Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH:17]=[CH2:18])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:19])[C:6]([C:20]([OH:22])=[O:21])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:23][NH:24][CH:25]1[CH:33]=[CH:32][CH2:31][CH:30]2[CH:26]1[CH2:27][NH:28][CH2:29]2.C1N2CCN(CC2)C1.O>C(#N)C.CN(C)C=O>[CH3:23][NH:24][CH:25]1[CH:33]=[CH:32][CH2:31][CH:30]2[CH:26]1[CH2:27][N:28]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:19])[C:6]([C:20]([OH:22])=[O:21])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[C:9]([CH:17]=[CH2:18])[C:10]=1[F:16])[CH2:29]2
Reactant: CNC1C=CCC2CNCC21
Reactant: C=Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Agent: C1CN2CCN1CC2
Solvent: CC#N
Solvent: O
Solvent: CN(C)C=O
Product: C=Cc1c(F)c(N2CC3CC=CC(NC)C3C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 76.1 %

Procedure:
0.46 g of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-5-vinyl-3-quinolinecarboxylic acid, 0.34 g of 4-methylamino-1,3,3a,4,7,7a-hexahydro-isoindole and 0.18 g of DABCO are refluxed for 2 hours in a mixture of 3 ml of acetonitrile and 1.5 ml of dimethylformamide. At room temperature, the reaction mixture is treated with 20 ml of water, and the product is filtered off with suction, washed with water and dried. 0.5 g of 7-(4-methylamino-1,3,3a,4,7,7a-hexahydro-isoindol-2-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-5-vinyl-3-quinolinecarboxylic acid is obtained.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:16])[C@@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:17]([OH:26])(=O)[CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=O>CCOC(C)=O>[CH2:2]([O:9][C:10]([C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:22](=[O:24])[CH2:21][CH2:20][CH2:19][CH2:18][C:17]([N:12]1[CH2:13][CH2:14][CH2:15][C@H:11]1[C:10]([O:9][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:16])=[O:26])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)CCCCC(=O)O
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)[C@@H]1CCCN1C(=O)CCCCC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Yield: 100.3 %

Procedure:
Using General Procedure A with 1.0 g (4.1 mmol) L-Proline benzyl ester hydrochloride and 300 mg (2.1 mmol) adipic acid afforded, after flash chromatography (EtOAc), 1.07 g (100%) of the title compound as a colorless oil. MS m/e (%): 521 (M+H+, 100).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:27][C:28]2[CH:38]=[CH:37][C:31](/[CH:32]=[CH:33]/[C:34]([O-:36])=[O:35])=[CH:30][CH:29]=2)[CH:4]=[C:5]([CH3:26])[C:6]=1[C:7](=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[C:39]([O:43][CH3:44])(=[O:42])[CH:40]=[CH2:41].[N+]([C:48]1C=CC=C[CH:49]=1)([O-])=O.[Na+].[Cl-]>>[CH3:44][O:43][C:39]([CH2:40][CH2:41][C:4]1[N:3]([CH2:27][C:28]2[CH:29]=[CH:30][C:31](/[CH:32]=[CH:33]/[C:34]([O:36][CH2:48][CH3:49])=[O:35])=[CH:37][CH:38]=2)[C:2]([CH3:1])=[C:6]([C:7](=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:5]=1[CH3:26])=[O:42]
Reactant: CCCCCCCCCCCCCCCCCC(=O)c1c(C)cn(Cc2ccc(/C=C/C(=O)[O-])cc2)c1C
Reactant: O=[N+]([O-])c1ccccc1
Reactant: C=CC(=O)OC
Agent: [Cl-]
Agent: [Na+]
Product: CCCCCCCCCCCCCCCCCC(=O)c1c(C)c(CCC(=O)OC)n(Cc2ccc(/C=C/C(=O)OCC)cc2)c1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.1 ml of BF3/ethyl ether complex is added to a solution of 275 mg (0.5 mmol) of (E)-4-[(2,4-dimethyl-3-octadecanoylpyrrol-1-yl)methyl]cinnamate and 0.25 ml of methyl acrylate in 5 ml of absol. nitrobenzene. The mixture is stirred at room temperature for 24 h. Addition of saturated NaCl solution is followed by extraction with ether. After drying over Na2SO4, the solvent is distilled off, and the residue is purified by CC (silica gel, 1. petroleum ether/ethyl acetate 9+1, 2. petroleum ether/ethyl acetate 8+2). The product fractions are concentrated; the remaining oil crystallizes after some time.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:25])(=[O:24])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9](O)=[O:10])[CH:7]=1.[CH2:26]([NH2:30])[CH2:27][CH2:28][CH3:29].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C.O.CO>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:24])(=[O:25])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9]([NH:30][CH2:26][CH2:27][CH2:28][CH3:29])=[O:10])[CH:7]=1
Reactant: CCCCN
Reactant: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CC(=O)O)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: CCCCNC(=O)Cc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Reaction time: 16 h
Yield: 54.6 %

Procedure:
To a stirred solution of 2-(5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)acetic acid (360 mg, 1 mmol) and n-butylamine (0.6 mL, 6 mmol) in 10 mL of DMF was added PyBOP (780 mg, 1.5 mmol) and TEA (0.5 mL, 3.56 mmol). The reaction mixture was stirred for 16 hours. After water was added, the reaction mixture was extracted with ethyl acetate and washed with water, 1N HCl and brine. The organic layer was dried over Na2SO4 and concentrated. The crude residue was first purified by ISCO CombiFlash Rf silica chromatography eluted with 88:10:2 chloroform:MeOH:H2O to give the desired product as a yellow solid (228 mg, yield 54%). MS calcd for (C19H24BN3O5S): 417.2. MS found (ESI negative): (M−H)−=416.2. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.88 (s, 1H), 9.17 (s, 1H), 7.96 (t, J=5.2 Hz, 1H), 7.42 (m, 2H), 7.22 (d, J=8 Hz, 1H), 7.11 (dd, J=8, 2 Hz, 1H), 6.46 (d, J=2.4 Hz, 1H), 6.35 (dd, J=2.4, 8.8 Hz, 1H), 5.93 (bs, 2H), 4.87 (s, 2H), 3.77 (s, 2H), 3.08 (m, 2H), 1.39 (m, 2H), 1.30 (m, 2H), 0.87 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]2[CH2:16][CH2:15][N:14](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C1(O)C=CC=CC=1>Br>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCC(S(=O)(=O)c3ccc(Cl)cc3)CC2)cc1
Agent: Br
Solvent: Oc1ccccc1
Product: Cl
Product: O=S(=O)(c1ccc(Cl)cc1)C1CCNCC1
Yield: 104.3 %

Procedure:
A mixture of 10.14 g (0.0246 mole) of 4-[(4-chlorophenyl)sulfonyl]-1-[(4-methylphenyl)sulfonyl]piperidine and 40 ml of phenol in 120 ml of 48% hydrobromic acid was refluxed for one hr and quenched in 800 ml of water. The mixture was made basic with 50% sodium hydroxide and then extracted with methylene chloride. The methylene chloride extract was dried over magnesium sulfate and the volume was reduced to 200 ml in vacuo. Excess ethereal hydrogen chloride was added to give a white precipitate, the hydrochloride salt. Recrystallization of the salt from methanoldiethyl ether gave 3.80 g (52.0%) of a crystalline solid, m.p. 280°-281.5° C. with decomposition. An additional 0.77 g (10.6%) of product was obtained from the filtrate.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[C:14]1[O:15][CH2:16][C:17]([CH3:20])([CH3:19])[N:18]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH3:30])[CH:24]=1>CCCC(C)C.O1CCCC1>[CH2:29]([C:25]1[CH:24]=[C:23]([CH2:22][CH2:6][C:7]2[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=2[C:14]2[O:15][CH2:16][C:17]([CH3:20])([CH3:19])[N:18]=2)[CH:28]=[CH:27][CH:26]=1)[CH3:30]
Reactant: Cc1ccc(C2=NC(C)(C)CO2)c(C)c1
Reactant: CCc1cccc(CBr)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCC(C)C
Product: CCc1cccc(CCc2cc(C)ccc2C2=NC(C)(C)CO2)c1
Reaction time: 1 h

Procedure:
n-Butyllithium (16.8 ml of a 2.5M solution in isohexane) was added dropwise to a stirred solution of the product of step (iii) (8.13 g) in dry tetrahydrofuran (ISOml) at 0° C. under nitrogen. After 1 hour, the product of step (ii) (8.0 g) in tetrahydrofliran (60 ml) was added. After 1 hour, the reaction was quenched with aqueous ammonium chloride and partitioned between ethyl acetate and water. The organic solution was dried (MgSO4) and evaporated. Purification was by chromatography eluting with 5% ethyl acetate in isohexane. Yield 4.93 g.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[CH:8]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[CH2:7][N:6]([CH3:20])[CH2:5][C:4]=2[N:3]=1.N(CC)CC.[CH2:26]([N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[CH2:27][C:28]#[CH:29].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CN(C=O)C.[Cu]I.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>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]2[CH2:7][N:6]([CH3:20])[CH2:5][C:4]3[N:3]=[C:2]([C:29]#[C:28][CH2:27][CH2:26][N:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)[CH:11]=[CH:10][C:9]2=3)=[CH:13][CH:14]=1
Reactant: COc1ccc(C2CN(C)Cc3nc(Cl)ccc32)cc1
Reactant: C#CCCN1CCCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCNCC
Product: COc1ccc(C2CN(C)Cc3nc(C#CCCN4CCCCC4)ccc32)cc1
Temperature: 25 °C
Yield: 32.1 %

Procedure:
A flask containing a mixture of 2-chloro-5-(4-methoxy-phenyl)-7-methyl-5,6,7,8-tetrahydro-[1,7]naphthyridine (0.080 g, 0.28 mmol), Et2NH (1.0 mL), 1-but-3-ynyl-piperidine (0.077 g, 0.56 mmol), CuI (5.3 mg, 27.8 umol), PPh3 (36 mg, 0.14 mmol), and Pd(PPh3)2Cl2 (0.020 g, 0.028 mmol) in DMF (0.5 mL) was evacuated and back-filled with N2 (3×). The mixture was heated at 105 C for 18 h, then was cooled to rt, diluted with satd. aq. NaHCO3, and extracted with DCM. The combined organic layers were washed with H2O, dried, and concentrated. The residue was purified (SiO2; 0-6% 2 M NH3 in MeOH/DCM) to give the title compound (35 mg, 33%). MS (ESI): mass calcd. for C25H31N3O, 389.25; m/z found, 390.6 [M+H]+. 1H NMR (CDCl3): 7.15-7.08 (m, 2H), 7.06 (d, J=8.7, 2H), 6.83 (d, J=8.7, 2H), 4.23-4.17 (m, 1H), 3.91-3.85 (m, 1H), 3.79 (s, 3H), 3.66-3.59 (m, 1H), 3.05-2.99 (m, 1H), 2.76-2.62 (m, 4H), 2.56-2.46 (m, 5H), 2.45 (s, 3H), 1.68-1.58 (m, 4H), 1.49-1.40 (m, 2H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9](Cl)=[O:10])[CH:4]=1.C[N:13]([CH3:15])[NH2:14].[CH:16](N(CC)C(C)C)(C)C>C1COCC1.O.CCOC(C)=O>[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([N:13]([CH3:15])[NH:14][CH3:16])=[O:10])[CH:4]=1
Reactant: CN(C)N
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Cl)c1cc(Cl)ccn1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CNN(C)C(=O)c1cc(Cl)ccn1
Reaction time: 0.25 h
Yield: 55.9 %

Procedure:
To a suspension of 4-chloropicolinoyl chloride hydrochloride (352 mg, 2.0 mmol, 1.0 eq) in 10 mL of THF were added N,N-dimethylhydrazine (120 mg, 2.0 mmol, 1.0 eq) and N,N-diisopropylethylamine (383 μL, 2.2 mmol, 1.1 eq) at room temperature. The reaction mixture was stirred for 15 min and diluted with water (25 mL) and EtOAc (50 mL). The separated organic layer was washed with brine (25 mL), saturated sodium bicarbonate solution (25 mL) and dried over sodium sulfate. Concentration under reduced pressure gave the title compound as colorless solid (223 mg, 56%), which was used without further purification. MH+=200, Rt=1.42 min.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][CH:7]2[CH2:10][N:9]([CH2:11][CH2:12][C@H:13]([NH2:15])[CH3:14])[CH2:8]2)=[CH:4][CH:3]=1.C1([O:24][C:25](=O)[NH:26][C:27]2[S:28][C:29]([CH2:32][CH3:33])=[N:30][N:31]=2)C=CC=CC=1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]2[CH2:10][N:9]([CH2:11][CH2:12][C@H:13]([NH:15][C:25]([NH:26][C:27]3[S:28][C:29]([CH2:32][CH3:33])=[N:30][N:31]=3)=[O:24])[CH3:14])[CH2:8]2)=[CH:16][CH:17]=1
Reactant: C[C@@H](N)CCN1CC(Oc2ccc(Cl)cc2)C1
Reactant: CCc1nnc(NC(=O)Oc2ccccc2)s1
Solvent: CS(C)=O
Product: CCc1nnc(NC(=O)N[C@H](C)CCN2CC(Oc3ccc(Cl)cc3)C2)s1

Procedure:
A solution of (R)-3-[3-(4-chloro-phenoxy)-azetidin-1-yl]-1-methyl-propylamine (0.145 mg, 0.569 mmol) and (5-ethyl-[1,3,4]thiadiazol-2-yl)-carbamic acid phenyl ester (0.142 mg, 0.569 mmol) in DMSO is stirred at room temperature for 4 hours then partitioned between ethylacetate and water. The organic phase is washed with brine and dried over magnesium sulphate and evaporated. The crude product is recrystallised from hot ethylacetate to afford 1-{(R)-3-[3-(4-Chloro-phenoxy)-azetidin-1-yl]-1-methyl-propyl}-3-(5-ethyl-[1,3,4]thiadiazol-2-yl)-urea. [M+H] 410.14.
Reaction SMILES: [C:1]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:9])[CH2:2][CH2:3][C:4]([O:6][CH2:7]Cl)=[O:5].[O:15]1[CH2:20][CH2:19][O:18][C:17]2[CH:21]=[C:22]([C:25]3[C:29]4[O:30][C:31]([N:35]5[CH2:40][CH2:39][O:38][CH2:37][CH2:36]5)=[CH:32][C:33](=[O:34])[C:28]=4[S:27][CH:26]=3)[CH:23]=[CH:24][C:16]1=2.[I-:41].[Na+]>C(#N)C>[I-:41].[C:11]([O:10][C:1](=[O:9])[CH2:2][CH2:3][C:4]([O:6][CH2:7][O:34][C:33]1[CH:32]=[C:31]([N:35]2[CH2:36][CH2:37][O:38][CH2:39][CH2:40]2)[O+:30]=[C:29]2[C:25]([C:22]3[CH:23]=[CH:24][C:16]4[O:15][CH2:20][CH2:19][O:18][C:17]=4[CH:21]=3)=[CH:26][S:27][C:28]=12)=[O:5])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=c1cc(N2CCOCC2)oc2c(-c3ccc4c(c3)OCCO4)csc12
Reactant: CC(C)(C)OC(=O)CCC(=O)OCCl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)CCC(=O)OCOc1cc(N2CCOCC2)[o+]c2c(-c3ccc4c(c3)OCCO4)csc12
Temperature: 70 °C
Reaction time: 18 h

Procedure:
A 10 mL vial was charged with a magnetic stirring bar, tert-butyl chloromethyl succinate (24 mg, 0.107 mmol), acetonitrile (2 mL), 3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-morpholino-7H-thieno[3,2-b]pyran-7-one (28) (20 mg, 0.054 mmol) and sodium iodide (12 mg, 0.081 mmol). The reaction mixture was magnetically stirred for 18 hours at 70° C. to give 7-((4-tert-butoxy-4-oxobutanoyloxy)methoxy)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-morpholinothieno[3,2-b]pyran-4-ium iodide (81).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)=[CH:14][C:15]([CH3:20])([CH3:19])[O:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>C(O)C.[Pd]>[CH3:19][C:15]1([CH3:20])[CH2:14][CH:13]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:29])([F:28])[F:30])[CH:22]=2)[C:12]2[C:17](=[CH:18][C:9]([OH:8])=[CH:10][CH:11]=2)[O:16]1
Reactant: CC1(C)C=C(c2cccc(C(F)(F)F)c2)c2ccc(OCc3ccccc3)cc2O1
Agent: [Pd]
Solvent: CCO
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)CC(c2cccc(C(F)(F)F)c2)c2ccc(O)cc2O1
Reaction time: 18 h
Yield: 98 %

Procedure:
7-Benzyloxy-2,2-dimethyl-4-(3-trifluoromethylphenyl)-2H-chromene (10.0 g) was dissolved in ethanol (100 ml) and 10% Pd/C (1 g) added. This was hydrogenated at 60° and 5 atmospheres pressure for 18 hours. Filtration through kiesleguhr and evaporation of the solvent under reduced pressure gave an oil which solidified on addition of carbon tetrachloride. Recrystallisation from carbon tetrachloride gave the title compound (7.7 g), m.p. 63°-68° C., (analysing as compound plus 1 mole of carbon tetrachloride).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[CH:15]=NC=[N:12]1.C(=O)([O-])[O-].[K+].[K+].O.[CH3:23][N:24]1CCCC1=O>>[NH:24]1[CH:23]=[C:15]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[N:11]=[N:12]1
Reactant: CN1CCCC1=O
Reactant: c1nc[nH]n1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=[N+]([O-])c1ccc(-c2c[nH]nn2)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 85 %

Procedure:
A 7 g portion of 4-fluoronitrobenzene, 7 g of 1,2,4-triazole and 7.6 g of potassium carbonate were dissolved in 40 ml of N-methylpyrrolidone and stirred at 100° C. for 4 hours. After cooling to room temperature, the reaction solution was poured into water and extracted with ethyl acetate. After washing with 1N hydrochloric acid and water in that order and subsequent drying, the solvent was removed by evaporation under a reduced pressure to obtain 8 g of 4-triazolylnitrobenzene with a yield of 85%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[O:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10](Br)[CH:9]=2)=[O:4].[O:18]([C:25]1[CH:30]=[CH:29][C:28](OB(O)O)=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.CCOC(C)=O.O.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>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[O:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([C:28]1[CH:29]=[CH:30][C:25]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:26][CH:27]=1)[CH:9]=2)=[O:4]
Reactant: OB(O)Oc1ccc(Oc2ccccc2)cc1
Reactant: COC(=O)c1c(O)c2ccc(Br)cc2oc1=O
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: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1c(O)c2ccc(-c3ccc(Oc4ccccc4)cc3)cc2oc1=O
Yield: 68.7 %

Procedure:
A mixture of 7-bromo-4-hydroxy-2-oxo-2H-chromene-3-carboxylic acid methyl ester (256 mg, 0.855 mmol), 4-phenoxyphenylboric acid (211 mg, 0.984 mmol), Pd(PPh3)4 (99 mg, 0.086 mmol) and aqueous sodium carbonate solution (1.1 mL, 2 M) in 1,2-dimethoxyethane (5 mL) was refluxed for 2.5 h. Then cooled, the slurry was diluted with EtOAc and water, solids were filtered off over Celite; EtOAc phase was separated from aqueous, washed with sat. NaCl solution, dried over sodium sulfate, filtered, and concentrated; the crude material was crystallized from dichloromethane and methanol to give the desired product as white micro crystals (228 mg). 1H NMR (200 MHz, CDCl3): δ (ppm)=14.58 (s, 1H), 8.04 (d, 1H, J=8.4 Hz), 7.61-7.04 (m, 11H), 4.04 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][C:5]2([CH3:14])[CH3:13].[H-].[Na+].[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:23][C:22]1[CH:25]=[CH:26][C:19]([O:18][CH3:17])=[CH:20][CH:21]=1)[C:7](=[O:12])[CH2:6][C:5]2([CH3:14])[CH3:13]
Reactant: COc1ccc(CCl)cc1
Reactant: CC1(C)CC(=O)Nc2ccc(Br)cc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)CC(C)(C)c3cc(Br)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-bromo-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one (0.5 g, 1.97 mmol) in THF (25 mL) was added 60% NaH (0.12 g, 2.95 mmol) suspended in mineral oil. The resulting reaction mixture was stirred at room temperature for 30 min., 4-methoxybenzyl chloride (0.34 g, 2.17) added, and heated under reflux for 20 h. The reaction was cooled to room temperature then quenched slowly with water. After extraction with ethyl acetate, the organic layer was dried (MgSO4), evaporated and the residue purified by chromatography (SiO2 3:7 ethyl acetate/hexane). The white crystalline product was obtained (0.35 g, 48%); mp 118-119° C., 1H NMR (DMSO-d6) δ 1.23 (s, 6H), 2.59 (s, 2H), 3.70 (s, 3H), 3.72 (s, 1H), 4.41 (d, 1H, J=5.86 Hz), 5.09 (s, 1H), 6.87 (m, 2H), 7.01 (d, 1H, J=8.78 Hz), 7.17 (d, 1H, J=8.98 Hz), 7.23 (d, 1H, J=8.79), 7.34 (dd, 1H, J=6.59 and 2.2 Hz), 7.43(d, 1H, J=2.2 Hz); MS (APCI (+)) [M+H]+=374/376.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][NH:9]2)=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23](Cl)=[O:24].[CH3:26][NH:27][CH3:28]>C1COCC1.C(OCC)(=O)C>[CH3:26][N:27]([CH3:28])[CH2:22][C:23]([N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:12]([O-:14])=[O:13])=[C:3]([O:2][CH3:1])[CH:11]=2)[CH2:7][CH2:8]1)=[O:24]
Reactant: COc1cc2c(cc1[N+](=O)[O-])CCN2
Reactant: CNC
Reactant: O=C(Cl)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1[N+](=O)[O-])CCN2C(=O)CN(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
To a solution of 6-(methyloxy)-5-nitro-2,3-dihydro-1H-indole (1.1 g, 5.67 mmol) and potassium carbonate (2.34 g, 17.17 mmol) in THF (250 mL) was added bromoacetyl chloride (0.98 g, 6.23 mmols) via a dropwise addition. After stirring 2 hrs at rt, catalytic Kl was added followed by a 2.0M solution of dimethylamine in tetrahydrofuran (17 mL). After overnight stirring, the reaction was diluted with ethyl acetate and washed with water (200 mL). The organic layer was adsorbed onto silica gel and purified by column chromatography (DCM to 10% MeOH/DCM) to afford N,N-dimethyl-2-[6-(methyloxy)-5-nitro-2,3-dihydro-1H-indol-1-yl]-2-oxoethanamine (0.55 g, 35% over two steps). ESIMS (M+H)+=280.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:13][CH2:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH:21](=O)[CH3:22].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:21][CH3:22])[CH2:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Cl)cc(NCC2CCOCC2)c1C
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCN(CC1CCOCC1)c1cc(Cl)cc(C(=O)OC)c1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of methyl 5-chloro-2-methyl-3-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzoate (0.40 g, 1.35 mmol) and acetaldehyde (0.120 g, 2.71 mmol) in dichloroethane (5 mL), acetic acid (0.48 g, 8.1 mmol) was added and the reaction stirred at room temperature for 10 minutes. Then sodium triacetoxyborohydride (0.663 g, 4.05 mmol) was added at 0° C. and the reaction stirred for 3 h at room temperature. On completion, the solvent was removed under reduced pressure and the crude material purified by column chromatography to the title compound (0.38 g, 86%).
Reaction SMILES: [Na+:1].[Na+].[Na+].[NH2:4][C:5]1[CH:6]=[C:7]([S:23]([O-:26])(=[O:25])=[O:24])[CH:8]=[C:9]2[C:14]=1[C:13]([S:15]([O-:18])(=[O:17])=[O:16])=[CH:12][C:11]([S:19]([O-:22])(=[O:21])=[O:20])=[CH:10]2.[OH-].[Na+].[N+:29]([C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1)([O-:31])=[O:30].Cl>O.C(OCC)C>[Na+:1].[Na+:1].[Na+:1].[N+:29]([C:32]1[CH:33]=[CH:34][C:35]([C:36]([NH:4][C:5]2[CH:6]=[C:7]([S:23]([O-:26])(=[O:25])=[O:24])[CH:8]=[C:9]3[C:14]=2[C:13]([S:15]([O-:18])(=[O:17])=[O:16])=[CH:12][C:11]([S:19]([O-:22])(=[O:20])=[O:21])=[CH:10]3)=[O:37])=[CH:39][CH:40]=1)([O-:31])=[O:30]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1cc(S(=O)(=O)[O-])cc2cc(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: O=C(Nc1cc(S(=O)(=O)[O-])cc2cc(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])c12)c1ccc([N+](=O)[O-])cc1
Reaction time: 0.25 h
Yield: 238.6 %

Procedure:
To a solution of 27.0 g of 8-amino-1,3,6-naphthalenetrisulfonic acid trisodium salt in 100 ml of water and 60 ml of N sodium hydroxide is added 22.5 g of p-nitrobenzoyl chloride and 30 ml of diethyl ether. The reaction mixture is shaken in a separatory funnel for about 15 minutes, and another 60 ml portion of base is added. After shaking for 15 minutes the procedure is repeated with two additional 60 ml portions of base. The reaction mixture is acidified with 7.5 ml of concentrated hydrochloric acid and diluted with 250 ml of water, then extracted 9 times with 300 ml portions of ether. The aqueous phase is neutralized with 5 N sodium hydroxide and allowed to stand overnight at room temperature, then is filtered through diatomaceous earth. The filtrate is concentrated to a low volume in vacuo at 55°-60° C. The crystalline solid formed is collected by filtration, washed and slurried with absolute ethyl alcohol to yield 28.6 g of 8-(p-nitrobenzamido)-1,3,6-naphthalenetrisulfonic acid trisodium salt.