Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([NH:14][C:15]2[CH:16]=[C:17]3[C:26](=[CH:27][C:28]=2Br)[O:25][CH2:24][C:23]2[N:18]3[CH:19]([CH3:31])[C:20](=[O:30])[NH:21][N:22]=2)([CH3:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[F:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1B(O)O>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([NH:14][C:15]2[CH:16]=[C:17]3[C:26](=[CH:27][C:28]=2[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[F:38])[O:25][CH2:24][C:23]2[N:18]3[CH:19]([CH3:31])[C:20](=[O:30])[NH:21][N:22]=2)([CH3:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1C(=O)NN=C2COc3cc(Br)c(NC4(C)CCN(C(=O)OC(C)(C)C)C4)cc3N21
Reactant: OB(O)c1ccccc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC1C(=O)NN=C2COc3cc(-c4ccccc4F)c(NC4(C)CCN(C(=O)OC(C)(C)C)C4)cc3N21
Temperature: 90 °C
Yield: 92.8 %

Procedure:
A mixture of 3-(7-bromo-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-3-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.230 g, 0.465 mmol), K2CO3 (0.129 g, 0.930 mmol), (2-fluorophenyl)boronic acid (0.098 g, 0.698 mmol) and PdCl2(dppf)-CH2Cl2 adduct (0.038 g, 0.047 mmol) in dioxane (4 mL) and water (0.66 mL) was heated at 90° C. for 14 h. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified by prep-TLC (eluting with 10% EtOAc in petroleum ether) to give 3-[7-(2-fluoro-phenyl)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino]-3-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.220 g, 93%) as a pale solid. 1H-NMR (400 MHz, CDCl3) δ 8.09-8.00 (brs, 1H), 7.41-7.31 (m, 1H), 7.24-7.19 (m, 2H), 7.19-7.08 (m, 1H), 6.73 (s, 1H), 6.46 (s, 1H), 4.79-4.66 (m, 1H), 4.64-4.47 (m, 1H), 3.55-3.08 (m, 4H), 2.16-1.93 (m, 2H), 1.58-1.55 (m, 3H), 1.50-1.37 (m, 12H). LC/MS (Table 1, Method 25) Rt=0.895 min; MS m/z: 510 [M+1]+.
Reaction SMILES: S(=O)(=O)(O)O.O.C(C1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)#N.[C:22]([OH:25])(=[O:24])[CH3:23]>>[OH:21][C:18]1[CH:19]=[CH:20][C:15]([C:12]2[CH:13]=[CH:14][C:23]([C:22]([OH:25])=[O:24])=[CH:10][CH:11]=2)=[CH:16][CH:17]=1
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1ccc(-c2ccc(O)cc2)cc1

Procedure:
A mixture of concentrated sulphuric acid (115 ml) and water (115 ml) was added dropwise to a stirred suspension of 4-cyano-4'-hydroxybiphenyl 39 (25.62 g, 131.4 mmol) in glacial acetic acid (400 ml). The mixture was heated under reflux for 48 hours, the cooled reaction mixture was then poured into water (600 ml) with stirring and the white precipitate filtered off. The aqueous filtrate was then washed with diethyl ether (4×70 ml); the combined extracts were then washed with water (50 ml), dried (MgSO4) filtered and evaporated to give a white solid, both crops of product were combined, dried thoroughly and recrystallised (glacial acetic acid) and dried in vacuo (P2O5, 0.30 mm Hg, 50° C., 5 hours).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](/[C:9](/[CH3:16])=[CH:10]\[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:7][CH:8]=1)#[N:2].[Br:17]N1C(=O)CCC1=O.ClCCl>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[C:1]([C:3]1[CH:4]=[C:5](/[C:9](/[CH2:16][Br:17])=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)/C=C(/C)c1cccc(C#N)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)/C=C(\CBr)c1cccc(C#N)c1
Yield: 28.1 %

Procedure:
To a solution of ethyl (Z) 3-(3-cyanophenyl)-2-butenoate (2 g, 9.3 mmol) in 50 ml carbon tetrachloride was added N-bromosuccinimide (1.74 g, 9.77 mmol) and benzoyl peroxide (40 mg, 0.165 mmol). Reaction mixture was heated to reflux and stirred over night. Reaction was allowed to cool to room temperature to which 50 ml dichloromethane was added. Organic was washed with 2×50 ml water, dried over magnesium sulfate, filtered and concentrated in vacuo. Crude residue was chromatographed on silica gel using 2.5% EtOAc in hexane as the eluent to give ethyl (Z) 3-(3-cyanophenyl)-4-bromo-2-butenoate (0.77 g, 29%) as a clear oil (note: NOE experiment showed compound isomerized during bromination). H1NMR (CDCl3) 1.311-1.347 (t, 3H); 4.239-4.292 (m, 2H); 4.92 (s, 2H); 6.18 (s, H); 7.514-7.801 (m, 4H). ES-MS (M+H+): 293.95 and 296.0
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][O:9][C:10]2[CH:23]=[CH:22][C:13]3[C@H:14]([CH2:17][C:18]([O:20]C)=[O:19])[CH2:15][O:16][C:12]=3[CH:11]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[C:24]1[C:29]([CH3:30])=[CH:28][C:27]([O:31][C@H:32]2[CH2:36][CH2:35][O:34][CH2:33]2)=[CH:26][C:25]=1[CH3:37].[OH-].[Li+]>O1CCCC1.CO>[CH3:1][C:2]1[C:7]([CH2:8][O:9][C:10]2[CH:23]=[CH:22][C:13]3[C@H:14]([CH2:17][C:18]([OH:20])=[O:19])[CH2:15][O:16][C:12]=3[CH:11]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[C:24]1[C:25]([CH3:37])=[CH:26][C:27]([O:31][C@H:32]2[CH2:36][CH2:35][O:34][CH2:33]2)=[CH:28][C:29]=1[CH3:30]
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(O[C@H]5CCOC5)cc4C)c3C)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(O[C@H]2CCOC2)cc(C)c1-c1cccc(COc2ccc3c(c2)OC[C@H]3CC(=O)O)c1C
Reaction time: 2 h
Yield: 81.9 %

Procedure:
Methyl 2-((S)-6-((2,2′,6′-trimethyl-4′-(((S)-tetrahydrofuran-3-yl)oxy)biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 12f (100 mg, 0.20 mmol) was dissolved in 4 mL of a mixture of the solvents tetrahydrofuran and methanol (V/V=1:1), followed by addition of 2M aqueous lithium hydroxide solution (1 mL, 2 mmol). The reaction solution was stirred for 2 hours. The resulting solution was concentrated under reduced pressure. The residue was mixed with 10 mL of water, 1M hydrochloric acid was added dropwise to adjust the pH to 1˜2 and extracted with ethyl acetate (20 mL×2). The combined organic extracts were washed with saturated sodium chloride solution (30 mL), dried with anhydrous magnesium sulphate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purifed using a method of preparative separation to obtain the title compound 2-((S)-6-((2,2′,6′-trimethyl-4′-(((S)— tetrahydrofuran-3-yl)oxy)biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid 12 (80 mg, yield 83.0%) as a white solid.
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]([OH:18])=O)=[CH:15][C:10]=2[N:9]=[CH:8]1)(=[O:4])=[O:3].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH2:38][CH:39]1[CH:46]2[CH2:47][C:42]3([OH:49])[CH2:43][CH:44]([CH2:48][CH:40]1[CH2:41]3)[CH2:45]2.CCN=C=NCCCN(C)C.Cl.N#N>CN(C=O)C.O>[OH:49][C:42]12[CH2:47][CH:46]3[CH2:45][CH:44]([CH2:48][CH:40]([CH:39]3[NH:38][C:16]([C:14]3[CH:13]=[CH:12][C:11]4[N:7]([CH2:6][CH2:5][S:2]([CH3:1])(=[O:3])=[O:4])[CH:8]=[N:9][C:10]=4[CH:15]=3)=[O:18])[CH2:41]1)[CH2:43]2
Reactant: CS(=O)(=O)CCn1cnc2cc(C(=O)O)ccc21
Reactant: NC1C2CC3CC1CC(O)(C3)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)CCn1cnc2cc(C(=O)NC3C4CC5CC3CC(O)(C5)C4)ccc21
Temperature: 25 °C
Yield: 16.2 %

Procedure:
To a solution of 1-(2-methanesulfonylethyl)-1H-benzoimidazole-5-carboxylic acid (0.2 g, 0.74 mmol) in DMF (5 mL) was added HOBt (0.15 g, 0.89 mmol), DIPEA (0.4 mL, 2.23 mmol), 4-aminoadamantan-1-ol (0.15 g 0.89 mmol) and EDCl (0.21 g, 1.11 mmol) successively under N2 atmosphere. The reaction mixture was allowed to stir over night at room temperature. It was diluted with water and extracted with CHCl3. The organic layer was washed with saturated NaHCO3 solution, brine and dried over anhydrous Na2SO4. Concentration of the organic layer gave 1-(2-methanesulfonylethyl)-1H-benzoimidazole-5-carboxylic acid (5-hydroxyadamantan-2-yl)-amide (0.05 g). MS-ESI m/z 418 (M+1); 1H NMR (300 MHz, CDCl3) δ 8.2 (s, 1H), 8.1 (s, 1H), 7.9 (d, 1H), 7.5 (d, 1H), 6.4 (d, 1H), 4.8 (t, 2H), 4.2 (m, 1H), 3.6 (t, 2H), 2.7 (s, 3H), 2.4 (s, 2H), 2.3 (m, 1H), 1.8 (m, 11H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([NH2:17])=O)=[C:10]3[C@@H:9]3[CH2:18][CH2:19][N:8]3[C:7](=[O:20])[C:6]=2[CH:21]=1.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]#[N:17])=[C:10]3[C@@H:9]3[CH2:18][CH2:19][N:8]3[C:7](=[O:20])[C:6]=2[CH:21]=1
Reactant: NC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1cc(Cl)ccc1-2
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1COCCO1
Product: N#Cc1ncn2c1[C@@H]1CCN1C(=O)c1cc(Cl)ccc1-2
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 78.3 %

Procedure:
2.38 g (7.85 mmol) of (S)-7-chloro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxamide were suspended in 15 ml of dioxan and 1.4 ml of pyridine and treated dropwise at a temperature of about 10° with 1.2 ml (8.25 mmol) of trifluoroacetic anhydride. The mixture was stirred at room temperature for 45 min. and a further 0.26 ml of pyridine and 0.11 ml of trifluoroacetic anhydride were added. The reaction mixture was stirred for 30 min. Thereupon, the solvent was removed in a vacuum and the residue was triturated with 30 ml of water. The crude material was chromatographed on 50 g of silica gel (methylene chloride/acetone 9:1). The product was recrystallized from acetonitrile. There were obtained 1.75 g (80%) of (S)-7-chloro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carbonitrile of m.p. 258°-261°.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12]([CH3:28])([CH2:15][N:16]1[CH:24]=[C:23]2[C:18]([C:19]([Cl:27])=[C:20]([Cl:26])[CH:21]=[C:22]2[Cl:25])=[N:17]1)[C:13]#[N:14]>C1COCC1>[C:13]([C:12]([NH:11][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([I:1])=[CH:3][CH:4]=1)([CH3:28])[CH2:15][N:16]1[CH:24]=[C:23]2[C:18]([C:19]([Cl:27])=[C:20]([Cl:26])[CH:21]=[C:22]2[Cl:25])=[N:17]1)#[N:14]
Reactant: CC(N)(C#N)Cn1cc2c(Cl)cc(Cl)c(Cl)c2n1
Reactant: O=C(Cl)c1ccc(I)cc1
Solvent: C1CCOC1
Product: CC(C#N)(Cn1cc2c(Cl)cc(Cl)c(Cl)c2n1)NC(=O)c1ccc(I)cc1

Procedure:
Using a procedure similar to that described in Example 60, except using a solution of 4-iodobenzoyl chloride (0.16 mmole) in THF and a solution of 2-amino-2-methyl-3-(4,6,7-trichloro-2H-indazol-2-yl)propionitrile (0.075 mmole, described in Example 147) in THF mixed with TEA (3% v./v.), the title compound was isolated as solid residue (13.9 mg). It was dissolved in DMSO for further biological evaluation and analyzed by LCMS. MS (ES): M/Z [M+H]=533, RT=0.77 min.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([F:29])[C:3]=1[O:4][C:5]1[CH:20]=[CH:19][C:8]2[N:9]([CH3:18])[C:10](=[O:17])[C:11]([CH3:16])([C:13](=O)[CH3:14])[O:12][C:7]=2[CH:6]=1.[CH3:30][O:31][NH3+:32].[Cl-]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:24]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:22]=[C:21]([F:29])[C:3]=1[O:4][C:5]1[CH:20]=[CH:19][C:8]2[N:9]([CH3:18])[C:10](=[O:17])[C:11]([CH3:16])([C:13](=[N:32][O:31][CH3:30])[CH3:14])[O:12][C:7]=2[CH:6]=1
Reactant: CO[NH3+]
Reactant: CC(=O)C1(C)Oc2cc(Oc3c(F)cc(C(F)(F)F)cc3Cl)ccc2N(C)C1=O
Agent: [Cl-]
Solvent: c1ccncc1
Product: CON=C(C)C1(C)Oc2cc(Oc3c(F)cc(C(F)(F)F)cc3Cl)ccc2N(C)C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.7 %

Procedure:
7-(2-Chloro-6-fluoro-4-trifluoromethylphenoxy)-2,4-dimethyl-2-acetyl-3,4-dihydro-3-oxo-2H-1,4-benzoxazine (Compound 93) (0.3 g) obtained in Example 15 was dissolved in pyridine (4 ml), o-methylhydroxylamine hydrochloride (0.1 g) was added, and the mixture was stirred at room temperature for 4 hours, and further, at 60° C. for one hour. The reaction mixture was then poured into ice-water, and the mixture was extracted twice with ethyl acetate (20 ml). The extract was washed with 1N-hydrochloric acid and then with saturated aqueous sodium chloride, and dried over magnesium sulfate. The solvent was evaporated under a reduced pressure, and the residue was purified by silica gel chromatography (eluant: n-hexane/ethyl acetate=4/1) to give 0.3 g of the title compound (colorless oil).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17]([OH:19])=[O:18].[N+](=[CH2:22])=[N-]>CCOCC>[CH3:22][O:18][C:17](=[O:19])[CH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[NH:9][C:3]1[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: Cc1cccc(Cl)c1Nc1ccccc1CC(=O)O
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)Cc1ccccc1Nc1c(C)cccc1Cl
Reaction time: 2 h

Procedure:
To a solution of 10 g of [o-(3-chloro-o-toluidino)-phenyl]-acetic acid (M.P. 124° - 125°) in 100 ml of ether are slowly added dropwise 100 ml of 2% ethereal diazomethane solution. The solution is allowed to stand for 2 hours at room temperature, and then concentrated to dryness at 40° under 11 Torr. The residue is dissolved in 100 ml of ether. The ether solution is extracted with 40 ml of 2 N sodium hydrogen carbonate solution and water, dried over sodium sulphate, and concentrated at 40° under 11 Torr. The residue is crystallised from benzine. The obtained [o-(3-chloro-o-toluidino)-phenyl]-acetic acid methyl ester melts at 47° - 48°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]2[CH:12]=[C:13]([C:16]3[C:17]([C:40]4[CH:46]=[CH:45][C:43]([NH2:44])=[CH:42][CH:41]=4)=[N:18][N:19]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:20]=3)[CH:14]=[CH:15][C:10]2=[N:9][CH:8]=1.[CH3:47][S:48](Cl)(=[O:50])=[O:49]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]2[CH:12]=[C:13]([C:16]3[C:17]([C:40]4[CH:46]=[CH:45][C:43]([NH:44][S:48]([CH3:47])(=[O:50])=[O:49])=[CH:42][CH:41]=4)=[N:18][N:19]([C:21]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:20]=3)[CH:14]=[CH:15][C:10]2=[N:9][CH:8]=1
Reactant: Nc1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(-c4ccccn4)n3c2)cc1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)Nc1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(-c4ccccn4)n3c2)cc1

Procedure:
26 mg 4-{4-[3-(2-pyridyl)imidazo[1,2-a]pyridin-6-yl]-1-trityl-1H-3-pyrazolyl}aniline obtained in Example 49 and 9 μL methyl sulfonyl chloride were reacted in the same manner as in Example 20, to give 14 mg of the title compound as a colorless amorphous.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][O:12][CH3:13])=[C:6]([CH:9]=1)[CH:7]=[O:8].[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][O:12][CH3:13])=[C:6]([CH:9]=1)[CH2:7][OH:8]
Reactant: COCOc1ccc(Br)cc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COCOc1ccc(Br)cc1CO
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of 5-bromo-2-methoxymethoxybenzaldehyde (5.00 g) in methanol (50 ml) was added, at 0° C., sodium borohydride (0.46 g). The mixture was stirred for 30 minutes at the same temperature, which was then concentrated. To the concentrate was added ethyl acetate, and the mixture was washed with an aqueous solution of potassium hydrogensulfate and a saturated aqueous saline solution, successively. The organic layer was dried (anhydrous magnesium sulfate), which was then concentrated to leave 5-bromo-2-methoxymethoxybenzyl alcohol (5.04 g) as a pale yellow oily product.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N+:18]([O-:20])=[O:19])=[CH:10][C:9]=1[N+:21]([O-:23])=[O:22].[C:24]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])(=[O:31])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>C1COCC1>[N+:21]([C:9]1[CH:10]=[C:11]([N+:18]([O-:20])=[O:19])[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]=1[CH:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:24]([O:32][C:33]([CH3:36])([CH3:34])[CH3:35])=[O:31])([O-:23])=[O:22]
Reactant: CCOC(=O)CC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c2ccccc2c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OC(C)(C)C)c1c([N+](=O)[O-])cc([N+](=O)[O-])c2ccccc12
Yield: 78.6 %

Procedure:
K2CO3 (4.04 g, 29.22 mmol) was added to a solution of 1-chloro-2,4-dinitronaphthalene (6.04 g, 23.91 mmol) and t-butyl ethyl malonate (5.0 g, 26.50 mmol) in THF (50 mL), and the mixture was heated reflux overnight. The mixture was cooled and filtered, then the filtrate was concentrated under reduced pressure. Flash chromatography (20-50% AcOEt-Petroleum ether gradient elution) afforded t-butyl ethyl (2,4-dinitronaphthalen-1-yl)malonate (7.6 g, 54%) as a pale red solid. M.p. 86-88° C.; 1H NMR (CDCl3, 500 MHz) δ 8.65 (s, 1H), 8.55 (dd, 0.5, 8.5, 1H), 8.36 (dd, 0.5, 9.0, 1H), 7.89 (dt, 1.0, 8.0, 1H), 7.81 (dt, 1.5, 9.0, 1H), 5.64 (s, 1H), 4.26 (q, 7.0, 2H), 1.44 (s, 9H), 1.24 (t, 7.0, 3H); IR (neat) 2980, 1745, 1537, 1368, 1346, 1306, 1253, 1147, 1027, 850, 832, 801, 774, 761 cm−1. FABMS (NBA) m/z 405 (M+H+, 5).
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[C:7](Br)[C:6]([F:11])=[C:5]([F:12])[C:3]=1[NH2:4].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1.C(O)C>[F:1][C:2]1[C:8]([F:9])=[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]([F:11])=[C:5]([F:12])[C:3]=1[NH2:4]
Reactant: Nc1c(F)c(F)c(Br)c(F)c1F
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: c1ccccc1
Product: Nc1c(F)c(F)c(-c2ccccc2)c(F)c1F
Temperature: 25 °C

Procedure:
2,3,5,6-Tetrafluoro-4-bromoaniline (13.8 g, 56.7 mmol) is dissolved in benzene (200 mL) and treated with 1.5 equivalents of phenylboronic acid (10.4 g, 85.1 mmol) and a catalytic amount of tetrakistriphenylphosphine palladium(0) (4.2 g, 3.6 mmol) as a solution in ethanol (30 mL). Sodium carbonate (60 mL of 2 M aqueous solution) is added and the reaction mixture stirred and heated to reflux temperature for 24 hours. After cooling to room temperature the mixture is partitioned between Et2O (500 mL) and water (250 mL). The organic layer is washed with brine, dried (MgSO4) and concentrated by rotary evaporator. The residual oil is purified by flash chromatography (9:1 hexanes/EtOAc) to give 2,3,5,6-tetrafluoro-4-phenylaniline as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([O:15]CC)=[O:14])=[CH:10][C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[OH-].[K+]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=[O:14])=[CH:10][C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2ccc(OC)cc2)c(-c2ccc(F)cc2)s1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(-c2cc(C(=O)O)sc2-c2ccc(F)cc2)cc1
Yield: 80.2 %

Procedure:
A mixture of ethyl 5-(4-fluorophenyl)-4-(4-methoxyphenyl)thiophene-2-carboxylate (2.3 g) and potassium hydroxide (640 mg) in methanol (20 ml) was refluxed overnight. The solvent was evaporated, and the residue was dissolved in water, acidified and extracted with chloroform. The extract was washed with water, dried over magnesium sulfate and concentrated to dryness. The residue was washed with ethanol to give crystals of 5-(4-fluorophenyl)-4-(4-methoxyphenyl)thiophene-2-carboxylic acid (1.7 g).
Reaction SMILES: C[O:2][C:3]1[N:8]=[C:7]2[C:9]([CH:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[CH:10][NH:11][C:6]2=[CH:5][CH:4]=1>Br.C(O)(=O)C>[OH:2][C:3]1[N:8]=[C:7]2[C:9]([CH:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[CH:10][NH:11][C:6]2=[CH:5][CH:4]=1
Reactant: COc1ccc2[nH]cc(C3CCN(C)CC3)c2n1
Agent: Br
Solvent: CC(=O)O
Product: CN1CCC(c2c[nH]c3ccc(O)nc23)CC1
Yield: 94.1 %

Procedure:
A solution of 1.00 gm (4.1 mMol) 5-methoxy-3-(1-methyl-piperidin-4-yl)pyrrolo[3,2-b]pyridine in 20 mL hydrogen bromide (30% in acetic acid) was heated at reflux for 48 hours. Additional 5 mL aliquots of hydrogen bromide in acetic acid were added at about 8 and 24 hours. The reaction mixture was concentrated under reduced pressure and the residue treated with 1 mL saturated aqueous sodium bicarbonate. The resulting mixture was taken up in methanol and passed over a VARIAN BOND ELUT SCX™ (Varian, Harbor City, Calif., U.S.A.) ion exchange column which had been preactivated with 10% acetic acid in methanol. The column was washed with three volumes of methanol which were discarded, and then with methanol containing ammonia. Fractions containing product were combined and concentrated under reduced pressure to provide 0.892 gm (94%) of the title compound. An analytical sample was further subjected to flash silica gel chromatography, eluting with dichloromethane containing from 10-40% methanol. Fractions containing product were combined and concentrated under reduced pressure. The residue was crystallized from methanol.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[O:27][C@H:26]([CH2:28][O:29]C(=O)C2C=CC=CC=2)[C@@H:16]([O:17]C(=O)C2C=CC=CC=2)[C@H:6]1[O:7]C(=O)C1C=CC=CC=1)(=O)[CH3:2].OC1C=[CH:45][C:42]([CH:43]=[O:44])=[CH:41][CH:40]=1.B(F)(F)F>ClCCl>[O:4]([C:1]1[CH:2]=[CH:45][C:42]([CH:43]=[O:44])=[CH:41][CH:40]=1)[C@@H:5]1[O:27][C@H:26]([CH2:28][OH:29])[C@@H:16]([OH:17])[C@H:6]1[OH:7]
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(=O)O[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: FB(F)F
Solvent: ClCCl
Product: O=Cc1ccc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 1-O-acetyl-2,3,5-tri-O-benzoylβ-D-ribofuranose (1 g, 2.0 mmol), p-hydroxybenzaldehyde (0.5 g, 4.1 mmol), and boron trifluoride diethyletherate (0.12 ml, 1 mmol) in 20 ml of dry dichloromethane was stirred overnight at room temperature. The solvent was removed in vacuo and the residue extracted with ethyl acetate and brine. The organic layer was dried with sodium sulfate, filtered and the solvents were removed in vacuo. The residue was not purified further, but suspended in methanol and the pH adjusted to 11 with 1.0 N aqueous NaOH. This was stirred and with occasional readjustment of the pH until t.l.c. on silica gel (eluant 1:1 ethyl acetate/hexanes) indicated only material at the solvent front or baseline. Silica gel was added directly to the reaction material and the solvent removed in vacuo. The powder was added to a column of silica gel and purified by flash chromatography with 100% ethyl acetate as eluant. The title compound was obtained as a colourless syrup.
Reaction SMILES: OS(O)(=O)=O.[CH3:6][N:7]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[C:8]1[C:15]([OH:17])=[O:16].O.[CH3:19]O>>[CH3:6][N:7]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[C:8]1[C:15]([O:17][CH3:19])=[O:16]
Reactant: Cn1cc([N+](=O)[O-])cc1C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1cc([N+](=O)[O-])cn1C

Procedure:
A cold solution of H2SO4 (2.9 mL) in MeOH (28.96 mL) was added to 1-methyl-4-nitropyrrole-2-carboxylic acid (2.897 g, 2.35 mmol). The mixture was refluxed for 24 hr. Water was added and the mixture extracted CHCl3. The organic layer was dried (MgSO4), and the solvent evaporated under vacuum to afford the creamy white product. NMR as previously reported.
Reaction SMILES: [C:1]([C:6](=[C:12](OC)[CH2:13][CH3:14])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(OCC)=[O:2].C(O)(=O)C.[CH:21]([NH2:23])=[NH:22].[OH-].[K+].C(O)(=O)C>C(O)C>[CH2:13]([C:12]1[N:23]=[CH:21][N:22]=[C:1]([OH:2])[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:14]
Reactant: N=CN
Reactant: CCOC(=O)C(C(=O)OCC)=C(CC)OC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1c(O)ncnc1CC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of ethyl 2-carboethoxy-3-methoxy-2-pentenoate (11.00 g, 47.77 mmol) in ethanol (40 ml) was stirred under ice-cooling. To the mixture was added a formamidine acetic acid salt (5.96 g, 57.25 mmol), followed by addition of an aqueous solution of potassium hydroxide (85% potassium hydroxide 6.94 g (105.13 mmol)/water 40 ml). Then, the mixture was stirred at room temperature for 16 hours and the pH was adjusted to 7 by adding acetic acid.