Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[Br:13].O[CH:15]([CH3:19])[C:16](=O)[CH3:17].[C:20](#[N:24])[CH2:21][C:22]#[N:23]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[NH2:23][C:22]1[N:1]([C:2]2[C:3]([Br:13])=[CH:4][C:5]([C:9]([F:12])([F:10])[F:11])=[CH:6][C:7]=2[Br:8])[C:15]([CH3:19])=[C:16]([CH3:17])[C:21]=1[C:20]#[N:24]
Reactant: N#CCC#N
Reactant: Nc1c(Br)cc(C(F)(F)F)cc1Br
Reactant: CC(=O)C(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1c(C#N)c(N)n(-c2c(Br)cc(C(F)(F)F)cc2Br)c1C
Yield: 15.9 %

Procedure:
In 15 ml of toluene, 5.5 g of 4-amino-3,5-dibromobenzotrifluoride, 1.9 g of acetoin, and 34 mg of p-toluenesulfonic acid were dissolved. The reaction solution was heated under reflux for 2.5 hours while conducting azeotropic dehydration. To the reaction mixture, 1.42 g of malononitrile was added. The reaction mixture was heated for 4 hours while being concentrated at 180° C. Water was added to the reaction mixture. The reaction mixture was extracted with chloroform, and subsequently, the extract was dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=5:1), and was allowed to stand for crystallization to yield 1.2 g of 2-amino-4,5-dimethyl-1-(2,6-dibromo-4-trifluoromethylphenyl)pyrrole-3-carbonitrile.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[CH2:9][CH3:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[I-:24].[Na+]>ClCCl.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([I:24])[CH2:9][CH3:10])=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: CCC(O)c1ccc(F)cc1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(I)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.1 %

Procedure:
The obtained 4-fluorophenylpropan-1-ol (4.83 g, 31.3 mmol) was dissolved in dichloromethane (50 ml), and triethylamine (6.55 ml, 47.0 mmol) and methanesulfonyl chloride (2.91 ml, 37.6 mmol) were added thereto in the ice bath followed by stirring under a nitrogen atmosphere for 30 minutes. The reaction mixture was diluted with dichloromethane (50 ml), and washed with 10% hydrochloric acid and subsequently with a saturated aqueous sodium chloride solution, and then dried over magnesium sulfate. The solvent was evaporated in vacuo, and the residue was dissolved in acetone (100 ml), and then sodium iodide (9.39 g, 62.6 mmol) was added thereto followed by stirring under a nitrogen atmosphere for 2 hours at 50° C. The reaction mixture was diluted with ethyl acetate (250 ml), and washed with 10% aqueous sodium thiosulfate solution and subsequently with a saturated aqueous sodium chloride solution, and then dried over magnesium sulfate. The solvent was evaporated in vacua, and the residue was purified by flash chromatography on a silica gel column (elution solvent; hexane:ethyl acetate=5 :1-2:1) to afford 4-fluorophenyl-1-iodopropane (7.12 g, 86% yield) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[C:3]=1[OH:15].N1C=CC=CC=1.C1C([N+]([O-])=O)=CC=C([Cl-][C:32]([O-])=[O:33])C=1>C(Cl)Cl>[C:8]([C:6]1[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[C:3]2[O:15][C:32](=[O:33])[NH:1][C:2]=2[CH:7]=1)([CH3:9])([CH3:10])[CH3:11]
Reactant: CC(C)(C)c1cc(N)c(O)c([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)c1cc([N+](=O)[O-])c2oc(=O)[nH]c2c1
Reaction time: 24 h
Yield: 70 %

Procedure:
To a solution of 2-amino-4-tert-butyl-6-nitrophenol (300 mg, 1.43 mmol) and pyridine (0.30 mL) in methylene chloride (30 mL) was added 4-nitrophenylchloroformate (280 mg, 1.39 mmol). The mixture was stirred for 24 h. The resulting solution was washed with aqueous sodium bicarbonate (2×20 mL), dried over solid magnesium sulfate and concentrated to an orange solid. Column chromatography (silica gel, eluant=40% EtOAc/petroleum ether) afforded 5-tert-butyl-7-nitro-3H-benzoxazol-2-one (70%).
Reaction SMILES: I/[CH:2]=[CH:3]\[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:10]1([C:16]#[CH:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:16]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)#[C:17][CH:2]=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: C#Cc1ccccc1
Reactant: CCCCCC/C=C\I
Product: CCCCCCC=CC#Cc1ccccc1

Procedure:
The modified procedure was used to convert (Z)-1-Iodo-oct-1-ene and phenyl acetylene to the title product. Purification by flash chromatography (hexane as the eluent) gave the analytically pure product as a colorless oil (420 mg, 98% yield). 1H NMR (400 MHz, CDCl3) δ 7.44-7.41 (m, 2H), 7.29-7.27 (m, 3H), 5.99-5.92 (m, 1H), 5.67-5.65 (d, J=10.7, 1H), 2.42-2.36 (m, 2H), 1.46-1.43 (m, 2H), 1.37-1.29 (m, 6H), 0.89-0.86 (m, 3H). 13C NMR (100 MHz, CDCl3) δ 144.36, 131.42, 128.30, 127.96, 123.82, 109.06, 93.46, 86.57, 31.76, 30.45, 28.96, 28.91, 22.70, 14.16. Anal. Calcd. for C16H20: C, 90.51; H, 9.49; Found C, 90.24; H, 9.47.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:11]([Cl:12])=[C:10]([O:13][CH:14]([F:16])[F:15])[N:9]([CH3:17])[N:8]=2)[N:5]=[CH:4][CH:3]=1.[C:18]([O:21]C(=O)C)(=O)[CH3:19].[N+:25]([O-])([OH:27])=[O:26]>C(O)(=O)C>[Cl:12][C:11]1[C:7]([N:6]2[C:2]([NH:1][C:18](=[O:21])[CH3:19])=[C:3]([N+:25]([O-:27])=[O:26])[CH:4]=[N:5]2)=[N:8][N:9]([CH3:17])[C:10]=1[O:13][CH:14]([F:15])[F:16]
Reactant: O=[N+]([O-])O
Reactant: Cn1nc(-n2nccc2N)c(Cl)c1OC(F)F
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1c([N+](=O)[O-])cnn1-c1nn(C)c(OC(F)F)c1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.3 g (5.0 mmol) 5-Amino-1-(4-chloro-5-difluoromethoxy-1-methyl-3-pyrazolyl)pyrazole was dissolved in 20 ml acetic acid and treated with 0.55 g (5.4 mmol) acetic anhydride. After stirring for 2 hours at room temperature the reaction solution was cooled to 0° C. and 0.4 g (6.4 mmol) concentrated nitric acid added. After stirring for 8 hours at room temperature, the reaction mixture was poured into ice water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate 1:1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:10](=O)[CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[N:9][N:8]=2)[CH:7]=1
Reactant: CN1CCN(CC(=O)NNc2ccc(F)cn2)CC1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN1CCN(Cc2nnc3ccc(F)cn23)CC1
Reaction time: 18 h
Yield: 88.7 %

Procedure:
Intermediate 14a (570 mg, 2.13 mmol) was dissolved in THF (20.0 mL) and cooled in an ice/water bath. Triphenylphosphine (1.12 g, 4.27 mmol) was added followed by triethylamine (1.19 mL, 8.54 mmol) and hexachloroethane (1.01 g, 4.27 mmol). The reaction was stirred for 18 h. The mixture was loaded onto an SCX-2 cartridge, washing with MeOH and eluting with 2M NH3 in MeOH. The residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM, to give the title compound (470 mg, 1.89 mmol, 89%). LCMS (Method 1): Rt 0.36 min, m/z 250 [MH+].
Reaction SMILES: C(OC([NH:11][C@H:12]([C:16]([O:18][CH2:19][C:20]1[N:21]([CH2:34][CH2:35][CH2:36][CH2:37][NH:38][S:39]([CH3:42])(=[O:41])=[O:40])[C:22]2[C:31]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[N:25]=[C:24]([NH2:32])[C:23]=2[N:33]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])=O)C1C=CC=CC=1.CO.C1COCC1.Cl>[Pd].O>[NH2:11][C@H:12]([C:16]([O:18][CH2:19][C:20]1[N:21]([CH2:34][CH2:35][CH2:36][CH2:37][NH:38][S:39]([CH3:42])(=[O:40])=[O:41])[C:22]2[C:31]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[N:25]=[C:24]([NH2:32])[C:23]=2[N:33]=1)=[O:17])[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCc1nc2c(N)nc3ccccc3c2n1CCCCNS(C)(=O)=O
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[C@H](N)C(=O)OCc1nc2c(N)nc3ccccc3c2n1CCCCNS(C)(=O)=O
Reaction time: 18 h
Yield: 42.8 %

Procedure:
To a hydrogenation bottle was added (4-amino-1-{4-[(methylsulfonyl)amino]butyl}-1H-imidazo[4,5-c]quinolin-2-yl)methyl N-[(benzyloxy)carbonyl]-L-valinate (1.5 g, 2.5 mmol) followed by a mixture of methanol (30 mL), THF (15 mL) and water (5 mL) and conc HCl (5 mL). To this was added Pd/C (90 mg) and the reaction was hydrogenated at 40 psi (2.8×105 Pa) overnight. To the reaction mixture was added conc. HCl (5 mL) and Pd/C (90 mg) and the reaction was hydrogenated at 40 psi (2.8×105 Pa) for 18 hours. The reaction was filtered through CELITE filter aid and the filtrate was evaporated to afford a clear oil. The product was isolated by prep HPLC (ISCO Combiflash Separation System, Biotage Si 40+M column, eluted with a gradient of 0-8% methanol in dichloromethane with 1% ammonium hydroxide) to provide (4-amino-1-{4-[(methylsulfonyl)amino]butyl}-1H-imidazo[4,5-c]quinolin-2-yl)methyl L-valinate (0.495 g) as an off white solid, mp 161-163° C.; MS (ESI) m/z 463 (M+H)+; Anal. Calcd for C21H30N6O4S: C, 54.53; H, 6.54; N, 18.17. Found C, 53.96; H, 6.62; N, 17.85, delta C=0.57.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[CH:15]=[CH:16][O:17][C:11]=2[N:10]=[C:9]1[CH:18]([NH:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1.C([BH3-])#N.[Na+].O1CCCC1>CO.C(O)(=O)C>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[CH:15]=[CH:16][O:17][C:11]=2[N:10]=[C:9]1[CH:18]([N:21]([CH2:32][C:31]1[CH:34]=[CH:35][C:28]([Br:27])=[CH:29][CH:30]=1)[CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH2:19][CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CCC(NCCN(C)C)c1nc2occc2c(=O)n1Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCC(c1nc2occc2c(=O)n1Cc1ccccc1)N(CCN(C)C)Cc1ccc(Br)cc1
Temperature: 60 °C

Procedure:
A solution of 3-benzyl-2-(1-{[2-(dimethylamino)ethyl]amino}-propyl)furo[2,3-d]pyrimidin-4(3H)-one (1-6, 1 equiv) and 4-bromobenzaldehyde (2 equiv) in methanol is treated with a solution of sodium cyanoborohydride in tetrahydrofuran (1M, 2 equiv). Acetic acid is added to obtain a pH of 6–7 and the reaction is warmed at 60° C. for 18 h. An additional 2 equivalents of 4-bromobenzaldehyde and sodium cyanoborohydride are added after 18, 42 and 66 hours while maintaining the pH at 6–7 with acetic acid. After warming 90 h at 60° C., the reaction is concentrated and the residue is partitioned between EtOAc and aqueous saturated NaHCO3 solution. The organic layer is washed with brine, dried (MgSO4) and concentrated. The residue is purified by flash chromatography. Elution with EtOAc to 5% NH3-EtOH/EtOAC gives 3-benzyl-2-(1-{(4-bromobenzyl)[2-(dimethylamino)ethyl]amino}propyl)furo[2,3-d]pyrimidin-4(3H)-one (2-1).
Reaction SMILES: CC1(C)C[O:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:18]=[CH:17][C:16]([CH2:19][OH:20])=[CH:15][CH:14]=2)=N1.Cl.C([OH:25])C>>[OH:20][CH2:19][C:16]1[CH:17]=[CH:18][C:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:4]([OH:5])=[O:25])=[CH:14][CH:15]=1
Reactant: CCO
Reactant: CC1(C)COC(c2ccccc2-c2ccc(CO)cc2)=N1
Agent: Cl
Product: O=C(O)c1ccccc1-c1ccc(CO)cc1
Temperature: 25 °C
Yield: 81 %

Procedure:
2.0 g (7.11 mmol) of 4,4-dimethyl-2-(4'-hydroxymethylbiphenyl-2-yl)oxazoline was dissolved in ethanol (30 ml). 2N hydrochloric acid (10 ml) was added thereto, followed by heating under reflux for 3 hours. After the reaction liquid was cooled and concentrated, a saturated aqueous solution of sodium hydrogen-carbonate (100 ml) was added thereto, followed by the extraction with chloroform. After the organic phase was washed with water and dried, it was subjected to vacuum concentration. A 20% aqueous solution of sodium hydroxide (20 ml) and ethanol (20 ml) were added to the residue, followed by heating under reflux for 8 hours. After the reaction liquid was cooled to room temperature and adjusted to pH 6 with hydrochloric acid, it was extracted with chloroform. After the organic phase was washed with water and dried, it was subjected to vacuum concentration. The residue was purified by silica gel column chromatography (a chloroform/methanol system) to give 1.31 g of the title compound (yield 81%).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([Br:7])[S:4][C:3]=1[CH:8]=[O:9].[CH2:10](O)[CH2:11][OH:12]>C1(C)C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:6]=[C:5]([Br:7])[S:4][C:3]=1[CH:8]1[O:12][CH2:11][CH2:10][O:9]1
Reactant: O=Cc1sc(Br)cc1Br
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Brc1cc(Br)c(C2OCCO2)s1
Yield: 80.8 %

Procedure:
A mixture consisting of the product from Step A (11.0 g, 40.7 mmol), TsOH (0.25 g) and ethylene glycol (5.06 g, 81.5 mmol) in toluene (150 mL) was heated at reflux temperature for 1.5 h, water was removed by a Dean-Stark trap. The reaction mixture was cooled and poured into a saturared aqueous solution of sodium bicarbonate (100 mL). The organic layer was separated, dried (MgSO4), and evaporated to dryness. Purification of this crude material by column chromatography (silica, 6% ethyl acetate/hexane) gave 10.33 g of an oil (81%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8](=[O:9])[O:7][CH:6]([CH2:10][CH2:11][C:12]([O:14]C)=[O:13])[C:5]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:2].[OH-].[Na+].O>CO>[CH2:1]([O:3][C:4]1[C:8](=[O:9])[O:7][CH:6]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])[C:5]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:2]
Reactant: CCOC1=C(c2ccccc2)C(CCC(=O)OC)OC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCOC1=C(c2ccccc2)C(CCC(=O)O)OC1=O
Reaction time: 0.5 h
Yield: 63.6 %

Procedure:
To a solution of methyl 3-(4-ethoxy-5-oxo-3-phenyl2,5-dihydro-2-furyl)propionate (0.20 g) in methanol (2 ml) was added 1N sodium hydroxide solution (0.8 ml) during a period of a few minutes at ambient temperature. The solution was stirred for 30 minutes at the same temperature and then poured into water (10 ml). The mixture was washed with diethyl ether and the aqueous layer was adjusted to pH 1 with aqueous 10% hydrochloric acid. The separated oil was extracted with ethyl acetate twice. The combined organic layers were washed with water three times, dried, and evaporated to dryness. The residue was crystallized from a mixture of diethyl ether and n-hexane to yield 3-(4-ethoxy-5-oxo-3-phenyl2,5-dihydro-2-furyl)propionic acid (121 mg) as a crystal.
Reaction SMILES: [CH3:1][N:2]1[C:6]([OH:7])=[C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[C:4]([CH3:16])=[N:3]1.Cl[C:18]1[N:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:25])[N:19]=1>>[CH3:1][N:2]1[C:6]([O:7][C:18]2[N:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:25])[N:19]=2)=[C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[C:4]([CH3:16])=[N:3]1
Reactant: Cc1cc(C)nc(Cl)n1
Reactant: Cc1nn(C)c(O)c1Sc1ccc(Cl)cc1
Product: Cc1cc(C)nc(Oc2c(Sc3ccc(Cl)cc3)c(C)nn2C)n1
Reaction time: 3 h
Yield: 85.4 %

Procedure:
A mixture of 0.255 g (1.00 mmol) of 1,3-dimethyl-4-(4-chlorophenylthio)-5-hydroxypyrazole and 0.43 g (3.00 mmol) of 2-chloro-4,6-dimethylpyrimidine was heated on a bath of which temperature was 130° C. for 3 hours with stirring. After completing the reaction, the reaction mixture was purified by means of silica gel column chromatography (developing solution: ethyl acetate) to give 0.308 g of 1,3-dimethyl-4-(4-chlorophenylthio)-5-(4,6-dimethylpyrimidine-2-yloxy)pyrazole.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=2)[N:3]=1.[O:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH:17]([NH2:24])[CH2:16]1>>[O:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH:17]([NH:24][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=3)[N:3]=2)[CH2:16]1
Reactant: NC1COc2ccccc21
Reactant: O=[N+]([O-])c1ccc2nc(Cl)ccc2c1
Product: O=[N+]([O-])c1ccc2nc(NC3COc4ccccc43)ccc2c1

Procedure:
(2,3-Dihydro-benzofuran-3-yl)-(6-nitro-quinolin-2-yl)-amine was prepared according to step A in general example 2 from 2-chloro-6-nitro-quinoline and 2,3-dihydro-benzofuran-3-ylamine (CAS no.: 109926-23-4); MS: m/e=308.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1>C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][O:12]2)=[C:4]([Cl:11])[N:3]=1
Reactant: C1=COCCC1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Product: Clc1nc(Cl)c2ncn(C3CCCCO3)c2n1
Temperature: 50 °C
Yield: 102.1 %

Procedure:
To 2,6-dichloropurine (25.0 g) (available from, for example, Aldrich, UK) was added ethyl acetate (260 mL), followed by p-toluenesulfonic acid (0.253 g). The mixture was heated to 50° C. and then 3,4-dihydro-2H-pyran (16.8 g) was added. The reaction mixture was then heated at 50° C. for 4 hours. The reaction mixture was evaporated in vacuo to give the title compound as a yellow solid (36.9 g).
Reaction SMILES: [C@@H:1]1([C:12]2[C:13](=O)OC3C(C=2)=CC=CC=3)[O:9][C@H:8]([CH2:10][OH:11])[C@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].[CH3:23][CH2:24][C:25]1([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:32](=[O:33])[NH:31][C:29](=[O:30])[NH:28][C:26]1=[O:27].Br[CH2:41][CH2:42][CH2:43][CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46]>>[C@@H:1]1([C:12]2[CH:49]=[C:48]3[C:42]([CH:43]=[C:44]([C:29]([NH:28][CH2:26][CH2:25][CH2:23][CH2:24][C:25]4([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[C:32](=[O:33])[NH:31][C:29](=[O:30])[NH:28][C:26]4=[O:27])=[O:30])[C:45](=[O:46])[O:47]3)=[CH:41][CH:13]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3]
Reactant: CCC1(c2ccccc2)C(=O)NC(=O)NC1=O
Reactant: O=c1oc2ccccc2cc1[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Reactant: CCOC(=O)CCCCBr
Product: O=C1NC(=O)C(CCCCNC(=O)c2cc3ccc([C@@H]4O[C@H](CO)[C@H](O)[C@H](O)[C@H]4O)cc3oc2=O)(c2ccccc2)C(=O)N1

Procedure:
The above-described synthesis of the β-galactosylcoumarin-phenobarbital conjugate (n=4) can be modified to yield label conjugates wherein n=2 through 6 by replacing the starting material ethyl 5-bromopentanoate with the appropriate ethyl ω-bromoalkanoate as follows:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([CH3:8])=[CH2:7])=[CH:4][CH:3]=1.[H][H]>[Pt]=O.C(O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]([CH3:8])[CH3:7])=[CH:4][CH:3]=1
Reactant: C=C(C)c1ccc(Br)cc1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: CC(C)c1ccc(Br)cc1
Yield: 80.5 %

Procedure:
A 23.2 g quantity of p-bromo-α-methylstyrene (118 mmole), approximately 100 mg platinum oxide, and 150 ml absolute ethanol were shaken on a Paar Hydrogenator for four hours, beginning with an initial hydrogen pressure of 50 psi. The material was then filtered through a celite plug and the solvent removed by distillation at atmospheric pressure. The residue resulting was distilled using a water aspirator vacuum to produce 18.9 g (80.4% yield) of p-bromocumene, bp 88°-92° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH:18]([C:19]([NH:21][O:22][CH2:23][C:24]2[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=2)[C:27](O)=[O:28])=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:33])[N:10]1[CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]1[NH:40][S:41]([CH3:44])(=[O:43])=[O:42].C1N=CN(C(N2C=NC=C2)=O)C=1.C(=O)(O)O.[NH2:61][C:62]([NH2:64])=[NH:63]>CN(C=O)C>[NH2:63][C:62](=[N:61][C:27]([C:26]1[CH:25]=[C:24]([CH:32]=[CH:31][CH:30]=1)[CH2:23][O:22][NH:21][C:19]([CH:18]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:33])[N:10]([CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]2[NH:40][S:41]([CH3:44])(=[O:42])=[O:43])[CH:9]1[C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])=[O:20])=[O:28])[NH2:64]
Reactant: N=C(N)N
Reactant: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCc2cccc(C(=O)O)c2)C1c1ccc(Cl)cc1Cl
Agent: O=C(O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCc2cccc(C(=O)N=C(N)N)c2)C1c1ccc(Cl)cc1Cl
Temperature: 50 °C
Reaction time: 1 h
Yield: 55.5 %

Procedure:
A mixture of 590 mg of 3-{[({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}benzoic acid, 217 mg of CDI, and 9 ml of DMF was stirred at 50° C. for 1 hour, and 241 mg of guanidine carbonate was then added thereto, followed by stirring at the same temperature for 3 hours. The reaction solution was left to be cooled and the solvent was then evaporated under reduced pressure. The residue was diluted with ethyl acetate, and washed with a saturated aqueous sodium hydrogen carbonate solution and then with a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent:chloroform-methanol) and recrystallized from acetonitrile to obtain 348 mg of (3RS,4RS)—N-({3-[(diaminomethyl ene)carb amoyl]benzyl}oxy)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colorless solid.
Reaction SMILES: C(OC([NH:11][CH:12]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH:13]([OH:29])[C:14]([NH:16][C@H:17]([C:19]([N:21]1[CH2:28][CH2:27][CH2:26][C@H:22]1[C:23]([OH:25])=[O:24])=[O:20])[CH3:18])=[O:15])=O)C1C=CC=CC=1.[H][H]>CO.O.[Pd]>[NH2:11][CH:12]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH:13]([OH:29])[C:14]([NH:16][C@H:17]([C:19]([N:21]1[CH2:28][CH2:27][CH2:26][C@H:22]1[C:23]([OH:25])=[O:24])=[O:20])[CH3:18])=[O:15]
Reactant: C[C@H](NC(=O)C(O)C(Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: CO
Product: C[C@H](NC(=O)C(O)C(N)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Yield: 89.4 %

Procedure:
Crude (S,S)-1-[N-[3-[(benzyloxycarbonyl)amino]-2-hydroxy-1-oxo-4-phenylbutyl]-L-alanyl]-L-proline (about 2 mmol) is dissolved in 50 ml of methanol and 25 ml of water. After sweeping the system with argon 0.5 g of 10% palladium on charcoal is added. While stirring, a slow stream of hydrogen is passed over the surface for eighteen hours. The catalyst is removed by filtration through diatomaceous earth and the pad is washed with methanol. The filtrate is taken to dryness in vacuo and methanol is added four times and removed in vacuo leaving 0.65 g of a glass. This material is combined with that from another run. Most of this material is dissolved in 5 ml water and is applied to a column packed with 12 ml AG50WX2 (H+) resin. The column is eluted with water until the eluate is no longer strongly acidic and then is eluted with pH 6.5 buffer. Fractions positive to ninhydrin are pooled. It appears that some of the product has precipitated on the column so when fractions give only a very weak test with ninhydrin the remaining product is eluted with 2 N NH4OH. The two pools are worked up separately by taking to dryness in vacuo and adding water and again taking to dryness. Electrophoresis on the two materials are identical; -5.3 cm (pH 1.9 buffer, 2000 V, 30 min., detected ninhydrin and I2). The two pools are combined, triturated with water, the solid harvested by filtration, washed with more water and then with methanol. Drying in vacuo over P2O5 at 75° C. gives the analytical sample (412 mg), [α]D =-120° (c=0.64, acetic acid).