Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:10].C([O-])([O-])=O.[Cs+].[Cs+].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>COCCOC.[Cu]I>[O:10]1[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N:8]=[C:9]1[C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)Nc1ccccc1Br
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1c1nc2ccccc2o1
Temperature: 85 °C
Yield: 57.6 %

Procedure:
In a 25 mL flask, tert-butyl (2R)-2-{[(2-bromophenyl)amino]carbonyl}pyrrolidine-1-carboxylate (194 mg, 0.53 mmol; which may be prepared as described in Step 1) was dissolved in DME (4 mL) under nitrogen at room temperature. CuI (6 mg, 0.03 mmol), Cs2CO3 (261 mg, 0.80 mmol) and 1,10-phenanthroline (26 mg, 0.14 mmol) were added then the reaction mixture was heated at 85° C. for 24 h. The mixture was cooled to room temperature and concentrated to dryness. The residue was dissolved in dichloromethane and filtered on Celite to eliminate the cupper residue. The filtrate was concentrated and the residue purified on preparative TLC (Pentane/EtOAc, 85/15 to 50/50) to give the title compound (88 mg, 58%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][N:16](C)[CH3:17])=[CH:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:6]=2[CH:26]=1.C(=O)(O)[O-].[K+].ClC(OC1C=CC=CC=1)=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][NH:16][CH3:17])=[CH:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:6]=2[CH:26]=1
Reactant: CN(C)Cc1cnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Agent: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CNCc1cnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Reaction time: 24 h

Procedure:
A stirred suspension of 8-chloro-6-(o-chlorophenyl)-1-[(dimethylamino)methyl]-4H-imidazo[1,2-a][1,4]benzodiazepine (3.95 g, 10 mmole) and potassium bicarbonate (17 g, 17 mmole) in 280 ml. of chloroform is treated with phenyl chloroformate (12.97 g, 87 mmole) and refluxed for 50 hours. The resulting mixture is cooled, washed with water (100 ml) and the solvent is removed in vacuo. The residue is dissolved in 170 ml. of methanol and the resulting solutionis treated with 100 ml. of 5.6 g of potassium hydroxide and 10 g of potassium bicarbonate. This mixture is stirred under nitrogen for 24 hours, acidified with concentrated hydrochloric acid, diluted with water, and extracted with 500 ml. of ether. The ether phase is dried over anhydrous sodium sulfate, and the ether is removed in vacuo. The thus obtained material is dissolved in a mixture of 800 ml. of ethanol and aqueous 50% potassium hydroxide (200 ml) and refluxed under nitrogen for 24 hours. This solution is treated with 200 ml. of concentrated hydrochloric acid and the ethanol is removed in vacuo. The remaining aqueous phase is extracted with ether, and the ether is discarded. The aqueous phase is then made basic, pH 9.0 and re-extracted with methylene chloride (800 ml). The methylene chloride is dried over anhydrous sodium sulfate and the solvent is removed in vacuo. The resulting oil is crystallized to give 8-chloro-6-(o-chlorophenyl)-1-[(methylamino)methyl]-4H-imidazo[1,2-a][1,4]benzodiazepine.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:19][CH3:20])[C@@:4]1([CH3:18])[C@@H:9]2[O:10][C@@H:8]2[C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1.[Cl:21]([C:24]1[CH:25]=[C:26]([NH:30][CH2:31][C:32]2[NH:33][CH:34]=[CH:35][N:36]=2)[CH:27]=[CH:28][CH:29]=1)(=O)=O>>[CH3:1][O:2][CH:3]([O:19][CH3:20])[C@@:4]1([CH3:18])[C@H:9]([OH:10])[C@@H:8]([N:30]([C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([Cl:21])[CH:25]=2)[CH2:31][C:32]2[NH:33][CH:34]=[CH:35][N:36]=2)[C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1
Reactant: COC(OC)[C@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H]2O[C@H]21
Product: COC(OC)[C@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H](N(Cc2ncc[nH]2)c2cccc(Cl)c2)[C@H]1O
Yield: 38.9 %

Procedure:
The title compound (337 mg, 39%) was prepared using (2R,3R,4R)-3,4-dihydro-2-dimethoxymethyl-3,4-epoxy-2-methyl-6-nitro-2H-1-benzopyran (500 mg, 1.77 mmol) and 3-chloroxyphenyl-1H-imidazol-2-ylmethylamine (366 mg, 1.77 mmol), according to the same procedure used for the preparation of example 1 above.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12]O)=[CH:8][C:7]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1C=CC=CC=1.C1(C)C=CC=CC=1>[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][Cl:3])=[CH:8][C:7]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(F)c(Oc2ccccc2)c1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Fc1ccc(CCl)cc1Oc1ccccc1
Temperature: 45 °C
Reaction time: 1 h
Yield: 481.6 %

Procedure:
To a stirred solution of 12.6 grams (0.106 mole) of thionyl chloride and one drop (catalyst) of pyridine in 25 mL of toluene was added dropwise a solution of 19.5 grams (0.088 mole) of 4-fluoro-3-phenoxyphenylmethanol in 30 mL of toluene at such a rate as to maintain the reaction mixture temperature at 25°-35° C. Upon completion of the 45 minute addition time, the reaction mixture was warmed to 45° C. where it was stirred during a one hour period. After this time the reaction mixture was cooled, and the excess thionyl chloride was removed under reduced pressure. The residue, 23.5 grams of a semi-solid mixture, was combined with 114.2 grams of the same material from a previous reaction. The combination was distilled under reduced pressure yielding 100.3 grams of 4-fluoro-3-phenoxyphenylmethyl chloride; b.p. 98°-105° C./0.025-0.055 mm. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([NH2:16])=[O:15])[CH2:9]2)=[C:4]([N+:17]([O-])=O)[CH:3]=1.[H][H].[ClH:22]>C1COCC1.C(OCC)(=O)C.[Pd]>[ClH:22].[NH2:17][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([NH2:16])=[O:15])[CH2:9]1
Reactant: [H][H]
Reactant: NC(=O)C1CCCN(c2ccc(F)cc2[N+](=O)[O-])C1
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NC(=O)C1CCCN(c2ccc(F)cc2N)C1

Procedure:
The solution of 2.67 g of 1-(4-fluoro-2-nitrophenyl)piperidine-3-carboxamide in 100 ml of THF was admixed with 260 mg of Pd/C. This mixture was hydrogenated in a shaking vessel at atmospheric pressure until the theoretical amount of hydrogen had been taken up. The mixture is then acidified with hydrogen chloride dissolved in ethyl acetate, the solid is filtered off with suction and washed with methanol, and the filtrate is concentrated under reduced pressure. The residue is triturated with tert-butyl methyl ether and the solid is filtered off with suction and dried under reduced pressure.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:36])[C:15]2[C:16]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)=[N:17][C:18]3[C:23]([N:24]=2)=[CH:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][CH:19]=3)[CH2:10][CH2:9]1)=O)(C)(C)C.CO>Cl>[F:35][C:32]1[CH:33]=[CH:34][C:29]([C:16]2[C:15]([N:14]([CH3:36])[CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[N:24][C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:25]([O:27][CH3:28])=[O:26])[CH:22]=3)[N:17]=2)=[CH:30][CH:31]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N(C)C3CCN(C(=O)OC(C)(C)C)CC3)nc2c1
Agent: Cl
Solvent: CO
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N(C)C3CCNCC3)nc2c1
Yield: 59.7 %

Procedure:
The solution of methyl 3-((1-(tert-butoxycarbonyl)piperidin-4-yl)(methyl)amino)-2-(4-fluorophenyl)quinoxaline-6-carboxylate (210 mg, crude) in hydrogen chloride(g)/MeOH (50 mL) was stirred overnight at room temperature and then concentrated in vacuo. The residue was dissolved in water (50 mL) and adjusted to pH 8 with sodium bicarbonate, extracted with dichloromethane (5×30 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo. The product was precipitated by the addition ether (20 mL) to afford methyl 2-(4-fluorophenyl)-3-(methyl(piperidin-4-yl)amino)quinoxaline-6-carboxylate as a yellow solid (100 mg).
Reaction SMILES: I[C:2]1[C:10]2[CH:9]=[N:8][CH:7]=[N:6][C:5]=2[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=1.C([Mg]Cl)(C)C.[C:26]([O:30][C:31](=[O:49])[N:32]([CH2:41][C:42]1[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=1)[C:33]1[CH:38]=[CH:37][C:36]([CH:39]=[O:40])=[CH:35][N:34]=1)([CH3:29])([CH3:28])[CH3:27].C(=O)(O)[O-].[Na+]>O1CCCC1>[C:26]([O:30][C:31](=[O:49])[N:32]([CH2:41][C:42]1[CH:43]=[CH:44][C:45]([Cl:48])=[CH:46][CH:47]=1)[C:33]1[CH:38]=[CH:37][C:36]([CH:39]([OH:40])[C:2]2[C:10]3[CH:9]=[N:8][CH:7]=[N:6][C:5]=3[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=2)=[CH:35][N:34]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cncnc21
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(Cl)cc1)c1ccc(C=O)cn1
Agent: CC(C)[Mg]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(C(O)c2ccc(N(Cc3ccc(Cl)cc3)C(=O)OC(C)(C)C)nc2)c2cncnc21
Temperature: -20 °C
Yield: 51.7 %

Procedure:
5-Iodo-7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimidine (38, 0.160 g, 0.4 mmol) was dissolved in 0.7 mL of tetrahydrofuran under an atmosphere of nitrogen. The reaction was cooled to −20° C. and isopropylmagnesium chloride (0.24 mL, 2.0 M in tetrahydrofuran, 0.48 mmol) was added and the reaction was stirred and allowed to come to 0° C. The reaction was cooled to −20° C. and (4-chloro-benzyl)-(5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester (13, 0.110 g, 0.32 mmol) in 2.0 mL of tetrahydrofuran was added to the reaction mixture. The reaction was stirred, allowing to come to 0° C., then poured into aqueous saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with a gradient of 10-80% ethyl acetate in hexanes. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound (43, 0.103 g, 52%). MS (ESI) [M+H+]+=622.94.
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Br:8])[N:7]=1.[NH2:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[C:14]([N+:21]([O-:23])=[O:22])[CH:13]=1>C(O)(C)C>[Br:8][C:6]1[N:7]=[C:2]([NH:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[C:14]([N+:21]([O-:23])=[O:22])[CH:13]=2)[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=1
Reactant: Cn1cc(Br)nc(Br)c1=O
Reactant: Nc1ccc(C(=O)O)c([N+](=O)[O-])c1
Solvent: CC(C)O
Product: Cn1cc(Br)nc(Nc2ccc(C(=O)O)c([N+](=O)[O-])c2)c1=O
Temperature: 90 °C
Yield: 85 %

Procedure:
3,5-Dibromo-1-methyl-1H-pyrazin-2-one (1.0 g, 3.73 mmol) and 4-amino-2-nitrobenzoic acid (0.68 g, 3.73 mmol) are dissolved in isopropanol (20 mL) and heated at 90° C. for 4 hours. The reaction is cooled to room temperature and the resulting suspension is filtered. The filter cake is then washed with ethyl ether (3×100 mL) and air dried to give 4-(6-bromo-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino)-2-nitro-benzoic acid (3) as a tan solid (1.17 g).
Reaction SMILES: Br[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][N:7]=1.[CH3:9][S:10]([C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1)(=[O:12])=[O:11].[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>CC#N.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:6]2[N:7]=[CH:2][C:3]([NH2:8])=[N:4][CH:5]=2)=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: Nc1nccnc1Br
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2cnc(N)cn2)cc1
Temperature: 60 °C
Yield: 88 %

Procedure:
Bromopyrazin-2-amine (2.0 g, 11.49 mmol), (4-methylsulfonylphenyl)boronic acid (2.758 g, 13.79 mmol) and K3PO4 (4.878 g, 22.98 mmol) were combined in MeCN (40 mL)/Water (10 mL) and Pd[P(tBu)3]2 (216 mg, 0.4227 mmol) was added. The reaction was heated at 60° C. for 1 hour. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was triturated with water, then Et2O then dried in vacuo to give the sub-title compound as a beige solid which was used without further purification (2.53 g, 88% Yield). 1H NMR (400.0 MHz, DMSO) δ 3.20 (s, 3H), 6.80 (br s, 2H), 7.94 (d, 2H), 8.00 (d, 1H), 8.17 (d, 2H) and 8.64 (d, 1H) ppm.
Reaction SMILES: [Br:1][C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[C:5]([Cl:11])=[C:4]([C:12]([O:14]C)=[O:13])[CH:3]=1.[OH-].[Na+]>CCO>[Br:1][C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[C:5]([Cl:11])=[C:4]([C:12]([OH:14])=[O:13])[CH:3]=1
Reactant: COC(=O)c1cc(Br)c2sccc2c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc(Br)c2sccc2c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
To a solution of methyl 7-bromo-4-chlorobenzo[b]thiophene-5-carboxylate 96 (1.06 g, 3.3 mmol) in aqueous EtOH (40 mL) was added NaOH (400 mg, 10 mmol). The reaction mixture was stirred for 3 hours at room temperature. After the reaction was completed, the volatile solvent was removed under reduced pressure, acidification with 1 N HCl was accomplished. Drying with MgSO4 was followed by normal work-up with EtOAc. After evaporating volatile solvent, the residue was used without further purification in ˜88% yield.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1)#[N:2].[F-].[Cs+].C[Si](C)(C)[C:15]1SC=[N:17][CH:16]=1>C1COCC1>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]([C:3]2[CH:10]=[CH:9][C:15]([C:16]#[N:17])=[CH:5][CH:4]=2)=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: C[Si](C)(C)c1cncs1
Reactant: N#Cc1ccc(C=O)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Product: N#Cc1ccc(C(=O)c2ccc(C#N)cc2)cc1

Procedure:
15.7 g of 4-cyanobenzaldehyde and 9.1 g of caesium fluoride are added to a solution of 9.4 g of 5-trimethylsilylthiazole in 0.56 l of THF, and the mixture is heated under reflux for 16 hours. The solid material is filtered off and the solvent is concentrated. Column chromatography (SiO2, hexane/ethyl acetate 1:2) yields first (a) 5-(4-cyanobenzoyl)-thiazole [Rf hexane/ethyl acetate 1:2)=0.65], m.p. (after crystallisation from ethyl acetate) 181°-182°; 1H-NMR (CDCl3): δ (ppm)=8.88 and 8 (m,4H), 8.36 (s,1H), 9.14 (s,1H), and then (b)4-(α-hydroxy-5-thiazolylmethyl)-benzonitrile [Rf (hexane/ethyl acetate 1:2)=0.35], m.p. (after crystallisation from toluene) 115°-117°; 1H-NMR (CDCl3): δ (ppm)=3.05 (d,1H), 6.2 (d,1H), 7.58 and 7.7 (m,4H), 7.73 (s,1H), 8.78 (s,1H).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[CH3:10][C:11]([CH3:16])([CH3:15])[CH2:12][CH2:13][NH2:14].C(N(C(C)C)CC)(C)C.C(#N)C>ClCCl.[OH-].[Na+]>[CH3:10][C:11]([CH3:16])([CH3:15])[CH2:12][CH2:13][NH:14][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1
Reactant: ClCCN1CCOCC1
Reactant: CC(C)(C)CCN
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CCNCCN1CCOCC1

Procedure:
Into a microwave reactor was placed 4-(2-chloroethyl)-morpholine (1.5 g, 8.1 mmol), 3,3-dimethylbutylamine (2.2 mL, 16 mmol), diisopropylethylamine (3.1 mL, 18 mmol), and acetonitrile (30 mL). The resulting mixture was microwaved at 130° C. for 30 minutes and then diluted with dichloromethane and 1N sodium hydroxide. The layers were separated, and the organic extract was washed with brine, dried over magnesium sulfate, filtered, and concentrated to yield an orange oil. The oil was purified on a silica gel column, eluting with 15% of 10:1 (MeOH:NH4OH) in EtOAc to yield a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[CH:16][CH:15]=1)[C:7]([OH:9])=[O:8])([O-])=O.[CH:30](O)=O>C(OC)(OC)OC.C(Cl)Cl.[Fe]>[N:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[O:23][CH2:22][CH2:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([N:13]2[C:12]3[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=3[N:1]=[CH:30]2)=[CH:15][CH:16]=1
Reactant: O=CO
Reactant: O=C(O)c1ccc(Nc2ccc(OCCOc3ccccn3)cc2)c([N+](=O)[O-])c1
Agent: [Fe]
Solvent: ClCCl
Solvent: COC(OC)OC
Product: O=C(O)c1ccc2c(c1)ncn2-c1ccc(OCCOc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-Nitro-4-({4-[2-(pyridin-2-yloxy)ethoxy]phenyl}amino)benzoic acid (6.00 g, 15.20 mmol), iron powder (8.49 g, 152.00 mmol), and formic acid (68 mL) were dissolved in dry trimethyl orthoformate (175 mL). The reaction was allowed to stir at rt. After 18 h, the reaction mixture was diluted with CH2Cl2 and filtered through Celite to give a bright orange solid. The crude mixture was recrystallized from methanol to give 1-{4-[2-(pyridin-2-yloxy)ethoxy]phenyl}-1H-benzimidazole-5-carboxylic acid as a yellow-tan powder. 1H NMR (d6-DMSO, 400 MHz): δ 8.61 (d, J=2.4 Hz, 1H), 8.32 (d, J=1.6 Hz, 1H), 8.19 (ddd, J=5.2, 1.6, 0.8 Hz, 1H), 7.93 (dd, J=8.8, 1.6 Hz, 1H), 7.73 (ddd, J=8.8, 6.8, 1.8, Hz, 1H), 7.61 (ddd, J=4.8, 2.8, 2.8 Hz, 2H), 7.58 (s, 1H), 7.24 (ddd, J=5.2, 3.2, 3.2 Hz, 2H), 7.01 (ddd, J=6.8, 5.2, 1.2 Hz, 1H), 6.88 (dd, J=8.4, .4.0 Hz, 1H), 4.64 (t, J=4.2 Hz, 2H), 4.43 (t, J=4.6 Hz, 2H). MS(ES+): m/z 376.47 (10) [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[C:17]([S:19](=[O:24])(=[O:23])[N:20]([CH3:22])[CH3:21])[CH:16]=[CH:15][C:11]=1[C:12](O)=[O:13].[O:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[O:31][NH2:32].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>O1CCCC1.ClCCl>[O:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[O:31][NH:32][C:12](=[O:13])[C:11]1[CH:15]=[CH:16][C:17]([S:19](=[O:24])(=[O:23])[N:20]([CH3:22])[CH3:21])=[CH:18][C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[Cl:1]
Reactant: CN(C)S(=O)(=O)c1ccc(C(=O)O)c(Nc2ccc(I)cc2Cl)c1
Reactant: NOC1CCCCO1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)S(=O)(=O)c1ccc(C(=O)NOC2CCCCO2)c(Nc2ccc(I)cc2Cl)c1
Reaction time: 0.5 h

Procedure:
A solution comprised of 2-(2-chloro-4-iodo-phenylamino)-4-dimethylsulfamoyl-benzoic acid, O-(tetrahydro-2H-pyran-2-yl)-hydroxylamine (1.25 molar equivalents), benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (1.25 molar equivalents), and diisopropylethylamine (3 molar equivalents) in 1:1 v/v tetrahydrofuran-dichloromethane is stirred for 30 minutes. The reaction mixture is concentrated in vacuo and the residue is purified by flash chromatography; elution with dichloromethane affords the desired product. The product may be recrystallized with an appropriate solvent like methanol if further purification is necessary.
Reaction SMILES: [C:1]1([CH2:7][CH:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:10]([Mg]Br)=[CH2:11]>O1CCCC1>[CH:10]([CH:8]([OH:9])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[CH2:11]
Reactant: O=CCc1ccccc1
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: C=CC(O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 101.2 %

Procedure:
A solution of phenylacetaldehyde(600 mg, 5 mmol) in 12 ml of tetrahydrofuran was added dropwise over about 10 minutes to a solution of vinyl magnesium bromide (10 ml; 1M in tetrahydrofuran; 10 mmol) in 12 ml of tetrahydrofuran at 0° C. The internal temperature was maintained below 5° C. during the addition. After stirring for 1 hour at 0° C., the reaction was quenched by adding about 25 ml of saturated ammonium chloride solution. The resulting mixture was extracted with 100 ml of ethyl ether. The organic layer was washed with saturated ammonium chloride solution(50 ml) and brine(50 ml). Drying over magnesium sulfate and concentrating afforded 750 mg of the title product as a light orange liquid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([CH2:10][CH3:11])[C:5]([CH2:6][NH2:7])=[C:4]([CH2:12][CH3:13])[CH:3]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:12][CH3:13])[C:5]([CH2:6][N:7]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:8]([CH2:10][CH3:11])[CH:9]=1
Reactant: BrCCCCCBr
Reactant: CCc1cc(Br)cc(CC)c1CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCc1cc(Br)cc(CC)c1CN1CCCCC1
Temperature: 100 °C
Yield: 57.5 %

Procedure:
4-Bromo-2,6-diethylbenzylamine (90 mg, 0.37 mmol), 1,5-dibromopentane (56 pt, 0.41 mmol) and potassium carbonate (206 mg, 1.5 mmol) were suspended in dioxane (5 mL) and heated at 100° C. overnight. The reaction mixture was then cooled to ambient temperature, the solid removed by filtration and the filtrate concentrated in vacuo to afford an orange oil. The resultant oil was purified by flash chromatography (silica, 12 g column, ISCO, 0-10% methanol in DCM) to afford the title compound as yellow oil (66 mg, 58%). 1H NMR (CDCl3, 300 MHz): 7.16 (s, 2H), 3.38 (s, 2H), 2.80-2.62 (m, 4H), 2.35 (s, 4H), 1.54-1.34 (m, 6H), 1.27-1.13 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:17](=[O:18])[NH:16][C:15]2[C:10]1=[N:11][C:12]([NH:24][C@H:25]1[CH2:29][CH2:28][NH:27][CH2:26]1)=[N:13][C:14]=2[C:19]([O:21]CC)=O.C(OC([N:37]1CC[C@H](NC2N=C3C(NC(=O)N3C3C=CC=CC=3OC)=C(C(OCC)=O)N=2)C1)=O)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:17](=[O:18])[NH:16][C:15]2[C:10]1=[N:11][C:12]([NH:24][C@H:25]1[CH2:29][CH2:28][NH:27][CH2:26]1)=[N:13][C:14]=2[C:19]([NH2:37])=[O:21]
Reactant: CCOC(=O)c1nc(N[C@H]2CCN(C(=O)OC(C)(C)C)C2)nc2c1[nH]c(=O)n2-c1ccccc1OC
Reactant: CCOC(=O)c1nc(N[C@H]2CCNC2)nc2c1[nH]c(=O)n2-c1ccccc1OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccccc1-n1c(=O)[nH]c2c(C(N)=O)nc(N[C@H]3CCNC3)nc21
Reaction time: 2 h
Yield: 100 %

Procedure:
(S)-Ethyl 9-(2-methoxyphenyl)-8-oxo-2-(pyrrolidin-3-ylamino)-8,9-dihydro-7H-purine-6-carboxylate. (S)-Ethyl 2-(1-(tert-butoxycarbonyl)pyrrolidin-3-ylamino)-9-(2-methoxy-phenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxylate (0.369 g, 0.668 mmol) were dissolved in dichloromethane (3 mL) and trifluoroacetic acid (1 mL). The solution was stirred for two hours and condensed under reduced pressure to afford the crude title compound (0.300 g, 100%). MS (ESI) m/z 399.3 [M+1]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:10]([CH2:13][CH2:14][CH2:15][CH3:16])[C:8](=[O:9])[C:7]2=[CH:17][CH:18]=1)([O-])=O.[H][H]>N.O[V](=O)=O.[O-2].[O-2].[Ti+4].[Pd].O>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:10]([CH2:13][CH2:14][CH2:15][CH3:16])[C:8](=[O:9])[C:7]2=[CH:17][CH:18]=1
Reactant: CCCCN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Reactant: [H][H]
Agent: O=[V](=O)O
Agent: [Pd]
Agent: [Ti+4]
Solvent: O
Product: CCCCN1C(=O)c2ccc(N)cc2C1=O
Temperature: 65 °C
Reaction time: 68 h
Yield: 77.3 %

Procedure:
0.001 g of ammonium vanadate and 0.5 g of titanium dioxide extrudate containing 1% by weight of metallic palladium and having a particle size of 3 mm (from Johnson Matthey) are added to a suspension consisting of 50 ml of water and 2.5 g of 4-nitro-N-butylphthalimide. After displacing the air with nitrogen, the latter is replaced by hydrogen at atmospheric pressure and the suspension is stirred at 65° C. for 68 hours. During this time, 97% of the theoretical amount of hydrogen, based on the 4-nitro-N-butylphthalimide, is absorbed. The resulting suspension is then sieved through a sieve having a mesh width of 1 mm. The material remaining on the sieve is washed with 50 ml of water and the combined aqueous phases are then filtered through a paper filter and washed with 250 ml of water. Drying at 80° C. under reduced pressure (125 mbar) gives 1.7 g (80%) of 4-amino-N-butylphthalimide.