Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH2:10].[CH2:11](O)[CH:12](O)[CH2:13]O.[Na+].[N+](C1C=C(S([O-])(=O)=O)C=CC=1)([O-])=O.[OH-].[Na+]>CS(O)(=O)=O>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[CH:5]=[C:4]2[C:3]=1[N:10]=[CH:13][CH:12]=[CH:11]2
Reactant: CCc1ccc(N)c(Br)c1
Reactant: OCC(O)CO
Agent: CS(=O)(=O)O
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: [Na+]
Product: CCc1cc(Br)c2ncccc2c1
Temperature: 135 °C
Yield: 68.8 %

Procedure:
A mixture of 2-bromo-4-ethylphenylamine (1.6 g, 8.0 mmol), propane-1,2,3-triol (1.84 g, 2.5 equiv), FeSO4 (0.067 g, 0.30 equiv), 3-nitrobenzenesulfonic acid sodium salt (1.13 g, 0.63 equiv) in 4.5 mL of methanesulfonic acid was heated at 135° C. for 3 hours and then cooled to room temperature. 2 N Aqueous NaOH (˜40 mL) was added and the mixture was extracted with EtOAc (3×50 mL). The organic layer was washed with saturated aqueous NaHCO3 (200 mL) and brine (200 mL), dried over magnesium sulfate and concentrated. The residue was purified by silica gel flash column chromatography using 5% to 20% EtOAc in hexane to afford the title compound as a black solid (1.3 g). MS (ES) m/z 235.9 (M+H+).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]=[O:9]>O.O.C(O)(=O)C(O)=O>[CH:1]1[CH:2]=[C:3]([CH2:4][C:6]2[C:1]([OH:7])=[CH:2][CH:3]=[CH:4][CH:5]=2)[C:8]([OH:9])=[CH:5][CH:6]=1
Reactant: Oc1ccccc1
Reactant: C=O
Agent: O=C(O)C(=O)O
Solvent: O
Product: Oc1ccccc1Cc1ccccc1O
Temperature: 70 °C
Yield: 30.4 %

Procedure:
There were mixed 2000 g of phenol and 172.5 g of 37% formalin (P/F=10) and then 5.6 g of oxalic acid dihydrate was added to the mixture, followed by reacting the mixture with heating at 70° C. for 4 hours. Then the reaction system thus obtained was heated to 160° C. under atmospheric pressure to remove the water and a small amount of phenol and further heated at a pressure of 20 mm Hg till the temperature reached 170° C. to remove unreacted phenol. Then the product was heated at 210° C. and a pressure of 6 mm Hg to further remove the remaining unreacted phenol to give 350 g of a crude bisphenol F.
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.[C:4]([N:8]([CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:7])[CH2:5][CH3:6]>C1(C)C=CC=CC=1.CO>[OH:3][CH2:2][CH2:1][N:18]1[CH2:17][CH2:16][CH:15]([N:8]([C:4](=[O:7])[CH2:5][CH3:6])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:20][CH2:19]1
Reactant: CCC(=O)N(c1ccccc1)C1CCNCC1
Reactant: C1CO1
Solvent: CO
Solvent: Cc1ccccc1
Product: CCC(=O)N(c1ccccc1)C1CCN(CCO)CC1
Temperature: 15 °C

Procedure:
A solution, cooled to 15° C., containing 100 mmol of ethylene oxide in toluene is added slowly to 100 mmol of 4-(N-propionylanilino)piperidine in solution in 100 ml of anhydrous methanol cooled to 15° C. After returning to room temperature and removal of the azeotrope formed by distillation, the expected product is obtained after evaporation to dryness.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH2:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][NH:15]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:15]3[CH2:16][CH2:17][C:18]4[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:14]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: c1ccc2c(c1)CCNC2
Product: O=C(c1cc2ncc(Cl)cn2n1)N1CCc2ccccc2C1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1,2,3,4-Tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.C([Li])CCC.[CH3:14][C:15](N(C)C)=[O:16].[Cl-].[NH4+]>CCOCC.O>[C:15]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1)(=[O:16])[CH3:14]
Reactant: Brc1cccc(Br)n1
Reactant: CC(=O)N(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Product: CC(=O)c1cccc(Br)n1
Temperature: -60 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
A 5 L 3-neck flask was charged with 2,6-dibromopyridine (181 g; 0.75 mole) and 2.0 L ether. The suspension was stirred under nitrogen at -60° C. and then n-butyllithium (300 mL; 2.5M) was added from a pressure equalizing dropping funnel over 20 minutes. The bath was lowered and the near solution was allowed to warm to -50° C. After 15 minutes, the dark yellow solution was re-cooled to -78° C. in a dry ice/ether bath and dimethylacetamide (70 g; 0.86 mole) in 70 mL ether was added at such a rate that the temperature did not exceed -75° C. The addition took about one hour for completion, after which the bath was removed to allow the reaction to warm to -60° C. A solution of ammonium chloride (50 g; 0.93 mole) in 150 mL of H2O was added dropwise over 10 minutes under nitrogen and the temperature rose to -40° C. The mixture was stirred for 45 minutes and the layers were separated. The aqueous layer was back-extracted with 500 mL ether and the pooled organic layers were washed twice with H20 and once with saturated salt solution. The organic layer was dried over MgSO4 and, after evaporating to dryness, gave 150 g of yellow oil. This material, after pooling with another run of the same scale, was kugelrohred at 80° C./0.1 mm Hg to give 257 g (86%) of a near colorless oil that crystallized readily on cooling; silica gel TLC system: 90 hexane: 10 ether.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH:14]=[CH:15][N+:16]([O-:18])=[O:17])=[C:5]2[C:9](=[C:10]([O:12][CH3:13])[CH:11]=1)[NH:8][CH:7]=[CH:6]2.C([O-])(O)=O.[Na+]>[N+](C)([O-])=O>[CH3:1][O:2][C:3]1[C:4]([CH:14]([CH2:15][N+:16]([O-:18])=[O:17])[CH2:15][N+:16]([O-:18])=[O:17])=[C:5]2[C:9](=[C:10]([O:12][CH3:13])[CH:11]=1)[NH:8][CH:7]=[CH:6]2
Reactant: COc1cc(OC)c2[nH]ccc2c1C=C[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C[N+](=O)[O-]
Product: COc1cc(OC)c2[nH]ccc2c1C(C[N+](=O)[O-])C[N+](=O)[O-]
Yield: 125.4 %

Procedure:
A solution of 5,7-dimethoxy-4-nitroethenylindole (0.82 g, 3.3 mmol) and NaHCO3 (0.33 g) in nitromethane (15 cm3) was refluxed under nitrogen for 30 hours. The mixture was then concentrated under reduced pressure and then partitioned between water (10 cm3) and ethyl acetate (10 cm3). The organic layer was washed with saturated aqueous NaHCO3 (10 cm3), then brine (10 cm3), dried over MgSO4 and evaporated under reduced pressure to give a crude solid, which was purified by chromatography on silica, eluting with petrol:ethyl acetate (80:20) to give 5,7-dimethoxy-4-{2′-nitro-1′-(nitromethyl)ethyl}indole as a pale yellow solid (0.64 g, 63%)
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[Cl:11][S:12](O)(=[O:14])=[O:13]>C(Cl)(Cl)Cl>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([S:12]([Cl:11])(=[O:14])=[O:13])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=S(=O)(O)Cl
Reactant: CCCCc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCCCc1ccc(S(=O)(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 88 %

Procedure:
To a solution of butylbenzene (4.13 g, 30.8 mmol) in CHCl3 (50 mL) was added chlorosulfonic acid (17 mL, 29.8 g, 256 mmol) and the mixture was stirred at rt for 20 h. The mixture was poured on ice (200 mL) and extracted with EtOAc (3×100 mL). The combined extracts were washed with water, a solution of NaHCO3, and water, dried (Na2SO4), and concentrated in vacuo. The yellow oily residue (ca 88% yield) was used without further purification in the next reaction; 1H NMR (300 MHz, CDCl3) δ 0.94 (t, 3H, J=7 Hz), 1.34-1.41 (m, 2H), 1.62-1.67 (m, 2H), 2.73 (t, 2H, J=8 Hz), 7.41 (d, 2H, J=8 Hz), 7.94 (d, 2H, J=8 Hz).
Reaction SMILES: [NH2:1][C:2]1([F:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:3]1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[Br:17][CH2:18][C:19](Br)=[O:20]>ClCCl.O>[Br:17][CH2:18][C:19]([NH:1][C:2]1([F:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:3]1[C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:5])=[O:20]
Reactant: O=C(Br)CBr
Reactant: NC1(F)C=CC=CC1C(=O)c1ccccc1
Solvent: O
Solvent: ClCCl
Product: O=C(CBr)NC1(F)C=CC=CC1C(=O)c1ccccc1
Temperature: -10 °C

Procedure:
To a cooled (-10° C.), stirred suspension of 2-amino-2-fluorobenzophenone (19.40 g, 0.090 mol) in dichloromethane (130 mL) and water (10 mL) was added a solution of bromoacetylbromide (9.0 mL, 0.104 mol) in dichloromethane (30 mL), keeping the temperature of the reaction mixture at -10° C. After addition the reaction mixture was stirred whilst warming to room temperature (21/2hours). The organic layer was collected, washed with water (2×100 mL) then concentrated to approximately 70 mL. Hexane (70 mL) was added and the required product collected by filtration (25.6 g, 83%): mp 120°-121° C. Rf 0.30 in diethyl ether/n-hexane (1:1) on silica; 1H NMR (CDCl3) δ4.05 (2H,s), 7.10-7.64 (7H, m), 8.70 (1H, d, J=8 Hz), 11.95 (1H, broad s); MS, m/z 335 (M+ ). Anal. Calcd. for C15H11BrFNO2 :C, 53.59; H, 3.30; N, 4.17. Found: C, 53.32; H, 3.33; N, 4.00.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:26]=[CH:25][CH:24]=[CH:23][C:7]=2[O:8][CH2:9][C:10]([C:12]2[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=2[C:14]([O:16]CC)=[O:15])=[O:11])[N:3]=[CH:2]1.[Li+].[OH-].Cl.N>O1CCCC1.O>[NH:1]1[CH:5]=[C:4]([C:6]2[CH:26]=[CH:25][CH:24]=[CH:23][C:7]=2[O:8][CH2:9][C:10]([C:12]2[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=2[C:14]([OH:16])=[O:15])=[O:11])[N:3]=[CH:2]1
Reactant: CCOC(=O)c1ccccc1C(=O)COc1ccccc1-c1c[nH]cn1
Agent: Cl
Agent: N
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1C(=O)COc1ccccc1-c1c[nH]cn1
Reaction time: 5 h
Yield: 46 %

Procedure:
To a solution of ethyl 2-(2-(2-(1H-imidazol-4-yl)phenoxy)acetyl)benzoate (0.142 mmol) in a mixture of tetrahydrofuran (2 mL) and water (1 mL) was added LiOH.H20 (0.713 mmol). After stirring for 5 h the reaction mixture was acidified with 6N HCl and treated with NH3 (solution in ethanol) till the pH was basic, the solution was concentrated under reduced pressure and subjected to column chromatography to afford the final product. Yield 46%. (CDCl3+CD3OD): 4.69 (s, 2H), 6.87 (d, 1H, J=6.18 Hz), 6.95 (t, 1H, J=5.55 Hz), 7.19 (t, 1H, J=5.79 Hz), 7.38 (d, 1H, J=5.10 Hz), 7.47-7.56 (m, 4H), 7.79 (d, 1H, J=5.00 Hz), 8.21 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[N:16]=[C:15]([CH2:17][C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[F:25])[C:14]([CH2:26][CH2:27][C:28](O)=[O:29])=[CH:13][C:12]=2[F:31])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.N1(O)C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[N:16]=[C:15]([CH2:17][C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[F:25])[C:14]([CH2:26][CH2:27][C:28]([N:36]3[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]3)=[O:29])=[CH:13][C:12]=2[F:31])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(O)CCc1cc(F)c(S(=O)(=O)c2ccc(Cl)cc2)nc1Cc1cc(F)ccc1F
Reactant: CN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CN1CCN(C(=O)CCc2cc(F)c(S(=O)(=O)c3ccc(Cl)cc3)nc2Cc2cc(F)ccc2F)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 181 %

Procedure:
To a dichloromethane (3 ml) solution of 3-[6-(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl-5-fluoropyridin-3-yl]propionic acid (100 mg, 0.21 mmol) were added 1-methylpiperazine (0.026 ml, 0.23 mmol), benzotriazol-1-ol (32 mg, 0.23 mmol), 4-methylmorpholine (0.026 ml, 0.23 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (45 mg, 0.23 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 hours. After the reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate, the organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel chromatography. The fraction obtained from the dichloromethane:methanol=19:1 eluate was concentrated under reduced pressure. The residue was dissolved in ethanol (3 ml), followed by the addition of 1N hydrochloric acid (0.224 ml). After stirring at room temperature for 30 minutes, the reaction mixture was concentrated under reduced pressure. The residue thus obtained was washed with ethanol and collected by filtration to give the title compound (111 mg, 0.19 mmol, 89%) as a white solid.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH:2]=[CH2:3].Br[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[OH-].[Na+]>O>[CH2:1]([N:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:2]=[CH2:3]
Reactant: C=CCNc1ccccc1
Reactant: CCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CCN(CCCCC)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.2 %

Procedure:
N-Allylphenylamine (1.95 g, 14.7 mmol) and bromopentane (2.22 g, 14.7 mmol) were stirred at 80° C. for 16 hours. After cooled to room temperature, the mixture was treated with a solution of sodium hydroxide(714 mg, 17.9 mmol) in water (1.5 ml), stirred for 30 minutes and extracted with ether (80 ml). The extract was dried over potassium carbonate, filterd and concentrated in vacuum. The residue was chromatographed on silica gel to give N-allyl-N-pentylphenylamine (1.68 g) in 56% yield as a colorless oil.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14](C(OCC3C=CC=CC=3)=O)[CH2:13][CH2:12]2)=[C:7]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:6]=1>CCO>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[C:7]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:6]=1
Reactant: COc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2)c(S(C)(=O)=O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C2CCNCC2)c(S(C)(=O)=O)c1

Procedure:
To a solution of KOH (1.50 g) in 20 mL of 1:1 EtOH:H20 was added 1.23 g of 4-(4-methoxy-2-methylsulfonylphenyl)-N-Cbz-piperidine. The resulting mixture was heated reflux under N2 atmosphere for 18 h, evaporated, dissolved in 10 mL H2O, and extracted with CHCl3. The organic extracts were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by chromatography (20:1 DCM in methanol containing 0.5% aqueous NH4OH). MS m/z 270 (M+H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].[CH2:34]([C:38]1[O:42][N:41]=[C:40]([C:43](O)=[O:44])[CH:39]=1)[CH:35]([CH3:37])[CH3:36].[B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C.C(N(C(C)C)CC)(C)C>>[CH2:34]([C:38]1[O:42][N:41]=[C:40]([C:43]([N:29]2[CH2:28][CH2:27][CH:26]([N:23]3[C:19]4=[N:20][CH:21]=[N:22][C:17]([O:16][C:15]5[CH:14]=[CH:13][C:12]([S:9]([CH3:8])(=[O:11])=[O:10])=[CH:33][CH:32]=5)=[C:18]4[CH:25]=[N:24]3)[CH2:31][CH2:30]2)=[O:44])[CH:39]=1)[CH:35]([CH3:37])[CH3:36]
Reactant: CC(C)Cc1cc(C(=O)O)no1
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Cc1cc(C(=O)N2CCC(n3ncc4c(Oc5ccc(S(C)(=O)=O)cc5)ncnc43)CC2)no1
Yield: 11.7 %

Procedure:
(5-Isobutyl-isoxazol-3-yl)-{4-[4-(4-methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidin-1-yl}-methanone (8 mg, 12%) was prepared as a white solid using the conditions described in Example 152, by the reaction of 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 27, 63 mg, 0.13 mmol) with 5-isobutyl-isoxazole-3-carboxylic acid (Matrix Scientific, Columbia, S.C., USA; 26 mg, 0.15 mmol) in the presence of TSTU (O—(N-succinimidyl)-1,1,3,3-tetramethyluronium tetrafluoroborate; 78 mg, 0.26 mmol) and diisopropylethylamine (0.14 mL, 0.8 mmol).
Reaction SMILES: [CH2:1]([CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18]C)[CH:16]=2)[O:11][CH2:10][CH:9]1[NH:20][C:21](=[O:25])[O:22][CH2:23][CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH2:1]([CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=2)[O:11][CH2:10][CH:9]1[NH:20][C:21](=[O:25])[O:22][CH2:23][CH3:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)NC1COc2ccc(OC)cc2C1Cc1ccccc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)NC1COc2ccc(O)cc2C1Cc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3.19 g (9.3 mmol) of ethyl 4-benzyl-6-methoxychroman-3-ylcarbamate under nitrogen atmosphere were dissolved in 90 ml of methylene dichloride. At 0° C. 28.0 ml (28.0 mmol, 1 M in methylene dichloride) of boron tribromide were added. The reaction mixture was stirred at 0° C. for 2 hours. At 0° C. saturated sodium hydrogencarbonate solution was added to the reaction mixture. The phases were separated and the aqueous phase was extracted with methylene dichloride. The combined organic layers were washed with brine, dried over MgSO4 and the solvent was evaporated to yield 3.0 g (9.2 mmol, 99) of the crude product.
Reaction SMILES: C(OC([N:8]([C:16]1[C:21]([C:22]#[CH:23])=[N:20][C:19]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([C:30]([C:33]#[N:34])([CH3:32])[CH3:31])[CH:25]=2)=[CH:18][N:17]=1)C(=O)OC(C)(C)C)=O)(C)(C)C.[Cl:35][CH2:36][C:37]1[CH:46]=[CH:45][C:40]([C:41](Cl)=[N:42][OH:43])=[CH:39][CH:38]=1.CCN(CC)CC>>[NH2:8][C:16]1[N:17]=[CH:18][C:19]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([C:30]([CH3:31])([CH3:32])[C:33]#[N:34])[CH:25]=2)=[N:20][C:21]=1[C:22]1[O:43][N:42]=[C:41]([C:40]2[CH:45]=[CH:46][C:37]([CH2:36][Cl:35])=[CH:38][CH:39]=2)[CH:23]=1
Reactant: ON=C(Cl)c1ccc(CCl)cc1
Reactant: C#Cc1nc(-c2ccnc(C(C)(C)C#N)c2)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Product: CC(C)(C#N)c1cc(-c2cnc(N)c(-c3cc(-c4ccc(CCl)cc4)no3)n2)ccn1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A mixture of tert-butyl N-tert-butoxycarbonyl-N-[5-[2-(1-cyano-1-methyl-ethyl)-4-pyridyl]-3-ethynyl-pyrazin-2-yl]carbamate (300 mg, 0.6472 mmol), 4-(chloromethyl)-N-hydroxybenzimidoyl chloride (158.5 mg, 0.7766 mmol) and Et3N (98.24 mg, 135.3 μL, 0.9708 mmol) were stirred at ambient temperature for 60 hours. A further aliquot of 4-(chloromethyl)-N-hydroxybenzimidoyl chloride (50.0 mg, 0.2450 mmol) and Et3N (36.30 mg, 50.0 μL, 0.3587 mmol) were added and the reaction mixture stirred at ambient temperature for a further 24 hours. The reaction mixture was partitioned between DCM and saturated aqueous NaHCO3 and the layers separated. The aquoeus layer was extracted with DCM (×3) and the combined organic extracts dried (MgSO4), filtered and concentrated in vacuo. The residue was dissolved in DCM (10 mL) and TFA (2 mL) was added. The reaction mixture was stirred at ambient temperature for 1 hour then concentrated in vacuo. The residue was partitioned between DCM and saturated aqueous NaHCO3 and the layers separated. The aquoeus layer was extracted with DCM (×3) and the combined organic extracts dried (MgSO4), filtered and concentrated in vacuo yielding 2-(4-(5-amino-6-(3-(4-(chloromethyl)phenyl)isoxazol-5-yl)pyrazin-2-yl)pyridin-2-yl)-2-methylpropanenitrile as a yellow solid that was used without further purification
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[C:13]([OH:15])=[O:14].OS(O)(=O)=O.[CH3:21]O>>[OH:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[C:13]([O:15][CH3:21])=[O:14]
Reactant: CO
Reactant: O=C(O)c1[nH]c2ccccc2c1CCO
Agent: O=S(=O)(O)O
Product: COC(=O)c1[nH]c2ccccc2c1CCO

Procedure:
To a solution of 3-(2-hydroxyethyl)-1H-indole-2-carboxylic acid (5.589 g, 26.1 mmol) in methanol (75 mL) was added concentrated H2SO4 (3 mL), and the mixture was refluxed overnight. The solvent was removed under a reduced pressure and the residual oil was dissolved in EtOAc. The organic solution was washed with a saturated aqueous NaHCO3 solution, dried over Na2SO4, and concentrated to give 5.670 g of methyl 3-(2-hydroxyethyl)-1H-indole-2-carboxylate as an oil. This material was used for the next reaction without further purification: 1H NMR (CDCl3) δ 2.21 (brs, 1H), 3.40 (t, J=6.5 Hz, 2H), 3.88 (s, 3H), 3.94 (t, J=6.5 Hz, 2H), 7.14 (ddd, J=1.7, 6.3, and 8.1 Hz, 1H), 7.2–7.4 (m, 2H), 7.70 (d, J=8.1 Hz, 1H), 9.07 (brs, 1H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[N:19]3[C:20]4[C:15]([CH:16]([O:21]C(C56C(C)(C)C(C)(CC5)C(=O)O6)=O)[CH2:17][CH2:18]3)=[CH:14][CH:13]=[CH:12][C:11]=4[N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[C:1]1([CH2:7][CH2:8][C:9]2[N:19]3[C:20]4[C:15]([CH:16]([OH:21])[CH2:17][CH2:18]3)=[CH:14][CH:13]=[CH:12][C:11]=4[N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC12CCC(C(=O)OC3CCn4c(CCc5ccccc5)nc5cccc3c54)(OC1=O)C2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: OC1CCn2c(CCc3ccccc3)nc3cccc1c32
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A portion (2.7 g) of the less polar fraction of 5,6-dihydro-2-(2-phenylethyl)-6-((-)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carbonyloxy)-4H-imidazo[4,5,1-ij]quinoline obtained in Step 1 was dissolved in methanol (200 mL), followed by the addition of 2N aqueous sodium hydroxide (60 mL) and subsequent stirring at room temperature for 2 hrs; thereafter, the mixture was concentrated under reduced pressure and, to the residue was added water followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, then the solvents was removed under reduced pressure, and the residue was recrystallized from acetone-hexane to yield the titled (+)-5,6-dihydro-2-(2-phenylethyl)-4H-imidazo[4,5,1-ij]quinolin-6-ol (1.2 g). The more polar fraction (3.7 g) was similarly treated to yield the titled (-)-5,6-dihydro-2-(2-phenylethyl)-4H-imidazo[4,5,1-ij]quinolin-6-ol (1.7 g).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:12]3[NH:20][C:19]4[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=4[CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:22]1([C:28](B(O)O)=[CH2:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CC([O-])=O.[K+]>CCO>[C:22]1([C:28]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[C:5]([C:12]4[NH:20][C:19]5[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=5[CH:13]=4)[CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[CH2:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C=C(B(O)O)c1ccccc1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCO
Product: C=C(c1ccccc1)c1ccc2cccc(-c3cc4c([nH]3)CCNC4=O)c2n1
Temperature: 80 °C
Reaction time: 23 h
Yield: 77.1 %

Procedure:
A mixture of 2-(2-chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 200 mg, 0.672 mmol), (1-phenylvinyl)boronic acid (Aldrich; 139.1 mg, 0.941 mmol), PdCl2(APhos)2 (23.8 mg, 0.034 mmol), and KOAc (131.8 mg, 1.34 mmol) in EtOH (3.4 mL) was stirred under argon in a sealed tube at 80° C. for 23 h. The mixture was concentrated onto silica gel, and chromatographically purified (silica gel, 0-10% MeOH/DCM) to provide 2-(2-(1-phenylvinyl)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (189.2 mg, 0.518 mmol, 77% yield) as an orange solid: 1H NMR (400 MHz, CDCl3) δ ppm 12.05 (1H, br. s.), 8.23 (1H, d, J=8.8 Hz), 8.08 (1H, d, J=7.4 Hz), 7.81 (1H, d, J=8.6 Hz), 7.64 (1H, d, J=8.0 Hz), 7.54 (1H, d, J=7.8 Hz), 7.46-7.52 (2H, m), 7.41-7.46 (3H, m), 7.14 (1H, s), 6.01 (1H, s), 5.85 (1H, s), 5.47 (1H, br. s.), 3.47 (2H, td, J=6.9, 1.9 Hz), 2.33 (2H, t, J=6.8 Hz). m/z (ESI, +ve) 366.2 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH:13]1([NH2:22])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1>>[CH:13]1([NH:22][C:10]([C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][O:3][C:4]=3[CH:9]=2)=[O:12])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1
Reactant: NC1CCc2ccccc21
Reactant: O=C(O)c1ccc2c(c1)OCO2
Product: O=C(NC1CCc2ccccc21)c1ccc2c(c1)OCO2

Procedure:
Prepared in a similar manner to example 4 using benzo[1,3]dioxole-5-carboxylic acid and indan-1-ylamine. MS (M+H, 282.2).