Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C.CN([CH2:8][N:9]([CH3:11])[CH3:10])C.[Cl:12][C:13]1[C:21]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[CH:16][NH:17]2.[OH-].[Na+]>ClCCl>[CH3:11][N:9]([CH2:8][C:15]1[C:14]2[C:18](=[CH:19][CH:20]=[C:21]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:13]=2[Cl:12])[NH:17][CH:16]=1)[CH3:10]
Reactant: CN(C)CN(C)C
Reactant: Clc1c(OCc2ccccc2)ccc2[nH]ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)Cl
Product: CN(C)Cc1c[nH]c2ccc(OCc3ccccc3)c(Cl)c12
Reaction time: 0.08 h
Yield: 50.6 %

Procedure:
Acetyl chloride (6.42 g, 81.7 mmol) was added dropwise to a stirred solution of bis-dimethylamino-methane (BDAM) (8.34 g, 81.7 mmol) in dry dichloromethane (100 ml), while cooling in an ice bath. After 5 minutes, a solution of 4-chloro-5-benzyloxyindole (15.6 g, 60.7 mmol) in dichloromethane (100 ml) was added, dropwise, followed by addition of 10% aqueous sodium hydroxide (300 ml) after a further 10 minutes. The mixture was extracted with dichloromethane, and the extracts dried (Na2SO4) and stripped to a crude solid which was purified by chromatography (SiO2 ; CHCl3 /MeOH/NH4OH) and recrystallised from ethanol to give 3- dimethylaminomethyl-4-chloro-5-benzyloxyindole (9.66 g), m.p. 137°-9° C.
Reaction SMILES: C([O-])(C)(C)C.[K+].Cl[CH2:8][C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH2:16][CH:15]([NH:20][S:21]([C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=1)(=[O:23])=[O:22])[CH2:14]2)=[O:10].[C:31]([O:39][CH2:40][CH3:41])(=[O:38])[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].C(O)(=O)C>CS(C)=O.O>[C:31]([CH:32]([CH2:8][C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH2:16][CH:15]([NH:20][S:21]([C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=1)(=[O:23])=[O:22])[CH2:14]2)=[O:10])[C:33]([O:35][CH2:36][CH3:37])=[O:34])([O:39][CH2:40][CH3:41])=[O:38]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1ccc(S(=O)(=O)NC2Cc3ccc(C(=O)CCl)cc3C2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C(CC(=O)c1ccc2c(c1)CC(NS(=O)(=O)c1ccc(C)cc1)C2)C(=O)OCC
Reaction time: 8 h

Procedure:
10.6 g (0.095 mol) of potassium tert.-butanolate, followed by 23.0 g (0.063 mol) of (2-p-toluenesulphonamido-indan-5-yl) chloromethyl ketone, are added to 15.2 g (0.095 mol) of diethyl malonate in 25 ml of dimethyl sulphoxide. The mixture is allowed to stand overnight and is neutralised with glacial acetic acid, and water and petroleum ether are added. The reaction product which is precipitated is separated off and dissolved in ethyl acetate. The organic phase is washed with water, dried and evaporated, and the residue obtained is purified by chromatography over 600 g of silica gel using 98:2 ethylene chloride/ethanol.
Reaction SMILES: [CH3:1][N:2]([CH3:34])[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[CH:12]=[C:11]([C:13]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[C:20]([CH3:32])[CH:19]=3)([CH2:16][CH3:17])[CH2:14][CH3:15])[S:10][C:9]=2[CH:33]=1)=[O:4].[BH4-].[Na+]>>[CH3:34][N:2]([CH3:1])[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[CH:12]=[C:11]([C:13]([CH2:16][CH3:17])([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]([OH:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[C:20]([CH3:32])[CH:19]=3)[CH2:14][CH3:15])[S:10][C:9]=2[CH:33]=1)=[O:4]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc2ccc(C(=O)N(C)C)cc2s1
Agent: [BH4-]
Agent: [Na+]
Product: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1cc2ccc(C(=O)N(C)C)cc2s1
Yield: 99.4 %

Procedure:
2-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzo[b]thiophene-6-carboxylic acid dimethylamide (90 mg, 0.188 mmol) is reduced using NaBH4 (14 mg, 0.376 mmol) in a reaction analogous to Example 2 to afford the title compound (90 mg, 100%).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[H-].[Na+].[F:11][C:12]1[CH:13]=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[CH:16][C:17]=1F>O1CCCC1>[F:11][C:12]1[CH:13]=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[CH:16][C:17]=1[O:1][CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: CN1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCC(Oc2ccc([N+](=O)[O-])cc2F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.5 %

Procedure:
A solution of 4-hydroxy-1-methylpiperidine (0.30 g, 2.65 mmol) in anhydrous tetrahydrofuran (6 ml) was added dropwise to a suspension of 60% sodium hydride (0.054 g, 2.27 mmol) in anhydrous tetrahydrofuran (6 ml) under ice cooling, and the mixture was stirred at room temperature for 1 hour. 3,4-Difluoronitrobenzene (0.30 g, 1.89 mmol) was added to the reaction mixture under ice cooling, and the mixture was refluxed for 3 hours. Ice water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (0.18 g, 38%) as a yellow crystal.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:9]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][C:12]=1[OH:20])=[O:10].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:16][C:15](=[O:17])[C:14]1[CH:18]=[CH:19][C:11]([CH:9]=[O:10])=[C:12]([O:20][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1ccc(C(=O)O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(C(=O)OCc2ccccc2)cc1OCc1ccccc1
Temperature: 50 °C
Reaction time: 5 h
Yield: 95.1 %

Procedure:
Benzyl bromide (2.17 ml, 18.3 mmol) was added to a solution of 4-formyl-3-hydroxy-benzoic acid (1.01 g, 6.10 mmol) and potassium carbonate (3.37 g, 24.4 mmol) in DMF (10 ml), and the mixture was stirred at 50° C. for five hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 3-benzyloxy-4-formyl-benzoic acid benzyl ester (2.01 g, 95%).
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[NH:5][CH:4]=1)=[O:2].[BH4-].[Na+]>CO>[OH:2][CH2:1][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[NH:5][CH:4]=1
Reactant: COC(=O)c1ccc2[nH]cc(C=O)c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc2[nH]cc(CO)c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 350 mg portion of methyl 3-formyl-1H-indole-5-carboxylate was suspended in 10 ml of methanol, and 90 mg of sodium borohydride was added at 0° C., followed by stirring at room temperature for 30 minutes. After evaporation of the solvent, ethyl acetate and water were added thereto, and the ethyl acetate layer was washed with water and saturated brine and then dried over anhydrous sodium sulfate. By evaporating the solvent under a reduced pressure, 337 mg of methyl 3-(hydroxymethyl)-1H-indole-5-carboxylate was obtained as a colorless solid.
Reaction SMILES: [CH2:1]1[C@H:5]([N:6]2[C:10]3N=CN=[C:14]([NH2:15])[C:9]=3N=C2)O[C@H:3](COP(OP(OP(O)(O)=O)(O)=O)(O)=O)[C@H:2]1O.P(OC[C@H]1O[C@@H]([N:50]2C3N=C(N)NC(=O)C=3N=C2)C[C@@H]1O)(OP(OP(O)(O)=O)(O)=O)(=O)O.P(OC[C@H]1O[C@@H](N2C=CC(N)=NC2=O)C[C@@H]1O)(OP(OP(O)(O)=O)(O)=O)(=O)O.OP(=O)(OC[C@H]1O[C@@H](N2C=C(C)C(=O)NC2=O)C[C@@H]1O)OP(=O)(OP(=O)(O)O)O>>[NH2:50][CH2:3][CH2:2][CH2:1][CH2:5][NH:6][CH2:10][CH2:9][CH2:14][NH2:15]
Reactant: Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)[nH]1
Reactant: Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O1
Agent: Cc1cn([C@H]2C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)[nH]c1=O
Agent: Nc1ccn([C@H]2C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)n1
Product: NCCCCNCCCN

Procedure:
0.2 mM each DATP, dGTP, dCTP, dTTP
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([S:18]([CH3:21])(=[O:20])=[O:19])=[C:10]2[C:22]2[C:23]([CH3:28])=[N:24][O:25][C:26]=2[CH3:27])=[CH:5][CH:4]=1.B(Br)(Br)Br.O.CCOC(C)=O>C(Cl)Cl>[CH3:28][C:23]1[C:22]([C:10]2[N:9]([C:6]3[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=3)[C:17]3[C:12]([C:11]=2[S:18]([CH3:21])(=[O:20])=[O:19])=[CH:13][CH:14]=[CH:15][CH:16]=3)=[C:26]([CH3:27])[O:25][N:24]=1
Reactant: COc1ccc(-n2c(-c3c(C)noc3C)c(S(C)(=O)=O)c3ccccc32)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1noc(C)c1-c1c(S(C)(=O)=O)c2ccccc2n1-c1ccc(O)cc1
Temperature: -78 °C
Yield: 27 %

Procedure:
4-(1-(4-Methoxyphenyl)-3-(methylsulfonyl)-1H-indol-2-yl)-3,5-dimethylisoxazole was dissolved in 2 ml of dry DCM and cooled to −78° C. under nitrogen. BBr3 (31 μl, 0.33 mmol) was added and the temperature was allowed to warm to RT for 2 h. Water and EtOAc were added and the phases were separated. After evaporation of the solvents, the residue was purified by preparative HPLC to provide 4-[2-(3,5-dimethyl-isoxazol-4-yl)-3-methanesulfonyl-indol-1-yl]-phenol in 27% yield. ES/MS m/z: 383.11 (M+H), 381.13 (M−H); 1H NMR (acetone-d6, 500 MHz): 8.12 (m, 1H), 7.39-7.34 (m, 2H), 7.25-7.19 (m, 3H), 6.98 (m, 2H), 3.06 (s, 3H), 2.30 (s, 3H) and 2.09 (s, 3H).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](I)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][O:13][CH2:14][CH2:15][O:16][CH2:17][C:18](=[CH2:26])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(N(CC)CC)C>ClCCl.O>[CH3:12][O:13][CH2:14][CH2:15][O:16][CH2:17]/[C:18](=[CH:26]\[S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8])/[C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20]
Reactant: C=C(COCCOC)C(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)I)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCOC/C(=C\S(=O)(=O)c1ccc(C)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of p-toluenesulphonyl iodide (19.39 g, 68.7 mmol) in dichloromethane (50 mL) at room temperature under a nitrogen atmosphere was added tert-butyl 2-(2-methoxyethoxymethyl)acrylate (9.91 g, 45.8 mmol). The mixture was stirred at room temperature for 16 hours, cooled to 0° C. and triethylamine (12.7 mL, 91.6 mmol) added dropwise. The reaction was stirred at 0° C. for 0.5 hours and at room temperature for 4 hours, diluted with distilled water (100 mL) and the layers separated. The aqueous layer was further extracted with dichloromethane (25 mL) and the combined organic extracts were washed with 1.0M aqueous hydrochloric acid solution (100 mL), 5% aqueous sodium thiosulphate solution (25 mL) and distilled water (50 mL). The dichloromethane phase was concentrated under reduced pressure to give a brown oil (17.48 g, quantitative). The crude product was purified by chromatography on silica by gradient elution with hexane/ethyl acetate mixtues to give, after combination and evaporation of appropriate fractions, the title compound as a pale yellow oil (16.2 g, 95%) which crystallised on standing, m.pt.=40°-41° C., Rf =0.3 (silica; hexane/ethyl acetate, 2:1).
Reaction SMILES: [C:1]1(/[C:7](/[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:8]\[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:21](O)=[O:22]>>[CH:21]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]/[CH:8]=[C:7](\[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)/[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: OCCCCC/C=C(\c1ccccc1)c1cccnc1
Reactant: O=CO
Product: O=COCCCCC/C=C(\c1ccccc1)c1cccnc1
Yield: 91 %

Procedure:
(E)-7-Phenyl-7-(3-pyridyl)-6-hepten-1-ol (1.2 g, 4.5 mmoles) was added to formic acid (10 ml) and the mixture was refluxed for 7 hours. After cooling, the mixture was concentrated under reduced pressure and the resulting oil was subjected to silica gel column chromatography using isopropyl ether-ethyl acetate (1:1) as the eluent to give 1-formyloxy-(E)-7-phenyl-7-(3-pyridyl)-6-heptene (1.2 g, 91%) (Compound Id-20) as an oil.
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.Cl[CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][S:47](=[O:51])(=[O:50])[CH2:46][CH2:45]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(#N)C.[I-].[K+]>[O:50]=[S:47]1(=[O:51])[CH2:48][CH2:49][N:44]([CH2:43][CH2:42][NH:1][C@:2]23[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]2[C@@H:4]2[C@@:17]([CH3:20])([CH2:18][CH2:19]3)[C@@:16]3([CH3:21])[C@@H:7]([C@:8]4([CH3:34])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:22])([CH3:23])[C:11]([C:24]3[CH:25]=[CH:26][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:32][CH:33]=3)=[CH:10][CH2:9]4)[CH2:6][CH2:5]2)[CH2:45][CH2:46]1
Reactant: O=S1(=O)CCN(CCCl)CC1
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: O=P([O-])([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 120 °C
Yield: 73 %

Procedure:
A mixture of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-1-isopropenyl-5a,5b,8,8,11a-pentamethyl-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (600 mg, 1.10 mmol), 4-(2-chloroethyl)thiomorpholine 1,1-dioxide (600 mg, 2.56 mmol) (prepared as described in WO2002045652), anhydrous potassium phosphate (3.00 g, 14.1 mmol) and potassium iodide (10 mg, 0.060 mmol) in acetonitrile (50 mL) was placed in 150 mL AceGlass resealable pressure vessel. The white suspension was blanketed with nitrogen. The vessel was sealed and warmed to 115-125° C. for 48 h. The crude reaction was filtered through a short bed of silica gel and washed with ethyl acetate. The filtrate was concentrated in vacuo and purified by silica gel chromatography eluted with ethyl acetate and hexanes (0-50%) to afford the title compound as a colorless foam (566 mg, 73%). 1H NMR (500 MHz, CHLOROFORM-d) δ 7.95 (d, J=8.2 Hz, 2H), 7.22 (d, J=8.2 Hz, 2H), 5.31 (d, J=4.6 Hz, 1H), 4.74 (d, J=1.8 Hz, 1H), 4.62 (s, 1H), 3.93 (s, 3H), 3.22-2.99 (m, 9H), 2.79-2.55 (m, 4H), 2.52-2.42 (m, 1H), 2.18-2.09 (m, 1H), 1.99-1.02 (m, 20H), 1.72 (s, 3H), 1.11 (s, 3H), 1.01 (s., 3H), 1.10 (s, 3H), 0.95 (s, 3H), 0.95 (s., 3H). LCMS: m/e 705.51 (M+H)+, 3.01 min (method 10).
Reaction SMILES: C(=O)([O-])[O-].[CH:5]1[C:10](N=C=S)=[CH:9][C:8]2[C:14]([O:16][C:17]3([C:27]4[CH:28]=[CH:29][C:30]([OH:32])=[CH:31][C:26]=4[O:25][C:19]4[CH:20]=[C:21]([OH:24])[CH:22]=[CH:23][C:18]3=4)[C:7]=2[CH:6]=1)=[O:15].C1(=O)OC(=O)CC1>O.CS(C)=O>[CH:5]1[CH:10]=[CH:9][C:8]([C:14]([OH:16])=[O:15])=[C:7]([C:17]2[C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][C:19]=3[O:25][C:26]3[C:27]=2[CH:28]=[CH:29][C:30]([CH:31]=3)=[O:32])[CH:6]=1
Reactant: O=C1OC2(c3ccc(O)cc3Oc3cc(O)ccc32)c2ccc(N=C=S)cc21
Agent: O=C([O-])[O-]
Agent: O=C1CCC(=O)O1
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Each of the HA-DETA, HA-DAHP, and HA-DAP obtained in Example 4-2 and Example 4-3-1 was dissolved in distilled water (Milli Q water), so as to prepare a solution of a concentration of 20.0 mg/ml. Thereafter, a 0.2 M carbonate buffer (pH 9.0) was added to the prepared solution, resulting in a concentration of 10.0 mg/ml. Thereafter, fluorescein isothiocyanate that was 0.07 mole times to an HA unit was dissolved in DMSO that was 1/10 the volume of a modified HA solution. The DMSO solution was then added to the above solution, and the obtained mixture was then stirred in the dark at room temperature for 1 hour. Thereafter, succinic anhydride that was 40 mole times to the HA unit was dissolved in DMSO that was 1/10 the volume of the HA-AM solution. The DMSO solution was then added to the above solution, and the obtained mixture was then stirred in the dark at room temperature for 30 minutes. Thereafter, each sample was dialyzed against large excess amount of 0.5 M NaCl aqueous solution for purification, and the external dialysis solution was then exchanged with distilled water (Milli Q water), followed by further dialysis and purification (Spectrapore 4; molecular weight cut off (MWCO): 12 k-14 kDa). The obtained aqueous solution was freeze-dried, so as to obtain a fluorescein-labeled modified HA.
Reaction SMILES: Cl[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[Cl:9][C:10]1[CH:11]=[C:12]([CH:15]=[C:16]([O:18][C:19]2[C:20]([CH3:28])=[N:21][N:22]([CH2:25][CH2:26][OH:27])[C:23]=2[CH3:24])[CH:17]=1)[C:13]#[N:14].N1C=CN=C1.O>CN(C)C=O>[Si:2]([O:27][CH2:26][CH2:25][N:22]1[C:23]([CH3:24])=[C:19]([O:18][C:16]2[CH:15]=[C:12]([CH:11]=[C:10]([Cl:9])[CH:17]=2)[C:13]#[N:14])[C:20]([CH3:28])=[N:21]1)([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1nn(CCO)c(C)c1Oc1cc(Cl)cc(C#N)c1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nn(CCO[Si](C)(C)C(C)(C)C)c(C)c1Oc1cc(Cl)cc(C#N)c1
Reaction time: 72 h
Yield: 82.1 %

Procedure:
Chloro-t-butyldimethylsilane (2.78 g, 18.5 mmol) was added in one portion to a stirred solution of the pyrazole of Example 114 (4.89 g, 16.8 mmol) and imidazole (1.48 g, 21.8 mmol) in N,N-dimethylformamide (30 ml) at room temperature under nitrogen. The reaction was stirred for 3 days and water (200 ml) was added. The aqueous phase was extracted with diethyl ether (3×200 ml) and the combined organic phases were washed with water (2×50 ml) and brine (2×50 ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane to provide the title compound (5.60 g) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:13]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O>N1C=CC=CC=1>[CH3:11][C:8]1[CH:9]=[CH:10][C:2]2[N:1]=[C:13]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:5][C:4](=[O:6])[C:3]=2[CH:7]=1
Reactant: Cc1ccc(N)c(C(=O)O)c1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Product: Cc1ccc2nc(Oc3ccccc3)oc(=O)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.4 %

Procedure:
A solution of 2-amino-5-methylbenzoic acid (1.0 g, 6.6 mmol) in pyridine (10 ml) was cooled to 0° C. and treated dropwise with phenyl chloroformate (3.3 ml, 26 mmol). The resulting mixture was allowed to warm to room temperature and stirred for 16 h, after which time the pyridine was removed in vacuo. The residue was washed with water (20 ml) and dried in vacuo. Recrystallisation from toluene afforded the desired product as a pale brown solid (692 mg, 41%); δH (400 MHz, DMSO-d6) 2.40 (3H, s, CH3), 7.33-7.45 (3H, m, Ph), 7.48-7.55 (3H, m, Ph), 7.63 (1H, d, J 8, Ph), 7.89 (1H, s, Ph-H5); m/z (ES+) 254 (MH+).
Reaction SMILES: C1COCC1.[Cl:6][C:7]1[N:8]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]3OCC[O:19]3)=[CH:14][C:13]=2[O:23][CH3:24])[CH:9]=[CH:10][N:11]=1.Cl.[OH-].[Na+]>C(OCC)(=O)C>[Cl:6][C:7]1[N:8]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]=[O:19])=[CH:14][C:13]=2[O:23][CH3:24])[CH:9]=[CH:10][N:11]=1
Reactant: COc1cc(C2OCCO2)ccc1-n1ccnc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(C=O)ccc1-n1ccnc1Cl
Reaction time: 2 h
Yield: 100 %

Procedure:
To a THF (40 mL) solution of 2-chloro-1-(4-[1,3]dioxolan-2-yl-2-methoxyphenyl)-1H-imidazole (3.19 g), 5N hydrochloric acid (15 mL) was added and the reaction solution was agitated for 2 hours. The reaction mixture was made basic with 5N sodium hydroxide aqueous solution, ethyl acetate was added and the organic layer was partitioned. The organic layer obtained was washed with a saturated saline solution, dried with anhydrous magnesium sulfate and concentrated under reduced pressure to yield 2.69 g of the title compound. The physical properties of the compound are as follows.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32]C)[CH:10]1[CH2:19][CH2:18][CH2:17][C:16]2[CH:15]=[C:14]([C:20]([O:22][CH3:23])=[O:21])[CH:13]=[CH:12][C:11]1=2)C.B(Br)(Br)Br.CO>ClCCl>[OH:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][CH2:24][N:9]([CH2:8][CH2:7][CH2:6][CH2:5][C:4]([O:3][CH3:1])=[O:34])[CH:10]1[CH2:19][CH2:18][CH2:17][C:16]2[CH:15]=[C:14]([C:20]([O:22][CH3:23])=[O:21])[CH:13]=[CH:12][C:11]1=2
Reactant: CCOC(=O)CCCCN(CCc1ccccc1OC)C1CCCc2cc(C(=O)OC)ccc21
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: COC(=O)CCCCN(CCc1ccccc1O)C1CCCc2cc(C(=O)OC)ccc21
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Under argon, 653 mg (1.4 mmol) of the compound from Example 2A were dissolved in 12 ml of dichloromethane and the mixture was cooled to 0° C. 4.6 ml (4.6 mmol) of a 1 M solution of boron tribromide in dichloromethane were slowly added dropwise and the mixture was stirred at 0° C. for another 4 h (clear yellow solution). 7 ml of abs. methanol were then added and the mixture was heated under reflux overnight. The mixture was then concentrated to dryness under reduced pressure and the residue was partitioned between ethyl acetate and 10% strength aqueous sodium carbonate solution. The aqueous phase was re-extracted with ethyl acetate, and the combined organic phases were washed with saturated sodium chloride solution and dried over sodium sulphate. After concentration, the residue (519 mg of a brown oil) was purified by column chromatography on silica gel (mobile phase: gradient isohexane/4-32% ethyl acetate).
Reaction SMILES: Cl.[CH3:2][N:3](C)CCCN=C=NCC.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([OH:24])=O)=[CH:17][CH:16]=1.O.ON1C2C=CC=CC=2C=NN1.CN>O1CCCC1>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([NH:3][CH3:2])=[O:24])=[CH:17][CH:16]=1
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: ON1NN=Cc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)Cc1ccc(OC)cc1
Reaction time: 0.5 h
Yield: 83.5 %

Procedure:
Solid 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.60 g) was added to a stirred suspension of (4-methoxyphenyl)acetic acid (0.50 g) and 1-hydroxybenzotriazine hydrate (0.40 g) in 10 mL tetrahydrofuran. The mixture was stirred for 30 min, then methylamine (2.0 M in THF, 6.0 mL) was added. Stirring was continued for 12 h and the volatile material was subsequently evaporated. The crude residue was dissolved in 50 mL of EtOAc and washed twice with 50 mL of 1 M hydrochloric acid, twice with 50 mL of saturated sodium bicarbonate, and twice with 50 mL of saturated sodium chloride. Evaporation of the ethyl acetate gives 0.45 g of 2-(4-methoxyphenyl)-N-methylacetamide.