Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([Br:11])=[N:8][C:7]=1[CH3:12])=[O:5])C.O.[OH-].[Li+].Cl>O1CCCC1.O.C(OCC)(=O)C>[Br:11][C:9]1[S:10][C:6]([C:4]([OH:5])=[O:3])=[C:7]([CH3:12])[N:8]=1
Reactant: CCOC(=O)c1sc(Br)nc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nc(Br)sc1C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.6 %

Procedure:
To a solution of 2-bromo-4-methyl-thiazole-5-carboxylic acid ethyl ester (3.0 g, 12 mmol) in tetrahydrofuran (THF, 50 mL) and water (5 mL) was added lithium hydroxide hydrate (1.0 g, 24 mmol). The reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was diluted with water and ethyl acetate. The aqueous layer was made acidic to pH 1 with 2 N hydrochloric acid (HCl) and then was extracted with ethyl acetate. The organic extracts were dried over sodium sulfate (Na2SO4), filtered and concentrated to provide product as an orange solid (2.6 g, 98%): mp 152-155° C.; 1H NMR (300 MHz, CDCl3) δ 2.74 (s, 3H); ESIMS m/z 221 (M-1).
Reaction SMILES: [C:1]([O-:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]CCCCC.[Na+].[C:22]([O-])(=[O:40])[CH2:23]CCCCCCCCCCCCCCCC.[K+].C([O:45]CCOCCO)C>>[C:13]1(=[O:45])[O:40][CH2:22][CH2:23][O:20][C:1](=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: CCCCCCCCCCCCCCCCCC(=O)[O-]
Reactant: CCOCCOCCO
Agent: [K+]
Agent: [Na+]
Product: O=C1CCCCCCCCCCCC(=O)OCCO1
Yield: 73.2 %

Procedure:
Repeating Example X, a double metal salt was prepared except that sodium stearate was substituted for the potassium stearate and the ethyl cellusolve was replaced with diethylene glycol monoethyl ether. The resulting double metal salt NaAl(OC2H4OC2H4OC2H5)3 (OOCC17H35) was used as the catalyst for the continuous depolymerization of poly(ethylene brassylate) in accordance with the procedure and conditions of Example I. Ethylene brassylate was continuously produced and distilled from the reactor at a rapid rate and the overall yield was 73.2 percent. Comparable results are obtained using the double metal salt NaAl(OC2H4OC2H5)3 (OOCC6H5) obtained by the reaction of sodium benzoate and aluminum tricellusolve (Al(OC2H4OC2H5)3).
Reaction SMILES: [CH:1]([S:4]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=1[CH:16]1[CH:20]([C:21]([O:23][CH3:24])=[O:22])[CH2:19][CH2:18][N:17]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])(=[O:6])=[O:5])([CH3:3])[CH3:2]>[Pd].CO>[NH2:13][C:10]1[CH:11]=[CH:12][C:7]([S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])=[C:8]([CH:16]2[CH:20]([C:21]([O:23][CH3:24])=[O:22])[CH2:19][CH2:18][N:17]2[C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[CH:9]=1
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)C1c1cc([N+](=O)[O-])ccc1S(=O)(=O)C(C)C
Agent: [Pd]
Solvent: CO
Product: COC(=O)C1CCN(C(=O)OC(C)(C)C)C1c1cc(N)ccc1S(=O)(=O)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To palladium on carbon (0.5 g) was added 20E in methanol (50 mL) carefully under a stream of nitrogen. The vessel was flushed and degassed with nitrogen gas (3×) and a balloon containing hydrogen gas was introduced. The reaction was stirred at rt overnight. The catalyst was filtered through celite and washed with methanol several times. The filtrate and the combined washings were evaporated and dried to give 2.0 g of crude 20F.
Reaction SMILES: Br[C:2]1[C:3]([CH2:17][O:18][CH:19]2[CH:24]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][O:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[O:43][CH3:44])=[CH:27][CH:26]=3)[CH2:23][CH2:22][N:21](C(OCC3C=CC=CC=3)=O)[CH2:20]2)=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:8]=[C:7]2[CH3:16].C(N(CC)CC)C>CO.[Pd]>[CH3:44][O:43][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=1[CH2:36][O:35][CH2:34][CH2:33][CH2:32][O:31][C:28]1[CH:27]=[CH:26][C:25]([CH:24]2[CH2:23][CH2:22][NH:21][CH2:20][CH:19]2[O:18][CH2:17][C:3]2[CH:2]=[C:10]3[C:6]([C:7]([CH3:16])=[CH:8][N:9]3[CH2:11][CH2:12][CH2:13][O:14][CH3:15])=[CH:5][CH:4]=2)=[CH:30][CH:29]=1
Reactant: COCCCn1cc(C)c2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCCOCc4ccccc4OC)cc3)c(Br)c21
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: COCCCn1cc(C)c2ccc(COC3CNCCC3c3ccc(OCCCOCc4ccccc4OC)cc3)cc21

Procedure:
The solution of 0.150 g of benzyl 3-[7-bromo-1-(3-methoxypropyl)-3-methyl-1H-indol-6-ylmethoxy]-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 5.0 ml of methanol is admixed with 0.027 ml of triethylamine and hydrogenated in the presence of 30 mg of 5% Pd/C at room temperature over 16 hours. The reaction mixture is clarified by filtration and the filtrate is concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F).
Reaction SMILES: C([O:5][C:6](=[O:23])[CH2:7][N:8]([C:16]([C:18]1[NH:19][CH:20]=[CH:21][CH:22]=1)=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH:19]1[CH:20]=[CH:21][CH:22]=[C:18]1[C:16]([N:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:7][C:6]([OH:23])=[O:5])=[O:17]
Reactant: CC(C)(C)OC(=O)CN(Cc1ccccc1)C(=O)c1ccc[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CN(Cc1ccccc1)C(=O)c1ccc[nH]1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution containing 2.85 (9.01 mmol) of (Pyrrole-2-carbonyl)-N-(benzyl)glycine-t-butyl ester in 50 mL of anhydrous dichloromethane cooled to 0° C. was added 25 mL of TFA dropwise. After 90 minutes an additional 25 mL of TFA was added and allowed to stir for 30 minutes. The mixture was evaporated in vacuo to afford 2.19 g of (Pyrrole-2-carbonyl)-N-(benzyl)glycine as a tan solid. FAB MS [M+H] m/z; Calcd. 259, Found 259.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:14]2[C:9](=[CH:10][C:11]([Cl:15])=[CH:12][CH:13]=2)[NH:8][N:7]=1)=[O:4].[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1>C(#N)C>[Cl:15][C:11]1[CH:10]=[C:9]2[C:14]([C:6]([NH:5][C:3](=[O:4])[CH2:2][N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[N:7][NH:8]2)=[CH:13][CH:12]=1
Reactant: C1CCNC1
Reactant: O=C(CCl)Nc1n[nH]c2cc(Cl)ccc12
Solvent: CC#N
Product: O=C(CN1CCCC1)Nc1n[nH]c2cc(Cl)ccc12

Procedure:
The process is performed as in Example 75, starting with 500 mg of 2-chloro-N-(6-chloro-1H-indazol-3-yl)acetamide, 15 cm3 of acetonitrile and 0.51 cm3 of pyrrolidine. The reaction medium is refluxed for 2 hours and then concentrated to dryness under reduced pressure (2 kPa; 50° C.); the crude product obtained is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2 cm), eluting with a methylene chloride/methanol/aqueous ammonia mixture (95/5/1 by volume). The fractions containing the expected product are combined, evaporated under reduced pressure (2 kPa; 50° C.) and dried (90 Pa; 45° C.) to give 440 mg of N-(6-chloro-1H-indazol-3-yl)-1-pyrrolidineacetamide in the form of an off-white powder melting at 168° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6](B3OC(C)(C)C(C)(C)O3)[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=2)[CH2:3][CH2:2]1.[F:23][C:24]1[CH:25]=[C:26]([CH:36]([NH:38][C:39]([C:41]2[O:42][C:43](Br)=[CH:44][CH:45]=2)=[O:40])[CH3:37])[CH:27]=[C:28]([F:35])[C:29]=1[NH:30][S:31]([CH3:34])(=[O:33])=[O:32].C([O-])([O-])=O.[Cs+].[Cs+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:23][C:24]1[CH:25]=[C:26]([CH:36]([NH:38][C:39]([C:41]2[O:42][C:43]([C:6]3[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=[C:4]([CH:1]4[CH2:2][CH2:3]4)[CH:5]=3)=[CH:44][CH:45]=2)=[O:40])[CH3:37])[CH:27]=[C:28]([F:35])[C:29]=1[NH:30][S:31]([CH3:34])(=[O:33])=[O:32]
Reactant: CC1(C)OB(c2cc(C3CC3)cc(C(F)(F)F)c2)OC1(C)C
Reactant: CC(NC(=O)c1ccc(Br)o1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(NC(=O)c1ccc(-c2cc(C3CC3)cc(C(F)(F)F)c2)o1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 18.2 %

Procedure:
2-(3-Cyclopropyl-5-trifluoromethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (120 mg, 0.26 mmol) and 5-Bromo-furan-2-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (110 mg, 0.26 mmol) was reacted using Pd(PPh3)2Cl2 (18 mg, 0.03 mmol), Cs2CO3 (250 mg, 0.77 mmol) as described in example 102 to give the title compound (25 mg, 18%) after purification by flash chromatography on silica gel (hexane: EtOAc=1:1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:8][CH:9]=1)([O-])=O.CN(C=O)C.O>C1COCC1.[Ni]>[N:10]1([C:7]2[N:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=[N+]([O-])c1ccc(N2CCCC2)nc1
Agent: [Ni]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(N2CCCC2)nc1
Reaction time: 2 h
Yield: 96.7 %

Procedure:
5-Nitro-2-(pyrrolidin-1-yl)pyridine (9.52 g, 49.3 mmol) was dissolved in THF (50 mL) and DMF (40 mL) and added to a pressure bottle containing Raney-nickel 2800, water slurry (45%) (9.52 g, 162 mmol). The mixture was stirred for 2 hours at 30 psi under H2 gas. The solution was filtered through a nylon membrane, washed with CH3OH and the filtrate concentrated in vacuo to give the title compound (7.78 g, 97%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.81-1.91 (m, 4 H) 3.17-3.29 (m, 4 H) 4.30 (s, 2 H) 6.25 (d, J=8.7, 1 H), 6.90 (dd, J=2.8, 8.7, 1 H), 7.55 (d, J=2.6, 1 H); MS (ESI) m/z 164 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[N:5]=[C:4]([NH2:14])[N:3]=1.[C:15](#[N:17])C>>[NH2:14][C:4]1[N:3]=[C:2]([C:15]#[N:17])[C:7]([CH3:8])=[C:6]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[N:5]=1
Reactant: CC#N
Reactant: Cc1c(Cl)nc(N)nc1-c1ccco1
Product: Cc1c(C#N)nc(N)nc1-c1ccco1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
A solution of 4-chloro-6-(2-furyl)-5-methylpyrimidine-2-amine (80 mg, 0.38 mmol) in acetonitrile (4 mL) was treated with polymer supported cyamide (0.636 mg, 1.91 mmol), stirred at 140° C. in the microwave for 30 min, filtered to remove the resin and the filter cake washed with acetonitrile. The filtrate was concentrated in vacuo to give the title compound (50 mg, 65%) as off-white solid; NMR δH (400 MHz, DMSO) 2.48 (3H, s), 6.75 (1H, dd, J 1.7, 3.5 Hz), 7.04 (2H br s), 7.28 (1H, dd, J 0.7, 3.5 Hz) and 8.00 (1H, dd, J 0.7, 1.7 Hz); M/Z 201 (M=H)+; HPLC 1.1 min. (50/80).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)=[O:22]>C(Cl)Cl>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([O:13][C:21](=[O:22])[O:23][C:24]3[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=3)=[CH:11][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Oc1ccc(-c2ccccc2)cc1)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 2 h
Yield: 91.6 %

Procedure:
A solution of 4-phenylphenol (25.0 g, 0.15 mol) and pyridine (11.89 ml, 0.15 mol) in 250 ml of methylene chloride were added dropwise under nitrogen to a solution of 4-nitrophenyl chloroformate (29.65 g, 0.15 mol) in 200 ml of methylene chloride at ice bath temperature. The reaction was stirred at ice bath temperature for approximately two hours and then overnight at room temperature. The reaction was extracted one time with 1N HCl, multiple times with saturated Na2CO3, dried (MgSO4) and the solvent removed under reduced pressure to give 46.05 g of light yellow crystals. Recrystallization from methylene chloride-diisopropyl ether gave the title compound as light yellow crystals, mp 138-140° C.
Reaction SMILES: N.[C:2]([NH:6][S:7]([C:10]1[CH:19]=[C:18]([C:20](=[O:22])[NH2:21])[CH:17]=[CH:16][C:11]=1[C:12]([O:14]C)=O)(=[O:9])=[O:8])([CH3:5])([CH3:4])[CH3:3].[CH3:23][NH:24][CH3:25]>CO>[CH3:23][N:24]([CH3:25])[C:12](=[O:14])[C:11]1[CH:16]=[CH:17][C:18]([C:20](=[O:22])[NH2:21])=[CH:19][C:10]=1[S:7](=[O:8])(=[O:9])[NH:6][C:2]([CH3:3])([CH3:4])[CH3:5]
Reactant: COC(=O)c1ccc(C(N)=O)cc1S(=O)(=O)NC(C)(C)C
Reactant: CNC
Agent: N
Solvent: CO
Product: CN(C)C(=O)c1ccc(C(N)=O)cc1S(=O)(=O)NC(C)(C)C
Reaction time: 7 h

Procedure:
Similarly to Examples A5 to A6, and using ammonia as basic reagent in Example A5, methyl 2-tert-butylsulfamoyl-4-carbamoylbenzoate was prepared first. At room temperature, 3.0 g (0.01 mol) of this compound were subsequently added to a solution of 45 g (1.0 mol) of dimethylamine in 60 ml of methanol, and the reaction mixture was left standing at room temperature for 7 h. The mixture was concentrated and the desired product was isolated by silica gel column chromatography (mobile phase: ethyl acetate; Rf≈0.2). This gave 1.0 g (31% of theory) of N,N-dimethyl-2-tert-butylsulfamoyl-4-carbamoylbenzamide of a glass-like consistency.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:5]([NH:16][CH2:17][CH2:18][NH:19][C:20](=[O:22])[CH3:21])=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][CH3:15])=[CH:9][CH:8]=2.OCC1C(NCCNC(=O)C)=NC2C(C=1)=CC(OC)=CC=2.[CH2:44]([C:46]1[C:55]2[C:50](=[CH:51][C:52]([O:58][CH3:59])=[C:53]([O:56][CH3:57])[CH:54]=2)[CH:49]=[C:48]([OH:60])[N:47]=1)[CH3:45].[Li+].[OH-]>C1COCC1.C(Cl)Cl>[CH2:44]([C:46]1[C:55]2[C:50](=[CH:51][C:52]([O:58][CH3:59])=[C:53]([O:56][CH3:57])[CH:54]=2)[C:49]([CH2:3][C:4]2[C:5]([NH:16][CH2:17][CH2:18][NH:19][C:20](=[O:22])[CH3:21])=[N:6][C:7]3[C:12]([CH:13]=2)=[CH:11][C:10]([O:14][CH3:15])=[CH:9][CH:8]=3)=[C:48]([OH:60])[N:47]=1)[CH3:45]
Reactant: COc1ccc2nc(NCCNC(C)=O)c(CCl)cc2c1
Reactant: CCc1nc(O)cc2cc(OC)c(OC)cc12
Agent: COc1ccc2nc(NCCNC(C)=O)c(CO)cc2c1
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCc1nc(O)c(Cc2cc3cc(OC)ccc3nc2NCCNC(C)=O)c2cc(OC)c(OC)cc12
Temperature: 160 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of N-(2-(3-(chloromethyl)-6-methoxyquinolin-2-ylamino)ethyl)acetamide hydrochloride SLA 41174 (350 mg, 1.02 mmol) in THF (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 1-ethyl-6,7-dimethoxyisoquinolin-3-ol SLA 28136 (237 mg, 1.02 mmol) followed by a 2 N aq. LiOH solution (1.02 mL, 2.0 mmol) and the mixture was stirred at 160° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (150 mL), washed with brine (20 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 90:10) provided N-(2-(3-((1-ethyl-3-hydroxy-6,7-dimethoxyisoquinolin-4-yl)methyl)-6-methoxyquinolin-2-ylamino)ethyl)acetamide. The product was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (2 mL) and the solution was stirred for 5 min at RT then concentrated at 40° C. under vacuum to give N-(2-(3-((1-ethyl-3-hydroxy-6,7-dimethoxyisoquinolin-4-yl)methyl)-6-methoxyquinolin-2-ylamino)ethyl)acetamide dihydrochloride 69 as a yellow solid (83.5 mg, 17% yield).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10](O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18].[OH-].[K+].[OH-].[Na+]>CCCC[O-].CCCC[O-].CCCC[O-].CCCC[O-].[Ti+4].O>[C:1]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)CCCCCCCO
Reactant: O=C(O)c1ccccc1
Agent: [Ti+4]
Agent: CCCC[O-]
Agent: [K+]
Solvent: O
Product: CC(C)CCCCCCCOC(=O)c1ccccc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A 4 liter distillation flask with top-mounted water separator and reflux condenser and also with a sampling port and thermometer was charged with 976 g of benzoic acid (8 mol), 1872 g (12 mol) of isodecanol (Exxal 10, ExxonMobil) and 0.59 g of butyl titanate (0.06% based on the amount of acid) and this initial charge was heated at boiling under a nitrogen atmosphere. The water of reaction produced during the esterification was taken off at regular intervals. When the acid number fell below 0.1 mg KOH/g, after about 3 hours, the excess alcohol was distilled off under reduced pressure through a 10 cm column with Raschig rings. Thereafter the mixture was cooled to 80° C. and transferred to a 4 liter reaction flask with dip tube, top-mounted dropping funnel and column, and attached to a Claisen bridge. It was then neutralized with 5% strength by weight aqueous sodium hydroxide solution (10-fold excess of alkali). The mixture was subsequently heated to 190° C. under reduced pressure (10 mbar). Then 8% by weight of fully demineralized water, based on the amount of crude ester employed, were added dropwise at constant temperature through the dropping funnel. After the water had been added the heating was shut off and cooling took place under reduced pressure. At room temperature, the ester was filtered off on a suction filter with filter paper and filter aid. Gas chromatography indicated a purity for the ester of 99.7%.
Reaction SMILES: COC([C:5]1([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1)=O.[OH-].[K+].Cl.[OH-].[Na+]>CS(C)=O.O>[NH:8]1[CH2:7][CH2:6][CH:5]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH2:10][CH2:9]1
Reactant: COC(=O)C1(c2ncnc3ccccc23)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: c1ccc2c(C3CCNCC3)ncnc2c1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
A mixture of crude 4-quinazolin-4-yl-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (4.58 g), as prepared in the previous step, DMSO (7.5 mL), and 10 M KOH (aq) (7.5 mL) was vigorously stirred at 100° C. for 12 h. After cooling to rt, the reaction was cautiously treated with 6 M HCl (18.4 mL) (gas evolution!) and water (19 mL), and the mixture with heavy precipitate was stirred at 100° C. for 10 min. The resulting amber translucent solution was allowed to cool to rt, made basic with 2.5 M NaOH (20 mL) and water (10 mL), shaken to dissolve the DMSO into the aqueous milieu, and extracted with DCM (2×75 mL). The organic layers were combined, dried (Na2SO4), and concentrated under reduced pressure to give the impure title compound as an amber translucent syrup (2.63 g, “100%” crude yield from 4-chloroquinazoline). 1H-NMR (300 MHz, CDCl3) δ 9.27 (s, 1H), 8.17 (dd, 1H), 8.06 (m, 1H), 7.89 (m, 1H), 7.65 (m, 1H), 3.75 (m, 1H), 3.45-3.35 (m, 2H), 3.04-2.92 (m, 2H), 2.1-1.8 (m, 5H). LC/MS (ESI): calcd mass 213.1, found 214.0 (MH)+.
Reaction SMILES: Cl.[CH2:2]([N:6]1[CH2:15][CH2:14][C:13]2[C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[CH2:10][CH2:9][C:8]=2[CH2:7]1)[CH2:3][CH2:4][CH3:5].[Li].N>C1COCC1.NC1C=CC=CC=1>[CH2:2]([N:6]1[CH2:15][CH2:14][C@@H:13]2[C@H:8]([CH2:9][CH2:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=32)[CH2:7]1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCN1CCC2=C(CCc3ccccc32)C1
Agent: Cl
Agent: N
Agent: [Li]
Solvent: Nc1ccccc1
Solvent: C1CCOC1
Product: CCCCN1CC[C@H]2c3ccccc3CC[C@@H]2C1
Reaction time: 2 h
Yield: 34.8 %

Procedure:
A solution of 0.104 g (0.374 mmol) of 3-butyl-1,2,3,4,5,6-hexahydro-benz[f]isoquinoline hydrochloride in 4 ml of anhydrous THF and 0.2 ml of aniline was added dropwise to a solution of 22 mg of lithium wire in 50 ml of liquid ammonia, cooled by a dry-ice/acetone bath. The cooling bath was then removed and the mixture was stirred under nitrogen for 2 h before quenching carefully with water (2 ml) and allowing the solvents to evaporate overnight. The residue was partitioned between ether and water, and the aqueous layer was reextracted with more ether. The combined ether extracts were dried (K2CO3) and evaporated in vacuo to leave a brown oil. This was chromatographed on flash silica eluting with 50% ethyl acetate/petroleum ether to give 31.7 mg (35%) of the title product as a colourless oil. The hydrochloride salt was made using ethereal hydrogen chloride. Upon evaporation of the solvent, the title product hydrochloride was obtained as a white solid, m.p. 217°-221° C. (dec). NMR δ(D2O) 0.96 (3H, t, J=7 Hz), 1.41 (2H, m), 1.51-1.92 (6H, m), 2.66-2.75 (2H, m), 2.86-2.95 (3H, m), 3.12-3.19 (3H, m), 3.63 (1H, m), 3.77 (1H, m), 7.22-7.28 (3H, m), 7.34-7.37 (1H, m). m/z (CI+, NH3) 244 (M+H)+, 200 (M--CH2CH2CH3)+. Analysis calcd. for C17H26ClN: C, 72.96; H, 9.36; N, 5.01%. Found: C, 72.86; H, 9.31; N, 4.80%.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:21]([N:22]([CH:24]([CH3:26])[CH3:25])[CH3:23])=[N:20][C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:27]([O:29]C)=[O:28])[CH:18]=4)[N:13]=3)=[CH:9][CH:10]=2)[CH:5]=[N:4]1)[CH3:2].[OH-].[Na+].O>O1CCCC1>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:21]([N:22]([CH:24]([CH3:25])[CH3:26])[CH3:23])=[N:20][C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:27]([OH:29])=[O:28])[CH:18]=4)[N:13]=3)=[CH:9][CH:10]=2)[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc2cc(-c3nc4ccc(C(=O)OC)cc4nc3N(C)C(C)C)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCn1ncc2cc(-c3nc4ccc(C(=O)O)cc4nc3N(C)C(C)C)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.9 %

Procedure:
To a solution of methyl 2-(1-ethyl-1H-indazol-5-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (80 mg, 0.20 mmol) in tetrahydrofuran (25 mL) was added sodium hydroxide (34 mg, 0.85 mmol) and water (2 mL) with stirring overnight at room temperature. The reaction mixture was concentrated under vacuum, dissolved in water (20 mL) and adjusted to pH 5 with HCl (3N). The solids were collected by filtration to afford 2-(1-ethyl-1H-indazol-5-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylic acid as yellow solid (18.6 mg, 24%).
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[C:4]([C:6]([CH2:14][CH3:15])([CH2:12][CH3:13])[C:7](OCC)=[O:8])=O)[CH3:2].CC(OC(C)=O)=O.O.C(Cl)(Cl)Cl>C1COCC1>[CH2:16]([N:3]([CH2:1][CH3:2])[CH2:4][C:6]([CH2:14][CH3:15])([CH2:12][CH3:13])[CH2:7][OH:8])[CH3:17]
Reactant: CCOC(=O)C(CC)(CC)C(=O)N(CC)CC
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CCN(CC)CC(CC)(CC)CO
Reaction time: 0.2 h
Yield: 48.9 %

Procedure:
To THF (300 ml.) is added LiA1H4 (1.2 g), the mixture is refluxed for 20 min, and an additional quantity of LiAIH4 (15.8 g., 0.42 mole) is added in two portions at 5°-21° over 1 min with mechanical stirring. The mixture is cooled to 5° and a solution of ethyl 2-(N,N-diethylcarbamoyl)-2-ethylbutyrate (29 g., 0.12 mole) in THF (80 ml.) is added at 5°-11° in 5 min. The temperature (exothermic) is allowed to rise to 60 over 12 min, is maintained at 49°-53° for 7 min, is heated gradually to reflux over 10 min, and then is refluxed for 6 hours. After it stands at room temperature for 18 hours, the reaction mixture is treated with Ac2O (55 ml.) at 10°-20°, is stirred in an ice bath for 0.5 hour, is treated with H2O (150 ml.) at 10°-18°, and finally is treated with CHCl3 (250 ml.) at 10°-22° with slow stirring. The CHCl3 -layer is washed with H2O (50 ml.), is dried over MgSO4, is filtered, and is concentrated to dryness under reduced pressure. The resultant oil (30 ml.) is treated with 10% HCl (280 ml.) and is subjected to steam distillation for 1.3 hours, collecting 1 liter of distillate. The distillate is concentrated to 50 ml. by distillation under reduced pressure, is made basic with solid NaC2O3 to pH 8-9 in the cold, is extracted with ether, is dried over MgSO4 and activated charcoal, is filtered, and concentrated to dryness. The residual oil (12 g. plus 5.0 g. from previous run) is distilled at 60°-68°/1 mm to yield 11 g (35%) of 3-diethylamino-2,2-diethylpropanol.