Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].C[O:4][C:5]1[CH:14]=[C:13]2[C:8]([C@@H:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([CH2:41][CH2:42][CH2:43][C:44]([F:50])([F:49])[C:45]([F:48])([F:47])[F:46])(C(OC)=O)[C:33]([O:35]C)=[O:34])[C@:10]([C:16]3[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=3)([CH3:15])[CH2:11][S:12]2)=[CH:7][CH:6]=1.Cl.B(Br)(Br)Br>O.C(O)C.ClCCl>[OH:4][C:5]1[CH:14]=[C:13]2[C:8]([C@@H:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH:32]([CH2:41][CH2:42][CH2:43][C:44]([F:50])([F:49])[C:45]([F:46])([F:47])[F:48])[C:33]([OH:35])=[O:34])[C@:10]([C:16]3[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=3)([CH3:15])[CH2:11][S:12]2)=[CH:7][CH:6]=1
Reactant: COC(=O)C(CCCCCCCC[C@@H]1c2ccc(OC)cc2SC[C@]1(C)c1ccc(OC)cc1)(CCCC(F)(F)C(F)(F)F)C(=O)OC
Agent: BrB(Br)Br
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: C[C@]1(c2ccc(O)cc2)CSc2cc(O)ccc2[C@H]1CCCCCCCCC(CCCC(F)(F)C(F)(F)F)C(=O)O
Temperature: 0 °C
Yield: 56.6 %

Procedure:
A solution of potassium hydroxide (22.35 g, 398.4 mmol) in water (70 ml) was added to a solution of dimethyl 2-{8-[(3S,4S)-7-methoxy-3-(4-methoxyphenyl)-3-methylthiochroman-4-yl]octyl}-2-(4,4,5,5,5-pentafluoropentyl)malonate (7.0 g, 9.96 mmol) in ethanol (140 ml), followed by heating under reflux for 15 hours. The reaction mixture was adjusted to pH 4 by addition of hydrochloric acid at 0° C. and then concentrated under reduced pressure. Water was added to the residue, which was then extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. After distilling off the solvent, a solution of boron tribromide in dichloromethane (1N, 59.76 ml, 59.76 mmol) was added to a solution of the residue in dichloromethane (100 ml) at −78° C. The resulting mixture was stirred and warmed to 0° C. over 3 hours. Water was added to the reaction mixture, which was then extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After distilling off the solvent, toluene (50 ml) was added to the residue, followed by heating under reflux for 72 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate/dichloromethane=5/1/1) to give 10-[(3S,4S)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)decanoic acid (3.4 g, Yield 57.8%).
Reaction SMILES: [C:1]1([N:7]2[C:15]3[CH2:14][CH2:13][NH:12][CH2:11][C:10]=3[N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:16][C:17]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](O)=[O:20].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:16][C:17]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([N:12]1[CH2:13][CH2:14][C:15]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=[N:9][C:10]=2[CH2:11]1)=[O:20]
Reactant: c1ccc(-n2nnc3c2CCNC3)cc1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1cccc(Cl)c1Cl)N1CCc2c(nnn2-c2ccccc2)C1
Reaction time: 8 h
Yield: 75.6 %

Procedure:
A solution of 1-phenyl-4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine (17 mg, 0.085 mmol) and 2,3-dichlorobenzoic acid (18 mg, 0.093 mmol) in DCM (8 ml) was treated with Et3N (35 μL, 0.25 mmol) followed by HATU (38 mg, 0.1 mmol). The reaction was stirred overnight, then concentrated to minimum volume and purified on 16 g SiO2 with 0-3.5% NH3 in MeOH/CH2Cl2 to give 24 mg (75%) of 5-[(2,3-dichlorophenyl)carbonyl]-1-phenyl-4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine. MS (ESI): mass calcd. for C18H14Cl2N4O, 372.0; m/z found, 373.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.63-7.42 (m, 5H), 7.38-7.17 (m, 2H), 5.23-4.88 (m, 1H), 4.54 (q, J=15.7 Hz, 1H), 4.23 (dt, J=13.2, 5.5 Hz, 1.0H), 4.10-4.00 (m, 1.0H), 3.65-3.48 (m, 1H), 3.03 (t, J=5.7 Hz, 1H), 3.00-2.74 (m, 1H).
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[CH:42]=[C:43]([NH2:47])[CH:44]=[N:45][CH:46]=2)[CH2:37][CH2:36]1.Cl[C:49]1[C:58]2[C:53](=[CH:54][C:55]([F:60])=[CH:56][C:57]=2[F:59])[N:52]=[C:51]([C:61]2[CH:62]=[N:63][C:64]([O:67][CH2:68][CH3:69])=[CH:65][CH:66]=2)[C:50]=1[CH3:70].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:68]([O:67][C:64]1[N:63]=[CH:62][C:61]([C:51]2[C:50]([CH3:70])=[C:49]([NH:47][C:43]3[CH:44]=[N:45][CH:46]=[C:41]([N:38]4[CH2:39][CH2:40][O:35][CH2:36][CH2:37]4)[CH:42]=3)[C:58]3[C:53](=[CH:54][C:55]([F:60])=[CH:56][C:57]=3[F:59])[N:52]=2)=[CH:66][CH:65]=1)[CH3:69]
Reactant: CCOc1ccc(-c2nc3cc(F)cc(F)c3c(Cl)c2C)cn1
Reactant: Nc1cncc(N2CCOCC2)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: CCOc1ccc(-c2nc3cc(F)cc(F)c3c(Nc3cncc(N4CCOCC4)c3)c2C)cn1

Procedure:
The Buchwald coupled product was prepared according to Procedure H using dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.023 g, 0.048 mmol), 5-morpholinopyridin-3-amine (0.064 g, 0.36 mmol), 4-chloro-2-(6-ethoxypyridin-3-yl)-5,7-difluoro-3-methylquinoline (0.1 g, 0.30 mmol), Pd2dba3 (0.011 g, 0.012 mmol) and sodium tert-butoxide (0.072 g, 0.75 mmol) in toluene (3.0 mL) at 100° C. for 43 h. The crude product was purified by column chromatography on silica gel (0 to 100% DCM/MeOH/ammonium hydroxide (90/9/1)) to give the desired product 2-(6-ethoxypyridin-3-yl)-5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)quinolin-4-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.47 (1H, d, J=1.4 Hz), 8.45-8.47 (1H, dd, J=2.4, 0.6 Hz), 8.02 (1H, dd, J=8.5, 2.4 Hz), 7.80 (1H, d, J=2.5 Hz), 7.62 (1H, m), 7.59 (1H, d, J=2.2 Hz), 7.39-7.46 (1H, m), 6.92-6.96 (1H, d, J=8.4, 0.6 Hz), 6.57 (1H, t, J=2.4 Hz), 4.39 (2H, q, J=7.0 Hz), 3.67-3.76 (4H, m), 3.05-3.13 (4H, m), 2.16 (3H, s), 1.36 (3H, t, J=7.0 Hz). Mass Spectrum (ESI) m/e=478.3 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:13]3[NH:12][C@H:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C@@H:10]([O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[C:9](=[O:27])[C:8]=3[CH:7]=[CH:6][N:5]2[CH:28]=1.[C:29](Cl)(=[O:31])[CH3:30].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:29]([N:12]1[C:13]2[C:4]3=[N:3][C:2]([CH3:1])=[CH:28][N:5]3[CH:6]=[CH:7][C:8]=2[C:9](=[O:27])[C@H:10]([O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:23])[CH3:24])[C@H:11]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)Cl
Reactant: Cc1cn2ccc3c(c2n1)N[C@H](c1ccccc1)[C@@H](OC(=O)C(C)(C)C)C3=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(=O)N1c2c(ccn3cc(C)nc23)C(=O)[C@H](OC(=O)C(C)(C)C)[C@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a of 0° C. cooled solution of 7.00 g (18.5 mmol) (8R,9R)-2-methyl-9-phenyl-8-pivaloyloxy-7.8.9.10-tetrahydroimidazo[1.2-h][1.7]naphthyridin-7-one in toluene (70 ml) is added 4.10 ml (55.5 mmol) acetyl chloride and 7.70 ml (55.5 mmol) triethylamine and the reaction mixture is stirred for 1 h at 0° C. Afterwards further 4.10 ml (55.5 mmol) acetyl chloride and 7.70 ml (55.5 mmol) triethylamine are added to the reaction mixture and it is warmed up to 25° C. and stirred at this temperature for 1 h. Subsequently the reaction is quenched by adding of saturated aqueous ammonium chloride solution. This mixture is extracted twice with dichloromethane. The combined organic layers are washed with brine, dried over sodium sulphate and evaporated in vacuo. The crude product is crystallised from diethyl ether to provide 5.4 g (12.7 mmol/70%) of the title compound as a colourless solid with a melting point of 168–169° C. (diethyl ether).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[C:5]([NH:7][C:8]1[CH:9]=[C:10]([NH:15][C:16]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[N:24]=[CH:23][CH:22]=[CH:21]3)=[O:17])[CH:11]=[CH:12][C:13]=1[CH3:14])=[O:6].[O:31]1[CH2:36][CH2:35][N:34]([CH2:37][CH2:38]Cl)[CH2:33][CH2:32]1>>[O:31]1[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][O:1][C:2]2[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=2)[C:5]([NH:7][C:8]2[CH:9]=[C:10]([NH:15][C:16]([C:18]3[CH:19]=[C:20]4[C:25](=[CH:26][CH:27]=3)[N:24]=[CH:23][CH:22]=[CH:21]4)=[O:17])[CH:11]=[CH:12][C:13]=2[CH3:14])=[O:6])[CH2:33][CH2:32]1
Reactant: Cc1ccc(NC(=O)c2ccc3ncccc3c2)cc1NC(=O)c1cccc(O)c1
Reactant: ClCCN1CCOCC1
Product: Cc1ccc(NC(=O)c2ccc3ncccc3c2)cc1NC(=O)c1cccc(OCCN2CCOCC2)c1
Temperature: 40 °C
Yield: 41 %

Procedure:
Using an analogous procedure to that described in Example 7 except that the reaction mixture was heated to 70° C. rather than 40° C., N-[3-(3-hydroxybenzamido)-4-methylphenyl]quinoline-6-carboxamide was reacted with 2-morpholinoethyl chloride to give the title compound in 41% yield, m.p. 216-217° C.; NMR Spectrum: (DMSOd6) 2.21 (s, 3H), 2.47 (m, 4H), 2.73 (t, 2H), 3.59 (t, 4H), 4.18 (t, 4H), 7.17 (m, 1H), 7.24 (d, 1H), 7.42 (t, 1H), 7.54 (s, 2H), 7,61 (m, 2H), 7.87 (s, 1H), 8.15 (d, 1H), 8.23 (m, 1H), 8.52 (m, 1H), 8.61 (s, 1H), 9.0 (d, 1H), 9.9 (s, 1H), 10.49 (s, 1H); Mass Spectrum: M+H+ 511.
Reaction SMILES: [CH:1]1([CH2:4][NH2:5])[CH2:3][CH2:2]1.O=C1CCC(=O)N1[O:13][C:14](=O)[C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22](=[O:31])[N:23]([CH3:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:17][CH:16]=1>>[CH:1]1([CH2:4][NH:5][C:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22](=[O:31])[N:23]([CH3:30])[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:17][CH:16]=2)=[O:13])[CH2:3][CH2:2]1
Reactant: NCC1CC1
Reactant: CN(C(=O)Oc1ccc(C(=O)ON2C(=O)CCC2=O)cc1)c1ccccc1
Product: CN(C(=O)Oc1ccc(C(=O)NCC2CC2)cc1)c1ccccc1

Procedure:
The title product was prepared from cyclopropylmethylamine and 4-(methyl-phenyl-carbamoyloxy)-benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester. The crude product was used without further purification (100%, semi-crystal oil). HPLC-MS m/z=325.1 (M+1), Rt: 3.40 min.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([CH3:23])[CH2:11][N:12]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][CH2:14][C:13]1=[O:22])(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:8][CH2:9][C@@H:10]([CH3:23])[CH2:11][N:12]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][CH2:14][C:13]1=[O:22]
Reactant: C[C@H](CO[Si](C)(C)C(C)(C)C)CN1C(=O)COc2ccccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@H](CO)CN1C(=O)COc2ccccc21
Yield: 97.3 %

Procedure:
The compound (S)-4-[3-(tert-Butyldimethylsilanyloxy)-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one (108LM24-21) (3.92 g, 11.7 mmol) and TBAF (4.78 g, 15.2 mmol) in THF (30 mL) were reacted according to GP3 to give the title compound (108LM26-23) (2.52 g, 98%). 1H NMR (CDCl3) δ 7.05-6.95 (m, 4H), 4.63 (s, CH2), 4.23 (dd, J=10.3 Hz, J=13.9 Hz, 1H), 3.56 (dd, J=4.8 Hz, J=13.9 Hz, 1H), 3.52-3.49 (m, 1H), 3.46-3.38 (m, 1H), 2.92-2.85 (m, 1H), 2.09-1.97 (m, 1H), 1.06 (d, J=7.3 Hz, CH3).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=1.Cl.N1C=CC=CC=1>>[N+:13]([C:5]1[CH:4]=[C:3]([OH:2])[CH:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=1)([O-:15])=[O:14]
Reactant: COc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Agent: Cl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cc(O)cc(C(F)(F)F)c1
Temperature: 210 °C

Procedure:
1-Methoxy-3-nitro-5-trifluoromethyl-benzene (10 g, Aldrich) and pyridine-HCl (41.8 g, Aldrich) were mixed together and heated neat at 210° C. in an open flask. After 2.5 h the mixture was cooled to RT and partitioned between 1N HCl and EtOAc. The EtOAc fraction was washed with 1N HCl (4×), brine (1×), dried with Na2SO4, filtered and concentrated in vacuo to form 3-nitro-5-trifluoromethyl-phenol as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].[N:12]([O-])=O.[Na+].S(=O)(=O)(O)N.O.O.[Sn](Cl)(Cl)(Cl)Cl.[OH-].[Na+]>Cl.O.C1C([O-])=C(Cl)C(Cl)=C(Cl)C=1.C1C([O-])=C(Cl)C(Cl)=C(Cl)C=1.[Zn+2]>[NH:1]([C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8])[NH2:12]
Reactant: O=N[O-]
Reactant: NC(=O)c1cc(N)ccc1Cl
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: NS(=O)(=O)O
Solvent: O
Product: NNc1ccc(Cl)c(C(N)=O)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 29.4 %

Procedure:
Title compound 9B, 5-amino-2-chloro-benzamide (1.05 g, 6.13 mmol) was dissolved in a concentrated aqueous solution of HCl (10 ml) and cooled to 0° C. To this a cooled solution of NaNO2 (0.54 g, 1.5 eq, 9.19 mmol) in water (4 ml) was added over 15 minutes whilst maintaining the temperature below 10° C. The reaction was then cooled to 0° C. and stirred for 1 hour. To the reaction mixture sulfamic acid (0.3 g, 0.5 eq, 3.06 mmol) was added portion wise over a 20 minute period, a solution of tin chloride dihydrate (4.15 g, 3.0 eq, 18.4 mmol) in a concentrated aqueous HCl solution (4 ml) was then added drop wise over a 20 minute period whilst maintaining the temperature below 15° C. The reaction mixture then stirred at 0° C. for 2 hours then basified to pH 14 with 5M NaOH (aq) whilst maintaining the reaction temperature below 30° C. The reaction mixture was then rapidly extracted with ethyl acetate (2×50 ml), the organics combined, washed with brine, dried over Na2SO4 and solvent removed in vacuo to give the title compound (0.33 g, 1.8 mmol, 29%). LC-MS: [M+H]+=186, Rt=0.53 min, 96% purity.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1>C(Cl)(Cl)Cl>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[NH:11][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Nc1ccccn1
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1cccnc1Nc1ccccn1
Temperature: 150 °C
Reaction time: 2 h
Yield: 36 %

Procedure:
31.6 g of 2-chloro-3-nitro-pyridine and 56.5 g of 2-amino-pyridine were well mixed in a mortar and the mixture was slowly heated on an oil bath to the melting point. At 150° C. a lively reaction started and the temperature spontaneously rose to 160° C. The heating was suspended until the isothermic reaction ceased and heating at 150° C. was continued for 2 hours. The mixture was cooled and the fused mass was taken up in 500 ml of chloroform. The mixture was concentrated and was chromatographed over silica gel. Elution with about 3 liters of a 1-0.75-1.2 chloroform-benzene-ether mixture yielded unreacted 2-chloro-3-nitro-pyridine and evaporation of the eluent yielded 20 g of raw product which was crystallized from 95% ethanol to obtain 15.5 g (36% yield) of 2-(2-pyridylamino)-3-nitro-pyridine in the form of orange-yellow needles melting at 121°-123° C. The product was soluble in 2 N hydrochloric acid.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:17]=[CH:16][C:8]([CH:9]([OH:15])[C@@H:10]([C:12]([OH:14])=[O:13])[NH2:11])=[CH:7][CH:6]=1.[CH3:18]OS(OC)(=O)=O.Cl>[OH-].[Na+]>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH:9]([OH:15])[C@@H:10]([C:12]([OH:14])=[O:13])[NH:11][CH3:18])=[CH:16][CH:17]=1
Reactant: COS(=O)(=O)OC
Reactant: COCOc1ccc(C(O)[C@H](N)C(=O)O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CN[C@H](C(=O)O)C(O)c1ccc(OCOC)cc1
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 23.4 %

Procedure:
To a solution of O-methoxymethyl-β-hydroxytyrosine (21.0 g) in 1N-sodium hydroxide (250 ml) was added dimethylsulfate (16.5 g). After stirring for 20 min. at 90° C., the solution was acidified with diluted hydrochloric acid in ice bath. The acidic solution was washed with diethyl ether and adjusted to pH 6.0 with 1N-sodium hydroxide. After evaporation, the solid was collected by filtration to give O-methoxymethyl-N-methyl-β-hydroxytyrosine (5.2 g).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]3=[CH:9][CH:10]=2)[O:5][C:4](=[O:16])[CH:3]=1.[CH2:17](C1C=CC=C2C=1C=CC=C2O)[CH3:18]>>[OH:1][C:2]1[C:11]2[C:6](=[C:7]3[CH:15]=[CH:14][CH:13]=[C:12]([CH2:17][CH3:18])[C:8]3=[CH:9][CH:10]=2)[O:5][C:4](=[O:16])[CH:3]=1
Reactant: CCc1cccc2c(O)cccc12
Reactant: O=c1cc(O)c2ccc3ccccc3c2o1
Product: CCc1cccc2c1ccc1c(O)cc(=O)oc12
Yield: 25 %

Procedure:
The procedure was identical to that used for the preparation of 10a: 25% yield (starting with 5-ethyl-1-naphthol 9c); 1H NMR (DMSO) δ 1.31 (3H, t, J=7.2 Hz, CH3CH2—), 3.12 (2H, q, J=7.2 Hz, CH3CH2—), 5.69 (1H, s, H-3), 7.61 (2H, m, H-8, 9), 7.85 (1H, d, J=8.7 Hz, H-5), 7.99 (1H, d, J=8.7 Hz, H-6), 8.25 (1H, d, J=7.8 Hz, H-10).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].C(N(CC)CC)C.[C:16](Cl)(=[O:19])[CH:17]=[CH2:18]>C(Cl)(Cl)Cl>[C:16]([O:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8])(=[O:19])[CH:17]=[CH2:18]
Reactant: O=C1CCC(=O)N1O
Reactant: C=CC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C=CC(=O)ON1C(=O)CCC1=O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of N-hydroxysuccinimide (NAS) (1.15 g, 10.0 mmol) and triethylamine (1.53 ml) in chloroform (15 ml), acryloyl chloride (0.99 g, 11.0 mmol), cooled at 0° C., was added dropwise, under mechanical stirring, over a period of 30-min. After an additional stirring of 20 min at 0° C., the solution was washed with ice-cold water (8 ml for 2 times), dried on Na2SO4 and then filtered. 2,5-Di-tert-butylhydroquinone (0.5 mg) (polymerization inhibitor) was added to the chloroform solution, which was concentrated to a volume of 3 ml, using a rotary evaporator and filtered. Ethyl acetate (3 ml) and n-hexane (2 ml) were slowly added while stirring to the chloroform solution, which was left at 0° C. for several hours. The precipitate, a colorless solid, was separated by filtration and washed with an ice-cold solution of ethyl acetate/n-hexane (4/1) and then washed only with n-hexane.
Reaction SMILES: [NH2:1][N:2]=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][CH:12]([NH:15][C:16]([NH:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[O:17])[C:11]2=[O:24])=[CH:6][CH:5]=1.F[C:26](F)(F)[C:27]([O-])=O>>[NH2:1][N:2]=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][CH:12]([NH:15][C:16]([NH:18][C@H:19]([CH:26]=[CH2:27])[CH2:20][C:21]([OH:23])=[O:22])=[O:17])[C:11]2=[O:24])=[CH:6][CH:5]=1
Reactant: O=C([O-])C(F)(F)F
Reactant: NN=Cc1ccc(N2CCC(NC(=O)NCCC(=O)O)C2=O)cc1
Product: C=C[C@H](CC(=O)O)NC(=O)NC1CCN(c2ccc(C=NN)cc2)C1=O

Procedure:
3-[[[[1-[4-(aminoiminomethyl)phenyl]-2-oxo-3-pyrrolidinyl]amino]carbonyl]amino]propanoic acid, trifluoroacetate;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:9][C:8](=[O:10])[N:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]=2[CH:16]=1.[H-].[Na+].Br[CH:20]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22].[Cl-].[NH4+]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]([CH:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:8](=[O:10])[N:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]=2[CH:16]=1
Reactant: CCOC(=O)n1c(=O)[nH]c2ccc(Cl)cc21
Reactant: CCOC(=O)C(Br)c1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(c1ccccc1)n1c(=O)n(C(=O)OCC)c2cc(Cl)ccc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1.38 g (5.73 mmol) of ethyl 6-chloro-2-oxo-2,3-dihydrobenzimidazole-1-carboxylate (Va) were dissolved in dry DMF (20 ml) in a heat-dried flask under a nitrogen atmosphere. 240 mg (6.02 mmol) of sodium hydride (60% suspension in mineral oil) were added while stirring at 0° C., and the reaction solution was then stirred at room temperature for 30 min. After renewed cooling in an ice bath, 1.53 g (6.31 mmol) of ethyl bromo-phenylacetate were added, and the mixture was stirred while cooling in ice for 1 h and then at room temperature for 2 h. The reaction solution was diluted with ethyl acetate, mixed with 10% aqueous ammonium chloride solution and then extracted with ethyl acetate (4×). The combined organic phases were washed with water and saturated NaCl solution, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel (mobile phase 50% ethyl acetate in heptane). Yield: 2.03 g (88%) of colorless oil
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:24])[C:7]([C:21]([OH:23])=[O:22])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[C:13]=2[F:20])=[CH:4][C:3]=1[F:25].[N+:26]([O-])([O-:28])=[O:27].[K+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:24])[C:7]([C:21]([OH:23])=[O:22])=[CH:8][N:9]2[C:12]2[CH:17]=[C:16]([N+:26]([O-:28])=[O:27])[C:15]([F:18])=[C:14]([F:19])[C:13]=2[F:20])=[CH:4][C:3]=1[F:25]
Reactant: O=C(O)c1cn(-c2ccc(F)c(F)c2F)c2nc(Cl)c(F)cc2c1=O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C(O)c1cn(-c2cc([N+](=O)[O-])c(F)c(F)c2F)c2nc(Cl)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 86.2 %

Procedure:
To 10 ml of conc. sulfuric acid was added 890 mg of 7-chloro-6-fluoro-1,4-dihydro-4-oxo-1-(2,3,4-trifluorophenyl)-1,8-naphthyridine-3-carboxylic acid. Potassium nitrate (730 mg) was added in portions to the solution, which was stirred at room temperature for 2 days. The reaction solution was allowed to cool, poured into ice water, and stirred overnight. The precipitated solid was collected by filtration, washed with water, ethanol and diethyl ether to give 860 mg of the title compound.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][C:30]1[S:34][C:33]([CH:35]=O)=[CH:32][CH:31]=1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:35][C:33]3[S:34][C:30]([CH3:29])=[CH:31][CH:32]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: Cc1ccc(C=O)s1
Product: Cc1ccc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)s1

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 5-methyl-thiophene-2-carbaldehyde. MS (ESI) m/z 489.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>[OH-].[K+]>[C:11]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)c1ccc(N)cc1
Agent: [K+]
Agent: [OH-]
Product: CC(=O)Nc1ccc(C(C)=O)cc1
Temperature: 25 °C
Yield: 67.1 %

Procedure:
To 250 ml of KOH dried pyridine was added 50 g (0.37 mole) of p-aminoacetophenone and 39.6 g of acetic anhydride. After one and a half hours of stirring at room temperature, the solution had become a thick suspension of a white solid. Filtration and drying gave 44 g of p-acetamidoacetophenone. This solid (44 g, 0.25 mole) was then suspended in 500 ml methylene chloride and treated with 44 g Br2 (0.275 mole). The reaction was allowed to proceed overnight whereupon it was stripped and dried under high vacuum, then suspended in 200 ml absolute EtOH and treated with 60 g 2-amino-2-thiazoline (0.59 mole). The reaction was stirred for 2 days then stripped, taken up in water and extracted with methylene chloride. The organic phase was washed with water, brine and was dried with sodium sulfate. Flash column chromatography with 2% MeOH/98% CH2Cl2 gave 10.2 g (0.039 mole) of the Formula (III) compound, 6-acetamidophenyl-2,3-dihydroimidazo[2,1-b]thiazole.