Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][N:9]1[CH2:27][CH2:26][N:12]2[C:13]3[C:18]([NH:19][C:20](=[O:21])[CH:11]2[CH2:10]1)=[CH:17][C:16]([C:22]([F:25])([F:24])[F:23])=[CH:15][CH:14]=3.C(O)C.Cl>[Pt]=O.O>[F:25][C:22]([F:23])([F:24])[C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]1[CH2:26][CH2:27][N:9]([CH2:8][CH2:7][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][NH:1]3)[CH2:10][CH:11]1[C:20](=[O:21])[NH:19]2
Reactant: O=C1Nc2cc(C(F)(F)F)ccc2N2CCN(CCc3ccccn3)CC12
Agent: O=[Pt]
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C1Nc2cc(C(F)(F)F)ccc2N2CCN(CCC3CCCCN3)CC12

Procedure:
A mixture of 5 g. (0.014 mole) of 2,3,4,4a-tetrahydro-3-[2-(2-pyridinyl)ethyl]-8-(trifluoromethyl)-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one, 60 ml. of ethanol, 120 ml. of water, 12 ml. of concentrated hydrogen chloride and 1 g. of platinum oxide catalyst is hydrogenated in a Parr apparatus for 2 hours. The catalyst is filtered and the solvents removed. The residue was crystallized from ethanol and recrystallized from methanol to yield 4.5 g. of the title compound as the dihydrochloride salt, m.p. 283°-286° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:29]3[C:30]([CH:33]=O)=[CH:31][CH:32]=[C:28]3[C:8]3([CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([O:25][CH3:26])[CH:16]=4)[CH2:10][CH2:9]3)[O:7][C:6]=2[CH:35]=1.Cl.[NH2:37]O.C([O-])(=O)C.[Na+].CC(OC(C)=O)=O.C([O-])(O)=O.[Na+]>C(O)C.O.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:29]3[C:30]([C:33]#[N:37])=[CH:31][CH:32]=[C:28]3[C:8]3([CH2:9][CH2:10][N:11]([C:14](=[O:27])[C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([O:25][CH3:26])[CH:16]=4)[CH2:12][CH2:13]3)[O:7][C:6]=2[CH:35]=1
Reactant: NO
Reactant: COc1cc(C(=O)N2CCC3(CC2)Oc2cc(Cl)ccc2-n2c(C=O)ccc23)ccc1C(F)(F)F
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: COc1cc(C(=O)N2CCC3(CC2)Oc2cc(Cl)ccc2-n2c(C#N)ccc23)ccc1C(F)(F)F
Temperature: 95 °C

Procedure:
To a solution of 7-chloro-1′-(3-methoxy-4-(trifluoromethyl)benzoyl)spiro-[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbaldehyde (310 mg, 0.61 mmol) in ethanol (1.5 mL) was added an aqueous solution of hydroxylamine hydrochloride (190 mg, 2.7 mmol) and sodium acetate (380 mg, 4.6 mmol) in water (1.5 mL). The mixture was heated at 95° C. for 2 hours. The reaction mixture was cooled to 25° C., water was added and the white precipitate that formed was collected by filtration, washed thoroughly with water and dried by azeotrope with toluene. The solid was dissolved in Ac2O (1.1 mL, 12 mmol) and was heated at 140° C. for 3.5 hours. The mixture was cooled to 25° C., poured into ice, diluted with dichloromethane (30 mL), and neutralized with NaHCO3 (2 g). The organic phase was separated, and the aqueous phase further extracted twice with dichloromethane. The organic layers were combined, washed with brine, dried, filtered, concentrated to a yellow oil that was purified by column chromatography (silica gel, 5-30% AcOEt in hexanes) to yield 7-chloro-1′-(3-methoxy-4-(trifluoromethyl)benzoyl)spiro[benzo-[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbonitrile. 1H NMR (400 MHz, CDCl3) δ 8.06 (t, J=10.1 Hz, 1H), 7.70 (s, 1H), 7.64 (dd, J=8.6, 1.6 Hz, 1H), 7.17 (d, J=2.2 Hz, 1H), 7.10 (dd, J=8.7, 2.2 Hz, 1H), 7.03 (dd, J=10.4, 6.3 Hz, 2H), 6.13 (d, J=4.0 Hz, 1H), 4.61 (s, 1H), 3.96 (d, J=20.2 Hz, 3H), 3.89-3.06 (m, 3H), 2.16-1.81 (m, 4H). ESI-MS m/z calc. 501.9, found 502.0 (M+1)+; Retention time: 2.17 minutes (3 min run).
Reaction SMILES: C([O:4][CH:5]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C:7](=[CH:8][C:9](=[O:34])[C@@H:10]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:33])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[CH:15]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH3:16])[CH2:6]1)(=O)C.[CH3:35][Mg]Cl>O1CCCC1>[Si:18]([O:17][CH:15]([C@@H:14]1[C@:25]2([CH3:33])[C@H:11]([C@H:10]3[C@H:28]([CH2:27][CH2:26]2)[C@:29]2([CH3:32])[C:7]([CH2:6][CH:5]([OH:4])[CH2:31][CH2:30]2)=[CH:8][C:9]3([CH3:35])[OH:34])[CH2:12][CH2:13]1)[CH3:16])([C:21]([CH3:23])([CH3:22])[CH3:24])([CH3:20])[CH3:19]
Reactant: CC(=O)OC1CC[C@@]2(C)C(=CC(=O)[C@H]3[C@@H]4CC[C@H](C(C)O[Si](C)(C)C(C)(C)C)[C@@]4(C)CC[C@@H]32)C1
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC(O[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H]2[C@H]3[C@H](CC[C@]12C)[C@@]1(C)CCC(O)CC1=CC3(C)O
Temperature: 25 °C

Procedure:
A solution of 3-acetoxy-20-tert-butyldimethylsilyloxy-pregn-5-en-7-one (279 gm, 0.57 mol, product of Step 3) in tetrahydrofuran (5.6 L) was cooled to 4° C. A 3M solution of methyl magnesium chloride in tetrahydrofuran (1.037 L, 3.1 mol) was added at such a rate as to keep the temperature ≤0° C. The ice bath was removed and the reaction allowed to warm to room temperature overnight. The reaction was cooled in an ice bath and quenched with a 20% solution of ammonium chloride (3 L). The organic layer was removed and the aqueous layer extracted with ethyl acetate. The organic layers were combined, washed with saturated salt solution, and dried over anhydrous magnesium sulfate. The solution was filtered through a pad of anhydrous sodium sulfate and the solvent removed by rotoevaporation to yield the title compound.
Reaction SMILES: CN(C)S([N:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]=[C:7]1[CH2:17][NH:18][C:19]1[CH:28]=[N:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1)(=O)=O.Cl>CO>[C:11]1([C:9]2[N:8]=[C:7]([CH2:17][NH:18][C:19]3[CH:28]=[N:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)[NH:6][CH:10]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CN(C)S(=O)(=O)n1cc(-c2ccccc2)nc1CNc1cnc2ccccc2n1
Agent: Cl
Solvent: CO
Product: c1ccc(-c2c[nH]c(CNc3cnc4ccccc4n3)n2)cc1
Temperature: 120 °C

Procedure:
N,N-Dimethyl-4-phenyl-2-((quinoxalin-2-ylamino)methyl)-1H-imidazole-1-sulfonamide was dissolve in MeOH (5 mL) and 1 M HCl aqueous solution (4.5 mL) was added. The suspension was heated in the microwave (120° C., 40 min) and then poured into a separatory funnel. The phases were separated and the aqueous phase (pH about 2) was washed with Et2O (2×20 mL). The combined organic layers were discarded and the aqueous phase was made basic (pH about 10) by the slow addition of saturated aqueous K2CO3 (10 mL). The basic aqueous phase was extracted with EtOAc (3×40 mL). The combined organic phases were washed with saturated aqueous NaCl (1×50 mL), dried (Na2SO4), filtered and concentrated to give crude N((4-phenyl-1H-imidazol-2-yl)methyl)quinoxalin-2-amine. The material was purified by reverse phase HPLC (Gilson) to give N-((4-phenyl-1H-imidazol-2-yl)methyl)quinoxalin-2-amine as a clear oil. LC-MS m/z 302 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.[NH2:44][C:45]1([CH2:48][NH:49][C:50](=[O:56])[O:51][C:52]([CH3:55])([CH3:54])[CH3:53])[CH2:47][CH2:46]1>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:44][C:45]5([CH2:48][NH:49][C:50](=[O:56])[O:51][C:52]([CH3:54])([CH3:53])[CH3:55])[CH2:47][CH2:46]5)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCC1(N)CC1
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(F)cc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC4(CNC(=O)OC(C)(C)C)CC4)c3n2)c2ccc(F)cc21
Reaction time: 16 h

Procedure:
To a stirred solution of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (0.10 g, 0.32 mmol), EDCI (0.123 g, 0.64 mmol), DMAP (0.122 g, 1 mmol) and DIPEA (0.11 g, 0.90 mmol) in 6 mL of DMF was added tert-butyl (1-aminocyclopropyl)methylcarbamate (0.20 g, 1.07 mmol) in one portion at room temperature and stirred for 16 hours. The mixture was poured into 50 mL of water, and filtered. The filter cake was washed with water, dried and used in the next step without further purification. MS: (M+H)+=480.2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH:15]=[CH:16][CH2:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=2)=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:31]O>>[CH2:1]([O:8][C:9]1[C:10]([CH:15]=[CH:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:22]([O:24][CH3:31])=[O:23])=[CH:25][CH:26]=2)=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO
Reactant: O=C(O)c1ccc(CC=Cc2ncccc2OCc2ccccc2)cc1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(CC=Cc2ncccc2OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 49 %

Procedure:
4-[3-(3-Benzyloxy-2-pyridyl)prop-2-enyl)benzoic acid (0.1 g, 0.29 mmol) was dissolved in methanol (5 ml) and cooled to 0° C. To the solution was added thionyl chloride (0.086 g, 0.73 mmol). The reaction was allowed to warm to ambient temperature and stirred at ambient temperature for 18 hours. The reaction mixture was then evaporated, the residue partitioned between ethyl acetate and water and the organic phase dried (MgSO4) and evaporated. The residue was purified by chromatography (SiO2 EtOAc/CH2Cl2) to give methyl 4-[3-(3-benzyloxy-2-pyridyl)prop-2-enyl]benzoate as an oil (0.05 g, 49%).
Reaction SMILES: Cl.Cl.[OH:3][CH:4]([C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=2)[N:29]=[CH:28][CH:27]=1)[CH2:5][CH2:6][C@@H:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][S:15][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:9][C@@H:8]1[CH2:21][C:22]([O:24]C)=[O:23].[OH-].[Na+].C(Cl)(Cl)Cl>O1CCOCC1.C(OCC)C>[OH:3][CH:4]([C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=2)[N:29]=[CH:28][CH:27]=1)[CH2:5][CH2:6][C@@H:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][S:15][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:9][C@@H:8]1[CH2:21][C:22]([OH:24])=[O:23]
Reactant: COC(=O)C[C@H]1CN(CCSC2CCCC2)CC[C@H]1CCC(O)c1ccnc2ccc(OC)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: COc1ccc2nccc(C(O)CC[C@@H]3CCN(CCSC4CCCC4)C[C@@H]3CC(=O)O)c2c1
Temperature: 65 °C
Reaction time: 6 h
Yield: 99.4 %

Procedure:
A solution of 1.6 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclopentylthio)ethyl]piperidine-3-acetate dihydrochloride in 30 cm3 of dioxane, to which had been added 2.6 cm3 of 5N aqueous sodium hydroxide solution, was stirred for 6 hours at a temperature in the region of 65° C. After concentrating the reaction mixture under reduced pressure (5 kPa) at a temperature in the region of 40° C., a residue was obtained, which residue was taken up in 2 times 30 cm3 of chloroform and which was concentrated as under the above conditions. The residue was purified by chromatography at atmospheric pressure on a column of silica gel (particle size 20-45 μm; diameter 3 cm; silica volume 100 cm3), elution was carried out with a chloroform/methanol/28% aqueous ammonia (12/3/0.5 by volume) mixture, and 30-cm3 fractions were collected. The fractions comprising the expected product were combined and concentrated as above. 1.5 g of a colorless lacquer were obtained, which product was taken up in 20 cm3 of diethyl ether, filtered, and washed with 2 times 10 cm3 of diethyl ether. The product was dried under partial pressure (5 kPa) and then to constant weight in an oven under reduced pressure (10 Pa) at a temperature in the region of 40° C. 1.35 g of (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclopentylthio)ethyl]piperidine-3-acetic acid were obtained in the form of a white solid.
Reaction SMILES: [C:1]1([C:7]2([CH:17]=[O:18])[CH2:16][CH2:15][C:10]3([O:14][CH2:13][CH2:12][O:11]3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][Mg]Br.[Cl-].[NH4+].O>O1CCCC1.C(OCC)(=O)C>[CH3:19][CH:17]([C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9][C:10]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:15][CH2:16]1)[OH:18]
Reactant: C[Mg]Br
Reactant: O=CC1(c2ccccc2)CCC2(CC1)OCCO2
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(O)C1(c2ccccc2)CCC2(CC1)OCCO2
Temperature: 25 °C
Yield: 94.8 %

Procedure:
A solution of 8-phenyl-1,4-dioxaspiro[4.5]decane-8-carboxaldehyde (J. Med. Chem. 1975, 18, 593-599; 4 g, 16.2 mmol) in tetrahydrofuran (100 mL) was added dropwise to a solution of methyl magnesium bromide (3.0M in ether, 8.1 mL, 24.3 mmol) in tetrahydrofuran (50 mL) at 0° C. The mixture was allowed to warm to room temperature over 4 hours, then aqueous ammonium chloride (saturated, 75 mL), water (75 mL) and ethyl acetate (100 mL) were added. The layers were separated and the organic fraction was dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (4.03 g, 96%). 1H NMR (360 MHz, CDCl3) δ 0.96 (3H, d, J 6.5 Hz), 1.12 (1H, br s), 1.40-1.66 (4H, m), 1.76-1.86 (2H, m), 2.24-2.28 (1H, m), 2.46-2.51 (1H, m), 3.61-3.64 (1H, m), 3.58-3.96 (4H, m), and 7.21-7.38 (5H, m).
Reaction SMILES: [O:1]=[S:2]1(=[O:32])[C:8]2[CH:9]=[CH:10][C:11]([O:13][CH2:14][C:15]([O:17]CC)=[O:16])=[CH:12][C:7]=2[N:6]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:5][C:4]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:26][CH3:27])[CH2:3]1.[OH-].[Na+].C(O)C>CC(O)=O>[O:32]=[S:2]1(=[O:1])[C:8]2[CH:9]=[CH:10][C:11]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:12][C:7]=2[N:6]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:5][C:4]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:26][CH3:27])[CH2:3]1
Reactant: CCCCC1(CC)CN(c2ccccc2)c2cc(OCC(=O)OCC)ccc2S(=O)(=O)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: CCCCC1(CC)CN(c2ccccc2)c2cc(OCC(=O)O)ccc2S(=O)(=O)C1
Yield: 79.2 %

Procedure:
1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-(ethoxycarbonylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 3; 110 mg, 0.24 mmol) and sodium hydroxide (100 mg, 2.5 mmol) were added to ethanol (5 ml, 95%). The mixture was refluxed for 1 h. AcOH (0.30 ml) was added and the reaction mixture was evaporated under reduced pressure. The residue was extracted with DCM/water. The DCM layer was separated, dried and evaporated under reduced pressure. The residue crystallised when treated with hexane. 82 mg (79%) of the title compound was obtained. NMR (500 MHz): 0.7-0.9 (m, 6H), 1.1-1.7 (m, 8H), 3.1-3.25 (m, 2H), 3.6-3.8 (br d, 2H), 4.6 (s, 2H), 6.9-7.1 (m, 5H), 7.2-7.3 (m, 2H),
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([N+:18]([O-:20])=[O:19])[C:13]=1[NH:14][C:15](=[O:17])[CH3:16])[C:8]([OH:10])=[O:9])(=O)C.Cl>[OH-].[Na+].O>[C:15]([NH:14][C:13]1[C:12]([N+:18]([O-:20])=[O:19])=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=1[OH:4])(=[O:17])[CH3:16]
Reactant: CC(=O)Nc1c(OC(C)=O)cc(C(=O)O)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Nc1c(O)cc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.7 %

Procedure:
Compound 104 (0.850 g, 3.54 mmol) was dissolved in 0.1N NaOH (80 mL), and the mixture was stirred at room temperature for 4 hours. This was acidified with concentrated HCl (2 mL), diluted with water (20 mL), and extracted with ethyl acetate (3×60 mL). The combined extracts were dried (Na2SO4) and concentrated on a rotary evaporator to give crystalline 105 (0.712 g, 98.4% yield): mp 256-259° C. (methanol).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.[CH2:9]([O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=1)[CH3:10]>>[CH2:9]([O:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:6]([C:3]2[CH:4]=[CH:5][O:1][CH:2]=2)=[O:8])=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=1)[CH3:10]
Reactant: CCOc1ccc(N)c([N+](=O)[O-])c1
Reactant: O=C(O)c1ccoc1
Product: CCOc1ccc(NC(=O)c2ccoc2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared from 3-furoic acid and 4-ethoxy-2-nitroaniline as a yellow solid as described in Example 15. 1H NMR (DMSO-d6): 10.25 (s, 1H), 8.36 (d, J=2.4, 1H), 7.83-7.81 (m, 1H), 7.53-7.47 (m, 2H), 7.35-7.31 (m, 1H), 6.94 (d, J=2.4, 1H), 4.12 (q, J=6.9, 2H), 1.35 (t, J=6.9, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].[BrH:13].OO.S(=O)(O)[O-].[Na+].[OH-].[Na+]>O.C(O)(=O)C>[NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]([Br:13])=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5]
Reactant: Br
Reactant: CNC(=O)c1cccc(C)c1N
Agent: O=S([O-])O
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CNC(=O)c1cc(Br)cc(C)c1N
Temperature: 12 °C
Reaction time: 2.5 h

Procedure:
A mixture of 2-amino-N,3-dimethylbenzamide (i.e. the product of Step A of Example 5) (14 g, 85 mmol), acetic acid (50 mL), and water (50 mL) was cooled to 12° C., and concentrated hydrobromic acid (28.5 g, 0.34 mol) was added over 10 minutes at this temperature. Then 30% aqueous hydrogen peroxide (9 g, 0.08 mol) was added over 5 minutes at 10-11° C., and the mixture was allowed to warm slowly to room temperature while being stirred for 2.5 h. Then more concentrated hydrobromic acid (2.9 g) was added, and the mixture was stirred overnight at room temperature. To the mixture was then added water (50 mL) and sodium bisulfite (1.5 g), and then the pH was adjusted to 5-6 by the addition of 50% aqueous sodium hydroxide (˜15 mL). The mixture was filtered, and the solids were washed with water and dried in vacuo to afford the title compound, 19.5 g (94%).
Reaction SMILES: Br[CH2:2][CH:3]=[O:4].[CH3:5][CH:6]([NH2:12])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[OH-].[Na+]>O>[CH3:5][CH:6]([NH:12][CH2:2][CH:3]=[O:4])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: O=CCBr
Reactant: CCCCCC(C)N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCC(C)NCC=O
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
The diethylacetal of 2-bromoacetaldehyde (40 grams) and 1-methylhexylamine (50 grams) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture was heated at a temperature of about 100° C. for a period of about 3 hours. After this time sodium hydroxide (10 grams) dissolved in water (100 ml) was added and the resulting mixture stirred for about 30 minutes. The reaction mixture was then extracted with ether. The ether extract was separated, dried over magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product the diethylacetal of 2-(1-methylhexylamino)acetaldehyde having a boiling point of 110° C. at 1 mm of Hg pressure.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([CH2:13][CH2:14][CH2:15][CH3:16])=[N:7][C:6]2=[O:17].[C:18]([O-:21])(=[O:20])[CH3:19].[Na+]>CN(C=O)C>[C:18]([O:21][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([CH2:13][CH2:14][CH2:15][CH3:16])=[N:7][C:6]2=[O:17])(=[O:20])[CH3:19]
Reactant: CC(=O)[O-]
Reactant: CCCCc1nc(=O)c2cc(CBr)ccc2[nH]1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1nc(=O)c2cc(COC(C)=O)ccc2[nH]1
Temperature: 60 °C
Yield: 68 %

Procedure:
To a solution of 2.1 g (7.0 mmol) of the quinazolinone prepared in Example 18 in 15 mL of dry DMF was added 1.74 g (20.0 mmol) of sodium acetate. The mixture was heated to 60° C. for 3 hours. The reaction mixture was concentrated in vacuo and the residue dissolved in 100 mL of CH2Cl2. The solution was washed with water (3×20 mL), brine (1×20 mL) and dried over MgSO4. The mixture was filtered and concentrated in vacuo. The residue was recrystallized from MeOH/H2O to give the titled compound as a colorless solid. 68% yield. 1H-NMR (CDCl3): 0.99 (t, 3H, J=7.32 Hz), 1.50 (m, 2H), 1.83 (m, 2H), 2.14 (t, 3H), 2.77 (3 line m, 2H, J=7.71 Hz), 5.23 (s, 2H), 7.69-7/78 (m, 2H), 8.25 (s, 1H), 10.90 (bs, 2H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:12])[CH3:3].[Mg].[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1.[Cl-].[NH4+]>C(OCC)C.O>[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][C:6]2([OH:12])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:5]2[CH2:4][N:2]([CH3:1])[CH3:3])=[CH:17][CH:16]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: CN(C)CC1CCCCCC1=O
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Product: CN(C)CC1CCCCCC1(O)Cc1ccc(Cl)cc1
Reaction time: 2 h
Yield: 71 %

Procedure:
A solution of 32.00 g of 2-dimethylaminomethylcycloheptanone in 190 ml of absolute diethyl ether was added dropwise at 20° C., with stirring, to a freshly prepared solution of the Grignard reagent comprising 6.17 g of magnesium turnings and 40.50 g of 4-chlorobenzyl chloride in 500 ml of absolute diethyl ether. When the addition was complete, stirring was continued for a further 2 hours at 20° C. Decomposition was then effected, while cooling with ice, by the dropwise addition of 100 ml of a saturated ammonium chloride solution followed by 200 ml of distilled water. The organic phase was separated off, and the aqueous phase was extracted twice using 200 ml of ethyl acetate each time. The combined organic extracts were washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated by evaporation in vacuo. The oily residue was purified by column chromatography with ethyl acetate as eluant, 39.69 g of the title compound being obtained in the form of the free base. This was dissolved in 270 ml of 2-butanone and converted into the hydrochloride by addition of 2.8 ml of water and 17.4 ml of trimethylchlorosilane. 37.30 g (59.4% of theory) of the title compound as a diastereoisomeric mixture were obtained in the form of colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([OH:9])=[O:8])[N:3]=1.O=S(Cl)Cl.[CH3:14]O>>[NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([O:9][CH3:14])=[O:8])[N:3]=1
Reactant: Nc1nc(C(=O)O)n[nH]1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1n[nH]c(N)n1
Temperature: 70 °C
Reaction time: 48 h
Yield: 65 %

Procedure:
To a solution of 5-amino-1H-1,2,4-triazole-3-carboxylic acid (3.9 g, 30.45 mmol) in methanol (100 ml) was added SOCl2 (12 g, 100.84 mmol). The resulting solution was stirred for 48 h at 70° C. The resulting mixture was concentrated under vacuum, dissolved in water (100 ml), the pH was adjusted to 8 with NaHCO3 solution, and then extracted with dichloromethane (3×50 ml). The organic layer was dried over anhydrous magnesium sulfate and concentrated under vacuum to afford methyl 5-amino-1H-1,2,4-triazole-3-carboxylate as a white solid (800 mg, 65%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C(O[CH:16](N(C)C)[N:17]([CH3:19])[CH3:18])(C)(C)C>>[CH3:16][N:17]([CH:19]=[CH:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:10])[CH3:18]
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Product: CN(C)C=CC(=O)c1ccc(Cl)cc1

Procedure:
1-(4-Chloro-phenyl)-ethanone (49 mg, 0.3 mmol) was reacted with tert.-butoxy-bis-(dimethylamino)-methane using in analogous manner the procedure described in example 28a) to give crude title compound (87 mg) as a yellow solid which was used directly in the next step.
Reaction SMILES: [C:1]([O:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])(OC(C)(C)C)=O.O.Cl.[OH:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[CH2:24])=[CH:21][CH:20]=1>N1C=CC=CC=1>[OH:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[CH2:24])=[CH:21][CH:20]=1.[C:12]([O:11][C:9]([O:8][C:1]1[CH:24]=[CH:23][C:22]([CH:25]=[CH2:26])=[CH:21][CH:20]=1)=[O:10])([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: C=Cc1ccc(O)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: C=Cc1ccc(OC(=O)OC(C)(C)C)cc1
Temperature: 25 °C

Procedure:
In 40 ml of pyridine was dissolved poly p-hydroxystyrene (VP-8000, manufactured by Nippon Soda Co., Ltd., weight average molecular weight 1000), and 1.28 g of di-t-butyl dicarbonate was added to the solution with stirring at room temperature. After carrying out the reaction at room temperature for 3 hours, the reaction liquid was added to a solution of 1 liter of ion-exchanged water and 20 g of concentrated hydrochloric acid. The powder precipitated was collected by filtration, washed with water, and dried to obtain a p-hydroxystyrene/p-(t-butyloxycarbonyloxy)-styrene copolymer (60/40).