[CH:38][C:37]([CH2:40]Br)=[CH:36][CH:35]=1)[CH3:31]>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:29])[C:13]2[CH:18]=[C:17]([O:19][CH2:40][C:37]3[CH:36]=[CH:35][C:34]([C:33]([O:32][CH2:30][CH3:31])=[O:42])=[CH:39][CH:38]=3)[CH:16]=[C:15]([O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=3)[CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(CBr)cc1
Reactant: CCOC(=O)N1CCN(C(=O)c2cc(O)cc(Oc3ccc(C#N)cc3)c2)CC1
Product: CCOC(=O)c1ccc(COc2cc(Oc3ccc(C#N)cc3)cc(C(=O)N3CCN(C(=O)OCC)CC3)c2)cc1
Yield: 83.5 %

Procedure:
Using 0.52 g (1.31 mmol) of 4-[3-(4-cyano phenoxy)-5-hydroxy benzoyl]-piperazine-1-carboxylic acid ethyl ester and 4-bromomethyl-benzoic acid ethyl ester (0.318 g, 1.31 mmol) and following the procedure of Example 42(b) affored 0.61 g of the required product. Percentage purity (LCMS): 60.0% (M+1)=557.2+1.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.FC(F)(F)C(O)=[O:14].OO.CSC>>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:14]
Reactant: O=C(O)C(F)(F)F
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: OO
Solvent: CSC
Product: O=[N+]([O-])c1ccc[n+]([O-])c1Cl
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
2-Chloro-3-nitropyridine (0.69 g, 4.35 mmol) was chilled to 0° C. and trifluoroacetic acid (9 mL) was slowly added followed by 30% hydrogen peroxide (1 mL). The solution was warmed to 70° C. for 1.5 hours, cooled to 0° C. and excess peroxide was decomposed by dropwise addition of dimethylsulfide (1 mL) and stirring 0.5 hours. The reaction was concentrated at reduced pressure onto silica gel and flash chromatographed (1×3 inches). Elution proceeded as follows: 50% ethyl acetate/hexane (175 mL), nil; 75% ethyl acetate/hexane (175 mL), 0.589 g (77%) of 2-chloro-3-nitropyridine-N-oxide as an orange solid suitable for use without further purification. A sample recrystallized from ethyl acetate/hexane had mp 98°-100° C. Analysis calculated for C5H3ClN2O3 : C, 34.41; H, 1.73; N, 16.05. Found: C, 34.75; H, 1.67; N, 15.80.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([CH3:33])=[C:9]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][C:23]=1[Cl:32])[C:10]([O:17][CH:18]([F:20])[F:19])=[N:11]2.CO.[OH-].[Li+].O>C(O)(=O)C>[Cl:32][C:23]1[CH:24]=[C:25]([S:28]([CH3:31])(=[O:29])=[O:30])[CH:26]=[CH:27][C:22]=1[CH2:21][C:9]1[C:10]([O:17][CH:18]([F:19])[F:20])=[N:11][C:12]2[C:7]([C:8]=1[CH3:33])=[C:6]([O:5][CH2:4][C:3]([OH:34])=[O:2])[CH:15]=[CH:14][C:13]=2[F:16]
Reactant: COC(=O)COc1ccc(F)c2nc(OC(F)F)c(Cc3ccc(S(C)(=O)=O)cc3Cl)c(C)c12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: Cc1c(Cc2ccc(S(C)(=O)=O)cc2Cl)c(OC(F)F)nc2c(F)ccc(OCC(=O)O)c12

Procedure:
A solution of [3-(2-chloro-4-methanesulfonylbenzyl)-2-difluoromethoxy-8-fluoro-4-methylquinolin-5-yloxy]acetic acid methyl ester (0.22 g), methanol (8.0 mL), 5.0 M aqueous lithium hydroxide solution (0.4 mL) and water (0.8 mL) was stirred at room temperature for 2 hours. The pH of the solution was adjusted to 4 by the addition of glacial acetic acid and the solvent removed under reduced pressure. The residue was diluted with water (4.0 mL) and the solid collected by filtration, washed with water and methanol and dried to afford to title compound as a white solid, 0.17 g.
Reaction SMILES: [F:1][CH:2]([F:28])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][N:14]([C:16]([N:18]3[CH2:23][CH2:22][S:21](=[O:24])[CH2:20][CH2:19]3)=[O:17])[CH2:13][CH:12]([C:25](O)=[O:26])[CH2:11]2)=[CH:6][CH:5]=1.O[N:30]=[C:31]([O:33][CH2:34][CH3:35])[NH2:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:1][CH:2]([F:28])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:11][CH:12]([C:25]3[O:26][N:32]=[C:31]([O:33][CH2:34][CH3:35])[N:30]=3)[CH2:13][N:14]([C:16]([N:18]3[CH2:23][CH2:22][S:21](=[O:24])[CH2:20][CH2:19]3)=[O:17])[CH2:15]2)=[CH:8][CH:9]=1
Reactant: O=C(O)C1CC(c2ccc(OC(F)F)cc2)CN(C(=O)N2CCS(=O)CC2)C1
Reactant: CCOC(N)=NO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1noc(C2CC(c3ccc(OC(F)F)cc3)CN(C(=O)N3CCS(=O)CC3)C2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
185 mg (0.37 mmol) of the compound from Example 42A and 50 mg (0.48 mmol) of ethyl N′-hydroxyimidocarbamate [G. Zinner, G. Nebel, Arch. Pharm. 1970, 303, 385-390] were initially charged in 1.0 ml of DMF and reacted with 210 mg (0.55 mmol) of HATU and 0.19 ml (143 mg, 1.1 mmol) of N,N-diisopropylethylamine. The mixture was stirred at RT for 15 minutes and then the reaction mixture was partitioned between water and ethyl acetate. The organic phase was washed repeatedly with water, dried over sodium sulphate and concentrated under reduced pressure. The residue was dissolved in 2.0 ml of acetic acid and heated to reflux for 1 h. The reaction mixture was purified by means of preparative HPLC. Yield: 62 mg (33% of theory)
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][CH:13]3[CH2:15][CH2:14]3)[C:7](=[O:16])[CH:6]3[CH2:17][O:18][CH2:19][CH2:20][N:5]3[C:4]=2[N:3]=1.IC.[CH3:23]C([O-])(C)C.[Na+]>CS(C)=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][CH:13]3[CH2:14][CH2:15]3)[C:7](=[O:16])[C:6]3([CH3:23])[CH2:17][O:18][CH2:19][CH2:20][N:5]3[C:4]=2[N:3]=1
Reactant: CC(C)(C)[O-]
Reactant: O=C1C2COCCN2c2nc(Cl)ncc2N1CC1CC1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CI
Product: CC12COCCN1c1nc(Cl)ncc1N(CC1CC1)C2=O
Temperature: 0 °C
Reaction time: 16 h
Yield: 88.1 %

Procedure:
To a round-bottomed flask equipped with a magnetic stirrer was added 2-chloro-5-(cyclopropylmethyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (745 mg, 2.53 mmol), DMSO (10 ml), iodomethane (0.189 ml, 3.03 mmol). The suspension was cooled to 0° C. and sodium 2-methylpropan-2-olate (292 mg, 3.03 mmol) was added. The reaction was removed from the ice-bath and stirred at 20° C. for 16 hours. The reaction solution was poured into water, extracted with ethyl acetate 3 times and the organic layer washed with saturated NaCl. The organic layer was collected, dried with Na2SO4, filtered and the filtrate concentrated in vacuo to furnish a light-brown solid. The solid was washed with a small amount of ethanol followed by diethyl ether to afford 2-chloro-5-(cyclopropylmethyl)-6a-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (641 mg, 2.228 mmol, 82% yield) as white solid. MS [M+H] found 309.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](C)C=[C:4]([Cl:9])[C:3]=1O.[C:11]1(=O)[O:15][CH2:14][CH2:13][O:12]1.N1C=CN=[CH:18]1>>[Cl:9][C:4]1[CH2:3][C:2]([Cl:1])([CH3:18])[CH:7]=[CH:6][C:11]=1[O:12][CH2:13][CH2:14][OH:15]
Reactant: Cc1cc(Cl)c(O)c(Cl)c1
Reactant: c1c[nH]cn1
Reactant: O=C1OCCO1
Product: CC1(Cl)C=CC(OCCO)=C(Cl)C1
Temperature: 150 °C

Procedure:
2,6-Dichloro-4-methylphenol (1 eq.), ethylene carbonate (1 eq.) and imidazole (0.5% loading) were combined and heated at 150° C. for 4 h to afford the title compound as a brown oil.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1.[CH3:21][C:22]1[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=1>>[CH3:21][C:22]1[CH:26]=[C:25]([CH3:27])[N:24]([C:2]2[N:11]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[N:23]=1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: Cc1cc(C)[nH]n1
Reactant: Cc1ccc(N)cc1
Product: Cc1ccc(Nc2nc(-n3nc(C)cc3C)nc3ccccc23)cc1

Procedure:
Was prepared according to Method B from 2,4-dichloroquinazoline, p-toluidine and 3,5-dimethylpyrazole. Mp. 210.4-216.2° C.
Reaction SMILES: [I:1]I.C(=O)(O)[O-].[Na+].[F:8][C:9]([F:18])([F:17])[C:10]1[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=1.NC(N)=S>C1COCC1.O>[F:8][C:9]([F:17])([F:18])[C:10]1[CH:11]=[C:12]([I:1])[C:13]([OH:16])=[CH:14][CH:15]=1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: II
Agent: NC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Oc1ccc(C(F)(F)F)cc1I
Reaction time: 8 h

Procedure:
A mixture of iodine (91.6 mmol, 23.2 g) and sodium bicarbonate (91.6 mmol, 7.7 g) was added to a solution of α,α,α-trifluoro-p-cresol (83.3 mmol, 13.5 g) in THF (90 mL) and H2O (90 mL) and the reaction mixture was allowed to stand at room temperature overnight. Sufficient thiourea (5% solution) was added to remove the excess iodine as indicated by the color change of the reaction from deep violet to brown. The reaction mixture was extracted with ether (3×100 mL), the extract was dried, filtered and the filtrate was concentrated to obtain a brown oil. This oil was distilled (bp 105° C. at 44 mm Hg) to obtain α,α,α-trifluoro-o-iodo-p-cresol (4.1 g, 75% pure, admixed with the starting α,α,α-trifluoro-p-cresol).