Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:35][N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[C:8]2[CH:9]([C:13]([O:15][CH3:16])=[O:14])[NH:10][CH2:11][CH2:12][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[CH2:36]=[C:37]1[O:41][C:39](=[O:40])[CH2:38]1>CO>[CH2:1]([C:5]1[N:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:35][N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[C:8]2[CH:9]([C:13]([O:15][CH3:16])=[O:14])[N:10]([C:39](=[O:40])[CH2:38][C:37]([CH3:36])=[O:41])[CH2:11][CH2:12][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C=C1CC(=O)O1
Reactant: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnn[nH]3)cc1)C(C(=O)OC)NCC2
Solvent: CO
Product: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnn[nH]3)cc1)C(C(=O)OC)N(C(=O)CC(C)=O)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.2 %

Procedure:
To a mixture of methyl 2-n-butyl-3-{2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (0.50 g) and methanol (10 ml) is added diketene (0.20 g), and the mixture is stirred at room temperature for two hours. The solvent is distilled off under reduced pressure, and to the residue is added chloroform. The mixture is washed and dried, and evaporated under reduced pressure to remove the solvent. The resulting residue is purified by silica gel column chromatography (solvent; chloroform/ethyl acetate/methanol) to give methyl 2-n-butyl-5-acetoacetyl-3-{2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl-4,5,6,7-tetrahydroimidazo[4,5-c]-pyridine-4-carboxylate (0.29 g) as foam.
Reaction SMILES: COC([N:5]1[C:13]2[C:8](=[C:9]([NH:14][C:15]([O:17]N3C(=O)CCC3=O)=O)[CH:10]=[CH:11][CH:12]=2)[CH:7]=[N:6]1)=O.[O:25]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[O:28][CH2:27][CH:26]1[CH2:35][NH2:36].C(N(C(C)C)CC)(C)C.C(N(CC)CC)C>CN(C)C=O.O.CO>[O:25]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[O:28][CH2:27][CH:26]1[CH2:35][NH:36][C:15]([NH:14][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[CH:7]=[N:6][NH:5]2)=[O:17]
Reactant: COC(=O)n1ncc2c(NC(=O)ON3C(=O)CCC3=O)cccc21
Reactant: NCC1COc2ccccc2O1
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1COc2ccccc2O1)Nc1cccc2[nH]ncc12
Temperature: 25 °C
Yield: 92.2 %

Procedure:
The product of Example 24D (635 mg, 1.9 mmol) was added to a solution of 1-(2,3-dihydro-1,4-benzodioxin-2-yl)methanamine (315 mg, 1.9 mmol) and diisopropylethylamine (0.34 mL, 1.9 mmol) in N,N-dimethylformamide (5 mL) under nitrogen atmosphere at ambient temperature. After 30 minutes the reaction solution was diluted with water (50 mL), the resulting precipitate was filtered off, washed with water and air-dried. The wet cake was added to a solution of methanol (25 mL), water (3 mL) and triethylamine (0.54 mL, 3.8 mmol). The mixture was refluxed for an hour, cooled to room temperature, diluted with water (100 mL), collected the white precipitate by filtration, rinsed with water and air-dried. The wet cake was vacuum dried to constant weight to provide the title compound (568 mg, 92%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ: 3.41-3.56 (m, 2H), 3.98 (dd, 1H), 4.26-4.33 (m, 1H), 4.36 (dd, 1H), 6.68 (t, 1H), 6.81-6.94 (m, 4H), 7.06 (d, 1H), 7.20 (t, 1H), 7.62 (d, 1H), 8.09 (s, 1H), 8.80 (s, 1H), 13.00 (s, 1H). MS (ESI) m/z: 325.1 (M+H)+; Anal. Calc'd for C17H16N4O3: C, 62.95; H, 4.97; N, 17.27. Found: C, 62.66; H, 4.83; N, 16.99.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:12])[C:6](=[CH:10][CH:11]=1)[C:7]([OH:9])=[O:8].[CH:13](N(CC)C(C)C)(C)C.ClCOC.[OH-].[Na+].Cl>C(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([O:12][CH3:13])[CH:4]=1
Reactant: COc1ccc(C(=O)O)c(O)c1
Reactant: CCN(C(C)C)C(C)C
Agent: COCCl
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C(=O)O)c(OC)c1
Reaction time: 42 h
Yield: 114.9 %

Procedure:
12.05 g of 4-methoxysalicylic acid was dispersed in 200 ml of methylene chloride in argon atmosphere. To the dispersion were added 27.70 g of N,N-diisopropylethylamine and 19.20 g of chloromethylmethyl ether, and the mixture was agitated for 42 hours. The reaction mixture was poured into water, and extracted with methylene chloride. The extract was dried over anhydrous sodium sulfate. The solvent was distilled off in evacuated atomosphere, and 300 ml of methanol was added to the residue. To the mixture was added a solution which has been prepared by dissolving 8.50 g of sodium hydroxide in 20 ml of water. The mixture was agitated for 20 hours, neutralized with 6N aqueous hydrochloric acid, and the solvent was distilled off in evacuated atomosphere. The mixture was adjusted to pH 1 with 1N aqueous hydrochloric acid, and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off in evacuated atomosphere to produce 15 g of 4-methoxy-2-methoxy benzoic acid. To the product were added 8.50 g of 2-mercaptothiazoline, 15.34 g of N,'N-dicyclohexylcarbodiimide, 0.86 g of 4-dimethylaminopyridine, and 400 ml of 1,2-dichloroethane, and the mixture was agitated for 18 hours. The reaction mixture was filtered and the precipitate was washed with benzene. The filtrate and the wash liquid were combined, washed with 2N aqueous solution of sodium hydroxide, water, and saturated aqueous solution of sodium chloride in this order, and dried over anhydrous sodium sulfate. The solvent was distilled off in evacuated atomosphere, and the residue was subjected to a column chromatography using silica gel. There was obtained 12.36 g of N-(4-methoxy-2-methoxymethoxybenzoyl)thiazolidine-2-thion from fractions eluted with methylene chloride.
Reaction SMILES: [C:1]1([CH3:23])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[NH:9][C:10]1[S:11][C:12]2[C:18]([N+:19]([O-])=O)=[CH:17][C:16]([CH3:22])=[CH:15][C:13]=2[N:14]=1.O.O.[Sn](Cl)Cl.[OH-].[Na+]>CN(C=O)C>[C:1]1([CH3:23])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[NH:9][C:10]1[S:11][C:12]2[C:18]([NH2:19])=[CH:17][C:16]([CH3:22])=[CH:15][C:13]=2[N:14]=1
Reactant: Cc1cc(C)c(Nc2nc3cc(C)cc([N+](=O)[O-])c3s2)c(C)c1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)c(Nc2nc3cc(C)cc(N)c3s2)c(C)c1
Temperature: 80 °C
Yield: 24.5 %

Procedure:
A mixture of N-mesityl-5-methyl-7-nitro-1,3-benzothiazol-2-amine (45 mg, 0.137 mmol) and tin(II) chloride dihydrate (124 mg, 0.550 mmol) in DMF (2 ml) was heated at 80° C. for 1 h. The mixture was poured into ice and the pH was made slightly basic (pH 7-8) by addition of 1N NaOH solution. The aqueous solution was extracted with AcOEt. The extract was washed with brine, dried over magnesium sulfate and concentrated under vacuum. The residue was purified by chromatography eluting with 20% AcOEt in n-hexane to afford 10 mg of the title compound.
Reaction SMILES: [N:1]1[N:2]([CH:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]([OH:13])=O)[CH:3]=[C:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[CH:5]2.[NH2:18][C:19]1[S:20][CH:21]=[CH:22][N:23]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CCN(CC)CC>CN(C=O)C>[N:1]1[N:2]([CH:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]([NH:18][C:19]2[S:20][CH:21]=[CH:22][N:23]=2)=[O:13])[CH:3]=[C:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[CH:5]2
Reactant: Nc1nccs1
Reactant: CC(C)CC(C(=O)O)n1cc2ccccc2n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)CC(C(=O)Nc1nccs1)n1cc2ccccc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of Compound 1 (640 mg, 2.76 mmol), 2-aminothiazole (284 mg, 2.76 mmol), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) (1.0 g, 2.76 mmol) and 0.2 mL of Et3N in DMF (4 mL) was stirred at room temperature for 2 hours to provide the title compound, which was then purified by HPLC. 1H NMR (400 MHz, DMSO-d6) δ: 7.74 (d, J=12.0 Hz, 1H), 7.60 (d, J=12.0 Hz, 1H), 7.51 (d, J=4.0 Hz, 1H), 7.25 (m, 2H), 7.05 (t, J=8.0, 8.0 Hz, 1H), 5.67 (m, 1H), 2.23 (m, 1H), 2.06 (m, 1H), 1.32 (m, 1H), 0.94 (d, J=8.0 Hz, 3H), 0.90 (d, J=8.0 Hz, 3H). [M+H] calc'd for C16H18OS, 314. found, 314.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]([CH:23]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][N:42]=[C:43]=[O:44])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[C:2]=[O:3].[NH2:45][C:46]1[NH:47][C:48]([CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH3:67])=[CH:49][C:50](=[O:52])[N:51]=1>N1C=CC=CC=1>[CH2:13]([CH:12]([CH:23]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][NH:42][C:43]([NH:45][C:46]1[NH:47][C:48]([CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH3:67])=[CH:49][C:50](=[O:52])[N:51]=1)=[O:44])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][NH:1][C:2]([NH:45][C:46]1[NH:47][C:48]([CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH3:67])=[CH:49][C:50](=[O:52])[N:51]=1)=[O:3])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCC(CCCCCCCCN=C=O)C(CCCCCCCCCC)CCCCCCCCN=C=O
Reactant: CCCCCCCCCCCCCCCc1cc(=O)nc(N)[nH]1
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCc1cc(=O)nc(NC(=O)NCCCCCCCCC(CCCCCCCCCC)C(CCCCCCCCCC)CCCCCCCCNC(=O)Nc2nc(=O)cc(CCCCCCCCCCCCCCC)[nH]2)[nH]1
Reaction time: 24 h
Yield: 99.3 %

Procedure:
In a 250 mL round-bottomed flask fitted with a reflux condensor was added 11,12-bis(8-isocyanatooctyl)docosane (diamer diisocyanate, Cognis Corp.) (5.18 g, 8.39 mmol) and 2-amino-6-pentadecylpyrimidin-4(1H)-one (5.67 g, 17.63 mmol) in Pyridine (50 mL) to give a white suspension. The mixture was heated to 75 deg/C under argon and stirred for 24 h. The pyridine was removed and the residue was taken up in chloroform. The hazy solution was filtered and the resulting clear solution was concentrated to 50 ml and the viscous solution was poured into a rapidly stirring solution (1 L) of MeOH upon which a white solid formed. The solid was collected by filtration and dried under vacuum for 24 h to give 10.5 g 1,1′-(9,10-didecyloctadecane-1,18-diyl)bis(3-(4-oxo-6-pentadecyl-1,4-dihydropyrimidin-2-yl)urea)
Reaction SMILES: [N:1]1([C:7]([NH:9][C:10]2[CH:11]=[C:12]([C:16]3[CH:25]=[N:24][C:23]4[C:22]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)=[N:21][C:20]([C:32]5[CH:33]=[N:34][C:35]([NH:38]C(=O)OC(C)(C)C)=[N:36][CH:37]=5)=[N:19][C:18]=4[CH:17]=3)[CH:13]=[CH:14][CH:15]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(Cl)Cl.C(O)(C(F)(F)F)=O>CO.C(Cl)(Cl)Cl>[NH2:38][C:35]1[N:34]=[CH:33][C:32]([C:20]2[N:21]=[C:22]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)[C:23]3[N:24]=[CH:25][C:16]([C:12]4[CH:11]=[C:10]([NH:9][C:7]([N:1]5[CH2:2][CH2:3][O:4][CH2:5][CH2:6]5)=[O:8])[CH:15]=[CH:14][CH:13]=4)=[CH:17][C:18]=3[N:19]=2)=[CH:37][N:36]=1
Reactant: CC(C)(C)OC(=O)Nc1ncc(-c2nc(N3CCOCC3)c3ncc(-c4cccc(NC(=O)N5CCOCC5)c4)cc3n2)cn1
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: Nc1ncc(-c2nc(N3CCOCC3)c3ncc(-c4cccc(NC(=O)N5CCOCC5)c4)cc3n2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.7 %

Procedure:
To a 25 mL round bottom flask, tert-butyl (5-(7-(3-(morpholine-4-carboxamido)phenyl)-4-morpholinopyrido[3,2-d]pyrimidin-2-yl)pyrimidin-2-yl)carbamate (0.035 g, 0.00006 mol) and DCM (5 mL) were added. To the same flask, TFA (0.013 g, 0.00012 mol) was added and the mixture stirred at room temperature for 3 hours. The volatiles were evaporated under reduced pressure to provide the crude residue. The crude residue was dissolved in 10% methanol in chloroform and washed with aqueous saturated sodium bicarbonate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to provide the crude product. The crude product was purified by preparative TLC (4% methanol in chloroform, double elution) to provide the title compound (0.015 g, 52%). 1H NMR (400 MHz, DMSO-d6): δ 9.19 (s, 2H), 9.02 (d, J=2.4 Hz, 1H), 8.72 (s, 1H), 8.24 (d, J=2.4 Hz, 1H), 8.04 (t, J=1.6 Hz, 1H), 7.64 (d, J=8.0 Hz, 1H), 7.54 (d, J=8.0 Hz, 1H), 7.46 (t, J=8.0 Hz, 1H), 7.20 (br s, 2H), 4.52 (br s, 4H), 3.84 (t, J=4.8 Hz, 4H), 3.65 (t, J=4.4 Hz, 4H), 3.48 (t, J=4.8 Hz, 4H): LC-MS (ESI): Calculated mass. 513.2, Observed mass [M+H]+: 514.2 (RT=0.19 min).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10]([F:11])=[CH:9][C:8]([Cl:12])=[C:7]([N+:13]([O-])=O)[CH:6]=1)(=[O:3])[CH3:2]>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[C:1]([NH:4][C:5]1[C:10]([F:11])=[CH:9][C:8]([Cl:12])=[C:7]([NH2:13])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc([N+](=O)[O-])c(Cl)cc1F
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cc(N)c(Cl)cc1F
Temperature: 90 °C
Yield: 60.4 %

Procedure:
Iron powder (31.9 g) were suspended in a 5% acetic acid solution (60 ml), and the suspension was heated to 90° C. A solution of 4-(N-acetylamino)-1-chloro-5-fluoro2-nitrobenzene (13.3 g) in acetic acid (100 ml) and ethyl acetate (70 ml) was dropwise added thereto, and the resultant mixture was refluxed at 80° C. for 2 hours. The reaction mixture was filtered by celite. The filtrate was extracted with ethyl acetate, and the extract was neutralized with a saturated sodium hydrogen carbonate solution. The organic layer was washed with water, dried and concentrated under reduced pressure to give 7.0 g of 4-(N-acetylamino)-2-amino-1-chloro-5-fluorobenzene. M.P., 140.5°-141.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N+:5]([O-])=[C:4]([CH3:9])[CH:3]=1.[Si]([C:14]#[N:15])(C)(C)C.CN(C)C(Cl)=O.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:9])[N:5]=[C:6]([C:14]#[N:15])[CH:7]=1
Reactant: C[Si](C)(C)C#N
Reactant: Cc1cc(Cl)cc[n+]1[O-]
Agent: CN(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1cc(Cl)cc(C#N)n1
Reaction time: 0.25 h
Yield: 75.5 %

Procedure:
4-chloro-2-methylpyridine-N-oxide (8.97 g, 62.5 mmol, 1.00 eq) was dissolved in CH2Cl2 and dried over MgSO4. The solution was added to a flame-dried round-bottom flask and CH2Cl2 was added to give a total volume of 188 mL. TMS-cyanide (10 mL, 75 mmol, 1.2 eq) was added and the reaction stirred for 15 minutes. Dimethylcarbamyl chloride (6.9 mL, 75 mmol, 1.2 eq) was added dropwise over 20 minutes, and the reaction was stirred for 24 hours. An additional one equivalent each of TMS-cyanide and dimethylcarbamyl chloride were added and the reaction was stirred for another 72 hours. The reaction was made basic with 10% K2CO3 and extraxcted with CH2Cl2 (3×). The combined organics were dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 7.2 g (75%) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.13 (d, J=1.6 Hz, 1H), 7.82 (d, J=1.7 Hz, 1H), 2.52 (s, 3H); ES-MS [M+1]+: 153.2.
Reaction SMILES: Br.[Br:2][C:3]1[CH:4]=[C:5]([CH2:10]Br)[C:6]([NH2:9])=[N:7][CH:8]=1.C[O:13][C:14](=O)[C:15]([NH2:18])([CH3:17])[CH3:16].C(N(CC)CC)C>CN(C=O)C.O>[Br:2][C:3]1[CH:8]=[N:7][C:6]2[NH:9][C:14](=[O:13])[C:15]([CH3:17])([CH3:16])[NH:18][CH2:10][C:5]=2[CH:4]=1
Reactant: COC(=O)C(C)(C)N
Reactant: Nc1ncc(Br)cc1CBr
Agent: Br
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC1(C)NCc2cc(Br)cnc2NC1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 45.2 %

Procedure:
A solution of 5-bromo-3-bromomethyl-pyridin-2-ylamine hydrobromide (11.0 g, 31.7 mmol) and 2-amino-2-methyl-propionic acid methyl ester (5.80 g, 49.5 mmol) in DMF (220 mL) was treated with triethylamine (9.0 mL, 18.5 mmol). After stirring at room temperature for 3 d, the mixture was diluted with H2O (400 mL) and then extracted with EtOAc (4×200 mL). The combined organic layers were washed with H2O (3×100 mL) and brine (100 mL), dried over Na2SO4, filtered and the solvent was removed in vacuo. Purification by flash column chromatography (silica gel, CH2Cl2/MeOH, 99:1) gave the title compound (3.87 g, 40%) as a light yellow solid: MS (ESI) m/e 302 (M+H)+.
Reaction SMILES: [OH:1][C:2]1([C:15]([OH:17])=[O:16])[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.S(=O)(=O)(O)O.[C:23](=O)([O-])O.[Na+]>CO>[CH3:23][O:16][C:15]([C:2]1([OH:1])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=2[C:9]2[C:14]1=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:17]
Reactant: O=C(O)C1(O)c2ccccc2-c2ccccc21
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1(O)c2ccccc2-c2ccccc21

Procedure:
50.4 g (0.223 mol) of 9-hydroxy-9-fluorenecarboxylic acid is dissolved in 500 mL of methanol, combined with 5 mL (0.089 mol) of concentrated sulfuric acid and refluxed for 1 hour. After cooling, 100 mL of sodium hydrogen carbonate solution (approx. pH 8) is added and the methanol is largely evaporated down. It is extracted with dichloromethane and water; the organic phase is dried and evaporated to dryness. The purification is carried out by recrystallization from ethyl acetate. Yield: 50.0 g of white crystals (93% of theoretical yield).
Reaction SMILES: Cl[CH2:2][F:3].[OH:4][C:5]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]([C:18]([F:21])([F:20])[F:19])=[N:16][N:15]=[N:14]2)=[CH:9][C:6]=1[CH:7]=[O:8].C(=O)([O-])[O-].[K+].[K+].[Br-].[Na+]>O.CN(C=O)C>[F:3][CH2:2][O:4][C:5]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]([C:18]([F:21])([F:20])[F:19])=[N:16][N:15]=[N:14]2)=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: O=Cc1cc(-n2nnnc2C(F)(F)F)ccc1O
Reactant: FCCl
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc(-n2nnnc2C(F)(F)F)ccc1OCF
Temperature: -78 °C
Reaction time: 3 h

Procedure:
A 500 mL nitrogen purged round bottom flask fitted with a dry-ice condenser was cooled to −78° C. and 50 mL (ca. 40 g by cylinder difference) of chlorofluoromethane was condensed. DMF (200 mL), 2-hydroxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzaldehyde (40 g, 0.155 mol), powdered potassium carbonate (22 g, 0.159 mol, 1.03 equiv) and sodium bromide (22 g, 0.21 mol) were carefully added. An additional 100 mL of DMF was added and the dry-ice bath was removed. The pale yellow suspension was warmed first to room temperature, then to 70-75° C. (oil bath). Gentle reflux was noted. After 3 h, an additional 30 g of NaBr was added. The condenser was kept cold for ca. 10 h and allowed to warm to room temperature overnight. The white suspension which resulted was diluted with 2 L of water and extracted with ether (1×1 L, 2×500 mL). The combined extracts were washed with water (4×250 mL) and brine (500 mL), dried with magnesium sulfate, filtered and the filtrate concentrated. During concentration the product began to crystallize. The filtrare was concentrated to a small volume and the mixture flushed with hexanes. The resulting slurry was cooled to 0° C., aged 1 hr, filtered, and the cake washed with hexanes. The yield upon drying was 42.2 g (93.8%) of white crystalline 2-fluoromethoxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzaldehyde: 1H NMR (CDCI3) δ 5.91 (d, JH-F=30.5 Hz, 2H), 7.47 (d, J=9 Hz, 1H), 7.72 (dd, J=9, 2.7 Hz, 1H), 8.02 (d, J=2.7 Hz, 1H), 10.49 (s, 1H). MS (EI) m/z 290. Anal. Calcd for C10H6F4N4O2: C, 41.39; H, 2.08; F, 26.19; N, 19.31. Found: C, 41.39; H, 1.98; F, 25.79; N, 19.53.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:12]2[N:11]=[CH:10][N:9]([C:13](=[O:19])[C:14]([CH3:18])([CH3:17])[CH2:15][CH3:16])[C:8]=2[C:7](=[O:20])[NH:6][C:5]1=[O:21].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH:27]=[CH2:28].O>CS(C)=O.C(OCC)(=O)C>[CH2:28]([N:6]1[C:7](=[O:20])[C:8]2[N:9]([C:13](=[O:19])[C:14]([CH3:17])([CH3:18])[CH2:15][CH3:16])[CH:10]=[N:11][C:12]=2[N:4]([CH3:3])[C:5]1=[O:21])[CH2:27][CH2:26][CH2:25][CH:24]=[CH2:23]
Reactant: CCC(C)(C)C(=O)n1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: C=CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: C=CCCCCn1c(=O)c2c(ncn2C(=O)C(C)(C)CC)n(C)c1=O
Reaction time: 0.25 h
Yield: 69.8 %

Procedure:
Sodium hydride (86 mg, 3.6 mmol) was added to a stirring solution of 3-methyl-7-(methylpivaloyl)xanthine 1404 (1.00 g, 3.6 mmol) in dimethyl sulfoxide (25 mL). After 15 minutes, 6-bromo-1-hexene (589 mg, 3.6 mmol) was added and stirring continued for 72 hours. The reaction mixture was then poured into water (70 mL) and extracted with dichloromethane (2×100 mL) and 20% ethanol/dichloromethane (1×100 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (50 mL) and dried over magnesium sulfate. The solvent was evaporated under vacuum to give a thick oil. Chromotograpy of the resulting thick oil using silica and ethyl acetate yielded 870 mg (67% yield) 1-(5-hexenyl)-3-methyl-7-(methylpivaloyl)xanthine (inventive compound no. 1441)
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[C:11]2[C:10]([S:12]([O-:15])(=[O:14])=[O:13])=[CH:9][CH:8]=[C:7]3[CH2:16][CH2:17][NH+:5]([C:6]=23)[CH:4]=[C:3]1/[CH:18]=[CH:19]/[CH:20]=[CH:21]/N(C1C=CC=CC=1)C(=O)C.[C:33]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]1([CH3:58])[C:50]2[C:49]([S:51]([O-:54])(=[O:53])=[O:52])=[CH:48][CH:47]=[C:46]3[CH2:55][CH2:56][NH+:44]([C:45]=23)[CH:43]=[C:42]1[CH3:57])([OH:35])=[O:34].N1C=CC=CC=1>C(OC(=O)C)(=O)C>[C:33]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]1([CH3:58])[C:50]2[C:45]3=[C:46]([CH2:55][CH2:56][NH+:44]3[CH:43]=[C:42]1/[CH:57]=[CH:21]/[CH:20]=[CH:19]/[CH:18]=[C:3]1\[C:2]([CH3:1])([CH3:32])[C:11]3[C:10]([S:12]([O-:15])(=[O:13])=[O:14])=[CH:9][CH:8]=[C:7]4[C:6]=3[N:5]\1[CH2:4][CH2:17][CH2:16]4)[CH:47]=[CH:48][C:49]=2[S:51]([OH:54])(=[O:53])=[O:52])([OH:35])=[O:34]
Reactant: CC1=C[NH+]2CCc3ccc(S(=O)(=O)[O-])c(c32)C1(C)CCCCCC(=O)O
Reactant: CC(=O)N(/C=C/C=C/C1=C[NH+]2CCc3ccc(S(=O)(=O)[O-])c(c32)C1(C)C)c1ccccc1
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC1(CCCCCC(=O)O)C(/C=C/C=C/C=C2/N3CCCc4ccc(S(=O)(=O)[O-])c(c43)C2(C)C)=C[NH+]2CCc3ccc(S(=O)(=O)O)c1c32
Temperature: 110 °C

Procedure:
To a stirring mixture of 6,6-dimethyl-5-((1E,3E)-4-(N-phenylacetamido)buta-1,3-dienyl)-1,2,3,6-tetrahydropyrrolo[3,2,1-ij]quinolinium-7-sulfonate and 6-(5-carboxypentyl)-5,6-dimethyl-1,2,3,6-tetrahydropyrrolo[3,2,1-ij]quinolinium-7-sulfonate in 5 mL acetic anhydride was added 5 mL pyridine. The reaction was heated to 110° C. for 2 hours. After cooling to room temperature the product was precipitated with ethyl acetate, washed with Et2O, and isolated by vacuum filtration. The final product was purified by reverse-phase HPLC yielding a blue solid. MS m/z calculated for C36H43N2O8S2 (M+H): 695.25. Found 695.3 (M+H, ESI+).
Reaction SMILES: N12CCCN=C1CCCCC2.[C:12]([C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13].[Cl:23][C:24]1[CH:25]=[C:26]([N+:31]([O-:33])=[O:32])[CH:27]=[CH:28][C:29]=1Cl>CN(C=O)C>[C:12]([C:16]1[CH:17]=[CH:18][C:19]([S:22][C:29]2[CH:28]=[CH:27][C:26]([N+:31]([O-:33])=[O:32])=[CH:25][C:24]=2[Cl:23])=[CH:20][CH:21]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)c1ccc(S)cc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)c1ccc(Sc2ccc([N+](=O)[O-])cc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Neat 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 1.2 mL, 7.8 mmol) was added dropwise to a solution of 4-tert-butylthiophenol (0.95 g, 5.7 mmol), 3,4-dichloronitrobenzene (1.0 g, 5.2 mmol), and DMF (15 mL). The solution was stirred for 1 h at ambient temperature then 1 h at 60° C. The mixture was allowed to cool and was poured over ice. The resulting yellow precipitate was collected and dried. The crude product was used without further purification.