Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:43]=[CH:42][CH:41]=[CH:40][C:3]=1[CH2:4][C:5]1[C:6]([O:16][C@@H:17]2[O:34][C@H:33]([CH2:35][O:36][C:37](=[O:39])[CH3:38])[C@@H:28]([O:29][C:30](=[O:32])[CH3:31])[C@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:18]2[O:19][C:20](=[O:22])[CH3:21])=[N:7][N:8]([CH2:13][CH2:14][OH:15])[C:9]=1[CH:10]([CH3:12])[CH3:11].[CH2:44](Br)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:44]([O:1][C:2]1[CH:43]=[CH:42][CH:41]=[CH:40][C:3]=1[CH2:4][C:5]1[C:6]([O:16][C@@H:17]2[O:34][C@H:33]([CH2:35][O:36][C:37](=[O:39])[CH3:38])[C@@H:28]([O:29][C:30](=[O:32])[CH3:31])[C@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:18]2[O:19][C:20](=[O:22])[CH3:21])=[N:7][N:8]([CH2:13][CH2:14][OH:15])[C:9]=1[CH:10]([CH3:12])[CH3:11])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: BrCc1ccccc1
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2nn(CCO)c(C(C)C)c2Cc2ccccc2O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OC[C@H]1O[C@@H](Oc2nn(CCO)c(C(C)C)c2Cc2ccccc2OCc2ccccc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 82.1 %

Procedure:
To a solution of 4-(2-hydroxybenzyl)-1-(2-hydroxyethyl)-5-isopropyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole (35 mg) in N,N-dimethylformamide (3 mL) were added benzyl bromide (20 mg) and potassium carbonate (18 mg), and the mixture was stirred at room temperature for 14 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=1/3—ethyl acetate) to give 4-(2-benzyloxybenzyl)-1-(2-hydroxyethyl)-5-isopropyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole (33 mg). To a solution of 4-(2-benzyloxybenzyl)-1-(2-hydroxyethyl)-5-isopropyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole (33 mg) in methanol (3 mL) was added sodium methoxide (28% methanol solution, 9 μL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol) to give the title compound (20 mg).
Reaction SMILES: [C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:12]3[CH:13]=[C:14]([F:19])[C:15]([I:18])=[C:16]([F:17])[C:11]=3[N:10]=[C:9]2S(C)(=O)=O)=[CH:3][CH:2]=1.[CH2:30]([O:32][C:33]([CH:35]1[CH2:37][CH:36]1[CH2:38][OH:39])=[O:34])[CH3:31].C1CCN2C(=NCCC2)CC1>CN(C=O)C.CCOC(C)=O.O>[C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:12]3[CH:13]=[C:14]([F:19])[C:15]([I:18])=[C:16]([F:17])[C:11]=3[N:10]=[C:9]2[O:39][CH2:38][CH:36]2[CH2:37][CH:35]2[C:33]([O:32][CH2:30][CH3:31])=[O:34])=[CH:3][CH:2]=1
Reactant: CCOC(=O)C1CC1CO
Reactant: CS(=O)(=O)c1nc2c(F)c(I)c(F)cc2n1Cc1ccc(-c2ccccc2)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1CC1COc1nc2c(F)c(I)c(F)cc2n1Cc1ccc(-c2ccccc2)cc1
Temperature: 80 °C

Procedure:
To a solution of 1-(biphenyl-4-ylmethyl)-4,6-difluoro-5-iodo-2-(methylsulfonyl)-1H-benzimidazole (Intermediate 5, 0.500 g, 0.954 mmol) and 2-hydroxymethyl-cyclopropanecarboxylic acid ethyl ester (Intermediate 10, 0.550 g, 3.81 mmol) in 3.2 mL of DMF was added DBU (0.575 mL, 3.81 mmol) dropwise via syringe. The reaction was heated at 80° C. for 2 h, and then diluted with EtOAc and H2O. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The resulting crude residue was purified on silica gel (eluted 2-15% then 15-20% EtOAc/hexanes: gradient elution) to furnish the desired product. LCMS: calculated for C27H23F2IN2O3 588.38, observed m/e 588.9 (M+H)+ (Rt 2.51/4 min).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([CH:19]2[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][CH3:28])=[O:26])[CH2:20]2)=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([O:16]C)=[O:15])=[C:10]([F:18])[CH:9]=1.[Li+].[OH-].Cl>C1COCC1.CO>[NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[C:10]([F:18])[CH:9]=2)=[N:6][C:5]([CH:19]2[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][CH3:28])=[O:26])[CH2:20]2)=[CH:4][N:3]=1
Reactant: COC(=O)c1ccc(-c2nc(C3CCCN(C(=O)OC)C3)cnc2N)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)N1CCCC(c2cnc(N)c(-c3ccc(C(=O)O)c(F)c3)n2)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To methyl 3-(5-amino-6-(3-fluoro-4-(methoxycarbonyl)phenyl)pyrazin-2-yl)piperidine-1-carboxylate (50 mg, 0.129 mmol) in THF (4 mL) and MeOH (2 mL) was added 1 M LiOH (0.500 mL, 0.500 mmol). The reaction mixture was stirred at room temperature for 4 h. The reaction mixture pH was adjusted to ˜3 with 2 N HCl, and product was extracted with ethyl acetate. The EtOAc layer was separated, washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was proceeded to next step without purification (40 mg, 83%). LCMS (m/z): 375.2 (MH+), 0.637 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14](=[O:19])[N:15]([O:17][CH3:18])[CH3:16])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:24].OS([O-])(=O)=O.[K+]>CN(C=O)C.O.CCOCC>[C:1]([O:5][C:6](=[O:20])[N:7]([C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14](=[O:19])[N:15]([O:17][CH3:18])[CH3:16])[CH2:10][CH2:9]1)[CH3:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: CON(C)C(=O)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Reactant: CI
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: CON(C)C(=O)[C@H]1CC[C@H](N(C)C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 24.18 g (82 mmol) of trans-[4-(Methoxy-methyl-carbamoyl)-cyclohexyl]-carbamic acid tert-butyl ester in 80 ml of DMF was treated at 0° C. with 5.37 g (123 mmol) of NaH (55% in oil) in small portions. The reaction was stirred for 1 h at 0° C., then treated slowly (20 min) with 40.9 ml (656 mmol) iodomethane and warmed up to RT over night. The reaction was cooled and neutralized with aqueous 10% KHSO4 and poured into water/Et2O (3×). The organic phase was washed with aqueous 10% NaCl, dried over Na2SO4 evaporated and purified by flash silica gel column (CH2Cl2/EtOAc 9:1 to 1:1) to yield 20.69 g (84%) of trans-[4-(Methoxy-methyl-carbamoyl)-cyclohexyl]-methyl-carbamic acid tert-butyl ester, MS: 301 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:17](=[NH:19])[NH2:18])=[N:9]2)=[CH:5][CH:4]=1.C[N:23](C)[CH:24](N(C)C)[CH:25]([O:28][CH3:29])[C:26]#N.N1CCCCC1>CC(C)CCO>[CH3:29][O:28][C:25]1[C:24]([NH2:23])=[N:19][C:17]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:21][CH:20]=3)[N:9]=2)=[N:18][CH:26]=1
Reactant: COc1ccc(Cn2nc(C(=N)N)c3ccccc32)cc1
Reactant: COC(C#N)C(N(C)C)N(C)C
Solvent: CC(C)CCO
Solvent: C1CCNCC1
Product: COc1ccc(Cn2nc(-c3ncc(OC)c(N)n3)c3ccccc32)cc1
Temperature: 100 °C
Reaction time: 72 h

Procedure:
6.45 g of 1-(4-methoxybenzyl)-1H-indazole-3-carboximidamide (23.0 mmol, 1 eq.), 5.40 g of 3,3-bis(dimethylamino)-2-methoxypropanenitrile (1-2-1, 31.5 mmol, 1.37 eq.) and 0.455 ml of piperidine (4.60 mmol, 0.2 eq.) were dissolved in 82.7 ml of dry 3-methylbutan-1-ol, put under a nitrogen atmosphere and stirred at 100° C. for 3 days. The mixture was cooled down at room temperature and stirred for 18 hours for crystallization. The resulting suspension was filtered off. The crystals were washed with cold methanol and dried in vacuo at 50° C. The crystallization was repeated twice with cold methanol to receive 2 further filter cakes and a combined yield of 6.87 g (19 mmol, 82.5%) of the analytically pure target compound.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:11]([C:15]1[CH:23]=[C:22]2[C:18]([CH:19]=[CH:20][NH:21]2)=[CH:17][CH:16]=1)([O:13][CH3:14])=[O:12].[CH3:24][S:25](Cl)(=[O:27])=[O:26].O>C1COCC1>[CH3:24][S:25]([N:21]1[C:22]2[C:18](=[CH:17][CH:16]=[C:15]([C:11]([O:13][CH3:14])=[O:12])[CH:23]=2)[CH:19]=[CH:20]1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc2ccn(S(C)(=O)=O)c2c1
Reaction time: 0.5 h

Procedure:
A solution of NaN(TMS)2 (1 M) in THF (11 mmol, 11 ml) was added dropwise to a -78° C solution of 6-carbomethoxyindole (876 mg, 5 mmol, prepared according to the procedure of Batcho, et al., Org. Synth. Coll. 7:34) in dry THF (10 ml). After stirring for 30 min, MeSO2Cl (1.47 mL) (Me=CH3) was added. The mixture was allowed to stir overnight then poured onto 100 ml of water. The mixture was extracted with CH2Cl2 (2×75 ml). The extracts were washed with brine, dried (Na2SO4), and the solvent was removed by rotary evaporation to give a light brown solid. The solid was purified by flash column chromatography (silica gel, 20% ethyl acetate/hexane) to give 510 mg of N-methanesulfonyl-6-carbomethoxyindole.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[C:5]([CH3:14])([CH3:13])[C:4](=[O:15])[C:3]=1[C:16](OCC)=[O:17].C(N(C(C)C)C(C)C)C.Cl.[NH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]>O1CCOCC1.CCOC(C)=O>[CH3:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[C:5]([CH3:13])([CH3:14])[C:4](=[O:15])[C:3]([C:16]([NH:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:17])=[C:2]2[OH:1]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCOC(=O)C1=C(O)c2cc(C)ccc2C(C)(C)C1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1ccc2c(c1)C(O)=C(C(=O)NCC(=O)OC(C)(C)C)C(=O)C2(C)C
Temperature: 80 °C
Reaction time: 1 h
Yield: 27.1 %

Procedure:
Ethyl 4-hydroxy-1,1,6-trimethyl-2-oxo-naphthalene-3-carboxylate (750 mg, 2734 μmol) was dissolved in 1,4-dioxane (2734 μL) and N-ethyl-N-isopropylpropan-2-amine (1429 μL, 8202 μmol). tert-Butyl 2-aminoacetate hydrochloride (687 mg, 4101 μmol) was added, and the reaction was stirred at 80° C. for 1 hour. The reaction mixture was cooled to ambient temperature, diluted with 100 mL of EtOAc, added to a separatory funnel, partitioned with NaHCO3 (saturated, aqueous), washed 2 times with 50 mL of NaHCO3 (saturated, aqueous), separated, dried over Na2SO4, and concentrated in vacuo to give the title compound (266 mg) as a white solid after flash chromatography. MS (m/z)=304 (M+H-tBu)+.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[C:3](=[CH:4][CH:5]=[C:6]([C:22]([NH2:24])=O)[C:7]=2[C:10]2[C:11]([C:19]([NH2:21])=O)=[CH:12][CH:13]=[C:14]3[O:18][CH2:17][O:16][C:15]=23)[O:2]1>P(Cl)(Cl)(Cl)=O>[CH2:1]1[O:9][C:8]2[C:3]3([O:18][CH2:17][O:16][C:15]4[CH:14]=[CH:13][CH:12]=[C:11]([C:19]#[N:21])[C:10]=4[C:7]=2[C:6]([C:22]#[N:24])=[CH:5][CH2:4]3)[O:2]1
Reactant: NC(=O)c1ccc2c(c1-c1c(C(N)=O)ccc3c1OCO3)OCO2
Solvent: O=P(Cl)(Cl)Cl
Product: N#CC1=CCC23OCOC2=C1c1c(C#N)cccc1OCO3
Temperature: 0 °C
Yield: 90.6 %

Procedure:
5,6-Methylenedioxy-5',6'-methylenedioxy-2,2'-biphenyldicarboxamide (8 g) is refluxed in phosphorus oxychloride (70 ml) for 4 hours. The reaction mixture is cooled and then poured into ice water. The precipitated crystals are separated by filtration and dissolved in chloroform. The solution is washed with water, dried and distilled to remove the solvent to give 5,6-methylenedioxy-5,6'-methylenedioxy-2,2'-biphenyldicarbonitrile (6.5 g) as colorless crystal. M.p. 213°-215° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:24][C:25]([N:27]2[CH2:31][CH2:30][N:29](N3CCCCC3)[C:28]2=[O:38])=[O:26])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]=[CH:20][N:21]([CH3:23])[CH:22]=3)[S:17][C:10]=12.[CH:39]1(N2CCNC2=O)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>>[CH:39]1([N:29]2[CH2:30][CH2:31][N:27]([C:25]([NH:24][C:4]3[CH:5]=[CH:6][C:7]([O:8][C:9]4[CH:14]=[CH:13][N:12]=[C:11]5[CH:15]=[C:16]([C:18]6[N:19]=[CH:20][N:21]([CH3:23])[CH:22]=6)[S:17][C:10]=45)=[C:2]([F:1])[CH:3]=3)=[O:26])[C:28]2=[O:38])[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: O=C1NCCN1C1CCCCC1
Reactant: Cn1cnc(-c2cc3nccc(Oc4ccc(NC(=O)N5CCN(N6CCCCC6)C5=O)cc4F)c3s2)c1
Product: Cn1cnc(-c2cc3nccc(Oc4ccc(NC(=O)N5CCN(C6CCCCC6)C5=O)cc4F)c3s2)c1
Yield: 68 %

Procedure:
Following the procedure described above for the compound 276 (example 113) but replacing 1-(piperidin-1-yl)imidazolidin-2-one (278) by 1-cyclohexylimidazolidin-2-one (281), the title compound 279 was obtained in 68% yield. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.69 (s, 1H), 8.44 (dd, J=5.5 Hz, 1H), 7.86 (s, 1H), 7.79 (dd, J=2.5 Hz, J=13 Hz, 1H), 7.72 (s, 1H), 7.68 (s, 1H), 7.46 (t, J=8.9 Hz, 1H), 7.35 (d, J=5.5 Hz, 1H), 6.58 (d, J=5.5 Hz, 1H), 3.8 (dd, J=7.6 Hz, J=8.0 Hz, 2H), 3.73 (s, 3H), 3.7-3.6 (m, 1H), 3.44 (dd, J=7.2 Hz, J=8.0 Hz, 2H), 1.79-1.60 (m, 5H), 1.47-1.41 (m, 2H), 1.36-1.29 (m, 2H), 1.7 (m, 1H). MS (m/z): (M+1) 535.2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13](O)=[O:14].C(N=C=NCCCN(C)C)C.O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([NH:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1)=[O:14]
Reactant: Nc1cc(Cl)ccn1
Reactant: O=C(O)c1cccc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1cc(Cl)ccn1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
2-Amino-4-chloropyridine (90 mg, 0.70 mmol, 1.1 eq), 3-chlorobenzoic acid (0.1 mg, 0.6 mmol, 1 eq), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (135 mg, 0.704 mmol, 1.10 eq) and 4-dimethylaminopyridine (7.8 mg, 0.064 mmol, 0.10 eq) were dissolved in CH2Cl2 (5 ml) and stirred at rt overnight. Water was added and the layers separated. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 160 mg (94%) of the title compound as a white solid: 1H NMR (400 MHz, DMSO-d6) δ 11.21 (s, 1H), 8.39 (d, J=5.4 Hz, 1H), 8.27 (d, J=1.6 Hz, 1H), 8.06 (t, J=1.8 Hz, 1H), 7.96 (dt, J=7.6, 1.2 Hz, 1H), 7.67 (ddd, J=8.0, 2.1, 1.0 Hz, 1H), 7.54 (t, J=7.9 Hz, 1H), 7.32 (dd, J=5.4, 2.0 Hz, 1H); ES-MS [M+1]+: 267.1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=2[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[Br:18]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:18][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=2[C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccccc1-c1ccc(C)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccccc1-c1ccc(CBr)cc1
Yield: 59.6 %

Procedure:
2.0 g (8.8 mmol) of methyl 2-(4'-methylphenyl)benzoate, 1.6 g (9.0 mmol) of N-bromosuccinimide and 0.05 g of α,α'-azobis(isobutyronitrile) [another name; 2,2'-azobis(isobutyronitrile)] were dissolved in carbon tetrachloride (110 ml), followed by heating under reflux for 2 hours. The resultant mixture was filtered to remove insolubles, and then vacuum concentration was effected. The residue was recrystallized from a n-hexane/isopropyl ether mixed solvent to give 1.6 g of the title compound (yield; 59%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2)([O-:3])=[O:2].[H-].[Na+].[CH3:15]I>CN(C=O)C>[CH3:15][N:8]1[C:9]2[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[CH:11][CH:10]=2)[CH:6]=[N:7]1
Reactant: CI
Reactant: O=[N+]([O-])c1cccc2[nH]ncc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ncc2c([N+](=O)[O-])cccc21
Yield: 82 %

Procedure:
A solution of 4-nitroindazole (prepared according to the literature procedures Davies, R. R. J.C.S., 1955, 2412-2423; Porter, H. D. Org. Synth. Collect. Vol I, 20, 73-74.) (2.01 g, 12.3 mmol) was added slowly to a cold (ice/water), stirred suspension of NaH (440 mg, 18.4 mmol) in DMF (20 mL) under N2. The mixture was stirred for 30 min, and a solution of MeI (1.91 g, 13.5 mmol) in DMF (10 mL) was then added. Workup gave 1-methyl-4-nitroindazole (1.79 g, 82%); mp (EtOAc/petroleum ether) 138-139° C. Hydrogenation of this (6.70 g, 37.9 mmol) in absolute EtOH (300 mL) in the presence of Pd/C (1.00 g) gave 4-amino-1-methylindazole (4.23 g, 76%). A mixture of 4-amino-1-methylindazole (4.10 g, 27.9 mmol) and 2-bromo-3-nitrobenzoic acid (6.86 g, 27.9 mmol) were then reacted in a mixture of isopropanol/N-methylmorpholine in the presence of copper powder and CuI as above, giving 2-[(1-methyl-1H-indazol-4-yl)amino]-3-nitrobenzoic acid (439 mg, 5 %); mp (EtOAc/n-hexane) 257-260° C.; Reductive cyclisation of 2-[(1-methyl-1H-indazol-4-yl)amino]-3-nitrobenzoic acid with NaBH4 in 2 M NaOH as above gave 3-methyl-3H-pyrazolo[4,3-a]phenazine-10-carboxylic acid as a dark yellow solid (54%); mp (acetone) 320-323° C. [(CD3)2SO] δ 4.28 (s, 3 H, NCH3), 8.07 (t, J=7.9 Hz, 1 H, H-8), 8.10 (d, J=9.6 Hz 1H, H-4 or H-5), 8.39 (d, J=9.6 Hz 1H, H-4 or H-5), 8.52-8.60 (m, 2H, H-7 and H-9), 8.76 (s, 1 H, H-2), 14.90 (br s, 1 H, COOH).
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[C:7]([NH:10][CH2:11][C@@H:12]1[O:16][C:15](=[O:17])[N:14]([C:18]2[CH:23]=[CH:22][C:21]([S:24][CH2:25][CH2:26][OH:27])=[C:20]([F:28])[CH:19]=2)[CH2:13]1)(=[O:9])[CH3:8]>O.CO>[C:7]([NH:10][CH2:11][C@@H:12]1[O:16][C:15](=[O:17])[N:14]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH2:25][CH2:26][OH:27])=[O:2])=[C:20]([F:28])[CH:19]=2)[CH2:13]1)(=[O:9])[CH3:8]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(SCCO)c(F)c2)C(=O)O1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc(S(=O)CCO)c(F)c2)C(=O)O1
Reaction time: 8 h

Procedure:
Sodium periodate (0.014 g, 0.065 mmol) in water (0.5 mL) was added to 5-(S)-acetamidomethyl-3-[4′-(2″-hydroxyethyl)thio-3′-fluorophenyl]-oxazo-lidine-2-one (0.020 g, 0.061 mmol) in methanol (1 mL), and the mixture was stirred at r.t overnight. Solvent was removed under vacuum, and the residue dissolved in ethyl acetate (ca. 5 mL). Resulting solution was washed with water, brine, and dried (MgSO4). Solvent was removed under vacuum, and the crude product purified by TLC (eluent: 10% methanol in dichloromethane). Yield 0.018 g (86%). MS (m/z): 345 [M+H]+. 1H NMR.
Reaction SMILES: [CH2:1]([CH:6]([CH2:9][OH:10])[CH2:7][OH:8])[CH2:2][CH2:3][CH2:4][CH3:5].[Br:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Br:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]2[O:10][CH2:9][CH:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:7][O:8]2)=[CH:14][CH:13]=1
Reactant: CCCCCC(CO)CO
Reactant: O=Cc1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCCC1COC(c2ccc(Br)cc2)OC1
Temperature: 25 °C

Procedure:
A mixture of compound from Example 6 (31 g, 0.21 mol), 4-bromobenzaldehyde (38.8 g, 0.21 mol) and 4-toluenesulphonic acid (110 mg) in dry toluene (200 cm3) was heated under reflux (3 h) using a Dean and Stark apparatus. On cooling to room temperature the mixture was poured into aqueous sodium hydrogen carbonate solution (5%, 70 cm3) and the separated organic layer washed with aqueous sodium hydrogen carbonate solution (5%, 2×60 cm3), water (2×60 cm3) and dried (MgSO4). The solvent was removed in vacuo and the residue purified by crystalliation from methanol to remove the cis-isomer.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH3:7].[CH2:8](Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1COCC1>[CH2:8]([C:4]1[S:3][C:2]([CH3:1])=[C:6]([CH3:7])[CH:5]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: BrCc1ccccc1
Reactant: Cc1ccsc1C
Solvent: C1CCOC1
Product: Cc1cc(Cc2ccccc2)sc1C
Yield: 77.1 %

Procedure:
The title compound was prepared according to the procedure in Example 5, step 1 using 2,3-dimethylthiophene (5.00 g, 44.6 mmol), 2.5M BuLi/hexanes (17.9 mL, 44.6 mmol) and benzyl bromide (5.30 mL, 44.6 mmol) in THF (44.6 mL). Purification on Biotage KP-Sil eluting with 1% EtOAc/pet ether gave 6.96 g (77%) of the title compound as an oil. 1H NMR (DMSO-d6) δ 2.01 (s, 3H), 2.21 (s, 3H), 3.98 (s, 2H), 6.58 (s, 1H), 7.18-7.37 (m, 5H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]=[O:9]>O>[CH:1]1[CH:2]=[C:3]([CH2:4][C:6]2[C:1]([OH:7])=[CH:2][CH:3]=[CH:4][CH:5]=2)[C:8]([OH:9])=[CH:5][CH:6]=1
Reactant: C=O
Reactant: Oc1ccccc1
Solvent: O
Product: Oc1ccccc1Cc1ccccc1O

Procedure:
Stoichiometrically excess phenol and formaldehyde are introduced into a preparation step 1 (from a reaction step to a phenol-removal step). More specifically, to a reactor equipped with, for instance, a stirring machine, a temperature control device, a reflux condenser, a complete condenser and a vacuum device, there are charged phenol, formaldehyde and an acid catalyst and these ingredients are reacted at a determined temperature for a desired period with stirring. Then the acid catalyst, the water formed during the reaction and the unreacted phenol are removed from the reaction product to give crude bisphenol F 2.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[CH:9][C:10]2[N:11]([CH:13]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:15]=2)[CH:12]=1)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[C:6]([C:7]1[CH:8]=[CH:9][C:10]2[N:11]([CH:13]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:15]=2)[CH:12]=1)#[CH:5]
Reactant: CCOC(=O)c1cn2cc(C#C[Si](C)(C)C)ccc2n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1ccc2nc(C(=O)OCC)cn2c1
Reaction time: 0.5 h
Yield: 74.9 %

Procedure:
To a solution of 500 mg of ethyl 6-[(trimethylsilyl)ethynyl]imidazo[1,2-a]pyridine-2-carboxylate in 10 mL of anhydrous tetrahydrofuran, cooled to 0° C. are added dropwise 1.58 mL of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran. The reaction mixture is stirred for 30 minutes, 5 mL of water are then added and the resulting mixture is extracted three times with 20 mL of dichloromethane. The product is purified by chromatography on silica, eluting with mixtures of ethyl acetate and hexane (from 1/3 to 1/1). The fractions containing the expected product are combined and concentrated to dryness under reduced pressure to give 280 mg of ethyl 6-ethynylimidazo[1,2-a]pyridine-2-carboxylate in the form of a yellow solid.
Reaction SMILES: C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.[Br:15][C:16]1[CH:17]=[C:18]2[C:22](=[C:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:24]=1)[NH:21][CH2:20][CH2:19]2>C(Cl)(Cl)Cl>[Br:15][C:16]1[CH:17]=[C:18]2[C:22](=[C:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:24]=1)[NH:21][CH:20]=[CH:19]2
Reactant: CCOC(=O)c1cc(Br)cc2c1NCC2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cc(Br)cc2cc[nH]c12
Reaction time: 2 h
Yield: 68380.8 %

Procedure:
DDQ (119.3 g. 525.7 mmol) was added in several portions to a solution of ethyl 5-bromo-2,3-dihydro-1H-indole-7-carboxylate (129.1 g, 0.48 mmol) in CHCl3 (1500 mL) and the mixture was stirred for 2 h. The reaction was filtered and the solid was washed with CHCl3 (3×500 mL). The filtrate was washed with 5% NaOH (3×500 mL), H2O (500 mL) and brine (500 mL) then dried over Na2SO4. The solution was evaporated and the residue was recrystallized with EtOH, giving 88 g (69%) of the title compound.