Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](Cl)=[N:6][CH:5]=1.[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[OH:20].O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([O:20][C:14]2[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=2[F:12])=[N:6][CH:5]=1
Reactant: Oc1ccc(F)cc1F
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Oc2ccc(F)cc2F)nc1

Procedure:
In Scheme D, Ra, Ra′, Rc, Rc′, Re, Rg and X are as previously defined. In Scheme D (step 1), the halide can be displaced by either a nucleophilic aromatic substitution or transition metal catalyzed reaction. For example, methyl-6-chloronicotinate and 2,4-difluorophenol is dissolved in a suitable solvent such as DMF. To the reaction mixture is added a suitable base such as potassium carbonate monohydrate and the heated at reflux for a period of 2 to 18 hours to yield [6-(2,4-Difluoro-phenoxy)-nicotinic acid methyl ester. The reaction is concentrated and purified according to techniques well known in the art. These resulting esters formed in Scheme E, Step 1 can be further elaborated to final compounds using the procedures described in Scheme B, step 2 and 3.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:20])=[C:11]([CH2:13][CH2:14][N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[N:12]=2)=[CH:4][CH:3]=1.[N:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[CH3:20][C:10]1[O:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:24]3[CH:25]=[CH:26][N:21]=[CH:22][CH:23]=3)=[CH:3][CH:4]=2)=[N:12][C:11]=1[CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: OB(O)c1ccncc1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1oc(-c2ccc(-c3ccncc3)cc2)nc1CCN1CCCC1
Yield: 82.6 %

Procedure:
2-(4-Bromo-phenyl)-5-methyl-4-(2-pyrrolidin-1-yl-ethyl)-oxazole (See Example 8) (7.23 g, 21.57 mmol), 4-pyridylboronic acid (3.98 g, 32.35 mmol), [1,1 bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with CH2Cl2 (1:1) (0.616 g, 0.755 mmol), and aqueous sodium carbonate (2M, 40 mL) are dissolved in 200 mL of dioxane and heated to reflux for 1.5 hours. The mixture is concentrated to a dark residue and purified by flash silica gel chromatography (gradient: 3-6% 2M NH3 in MeOH/dichloromethane) to provide the titled compound (5.94 g, 82.5% yield). MS (m/e): 334.2 (M+1)
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[S:9][C:10]2[CH:16]=[C:15]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=2[N:12]=1.[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24][NH2:25].CN1CCOCC1>CO>[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24][NH:25][S:17]([C:15]1[CH:14]=[CH:13][C:11]2[N:12]=[C:8]([C:3]3[C:4]([CH3:7])=[N:5][NH:6][C:2]=3[NH2:1])[S:9][C:10]=2[CH:16]=1)(=[O:19])=[O:18]
Reactant: CN(C)CCN
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)Cl)cc2s1
Solvent: CN1CCOCC1
Solvent: CO
Product: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)NCCN(C)C)cc2s1
Yield: 9.6 %

Procedure:
the title compound (11 mg) was prepared from crude 2-(5-amino-3-methyl-1H-pyrazol-4-yl)-benzothiazole-6-sulfonyl chloride (100 mg, 0.30 mmol), N1,N1-dimethylethane-1,2-diamine (67 μL, 0.60 mmol) and PS-NMM (0.320 g, 0.60 mmol) in 5 mL of methanol. MS (m/z, ES+): 381.4 (M+1, 50%). Yield=9%.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[N:21]=[CH:20][CH:19]=[CH:18]2>ClCCl>[CH3:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[N+:21]([O-:9])=[CH:20][CH:19]=[CH:18]2
Reactant: Cc1cccc2cccnc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1cccc2ccc[n+]([O-])c12

Procedure:
A solution of 2.45 g of m-chloroperbenzoic acid in 15 ml of dichloromethane is added dropwise to a solution of 1 g of commercially available 8-methylquinoline in 15 ml of dichloromethane. The reaction mixture is stirred over night diluted with 30 ml of dichloremethane and extracted two times each with 50 ml of halfsaturated aqueous sodium hydrogencarbonate solution. The organic layer is dried over magnesium sulfate, filtered and evaporated in vacuo. The residue is chromatographed on silica gel (dichloromethane/methanol 98:2). 1 g of the title compound are obtained as colourless solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:13]([OH:15])=[O:14])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH2:10][O:11][CH3:12].[Cl:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][C:18]=1[CH3:26]>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[C:7]([O:8][CH2:9][CH2:10][O:11][CH3:12])=[N:6][CH:5]=[C:4]([CH:3]=2)[C:13]([OH:15])=[O:14])=[CH:19][C:18]=1[CH3:26]
Reactant: Cc1cc(B(O)O)ccc1Cl
Reactant: COCCOc1ncc(C(=O)O)cc1Br
Product: COCCOc1ncc(C(=O)O)cc1-c1ccc(Cl)c(C)c1

Procedure:
The title compound was synthesized in analogy to Example BQ using 5-bromo-6-(2-methoxyethoxy)-3-pyridinecarboxylic acid (CAN 912454-34-3) and B-(4-chloro-3-methylphenyl)-boronic acid (CAN 161950-10-3) as starting materials; LC-MS (UV peak area/ESI) 94%, 322.0842 (M+H)+.
Reaction SMILES: C1C=C[NH+]=CC=1.[O-:7][Cr](Cl)(=O)=O.[CH3:12][S:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2(O)[CH2:24][CH2:23][CH:22]=[C:21]2[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:16][CH:15]=1>C(Cl)Cl.CCOCC>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:21]2[C:22](=[O:7])[CH2:23][CH2:24][C:20]=2[C:17]2[CH:18]=[CH:19][C:14]([S:13][CH3:12])=[CH:15][CH:16]=2)=[CH:26][CH:27]=1
Reactant: CSc1ccc(C2(O)CCC=C2c2ccc(F)cc2)cc1
Reactant: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CSc1ccc(C2=C(c3ccc(F)cc3)C(=O)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.9 %

Procedure:
To a suspension of PCC (4.5 g, 20.9 mmol) and 10 g of anhydrous 4 Å molecular sieves in 150 mL of CH2Cl2 was added a solution of 2.2 g (7.3 mmol) of 1-(4-(methylthio)phenyl)-2-(4-fluorophenyl)-2-cyclopenten-1-ol in 20 mL CH2Cl2. The mixture was stirred for 1 h at r.t. and then diluted with 300 mL of Et2O. After filtration and concentration, the residue was flash chromatographed with 2:1 hexane/EtOAc to give 1.5 g of the title product.
Reaction SMILES: [P:1](Cl)([O:6][CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9])([O:3][CH2:4][CH3:5])=[S:2].[OH-:13].[K+:14]>C(O)C>[K+:14].[P:1]([O-:13])([O:6][CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9])([O:3][CH2:4][CH3:5])=[S:2]
Reactant: CCOP(=S)(Cl)OCC(C)(C)C
Reactant: [OH-]
Agent: [K+]
Solvent: CCO
Product: CCOP([O-])(=S)OCC(C)(C)C
Temperature: 22 °C
Reaction time: 60 h

Procedure:
Sixty One grams (260 mmole) of O-ethyl O-neopentyl chlorothiophosphate and 33.7 g (530 mmole) of 88% potassium hydroxide were mixed in 300 ml of ethyl alcohol and stirred at 22° C. for 60 hours. The precipitated potassium chloride was filtered off and the ethyl alcohol removed in vacuo. The resulting solid was washed with hexanes and diethyl ether yielding the title compound, a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:21])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][C:13]=2[C:22]([O:24]C)=O.[NH3:26]>C1COCC1.[OH-].[NH4+]>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:21])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][C:13]=2[C:22](=[O:24])[NH2:26]
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1ccccn1
Reactant: N
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1ccccn1
Temperature: 35 °C
Yield: 54 %

Procedure:
A solution of the 9-[(2-pyridyl)methyl]-4-hydroxy-5-carbomethoxy carbazole (480 mg, 1.43 mmol) in 10 mL THF and 40 mL concentrated aqueous ammonium hydroxide was treated with a stream of NH3 gas to ensure saturation. The reaction vessel was capped and the mixture heated to 35° C. with stirring until tlc indicated complete consumption of starting material (20 hours). The THF was evaporated and the aqueous layer saturated with solid sodium chloride. The mixture was extracted three times with THF. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The foam was taken up in hot ethyl acetate and passed over a shoroom temperaturecolumn of silica gel using ethyl acetate as the eluent to afford 247 mg (54%) of the 9-[(2-pyridyl)methyl]-4-hydroxy-5-carbamoyl carbazole as a white solid. 1H NMR (DMSO-d6) δ10.46 (s, 1H), 8.81 (br s, 1H), 8.46 (d, 1H, J=5.8 Hz), 8.36 (br s, 1H), 7.8 (dd, 1H, J=2.9 and 6.4 Hz), 7.67-7.59 (m, 1H), 7.47-7.41 (m, 2H), 7.30-7.20 (m, 2H), 7.05 (d, 1H, J=7.9 Hz), 6.87 (d, 1H, J=8.3 Hz), 6.57 (d, 1H, J=7.8 Hz), and 5.73 (s, 2H). IR (KBr, cm−1) 3404, 3051, 1652, 1618, 1595, 1582, 1567, 1559, 1450, 1436, 1334, 1266, 1226, 776, 763 and 647. MS (ES) m/e 318 (M+1).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:14])([CH3:13])[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[C:15]1([C:21]2[CH:22]=[CH:23][C:24]3[N:25]([C:27]([C:30]4[CH:39]=[CH:38][C:37]5[C:32](=[C:33](O)[CH:34]=[CH:35][CH:36]=5)[N:31]=4)=[N:28][N:29]=3)[CH:26]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:13][C:3]([CH3:14])([CH2:2][O:1][C:33]1[CH:34]=[CH:35][CH:36]=[C:37]2[C:32]=1[N:31]=[C:30]([C:27]1[N:25]3[CH:26]=[C:21]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:22]=[CH:23][C:24]3=[N:29][N:28]=1)[CH:39]=[CH:38]2)[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:11])[CH3:10]
Reactant: Oc1cccc2ccc(-c3nnc4ccc(-c5ccccc5)cn34)nc12
Reactant: CC(C)(CO)CNC(=O)OC(C)(C)C
Product: CC(C)(CNC(=O)OC(C)(C)C)COc1cccc2ccc(-c3nnc4ccc(-c5ccccc5)cn34)nc12

Procedure:
Prepared as described in Example 9, Step A, using tert-butyl 3-hydroxy-2,2-dimethylpropylcarbamate in place of tert-butyl-4-hydroxypiperidine-1-carboxylate and 2-(6-phenyl-[1,2,4]triazolo[4,3-a]pyridine-3-yl)quinolin-8-ol in place of 2-([1,2,4]triazolo[4,3-a]pyridine-3-yl)quinolin-8-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9]O)[CH:5]=[C:4]([Cl:11])[C:3]=1[NH:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:39]>ClCCl>[Br:39][CH2:9][CH2:8][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([NH:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:4]([Cl:11])[CH:5]=1
Reactant: BrC(Br)(Br)Br
Reactant: CCOC(=O)CNc1c(Cl)cc(CCO)cc1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)CNc1c(Cl)cc(CCBr)cc1Cl
Reaction time: 1 h
Yield: 89.6 %

Procedure:
To a stirred solution of ethyl N-[2,6-dichloro-4-(2-hydroxyethyl)phenyl]aminoacetate (650 mg) and triphenylphosphine (700 mg) in dichloromethane (10ml) was added carbon tetrabromide (886 mg) under ice-cooling, and the mixture was stirred for 1 hour. Rough purification of the reaction mixture by flash column chromatography on silica gel (eluent: hexane/ethyl acetate=3/1) and further purification of the fraction by medium pressure liquid column chromatography on silica gel (eluent: hexane/dichloromethane=1/1) gave ethyl N-[4-(2-bromoethyl)-2,6-dichlorophenyl]-aminoacetate (708 mg).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:19])=[C:4]([N:8]2[C:16](=[O:17])[CH:15]3[CH:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)[C:9]2=[O:18])[CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+]>CO>[Br:1][C:2]1[C:3]([CH3:19])=[C:4]([N:8]2[CH:16]([OH:17])[CH:15]3[CH:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)[C:9]2=[O:18])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Br)cccc1N1C(=O)C2CCCCC2C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1c(Br)cccc1N1C(=O)C2CCCCC2C1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
A suspension of 2-(3-bromo-2-methylphenyl)hexahydro-1H-isoindole-1,3(2H)-dione (Intermediate 3-6, 4.5 g, 13.97 mmol) in methanol (150 mL) was treated with sodium borohydride (2.64 g, 69.8 mmol) and stirred at rt for 4 h. The mixture was concentrated, and the residue was dissolved in DCM, washed with NaHCO3 (aq) and water, and dried and concentrated to provide 2-(3-bromo-2-methylphenyl)-3-hydroxyoctahydro-1H-isoindol-1-one as a yellow solid (3.94 g, 87%). Mass spectrum m/z 324, 326 (M+H)+. Without purification, a portion of this material (1.8 g, 5.55 mmol) was dissolved in DCM (50 mL) and treated with triethylsilane (6.46 g, 55.5 mmol). The solution was treated dropwise at rt with TFA (2.14 mL, 27.8 mmol) and stirred at rt for 30 min. The mixture was concentrated and the residue was dissolved in DCM, washed with NaHCO3 (aq) and water. The organic phase was dried and concentrated. The residue was purified by column chromatography (eluting with hexane-EtOAc) to provide 2-(3-bromo-2-methylphenyl)octahydro-1H-isoindol-1-one (Intermediate 4-1, 1.35 g, 79%). 1H NMR (400 MHz, chloroform-d) δ 7.48-7.53 (1H, m), 7.06-7.09 (2H, m), 3.78 (1H, dd, J=9.5, 5.7 Hz), 3.19 (1H, dd, J=9.5, 2.4 Hz), 2.64-2.70 (1H, m), 2.45-2.54 (1H, m), 2.30 (3H, s), 2.10-2.17 (1H, m), 1.80-1.88 (1H, m), 1.62-1.71 (2H, m), 1.56-1.62 (1H, m), 1.40-1.51 (1H, m), 1.31 (2H, s). Mass spectrum m/z 308, 310 (M+H)+. Also isolated was 2-(3-bromo-2-methylphenyl)-2,3,4,5,6,7-hexahydro-1H-isoindol-1-one (Intermediate 4-2, 224 mg, 13%). 1H NMR (400 MHz, chloroform-d) δ 7.51-7.55 (1H, m), 7.05-7.14 (2H, m), 4.09 (2H, t, J=1.9 Hz), 2.28-2.37 (4H, m), 2.28 (3H, s), 1.73-1.85 (4H, m). Mass spectrum m/z 306, 308 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH:14]([NH:26][C:27]([C:29]2[CH:38]=[C:37]([O:39][CH3:40])[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]=2)=[O:28])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([O:24]C)=[O:23])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Li+].[OH-]>CO>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12]([CH:14]([NH:26][C:27]([C:29]2[CH:38]=[C:37]([O:39][CH3:40])[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]=2)=[O:28])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([OH:24])=[O:23])=[O:13])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)C(Cc2ccccc2C(=O)OC)NC(=O)c2cc(OC)c3ccccc3n2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCOC(=O)N1CCN(C(=O)C(Cc2ccccc2C(=O)O)NC(=O)c2cc(OC)c3ccccc3n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-2-(2-methoxycarbonylphenyl)ethyl]aminocarbonyl-4-methoxyquinoline (220 mg, 0.4 mmol) in methanol was added a solution of LiOH (3 mL, 0.25 M) and the resulting reaction mixture was stirred at ambient temperature overnight. The product was purified by preparative HPLC and lyophilization to afford 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-2-(2-carboxyphenyl)ethyl]aminocarbonyl-4-methoxyquinoline as an orange solid, 140 mg (50%); NMR (DMSO-d6), 1.08 (t, 3), 3.40 (m, 10), 4.00 (q, 2), 4.04 (s, 3), 5.28 (m, 1), 7.26 (t, 1), 7.34 (m, 2), 7.42 (s, 1), 7.82 (m, 2), 8.06 (d, 1), 8.14 (d, 1H), 8.88 (d, 1) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12].[CH3:13][NH:14][CH3:15]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:14]([CH3:15])[CH3:13])(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12]
Reactant: O=S(=O)(Cl)c1ccc(Br)c(F)c1
Reactant: CNC
Product: CN(C)S(=O)(=O)c1ccc(Br)c(F)c1
Reaction time: 16 h
Yield: 89 %

Procedure:
According to general procedure A, 4-Bromo-3-fluoro-benzenesulfonyl chloride (0.40 g, 1.46 mmol) and dimethylamine (10 mL, 33% in ethanol) were stirred together for 16 hours. 4-bromo-3-fluoro-N,N-dimethylbenzenesulfonamide (0.36 g, 89%) was provided after purification. HRMS: calcd for C8H9BrFNO2S, 280.95214; found (EI, M+.), 280.9516. HPLC purity 98.9% at 210-370 nm, 9.6 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:17])=[C:6]([C:8](=[O:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=1.[C:18](OC(=O)C)(=O)[CH3:19].C([O-])(=O)C.[Na+]>>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:17][C:18]([CH3:19])=[C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:8]2=[O:16]
Reactant: O=C(Cc1ccccc1)c1cc(Br)ccc1O
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Product: Cc1oc2ccc(Br)cc2c(=O)c1-c1ccccc1
Temperature: 25 °C
Yield: 97 %

Procedure:
Intermediate 1 (8.9 g, 30.56 mmoles) was taken in a RB flask and to this acetic anhydride (59 ml) and sodium acetate (17.5 g, 213 mmoles) were added and the mixture was refluxed for 12 h. After cooling to RT, the reaction mixture was quenched by the addition of ice cold water. The solid formed was filtered and washed with water. The product was dried under vacuum to afford the title compound as white solid (9.4 g, 97% yield). MP: 119-121° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): δ 8.35(d, J=2.4 Hz, 1H), 7.75(dd, J=11.3, 2.4 Hz, 1H), 7.46(t, 2H), 7.39(d, J=7.2 Hz, 1H), 7.36(d, J=8.8 Hz, 1H), 7.28(m,2H), 2.32(s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([CH:13]([CH3:15])[CH3:14])[C:6]([S:16][C:17]1[NH:21][C:20]([C:22]([F:25])([F:24])[F:23])=[N:19][N:18]=1)=[N:5]2.[CH2:26](N(CC)CC)C.IC>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([CH:13]([CH3:15])[CH3:14])[C:6]([S:16][C:17]1[N:21]([CH3:26])[C:20]([C:22]([F:23])([F:24])[F:25])=[N:19][N:18]=1)=[N:5]2
Reactant: CC(C)c1nc2cc(Cl)c(Cl)cc2nc1Sc1nnc(C(F)(F)F)[nH]1
Reactant: CCN(CC)CC
Solvent: CI
Solvent: C1CCOC1
Product: CC(C)c1nc2cc(Cl)c(Cl)cc2nc1Sc1nnc(C(F)(F)F)n1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the above 6,7-dichloro-2-isopropyl-3-(5-trifluoromethyl-4H-1,2,4-triazol-3-ylsulfanyl)quinoxaline (78 mg, 0.19 mmol) in tetrahydrofuran (5 ml) was added triethylamine (0.05 ml, 0.38 mmol) followed by addition of iodomethane (0.02 ml, 0.29 mmol). The reaction was stirred under nitrogen overnight at room temperature. Purification by flash column chromatography using ethyl acetate:hexanes 1:10 afforded the title compound.
Reaction SMILES: Cl[CH:2]([CH3:5])[CH:3]=[CH2:4].[CH3:6][O:7][CH:8]([O:16][CH3:17])[CH2:9][NH:10][C:11](=[O:15])[O:12][CH2:13][CH3:14].[OH-].[K+].O>CN(C)C=O>[CH2:4]=[CH:3][CH:2]([N:10]([CH2:9][CH:8]([O:7][CH3:6])[O:16][CH3:17])[C:11](=[O:15])[O:12][CH2:13][CH3:14])[CH3:5]
Reactant: C=CC(C)Cl
Reactant: CCOC(=O)NCC(OC)OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: C=CC(C)N(CC(OC)OC)C(=O)OCC

Procedure:
22 g (0.24 mol) of 3-chloro-1-butene are added to 35.5 g (0.2 mol) of ethyl N-(2,2-dimethoxyethyl)-carbamate and 26 g of powdered potassium hydroxide in 400 ml of dimethylformamide and the mixture is warmed overnight to 40° C. The salts are dissolved with water and the mixture is extracted several times with methylene chloride. The organic extracts are dried over potassium carbonate and concentrated, and the residue is distilled.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9](Br)=[N:8][C:7]=1[CH2:12][N:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5])[CH3:2].[Cl:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][C:37]=1[F:38].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:34]2[CH:35]=[CH:36][C:37]([F:38])=[C:32]([Cl:31])[CH:33]=2)=[N:8][C:7]=1[CH2:12][N:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5])[CH3:2]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(Br)sc1C(=O)OCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(-c2ccc(F)c(Cl)c2)sc1C(=O)OCC
Temperature: 25 °C
Yield: 56.6 %

Procedure:
A mixture of 2-bromo-4-{[(2,4-dimethoxy-benzyl)-ethoxycarbonylmethyl-amino]-methyl}-thiazole-5-carboxylic acid ethyl ester (1.04 g, 2.08 mmole), 3-chloro-4-fluorophenylboronic acid (726 mg, 4.16 mmole), cesium carbonate (2.04 g, 6.25 mmole) and tetrakis(triphenylphosphine)palladium (241 mg, 0.21 mmole) in dioxane (7 ml) was refluxed for 16 h before it was cooled to room temperature, quenched with water and filtered. The filtrate was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a yellow oil (649 mg). MS: (+) m/z 551.26 (M+H+)
Reaction SMILES: [NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[C:4](OS(C2C=CC(C)=CC=2)(=O)=O)[N:3]=1.[NH:25]1[CH2:30][CH2:29][CH:28]=[CH:27][CH2:26]1>C(Cl)(Cl)Cl>[NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[C:4]([N:25]2[CH2:26][CH:27]=[CH:28][CH2:29][CH2:30]2)[N:3]=1
Reactant: C1=CCNCC1
Reactant: COC(=O)Nc1cc(OS(=O)(=O)c2ccc(C)cc2)nc(N)[n+]1[O-]
Solvent: ClC(Cl)Cl
Product: COC(=O)Nc1cc(N2CC=CCC2)nc(N)[n+]1[O-]
Reaction time: 1.5 h

Procedure:
24.8 g (70 mmol) of methyl 2-amino-6-[(p-toluenesulfonyl)oxy]-4-pyrimidinecarbamate-3-oxide and 14.5 g (175 mmol) of 1,2,5,6-tetrahydropyridine are boiled at reflux under argon in 400 ml of chloroform. After 90 minutes, the resulting precipitate is filtered off and the chloroform solution is washed with water. The organic phase is separated, dried over sodium sulfate and evaporated under reduced pressure, whereby there is obtained a crystalline solid. A sample of this material is recrystallized from methylene chloride/ether. The thus-obtained methyl 2-amino-6-[3,6-dihydro-1(2H)-pyridyl]-4-pyrimidinecarbamate-3-oxide melts at 221°-223° with decomposition.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6](OC)=[O:7])[C:3]2[CH:10]=[CH:11][CH:12]=[CH:13][C:2]1=2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[S:1]1[CH:5]=[C:4]([CH2:6][OH:7])[C:3]2[CH:10]=[CH:11][CH:12]=[CH:13][C:2]1=2
Reactant: COC(=O)c1csc2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCc1csc2ccccc12
Yield: 105.4 %

Procedure:
An ether solution (50 ml) of methyl benzo[b]thiophene-3-carboxylate (15 g) was added dropwise to a suspension of lithium aluminium hydride (3.5 g) in ether (100 ml) followed by reflux for 2 h. Usual work-up gave benzo[b]thiophen-3-yl methanol (13.5 g) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH:17]([OH:19])[CH3:18])[C:13]([O:15][CH3:16])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:26](I)[CH3:27]>CN(C=O)C.C(OCC)(=O)C>[CH2:26]([N:11]([S:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)(=[O:9])=[O:10])[C@@H:12]([CH:17]([OH:19])[CH3:18])[C:13]([O:15][CH3:16])=[O:14])[CH3:27]
Reactant: CCI
Reactant: COC(=O)[C@@H](NS(=O)(=O)c1ccc(F)cc1)C(C)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN([C@H](C(=O)OC)C(C)O)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
Compound 9A (1 g, 3.0 mmol) dissolved in DMF (10 ml) was added with K2CO3 (1.1 equiv., 456 mg) and ethyl iodide (1.1 equiv., 0.316 ml) and the reaction was stirred at rt overnight. The reaction was diluted with ethyl acetate and washed several times with water and finally with Brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude residue by crystallization from ethyl ether and petroleum ether afforded 895 mg of a semisolid. Yield=93%. 1HNMR (DMSO, 200 MHz) δ 1.13 (3H, d, J=6.2 Hz), 1.26 (3H, t, J=7 Hz), 3.32 (3H, s), 3.41 (2H, q, J=7.8 Hz), 4.02 (1H, bs), 4.23 (1H, m), 5.13 (1H, d, J=4.6 Hz), 7.42 (2H, m), 7.84 (2H, m)