Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[Cu](C#N)C#N.C[N:18]([CH:20]=[O:21])C>O.OS(O)(=O)=O.[N+]([O-])([O-])=O.[Fe+2].[N+]([O-])([O-])=O>[C:20]([C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6])(=[O:21])[NH2:18]
Reactant: COc1ccc(C=O)cc1Br
Reactant: CN(C)C=O
Agent: N#C[Cu]C#N
Agent: [Fe+2]
Agent: O=S(=O)(O)O
Solvent: O
Product: COc1ccc(C=O)cc1C(N)=O
Temperature: 23 °C
Reaction time: 0.17 h
Yield: 45 %

Procedure:
3-Bromo-anisaldehyde (8.0 g, 37.2 mmol) and copper cyanide (4.0 g, 44.67 mmol) were stirred in DMF (100 mL) at 150° C. for 16 h. To this was added an iron nitrate solution (20 g iron(III) nitrate, 6 mL concentrated HCl, 40 mL H2O), and the mixture stirred 10 min before it was allowed to cool to 23° C. The reaction was then diluted with H2O (200 mL) and extracted with CHCl3 (3×80 mL). organic layers were combined and solvents were removed, taking care to pump off the residual DMF. The brown-green residue was once again dissolved in CHCl3 (100 mL) and washed with 1 N HCl (50 mL) and brine (50 mL). The material was dried (Na2SO4), and solvent was removed to give the crude nitrile as a tan solid. The nitrile was stirred in concentrated H2SO4 (60 mL) at 100° C. for 1 h. The solution was cooled, poured into H2O (250 mL), and extracted with CHCl3 (8×50 mL). Organics were dried (Na2SO4) and concentrated. The resulting solid was recrystallized from methanol to give 2.98 g (45%) of 3-carbamoyl-4-methoxy-benzaldehyde 41 as a white solid. 1H NMR (CDCl3) δ 9.92 (1 H, s), 8.28 (1 , s), 8.00 (1 H, d, J=9.0 Hz), 7.74 (1 H, br s), 7.69 (1 H, br s), 7.33 (1 H, d, J=9.0 Hz), 3.98 (3 H, s); IR (KBr) 3399, 3183, 1676, 1589, 1433, 1262, 1204 cm−1. Anal. (C9H9NO3) C, H, N.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](O)=[N:6][CH:7]=1.P(Cl)(Cl)([Cl:14])=O>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.C(#N)C>[Cl:14][C:5]1[C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]([F:1])=[CH:7][N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cc(F)cnc1O
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Solvent: CC#N
Product: O=[N+]([O-])c1cc(F)cnc1Cl
Temperature: 80 °C
Reaction time: 6 h
Yield: 70 %

Procedure:
5-fluoro-3-nitro-pyridin-2-ol (2 g, 12.7 mmol) and benzyltrimethyl ammonium chloride (1.17 g, 6.35 mmol) were dissolved in acetonitrile, and phosphorus oxychloride (3.5 ml, 38.1 mmol) was added thereto and stirred at 80° C. for 6 hours. The reaction mixture was cooled and poured into ice water to quench the reaction, and extracted with dichloromethane. The combined organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of dichloromethane:methanol=30:1. The fractions containing the product were collected and evaporated to obtain yellow liquid (1.57 g, 70%).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Li]CCCC.[B:25](OC)([O:28]C)[O:26]C>CCOCC>[C:14]1([CH2:13][O:12][C:3]2[CH:4]=[CH:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]=2[B:25]([OH:28])[OH:26])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Brc1c(OCc2ccccc2)ccc2ccccc12
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: CCOCC
Product: OB(O)c1c(OCc2ccccc2)ccc2ccccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
To a suspension of 1-bromo-2-(phenylmethoxy)naphthalene (6.26 g, 20.0 mmol) in Et2O (75 mL) at −78° C. was added n-BuLi (8.0 mL, 2.5 M, 20 mmol) in hexanes and the mixture was stirred at 0° C. for 1 h. After re-cooling to −78° C., the mixture was treated with trimethyl borate (2.5 mL, 22 mmol) and allowed to warm to room temperature overnight. The resulting mixture was quenched with 1 M HCl (50 mL) and stirred at room temperature for 45 min. The phases were separated and the extraction was completed with CH2Cl2. The combined organic extracts were dried (MgSO4) and evaporated in vacuo to give the title compound, 2-(phenylmethoxy)-1-napthaleneboronic acid as a white powder (4.62 g, 83%), which was used in the next step without further purification. For analytical purposes, a small amount of the product was re-crystallised from MeOH/H2O: mp 133.0-135.0° C. (MeOH/H2O); 1H NMR (250 MHz, d4-MeOH) δ5.20 (s, 2H), 7.28-7.60 (m, 9H), and 7.56-7.88 (m, 2H); 13C NMR (63 MHz, d4-MeOH) δ71.95, 115.4, 124.8, 127.7 (2C), 128.4, 128.9, 129.5, 129.6, 130.7 (2C?), 131.8, 137.2, 139.0 and 159.7;i IR (CHCl3) νmax 3609, 3490, 1592, 1509, 1386, and 1332 cm−1; MS (EI+) m/z (rel intensity) 278 (10%, M+), 234 (10), and 91 (100); HRMS calcd for C17H15BO3 (M+) 277.1151, found 277.1163. Anal. Calcd for C17H15BO3: C, 73.42; H, 5.44. Found: C, 73.07; H, 5.33.
Reaction SMILES: [C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:43])[C:11]2[CH:17]=[C:16]([CH2:18][NH:19][CH2:20][C:21]3[CH:42]=[CH:41][C:24]([C:25]([NH:27][C@H:28]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:26])=[CH:23][CH:22]=3)[CH:15]=[N:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[C:44](OC(=O)C)(=[O:46])C>C(O)=O>[C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:43])[C:11]2[CH:17]=[C:16]([CH2:18][N:19]([CH2:20][C:21]3[CH:42]=[CH:41][C:24]([C:25]([NH:27][C@H:28]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:26])=[CH:23][CH:22]=3)[CH:44]=[O:46])[CH:15]=[N:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:3])([CH3:5])[CH3:4]
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(CNCc2cnc3nc(NC(=O)C(C)(C)C)nc(O)c3c2)cc1)C(=O)OCC
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(CN(C=O)Cc2cnc3nc(NC(=O)C(C)(C)C)nc(O)c3c2)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1.0 g. (1.7 mmol) of diethyl N-[N-(2-pivaloylamino-4-hydroxypyrido[2,3-d]pyrimidin-6-ylmethyl)-4-aminomethylbenzoyl]-glutamate in 10 mL of 98% formic acid was added 0.35 g. (0.33 mL, 3.5 mmol) of acetic anhydride. The mixture was stirred at 25° C. for 1 h. The solvent was removed under reduced pressure and the solid dissolved in methylene chloride and extracted twice with a saturated solution of sodium bicarbonate. The aqueous layers were back extracted with methylene chloride, and the organic layers combined and dried over anhydrous magnesium sulfate. The solvent was evaporated to dryness to give a quantitative yield of diethyl N-[N-(2-pivaloylamino-4-hydroxypyrido[2,3-d]pyrimidin-6-ylmethyl)-N-formyl-4-aminomethylbenzoyl]-glutamate which can be employed for further processing without further purification; 1H NMR (Me2SO d6) delta 1.11-1.18 (m, 6H), 1.24 (s, 9H), 1.9-2.15 (m, 2H), 2.39-2.44 (m, 2H), 4.39-4.42 (m, 3H), 4.53-4.55 (m, 2H), 7.21-7.44 and 7.34-7.37 (m, 2H, AA'BB'), 7.76-7.78 and 7.81-7.84 (m, 2H, AA'BB'), 8.12 and 8.13 (s, 1H), 8.61-8.78 (m, 2H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][NH2:9])[CH2:4][CH2:3]1.[CH2:10]([N:12]1[C:16]2=[N:17][C:18]3[C:23]([C:24](Cl)=[C:15]2[CH:14]=[N:13]1)=[CH:22][C:21]([O:26][CH3:27])=[CH:20][CH:19]=3)[CH3:11].CS(C)=O.CCOCC>CO>[CH2:10]([N:12]1[C:16]2=[N:17][C:18]3[C:23]([C:24]([NH:9][CH2:8][CH:5]4[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]4)=[C:15]2[CH:14]=[N:13]1)=[CH:22][C:21]([O:26][CH3:27])=[CH:20][CH:19]=3)[CH3:11]
Reactant: NCC1CCC(O)CC1
Reactant: CCn1ncc2c(Cl)c3cc(OC)ccc3nc21
Solvent: CO
Solvent: CCOCC
Solvent: CS(C)=O
Product: CCn1ncc2c(NCC3CCC(O)CC3)c3cc(OC)ccc3nc21
Temperature: 25 °C
Yield: 31.3 %

Procedure:
A mixture of 4-hydroxycyclohexylmethylamine (2.2 g, 17.05 mmol), 1-ethyl-4-chloro-6-methoxy-1H-pyrazolo[3,4-b]quinoline (2.0 g, 7.66 mmol) and DMSO is heated at 110°-120° C. under a nitrogen atmosphere for 16 hours. The reaction mixture is poured into ice water, and the mixture is extracted with CH2Cl2 (4×50 ml). The organic layers are combined, dried over MgSO4 and evaporated to dryness. The residue is purified by column chromatography on silica gel eluting with CH2Cl2 /methanol (9/1), followed by a second silica gel column eluting with ethyl acetate to afford 1.3 g of crude product. The crude product is dissolved in warm methanol, cooled to room temperature and treated with an equivalent amount of methanesuflonic acid. Ether is added to the mixture and the solid which forms is collected by filtration, washed with ether and recrystallized from isopropanol to afford 0.85 g of 1-ethyl-6-methoxy-N-(4-hydroxycyclohexylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine. CH3SO3H, as yellow crystals, m.p. 256°-258° C. (dec.)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13](O)=[O:14])=[C:4]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=2)(=[O:22])=[O:21])[CH:3]=1.[N:34]1([CH2:39][CH2:40][NH2:41])[CH2:38][CH2:37][CH2:36][CH2:35]1.C(Cl)CCl>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([NH:41][CH2:40][CH2:39][N:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)=[O:14])=[C:4]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:31])([F:32])[F:33])[CH:24]=2)(=[O:22])=[O:21])[CH:3]=1
Reactant: O=C(O)c1cccc(CSc2ccc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c1
Reactant: NCCN1CCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(NCCN1CCCC1)c1cccc(CSc2ccc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c1
Yield: 79.7 %

Procedure:
Following General Procedure R, the title compound (388 mg, 80%) was prepared from 3-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)benzoic acid (411 mg, 0.77 mmol), 2-(pyrrolidin-1-yl)ethanamine (0.15 ml, 1.15 mmol), EDC (294 mg, 1.53 mmol) and DMAP (cat.) in DMF (10 ml).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=2)N)=[CH:4][CH:3]=1.[CH3:22][N:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1>Cl>[CH3:22][N:23]1[CH2:28][CH2:27][C:26]2[N:10]([CH2:9][CH2:8][C:5]3[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=3)[C:12]3[CH:21]=[CH:20][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=3[C:25]=2[CH2:24]1
Reactant: COC(=O)c1ccc(N(N)CCc2ccc(C)nc2)cc1
Reactant: CN1CCC(=O)CC1
Agent: Cl
Product: Cc1ccc(CCn2c3c(c4cc(C(=O)O)ccc42)CN(C)CC3)cn1
Temperature: 100 °C
Reaction time: 18 h
Yield: 4.1 %

Procedure:
Methyl 4-(1-(2-(6-methylpyridin-3-yl)ethyl)hydrazinyl)benzoate (0.1 g, 0.350 mmoles) and 1-methylpiperidin-4-one (0.052 g, 0.350 mmoles) was taken up in 4 mL 1M HCl and heated at 100 degrees C. for 18 hr. LCMS of the reaction mixture shows the formation of the product. The reaction mixture was concentrated and purified by reverse phase HPLC.1 to give 5 mg of 2-Methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylic acid, as a white solid, 4% yield. 1 Batch Size-800 mg, Purity: —˜3% Since the compound is highly Polar First Purification Was carried on prep HPLC using Water (0.05% TFA) as eluent. Method Details: Sample preparation: Compound dissolved in Milli-Q Water (4.0 mL) Clear Brown solution Column: YMC ODS A, 500 mm×30 mm×10 μFlow: 301 mL/min Wavelength: monitored at 220 nm & 254 nm. Mobile Phase Mobile Phase A: 0.05% TFA in water Mobile Phase B: 0.05% TFA in Acetonitrile Gradient Program 0% B for 15 min 0% B to 50% B in 27 min. Column Washed with 100% methanol. Collected fractions were lyophilized. Lyophilized solid having purity 80% were dissolved in 250 μL and analyzed by following method. (Method details for analysis: Column Zorbax cyano, 150 mm×4.6×3.5μ), Flow: 1.2 mL/min, inj. Vol: 10.0 μL, Wavelength: 220 nm & 254 nm, Gradient Program: 0% B to 50% B in 5 min hold for 2 min 7.01 min to 10.0 min 0% B Second purification Total Vol: 250 μL Column: Zorbax cyano, 150 mm×4.6×3.5μ), Flow: 1.2 mL/min, inj. Vol: 10.0 μL, Wavelength: 220 nm & 254 nm, Mobile Phase Mobile Phase A: 0.05% TFA in water Mobile Phase B: 0.05% TFA in Acetonitrile Isocratic program 8% B for S min. number of injections: 25 Purity of pooled fraction: 98% Collected fractions were lyophilized Purity after lyophilization: 92.07%
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH2:23])(C)(C)C.C(O[C:30](=[O:53])[CH2:31][C:32](=O)[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[S:40][CH:41]=[C:42]([CH2:44][O:45]C3CCCCO3)[N:43]=2)[CH:34]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:45][CH2:44][C:42]1[N:43]=[C:39]([C:35]2[CH:34]=[C:33]([C:32]3[CH2:31][C:30](=[O:53])[NH:23][C:9]4[CH:10]=[C:11]([C:19]([F:20])([F:21])[F:22])[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])=[CH:13][C:8]=4[N:7]=3)[CH:38]=[CH:37][CH:36]=2)[S:40][CH:41]=1
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2nc(COC3CCCCO3)cs2)c1
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3nc(CO)cs3)c1)=N2

Procedure:
The title compound was prepared from [2-amino-5-(methyl-propyl-amino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (0.17 g) (Example J35) and 3-oxo-3-[3-[4-(tetrahydro-pyran-2-yloxymethyl)-thiazol-2-yl]-phenyl]-propionic acid tert-butyl ester (Example K27) (0.23 g) according to the general procedure M. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (0.06 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:21])[C:13]([N:15]([CH3:20])[N:16]=C(C)C)=[O:14])[CH3:2].Cl>O1CCCC1>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:21])[C:13]([N:15]([CH3:20])[NH2:16])=[O:14])[CH3:2]
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N=C(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.9 %

Procedure:
To a 500 ml volume four-necked flask, 1-[(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methyl-2-(1-methylethylidene)hydrazine (18-a) (21.41 g) and tetrahydrofuran (150 ml) were added under a nitrogen atmosphere at room temperature. To the mixture, 10% by weight of hydrochloric acid (29.23 g) was added dropwise over 5 minutes, and stirred at room temperature for 1 hour. Then, the reaction mixture was concentrated under reduced pressure. To the residue was added water (80 ml), and extracted with tert-butyl methyl ether. The organic layer was concentrated under reduced pressure, and added hexane (50 ml). The precipitated crystal was collected by filtration and dried to give 12.70 g of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methylhydrazine ((12-2)-(11)-39).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C([O-])(=O)C.[Na+].[Br:15]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)(=O)C>[NH2:1][C:2]1[C:7]([Br:15])=[N:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1
Reactant: COc1ccc(N)cn1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(N)c(Br)n1
Temperature: 25 °C

Procedure:
A mixture of 1.83 g (14.7 mM) of 5-amino-2-methoxypyridine and 1.21 g (14.7 mM) of sodium acetate in 12 ml of acetic acid is prepared and 0.75 ml (14.7 mM) of bromine is added gently, with stirring and while maintaining at room temperature. The reaction mixture is kept stirring for 30 minutes, at room temperature, and 200 ml of saturated sodium thiosulfate solution are then added. The aqueous phase obtained is extracted twice with ethyl acetate. The combined organic phases are dried over magnesium sulfate and concentrated under reduced pressure. 3 g of the expected compound are obtained in the form of a violet-colored solid (quantitative yield).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.CS(C)=O.[OH-].[Na+].[CH:16]([O:18][CH2:19][CH2:20]Cl)=[CH2:17]>O>[CH:16]([O:18][CH2:19][CH2:20][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1)=[CH2:17]
Reactant: C=COCCCl
Reactant: OCc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: C=COCCOc1ccc(CO)cc1
Yield: 55 %

Procedure:
In a 500 mL three-neck round-bottom flask equipped with an overhead stirrer and a reflux condenser were placed 21.7 g of 4-hydroxybenzyl alcohol, and 65 mL of dimethyl sulfoxide. To this solution was slowly added 6.99 g of NaOH, while keeping the temperature below 45° C. After the solution was completed, 20.4 mL of 2-chloroethyl vinyl ether was added slowly while keeping the temperature at 60° C. The reaction mixture was heated at this temperature for 2 hours, and the progress of the reaction was followed by GC. After cooling, the reaction product was added dropwise to 500 mL of water. The precipitated product was then filtered and redissolved in 500 mL of diethyl ether. The ether layer was washed one time with 100 mL of 3% aqueous NaOH and two times with 100 mL portions of distilled water. The ether layer was dried with sodium sulfate, filtered and evaporated. A 55% yield of 2-(4-hydroxymethyl-phenoxy)ethyl vinyl ether was obtained.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:14](=[O:16])[CH3:15])[CH:8]=[C:9]([OH:13])[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].O=O.[Br-].[C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27]Br)(=[O:22])[CH3:21]>>[C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][O:13][C:9]1[CH:8]=[C:7]([C:14](=[O:16])[CH3:15])[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:10]=1[O:11][CH3:12])(=[O:22])[CH3:21]
Reactant: COc1c(O)cc(C(C)=O)cc1C(C)(C)C
Reactant: CC(=O)OCCCCBr
Agent: O=O
Agent: [Br-]
Product: COc1c(OCCCCOC(C)=O)cc(C(C)=O)cc1C(C)(C)C
Yield: 100.5 %

Procedure:
1-(3-tert-Butyl-5-hydroxy-4-methoxyphenyl)ethanone (O3.070; 6.9 g) was converted and worked up analogously to O2.071. The bromide used was 4-bromobutyl acetate (7.27 g). 10.5 g of the title compound were obtained.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[F:17][C:18]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:19]=1[C:20](Cl)=O.CCOCC>ClCCl>[F:17][C:18]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:19]=1[C:20]1[N:2]([CH3:1])[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:9]=1
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: CNc1ccccc1N
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: Cn1c(-c2ccc(F)cc2F)nc2ccccc21
Temperature: 0 °C
Reaction time: 6 h
Yield: 80.7 %

Procedure:
N-methyl-benzene 1,2-diamine (1.22 g, 10 mmol) and 40 ml of dichloromethane were charged in a 250 ml round bottle, 3 ml of triethylamine was then added, and the mixture was cooled to 0° C. 2,4-Difluoro-benzoyl chloride (1.77 g, 10 mmol) was dissolved in 40 ml of dichloromethane and then slowly added to the 250 ml round bottle. The reaction was conducted under a nitrogen atmosphere for 6 hours. After the reaction was complete, ether was added to form precipitation. The solid product was collected by filtration, washed with ether several times, and heated under reduced pressure to form 2-(2,4-difluoro-phenyl)-1-methyl-1H-benzoimidazole (yield=1.97 g, 81%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1/[CH:11]=[CH:12]/[C:13](=[O:15])[CH3:14].O.[C:17]([OH:21])(=[O:20])[CH:18]=O>C(O)(=O)C.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1/[CH:11]=[CH:12]/[C:13](=[O:15])/[CH:14]=[CH:18]/[C:17]([OH:21])=[O:20]
Reactant: COc1ccc(OC)c(/C=C/C(C)=O)c1
Reactant: O=CC(=O)O
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(OC)c(/C=C/C(=O)/C=C/C(=O)O)c1

Procedure:
A solution of 19 g (92 mmol) of (E)-4-(2,5-dimethoxyphenyl)but-3-en-2-one and 8.4 g (92 mmol) of glyoxylic acid monohydrate in 23.4 ml of acetic acid was boiled at reflux for 20 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was extracted twice with 3N sodium hydroxide solution. The combined aqueous phases were treated with 3N hydrochloric acid to produce a strongly acidic reaction and extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated. Crystallization of the residue from ether/ethyl acetate yielded (E,E)-6-(2,5-dimethoxyphenyl)-4-oxo-2,5-hexadienoic acid of melting point 145°-146°.
Reaction SMILES: [F:1][C:2]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([CH3:17])=[C:12]([CH:15]=[O:16])[C:13]([I:14])=[C:8]2[CH:7]=[CH:6]1.[Si](C#N)(C)(C)C.S(=O)(=O)(O)O.C[CH2:35][O:36][C:37](C)=[O:38]>ClCCl.[I-].[Zn+2].[I-]>[F:1][C:2]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([CH3:17])=[C:12]([CH:15]([OH:16])[C:37]([O:36][CH3:35])=[O:38])[C:13]([I:14])=[C:8]2[CH:7]=[CH:6]1
Reactant: Cc1nc2c(ccn2Cc2cccc(F)c2F)c(I)c1C=O
Reactant: CCOC(C)=O
Agent: C[Si](C)(C)C#N
Agent: O=S(=O)(O)O
Agent: [I-]
Solvent: ClCCl
Product: COC(=O)C(O)c1c(C)nc2c(ccn2Cc2cccc(F)c2F)c1I
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 73.8 %

Procedure:
Steps I-J: To a solution of 1-(2,3-difluorobenzyl)-4-iodo-6-methyl-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (9.40 g, 19.84 mmol) in dichloromethane (DCM) (250 mL) at 0° C. was added TMSCN (10.64 mL, 79 mmol) followed by zinc iodide (12.67 g, 39.7 mmol) and the mixture was stirred at 0° C. for 5 min and then at ambient temperature for 1 h. The mixture was diluted with dichloromethane and washed with cold water, dried (Na2SO4), concentrated and dried in vacuo The residue was cooled to 0° C. and methanol (250 mL) was added followed by dropwise addition of sulfuric acid (50.8 mL, 952 mmol) and the mixture was stirred at 75° C. for 24 h. The mixture was diluted with EtOAc and washed with water. The aq. phase was extracted with EtOAc (2×) and the combined organic layers were washed with saturated NaHCO3/water, dried (Na2SO4), concentrated to provide methyl 2-(1-(2,3-difluorobenzyl)-4-iodo-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-hydroxyacetate (7.95 g, 14.65 mmol, 73.8% yield) as a yellow foam. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.62 (s, 3 H), 3.34-3.57 (m, 1 H), 3.78 (s, 3 H), 5.38-5.57 (m, 2 H), 5.88 (s, 1 H), 6.34 (d, J=3.52 Hz, 1 H), 6.81-6.90 (m, 1 H), 6.90-7.00 (m, 1 H), 7.01-7.13 (m, 1 H), 7.20 (d, J=3.52 Hz, 1 H); LCMS (m/z) ES+=473 (M+1).
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9]C=1C.[C:17]([OH:20])(=[O:19])[CH3:18]>O.[O-2].[O-2].[O-2].[Cr+6]>[F:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:18]=1[C:17]([OH:20])=[O:19]
Reactant: CC(=O)O
Reactant: Cc1ccc([N+](=O)[O-])cc1F
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: O
Product: O=C(O)c1ccc([N+](=O)[O-])cc1F
Temperature: 95 °C
Reaction time: 2 h

Procedure:
Concentrated sulfuric acid (32 ml) was added carefully with stirring to a solution of 2-fluoro4-nitrotoluene (16.5 g, 0.106 mol) in acetic acid (200 ml). The mixture was warmed up to 95° C., and solution of chromium trioxide (37.1 g, 0.371 mol) in water (32 ml) was added dropwise with stirring over 2 h. The mixture was heated with stirring for another 30 minutes, allowed to cool down to r.t., and poured into water (1000 ml). The product was extracted with diethyl ether (3×200 ml). Combined ether layers were washed with water and evaporated to dryness. The residue was dissolved in 10% aqueous potassium carbonate and washed with ether. The aqueous layer was acidified with con. HCl, and the resulting white precipitate filtered and dried (16.3 g, 83%), m.p. 174-177° C. 1H NMR.