Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18])([OH:10])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[S:24](Cl)(=[O:26])=[O:25]>>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[C:3]([OH:10])([CH2:2][NH:1][S:24]([C:20]1[S:19][CH:23]=[CH:22][CH:21]=1)(=[O:26])=[O:25])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1
Reactant: NCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Reactant: O=S(=O)(Cl)c1cccs1
Product: O=S(=O)(NCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl)c1cccs1

Procedure:
Following the procedure described in the preceeding example but using 3-amino-2-(2,4-dichlorophenyl)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol and 2-thienylsulfonylchloride, the title compound was obtained in a similar yield: mp 169°-180° C.; 1H NMR (80 MHz, MeOH-d4)δ(TMS) 8.19 (s, 1H, CH=N), 7.74 (s, 1H, CH=N), 7.7-7.0 (m, 6H, arom), 4-95 (AB system, Δv=0.60, J=14.5 Hz, 2H, CH2 -Tr), 3.68 (AB system, Δv=0.13, J=14 Hz, 2H, CH2NH). Anal calcd. for C15H14Cl2N4O3S2 : C 41.58%; H 3.26%; N 12.93%. Found: C 42.39%; H 3.27%; N 13.06%.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C@@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][N:13]2[C:17]3=[N:18][C:19]([NH:22][C:23]4[CH:24]=[CH:25][C:26]([CH3:33])=[C:27]([S:29]([NH2:32])(=[O:31])=[O:30])[CH:28]=4)=[N:20][CH:21]=[C:16]3[CH:15]=[N:14]2)[CH2:8][CH2:7]1>C1COCC1>[CH3:33][C:26]1[CH:25]=[CH:24][C:23]([NH:22][C:19]2[N:18]=[C:17]3[N:13]([CH2:12][C@@H:9]4[CH2:8][CH2:7][C@H:6]([NH:5][C:1](=[O:3])[CH3:2])[CH2:11][CH2:10]4)[N:14]=[CH:15][C:16]3=[CH:21][N:20]=2)=[CH:28][C:27]=1[S:29](=[O:31])(=[O:30])[NH2:32]
Reactant: CC(=O)Cl
Reactant: Cc1ccc(Nc2ncc3cnn(C[C@H]4CC[C@@H](N)CC4)c3n2)cc1S(N)(=O)=O
Solvent: C1CCOC1
Product: CC(=O)N[C@H]1CC[C@@H](Cn2ncc3cnc(Nc4ccc(C)c(S(N)(=O)=O)c4)nc32)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Acetyl chloride (0.027 mL, 0.38 mmol) was added to a 10 mL vial charged with 5-(1-((cis-4-aminocyclohexyl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)-2-methylbenzenesulfonamide (0.15 g, 0.36 mmol, Example #C.1.1) and TEA (1 mL) in THF (4 mL). The reaction mixture was stirred at ambient temperature for about 2 h, then concentrated under reduced pressure. The crude product was purified by RP-HPLC (Table 2, Method b) to give N-(cis-4-((6-(4-methyl-3-sulfamoylphenylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)cyclohexyl)acetamide (0.021 g, 13%) as a white solid. LC/MS (Table 2, Method a) Rt=1.71 min; MS m/z: 458 (M+H)+.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([CH3:7])[NH:5][C:4](=[O:8])[CH2:3]1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])(=O)=O.O>C1COCC1>[Si:23]([O:1][C@@H:2]1[C@H:6]([CH3:7])[NH:5][C:4](=[O:8])[CH2:3]1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: C[C@@H]1NC(=O)C[C@@H]1O
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: C1CCOC1
Solvent: Cc1cccc(C)n1
Solvent: O
Product: C[C@@H]1NC(=O)C[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 76 %

Procedure:
A solution of (4S,5S)-4-hydroxy-5-methylpyrrolidin-2-one (3.0 g) in THF (50 mL) was cooled to 0° C., 2,6-lutidine (4.55 mL) and tert-butyldimethylsilyl trifluoromethanesulfonate (6.6 mL) were added thereto and, after warming to room temperature, the mixture was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=9/1→1/2) to give the title compound as a colorless solid (yield: 4.54 g, 76%).
Reaction SMILES: Cl.[NH2:2][N:3]1[CH2:8][CH:7]=[CH:6][CH2:5][CH2:4]1.C(N(CC)CC)C.[F:16][C:17]1[CH:18]=[C:19]([N:23]=[C:24]=[O:25])[CH:20]=[CH:21][CH:22]=1>C(Cl)Cl>[F:16][C:17]1[CH:18]=[C:19]([NH:23][C:24]([NH:2][N:3]2[CH2:4][CH:5]=[CH:6][CH2:7][CH2:8]2)=[O:25])[CH:20]=[CH:21][CH:22]=1
Reactant: O=C=Nc1cccc(F)c1
Reactant: NN1CC=CCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(F)c1)NN1CC=CCC1
Reaction time: 1 h
Yield: 60.8 %

Procedure:
To a solution of N-amino-1,2,3,6-tetrahydropyridine hydrochloride (1.346 g) and triethylamine (1.012 g) in dry methylene chloride (40 ml) was added a solution of 3-fluorophenyl isocyanate (1.37 g) in dry methylene chloride under ice-bath cooling. After stirring for one hour, the reaction mixture was evaporated to dryness. The residue was extracted with ethyl acetate (100 ml). The extract was washed with water, evaporated to dryness and recystallized from ethyl acetate to give N-[[(3-fluorophenyl)carbamoyl]amino]-1,2,3,6-tetrahydropyridine (1.43 g). mp: 136.5°-138.5° C.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:13]3[CH:12]=[C:11]([NH:14][C:15](=[O:21])OC(C)(C)C)[N:10]=[CH:9][C:8]=3[CH:7]=[CH:6]2)[CH2:3][CH2:2]1.N1C=CC=CC=1.ClC([C:31]1[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=1)=O>Cl.O1CCOCC1>[CH:1]1([CH2:4][N:5]2[C:13]3[CH:12]=[C:11]([NH:14][C:15]([C:31]4[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=4)=[O:21])[N:10]=[CH:9][C:8]=3[CH:7]=[CH:6]2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)Nc1cc2c(ccn2CC2CC2)cn1
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: COC(=O)c1ccc(C(=O)Nc2cc3c(ccn3CC3CC3)cn2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 84.6 %

Procedure:
A mixture of tert-butyl 1-(cyclopropylmethyl)-1H-pyrrolo[3,2-c]pyridin-6-ylcarbamate (2C, 260 mg, 0.91 mmol) in 4M HCl in dioxane (3 ml) was stirred at room temperature for 15 h. The mixture was concentrated in vacuo and dissolved in pyridine (3 ml, 37 mmol). To the mixture, methyl 4-(chlorocarbonyl)benzoate (270 mg, 1.4 mmol) was added and stirred at room temperature for 3 hours. The mixture was extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The crude mixture was purified by chromatography (NH—SiO2, EtOAc) to give methyl 4-(1-(cyclopropylmethyl)-1H-pyrrolo[3,2-c]pyridin-6-ylcarbamoyl)benzoate (2D, 270 mg, 0.77 mmol, 85% yield) as a white powder. 1 H NMR (400 MHz, DMSO-d6) δ ppm 0.39-0.47 (m, 2 H) 0.50-0.59 (m, 2 H) 1.17-1.33 (m, 1 H) 3.89 (s, 3 H) 4.06 (d, J=7.07 Hz, 2 H) 6.57-6.59 (m, 1 H) 7.52 (d, J=3.28 Hz, 1 H) 8.03-8.09 (m, 2 H) 8.14-8.19 (m, 2 H) 8.34 (s, 1 H) 8.65 (s, 1 H) 10.86 (s, 1 H). ESI-MS: m/z 350.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[N:10][C:9]=2[CH:17]2[CH2:19][CH2:18]2)[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:21][C:22]1[O:26][N:25]=[C:24]([C:27]2([NH2:31])[CH2:30][CH2:29][CH2:28]2)[N:23]=1>>[CH3:21][C:22]1[O:26][N:25]=[C:24]([C:27]2([NH:31][C:14]([C:12]3[CH:11]=[N:10][C:9]([CH:17]4[CH2:19][CH2:18]4)=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[N:13]=3)=[O:16])[CH2:30][CH2:29][CH2:28]2)[N:23]=1
Reactant: Cc1nc(C2(N)CCC2)no1
Reactant: O=C(O)c1cnc(C2CC2)c(-c2cccc(Cl)c2)n1
Agent: Cl
Product: Cc1nc(C2(NC(=O)c3cnc(C4CC4)c(-c4cccc(Cl)c4)n3)CCC2)no1

Procedure:
The title compound was synthesized in analogy to Example 1e, using 6-(3-chloro-phenyl)-5-cyclopropyl-pyrazine-2-carboxylic acid and 1-(5-methyl-1,2,4-oxadiazol-3-yl)-cyclobutanamine hydrochloride (CAN 1170897-128-5) as starting materials, and isolated (43 mg, 58%) as white solid; MS (EI): 410.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13](=O)[CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[C:9]([CH2:25][CH2:26][CH3:27])[CH:8]=2)=[CH:4][CH:3]=1>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[C:17]4[CH:18]=[C:19]([O:22][CH3:23])[CH:20]=[CH:21][C:16]=4[O:15][CH:14]=3)=[C:9]([CH2:25][CH2:26][CH3:27])[CH:8]=2)=[CH:4][CH:3]=1
Reactant: CCCc1cc(Oc2ccc(Cl)cc2)ccc1C(=O)COc1ccc(OC)cc1
Solvent: Cc1ccccc1C
Product: CCCc1cc(Oc2ccc(Cl)cc2)ccc1-c1coc2ccc(OC)cc12
Temperature: 140 °C

Procedure:
A mixture of the product from Step 9 (0.46 g, 1.1 mmol) and Amberlyst-15 (0.50 g) in xylene (10 mL) was heated at 140° C. for 2 h. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by chromatography on silica gel to give the title product.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.[CH3:48][Si:49]([CH3:76])([CH3:75])[CH2:50][CH2:51][O:52][CH2:53][N:54]1[C:58]2[N:59]=[CH:60][N:61]=[C:62]([C:63]3[CH:64]=[N:65][N:66]([C:68]4([CH2:72][C:73]#[N:74])[CH2:71][NH:70][CH2:69]4)[CH:67]=3)[C:57]=2[CH:56]=[CH:55]1.Br[C:78]1[CH:79]=[CH:80][C:81]([C:84]([O:86][CH3:87])=[O:85])=[N:82][CH:83]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:73]([CH2:72][C:68]1([N:66]2[CH:67]=[C:63]([C:62]3[C:57]4[CH:56]=[CH:55][N:54]([CH2:53][O:52][CH2:51][CH2:50][Si:49]([CH3:75])([CH3:48])[CH3:76])[C:58]=4[N:59]=[CH:60][N:61]=3)[CH:64]=[N:65]2)[CH2:69][N:70]([C:78]2[CH:79]=[CH:80][C:81]([C:84]([O:86][CH3:87])=[O:85])=[N:82][CH:83]=2)[CH2:71]1)#[N:74]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ncnc21
Reactant: COC(=O)c1ccc(Br)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(N2CC(CC#N)(n3cc(-c4ncnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)cn1
Temperature: 100 °C
Reaction time: 8 h
Yield: 63.5 %

Procedure:
A mixture of 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (660 mg, 1.1 mmol), {3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile hydrochloride (4.76 g, 10.7 mmol), methyl 5-bromopicolinate (3.00 g, 13.9 mmol), palladium acetate (240 mg, 1.1 mmol) and cesium carbonate (10 g, 32 mmol) in toluene (120 mL) was de-gassed and recharged with nitrogen for three times. The reaction mixture was stirred at 100° C. overnight. After cooling the reaction mixture was quenched with water, and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with MeOH in dichloromethylene (0-5%) to afford the desired product (3.70 g, 63.6%). LCMS (M+H)+: m/z=545.3.
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][O:7][C:6]2[CH:15]=[CH:16][C:17]([CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:5]1=2>CO>[OH:3][CH:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][O:7][C:6]2[CH:15]=[CH:16][C:17]([CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:5]1=2
Reactant: COC(=O)Cc1ccc2c(c1)C(=O)c1ccccc1CO2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1ccc2c(c1)C(O)c1ccccc1CO2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1.4 g. of sodium borohydride, 200 ml. of methanol, and 4.0 g. of methyl 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetate is stirred at 5°-10° for four hours and then the methanol is removed under high vacuum. Water and tetrahydrofuran are added to the residue, and the solution is adjusted to a pH of 5-6 with the addition of acetic acid and stirred for two hours at room temperature. The mixture is extracted with chloroform, and the chloroform solution is dried over sodium sulfate and concentrated. Trituration of the solid with ether provides methyl 6,11-dihydro-11-hydroxydibenz[b,e]oxepin-2-acetate as colorless crystals, m.p. 85°-87°.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:5]=[CH:6][C:7]([CH3:36])=[C:8]([NH:10][C:11](=[O:35])[C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[N:28]=[C:27]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:14][CH:13]=2)[CH:9]=1)#[N:3].[CH2:37]([OH:39])C>>[CH3:36][C:7]1[CH:6]=[CH:5][C:4]([C:2](=[NH:3])[O:39][CH3:37])=[CH:9][C:8]=1[NH:10][C:11]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[N:28]=[C:27]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)=[CH:14][CH:13]=1)=[O:35]
Reactant: CCO
Reactant: Cc1ccc(C#N)cc1NC(=O)c1ccc(Nc2nc(-c3ccccc3)c3ccccc3n2)cc1
Agent: Cl
Product: COC(=N)c1ccc(C)c(NC(=O)c2ccc(Nc3nc(-c4ccccc4)c4ccccc4n3)cc2)c1
Yield: 100 %

Procedure:
Anhydrous hydrochloric acid gas was bubbled into a suspension of N-(5-cyano-2-methylphenyl)-4-[(4-phenylquinazolin-2-yl)amino]benzamide (273 mg, 0.60 mmol), prepared as described in Example 10, in absolute ethanol (5 mL) for 10 min and the flask was affixed with a drying tube and allowed to stand in the refrigerator overnight. The reaction was concentrated on a rotary evaporator to give methyl 4-methyl-3-[({4-[(4-phenylquinazolin-2-yl)amino]phenyl}carbonyl)amino]benzenecarboximidoate as a yellow solid (311 mg, 100%). 1H NMR (400 MHz, DMSO-d6): δ 11.90 (br s, 1H), 11.20 (br s, 1H), 10.40 (s, 1H), 9.95 (s, 1H), 8.20 (t, 2H), 8.03 (t, 2H), 7.87 (m, 3H), 7.82 (m, 3H), 7.65 (t, 3H), 7.43 (dt, 1H), 7.38 (d, 1H), 4.30 (s, 3H), 2.42 (s, 3H). MS (EI) for C30H25N5O2: 488.1 (MH+).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.CCO.O.[NH3:16]>>[Cl:11][C:4]1[N:3]=[C:2]([NH2:16])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: N
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Solvent: O
Solvent: CCO
Product: Nc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 89 %

Procedure:
2,6-Dichloro-3-nitropyridine 90 (10.0 g, 51.8 mmol) was dissolved in 37 ml of a 7N solution of NH3 in EtOH (0.26 mol, 5.0 eqv) and the solution was stirred at rt for 24 h. H2O (40 ml) was added and the resulting mixture was filtered to collect the crude yellow product. The solid material was dissolved in CH2Cl2 and then extracted with a 1N HCl solution. The aqueous extracts were combined and then neutralized with NaHCO3 before being re-extracted with CH2Cl2. The organic fractions were combined, dried (MgSO4), filtered, and concentrated in vacuo to yield 8.0 g of a yellow solid (89%): 1H NMR (400 MHz, d6-DMSO) d 6.77 (d, J=8.8 Hz, 1H), 8.27 (s, 2H), 8.39 (d, J=8.4 Hz, 1H); 13C NMR (125 MHz, d6-DMSO) d 111.89, 126.02, 138.28, 153.36, 154.88; HRMS (EI) Calcd for C5H4ClN3O2: 172.9997. Found 172.9996.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=2)[NH:12][CH:11]=[CH:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19]([N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C:27]1=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C[O-].[Na+]>CO>[C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=2)[NH:12][CH:11]=[C:10]3[C:29]2[CH2:30][CH2:31][N:26]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:27][CH:28]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCCCN1Cc1ccccc1
Reactant: NC(=O)c1cc(-c2ccccc2)cc2cc[nH]c12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1cc(-c2ccccc2)cc2c(C3=CCN(Cc4ccccc4)CC3)c[nH]c12
Temperature: 80 °C
Yield: 54.4 %

Procedure:
To the solution of 5-phenyl-1H-indole-7-carboxamide (3.11 g, 12 mmol) in methanol (100 mL) was added benzyl piperidone (7.4 g, 36 mmol), followed by 156 mL of NaOMe (0.5 M in MeOH). The reaction mixture was then heated at 80° C. overnight. The solution was cooled to ambient temperature and the solvent removed under reduced pressure, and the resulting residue redisolved in a bilayer of ethyl acetate and 5% sodium hydroxide solution. The organic phase washed with brine, dried over potassium carbonate, and the solvent removed under reduced pressure. The residue was purified by silica gel chromatography (CH2Cl2:MeOH:NH4OH=96:3:1) to provide the desired product (2.66 g, 51%).
Reaction SMILES: Br[C:2]1[C:10]2[CH:9]=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Mg].II.CON(C)[C:17](=[O:22])[CH2:18][CH2:19][CH:20]=[CH2:21]>O1CCCC1>[S:7]1[CH:8]=[CH:9][C:10]2[C:2]([C:17](=[O:22])[CH2:18][CH2:19][CH:20]=[CH2:21])=[CH:3][CH:4]=[CH:5][C:6]1=2
Reactant: Brc1cccc2sccc12
Reactant: C=CCCC(=O)N(C)OC
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CCCC(=O)c1cccc2sccc12
Temperature: 25 °C

Procedure:
A few drops of a solution of 4-bromobenzo[b]thiophene (5 g; prepared in a manner similar to that described in Example 9 Method A) in tetrahydrofuran (10 ml) was added under nitrogen to magnesium turnings (0.6 g). Two crystals of iodine were added and heat was applied to initiate the reaction. The remainder of the 4-bromobenzo[b]thiophene solution was added at reflux temperature over 30 minutes, the mixture was heated under reflux for 2 hours, then further tetrahydrofuran (10 ml) was added. A solution of N-methoxy-N-methylpent-4-enamide (5 g) in tetrahydrofuran (5 ml) was added, the mixture was heated under reflux for 3 hours, then it was cooled to ambient temperature and quenched by the addition of water (100 ml) and 5M hydrochloric acid (5 ml). The product was extracted into ethyl acetate (3×60 ml), the combined extracts were washed with water (100 ml) and saturated aqueous sodium chloride solution (100 ml), then they were dried (MgSO4), and the solvents were removed in vacuo. The residue was purified by flash chromatography over silica using 99:1 followed by a 98:2 mixtures of petroleum ether (b.p. 40-60° C.) and ethyl acetate as eluants. Appropriate fractions were combined and the solvents removed in vacuo to give 1-(benzo[b]thiophen-4-yl)pent-4-en-1-one (1.6 g) as a colourless oil which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:14][CH2:13][N:12]3[C:7](=[C:8]([C:22](O)=[O:23])[CH:9]=[C:10]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:11]3=[O:15])[C:6]=2[CH:25]=1.Cl.[OH:27][C@H:28]1[CH2:32][CH2:31][NH:30][CH2:29]1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)O.C(=O)([O-])O.[Na+]>CN(C)C=O.CN1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:14][CH2:13][N:12]3[C:7](=[C:8]([C:22]([N:30]4[CH2:31][CH2:32][C@H:28]([OH:27])[CH2:29]4)=[O:23])[CH:9]=[C:10]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:11]3=[O:15])[C:6]=2[CH:25]=1
Reactant: O=C(O)c1cc(-c2ccccc2)c(=O)n2c1-c1cc(Cl)ccc1CC2
Reactant: O[C@H]1CCNC1
Agent: CN(C)C(O)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: O=C(c1cc(-c2ccccc2)c(=O)n2c1-c1cc(Cl)ccc1CC2)N1CC[C@H](O)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.1 %

Procedure:
70.36 g of 10-chloro-6,7-dihydro-4-oxo-3-phenyl-4H-benzo[a]quinolizine-1-carboxylic acid are dissolved in 1600 ml of N,N-dimethylformamide under argon, whereupon 45 ml of 4-methylmorpholine, 27.2 g of (S)-3-hydroxypyrrolidine hydrochloride and 83.4 g of O-benzotriazol-1-yl-,N,N,N',N'-tetramethyluronium hexafluorophosphate are added in succession. The mixture is stirred at room temperature for about 18 hours and the yellow solution obtained is poured into 6000 ml of water and treated slowly with 2500 ml of saturated sodium hydrogen carbonate solution. The product obtained is filtered under suction and washed with 1000 ml of water. After drying in a vacuum at 70° there are obtained 83.3 g of crude product. By repeated recrystallization from a 120-fold amount of isopropanol and chromatography of the combined mother liquours on 1000 g of silica gel with methylene chloride/diethyl ether (9:1) and subsequently with methylene chloride/acetone (9:1), there are obtained 74.2 g (88%) of (S)-1-[ (10-chloro-6,7-dihydro-4-oxo-3-phenyl-4H-benzo[a]quinolizin-1-yl)carbonyl]-3-hydroxypyrrolidine with a m.p. of 257°-259°.
Reaction SMILES: Br[CH:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:14]([C:18]1[CH:23]=[CH:22][C:21]([SH:24])=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:14]([C:18]1[CH:19]=[CH:20][C:21]([S:24][CH:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:22][CH:23]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CCCCCCC(Br)C(=O)OCC
Reactant: CC(C)(C)c1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCC(Sc1ccc(C(C)(C)C)cc1)C(=O)OCC
Temperature: 25 °C
Yield: 56.5 %

Procedure:
A mixture of 5.0 g (0.02 mole) ethyl 2-bromooctanoate, 3.37 g (0.02 mole) p-t-butylthiophenol and 3.31 g (0.24 mole) potassium carbonate in 70 ml acetone was refluxed under nitrogen overnight. The reaction mixture was cooled to room temperature and filtered and the filtrate was concentrated in vacuo. The residue was chromatographed on 500 g silica gel, eluting with 6:4 methylene chloride/hexane to yield 3.8 g (57% yield) of the desired product as an oil.
Reaction SMILES: C1C=CC(CCN)=CC=1.C1([OH:16])C=CC=CC=1.CC1(C)S[C@@H]2[C@H](NC([C@H](N)C3C=CC=CC=3)=O)C(=O)N2[C@H]1C(O)=O.C[C@:42]1([OH:72])[C@@H:56]2[C:51](=[C:52](O)[C@:53]3([OH:69])[C:60](=[O:61])C(C(N)=O)=C(O)[C@@H](N(C)C)[C@@H]3C2)C(=O)C2C(O)=CC=CC1=2>>[CH:51](/[CH:56]=[CH:42]/[OH:72])=[CH:52]\[C:53]([C:60]([OH:16])=[O:61])=[O:69]
Reactant: Oc1ccccc1
Reactant: CN(C)[C@@H]1C(O)=C(C(N)=O)C(=O)[C@@]2(O)C(O)=C3C(=O)c4c(O)cccc4[C@@](C)(O)[C@H]3C[C@@H]12
Agent: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Agent: NCCc1ccccc1
Product: O=C(O)C(=O)/C=C/C=C/O

Procedure:
Screening for transformants carrying pheA and pheB. Transformants were spread on LB plates containing 1 mM phenol, 50 μg of ampicillin per ml, and 12.5 μg of tetracycline per ml and incubated overnight at 37° C. Colonies that became yellow (as a result of 2-hydroxymuconic semialdehyde) following spraying of a 0.1% of catechol solution were patched on LB plates containing 1 mM phenol. Colonies in which the yellow compound formed during growth without catechol addition were retained as putative carriers of both pheA and pheB.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]([O:21]C)=O)=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:18])[N:15]([CH3:17])[CH3:16])=[CH:10][CH:9]=2)=[CH:6][N:7]=1.[NH2:23][NH2:24]>CCO>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([N:15]([CH3:16])[CH3:17])=[O:18])=[CH:12][CH:13]=2)=[N:4][C:3]=1[C:19]([NH:23][NH2:24])=[O:21]
Reactant: NN
Reactant: COC(=O)c1nc(-c2ccc(C(=O)N(C)C)cc2)cnc1N
Solvent: CCO
Product: CN(C)C(=O)c1ccc(-c2cnc(N)c(C(=O)NN)n2)cc1
Temperature: 25 °C
Yield: 87 %

Procedure:
To a stirred solution of methyl 3-amino-6-[4-(dimethylcarbamoyl)phenyl]pyrazine-2-carboxylate (1.7011 g, 5.664 mmol) in EtOH (10.21 mL) was added hydrazine (726.1 mg, 711.2 μL, 22.66 mmol). The resultant solution was heated to reflux for 30 minutes and then allowed to cool to RT. The precipitate was filtered off and dried (1.47 g, 87% Yield). 1H NMR (400.0 MHz, DMSO) d 2.96 (s, 3H), 3.00 (s, 3H), 4.58 (d, J=4.4 Hz, 2H), 7.46 (d, J=8.4 Hz, 2H), 8.27-8.29 (m, 2H), 8.88 (s, 1H) and 10.09 (s, 1H) ppm; MS (ES+) 301.13
Reaction SMILES: C1N2CN3CN(C2)CN1C3.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=1[OH:19].FC(F)(F)[C:22](O)=[O:23]>>[Cl:11][C:12]1[CH:17]=[C:16]([CH:15]=[C:14]([CH3:18])[C:13]=1[OH:19])[CH:22]=[O:23]
Reactant: Cc1cccc(Cl)c1O
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Product: Cc1cc(C=O)cc(Cl)c1O
Temperature: 85 °C
Reaction time: 0.33 h
Yield: 35 %

Procedure:
Hexamethylenetetramine (19.60 g, 139.8 mmol) was added in portions to a solution of 2-chloro-6-methylphenol (20.00 g, 117.2 mmol) in trifluoroacetic acid (200 mL). There was a slight exotherm and effervescence was noted. The reaction mixture was heated in an oil-bath at 84-86° C. for 5 h, then it was cooled and evaporated (˜50° C., 0.2 mm). The residue was evaporated from hexane, then ice-water (500 mL) was added and the mixture was stirred for 20 min. Ether (100 mL) was added and the reaction was brought to approx. pH 5 by the careful portionwise addition of solid sodium hydrogen carbonate (49 g). The resulting mixture was extracted with ether (2×250 mL), and the ether layers were washed with brine, dried (MgSO4), filtered and concentrated to about 100 mL. The mixture was then left to crystallize over the weekend to give a solid which was filtered off and washed with ice-cold ether to give 3-chloro-4-hydroxy-5-methylbenzaldehyde (6.9 g, 35%) as a yellow solid. The mother liquor was evaporated and dichloromethane (30 mL) was added. The yellow solid was filtered off (2.9 g, 14%). The remaining solution was purified by HPLC (7% ethyl acetate/hexanes) to give a yellow solid (7.8 g, 39%). The overall yield was 17.6 g (88%).