Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OS(O)(=O)=O.[CH3:6][C:7]1([CH3:18])[CH2:13][CH2:12][CH2:11][NH:10][C:9]2[CH:14]=[CH:15][CH:16]=[CH:17][C:8]1=2.[N+:19]([O-])([OH:21])=[O:20]>>[CH3:6][C:7]1([CH3:18])[CH2:13][CH2:12][CH2:11][NH:10][C:9]2[CH:14]=[C:15]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:17][C:8]1=2
Reactant: O=[N+]([O-])O
Reactant: CC1(C)CCCNc2ccccc21
Agent: O=S(=O)(O)O
Product: CC1(C)CCCNc2cc([N+](=O)[O-])ccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
H2SO4 (2.5 ml) was cooled in a brine/ice bath. 5,5-Dimethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine (1.1 g, 6.3 mmol) was added drop wise. The resulting slurry was stirred for 30 min. HNO3 (0.26 ml, 6.3 mmol) and more H2SO4 (1.5 ml) were added slowly. The reaction was stirred at 0-15° C. for 2 h, poured into ice water, extracted with EtOAc, washed with brine, dried (MgSO4), filtered and concentrated to give 5,5-Dimethyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[b]azepine.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C1(C)C=CC=CC=1.Cl[CH2:15][CH2:16][CH2:17][C:18]#[N:19]>C(Cl)(Cl)Cl>[N:1]1([CH2:15][CH2:16][CH2:17][C:18]#[N:19])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: N#CCCCCl
Reactant: C1COCCN1
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: N#CCCCN1CCOCC1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
196.9 ml morpholine, 500 ml toluol and 100 ml chloroform were stirred in a round-bottomed flask under N2 atmosphere and at 80° C. After one hour 100 g 4-chlorobutyronitrile was added dropwise within one hour. The reaction was stirred one day at 80° C. and another day at room temperature. The mixture was fritted and the residue was washed two times with ether. The filtrate was concentrated and finally distilleed under vacuum. The product fractions were collected at 95-100° C. and 1.2-0.89 Torr. The purity of the colourless oil was judged by gas chromatography and 1H-NMR.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10](=[S:27])[O:11][CH:12]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[CH2:2]2.[Cl:28][CH2:29][C:30]([C:32]1[S:33][CH:34]=[CH:35][CH:36]=1)=[O:31]>C(OCC)(=O)C>[Cl-:28].[F:26][C:22]1[CH:21]=[C:20]([CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)[O:11][C:10]([NH:9][C@@H:3]2[CH:4]3[CH2:7][CH2:8][N+:1]([CH2:29][C:30](=[O:31])[C:32]4[S:33][CH:34]=[CH:35][CH:36]=4)([CH2:6][CH2:5]3)[CH2:2]2)=[S:27])[CH:25]=[CH:24][CH:23]=1
Reactant: O=C(CCl)c1cccs1
Reactant: Fc1cccc(C(OC(=S)N[C@H]2CN3CCC2CC3)c2cccc(F)c2)c1
Solvent: CCOC(C)=O
Product: O=C(C[N+]12CCC(CC1)[C@@H](NC(=S)OC(c1cccc(F)c1)c1cccc(F)c1)C2)c1cccs1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 72 h
Yield: 24.3 %

Procedure:
To a solution of (R)—O-bis(3-fluorophenyl)methyl quinuclidin-3-ylcarbamothioate (60 mg, 0.15 mmol) in ethyl acetate (1 ml), 2-chloro-1-(thiophen-2-yl)ethanone (27.3 mg, 0.17 mmol) was added. The reaction was stirred at room temperature for 3 days. The solvent was evaporated, and the residue was purified by flash chromatography (DCM/MeOH=75/25) to obtain (R)-3-((bis(3-fluorophenyl)methoxy)carbonothioylamino)-1-(2-oxo-2-(thiophen-2-yl)ethyl)-1-azoniabicyclo[2.2.2]octane chloride (20 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[NH:14][C:13]4[CH2:15][CH2:16][NH:17][CH2:18][C:12]=4[C:7]=3[CH:8]=[N:9]2)=[CH:4][CH:3]=1.F[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1.C([O-])([O-])=[O:29].[K+].[K+].CS(C)=O>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[NH:14][C:13]([CH2:15][CH2:16][NH:17][C:20]4[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=4)=[C:12]([CH:18]=[O:29])[C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(F)cc1
Reactant: Clc1ccc2c(c1)ncc1c3c([nH]c12)CCNC3
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ccc(NCCc2[nH]c3c(cnc4cc(Cl)ccc43)c2C=O)cc1
Yield: 4.1 %

Procedure:
A solution of 1.00 g (3.88 mmol) of 3-chloro-8,9,10,11-tetrahydro-7H-pyrido[3',4':4,5]pyrrolo[3,2-c]quinoline prepared according to the method reported in J. Heterocyclic Chemistry, 25, 535 (1988), 0.47 g (3.88 mmol) of p-fluorobenzonitrile, 0.54 g (3.88 mmol) of K2CO3 and 8 ml of dimethyl sulfoxide is stirred at 80° C. for 3 days. The reaction mixture is allowed to cool and is diluted with water producing a brown precipitate which is collected by filtration and dried. The crude product is purified by flash column chromatography (5% methanol in chloroform) to yield 0.06 g (4%) of the title compound as a yellow solid: m.p. 203°-206° C.; IR (KBr) 3380, 3200, 2200, 1650, 1600 cm-1 ; NMR (DMSO-d6) δ13.1 (s, 1H), 10.1 (s, 1H), 9.5 (s, 1H), 8.4 (d, 1H), 8.1 (d, 1H), 7.8-7.7 (m, 1H), 7.4 (d, 2H), 6.9 (t, 1H), 6.7 (d, 2H), 3.6 (q, 2H), 3.4 (t, 2H); m/e 375 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][C@@:11]([CH2:17][CH3:18])([C:14]([OH:16])=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[F:21][C:22]([F:36])([F:35])[C:23]1[CH:28]=[CH:27][N:26]=[C:25]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:24]=1.C(N(CC)CC)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[CH2:13][CH2:12][C@@:11]([CH2:17][CH3:18])([C:14]([N:32]2[CH2:33][CH2:34][N:29]([C:25]3[CH:24]=[C:23]([C:22]([F:36])([F:21])[F:35])[CH:28]=[CH:27][N:26]=3)[CH2:30][CH2:31]2)=[O:16])[CH2:10]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: FC(F)(F)c1ccnc(N2CCNCC2)c1
Reactant: CC[C@@]1(C(=O)O)CC[C@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC[C@@]1(C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)CC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.8 %

Procedure:
To a solution of (1R,3S)-3-[(tert-butoxycarbonyl)amino]-1-ethylcyclopentanecarboxylic acid (0.30 g, 1.2 mmol) and 1-[4-(trifluoromethyl)pyridin-2-yl]piperazine dihydrochloride (0.39 g, 1.3 mmol) in DMF (10 mL) under N2 was added triethylamine (0.65 mL, 4.7 mmol) and O-(Benzotriazol-1-yl)-N,N,N′,N-tetramethyluronium hexafluorophosphate (0.663 g, 1.75 mmol). After being stirred at room temperature overnight, the reaction was quenched with saturated NaHCO3 and extracted with methylene chloride three times. The combined extracts were dried (MgSO4), filtered, concentrated and purified by flash column chromatography to yield the desired product (400 mg, 72.9%). MS calculated for C23H34F3N4O3: (M+H) 471.3; found 371.2 (M+H-Boc).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:21])[CH:11]=[CH:12][C:13]=1[O:14][C@@H:15]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16]1.[F:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[F:32])[C:26](Cl)=[O:27].C(N(CC)CC)C>C1COCC1>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:21][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:31]([F:32])=[C:23]([F:22])[CH:24]=2)[CH:11]=[CH:12][C:13]=1[O:14][C@@H:15]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16]1
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Reactant: CN1CC[C@@H](Oc2ccc(N)cc2-c2c(Br)cnn2C)C1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN1CC[C@@H](Oc2ccc(NC(=O)c3ccc(F)c(F)c3)cc2-c2c(Br)cnn2C)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 19.5 %

Procedure:
A mixture of 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-((R)-1-methyl-pyrrolidin-3-yloxy)-phenylamine (88 mg, 0.25 mmole), 3,4-difluoro-benzoyl chloride (40 μL, 0.30 mmole), and triethylamine (70 μL, 0.5 mmole) in 1 mL THF was stirred at room temperature for 10 minutes. The mixture was purified by HPLC to give the title compound as a white solid (TFA salt, 24 mg, 19% yield). 1H NMR (CD3OD, 400 MHz) δ 2.17-2.31 (m, 1H), 2.71-2.84 (m, 2H), 2.87-2.97 (m, 2H), 3.14-3.25 (m, 1H), 3.38-3.48 (m, 1H), 3.72-3.79 (m, 1H), 3.75 (s, 3H), 3.89-3.97 (m, 1H), 5.17-5.24 (m, 1H), 7.17-7.30 (m, 1H), 7.41-7.47 (m, 1H), 7.56-7.62 (m, 1H), 7.63-7.69 (m, 1H), 7.78-89 (m, 1H), 7.88-7.93 (m, 2H). Exact mass calculated for C22BrH21F2N4O2 490.1, found 491.5, 493.5 (MH+).
Reaction SMILES: [F:1][C:2]1[C:29]([NH:30][S:31]([CH2:34][CH2:35][CH3:36])(=[O:33])=[O:32])=[CH:28][CH:27]=[C:26]([F:37])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:15](C)=[CH:14][N:13](S(C3C=CC=CC=3)(=O)=O)[C:10]2=[N:11][CH:12]=1)=[O:5].[C:38]([O-])([O-])=O.[K+].[K+]>CO.O>[F:1][C:2]1[C:29]([NH:30][S:31]([CH2:34][CH2:35][CH3:36])(=[O:33])=[O:32])=[CH:28][CH:27]=[C:26]([F:37])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[CH:15]=[C:14]([CH3:38])[NH:13][C:10]2=[N:11][CH:12]=1)=[O:5]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3c(c2)c(C)cn3S(=O)(=O)c2ccccc2)c1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]c(C)cc3c2)c1F

Procedure:
2,6-Difluoro-N-(3-methyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide (0.654 g, 1.19 mmol) was dissolved in MeOH (9 mL) and water (3 mL). K2CO3 (3.295 g, 23.84 mmol) was added, and the reaction mixture was stirred at reflux overnight. The solution was partitioned between water and EtOAc. The organic layer was washed with water (3×), brine, dried over Na2SO4 and concentrated to a solid. The solid was triturated with DCM to provide 2,6-difluoro-N-(2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide as a solid (148 mg, 30% for three steps). 1H NMR (400 MHz, DMSO-d6) δ 11.31 (br s, 1H), 10.85 (s, 1H), 9.79 (br s, 1H), 8.31 (br s, 2H), 7.51-7.57 (m, 1H), 7.24-7.29 (m, 2H), 3.11-3.15 (m, 2H), 2.26 (br s, 3H), 1.75-1.80 (m, 2H), 0.98-1.02 (m, 3H); m/z (APCI-neg) M−1=407.2.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.C[O:18][C:19]1[C:20](=O)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1>CO>[F:16][C:2]([F:1])([F:15])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([C:25]3[C:19](=[O:18])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccccc1=O
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Solvent: CO
Product: O=c1cccccc1N1CCN(c2cccc(C(F)(F)F)c2)CC1
Yield: 122.2 %

Procedure:
A mixture of 1-(3-trifluoromethylphenyl)-piperazine (2.3 g) and 2-methoxy-2,4,6-cycloheptatrien-1-one (2.0 g) in methanol (50 ml) was refluxed for 24 hr and evaporated. The residue was chromatographed on silica gel (100 g) using ethyl acetate. The eluates were evaporated and crystallized from ethyl acetate-benzene to give the title compound (4.08 g): mp 112°-114° C.; ir (CHCl3) 1570 cm-1 ; uv max (MeOH)350 (ε=10575) and 256 nm (ε=31730); nmr (CDCl3)δ 3.5 (m, 8H) and 7.0 (m, 9H); and Anal. Calcd for C18H17F3N2O: C, 64.66% H, 5.12% N, 8.38% and Found: C, 64.84% H, 5.17% N, 8.54%.
Reaction SMILES: [CH2:1]([NH:3][CH3:4])[CH3:2].CS(O[CH2:10][CH2:11][CH2:12][N:13]([C:15]([O:17][CH:18]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]/[CH:45]=[CH:46]\[CH2:47]/[CH:48]=[CH:49]\[CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]/[CH:27]=[CH:28]\[CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:16])[CH3:14])(=O)=O>CCO.C(Cl)Cl>[CH2:1]([N:3]([CH3:4])[CH2:10][CH2:11][CH2:12][N:13]([CH3:14])[C:15](=[O:16])[O:17][CH:18]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]/[CH:45]=[CH:46]\[CH2:47]/[CH:48]=[CH:49]\[CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]/[CH:27]=[CH:28]\[CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH3:2]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCC(CCCCCCCC/C=C\C/C=C\CCCCC)OC(=O)N(C)CCCOS(C)(=O)=O
Reactant: CCNC
Solvent: CCO
Solvent: ClCCl
Product: CCCCC/C=C\C/C=C\CCCCCCCCC(CCCCCCCC/C=C\C/C=C\CCCCC)OC(=O)N(C)CCCN(C)CC
Reaction time: 50 h
Yield: 64 %

Procedure:
A solution of ethylmethylamine (2 mL) in EtOH (10 mL) was treated with 3-((((6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yloxy)carbonyl)(methyl)amino)propyl methanesulfonate (500 mg, 0.7 mmol) in CH2Cl2 (2.5 mL). The solution was stirred (50 h), concentrated and subjected to chromatography (EtOAc) to yield (6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yl (3-(ethyl(methyl)amino)propyl)(methyl)carbamate (305 mg, 64%) as a pale yellow oil. Rf 0.41 (10% CH3OH—CH2Cl2), 1H NMR (400 MHz, CDCl3, δH) 5.47-5.34 (m, 8H, C═CH×8), 4.81-4.75 (m, 1H, CHO2CNR2), 3.33 (br. s, 2H, CH2NCH3), 2.94 (br. s, 3H, CO2NCH3), 2.83 (app. t, 4H), 2.45 (q, 2H, N(CH3)CH2CH3), 2.37 (t, 2H, CH2N(CH3)CH2CH3), 2.25 (s, 3H, N(CH3)CH2CH3), 2.14-2.07 (m, 8H, CH2HC═C×4), 1.81-1.70 (m, 4H, CH2×2), 1.62-1.50 (m, 4H, CH2×2), 1.46-1.25 (m, 34H, CH2×17), 1.09 (t, 3H, CH3NCH2CH3), 0.93 (t, 6H, H3×2), FW 685.16, C45H84N2O2.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][CH3:3].[H-].[Na+].Cl[C:8]1[N:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:9]=1[C:10]([NH2:12])=[O:11]>CN(C=O)C>[Cl:17][C:15]1[CH:14]=[CH:13][C:9]([C:10]([NH2:12])=[O:11])=[C:8]([O:4][CH2:1][CH2:2][CH3:3])[N:16]=1
Reactant: NC(=O)c1ccc(Cl)nc1Cl
Reactant: CCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCOc1nc(Cl)ccc1C(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.6 %

Procedure:
To a solution of propan-1-ol (2.94 mL, 39.26 mmol) in DMF (15 mL) at 0° C. was added sodium hydride (95% in mineral oil, 0.94 g, 39.26 mmol) in portions and stirred for 1 h at room temperature. This mixture was slowly added to a solution of 2,6-dichloro-nicotinamide (5.0 g, 26.17 mmol) in DMF (25 mL) at 0° C. The reaction mixture was stirred at room temperature overnight. DMF was removed under reduced pressure, and the resulting mixture was diluted with EtOAc (60 mL), washed with water (2×20 mL) and brine (2×10 mL) solution, dried over anhydrous Na2SO4, filtered, and concentrated to give yellow oil. Purification was accomplished by flash chromatography on silica gel using 5-60% EtOAc/hexanes gradient elution to yield the title compound (3.8 g, 68%) as a transparent oil. 1H NMR (400 MHz, CDCl3) δ ppm 8.46 (d, J=8.2 Hz, 1H), 7.69 (br. s., 1H), 7.06 (d, J=8.2 Hz, 1H), 5.86 (br. s., 1H), 4.48 (t, J=6.6 Hz, 2H), 1.99-1.79 (m, 2H), 1.07 (t, J=7.4 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[Br:6][CH2:7][C:8](Br)=[O:9]>ClCCl>[Br:6][CH2:7][C:8]([NH:5][CH2:4][CH2:3][O:2][CH3:1])=[O:9]
Reactant: O=C(Br)CBr
Reactant: COCCN
Solvent: ClCCl
Product: COCCNC(=O)CBr
Temperature: 0 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
2-methoxyethylamine (3.73 g, 0.0496 mol) was dissolved in dichloromethane (250 ml) and cooled to 0° C. Bromoacetyl bromide (2.16 ml, 0.0248 mol) was added dropwise, and the reaction was stirred overnight at room temperature. The reaction mixture was then washed with water (100 ml) and saturated aqueous sodium chloride (2×100 ml). The organic layer was separated and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to afford 2-bromo-N-(2-methoxyethyl)acetamide as a white solid in 75% yield.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[CH:12]=[C:13]([O:17][CH2:18][C@@H:19]([NH:24]C(=O)OC(C)(C)C)[CH2:20][CH:21]([CH3:23])[CH3:22])[C:14]([CH3:16])=[CH:15][C:10]=2[C:9]2[C:4](=[CH:5][N:6]=[CH:7][CH:8]=2)[C:3]1=[O:32].Cl.O1CCOCC1>CO>[NH2:24][C@@H:19]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:18][O:17][C:13]1[C:14]([CH3:16])=[CH:15][C:10]2[C:9]3[C:4](=[CH:5][N:6]=[CH:7][CH:8]=3)[C:3](=[O:32])[N:2]([CH3:1])[C:11]=2[CH:12]=1
Reactant: Cc1cc2c3ccncc3c(=O)n(C)c2cc1OC[C@H](CC(C)C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cc2c3ccncc3c(=O)n(C)c2cc1OC[C@@H](N)CC(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 49.5 %

Procedure:
In a 25 mL round-bottomed flask, (S)-tert-butyl (1-((6,9-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (80 mg, 0.182 mmol) was taken in MeOH (6 mL). The reaction mixture was cooled to 0° C. and a 4M solution of HCl in 1,4-dioxane (3.75 mL, 12 mmol) was added and the mixture stirred at RT for 2 h. The MeOH was removed and the crude product was dissolved in ethyl acetate (20 mL). The ethyl acetate layer was washed with water (10 mL) and dried over sodium sulfate. Removal of the solvent gave crude product which was purified by silica-gel column (MeOH—CHCl3 mixture) to afford (S)-8-((2-amino-4-methylpentyl)oxy)-6,9-dimethylbenzo[c][2,7]naphthyridin-5(6H)-one (0.03 g, 0.09 mmol, 49% yield) as yellow solid. LC/MS (ESI) m/e 340.2 [(M+H)+, calcd for C20H26N3O2, 340.4]; LC/MS retention time (method B): tR=1.33 min. HPLC retention time (method A): tR=8.58 min; HPLC retention time (method B): tR=8.12 min. 1H NMR (400 MHz, CD3OD) δ ppm 9.51 (s, 1H), 8.79 (d, J=6.02 Hz, 1H), 8.40 (d, J=5.77 Hz, 1H), 8.33 (s, 1H), 7.10 (s, 1H), 4.50 (dd, J=10.67, 3.14 Hz, 1H), 4.36 (dd, J=10.67, 5.90 Hz, 1H), 3.77-3.87 (m, 4H), 2.46 (s, 3H), 1.79-1.92 (m, 2H), 1.66-1.77 (m, 1H), 1.08 (dd, J=6.27, 4.02 Hz, 6H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:23])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=[CH:18][C:19]=2[CH3:20])=[CH:10][CH:9]=1)[NH2:6].[Cl:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[C:26]=1[C:27](O)=[O:28].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:2][O:3][C:4](=[O:23])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=[CH:18][C:19]=2[CH3:20])=[CH:12][CH:13]=1)[NH:6][C:27]([C:26]1[C:30]([CH3:34])=[CH:31][CH:32]=[CH:33][C:25]=1[Cl:24])=[O:28]
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2c(C)ccn(C)c2=O)cc1
Reactant: Cc1cccc(Cl)c1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@H](Cc1ccc(-c2c(C)ccn(C)c2=O)cc1)NC(=O)c1c(C)cccc1Cl
Reaction time: 72 h
Yield: 26.5 %

Procedure:
To a suspension of 4-(1,4-dimethyl-2-oxo-3-pyridinyl)-L-phenylalanine methyl ester hydrochloride salt (68 mg, 0.2 mmol), 2-chloro-6-methylbenzoic acid (45 mg, 0.25 mmol) and HBTU (95 mg, 0.25 mmol) in DMF (1.5 mL) was added DIEA (174 μL, 1.0 mmol) at room temperature. The resulting solution was stirred for 72 h, the mixture was poured into water (25 mL) and was extracted with ethyl acetate (2×15 mL). The combined ethyl acetate extracts were washed successively with 0.5 N HCl (25 mL), saturated NaHCO3 solution (25 mL), brine solution (25 mL) and were dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent gave the crude product, which was purified by silica gel chromatography using a Biotage (40 s) column to afford 24 mg (27% yield) of N-[(2-chloro-6-methylphenyl)carbonyl]-4-(1,4-dimethyl-2-oxo-3-pyridinyl)-L-phenylalanine methyl ester as an amorphous white solid. ES-HRMS m/e calcd for C25H25ClN2O4 (M+Na) 475.1395. found 475.1400. b) Preparation of N-[(2-chloro-6-methylphenyl)carbonyl]-4-(1,4-dimethyl-2-oxo-3-pyridinyl)-L-phenylalanine
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]12[CH2:19][CH:12]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=31)[C:11]1[C:6]2=[CH:7][CH:8]=[CH:9][CH:10]=1.[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C(OCC)(=O)C>[N:20]1([CH2:2][CH2:3][CH2:4][C:5]23[CH2:19][CH:12]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=42)[C:11]2[C:6]3=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: ClCCCC12CC(c3ccccc31)c1ccccc12
Reactant: C1CCNCC1
Solvent: CCOC(C)=O
Product: c1ccc2c(c1)C1CC2(CCCN2CCCCC2)c2ccccc21
Temperature: 100 °C

Procedure:
A mixture of 9-γ-chloropropyl-9,10-dihydro-9,10-methanoanthracene (50 mg) and piperidine (0.1 ml) was heated at 100° C. for 3 hours. The reaction mixture was diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to give 9-γ-piperidinopropyl-9,10-dihydro-9,10-methanoanthracene, which was converted into its hydrochloride. M.P. 280°-283° C.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[CH2:14][N:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[N:16]1.B1([O-])O[O:25]1.O.O.O.O.[Na+]>C(O)(=O)C>[CH3:1][S:2]([CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[CH2:14][N:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[N:16]1)=[O:25]
Reactant: CSCCn1c(Cn2nnc3ccccc32)nc2ccccc21
Reactant: [O-]B1OO1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CS(=O)CCn1c(Cn2nnc3ccccc32)nc2ccccc21
Temperature: 50 °C
Reaction time: 8 h
Yield: 79.8 %

Procedure:
1-[1-(2-Methylthio-ethyl)-1H-benzimidazol-2-ylmethyl]-1 H-benzotriazole (100 mg, 0.31 mmol) was dissolved in acetic acid (5 mL). Sodium perborate tetrahydrate (52 mg, 0.34 mmol) was added. The reaction mixture was stirred at 50° C. under nitrogen overnight. The acetic acid was evaporated under reduced pressure. Column chromatography (EtOAc, then EtOAc:MeOH=4:1) gave 84 mg (80%) of the title compound as a pale yellow solid.
Reaction SMILES: [Cl-].[Cl:2]C1N(C)CC[NH+]1C.[OH:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCCl>[OH:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([Cl:2])=[O:16])=[CH:13][CH:12]=1
Reactant: CN1CC[NH+](C)C1Cl
Reactant: O=C(O)c1ccc(O)cc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=C(Cl)c1ccc(O)cc1
Reaction time: 24 h
Yield: 72 %

Procedure:
To 9.72 g (0.0575 mole) of 2-chloro-1,3-dimethylimidazolinium chloride, 90 ml of 1,2-dichloroethane and 6.91 g (0.05 mole) of 4-hydroxybenzoic acid were added. To the mixture, 5.06 g (0.05 mole) of triethylamine was dropwise added over 30 minutes while maintaining the temperature of the mixture at 15°-20° C. Thereafter, the reaction was carried out at 15°-20° C. for 24 hours. The reaction mass was analyzed by gas chromatography and liquid chromatography. Unreacted 4-hydroxybenzoic acid remained 1.79 g (0.013 mole). 4-Hydroxybenzoyl chloride was obtained in the yield of 72%.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([OH:9])=[C:4]([Cl:10])[CH:3]=1.C(=O)=O.CC(C)=O.C[Si](Cl)(C)C.C([O:25][B:26](OCC)[O:27]CC)C>C1COCC1>[Cl:10][C:4]1[CH:3]=[C:2]([B:26]([OH:27])[OH:25])[CH:7]=[C:6]([F:8])[C:5]=1[OH:9]
Reactant: CCOB(OCC)OCC
Reactant: Oc1c(F)cc(Br)cc1Cl
Agent: C[Si](C)(C)Cl
Agent: O=C=O
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: OB(O)c1cc(F)c(O)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
4-Bromo-2-chloro-6-fluoro-phenol (0.500 g, 2.21 mmol) is dissolved in dry THF, the reaction mixture is cooled to −78° C. (dry-ice/acetone bath) and 2.5M n-butylithium (1.06 ml, 2.66 mmol) is slowly added drop wise with stirring for 5 minutes. TMSCl (0.298 ml, 2.33 mmol) is added drop wise maintaining the temperature below −70° C. and the reaction mixture is stirred for 30 minutes. Boric acid triethyl ester is then added (0.385 ml, 2.26 mmol) followed by the second addition of n-butylitlium (1.06 ml, 2.66 mmol) maintaining the temperature below −65° C. The reaction mixture is stirred at −70° C. for 30 minutes then quenched with 5M HCl (5 ml) and allowed to warm to room temperature with stirring for 30 minutes. The reaction mixture is diluted with water and EtOAc and the organic portion is washed with 5M NaOH. The aqueous layer is acidified with 5M HCl and extracted with EtOAc, this organic portion is washed with brine, dried over MgSO4 and concentrated in vacuo to afford the title compound as an off white solid.
Reaction SMILES: [CH3:1][O-].[Na+].C([O:6][C:7]([C:9]1[C:14](C(OCC)=O)=[CH:13][CH:12]=[C:11]([CH:20]2[CH2:22][CH2:21]2)[N:10]=1)=[O:8])C.[NH2:23][C:24]([CH3:31])([CH:28]([CH3:30])[CH3:29])[C:25]([NH2:27])=[O:26]>CO.C(O)C>[CH:20]1([C:11]2[NH:10][C:9]([C:1]3[NH:23][C:24]([CH:28]([CH3:30])[CH3:29])([CH3:31])[C:25](=[O:26])[N:27]=3)([C:7]([OH:6])=[O:8])[CH:14]=[CH:13][CH:12]=2)[CH2:21][CH2:22]1
Reactant: C[O-]
Reactant: CC(C)C(C)(N)C(N)=O
Reactant: CCOC(=O)c1ccc(C2CC2)nc1C(=O)OCC
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: CC(C)C1(C)NC(C2(C(=O)O)C=CC=C(C3CC3)N2)=NC1=O
Yield: 57.9 %

Procedure:
10 g of 30% sodium methoxide in methanol are added to a solution of 6 g of 6-cyclopropylpyridine-2,3-dicarboxylic acid diethyl ester and 3 g of 2-amino-2,3-dimethylbutyramide in 100 ml of ethanol and the reaction mixture is boiled under reflux for 3 hours. It is then concentrated, the residue is dissolved in a small amount of water, and the solution is saturated with sodium chloride. The pH is then adjusted to 4 with concentrated hydrochloric acid and the solution is extracted three times with 150 ml of ethyl acetate each time. The organic phase is dried over magnesium sulphate, filtered and concentrated. The residue crystallises from ether/hexane 1:2. In this manner 4 g of 6-cyclopropyl-2-(5-isopropyl-5-methyl-4-oxoimidazolin-2-yl)-pyridinecarboxylic acid having a melting point of 118°-121° are obtained.