Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]([OH:18])=[CH:6]2.[OH-].[K+].[ClH:21].[Cl:22][CH2:23][C:24]1[C:25]([NH:35][CH3:36])=[N:26][C:27]2[C:32]([CH:33]=1)=[CH:31][C:30]([CH3:34])=[CH:29][CH:28]=2.Cl.CO>C1(C)C=CC=CC=1>[ClH:22].[ClH:21].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]([OH:18])=[C:6]2[CH2:23][C:24]1[C:25]([NH:35][CH3:36])=[N:26][C:27]2[C:32]([CH:33]=1)=[CH:31][C:30]([CH3:34])=[CH:29][CH:28]=2
Reactant: CNc1nc2ccc(C)cc2cc1CCl
Reactant: CCCc1nc(O)cc2cc(OC)c(OC)cc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Product: CCCc1nc(O)c(Cc2cc3cc(C)ccc3nc2NC)c2cc(OC)c(OC)cc12
Temperature: 160 °C
Reaction time: 1.5 h
Yield: 5 %

Procedure:
To a solution of 6,7-dimethoxy-1-propylisoquinolin-3-ol RBO 35142 (250 mg, 1 mmol) in toluene (15 mL) in a 20 mL microwave vial was added a 2 N KOH solution (1 mL, 2 mmol) following by 3-(chloromethyl)-N,6-dimethylquinolin-2-amine hydrochloride MDE 32062 (352 mg, 1.2 mmol). The reaction mixture was stirred at 160° C. for 1.5 h under microwave irradiation then cooled to RT. The volatiles were removed under vacuum and the residue was taken back in a mixture of CH2Cl2:MeOH=9:1 (50 mL). The organic layer was washed with water (3×20 mL), brine (20 mL), dried over Na2SO4, filtered and evaporated to give yellow solid that was purified by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 90:10) to give, after evaporation and drying, 6,7-dimethoxy-4-(6-methyl-2-methylamino-quinolin-3-ylmethyl)-1-propyl-isoquinolin-3-ol (26 mg). This free base was dissolved in MeOH (5 mL) and a 0.19 N HCl solution in MeOH (600 μL, 0.11 mmol) was slowly added. The reaction mixture was stirred at 4° C. for 15 min. After evaporation of the solvent and drying under vacuum pump over P2O5, 6,7-dimethoxy-4-((6-methyl-2-(methylamino)quinolin-3-yl)methyl)-1-propylisoquinolin-3-ol hydrochloride 34 was obtained as a yellow solid (28.7 mg, 5% yield).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:21]([S:22][CH2:23][CH2:24][CH3:25])=[CH:20][C:19](=[O:26])[N:18]([CH2:27][CH2:28][CH3:29])[C:17]2=[O:30])=[CH:11][CH:10]=1)#[N:2].[N-:31]=[N+:32]=[N-:33].[Na+].[Cl-].[NH4+]>CN(C)C=O.C(Cl)Cl>[CH2:27]([N:18]1[C:19](=[O:26])[CH:20]=[C:21]([S:22][CH2:23][CH2:24][CH3:25])[N:16]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]3[NH:33][N:32]=[N:31][N:2]=3)=[CH:14][CH:13]=2)[C:17]1=[O:30])[CH2:28][CH3:29]
Reactant: CCCSc1cc(=O)n(CCC)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCSc1cc(=O)n(CCC)c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 115 °C
Yield: 48.3 %

Procedure:
A mixture of 1-(2'-cyanobiphenyl-4-yl)methyl-3-propyl-6-propylthiopyrimidine-2,4(1H,3H)-dione (0.77 g), sodium azide (1.8 g) and ammonium chloride (1.48 g) in dimethylformamide (10 ml) was heated at 115° C. for 84 hours. The reaction mixture was diluted with methylene chloride and then the precipitate was filtered. The filtrate was concentrated to dryness in vacuo. The resulting residue was extracted with methylene chloride water. The organic layer was washed with water, dried, and evaporated to dryness. The resulting residue was purified by column chromatography on silica gel to give yellow amorphous powders (0.41 g, 46%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]Cl)=[O:4].[CH3:13][C:14]1[S:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[CH:15]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[CH3:1][O:2][C:3](=[O:4])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11][C:15]1[C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[S:18][C:14]=1[CH3:13]
Reactant: Cc1cc2ccccc2s1
Reactant: COC(=O)c1ccccc1SCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COC(=O)c1ccccc1Sc1c(C)sc2ccccc12
Temperature: 0 °C
Reaction time: 4 h

Procedure:
2-(Methoxycarbonyl)phenyl sulfenyl chloride (10 mL 0.29 M solution in 1,2-dichloro-ethane, 2.9 mmol) is added to a solution of 2-methyl-benzo[b]thiophene (445 mg, 3mmol) in 5 mL 1,2-dichloro-ethane. The reaction mixture is cooled to 0° C. Aluminium chloride (400 mg, 3 mmol) is added and the reaction mixture is stirred for 4 hours at room temperature. The reaction is quenched with water. The organic phase is washed with brine, dried with MgSO4 and concentrated in vacuo. The residue is purified by flash chromatography on silica gel using ethyl acetate-heptane as eluent. This furnishes 651 mg (69%) of the title compound as an oil.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1.C([O-])(O)=O.[Na+].[O:15](C(OC(C)(C)C)=O)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=O.Cl>O1CCOCC1.O>[C:19]([O:18][C:16]([N:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1)=[O:15])([CH3:22])([CH3:21])[CH3:20]
Reactant: O=C(O)C1CCNCC1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reaction time: 3 h
Yield: 90.7 %

Procedure:
A solution of isonipecotic acid (18) (2.6 g, 20 mmol) in 1,4-dioxane/H2O (3:2, 100 mL) was treated with NaHCO3 (8.4 g, 100 mmol, 20 mL H2O), followed by t-Boc2O (4.8 g, 22 mmol) at room temperature. After stirring for 3 h, the solution was acidified with 1 N HCl (50 mL), extracted with EtOAc (3×100 mL). The combined organic extracts were washed with saturated solution of NaHCO3 (50 mL), brine (50 mL), dried over MgSO4 and concentrated to give a white solid (19) (4.16 g, 91%). 1H NMR (500 MHz, CDCl3) δ 4.02 (br s, 2H), 2.86 (t, J=12.0 Hz, 2H), 2.50 (tt, J=11.0, 4.0 Hz, 1H), 1.91 (dd, J=13.0, 2.5 Hz, 2H), 1.65 (m, 2H), 1.46 (s, 9H), MS (ESI−) m/z 228.65 (M−H−).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH:5]([C:13]1[C:18]([N+:19]([O-])=O)=[CH:17][N:16]=[C:15]([NH:22][CH:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][O:31][CH3:32])[CH2:25][CH2:24]2)[N:14]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH3:2]>CO.CCOC(C)=O.[Pd]>[CH2:1]([O:3][C:4](=[O:33])[CH:5]([C:13]1[C:18]([NH2:19])=[CH:17][N:16]=[C:15]([NH:22][CH:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][O:31][CH3:32])[CH2:25][CH2:24]2)[N:14]=1)[C:6]([O:8][C:9]([CH3:11])([CH3:12])[CH3:10])=[O:7])[CH3:2]
Reactant: CCOC(=O)C(C(=O)OC(C)(C)C)c1nc(NC2CCN(CCOC)CC2)ncc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C(=O)OC(C)(C)C)c1nc(NC2CCN(CCOC)CC2)ncc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
2-{2-[1-(2-Methoxy-ethyl)-piperidin-4-ylamino]-5-nitro-pyrimidin-4-yl}-malonic acid tert-butyl ester ethyl ester (5, 733 mgs, 1.6 mmol) was dissolved in a mixture of MeOH (15 mls) and EtOAc (5 mls) to which was added 10% Pd/C (137 mgs). The reaction mixture was stirred under an atmosphere of H2 at room temperature and pressure for 2 hrs, filtered through Celite with thorough washing with MeOH and the filtrate concentrated in vacuo to give 2-{5-amino-2-[1-(2-methoxy-ethyl)-piperidin-4-ylamino]-pyrimidin-4-yl}-malonic acid tert-butyl ester ethyl ester (6, 677 mgs, 99%) which was used in the next reaction without further purification. LC/MS Calcd for [M+H]+ 438, found 438.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:18]([CH2:19][CH3:20])[N:17]=[C:16]([O:21][CH3:22])[C:15]=2[CH3:23])[CH2:10][CH2:9]1)=O)(C)(C)C.N1CCCCC1>>[CH2:19]([N:18]1[C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[C:15]([CH3:23])[C:16]([O:21][CH3:22])=[N:17]1)[CH3:20]
Reactant: CCn1nc(OC)c(C)c1C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: C1CCNCC1
Product: CCn1nc(OC)c(C)c1C1CCNCC1

Procedure:
The title compound was prepared from 1-tert-butoxycarbonyl-4-(1-ethyl-3-methoxy-4-methyl-(1H)-pyrazol-5-yl)piperidine (Step E) using a procedure analogous to that described for Piperidine 14, Step F. 1H-NMR (500 MHz) δ 1.33 (t, J=7.1, 3H), 1.70–1.73 (m, 2H), 1.86–1.96 (m, 5H), 2.67–2.72 (m, 3H), 3.19–3.21 (m, 2H), 3.89 (s, 3H), 3.99 (q, J=7.1, 2H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:19]=[C:18]([CH2:20][O:21][C:22]2[N:29]=[CH:28][CH:27]=[CH:26][C:23]=2[CH:24]=[O:25])[O:17][N:16]=1.O1CCCC1.C(O)C.[BH4-].[Na+]>O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:19]=[C:18]([CH2:20][O:21][C:22]2[C:23]([CH2:24][OH:25])=[CH:26][CH:27]=[CH:28][N:29]=2)[O:17][N:16]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1cc(COc2ncccc2C=O)on1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1cc(COc2ncccc2CO)on1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a mixture of 2-[[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-5-isoxazolyl]methoxy]nicotinaldehyde (1.64 g), tetrahydrofuran (20 ml) and ethanol (20 mL) was added sodium borohydride (80 mg) at 0° C., and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the precipitated crystals were collected by filtration and recrystallized from ethyl acetate-isopropyl ether to give colorless needle crystals (1.50 g, 91%) of [2-[[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-5-isoxazolyl]methoxy]-3-pyridyl]methanol. melting point: 136-137° C.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:37]([CH3:38])=[CH:36][C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N:23]4[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]4)[CH:18]=3)[S:16][C:12]=2[C:11]=1[C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].Cl.C([O-])(O)=O.[Na+]>O1CCOCC1>[C:1]([O:5][C@@H:6]([C:10]1[C:37]([CH3:38])=[CH:36][C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[CH:18]=3)[S:16][C:12]=2[C:11]=1[C:39]1[CH:40]=[CH:41][C:42]([Cl:45])=[CH:43][CH:44]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc2nc(-c3cccc(N4CCN(C(=O)OC(C)(C)C)CC4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cc2nc(-c3cccc(N4CCNCC4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of (S)-2-tert-butoxy-2-(2-(3-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)acetic acid (from above) in 1,4-dioxane (5 mL) was added 4M HCl in 1,4-dioxane (1 mL, 4 mmol). The reaction was stirred at rt for 6 h. A saturated solution of NaHCO3 (10 mL) was added carefully. The layers were separated, and the organic layer was dried, filtered, and concentrated in vacuo and used without further purification. LCMS-ESI+: calc'd for C30H33ClN3O3S: 550.2 (M+H+); Found: 550.2 (M+H+).
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[CH3:33][O:34][C:35]1[CH:67]=[C:66]([O:68][CH3:69])[CH:65]=[CH:64][C:36]=1[C:37]([NH:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[CH:54]=[C:53]3[C:49]([CH2:50][N:51]([C@@H:56]([CH:61]([CH3:63])[CH3:62])[C:57]([O:59]C)=[O:58])[C:52]3=[O:55])=[CH:48][CH:47]=2)=[CH:42][CH:41]=1)=[O:38]>>[CH3:33][O:34][C:35]1[CH:67]=[C:66]([O:68][CH3:69])[CH:65]=[CH:64][C:36]=1[C:37]([NH:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[CH:54]=[C:53]3[C:49]([CH2:50][N:51]([C@@H:56]([CH:61]([CH3:63])[CH3:62])[C:57]([OH:59])=[O:58])[C:52]3=[O:55])=[CH:48][CH:47]=2)=[CH:42][CH:41]=1)=[O:38]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(OC)cc4OC)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: COc1ccc(C(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)O)C(C)C)C4)cc2)c(OC)c1
Yield: 80 %

Procedure:
The compound of example 156 was prepared analogous to compound of example 98 by hydrolysis of compound of example 155.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]([Mg]Br)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[NH4+]>C1COCC1>[C:1]1([CH2:7][CH2:8][CH:9]([OH:10])[CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CCCc1ccccc1
Reactant: Br[Mg]CCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(CCc1ccccc1)CCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 43.7 %

Procedure:
To a solution of 12.8 g (95.2 mmol) of 3-phenyl-propionaldehyde in anhydrous THF (100 mL) was added dropwise at 0° C. a 1.0M solution of 100 mL (100 mmol) of phenethyl magnesium bromide in THF, and the mixture was stirred for 2 hours at 0° C. The solution was poured over saturated ammonium chloride and extracted with ether (3×150 mL). The organic phase was dried (MgSO4) and evaporated to a solid, which was subject to column chromatography (EtOAc/Hexanes, 1:9) to yield 10.0 g (22.8%) of 8a as a white solid. TLC Rf=0.5 (EtOAc/Hexanes, 1:9)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH2:10][O:11][C:12]2[N:13]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[N:14]=[C:15]([C:17](=[O:47])[NH:18][C@H:19]([C:29]([N:31]3[CH2:36][CH2:35][N:34]([C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:46])([F:45])[F:44])[CH:38]=4)[CH2:33][CH2:32]3)=[O:30])[CH2:20][CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])[CH:16]=2)=[CH:8][CH:9]=1)=[O:4]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH2:10][O:11][C:12]2[N:13]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[N:14]=[C:15]([C:17](=[O:47])[NH:18][C@H:19]([C:29]([N:31]3[CH2:32][CH2:33][N:34]([C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:46])([F:44])[F:45])[CH:38]=4)[CH2:35][CH2:36]3)=[O:30])[CH2:20][CH2:21][C:22]([OH:24])=[O:23])[CH:16]=2)=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1ccc(COc2cc(C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N3CCN(c4cccc(C(F)(F)F)c4)CC3)nn2-c2ccccc2)o1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(COc2cc(C(=O)N[C@@H](CCC(=O)O)C(=O)N3CCN(c4cccc(C(F)(F)F)c4)CC3)nn2-c2ccccc2)o1

Procedure:
The crude 5-(5-{(S)-3-tert-Butoxycarbonyl-1-[4-(3-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-propylcarbamoyl}-2-phenyl-2H-pyrazol-3-yloxymethyl)-furan-2-carboxylic acid methyl ester was dissolved in a mixture of 2 ml of DCM and 1 ml of TFA. After 2 h at RT all volatiles were removed under reduced pressure and the residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid.
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[I:16]N1C(=O)CCC1=O>FC(F)(F)C(O)=O.C(Cl)Cl>[I:16][C:2]1[CH:3]=[CH:4][C:5]2[O:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13](=[O:15])[C:14]=2[CH:1]=1
Reactant: O=C1CCC(=O)N1I
Reactant: O=c1c2ccccc2oc2ccccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1c2ccccc2oc2ccc(I)cc12
Reaction time: 1 h
Yield: 54.3 %

Procedure:
A solution of xanthen-9-one (1.96 g, 10.0 mmol; Aldrich) in trifluoroacetic acid-CH2Cl2 (1:1, 40 mL) was chilled to 0° C. and treated with N-iodosuccinimide (NIS; 2.25 g, 10.0 mmol; Lancaster), added portionwise over 1 h. After an additional 1 h at 0° C., the ice bath was removed and stirring continued for 8 h. Residual oxidant was quenched with aq. NaS2O3 and the mixture was extracted with CH2Cl2. The organic phase was washed with NaHCO3, dried over MgSO4, and the residue purified by flash chromatography (120 g silica gel, 10-100% CH2Cl2-hexanes) to afford the title compound (1.75 g, 5.43 mmol; 54% yield): 1H NMR (300 MHz, CDCl3) δ ppm 8.66 (d, J=2 Hz, 1H), 8.34 (dd, J=8, 2 Hz, 1H), 7.98 (dd, J=9, 2 Hz, 1H), 7.75 (ddd, J=9, 7, 2 Hz, 1H), 7.50 (dd, J=8, 1 Hz, 1H), 7.40 (ddd, J=8, 7, 1 Hz, 1H), 7.28 (d, J=9 Hz, 1H); MS (DCI/NH3) m/z 323 (M+H)+, 340 (M+NH4)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.S(OC)(O[CH3:17])(=O)=O.[OH-].[Na+]>CC[N+](CC1C=CC=CC=1)(CC)CC.[Cl-].C(Cl)Cl>[CH3:17][N:8]1[C:9]2[C:4](=[CH:3][C:2]([CH3:1])=[CH:11][CH:10]=2)[CH2:5][CH2:6][C:7]1=[O:12]
Reactant: Cc1ccc2c(c1)CCC(=O)N2
Reactant: COS(=O)(=O)OC
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc2c(c1)CCC(=O)N2C
Yield: 98 %

Procedure:
Analogously to Example 13(b) of 9.6 g of 6-methyl-1,2,3,4-tetrahydroquinolin-2-one are reacted with TEBA and dimethyl sulphate in methylene chloride/50% strength sodium hydroxide solution. After extraction with methylene chloride there are obtained 10.2 g (98% of theory) of 1,6-dimethyl-1,2,3,4-tetrahydroquinolin-2-one as a tough oil. The oil is hydrolysed in aqueous-basic solution analogously to Example 3(b).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].Cl[CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=2)[O:24][C:25]=1[CH3:26].ClC1C=C(C=CC=1)C=O.O=P(Cl)(Cl)Cl.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=3)[O:24][C:25]=2[CH3:26])=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: Cc1oc(-c2cccc(Cl)c2)nc1CCl
Reactant: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Agent: O=C([O-])[O-]
Agent: O=Cc1cccc(Cl)c1
Agent: [Cs+]
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)C(Cc1ccc(OCc2nc(-c3cccc(Cl)c3)oc2C)cc1C)OCC

Procedure:
In analogy to the procedure described in example 144 a], [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 129 c]) was reacted with 4-chloromethyl-2-(3-chloro-phenyl)-5-methyl-oxazole (prepared from 3-chloro-benzaldehyde and diacetyl monoxyme followed by treatment with POCl3 in analogy to the procedures described in examples 21 a] and b]) in the presence of cesium carbonate and potassium iodide to yield [rac]-3-{4-[2-(3-chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 120 f] to yield [rac]-3-{4-[2-(3-chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionic acid as white solid.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.C(N(CC)CC)C.[Cl:25][C:26]1[CH:36]=[CH:35][CH:34]=[CH:33][C:27]=1[CH:28]=[CH:29][C:30](O)=[O:31].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[Cl:25][C:26]1[CH:36]=[CH:35][CH:34]=[CH:33][C:27]=1[CH:28]=[CH:29][C:30]([NH:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:31]
Reactant: O=C(O)C=Cc1ccccc1Cl
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C=Cc1ccccc1Cl
Yield: 99.8 %

Procedure:
The same procedures as in Example 2 were carried out from methyl L-tryptophanate hydrochloride (3.0 g), triethylamine (2.0 mL), 2-chlorocinnamic acid (2.6 g), WSC.HCl (2.7 g), and methylene chloride (80 mL), to give the captioned compound (4.5 g, 99%) as an oily product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[OH:14])=[N:11][CH:10]=[CH:9][CH:8]=2)([O-])=O>O.C(N(CC)CC)C.[Pt]>[NH2:1][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[OH:14])=[N:11][CH:10]=[CH:9][CH:8]=2
Reactant: O=[N+]([O-])c1cnc2cccnc2c1O
Agent: [Pt]
Solvent: CCN(CC)CC
Solvent: O
Product: Nc1cnc2cccnc2c1O
Reaction time: 8 h
Yield: 76.3 %

Procedure:
3-Nitro[1,5]naphthyridin-4-ol (40 g, 0.2 mol) was dissolved in water (80 mL) and triethylamine (60 mL), and the solution was added to a Parr vessel. Platinum on carbon (1.0 g of 5%) was added, and the mixture was shaken under hydrogen pressure (40 psi, 2.8×105 Pa) overnight. The vessel was pressurized again, and the mixture was shaken under hydrogen pressure for four hours. The vessel was purged with nitrogen, and the reaction mixture was filtered through a layer of CELITE filter agent. The filter cake was washed with water and methanol, and the filtrate was concentrated under reduced pressure to a volume of 150 mL. A precipitate formed and was isolated by filtration to provide 24.6 g of 3-amino[1,5]naphthyridin-4-ol as a yellow solid. The filter cake was washed again with water (500 mL at 80° C.), and the filtrate was concentrated to a volume of 100 mL. A precipitate formed and was isolated by filtration to provide an additional 10.7 g of 3-amino[1,5]naphthyridin-4-ol as a yellow solid.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][C:6]=1[C:7]([N:9]1[CH2:13][CH2:12][CH:11]([O:14]S(C)(=O)=O)[CH2:10]1)=[O:8])([CH3:3])[CH3:2].[CH3:27][C:28]([C:30]1[CH:35]=[CH:34][C:33](O)=[C:32]([F:37])[CH:31]=1)=[O:29]>>[F:37][C:32]1[CH:31]=[C:30]([C:28](=[O:29])[CH3:27])[CH:35]=[CH:34][C:33]=1[O:14][CH:11]1[CH2:12][CH2:13][N:9]([C:7](=[O:8])[C:6]2[CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=[CH:22][C:5]=2[O:4][CH:1]([CH3:3])[CH3:2])[CH2:10]1
Reactant: CC(=O)c1ccc(O)c(F)c1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(OS(C)(=O)=O)C1
Product: CC(=O)c1ccc(OC2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3OC(C)C)C2)c(F)c1
Yield: 62 %

Procedure:
Prepared in analogy to Example 3(c) from rac-methanesulfonic acid 1-(2-isopropoxy-5-methanesulfonyl-benzoyl)-pyrrolidin-3-yl ester (Example 14(a)) and 3-fluoro-4-hydroxyacetophenone. The crude material was purified by reversed phase HPLC (acetonitrile/water) to yield the title compound as an amorphous white solid (yield 62%). MS (m/e): 464.0 (M+H+, 100%).
Reaction SMILES: Br[C:2]1[CH:18]=[C:17]([CH3:19])[C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[O:7])=[C:4]([O:20][CH3:21])[CH:3]=1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[Cs+].[Cs+].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>CN1CCCC1=O.O.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]>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][NH:8][C:6](=[O:7])[C:5]2[C:17]([CH3:19])=[CH:18][C:2]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:3][C:4]=2[O:20][CH3:21])=[CH:11][CH:12]=1
Reactant: C1COCCN1
Reactant: COc1cc(Br)cc(C)c1C(=O)NCc1ccc(Cl)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1cc(N2CCOCC2)cc(C)c1C(=O)NCc1ccc(Cl)cc1
Temperature: 40 °C
Reaction time: 16 h
Yield: 28.4 %

Procedure:
To a stirred solution of 4-bromo-N-[(4-chlorophenyl)-methyl]-2-methoxy-6-methyl-benzamide (0.37 g, 1.02 mmol) in N-methyl-2-pyrrolidone (1 ml) is added morpholine (0.10 ml, 1.20 mmol) at RT. The reaction mixture is degassed and flushed with argon for 30 min followed by addition of caesium carbonate (0.49 g, 1.52 mmol). The reaction mixture is heated to 40° C. At this temperature are added tris(dibenzylideneacetone)dipalladium(0) (0.009 g, 0.01 mmol) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.019 g, 0.030 mmol) and stirred at 110° C. for 16 h. After completion of the reaction (monitored by TLC), the mixture is diluted with water (20 ml) and extracted with ethyl acetate (3×20 ml). The organic layer is washed with water (20 ml), brine (20 ml), dried over anhydrous sodium sulfate and evaporated to get the crude product, which is purified by column chromatography (silica gel, 20% acetone/hexane) to yield N-[(4-chlorophenyl)-methyl]-2-methoxy-6-methyl-4-morpholin-4-yl-benzamide (example 10) (0.11 g, 0.29 mmol, 29%). [M+H]+ 375.2.