Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:25])[C@@H:5]([OH:24])[CH2:6][NH:7][C:8]([C:10]1([CH2:19][S:20]C(=O)C)[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1)=[O:9])C.[OH-].[Na+].Cl>>[SH:20][CH2:19][C:10]1([C:8]([NH:7][CH2:6][C@@H:5]([C:4]([OH:25])=[O:3])[OH:24])=[O:9])[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1
Reactant: CCOC(=O)[C@@H](O)CNC(=O)C1(CSC(C)=O)Cc2ccccc2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)[C@@H](O)CNC(=O)C1(CS)Cc2ccccc2C1
Reaction time: 0.75 h

Procedure:
To the product of Example 6 (0.19 g, 0.52 mmol) in ETOH, add 1.0N NaOH (3.0 ml), stir 45 min and add 1.0N HCl (3.0 ml). Extract with EtOAc, dry and concentrate to obtain the title compound as a gum, [α]D26 =+2.8° (EtOH)
Reaction SMILES: CS(O)(=O)=[O:3].N(=[CH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10])O>>[NH:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8](=[O:3])[C:9]1=[O:10]
Reactant: CS(=O)(=O)O
Reactant: O=C(C=NO)Nc1ccccc1
Product: O=C1Nc2ccccc2C1=O
Temperature: 65 °C
Reaction time: 0.25 h

Procedure:
5 mL methanesulfonic acid was heated to 50° C. and slowly added to oximino acetanilide in batches, with the temperature being maintained at 60-70° C. After feeding, the temperature was raised to 70-80° C., and the reaction was carried out for 15 min. The reaction was finished by TLC detection. The reaction solution was poured into a crushed ice, and a red solid was precipitated. After placing at low temperature (0° C.) for 10 min, the red solid was filtered and dried to give crude isatin.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([NH:11][C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:3]=1[N+:16]([O-])=O.C([O-])=O.[NH4+].CN(C(/C=C/C1C[C@H]2C(S([O-])(=O)=O)NC3C=C4OCOC4=CC=3C(=O)N2C=1)=O)C.[Na+].[Br:53][C:54]1[CH:61]=[CH:60][C:57]([CH:58]=O)=[CH:56][CH:55]=1>C(O)C.[Pd]>[NH2:8][C:7]1[C:2]2[NH:1][C:58]([C:57]3[CH:60]=[CH:61][C:54]([Br:53])=[CH:55][CH:56]=3)=[N:16][C:3]=2[CH:4]=[C:5]([NH:11][C:12]([O:14][CH3:15])=[O:13])[CH:6]=1
Reactant: COC(=O)Nc1cc([N+](=O)[O-])c(N)c([N+](=O)[O-])c1
Reactant: O=Cc1ccc(Br)cc1
Agent: [Pd]
Agent: CN(C)C(=O)/C=C/C1=CN2C(=O)c3cc4c(cc3NC(S(=O)(=O)[O-])[C@@H]2C1)OCO4
Agent: O=C[O-]
Solvent: CCO
Product: COC(=O)Nc1cc(N)c2[nH]c(-c3ccc(Br)cc3)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 201.1 %

Procedure:
To a suspension of 4-amino-3,5-dinitro-1-(methoxycarbonyl)aminobenzene (311 mg, 1.2 mmol) in ethanol (24 mL), was added ammonium formate (1.8 g) and 10% Pd/C (120 mg) under nitrogen. The mixture was stirred at room temperature overnight. The Pd/C and excess ammonium formate were filtered off. The filtrate was treated with the sodium bisulfite adduct of 4-bromobenzaldehyde (715 mg, 0.84 mmol) at 0° C. After the solution was stirred for 12-16 h at room temperature under nitrogen, a trace of insoluble material was removed by filtration and the filtrate was concentrated on a rotary evaporator until approximately 60-70% of the solvent was removed. To the residue an equal volume of ethyl acetate was added, and the mixture was transferred to a separatory funnel. The organic layer was separated, and the water layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the desired product (610 mg, 48% yield) as brown powder: 1H-NMR (300 MHz, CD3OD) δ 3.73 (s, 3H), 6.53 (s, 1H), 7.16 (s, 1H), 7.64 (dd, 2H, J=6.6, 1.8 Hz), 7.88 (dd, 2H, J=6.6, 1.8 Hz); ESI MS m/z 361.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[N:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[Na]>C(O)C>[CH2:16]([O:15][C:13]([C:3]1[NH:4][N:5]=[N:1][C:2]=1[NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:14])[CH3:17]
Reactant: CCOC(=O)c1nnn(-c2ccccc2)c1N
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)c1[nH]nnc1Nc1ccccc1
Yield: 83.6 %

Procedure:
Ethyl 5-amino-1-phenyl-1,2,3-triazole-4-carboxylate (3.13 g; 0.0135 mole) was stirred at reflux with a solution of sodium (0.31 g; 0.135 atom) in ethanol (20 ml) for 3 hrs. and the mixture evaporated to dryness. The residual solid was dissolved in warm water, acidified and the precipitate filtered off to give 2.622 g (84%) of the title compound of mp 126-127° C. Recrystallisation from 90% ethanol gave material of mp 131-132° C. (lit mp 129-130° C.; O. Dimroth Annalen 364 183 [1909])
Reaction SMILES: CN1CCCC1=O.[NH2:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([F:16])=[C:11](F)[N:10]=1.[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>C(Cl)(Cl)Cl>[NH2:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([F:16])=[C:11]([NH:25][CH2:24][C:23]2[CH:26]=[CH:27][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)[N:10]=1
Reactant: Nc1nc(F)c(F)cc1F
Reactant: COc1ccc(CN)cc1
Solvent: ClC(Cl)Cl
Solvent: CN1CCCC1=O
Product: COc1ccc(CNc2nc(N)c(F)cc2F)cc1
Temperature: 140 °C
Reaction time: 24 h
Yield: 64.4 %

Procedure:
To 10 ml of N-methylpyrrolidone were added 3.90 g of 2-amino-3,5,6-trifluoropyridine and 7.60 g of p-methoxybenzylamine, and the mixture was stirred under nitrogen atmosphere at 140° C. for one day and allowed to cool. To the solution was added 50 ml of chloroform, and the solution was washed three times with 500 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was subjected to chromatography (silica gel, 32 g; eluent: chloroform) to obtain 4.50 g of the title compound as a pale yellow crude oil.
Reaction SMILES: C(OC[O:10][CH2:11][C@@H:12]([CH3:20])[CH2:13][CH2:14][CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[CH3:20][CH:12]([CH2:13][CH2:14][CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[CH2:11][OH:10]
Reactant: C[C@@H](CCCC(C)(C)O)COCOCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(CO)CCCC(C)(C)O
Reaction time: 120 h
Yield: 59.3 %

Procedure:
To a solution of an alcohol 7 (1.8 g, 0.01 mol) in ethyl acetate (20 mL) was added Pd/C (10%, 100 mg) at room temperature. The reaction mixture was stirred for 5 days and Pd/C (150 mg) was added 3 times per day. The reaction was then filtered, and the solvent was evaporated under reduced pressure. The crude oil was chromatographed on silica gel using hexane/EtOAc (1:1) as an eluent to give an oily diol 8 (0.95 g, 92%).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:10](=O)[CH2:9][CH:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])[CH2:7][C:6]=2[N:5]=[CH:4][CH:3]=1.[C:20]([NH:23][NH2:24])([NH2:22])=[NH:21].[ClH:25].Cl.O>C(O)C>[ClH:25].[NH:23]([N:24]=[C:10]1[CH2:9][CH:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[CH2:7][C:6]2[N:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:11]1=2)[C:20]([NH2:22])=[NH:21]
Reactant: Cc1ccccc1C1CC(=O)c2c(C)ccnc2C1
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1ccccc1C1CC(=NNC(=N)N)c2c(C)ccnc2C1
Yield: 97.5 %

Procedure:
A mixture of 4-methyl-7-(2-methylphenyl)-5,6,7,8-tetrahydroquinolin-5-one (0.30 g), aminoguanidine hydrochloride (0.14 g), concentrated hydrochloric acid (0.018 ml), water (0.018 ml) and ethanol (30 ml) was refluxed for 7 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The solution was washed with ethyl acetate and concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate-ethanol to give 5-guanidinoimino-4-methyl-7-(2-methylphenyl)-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 57) (0.4 g) as colorless crystals.
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:11]=2[N:10]=[C:9]1[CH:18]([NH:24][C:25](=[O:40])[C:26]1[CH:31]=[CH:30][C:29]([C:32]([N:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)=[O:33])=[C:28]([CH3:39])[CH:27]=1)[CH2:19][CH2:20][C:21](O)=[O:22])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH:63]([N:66](C(C)C)[CH2:67][CH3:68])(C)[CH3:64].C(NCC)C.FC(F)(F)C(O)=O.ClCl>O1CCCC1.C(OCC)(=O)C.C(O)C>[Cl:17][C:15]1[CH:14]=[CH:13][C:12]2[NH:8][C:9]([CH:18]([NH:24][C:25](=[O:40])[C:26]3[CH:31]=[CH:30][C:29]([C:32]([N:34]4[CH2:35][CH2:36][CH2:37][CH2:38]4)=[O:33])=[C:28]([CH3:39])[CH:27]=3)[CH2:19][CH2:20][C:21]([N:66]([CH2:67][CH3:68])[CH2:63][CH3:64])=[O:22])=[N:10][C:11]=2[CH:16]=1
Reactant: Cc1cc(C(=O)NC(CCC(=O)O)c2nc3cc(Cl)ccc3n2C(=O)OC(C)(C)C)ccc1C(=O)N1CCCC1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCNCC
Product: CCN(CC)C(=O)CCC(NC(=O)c1ccc(C(=O)N2CCCC2)c(C)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 76 %

Procedure:
Prepared analogously to Example 1g from N-[1-(1-tert-butoxycarbonyl-5-chlorobenzimidazol-2-yl)-3-hydroxycarbonylpropyl]-3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzamide, TBTU, diisopropylethylamine, and diethylamine in tetrahydrofuran followed by treatment analogously to Example 17 with trifluoroacetic acid. Yield: 76%; Rf value: 0.16 (silica gel; ethyl acetate/ethanol=9:1); C28H34ClN5O3 (524.06); mass spectrum: (M+H)+=524/526 (chlorine isotope).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]2[C:22](=[O:23])[C:21]3[S:24][CH:25]=[CH:26][C:20]=3[NH:19][C:18]2=[O:27])[CH2:11][CH2:10]1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>>[C:28]([N:19]1[C:20]2[CH:26]=[CH:25][S:24][C:21]=2[C:22](=[O:23])[N:17]([CH2:16][CH2:15][N:12]2[CH2:11][CH2:10][N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:14][CH2:13]2)[C:18]1=[O:27])(=[O:30])[CH3:29]
Reactant: COc1ccccc1N1CCN(CCn2c(=O)[nH]c3ccsc3c2=O)CC1
Reactant: CC(=O)OC(C)=O
Product: COc1ccccc1N1CCN(CCn2c(=O)c3sccc3n(C(C)=O)c2=O)CC1
Yield: 57 %

Procedure:
A solution of 3-[2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]thieno[3,2-d]pyrimidine-2,4-dione (2.6 g, 6.73 mmol) in acetic anhydride (30 ml) was heated to reflux for 5 hours. Acetic anhydride was removed in vacuo. The residue was dissolved in toluene, and the toluene was removed in vacuo. This process was repeated twice to remove any residual acetic anhydride. The residue was purified by flash chromatography on silica gel 60 (60 g) using 2.5% methanol in methylene chloride as eluant to give the product (1.65 g, 57% yield) as an off-white solid, mp 156°-158° C.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[S:7][C:8]([C:11]([OH:20])([C:16]([F:19])([F:18])[F:17])[C:12]([F:15])([F:14])[F:13])=[CH:9][N:10]=1)[CH2:2][CH2:3][CH3:4].[CH2:21]([N:23]=[C:24]=[O:25])[CH3:22]>C1C=CC=CC=1.CCOC(C)=O>[CH2:1]([N:5]([C:6]1[S:7][C:8]([C:11]([OH:20])([C:12]([F:13])([F:14])[F:15])[C:16]([F:19])([F:17])[F:18])=[CH:9][N:10]=1)[C:24]([NH:23][CH2:21][CH3:22])=[O:25])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1ncc(C(O)(C(F)(F)F)C(F)(F)F)s1
Reactant: CCN=C=O
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CCCCN(C(=O)NCC)c1ncc(C(O)(C(F)(F)F)C(F)(F)F)s1
Yield: 39 %

Procedure:
To a mixture of 2-[2-(butylamino)-1,3-thiazol-5-yl]-1,1,1,3,3,3-hexafluoropropan-2-ol (65 mg, 0.202 mmol) obtained from step 1 in benzene (2 ml) was added ethyl isocyanate (24 μL, 0.3 mmol) under a nitrogen atmosphere The reaction mixture was refluxed for 4 h. Solvent was removed under reduced pressure to obtain an oil, which was dissolved in EtOAc. The resulting solution was washed with H2O, saturated NaHCO3 and brine, and dried over MgSO4. The solvent was evaporated to yield a crude product which was purified by preparative TLC (EtOAC:hexanes, 1:3) to afford the corresponding product as a white solid (31 mg). 1H NMR δ0.92 (t, 3H), 1.20 (t, 3H), 1.37 (m, 2H) 1.67 (m, 2H), 3.37 (q, 2H), 3.83 (t, 2H), 4.24 (brs, 1H), 7.50 (s, 1H), 8.60 (brs, 1H); ESIMS: m/z 392 (M−H).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][CH2:6][NH2:7])[CH2:3][CH2:2]1.C([O:10][C:11]([C:13]1[N:14]=[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][N:24]([C:27](=[O:39])[C:28]4[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=4[C:35]([F:38])([F:37])[F:36])[CH2:23][CH2:22]3)=[N:17][N:16]2[CH:40]=1)=O)C>>[CH:1]1([CH2:4][CH2:5][CH2:6][NH:7][C:11]([C:13]2[N:14]=[C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][N:24]([C:27](=[O:39])[C:28]5[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=5[C:35]([F:36])([F:38])[F:37])[CH2:23][CH2:22]4)=[N:17][N:16]3[CH:40]=2)=[O:10])[CH2:3][CH2:2]1
Reactant: NCCCC1CC1
Reactant: CCOC(=O)c1cn2nc(N3CCN(C(=O)c4cc(F)ccc4C(F)(F)F)CC3)ccc2n1
Product: O=C(NCCCC1CC1)c1cn2nc(N3CCN(C(=O)c4cc(F)ccc4C(F)(F)F)CC3)ccc2n1
Yield: 46 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use 3-(cyclopropyl)propylamine in place of isoamylamine to react with 6-[4-(5-fluoro-2-trifluoromethylbenzoyl)piperazin-1-yl]imidazo[1,2-b]pyridazine-2-carboxylic acid ethyl ester, the title compound was obtained as a white solid in 46% yield (0.079 g). 1H NMR (300 MHz, CDCl3) δ 8.15 (d, J=0.6 Hz, 1H), 7.76-7.71 (m, 1H), 7.68 (d, J=9.9 Hz, 1H), 7.30-7.18 (m, 2H), 7.09-7.03 (m, 1H), 6.87 (d, J=9.9 Hz, 1H), 4.04-3.93 (m, 1H), 3.91-3.8 (m, 1H), 3.64-3.54 (m, 2H), 3.51-3.4 (m, 4H), 3.37-3.29 (m, 2H), 1.77-1.65 (m, 2H), 1.32-1.23 (m, 2H), 0.71-0.61 (m 1H), 0.42-0.37 (m, 2H), 0.08-0.03 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 165.9, 162.5, 162.3, 154.7, 138.4, 136.9, 135.6, 129.61, 129.6, 129.5, 126.4, 126.36, 125.0, 123.3, 122.9, 121.4, 118.1, 116.7, 116.5, 114.7, 114.57, 111.8, 46.2, 45.5, 41.2, 38.8, 31.9, 29.7, 10.4, 4.4. MS (ES+) m/z 519 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:26](=[O:28])[CH3:27])[CH:5]=[CH:6][C:7]=1[N:8]1[C:13]2=[N:14][C:15]3[C:20]([Cl:21])=[CH:19][CH:18]=[C:17]([CH:22]([OH:25])[CH2:23][CH3:24])[C:16]=3[N:12]2[CH2:11][CH2:10][CH2:9]1.[O:29]1CC[CH2:31][CH2:30]1.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[C:30]([O:25][CH:22]([C:17]1[C:16]2[N:12]3[CH2:11][CH2:10][CH2:9][N:8]([C:7]4[CH:6]=[CH:5][C:4]([C:26](=[O:28])[CH3:27])=[CH:3][C:2]=4[Cl:1])[C:13]3=[N:14][C:15]=2[C:20]([Cl:21])=[CH:19][CH:18]=1)[CH2:23][CH3:24])(=[O:29])[CH3:31]
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(C(C)=O)cc1Cl
Reactant: C1CCOC1
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCC(OC(C)=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(C(C)=O)cc1Cl
Temperature: 25 °C
Reaction time: 7 h
Yield: 70 %

Procedure:
To a solution of 1-{3-Chloro-4-[9-chloro-6-(1-hydroxypropyl)-3,4-dihydropyrimido[1,2-a]benzimidazol-1(2H)-yl]phenyl}ethanone (120.0 mg, 0.287 mmol) in pyridine (0.2 mL)/tetrahydrofuran (0.5 mL) was added acetic anhydride (0.5 mL) at 0° C. The reaction mixture was stirred at room temperature for 7 hrs. The mixture was concentrated. The residue was neutralized with aqueous saturated sodium hydrogen carbonate and extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 10-40% ethyl acetate/n-hexane gradient mixture. The residue was recrystallized from ethanol/n-hexane to give the title compound as a colorless powder (92.5 mg, 0.201 mmol, 70%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:9]2[CH2:11][CH2:10]2)=[C:6](I)[CH:7]=1.C([Mg]Cl)(C)C.C([O:20][B:21](OC(C)C)[O:22]C(C)C)(C)C>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:9]2[CH2:11][CH2:10]2)=[C:6]([B:21]([OH:22])[OH:20])[CH:7]=1
Reactant: Brc1ccc(C2CC2)c(I)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: OB(O)c1cc(Br)ccc1C1CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 5-bromo-2-cyclopropyliodobenzene (5.67 g, 0.018 mol) in anhydrous tetrahydrofuran (32 ml) at −78° C. is added isopropylmagnesium chloride (9.5 ml, 0.019 mol, 2M solution in THF) at such a rate as to maintain a temperature below −60° C. Once addition is complete the reaction mixture is stirred for 20 minutes at this temperature and then allowed to warm to room temperature and stir for an additional 2 hours. The solution is then cooled again to −78° C. and triisopropylborate (8.3 ml, 0.036 mol) is added dropwise. After stirring at this temperature for 10 minutes the solution is allowed to warm to room temperature and stir for an additional 2 hours. After quenching with 2M aqueous hydrochloric acid (20 ml) the reaction mixture is diluted with distilled water then extracted with ethyl acetate (×3). Organic fractions are combined, washed with distilled water and brine, then dried over magnesium sulfate and concentrated in vacuo. The crude solid is azeotroped with toluene (×3) then triturated with isohexane to afford 5-bromo-2-cyclopropylphenyl boronic acid as a cream solid.
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:6]=[C:7]([Si:10]([CH2:15][CH3:16])([CH2:13][CH3:14])[CH2:11][CH3:12])[O:8][CH:9]=1)[CH2:3][OH:4].C([Si](CC)(CC)C1OC=C(C=O)C=1)C.C[Si](C1C=COC=1C=O)(C)C.[C:42](Cl)(=[O:54])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53]>C(N(CC)CC)C>[OH:1][CH:2]([C:5]1[CH:6]=[C:7]([Si:10]([CH2:13][CH3:14])([CH2:11][CH3:12])[CH2:15][CH3:16])[O:8][CH:9]=1)[CH2:3][O:4][C:42](=[O:54])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53]
Reactant: CC[Si](CC)(CC)c1cc(C(O)CO)co1
Reactant: CCCCCCCCCCCC(=O)Cl
Agent: CC[Si](CC)(CC)c1cc(C=O)co1
Agent: C[Si](C)(C)c1ccoc1C=O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCC(=O)OCC(O)c1coc([Si](CC)(CC)CC)c1

Procedure:
4-(1,2-Dihydroxyethyl)-2-triethylsilylfuran (prepared substantially as described above using 5-triethylsilyl-3-furaldehyde in place of the corresponding trimethylsilyl furaldehyde) is reacted with dodecanoyl chloride in the presence of triethylamine to give 4-(1-hydroxy-2-dodecanoyloxyethyl)-2-triethylsilylfuran. Treating this 1-hydroxy compound with acetic anhydride and pyridine gives 4-(1-acetoxy-2-dodecanoyl-oxyethyl)-2-triethylsilylfuran.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:17]2[CH:21]=[N:20][CH:19]=[N:18]2)=[C:6]([CH:16]=1)[CH2:7][NH:8][C:9](=[O:15])[C@@H:10]1[CH2:14][CH2:13][CH2:12][NH:11]1.[C:22]([O:26][C:27]([NH:29][C@@H:30]([C:35](O)=[O:36])[CH2:31][CH:32]1[CH2:34][CH2:33]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C1C=C2N=NN(O)C2=CC=1.O.C(Cl)CCl.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:22]([O:26][C:27]([NH:29][C@@H:30]([C:35]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[C:9]([NH:8][CH2:7][C:6]1[CH:16]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)=[O:15])=[O:36])[CH2:31][CH:32]1[CH2:34][CH2:33]1)=[O:28])([CH3:24])([CH3:25])[CH3:23]
Reactant: CC(C)(C)OC(=O)N[C@H](CC1CC1)C(=O)O
Reactant: O=C(NCc1cc(F)ccc1-n1cncn1)[C@@H]1CCCN1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](CC1CC1)C(=O)N1CCC[C@H]1C(=O)NCc1cc(F)ccc1-n1cncn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 28 %

Procedure:
To a stirred solution of N-[5-fluoro-2-(1H-1,2,4-triazol-1-yl)benzyl]-L-prolinamide (86 mg, 0.25 mmol), N-(tert-butoxycarbonyl)-3-cyclopropyl-D-alanine (Example 31, Step C, 57 mg, 0.25 mmol) and HOBt hydrate (33 mg, 0.25 mmol) in DMF (2 mL) was added EDC (48 mg, 0.25 mmol). Diisopropylethylamine was then added in portions (0.1 mL total) to bring the pH of the solution to 6–7 as measured on wetted E. Merck pH indicator strips. The mixture was stirred at ambient temperature for 4 hours. The DMF was removed under reduced pressure and the residue was partitioned between EtOAc and saturated aqueous NaHCO3. The EtOAc layer was separated, dried over anhydrous MgSO4, and filtered. The filtrate solvent was removed under reduced pressure and the oily residue was purified by preparative reverse phase HPLC eluting with 95/5 to 5/95 1%TFA H2O/CH3CN in 30 min at a flow rate of 15 mL/min. The product fractions were combined and lyophilized to give 35 mg of the title compound. 1H NMR (400 MHz, CDCl3): δ 8.35 (s, 1H), 8.12 (s, 1H), 7.63 (m, 1H), 7.23–7.29 (m, 1H), 7.02–7.06 (m, 1H), 5.17 (d, J=5.5 Hz, 1H 4.62 (d, J=5.6 Hz, 1H), 4.22–4.41 (m, 4H), 3.94 (br, s, 1H), 3.60 (m, 1H), 2.34 (s, 1H), 1.98 (s, 2H), 1.44 (m, 1H), 1.30 (s, 9H), 0.71–0.73 (m, 1H), 0.47–0.51 (m, 2H), 0.12 (br s, 2H).
Reaction SMILES: C[O:2][C:3](=[O:33])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[NH:15][C:14]3[CH:16]=[C:17]([F:31])[C:18]([C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[N:26]([CH3:30])[CH:25]=[CH:24]5)=[C:19]([F:20])[C:13]=3[N:12]=2)[CH:7]=[CH:6][C:5]=1[CH3:32].CO.O.[OH-].[Na+]>C1COCC1>[F:20][C:19]1[C:13]2[N:12]=[C:11]([O:10][C:8]3[CH:7]=[CH:6][C:5]([CH3:32])=[C:4]([CH:9]=3)[C:3]([OH:33])=[O:2])[NH:15][C:14]=2[CH:16]=[C:17]([F:31])[C:18]=1[C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[N:26]([CH3:30])[CH:25]=[CH:24]2
Reactant: COC(=O)c1cc(Oc2nc3c(F)c(-c4ccc5c(ccn5C)c4)c(F)cc3[nH]2)ccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1ccc(Oc2nc3c(F)c(-c4ccc5c(ccn5C)c4)c(F)cc3[nH]2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 5-[4,6-difluoro-5-(1-methyl-1H-indol-5-yl)-1H-benzoimidazol-2-yloxy]-2-methyl-benzoic acid methyl ester (655 mg, 1.464 mmol) in THF:MeOH:H2O (7 mL) was treated with sodium hydroxide (1N, 3 mL) at room temperature. After 3 h, another 3 mL of sodium hydroxide (1N) was added and stirred at room temperature for another 1.5 h, and at 50° C. for another 1.5 h. The cooled reaction solution was concentrated on a rotavapor and the resulting aqueous solution was neutralized with 1N hydrogen chloride (6 mL), and the resulting white solid was collected through filtration (washed with water) and dried under high vacuum to give the desired product as a white solid. LC-MS: calculated for C24H17F2N3O3 434.41, observed m/e 434.6 (M+H)+ (Rt 1.52 min). 1H NMR (300 MHz, DMSO-d6): δ 7.78-7.15 (m, 8H), 6.45 (d, J=3.3 Hz, 1H), 3.81 (s, 3H), 2.53 (s, 3H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]([C:13]1[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][N:14]=1)([CH3:12])([CH3:11])[CH3:10]>C(#N)C>[Br:1][C:16]1[CH:15]=[N:14][C:13]([C:9]([CH3:12])([CH3:10])[CH3:11])=[CH:18][C:17]=1[NH2:19]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)c1cc(N)ccn1
Solvent: CC#N
Product: CC(C)(C)c1cc(N)c(Br)cn1

Procedure:
Procedure analogous to V. Canibano et al., Synthesis 2001, 14, 2175. 18.7 g (105 mmol) of N-bromosuccinimide are added in portions at 40° C. to a vigorously stirred, light-protected solution of 15.0 g (100 mmol) of 2-tertbutyl-4-aminopyridine [39919-69-2] in 500 ml of acetonitrile, and the mixture is stirred for a further 30 h. The solvent is removed in vacuo, the residue is taken up in 500 ml of dichloromethane, washed five times with 500 ml of water each time and once with 300 ml of sat. sodium chloride solution, the organic phase is dried over sodium sulfate, and the solvent is then removed in vacuo. The crude product is recrystallised from cyclohexane. Yield: 17.9 g (78 mmol), 78%. Purity: >95% according to 1H-NMR.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([NH2:13])[CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23](Cl)(=[O:25])=[O:24])([O-:16])=[O:15]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([NH:13][S:23]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N+:14]([O-:16])=[O:15])(=[O:24])=[O:25])[CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2
Reactant: COc1cc(N)c2ncccc2c1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Product: COc1cc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])c2ncccc2c1
Yield: 63.7 %

Procedure:
In a similar fashion using route 14 general procedure 26, 6-methoxyquinolin-8-amine (Intermediate 23) (350 mg, 2.01 mmol) and 2-nitrobenzenesulfonyl chloride (533 mg, 2.41 mmol) gave the title compound (460 mg, 64%).
Reaction SMILES: CN(C=O)C.[H-].[Na+].[CH2:8]([SH:11])[CH2:9][CH3:10].[NH2:12][C:13]1[N:21]=[C:20](Cl)[N:19]=[C:18]2[C:14]=1[N:15]=[CH:16][N:17]2[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>[Cl-].[Na+].O>[NH2:12][C:13]1[N:21]=[C:20]([S:11][CH2:8][CH2:9][CH3:10])[N:19]=[C:18]2[C:14]=1[N:15]=[CH:16][N:17]2[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Reactant: CCCS
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCSc1nc(N)c2ncn(Cc3ccccc3)c2n1
Temperature: 110 °C
Yield: 88.8 %

Procedure:
To DMF suspension (50 ml) containing sodium hydride (917 mg, 23 mmol, 60% in mineral oil) were added propanethiol (5.0 ml, 55 mmol) and 6-amino-9-benzyl-2-chloropurine (500 mg, 1.9 mmol) in order. The mixture was stirred under heating at 110° C. for 2.5 hours. Brine was added thereto and the mixture was extracted with ethyl acetate. The organic layer was dried on magnesium sulfate, filtered and the solvent in the filtrate was evaporated. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (505 mg, yield 87%).