Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:3]2[O:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)[C:4]=2[C:5]([NH2:8])=[N:6][CH:7]=1.C(OC(OCC)/C=C/B1OC(C)(C)[C:33]([CH3:39])([CH3:38])O1)C.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[CH2:5]([N:6]([CH2:7][CH3:2])[CH2:39]/[CH:33]=[CH:38]/[C:2]1[C:3]2[O:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)[C:4]=2[C:5]([NH2:8])=[N:6][CH:7]=1)[CH3:4]
Reactant: CCOC(/C=C/B1OC(C)(C)C(C)(C)O1)OCC
Reactant: Nc1ncc(I)c2onc(-c3ccc(Oc4ccccc4)cc3)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCN(CC)C/C=C/c1cnc(N)c2c(-c3ccc(Oc4ccccc4)cc3)noc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
7-Iodo-3-(4-phenoxyphenyl)isoxazolo [4,5-c]pyridin-4-amine (0. 100 g, 0.233 mmol) in 1,2-dimethoxyethane (4 mL) and water (2 mL) was reacted with an 2-[(E)-3,3-diethoxy-1-propenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.09 g, 0.35 mmol), sodium carbonate (0.05 g, 0.47 mmol) and tetrakis triphenylphosphine palladium (0) (0.02 g, 0.014 mmol) at 90° C. for 18 hours. The solvent was removed in vacuo and the residue was dissolved in acetone/water 95:5 (10 mL) then p-toluene sulfonic acid was added. The mixture was stirred at ambient temperature for 18 hours then evaporated and the residue dissolved in 1,2-dichloroethane (4 mL). Diethylamine (100 mg) was added followed by sodium triacetoxyborohydride (100 mg). The mixture was stirred for 18 hours then the concentrated and by preparative RP-HPLC (Rainin C18, 8 mm, 100 Å, 25 cm; 20% acetonitrile—-0.1M ammonium acetate isocratic for 5 minutes, then 20-80% acetonitrile—0.1M ammonium acetate over 30 min, 21 ml/min) followed by treatment with Silica-carbonate and lyophilization: 1H NMR (DMSO-d6, 400 MHz) δ8.08 (s, 1H), 7.7 (d, 2H), 7.46 (t, 2H), 7.16-7.25 (m, 5H), 6.6 (d, 1H), 6.49 (m, 1H), 6.33 (bs, 2H), 3.25 (d, 2H), 2.50 (q, 4H), 1.0 (t, 6H); Rt=2.90 min (Conditions a), MS m/e: 413 (M−H)−.
Reaction SMILES: [Na].C(O[C:5](=[O:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[CH3:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=1[N+:21]([O-:23])=[O:22].Cl>CCO>[CH2:9]([O:8][C:6](=[O:7])[C:5](=[O:11])[CH2:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=1[N+:21]([O-:23])=[O:22])[CH3:10]
Reactant: Cc1ccc(C#N)cc1[N+](=O)[O-]
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(=O)Cc1ccc(C#N)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Dissolve sodium metal (0.345 g) in absolute EtOH (25 mL), add diethyloxalate (10 mL) and then add 4-methyl-3-nitrobenzonitrile (1b, m=0, 1.6 g, Aldrich) as an EtOH solution (25 mL). Stir the reaction mixture at rt for 16 hours, neutralize the reaction by addition of 5N HCl (3 mL) and remove the EtOH under reduced pressure. Partition the residue between CH2Cl2 (100 mL) and H2O (50 mL). Wash the organic layer successively with H2O (50 mL) and brine (50 mL), dry (MgSO4) and concentrate to give a crude oil. Purify the oil by chromatography on SiO2 eluting with cyclohexane-EtOAc, 70-30 v/v, to afford gave after drying (40° C., house vacuum), the title compound (1.5 g) as yellow crystals, mp 118° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]([C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[C:12]([NH:19][CH3:20])[C:11]=1[C:21]#[N:22])([CH3:9])[C:6](=[O:8])[CH3:7])[CH3:2]>CCOC(C)=O.[Pd]>[CH2:1]([O:3][C:4](=[O:23])[C:5]([C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([NH:19][CH3:20])[C:11]=1[C:21]#[N:22])([CH3:9])[C:6](=[O:8])[CH3:7])[CH3:2]
Reactant: CCOC(=O)C(C)(C(C)=O)c1ccc([N+](=O)[O-])c(NC)c1C#N
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C(C)=O)c1ccc(N)c(NC)c1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 107 %

Procedure:
To a 500 mL Parr pressure flask was added 2-(2-cyano-3-methylamino-4-nitro-phenyl)-2-methyl-3-oxo-butyric acid ethyl ester (7.13 g, 16.5 mmol) as a solution in EtOAc (50 mL) followed by 10% palladium on carbon (1.0 g). The flask was purged under vacuum, then charged with hydrogen gas (50 psi). The flask was agitated at room temperature for while open to the ballast (caution: potential exotherm). After 8 hours, TLC analysis indicated that all starting material has been consumed. The reaction mixture was filtered through a pad of celite and washed with EtOAc. The resulting solution was concentrated to provide 2-(4-amino-2-cyano-3-methylamino-phenyl)-2-methyl-3-oxo-butyric acid ethyl ester (5.11 g, 77%) as a gray solid, which was used without further purification. 1H NMR (400 MHz, d6-DMSO) δ 6.70 (d, J=8.2 Hz, 1H), 6.33 (d, J=8.2 Hz, 1H), 6.17 (s, 2H), 4.90 (q, J1=5.1 Hz, J2=10.6 Hz, 1H), 4.21-4.15 (m, 2H), 2.95 (d, J=5.5 Hz, 2H), 2.22 (s, 3H), 1.66 (s, 3H), 1.2 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12]2[CH:13]=[C:14]([C:21](O)=[O:22])[C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:11]=2[O:10][C:9]([CH3:25])([CH3:24])[C:8]1=[O:26].[NH2:27][C@H:28]1[C@H:33]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:32][CH2:31][N:30]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:29]1>>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12]2[CH:13]=[C:14]([C:21]([NH:27][C@H:28]3[C@H:33]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH2:32][CH2:31][N:30]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:29]3)=[O:22])[C:15]([C:17]([F:19])([F:18])[F:20])=[CH:16][C:11]=2[O:10][C:9]([CH3:25])([CH3:24])[C:8]1=[O:26]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](c2ccccc2)[C@H](N)C1
Reactant: COCCCCN1C(=O)C(C)(C)Oc2cc(C(F)(F)F)c(C(=O)O)cc21
Product: COCCCCN1C(=O)C(C)(C)Oc2cc(C(F)(F)F)c(C(=O)N[C@@H]3CN(C(=O)OC(C)(C)C)CC[C@H]3c3ccccc3)cc21

Procedure:
Using 4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acid and tert-butyl (3S,4S)-3-amino-4-phenylpiperidine-1-carboxylate, the title compound was obtained in a similar manner to Reference Example 541.
Reaction SMILES: [CH2:1]([C:4]1[N:13]=[C:12]([SH:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH2:2][CH3:3].[OH-].[Na+].[CH3:17]I>O>[CH3:17][S:14][C:12]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:1][CH2:2][CH3:3])[N:13]=1
Reactant: CCCc1nc(S)c2ccccc2n1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCc1nc(SC)c2ccccc2n1
Reaction time: 0.17 h

Procedure:
A mixture of 2-propyl-4-mercaptoquinazoline (3.3 g.) and sodium hydroxide (0.68 g.) in water (7 ml.) was stirred for 10 minutes at 25°. Methyl iodide (1.1 ml.) was added and stirring was continued for 1 hour. The precipitate was recrystallized from hexane to give 4-methylthio-2-propylquinazoline; n.m.r. in CDCl3 : 1.1(t, 3H); 1.95(m, 2H); 2.7(s, 3H); 3.0(t, 2H); 7.2-8.1(complex, 4H).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[C:9]([C:11]3[O:15][CH:14]=[N:13][CH:12]=3)[N:8]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:7]=1.C(OC([N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:36]=[N:37][C:38]([NH2:41])=[CH:39][CH:40]=2)[CH2:30][CH2:29]1)=O)(C)(C)C>>[CH:16]1([N:8]2[C:6]3[N:7]=[C:2]([NH:41][C:38]4[CH:39]=[CH:40][C:35]([CH2:34][N:31]5[CH2:32][CH2:33][NH:28][CH2:29][CH2:30]5)=[CH:36][N:37]=4)[N:3]=[CH:4][C:5]=3[CH:10]=[C:9]2[C:11]2[O:15][CH:14]=[N:13][CH:12]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(N)nc2)CC1
Reactant: Clc1ncc2cc(-c3cnco3)n(C3CCCC3)c2n1
Product: c1ncc(-c2cc3cnc(Nc4ccc(CN5CCNCC5)cn4)nc3n2C2CCCC2)o1
Yield: 15 %

Procedure:
Following Buchwald Method B, 2-chloro-7-cyclopentyl-6-oxazol-5-y-l-7H-pyrrolo[2,3-d]pyrimidine (100 mg, 0.346 mmol) and 4-(6-amino-pyridin-3-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (106 mg, 0.363 mmol), followed by deprotection using General Procedure A to give (7-cyclopentyl-6-oxazol-5-yl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-(5-piperazin-1-ylmethyl-pyridin-2-yl)-amine (23 mg, 15%). MS (ESI) m/z 445.2 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:22]=[C:21](F)[CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:22]=[C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: COC(=O)c1ccc(F)cc1OCCCNC(=O)OC(C)(C)C
Product: COC(=O)c1ccc(N2CCOCC2)cc1OCCCNC(=O)OC(C)(C)C
Temperature: 130 °C
Yield: 16 %

Procedure:
Using methods substantially equivalent to those described in Example 1-G, except that the reaction mixture was heated to 130° C., methyl 2-(3-tert-butoxycarbonylamino-propoxy)-4-(morpholin-4-yl)benzoate (2.39 g, 6.06 mmol, 16%) was prepared from methyl 2-(3-tert-butoxycarbonylamino-propoxy)-4-fluorobenzoate and morpholine.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][CH2:8][CH2:9][CH2:10][S:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]([CH2:8][CH2:9][CH2:10][S:11][C:12]1[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=1)[C:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: c1csc(CNCCCSc2ccncc2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccccc1)N(CCCSc1ccncc1)Cc1cccs1
Yield: 35.9 %

Procedure:
To a solution of 2.5 g (9.45 mmol) of 4-[3-(N-(2-thienylmethyl)amino)propylthio]pyridine and 1.32 ml (9.45 mmol) of triethylamine in 50 ml of methylene chloride, 1.1 ml (9.45 mmol) of benzoyl chloride was added under ice-cooling with stirring. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and water and dried, and the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain 1.25 g of the desired compound (yield: 35.9%, yellow oil).
Reaction SMILES: C(O)(=O)C.CCN(CC)CC.[C:12]([C@@H:14]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)#[N:13].[N-:30]=[N+:31]=[N-:32].[Na+]>C1(C)C=CC=CC=1>[C:16]1([CH2:15][C@H:14]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:28])[CH3:27])[C:12]2[NH:32][N:31]=[N:30][N:13]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N[C@H](C#N)Cc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)c1nnn[nH]1
Temperature: 100 °C
Yield: 84.3 %

Procedure:
To a solution of acetic acid (93 μL, 1.62 mmol) in PhMe (2.0 mL) was added Et3N (226 μL, 1.624 mmol). (S)-tert-Butyl (1-cyano-2-phenylethyl)carbamate (100 mg, 0.41 mmol) was then added to the mixture followed by NaN3 (106 mg, 1.62 mmol). The resulting reaction mixture was heated at 100° C. for 2 h and then filtered, rinsing with EtOAc. The filtrate was concentrated in vacuo and purified using preparative HPLC to give the title compound (100 mg, 85%) as a white solid after lyophilization. 1H NMR (CDCl3) δ 7.37-7.20 (m, 3H), 7.12 (d, J=6.6 Hz, 2H), 5.56 (br s, 1H), 5.30 (d, J=6.2 Hz, 1H), 3.35 (d, J=6.4 Hz, 2H), 1.51-1.17 (m, 9H); MS (ESI+) m/z 290.2 (M+H)+.
Reaction SMILES: [CH:1]1([NH:4][CH:5]=[C:6]([C:12](=[O:25])[C:13]2[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[C:16]([F:22])=[C:15]([Cl:23])[C:14]=2F)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[CH:1]1([N:4]2[C:14]3[C:13](=[CH:18][C:17]([N+:19]([O-:21])=[O:20])=[C:16]([F:22])[C:15]=3[Cl:23])[C:12](=[O:25])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1cc([N+](=O)[O-])c(F)c(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cn(C2CC2)c2c(Cl)c(F)c([N+](=O)[O-])cc2c1=O

Procedure:
An amount of 0.088 g of ethyl 3-cyclopropylamino-2-(2,4-difluoro-3-chloro-5-nitro-benzoyl)acrylate is dissolved in 1 ml of ethyl acetate at 0° C . A quantity of 0.1 g of potassium carbonate is added. The desired product precipitates and is isolated by filtration.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH2:34][CH2:35][CH3:36])[CH:29]=[CH:30][CH:31]=2)[CH2:22][CH2:21]1>>[C:33]([NH:32][C:28]1[CH:27]=[C:26]([CH:23]2[CH2:24][CH2:25][N:20]([CH2:19][CH2:18][CH2:17][NH:16][C:13]([C:8]3([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[CH2:9][CH2:10][CH2:11][CH2:12]3)=[O:15])[CH2:21][CH2:22]2)[CH:31]=[CH:30][CH:29]=1)(=[O:37])[CH2:34][CH2:35][CH3:36]
Reactant: CCCC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCCC1
Product: CCCC(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(Cl)cc4)CCCC3)CC2)c1

Procedure:
Example 102 was prepared from 1-(4-chlorophenyl) cyclopentanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}butanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.51 (s, 1H), 7.42 (s, 1H), 7.34–7.24 (m, 6H), 6.95 (d, 1H, J=7.6 Hz), 6.57 (br s, 1H), 3.28 (dd, 2H, J=5.6, 11.6 Hz), 2.92 (d, 2H, J=12.0 Hz), 2.53–2.43 (m, 3H), 2.37–2.29 (m, 4H), 1.99–1.91 (m, 4H), 1.83–1.58 (m, 12H), 1.02 (t, 3H, J=7.6 Hz); ESMS m/e: 510.3 (M+H)+.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:13][N:14]([CH3:19])[CH2:15][CH2:16][CH2:17][NH2:18]>>[CH3:13][N:14]([CH3:19])[CH2:15][CH2:16][CH2:17][NH:18][C:1](=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CN(C)CCCN
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)NCCCN(C)C

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and N,N-dimethylpropane-1,3-diamine as starting materials to give the aimed compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([NH:22][C@H:23]([C:35]([OH:37])=[O:36])[CH2:24]CCCNC(=O)C(F)(F)F)=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(N[C@H](C(O)=O)CC1C=CC=CC=1)=O)C1C=CC=CC=1.FC(F)(F)C(NCCCC[C@@H](C(O)=O)N)=O>>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([NH:22][C@H:23]([C:35]([OH:37])=[O:36])[CH3:24])=[O:21])[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCCNC(=O)C(F)(F)F)C(=O)O)OCc1ccccc1
Agent: N[C@@H](CCCCNC(=O)C(F)(F)F)C(=O)O
Agent: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Product: C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)O

Procedure:
N-Benzyloxycarbonyl-L-phenylalanyl-Nε -trifluoroacetyl-L-lysine (m.p. 143°-147° C.) from N-benzyloxycarbonyl-L-phenylalanine and Nε -trifluoroacetyl-L-lysine (A. T. Moore, et al., J. Chem. Soc. (C), 2349-2359 (1966)).
Reaction SMILES: [C:1]([C:4]1[S:8][C:7](=[O:9])[NH:6][C:5]=1[CH3:10])(=[O:3])[CH3:2].C(O[CH:16](N(C)C)[N:17]([CH3:19])[CH3:18])(C)(C)C>CCOC(C)=O>[CH3:16][N:17]([CH3:19])[CH:18]=[CH:2][C:1]([C:4]1[S:8][C:7](=[O:9])[NH:6][C:5]=1[CH3:10])=[O:3]
Reactant: CC(=O)c1sc(=O)[nH]c1C
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: CCOC(C)=O
Product: Cc1[nH]c(=O)sc1C(=O)C=CN(C)C
Temperature: 80 °C

Procedure:
5-Acetyl-4-methyl-3H-thiazol-2-one (0.5 g, 3.18 mmol) and tert-butoxy-bis(dimethylamino)methane (Bredereck's reagent; 2.226 mL, 0.477 mmol) were combined and heated at 80° C. for 4 h. Removal of the excess solvent under reduced pressure gave a dark residue. Treatment of this residue with EtOAc afforded the title compound as a solid product, which was collected by filtration (0.074 g, 11%). Anal. RP-HPLC: tR 10.5 min (0-60% MeCN over 20 min). 1H-NMR (DMSO-d6): δ2.33 (3H, s, CH3), 2.70 (3H, s, NCH3), 3.09 (3H, s, NCH3), 5.07 (1H, d, CH, J=12.0), 7.55 (1H, d, J=12.0, CH), 11.23 (1H, s, NH). MS (ESI+) m/z 213.44 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]2[OH:29])[C:12]3=[O:30])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:37][N:38]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[N:39]1>C1COCC1.C(OCC)(=O)C.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]2[OH:29])[C:12]3=[O:30])=[CH:4][CH:3]=1.[OH:29][C@@H:24]1[CH2:25][CH2:26][CH2:27][CH2:28][C@H:23]1[N:13]1[C:12](=[O:30])[C:11]2[C:16](=[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]3=[C:9]([CH2:8][C:5]3[CH:6]=[N:7][C:2]([C:41]4[CH:40]=[N:39][N:38]([CH3:37])[CH:42]=4)=[CH:3][CH:4]=3)[CH:10]=2)[N:15]=[CH:14]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: O=c1c2cc(Cc3ccc(Cl)nc3)c3ccccc3c2ncn1[C@@H]1CCCC[C@H]1O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(-c2ccc(Cc3cc4c(=O)n([C@@H]5CCCC[C@H]5O)cnc4c4ccccc34)cn2)cn1
Temperature: 100 °C

Procedure:
rac-6-[(6-chloropyridin-3-yl)methyl]-3-[trans-2-hydroxycyclohexyl]benzo[h]quinazolin-4(3H)-one was prepared as described in Example 1. To a solution of rac-6-[(6-chloropyridin-3-yl)methyl]-3-[trans-2-hydroxycyclohexyl]benzo[h]quinazolin-4(3H)-one (0.080 g, 0.19 mmol) in 3 mL of THF under an atmosphere of nitrogen was added cesium carbonate (0.38 mL, 1 N aqueous, 0.38 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.079 g, 0.38 mmol), and bis(tri-tert-butylphosphine)palladium(0) (10 mol %). The reaction was heated at 100° C. for 20 h, cooled to rt, and diluted with ethyl acetate and water. The organic layer was removed and washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 100% ethyl acetate, to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 466.0 for [M+H]+: 1H NMR (400 MHz, CD3OD) δ 9.02-8.99 (m, 1H), 8.67 (br s, 1H), 8.61 (s, 1H), 8.33 (s, 1H), 8.23 (d, J=7.5 Hz, 1H), 8.03-8.00 (m, 2H), 7.82-7.62 (m, 4H), 4.60 (s, 2H), 4.10-4.04 (m, 1H), 3.89 (s, 3H), 2.08-2.00 (m, 1H), 1.93-1.83 (m, 1H), 1.90-1.72 (m, 3H), 1.38-1.30 (m, 4H).
Reaction SMILES: [CH2:1]([Hg:5][CH2:6][CH2:7][CH:8]=[CH2:9])[CH2:2][CH:3]=[CH2:4].C([Mg]Br)CC=C.BrCCC=C.[Mg]>O1CCCC1.O>[CH:1]([Hg:5][CH:6]=[CH:7][CH2:8][CH3:9])=[CH:2][CH2:3][CH3:4]
Reactant: C=CCC[Hg]CCC=C
Agent: C=CCCBr
Agent: C=CCC[Mg]Br
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: CCC=C[Hg]C=CCC
Yield: 60 %

Procedure:
Preparation of bis(3-butenyl)mercury: To a solution of 3-butenylmagnesium bromide, prepared from 25 g of 1-bromo-3-butene (187 mmole) and 5 g of magnesium (208 mmole) in 40 mL of tetrahydrofuran, was added dropwise, at 50° C. with stirring, a solution of 25.2 g of mercuric chloride (93 mmole) in tetrahydrofuran. After stirring for 2 hours at 60° C., the reaction mixture was hydrolyzed with water at 0°-5° C. Organic layer was separated from aqueous layer; the product was distilled to give bisbutenyl mercury in 60% yield. The yield of the desired product was confirmed by gas chromatography (GC) and 1H NMR.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[CH:6][C:5]=1[N+:14]([O-])=O)[CH3:2]>C(O)C.[Pd]>[NH2:14][C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:4]=1[NH:3][CH2:1][CH3:2])=[CH:12][CH:11]=[CH:10][CH:9]=2
Reactant: CCNc1c([N+](=O)[O-])cnc2ccccc12
Agent: [Pd]
Solvent: CCO
Product: CCNc1c(N)cnc2ccccc12
Yield: 82.2 %

Procedure:
A suspension of 1.34 g of 4-ethylamino-3-nitroquinoline in 40 ml of ethanol is hydrogenated in the presence of 10% palladium on carbon according to the procedure of Referential Example 1, followed by purification to give 0.95 g (82%) of 3-amino-4-ethylaminoquinoline A16 as an oil.
Reaction SMILES: [Li+].[OH-].C([O:5][C:6]([C:8]1[NH:9][C:10](=[O:35])[N:11]([CH:19]2[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])[CH2:20]2)[C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:7])C.Cl>O1CCOCC1>[CH2:28]([O:27][C:25]([N:21]1[CH2:22][CH2:23][CH2:24][CH:19]([N:11]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:8]([C:6]([OH:7])=[O:5])[NH:9][C:10]2=[O:35])[CH2:20]1)=[O:26])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCOC(=O)c1[nH]c(=O)n(C2CCCN(C(=O)OCc3ccccc3)C2)c1-c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1[nH]c(=O)n(C2CCCN(C(=O)OCc3ccccc3)C2)c1-c1ccccc1
Temperature: 55 °C

Procedure:
(2.6 g, 5.78 mmol) prepared in the previous step was combined with 26 mL of dioxane and 29 mL of 1N LiOH. The mixture was heated at 55° C. overnight. After the disappearance of 16D as monitored by LC/MS, the reaction was cooled to RT and approximately 50 mL of 1N HCl was added directly. The aqueous mixture was extracted with ethyl acetate (3×40 mL), washed with brine, dried over MgSO4, and concentrated in vacuo to afford 1-(1-(benzyloxycarbonyl)piperidin-3-yl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazole-4-carboxylic acid as an oil (16E) (2.43 g, quantitative yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.13 (d, J=9.60 Hz, 1H) 1.25 (br. s., 1H) 1.61-1.77 (m, 2H) 2.60 (br. s., 1H) 3.25 (br. s., 1H) 3.84-4.00 (m, 2H) 4.99 (s, 2H) 7.27-7.47 (m, 10H) 7.92-7.97 (m, 1H) 10.79 (s, 1H) 12.43 (br. s., 1H). This was used in next step without purification. ESI-MS: m/z 422.3 (M+H)+.
Reaction SMILES: [Na].[O-]CC.[Na+].O=[C:7]1[CH2:14][CH2:13][C:10]2([CH2:12][CH2:11]2)[CH2:9][CH:8]1[C:15]([O:17]CC)=O.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35][C:36](=[NH:38])[NH2:37])[CH2:29][CH2:28]2)=[CH:23][CH:22]=1>O.C(O)C>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([N:27]2[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35][C:36]3[NH:38][C:15](=[O:17])[C:8]4[CH2:9][C:10]5([CH2:11][CH2:12]5)[CH2:13][CH2:14][C:7]=4[N:37]=3)[CH2:29][CH2:28]2)=[CH:25][CH:26]=1
Reactant: N=C(N)CCCN1CCN(c2ccc(Cl)cc2)CC1
Reactant: CCOC(=O)C1CC2(CCC1=O)CC2
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CCO
Product: O=c1[nH]c(CCCN2CCN(c3ccc(Cl)cc3)CC2)nc2c1CC1(CC2)CC1
Temperature: 25 °C
Yield: 5.9 %

Procedure:
Sodium (0.094 g, 4.08 mmol) was added to ethanol (15 ml) under stirring condition at room temperature. The resulting mixture was stirred for 30 min. To this freshly prepared clear solution of sodium ethoxide, were added ethyl 6-oxospiro[2.5]octane-5-carboxylate (0.4 g, 2.03 mmol) and 4-(4-(4-chlorophenyl) piperazin-1-yl)butanimidamide (0.343 g, 1.223 mmol) and the reaction mixture was heated at 85° C. for 18 h. The progress of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain crude residue which was dissolved with water (15 ml). Aqueous layer was extracted with ethylacetate (2×30 ml). The combined organic layer was dried over sodium sulphate, filtered and solvent was removed under reduced pressure to obtain a crude product which was purified by flash chromatography over silica gel (100-200 mesh) using 3-4% methanol in dichloromethane as eluent to obtain title compound (0.030 g, 4% yield).