Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N-:1]([C:4]#[N:5])[C:2]#[N:3].[Na+].[C:7](#[N:11])[CH2:8][C:9]#[N:10].CC(O)CC>CN(C)C(=O)C>[NH2:3][C:2]([NH:1][C:4]#[N:5])=[C:8]([C:7]#[N:11])[C:9]#[N:10]
Reactant: N#C[N-]C#N
Reactant: N#CCC#N
Agent: [Na+]
Solvent: CCC(C)O
Solvent: CC(=O)N(C)C
Product: N#CNC(N)=C(C#N)C#N
Temperature: 147 °C
Reaction time: 0.25 h
Yield: 108.9 %

Procedure:
To a 1 liter flask is charged 89 gm(1.0 mole) of sodium dicyanamide and 282 ml of N,N-dimethylacetamide. The stirred mixture is heated to 147° C. and 72.6 gm (1.1 mole) of malononitrile in 72.6 gm of N,N-dimethylacetamide is added dropwise over 2 hours and 25 minutes. The mixture is stirred at 147° C. for an additional 3 hours and 15 minutes; then cooled to 60° C. Next the reaction mixture is charged to a 2 liter flask containing 1276 gm of 2-butanol and stirred overnight at room temperature. The slurry is then filtered, and the wet cake slurried in 319 gm 2-butanol and again filtered. The solids are dried overnight at 70° C. in a vacuum oven. There is obtained 144.9 gm of 1-amino-1-cyanamido-2,2-dicyanoethylene, sodium salt, 84.5% pure, or a 78.9% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:16]=2)[N:11]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[CH:10]=1.Br[C:38]1[CH:47]=[C:42]([C:43]([O:45][CH3:46])=[O:44])[C:41]([OH:48])=[CH:40][CH:39]=1.ClCCl>C([O-])(O)=O.[Na+].C(#N)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:46][O:45][C:43](=[O:44])[C:42]1[CH:47]=[C:38]([C:15]2[CH:16]=[C:17]3[C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[CH:10][N:11]([S:27]([C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=4)(=[O:29])=[O:28])[C:12]3=[N:13][CH:14]=2)[CH:39]=[CH:40][C:41]=1[OH:48]
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: COC(=O)c1cc(Br)ccc1O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CC#N
Product: COC(=O)c1cc(-c2cnc3c(c2)c(-c2ccccc2OC)cn3S(=O)(=O)c2ccc(C)cc2)ccc1O
Temperature: 90 °C
Yield: 90.8 %

Procedure:
To a solution of 3-(2-methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (502 mg, 1.00 mmol) in 1.5 mL saturated aqueous NaHCO3 and 5.0 mL acetonitrile was added methyl 5-bromosalicylate (253 mg, 1.10 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane (1:1) (41 mg, 0.05 mmol) in a microwave vial. The vial was capped, flushed with N2, evacuated under vacuum, and subsequently heated in a microwave at 90° C. for 300 seconds. The material was diluted with ethyl acetate and the organic layer was washed with saturated NaHCO3 (aq) and brine then dried over Na2SO4. The material was filtered then adsorbed onto silica gel and purified by flash chromatography with a gradient of ethyl acetate and hexane, affording the title compound as a hydroscopic white solid (480 mg, 91% yield). 1H NMR (500 MHz, CD3OD) δ8.55 (d, J=2.0 Hz, 1H), 8.06 (m, 4H), 7.96 (s, 1H), 7.77 (dd, J=2.5, 6.0 Hz, 1H), 7.52 (dd, J=2.0, 6.0 Hz, 1H), 7.40 (m, 3H), 7.16 (d, J=8.5 Hz,1H), 7.08 (m, 2H), 3.98 (s, 3H), 3.87 (s, 3H), 2.39 (s, 3H). MS: m/z 529.1 (M+H+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1.[CH3:15][N:16]([CH3:31])[CH2:17][CH2:18][N:19]([CH3:30])[C:20]1[S:21][C:22]2[CH:28]=[C:27]([NH2:29])[CH:26]=[CH:25][C:23]=2[N:24]=1>>[CH3:15][N:16]([CH3:31])[CH2:17][CH2:18][N:19]([CH3:30])[C:20]1[S:21][C:22]2[CH:28]=[C:27]([NH:29][C:10](=[O:12])[C:9]3[CH:8]=[CH:7][C:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)=[CH:14][CH:13]=3)[CH:26]=[CH:25][C:23]=2[N:24]=1
Reactant: CN(C)CCN(C)c1nc2ccc(N)cc2s1
Reactant: O=C(O)c1ccc(-c2cccs2)cc1
Product: CN(C)CCN(C)c1nc2ccc(NC(=O)c3ccc(-c4cccs4)cc3)cc2s1

Procedure:
The title compound is prepared by following General Method A, using 4-thiophen-2-yl-benzoic acid (0.098 g, 0.48 mmol), and N*2*-(2-dimethylamino-ethyl)-N*2*-methyl-benzothiazole-2,6-diamine (0.10 g, 0.40 mmol) to afford the title compound as a white solid. LC/MS: Retention time=4.37 min; (m/z): calcd for C23H24N4OS2 (M+H)+: 437.6; found: 437.3.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Br:9])[CH:6]=[C:5]([Cl:10])[C:3]=1N.N([O-])=O.[Na+].[I-:15].[K+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:8]=[C:7]([Br:9])[CH:6]=[C:5]([Cl:10])[C:3]=1[I:15]
Reactant: Nc1c(Cl)cc(Br)cc1Cl
Reactant: [I-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Clc1cc(Br)cc(Cl)c1I
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 65 %

Procedure:
2,6-Dichloro-4-bromoaniline (15.6 g, 64.8 mmol) was gradually added to concentrated sulfuric acid (40 ml). The mixture was then stirred at room temperature for 20 minutes. The mixture was then cooled to 0° C. To the mixture was then added gradually sodium nitrite (4.9 g, 71.22 mmol). The mixture was then stirred at a temperature of 0° C. to 5° C. for 2.5 hours. The mixture thus obtained was then added to ice-water (200 g). To the mixture was then added an aqueous solution of potassium iodide (12.9 g, 77.76 mmol) at 5° C. The mixture was then allowed to stand at 5° C. for 15 minutes and at room temperature for 1 hour. The mixture was then extracted with diethyl ether. The extract was washed with an aqueous solution of sodium thiosulfate, and then dried over magnesium sulfate. The solvent was then distilled off. The crude product thus obtained was then extracted with hexane (200 ml). The solvent was then distilled off. As a result, a crude product was obtained in an amount of 18.62 g. The crude product was then recrystallized from ethanol (75 ml). As a result, 2,6-dichloro-4-bromoiodobenzene was obtained (14.8 g; yield: 65%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7](OS(C)(=O)=O)[CH3:8].[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]1[C:35](=[O:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]1=[O:37])[CH3:21].CCN(C(C)C)C(C)C>CC#N.CN(C1C=CN=CC=1)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([N:22]([CH:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=1)[CH3:21])[CH2:23][CH2:24][CH2:25][CH2:26][N:27]1[C:35](=[O:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]1=[O:37])[CH3:8]
Reactant: CC(NCCCCN1C(=O)c2ccccc2C1=O)c1ccccn1
Reactant: CC(OS(C)(=O)=O)c1ccccn1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(c1ccccn1)N(CCCCN1C(=O)c2ccccc2C1=O)C(C)c1ccccn1
Temperature: 60 °C
Reaction time: 17 h

Procedure:
Using General Procedure A: To a stirred solution of methanesulphonic acid 1-pyridin-2-yl-ethyl ester (269 mg, 1.34 mmol) and 2-[4-(1-pyridin-2-yl-ethylamino)-butyl]-isoindole-1,3-dione (356 mg, 1.10 mmol) in CH3CN (5 mL) at room temperature was added DIPEA (0.30 mL, 1.72 mmol) and KI (13 mg, 0.078 mmol). After 3 hours the temperature was increased to 60° C. and the mixture stirred for another 17 hours. KI (23 mg, 0.139 mmol) and DMAP (35 mg, 0.286 mmol) were added and the reaction stirred for a further 2 hours. Work up and purification by flash chromatography (35:1:1 CH2Cl2:MeOH:NH4OH) afforded pure 2-{4-[bis-(1-pyridin-2-yl-ethyl)-amino]-butyl}-isoindole-1,3-dione as a mixture of diastereomers (139 mg, 30%). 1H NMR (CDCl3) δ 1.18-1.49 (m, 10H) containing 1.27 (d, 3H, J=7.0 Hz) and 1.42 (d, 3H, J=7.1 Hz), 2.51-2.80 (m, 2H), 3.44-3.52 (m, 2H), 4.03-4.12 (m, 2H), 6.98-7.07 (m, 2H), 7.31 (d, 1H, J=7.9 Hz), 7.45-7.61 (m, 3H) containing 7.47 (d, 1H, J=7.9 Hz), 7.66-7.70 (m, 2H), 7.76-7.81 (m, 2H), 8.43-8.48 (m, 2H). ES-MS m/z 429 [M+H].
Reaction SMILES: [CH3:1][N:2]([CH2:16][CH2:17][OH:18])[C:3](=[O:15])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:1][N:2]([CH2:16][CH2:17][O:18][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:3](=[O:15])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCCCCCCCCCC(=O)N(C)CCO
Product: CCCCCCCCCCCC(=O)N(C)CCOC(=O)c1ccccc1

Procedure:
N-methyl-N-(2-benzoyloxyethyl)lauramide was prepared by the procedure of example 1 from 26 gms. (0.1 mole) of N-methyl-N-(2-hydroxyethyl)lauramide and 14 gms. (0.1 mole) of benzoyl chloride. The structure of the final product was characterized on the basis of IR and NMR spectral analyses as described in example 1.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:16][CH:15]=1)(=[O:12])=[O:11])([O-:3])=[O:2].[C:26]1([C:32]2[N:33]=[C:34](/[CH:37]=[N:38]/[C:39]3[CH:44]=[CH:43][C:42]([CH2:45]O)=[CH:41][CH:40]=3)[S:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]([CH2:45][C:42]1[CH:41]=[CH:40][C:39](/[N:38]=[CH:37]/[C:34]2[S:35][CH:36]=[C:32]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:33]=2)=[CH:44][CH:43]=1)[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:16][CH:15]=1)(=[O:12])=[O:11])([O-:3])=[O:2]
Reactant: OCc1ccc(/N=C/c2nc(-c3ccccc3)cs2)cc1
Reactant: COC(=O)CCc1ccc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)CCc1ccc(N(Cc2ccc(/N=C/c3nc(-c4ccccc4)cs3)cc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-(4-{[(2-nitrophenyl)sulfonyl]amino}phenyl)propanoate (364 mg, 1.0 mmol), (4-{[(1E)-(4-phenyl-1,3-thiazol-2-yl)methylene]amino}phenyl)methanol (297 mg, 1.0 mmol) and triphenylphosphine (393 mg, 1.5 mmol) in tetrahydrofuran (4 mL) was added diethyl azodicarboxylate (40% toluene solution, 660 mg, 1.5 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was purified by silica gel column chromatography (5%-70% ethyl acetate/hexane) to give a yellow oil containing the title compound.
Reaction SMILES: [O:1]=[S:2]1(=[O:37])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([NH:11][C@@H:12]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]([C:29]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])[CH3:28])=[CH:20][CH:19]=2)[C:13]([O:15]C)=[O:14])=[N:3]1.[Li+].[OH-].Cl.O>C1COCC1.CO.O>[O:1]=[S:2]1(=[O:37])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([NH:11][C@@H:12]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]([C:29]([CH:31]3[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]3)=[O:30])[CH3:28])=[CH:20][CH:19]=2)[C:13]([OH:15])=[O:14])=[N:3]1
Reactant: COC(=O)[C@H](Cc1ccc(OCCN(C)C(=O)C2CCCCC2)cc1)NC1=NS(=O)(=O)c2ccccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CN(CCOc1ccc(C[C@H](NC2=NS(=O)(=O)c3ccccc32)C(=O)O)cc1)C(=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 42 %

Procedure:
The crude product from Step A was dissolved in a THF/MeOH/H2O mixture (6:0.1:1; 2 ml). Aqueous 1M LiOH solution (1.6 ml) was added and the mixture was stirred for 3 days at room temperature. Then the reaction mixture was neutralized with 1M HCl, a small amount of water was added and the mixture extracted with ethyl acetate. The solvent was evaporated. The product was purified by chromatography (SiO2/ethyl acetate/hexane). The yield was 42%. MS (ES) 513 (M+, 100%).
Reaction SMILES: [OH-].[K+].[CH2:3]([N:6]1[C:16]2[C:11](=[C:12]([OH:17])[CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][C:7]1=[O:8])[CH:4]=[CH2:5].[CH2:18]([OH:23])[CH:19]([OH:22])[CH2:20]Cl>CO>[CH2:3]([N:6]1[C:16]2[C:11](=[C:12]([O:17][CH2:20][CH:19]([OH:22])[CH2:18][OH:23])[CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][C:7]1=[O:8])[CH:4]=[CH2:5]
Reactant: C=CCN1C(=O)CCc2c(O)cccc21
Reactant: OCC(O)CCl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C=CCN1C(=O)CCc2c(OCC(O)CO)cccc21
Yield: 44 %

Procedure:
0.4 g of potassium hydroxide was dissolved in 40 ml of methanol, and 1.0 g of 1-allyl-5-hydroxy-3,4-dihydrocarbostyril and 1.5 g of glycerol α-monochlorohydrin were added to the resulting solution followed by refluxing the mixture for 6 hours. The mixture was then worked up in the same manner as described in Example 3 and recrystallized from ethyl acetate to give 0.6 g of 1-allyl-5-(2,3-dihydroxy)propoxy-3,4-dihydrocarbostyril as a colorless amorphous solid having a melting point of 96° - 97.5° C.
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([O:9][CH:10]([O:13][CH2:14][CH3:15])[CH2:11][OH:12])[CH3:8].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CO>C(OCC)(=O)C.O>[C:16]([O:12][CH2:11][CH:10]([O:13][CH2:14][CH3:15])[O:9][CH2:7][CH3:8])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(CO)OCC
Reactant: O=C(Cl)c1ccccc1
Solvent: O
Solvent: CO
Solvent: c1ccncc1
Product: CCOC(COC(=O)c1ccccc1)OCC
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 96.4 %

Procedure:
To a pyridine (30 ml) solution of glycol aldehyde diethylacetal (19.8 g, 148 mmol), benzoyl chloride (51.7 ml, 444 mmol) was added dropwise at −20 to 30° C. The mixture was stirred at room temperature for 167 hours and 50 minutes. After methanol and water were added to the mixture, extraction with ethyl acetate was performed. The obtained organic layer was washed with a saturated aqueous ammonium chloride solution, saturated aqueous sodium hydrogencarbonate solution, and a saturated saline solution. After dried over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography (elution solvent: heptane, ethyl acetate/heptane=1/9). Thereafter, purification by silica gel column chromatography (elution solvent: heptane, ethyl acetate/heptane=1/100, 1/30, 1/10) was performed again to obtain the title compound (34 g, yield: 96.4%) as a light green oil.
Reaction SMILES: N[C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1.O=S(Cl)Cl.[S:13](=[N:15]S(C)(=O)=O)=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[S:13]1[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH:8]=[N:15]1
Reactant: Cc1ccccc1N
Reactant: CS(=O)(=O)N=S=O
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: c1ccc2sncc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.1 %

Procedure:
To a solution of o-toluidine (10 g, 93.4 mmol) in 50 mL toluene was added SOCl2 (12.1 g, 102 mmol) dropwise at 0° C. After the addition was complete, the reaction mixture was heated to reflux and stirred overnight. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure to give a yellow oil. The oil was dissolved in toluene (100 mL), then a solution of N-sulfinylmethanesulfonamide (20.6 g, 146 mmol) was added dropwise, followed by pyridine (7.3 g, 93.4 mmol). The mixture was heated to reflux and stirred at that temperature overnight. Toluene was then removed under reduced pressure, the residue was dissolved in EtOAc (200 mL) and washed with water (2×200 mL). The organic layer was washed with brine, dried and evaporated to give the crude product. The crude product was purified by column chromatography (3% EtOAc/PE) to afford 6.2 g title compound as colorless oil. 1H NMR (CHLOROFORM-d) δ 9.22 (s, 1H), 7.88 (d, J=9.7 Hz, 1H), 7.80 (d, J=8.6 Hz, 1H), 7.46 (ddd, J=8.9, 6.5, 1.2 Hz, 1H), 7.26 (dd, J=7.9, 6.6 Hz, 1H).
Reaction SMILES: N#N.[Cl:3][C:4]1[CH:27]=[CH:26][CH:25]=[CH:24][C:5]=1[CH2:6][O:7][C:8](=[O:23])[NH:9][C:10]1[CH:11]=[N:12][N:13]([CH2:15][C:16]2[N:17]=[C:18]([CH:21]=[O:22])[S:19][CH:20]=2)[CH:14]=1.[CH3:28][Mg]Br>C1COCC1.[NH4+].[Cl-]>[Cl:3][C:4]1[CH:27]=[CH:26][CH:25]=[CH:24][C:5]=1[CH2:6][O:7][C:8](=[O:23])[NH:9][C:10]1[CH:11]=[N:12][N:13]([CH2:15][C:16]2[N:17]=[C:18]([CH:21]([OH:22])[CH3:28])[S:19][CH:20]=2)[CH:14]=1
Reactant: C[Mg]Br
Reactant: O=Cc1nc(Cn2cc(NC(=O)OCc3ccccc3Cl)cn2)cs1
Agent: N#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1nc(Cn2cc(NC(=O)OCc3ccccc3Cl)cn2)cs1
Temperature: -78 °C
Reaction time: 4.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [1-(2-formyl-thiazol-4-ylmethyl)-1H-pyrazol-4-yl]-carbamic acid 2-chloro-benzyl ester (155 mg, 0.41 mmol) in THF (4.0 mL) was treated at −78° C. with methylmagnesium bromide (0.41 mL of a 1M solution in THF, 0.41 mmol). The reaction mixture was stirred at −78° C. for 4.5 h then poured in sat. aq. NH4Cl (25 mL) and extracted with EA (2×25 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (90:10 CH2Cl2-MeOH) gave the title compound as a yellow oil. TLC: rf (90:10 CH2Cl2-MeOH)=0.28. LC-MS-conditions 02: tR=0.88 min; [M+H]+=393.11.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=O)[C:5]([OH:10])=[CH:4][CH:3]=1.Br[CH:12](C(OCC)=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][C:6]=2[CH:9]=1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: O=Cc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)c1cc2cc(Br)ccc2o1
Temperature: 90 °C
Reaction time: 16 h
Yield: 26.8 %

Procedure:
A mixture of 5-bromosalicylaldehyde 14 (10 g, 50 mmole), diethyl bromomalonate (13.1 g, 55 mmole), potassium carbonate (6.9 g, 50 mmole), and 2-butanone (80 ml) was stirred at 90° C. for 16 hrs. The solvent was removed under reduced pressure at 45° C., and the residue was acidified with 1M HCl, extracted, washed, dried, and evaporated. The residue was purified by chromatography to give about 3.6 g of ethyl 5-bromo-benzofuran-2-carboxylate 15, mp. 59-60° C.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([O:14][C:15](=[O:23])[NH:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([CH3:13])([CH3:12])[CH3:11].[Cl:24][C:25]1[N:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>C(Cl)Cl>[C:10]([O:14][C:15](=[O:23])[NH:16][CH:17]1[CH2:22][CH2:21][N:20]([S:31]([C:28]2[CH:29]=[N:30][C:25]([Cl:24])=[CH:26][CH:27]=2)(=[O:33])=[O:32])[CH2:19][CH2:18]1)([CH3:13])([CH3:11])[CH3:12]
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccc(Cl)nc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.1 %

Procedure:
Diisopropylethylamine (1.34 ml, 8.14 mmol) was added in one portion to a stirred solution of piperidin-4-yl-carbamic acid tert-butyl ester (0.5 g, 2.70 mmol) in DCM (20 ml) at room temperature. To this mixture was added 6-chloro-pyridine-3-sulfonyl chloride (0.57 g, 2.70 mmol) in one portion and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After this time the mixture was diluted with DCM (50 ml) and washed sequentially with HCl (1M solution, 20 ml), NaOH (1M solution, 20 ml) and brine (20 ml). The organic layer was separated, dried (MgSO4), filtered and concentrated to give the title compound (0.64 g, 65% yield) as a white solid. δH (500 MHz, DMSO) 8.76 (d, J=2.20 Hz, 1 H) 8.19 (dd, J=8.44, 2.57 Hz, 1 H) 7.82 (d, J=8.44 Hz, 1 H) 6.89 (d, J=7.70 Hz, 1 H) 3.48 (d, J=11.92 Hz, 2 H) 3.31 (br. s., 1 H) 2.59-2.68 (m, 2 H) 1.76 (d, J=10.27 Hz, 2 H) 1.30-1.46 (m, 11 H).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH2:14]O)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:36]>>[Cl:36][CH2:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:9]=1
Reactant: OCc1cccc(Oc2ccccc2)c1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: ClCc1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 94 %

Procedure:
To a solution of (3-phenoxy-phenyl)-methanol (2.00 g, 10.0 mmol) in carbon tetrachloride (40 mL) was added triphenylphosphine (3.15 g, 12.0 mmol) at room temperature. The reaction solution was stirred under nitrogen atmosphere for 5 hours and 40 minutes under reflux. The reaction mixture was cooled to room temperature and concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=10:1) to obtain the title compound (2.05 g, 94%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[CH:5]2.C1C(=O)N([Br:20])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[CH:5]2
Reactant: Cc1ccc2oc(=O)ccc2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: O=c1ccc2cc(CBr)ccc2o1

Procedure:
To a solution of 500 g (31.25 mmoles) of 6-methylcoumarin in 200 ml CCl4 is added 5.56 g (31.25 mmoles) of NBS. This solution is subjected to a sunlamp at reflux for 41/2 hours. After cooling, the reaction mixture is filtered and the filtrate concentrated in vacuo to yield a solid which upon trituration with ethyl acetate affords 6-bromomethylcoumarin which is used directly in the next step.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1>>[C:13]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:14]=[CH:15][CH:16]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[O:5])[N:7]=[CH:8]2)[CH:12]=1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3)c2)cn1
Reactant: COc1ccc(Br)cc1
Product: COc1ccc(C(=O)c2cn(-c3cccc(-c4ccccc4)c3)cn2)cc1

Procedure:
This compound was prepared by method C using compound 12a and 4-bromoanisole. HRMS (ESI+): m/z=355.1456 [M+H]
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([OH:11])=[CH:4][CH:3]=1.Br[C:13]1C=C(Br)N=C([N+]([O-])=O)C=1O.C([O-])([O-])=O.[K+].[K+].S(OC)(OC)(=O)=O>CN(C)C=O>[Br:1][C:2]1[N:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH3:13])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1nc(Br)cc(Br)c1O
Reactant: O=[N+]([O-])c1nc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Product: COc1ccc(Br)nc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 24 h

Procedure:
To a heterogeneous 60:40 mixture of 6-bromo-3-hydroxy-2-nitropyridine (30): 4,6-dibromo-3-hydroxy-2-nitropyridine (31) (2.18 g, 10 mmol), K2CO3 (2.08 g, 15 mmol) in N,N-dimethylformamide (DMF) (20 mL) was added dimethyl sulfate (DMS) (1.13 mL, 12 mmol) and the resulting mixture was stirred at 60° C. for 24 hours. The reaction mixture was poured over ice-water (100 mL), extracted with ethyl acetate (3×50 mL), and the organic phase was dried over anhydrous sodium sulfate. The solvent was then removed under reduced pressure to afford 6-bromo-3-methoxy-2-nitropyridine (32). LCMS: purity: 92%; MS (m/z): 233 (MH+).