Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([NH:39][CH2:40][CH2:41][O:42][C@@H:43]1[O:51][C@@H:50]([CH3:52])[C@@H:48]([OH:49])[C@@H:46]([OH:47])[C@@H:44]1[OH:45])[C@@H:3]([NH:22][CH:23]([CH2:34][CH2:35][CH2:36][CH:37]=[O:38])[C:24]([O:26]CC1C=CC=CC=1)=[O:25])[CH2:4][CH2:5][C:6](=[O:21])[NH:7][CH2:8][CH2:9][O:10][C@@H:11]1[O:19][C@@H:18]([CH3:20])[C@@H:16]([OH:17])[C@@H:14]([OH:15])[C@@H:12]1[OH:13].OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O>[OH-].[OH-].[Pd+2].CO>[O:1]=[C:2]([NH:39][CH2:40][CH2:41][O:42][C@@H:43]1[O:51][C@@H:50]([CH3:52])[C@@H:48]([OH:49])[C@@H:46]([OH:47])[C@@H:44]1[OH:45])[C@@H:3]([NH:22][CH:23]([CH2:34][CH2:35][CH2:36][CH:37]=[O:38])[C:24]([OH:26])=[O:25])[CH2:4][CH2:5][C:6](=[O:21])[NH:7][CH2:8][CH2:9][O:10][C@@H:11]1[O:19][C@@H:18]([CH3:20])[C@@H:16]([OH:17])[C@@H:14]([OH:15])[C@@H:12]1[OH:13]
Reactant: C[C@@H]1O[C@@H](OCCNC(=O)CC[C@H](NC(CCCC=O)C(=O)OCc2ccccc2)C(=O)NCCO[C@@H]2O[C@@H](C)[C@@H](O)[C@@H](O)[C@@H]2O)[C@@H](O)[C@H](O)[C@@H]1O
Agent: [Pd+2]
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Agent: [OH-]
Solvent: CO
Product: C[C@@H]1O[C@@H](OCCNC(=O)CC[C@H](NC(CCCC=O)C(=O)O)C(=O)NCCO[C@@H]2O[C@@H](C)[C@@H](O)[C@@H](O)[C@@H]2O)[C@@H](O)[C@H](O)[C@@H]1O
Reaction time: 16 h

Procedure:
A suspension of benzyl {[(2S)-1,5-dioxo-1,5-bis({2-[(α-L-fucopyranosyl)oxy]ethyl}amino)pentan-2-yl]amino}-6-oxohexanoate (380 mg, 0.511 mmol) and Pearlman's catalyst (50 mg, 0.071 mmol) in methanol (30 mL) was agitated under 50 Psi of H2 at room temperature on a Parr shaker. After 16 hours, catalyst was filtered off and the filtrate was concentrated to give the title compound. 1H NMR (CD3OD) δ 4.76-4.75 (m, 2H), 4.32-4.29 (m, 1H), 3.96-3.91 (m, 2H), 3.76-3.66 (m, 5H), 3.55-3.27 (m, 9H), 2.34-2.27 (m, 6H), 2.09-2.04 (m, 1H), 1.99-1.88 (m, 1H), 1.67-1.61 (m, 4H), 1.20 (d, J=6.7, 6H).
Reaction SMILES: N(C[C@@H](C1C=CC(OCC2C=CC=CC=2)=C2C=1C=CC(=O)N2)O)=[N+]=[N-].[Si]([O:33][CH2:34][C:35]1[CH:36]=[C:37]([C@@H:42]([OH:76])[CH2:43][NH:44][CH2:45][C:46]2[CH:75]=[CH:74][C:49]([C:50]([NH:52][CH2:53][C:54]3[C:55]([NH:67][CH:68]4[CH2:73][CH2:72][O:71][CH2:70][CH2:69]4)=[C:56]4[CH:64]=[N:63][N:62]([CH2:65][CH3:66])[C:57]4=[N:58][C:59]=3[CH2:60][CH3:61])=[O:51])=[CH:48][CH:47]=2)[CH:38]=[CH:39][C:40]=1[OH:41])(C(C)(C)C)(C)C>N1C=CC=CC=1>[CH2:65]([N:62]1[C:57]2=[N:58][C:59]([CH2:60][CH3:61])=[C:54]([CH2:53][NH:52][C:50](=[O:51])[C:49]3[CH:48]=[CH:47][C:46]([CH2:45][NH:44][CH2:43][C@H:42]([OH:76])[C:37]4[CH:38]=[CH:39][C:40]([OH:41])=[C:35]([CH2:34][OH:33])[CH:36]=4)=[CH:75][CH:74]=3)[C:55]([NH:67][CH:68]3[CH2:69][CH2:70][O:71][CH2:72][CH2:73]3)=[C:56]2[CH:64]=[N:63]1)[CH3:66]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccc(CNC[C@H](O)c2ccc(O)c(CO[Si](C)(C)C(C)(C)C)c2)cc1
Agent: [N-]=[N+]=NC[C@H](O)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Solvent: c1ccncc1
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccc(CNC[C@H](O)c2ccc(O)c(CO)c2)cc1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 3, using HF Pyridine in place of TBAF and Intermediate 46 as a substrate.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][NH:8][CH:9]=1)=[O:4].[H-].[Na+].Br[CH2:13][CH2:14][O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1.[I-].[Li+]>O1CCCC1.C(OCC)(=O)C.O>[CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][N:8]([CH2:13][CH2:14][O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[CH:9]=1)=[O:4]
Reactant: BrCCOC1CCCCO1
Reactant: COC(=O)c1c[nH]cn1
Agent: [H-]
Agent: [I-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cn(CCOC2CCCCO2)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Imidazole-4-carboxylic acid methyl ester (756 mg, 6 mmol) was added slowly to a stirred suspension of sodium hydride (248 mg, 6.2 mmol) in tetrahydrofuran (10 mL) under nitrogen. The reaction mixture was stirred at room temperature for 30 minutes before being treated dropwise with 2-(2-bromoethoxy)-tetrahydro-2H-pyran (1.34 g, 6.4 mmol) and lithium iodide (40 mg, 0.3 mmol). The reaction mixture was allowed to stir at room temperature under nitrogen for 72 hours and then at reflux for 24 hours. The reaction mixture was cooled and diluted with a mixture of ethyl acetate:water 1:1 (300 mL). The aqueous layer was separated and extracted with ethyl acetate (2×50 mL). The organics were combined, dried over magnesium sulphate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol 100:0 to 98:2 to 96:4 to yield the title product.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C@@H:5]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:6][CH2:7][CH2:8][CH3:9])[OH:4].NC[C@H]([C@@H](NC(=O)OC(C)(C)C)CCCC)O.C(N(CC)C(C)C)(C)C.[N:44]1([C:50](Cl)=[O:51])[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1>ClCCl>[OH:4][C@H:3]([C@@H:5]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][NH:1][C:50]([N:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1)=[O:51]
Reactant: O=C(Cl)N1CCOCC1
Reactant: CCCC[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CN
Agent: CCCC[C@H](NC(=O)OC(C)(C)C)[C@H](O)CN
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCC[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CNC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.2 %

Procedure:
To a solution of 100 mg (0.41 mmol) of tert-butyl (1S)-1-[(1S)-2-amino-1-hydroxyethyl]pentylcarbamate & tert-butyl (1S)-1-[(1R)-2-amino-1-hydroxyethyl]pentylcarbamate and 0.070 mL (0.41 mmol) of N,N-diisopropylethylamine in 2 mL dichloromethane was added 0.050 mL (0.41 mmol) 4-morpholinecarbonyl chloride. The reaction mixture was stirred at room temperature for 18 h, diluted with dichloromethane, and washed with 1N hydrochloric acid and brine. After drying over anhydrous magnesium sulfate, the solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography eluting with ethyl acetate to afford 130 mg (89%) of tert-butyl (1S)-1-{(1S)-1-hydroxy-2-[(4-morpholinylcarbonyl)amino]ethyl}pentylcarbamate & tert-butyl (1S)-1-{(1R)-1-hydroxy-2-[(4-morpholinylcarbonyl)amino]ethyl}pentylcarbamate. 1H-NMR (300 MHz, DMSO-d6): δ 6.55–6.36 (m, 2H), 5.00–4.65 (m, 1H), 3.60-3.23 (m, 9H), 3.10–2.80 (m, 2H), 1.40–1.05 (m, 15 H), 0.87 (m, 1H); ES-LCMS m/z 382 (M+Na).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:13][C:14]([OH:16])=[O:15])[CH2:9][C:10](O)=[O:11])=[C:4]([CH3:17])[CH:3]=1>C(Cl)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:14](=[O:16])[O:15][C:10](=[O:11])[CH2:9]2)=[C:4]([CH3:17])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1C(CC(=O)O)CC(=O)O
Solvent: CC(=O)Cl
Product: Cc1cc(Cl)ccc1C1CC(=O)OC(=O)C1
Reaction time: 1 h

Procedure:
To a solution of commercial 4-chloro-2-methylbenzaldehyde (5.16 g) and ethyl acetoacetate (8.69 g) in ethanol (10 ml) piperidine (1 ml) was added with stirring at rt. The mixture was kept at rt for 4 d. The precipitate was collected by suction filtration, washed with ethanol, and dried in vacuo to give 4.5 g of a light yellow solid (the bis-adduct of acetoacetate to the benzaldehyde). The powdered solid was added in portions to 40% NaOH (50 g) with stirring. The resulting yellow slurry was stirred at reflux for 2 h. After cooling in an ice bath the mixture was acidified by portionwise addition of conc. HCl (30 ml) to give a yellow resinous precipitate. The aqueous layer was extracted with ethyl acetate, the organic layer dried (sodium sulphate), and filtered. After evaporation of the solvent a crude was obtained which was recrystallised from benzene to afford 3-(4-chloro-2-methylphenyl)glutaric acid (1.43 g). The suspension of finely divided 3-(4-chloro-2-methylphenyl)glutaric acid in acetyl chloride (4 ml) was heated to reflux with stirring for 1 h. Further acetyl chloride (15 ml) was added and reflux continued for another hour. Then the excess of acetyl chloride is removed by distillation, petrol ether (55 ml) is added to the residue, and the solution is kept in the refrigerator. The precipitate is isolated by suction filtration, washed with petrol ether, and dried in vacuo to give 3-(4-chloro-2-methylphenyl)glutaric anhydride (0.9 g) as colourless solid.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:9]([O:16][CH2:17][CH2:18][C:19]1([CH3:22])[CH2:21][O:20]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[F:23][C:24]([F:48])([F:47])[O:25][C:26]1[CH:46]=[CH:45][C:29]([CH2:30][CH2:31][CH:32]2[CH2:37][CH2:36][N:35]([C:38]3[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=3)[CH2:34][CH2:33]2)=[CH:28][CH:27]=1.O>C(O)C>[CH2:9]([O:16][CH2:17][CH2:18][C:19]([CH3:22])([OH:20])[CH2:21][O:44][C:41]1[CH:40]=[CH:39][C:38]([N:35]2[CH2:34][CH2:33][CH:32]([CH2:31][CH2:30][C:29]3[CH:28]=[CH:27][C:26]([O:25][C:24]([F:47])([F:23])[F:48])=[CH:46][CH:45]=3)[CH2:37][CH2:36]2)=[CH:43][CH:42]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Oc1ccc(N2CCC(CCc3ccc(OC(F)(F)F)cc3)CC2)cc1
Reactant: CC1(CCOCc2ccccc2)CO1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(O)(CCOCc1ccccc1)COc1ccc(N2CCC(CCc3ccc(OC(F)(F)F)cc3)CC2)cc1
Yield: 83.8 %

Procedure:
A tripotassium phosphate (0.44 g, 2.1 mmol) was added to a solution of 2-[2-(Benzyloxy)ethyl]-2-methyloxirane (1.00 g, 5.2 mmol) and 4-{4-[4-(trifluoromethoxy)phenethyl]piperidin-1-yl}phenol (2.28 g, 6.2 mmol) in ethanol (10 ml), and then the mixture was heated at reflux overnight. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→50:50) to afford the title compound as a brown powder (2.43 g, 86%).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:10](=[O:12])[CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[CH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].C(=O)([O-])[O-].[K+].[K+].[CH2:24](I)[CH3:25]>CN(C)C=O>[CH2:24]([N:5]1[C:6]2[CH2:7][CH2:8][CH2:9][C:10](=[O:12])[C:11]=2[C:2](=[O:1])[C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4]1)[CH3:25]
Reactant: CCOC(=O)c1cnc2c(c1O)C(=O)CCC2
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CC)c2c(c1=O)C(=O)CCC2
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
By the method described in Japanese Patent Application No. 24956/1978, diethyl N-(3-oxo-1-cyclohexen-1-yl)-aminomethylenemalonate was prepared from 3-amino-2-cyclohexenone and diethyl ethoxymethylenemalonate. The product was cyclized under heat to form ethyl 4-hydroxy-5-oxo-5,6,7,8-tetrahydroquinonine-3-carboxylate, followed by hydrolysis. The resulting ethyl 4-hydroxy-5-oxo-5,6,7,8-tetrahydroquinoline-3-carboxylate (2.35 g) was suspended in 80 ml of dimethylformamide. The suspension was heated to 60° C., and 1.52 g of potassium carbonate and 1.54 g of ethyl iodide were added, and the mixture was stirred at 70° C. for 30 minutes. Further, 3.46 g of ethyl iodide was added, and the mixture was stirred for 1 hour. The insoluble matter was removed by filtration, and the mother liquor was concentrated to dryness. The product was extracted with chloroform, and the chloroform was distilled off. Methylene chloride was added to the residue, and the insoluble matter was collected by filtration. There was obtained 2.4 g of the captioned product as a light yellow powder. The nuclear magnetic resonance spectrum (DMSO-d6, 60 MC, TMS) had signals at δ1.2-1.5 (6H, m), 1.8-3.3 (6H, m), 4.0-4.5 (4H, m), and 8.4 (1H, s).
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[C@@H:7]([NH:24][S:25]([C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)(=[O:27])=[O:26])[CH2:8][NH:9][C:10](=[O:23])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([O:21]C)=O)=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:39][C:40]1[NH:41][CH2:42][CH2:43][CH2:44][N:45]=1>CN(C)C=O>[C:1]([O:5][C:6](=[O:38])[C@@H:7]([NH:24][S:25]([C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)(=[O:27])=[O:26])[CH2:8][NH:9][C:10](=[O:23])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19](=[O:21])[NH:39][C:40]2[NH:45][CH2:44][CH2:43][CH2:42][N:41]=2)=[CH:13][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CCc1ccc(C(=O)NC[C@H](NS(=O)(=O)c2cccc3ccccc23)C(=O)OC(C)(C)C)cc1
Reactant: NC1=NCCCN1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(CCC(=O)NC2=NCCCN2)cc1)NS(=O)(=O)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
47 mg (0.087 mmol) of (2S)-3-(4-(2-methoxycarbonyl-ethyl)-benzoylamino)-2-(naphthalene-1-sulfonylamino)-propionic acid tert-butyl ester was dissolved in 2 ml of dimethylformamide and 86 mg (0.87 mmol) of 2-amino-1,4,5,6-tetrahydropyrimidine was added. The reaction was stirred at room temperature for 20 hours. The solvent was removed in vacuo and the residue was chromatographed on silica gel eluting with dichloromethane/methanol (1/1), followed by dichloromethane/methanol/acetic acid/water (85/15/1.5/1.5). Yield 46 mg. MS (ES+): m/e=608.3 (M+H+).
Reaction SMILES: Cl.ClC1C=CC(NN)=CC=1.BrCC1(C2C=CC(F)=CC=2)CC1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]([CH2:32][C:33]2([C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)[CH2:35][CH2:34]2)N)=[CH:26][CH:25]=1.C(OC(OCC)CCCNC)C.ClC1C=C2[C:62](=CC=1)[N:61]([CH2:65][C:66]1([C:69]3[CH:74]=[CH:73]C(F)=CC=3)CC1)C=C2CCNC.C=O.C(O)(C(F)(F)F)=O>C(#N)C.C(N(CC)CC)C>[Cl:23][C:24]1[CH:29]=[C:28]2[C:27](=[CH:26][CH:25]=1)[N:30]([CH2:32][C:33]1([C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)[CH2:35][CH2:34]1)[C:74]1[CH2:73][N:61]([CH3:62])[CH2:65][CH2:66][C:69]2=1
Reactant: NN(CC1(c2ccc(F)cc2)CC1)c1ccc(Cl)cc1
Reactant: CNCCc1cn(CC2(c3ccc(F)cc3)CC2)c2ccc(Cl)cc12
Agent: C=O
Agent: CCOC(CCCNC)OCC
Agent: Cl
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CN1CCc2c(n(CC3(c4ccc(F)cc4)CC3)c3ccc(Cl)cc23)C1

Procedure:
The title compound is prepared by following General Methods 1, 3 and 4 by) using 4-chlorophenylhydrazine hydrochloride, 1-(1-(bromomethyl)cyclopropyl)-4-fluorobenzene, and triethylamine (General Method 1), 1-(4-chlorophenyl)-1-((1-(4-fluorophenyl)cyclopropyl)methyl)hydrazine and 4,4-diethoxy-N-methylbutan-1-amine (General Method 3) and 2-(5-chloro-1-((1-(4-fluorophenyl)cyclopropyl)methyl)-1H-indol-3-yl)-N-methylethanamine, formaldehyde and TFA in acetonitrile (General Method 4).
Reaction SMILES: [NH2:1][C@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:13]=[N:14][C:15]([C:18]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[O:19])=[CH:16][CH:17]=3)[CH:10]=2)[N:5]([C:26](=[O:28])[CH3:27])[C@@H:4]([CH3:29])[CH2:3]1.Cl[C:31]1[CH:36]=[N:35][CH:34]=[CH:33][N:32]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(N(C)C)=CC=CC=2)CCCCC1.CC(C)([O-])C.[Na+]>O1CCOCC1.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]>[CH3:29][C@H:4]1[CH2:3][C@@H:2]([NH:1][C:31]2[CH:36]=[N:35][CH:34]=[CH:33][N:32]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:13]=[N:14][C:15]([C:18]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[O:19])=[CH:16][CH:17]=3)[CH:10]=2)[N:5]1[C:26](=[O:28])[CH3:27]
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)N4CCOCC4)nc3)cc2[C@H](N)C[C@@H]1C
Reactant: Clc1cnccn1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)N4CCOCC4)nc3)cc2[C@H](Nc2cnccn2)C[C@@H]1C
Temperature: 120 °C
Yield: 52 %

Procedure:
1-((2S,4R)-4-amino-2-methyl-6-(6-(morpholine-4-carbonyl)pyridin-3-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone (for a preparation, see Intermediate 56) (80 mg, 0.203 mmol), 2-chloropyrazine (0.036 mL, 0.406 mmol), 2′-(dicyclohexylphosphino)-N,N-dimethyl-[1,1′-biphenyl]-2-amine (16.0 mg, 0.041 mmol), tris(dibenzylideneacetone)dipalladium(0) (18.6 mg, 0.020 mmol) and sodium tert-butoxide (27.3 mg, 0.284 mmol) were dissolved in 1,4-dioxane (2 mL). The mixture was degassed over a period of 15 mins before being heated under microwave irradiation to 120° C. for 25 mins. The mixture was partitioned between saturated aq. sodium bicarbonate (50 mL) and DCM (3×50 mL). The organic layers were combined, dried by passing through a hydrophobic frit and concentrated in vacuo. The resulting residue was purified by MDAP (HpH) to give 1-((2S,4R)-2-methyl-6-(6-(morpholine-4-carbonyl)pyridin-3-yl)-4-(pyrazin-2-ylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone (50 mg, 0.106 mmol, 52% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([B:8]([OH:10])[OH:9])[CH:5]=[CH:6][CH:7]=1.[CH3:11][C:12]([CH2:16]O)([CH2:14]O)[CH3:13]>>[Cl:1][C:2]1[CH:3]=[C:4]([B:8]2[O:10][CH2:13][C:12]([CH3:16])([CH3:14])[CH2:11][O:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(CO)CO
Reactant: OB(O)c1cccc(Cl)c1
Product: CC1(C)COB(c2cccc(Cl)c2)OC1
Yield: 65 %

Procedure:
The title compound (65%, crystals) was prepared from 3-chlorophenylboronic acid and neopentylglycol.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([OH:13])=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=[O:7].[N+:14]([O-])([OH:16])=[O:15]>C(O)(=O)C>[OH:13][C:4]1[C:3]([O:2][CH3:1])=[C:10]([O:11][CH3:12])[C:9]([N+:14]([O-:16])=[O:15])=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(C=O)c(O)c1OC
Solvent: CC(=O)O
Product: COc1c([N+](=O)[O-])cc(C=O)c(O)c1OC
Temperature: 0 °C

Procedure:
To a solution of 3,4-dimethoxy-2-hydroxybenzaldehyde (0.5 g) in acetic acid (10 ml) was added fuming nitric acid (0.12 ml). The reaction mixture was poured into ice water, the product extracted into ethyl acetate, washed with water, dried and evaporated. The product was triturated with water and filtered. Yield: 0.15 g.
Reaction SMILES: C[N:2]([CH3:12])[CH:3]=[CH:4][C:5]([C:7]1[CH:11]=[CH:10][O:9][CH:8]=1)=O.NC1[C:18]([Br:19])=[CH:17][NH:16][N:15]=1>C(O)(=O)C>[Br:19][C:18]1[CH:17]=[N:16][N:15]2[C:5]([C:7]3[CH:11]=[CH:10][O:9][CH:8]=3)=[CH:4][CH:3]=[N:2][C:12]=12
Reactant: Nc1n[nH]cc1Br
Reactant: CN(C)C=CC(=O)c1ccoc1
Solvent: CC(=O)O
Product: Brc1cnn2c(-c3ccoc3)ccnc12

Procedure:
A mixture of 0.01 mole of 3-dimethylamino-1-(3-furyl)-2-propen-1-one and 0.01 mole of 3-amino-4-bromopyrazole in glacial acetic acid is heated at reflux temperature for 6 hours. The solvent is removed to give the product of the example.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C1(C)C=CC=CC=1.O>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:2]2[CH:11]=[N:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: Clc1cnc2ccccc2n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2cnc3ccccc3n2)CC1

Procedure:
A mixture of 9.1 mmol 2-chloroquinoxaline, 10.0 mmol piperazine-1-carboxylic acid tert-butyl ester, 22.8 mmol potassium carbonate and 2.1 mmol potassium iodide in 20 ml of toluene was refluxed overnight. The reaction mixture was cooled, poured into water and extracted 3 times with ethyl acetate. The organic phase was dried, evaporated and the title compound was crystallised from methanol. Yellowish solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C@@:5]1([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[O:10][C:9](=[O:11])[N:8]([C@H:12]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH3:13])[CH2:7][CH2:6]1.CCN(CC)CC.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>>[CH:14]1([C@@H:12]([N:8]2[CH2:7][CH2:6][C@:5]([CH2:4][CH2:3][CH2:2][NH:1][S:35]([CH3:34])(=[O:37])=[O:36])([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[O:10][C:9]2=[O:11])[CH3:13])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C[C@@H](C1CCCCC1)N1CC[C@](CCCN)(c2ccc(F)cc2)OC1=O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: C[C@@H](C1CCCCC1)N1CC[C@](CCCNS(C)(=O)=O)(c2ccc(F)cc2)OC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.1 %

Procedure:
To a solution of (R)-6-(3-aminopropyl)-3-((S)-1-cyclohexylethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (30 mg, 0.10 mmol) was added Et3N (40 mg, 0.4 mmol) and MsCl (30 mg, 0.24 mmol) at 0° C. The reaction solution was stirred at rt for 2 h. The reaction was quenched by H2O and the mixture was extracted with CH2Cl2. The organic phase was concentrated to give the crude product, which was purified by preparative TLC to give N-(3-((R)-3-((S)-1-cyclohexylethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)propyl)methanesulfonamide (11.5 mg, 33%). LC-MS Method 2 tR=1.397 min, m/z=440.9; 1H NMR (CDCl3) 1.04 (d, 6H), 1.13-1.34 (m, 2H), 1.43-1.68 (m, 6H), 1.73-1.98 (m, 3H), 2.03-2.14 (m, 1H), 2.29 (d, 1H), 2.52 (tt, 1H), 2.85 (s, 3H), 2.92-3.08 (m, 3H), 3.68 (m, 1H), 3.88-3.98 (m, 1H), 4.33 (t, 1H), 7.01 (t, 2H), 7.22 (m, 2H).
Reaction SMILES: C([N:8]1[C:20]2[C:19]([CH3:21])=[C:18]3[N:22](C(OC(C)(C)C)=O)[C:23]4[CH:24]=[CH:25][C:26]([F:29])=[CH:27][C:28]=4[C:17]3=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([F:37])[CH:13]=2)(OC(C)(C)C)=O.FC(F)(F)C(O)=O>ClCCl>[F:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:18]1[C:19]([CH3:21])=[C:20]3[NH:8][C:9]4[CH:10]=[CH:11][C:12]([F:37])=[CH:13][C:14]=4[C:15]3=[CH:16][C:17]2=1
Reactant: Cc1c2c(cc3c4cc(F)ccc4n(C(=O)OC(C)(C)C)c13)c1cc(F)ccc1n2C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c2[nH]c3ccc(F)cc3c2cc2c1[nH]c1ccc(F)cc12
Yield: 89 %

Procedure:
A solution of 5,7-diBOC-2,10-difluoro-6-methylindolo[2,3-b]carbazole (4.45 g, 8.8 mmol) was stirred with a solution of 20% trifluoroacetic acid in dichloromethane (100 mL) at room temperature for two hours. The solvents were evaporated and the residue dissolved in ethyl acetate (200 mL). This was washed with saturated sodium bicarbonate solution (100 mL) and dried over magnesium sulfate. After evaporation of the solvent, the residue was chromatographed on silica gel, eluting with a gradient of dichloromethane and hexane (50% dichloromethane to 100% dichloromethane) to give 2,10-difluoro-6-methyl-5,7-dihydro-indolo[2,3-b]carbazole (2.4 g, 90% yield). 1H NMR (300 MHz) (DMSO-d6) δ 11.05 (2H, s, —NH), 8.67 (1H, s, arom), 7.89 (2H, dd, J=9.5, 2.6 Hz, arom), 7.43 (2H, dd, J=8.9, 4.4 Hz, arom), 7.17 ppm (2H, dt, J=9.5, 2.6 Hz, arom) and 2.70 ppm (3H, s, —CH3).
Reaction SMILES: CC1(C)C[O:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15](=O)[CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:3]1.OS(O)(=O)=O.O.[NH2:34]N.[OH-].[Na+]>C(O)(=O)C.O.C(O)C>[CH3:14][O:13][C:10]1[CH:9]=[C:8]2[C:7](=[CH:12][CH:11]=1)[C:4](=[O:5])[NH:3][N:34]=[C:15]2[CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NN
Reactant: COc1ccc(C2=NC(C)(C)CO2)c(C(=O)CCCCc2ccccc2)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: COc1ccc2c(=O)[nH]nc(CCCCc3ccccc3)c2c1
Reaction time: 5 h
Yield: 29.2 %

Procedure:
A solution of 1-[2-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-5-methoxy-phenyl]-5-phenyl-pentan-1-one (0.37 g, 1 mmole), prepared as described in example 18, in 5 ml of a mixture of water (0.5 ml), ethanol (5 ml), concentrated H2SO4 (0.4 ml) up to 10 ml with ethanol, was stirred at reflux for 20 hours, then concentrated to small volume, taken up in water, extracted with ethyl ether and the ethereal phase was washed with water, anhydrified and brought to dryness. The resultant oil was dissolved in acetic acid (10 ml) and dropwise added, under N2, with a solution of hydrazine monohydrate (0.45 ml, 3 mmoles) in acetic acid (2 ml). The mixture was stirred for 3 hours at 80° C., then overnight at room temperature and at 80° C. for further 5 hours, cooled, almost brought to dryness, taken up in water, basified with NaOH, extracted more times with ethyl acetate. The organic phases were washed with water/NaCl, anhydrified and concentrated. The residue was flash chromatographed (eluent: petroleum/ethyl acetate 6:4) to give 0.09 g of the title compound (yield: 29%).