Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][S:7][C:8](=[NH:10])[NH2:9].[Cl:11][CH2:12][C:13](=O)[CH2:14][C:15](OCC)=[O:16].C(=O)([O-])[O-].[Na+].[Na+]>O>[Cl:11][CH2:12][C:13]1[N:9]=[C:8]([S:7][CH3:6])[N:10]=[C:15]([OH:16])[CH:14]=1
Reactant: CSC(=N)N
Reactant: CCOC(=O)CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CSc1nc(O)cc(CCl)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
S-Methyl-2-thiopseudourea sulphate (20 g, 71.85 mmol), ethyl 4-chloroacetoacetate (10.755 ml, 79.04 mmol) and sodium carbonate (13.925 g, 107.78 mmol) were dissolved in water (100 ml) and stirred at room temperature overnight. The reaction was monitored by TLC, and once complete, the reaction precipitate was collected and the supernatant was neutralised with 6N hydrochloric acid to yield more reaction precipitate which was also collected. The accumulated precipitate was then washed with water (×3) and an off-white solid was obtained. This was dried in vacuo at 60° C. for 48 hours to yield the desired compound as a pale yellow/white solid, 43.2 g.
Reaction SMILES: C(OC(N1CCN([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C@@H:21]3[O:30][C:25]4=[N:26][CH:27]=[CH:28][CH:29]=[C:24]4[O:23][CH2:22]3)=[CH:17][CH:16]=2)CC1)=O)(C)(C)C.Cl.[CH:32]12[NH:39][CH:36]([CH2:37][CH2:38]1)[CH2:35][N:34]([C:40](=[O:42])[CH3:41])[CH2:33]2>>[O:23]1[C:24]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[O:30][C@@H:21]([C:18]2[CH:19]=[CH:20][C:15]([CH2:14][N:39]3[CH:32]4[CH2:38][CH2:37][CH:36]3[CH2:35][N:34]([C:40](=[O:42])[CH3:41])[CH2:33]4)=[CH:16][CH:17]=2)[CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1
Reactant: CC(=O)N1CC2CCC(C1)N2
Agent: Cl
Product: CC(=O)N1CC2CCC(C1)N2Cc1ccc([C@H]2COc3cccnc3O2)cc1

Procedure:
Compound 271 is synthesized from Intermediate C and Intermediate U according to General Method H. (LC/MS method 16: ES+ m/z 380.5 [M+H]+, Rt=2.52 min)
Reaction SMILES: [NH2:1][C@@H:2]1[C@H:6]([NH:7][C:8]2[N:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[C:23]([Cl:24])=[C:22]([O:25][CH3:26])[CH:21]=[C:20]([O:27][CH3:28])[C:19]=4[Cl:29])[CH:14]=3)[N:9]=2)[CH2:5][C@H:4]([C:30]([N:32]([CH3:34])[CH3:33])=[O:31])[CH2:3]1.CCN(C(C)C)C(C)C.[C:44](Cl)(=[O:47])[CH:45]=[CH2:46]>C(Cl)Cl>[C:44]([NH:1][C@@H:2]1[C@H:6]([NH:7][C:8]2[N:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[C:23]([Cl:24])=[C:22]([O:25][CH3:26])[CH:21]=[C:20]([O:27][CH3:28])[C:19]=4[Cl:29])[CH:14]=3)[N:9]=2)[CH2:5][C@H:4]([C:30]([N:32]([CH3:34])[CH3:33])=[O:31])[CH2:3]1)(=[O:47])[CH:45]=[CH2:46]
Reactant: C=CC(=O)Cl
Reactant: COc1cc(OC)c(Cl)c(-c2ccc3nc(N[C@@H]4C[C@H](C(=O)N(C)C)C[C@@H]4N)ncc3c2)c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)N[C@H]1C[C@@H](C(=O)N(C)C)C[C@H]1Nc1ncc2cc(-c3c(Cl)c(OC)cc(OC)c3Cl)ccc2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52.5 %

Procedure:
(1R,3S,4R)-3-amino-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)-N,N-dimethylcyclopentanecarboxamide (0.050 g, 0.099 mmol) was taken up in CH2Cl2 (25 ml) and cooled to 0° C., followed by addition of DIEA (0.017 ml, 0.099 mmol) then acryloyl chloride (8.86 μl, 0.109 mmol) slowly. The reaction mixture was stirred at 0° C. for 30 minutes. After the reaction was complete, it was loaded directly onto silica and purified via flash chromatography (0-10% CH2Cl2/MeOH; 12 g column) to afford (1S,3S,4R)-3-acrylamido-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)-N,N-dimethylcyclopentanecarboxamide (0.029 g, 0.052 mmol, 52.4% yield). MS (ES+) C27H29Cl2N5O4 requires: 558, found: 559 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([N:5]1[CH2:9][CH:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][OH:20])=[CH:14][CH:13]=2)[O:7][C@H:6]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:4])[CH3:3].[C:27](Cl)(=[O:29])[CH3:28]>N1C=CC=CC=1>[C:27]([O:20][CH2:19][CH2:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][CH:8]2[O:7][C@@H:6]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[CH2:9]2)=[CH:13][CH:14]=1)(=[O:29])[CH3:28]
Reactant: CC(C)(C)N1CC(COc2ccc(CCO)cc2)O[C@H]1c1ccccc1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)OCCc1ccc(OCC2CN(C(C)(C)C)[C@H](c3ccccc3)O2)cc1
Temperature: -15 °C
Reaction time: 3 h

Procedure:
The residue from Example 1, Step A (2.55 g, 6.3 mmol) was dissolved in pyridine (10 ml), cooled to -15° C. and acetyl chloride (547 mg, 6.9 mmol) was added. The mixture was stirred at 0° C. for 3 hours then at room temperature overnight. The solvent was removed in vacuo. To the residue, dil. Na2CO3 solution was added (30 ml) and the mixture was extracted with CHCl3 (50 ml then 20 ml). The combined CHCl3 extracts were washed with H2O (30 ml), dried over Na2SO4 and evaporated in vacuo. The residue was used directly in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[Br:10]C1C=C(C)C=CC=1F>>[Br:10][C:7]1[C:2]([Br:1])=[C:3]([CH3:9])[CH:4]=[CH:5][C:6]=1[F:8]
Reactant: Cc1ccc(F)cc1Br
Reactant: Cc1ccc(F)c(Br)c1
Product: Cc1ccc(F)c(Br)c1Br
Yield: 9 %

Procedure:
11 g of iron powder were added to a solution of 110 g (1 mole) of 4-fluorotoluene in 165 ml of carbon tetrachloride. 160 g (1 mole) of bromine were added dropwise to this mixture at room temperature, the mixture was subsequently stirred for 24 hours, the solvent was distilled off under normal pressure and the residue was fractionated under normal pressure over a 10 cm Vigreux column. 26.4 g of unreacted 4-fluorotoluene were obtained as the first fraction at a boiling point of 114° to 117° C., and 78 g of a mixture consisting of 66% of 2-bromo-4-fluorotoluene, 24% of 3-bromo-4-fluorotoluene and 9% of dibromo-4-fluorotoluene were obtained as the second fraction at a boiling point of 175° to 185° C. Relative to the 4-fluorotoluene reacted, the yield of 2-bromo-4-fluorotoluene plus 3-bromo-4-fluorotoluene was 48% and that of 3-bromo-4-fluorotoluene was 11.4%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH:13]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:16][OH:17].Cl>N1C=CC=CC=1>[OH:17][N:16]=[CH:13][C@@H:9]1[CH2:10][CH2:11][CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C=NO
Temperature: 25 °C
Reaction time: 17 h
Yield: 90.4 %

Procedure:
To a solution of (S)-t-butyl-2-formylpyrrolidine-1-carboxylate (40.94 g) in pyridine (411 mL), hydroxylamine monohydrochloride (28.56 g) was added at 0° C. and the mixture was stirred at room temperature for 17 hours. The reaction mixture was added to a mixture of AcOE (1.5 L) and hydrochloric acid (2 L, 3.0 N). The organic layer was separated, washed with saturated aqueous sodium bicarbonate (1 L), dried (MgSO4), filtered and concentrated to give the titled compound (39.78 g, colorless solid.)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.F[C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1.[F-].[K+].C1OCCOCCOCCOCCOCCOC1>CS(C)=O.O>[Br:17][C:14]1[CH:15]=[CH:16][C:11]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)=[CH:12][CH:13]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: Fc1ccc(Br)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Brc1ccc(-n2ccc3ccccc32)cc1
Temperature: 25 °C

Procedure:
A solution of 1H-indole (3.0 g, 25.6 mmol), 4-fluorobromobenzene (4.48 g, 25.6 mmol), potassium fluoride (40% wt on alumina; 3.0 g) and 18-crown-6 (690 mg, 2.56 mmol) in anhydrous DMSO (30 mL) was heated at 150° C. for 24 hours, and then cooled to room temperature. The reaction mixture was poured into water (50 mL) and extracted with diethyl ether (3×50 mL). The combined organic extract was washed with water (2×30 mL), brine (3×30 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification of the product by flash column chromatography, using 20% ethyl acetate/hexane as eluent, afforded the title compound has a pale yellow solid (5.5 g, 76%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:21])([F:20])[F:19])[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.Cl.[NH2:23][C@@H:24]1[CH2:29][CH2:28][C@H:27]([OH:30])[CH2:26][CH2:25]1.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1>[F:19][C:18]([F:21])([F:20])[O:17][C:13]1[CH:12]=[C:11]([C:8]2[N:6]3[N:7]=[C:2]([NH:23][CH:24]4[CH2:29][CH2:28][CH:27]([OH:30])[CH2:26][CH2:25]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: FC(F)(F)Oc1cccc(-c2cnc3ccc(Cl)nn23)c1
Reactant: N[C@H]1CC[C@@H](O)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: OC1CCC(Nc2ccc3ncc(-c4cccc(OC(F)(F)F)c4)n3n2)CC1
Temperature: 180 °C
Reaction time: 0.75 h
Yield: 31.9 %

Procedure:
To a solution of 6-chloro-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazine (200 mg, 0.64 mmol) and cis-4-aminocyclohexanol hydrogenchloride (367 mg, 3.19 mmol) in NMP (2.0 mL) was added NaHCO3 (268 mg, 3.19 mmol), the mixture was stirred at 180° C. for 45 mins under microwave irridation. The mixture was purified by flash chromatograph to give 4-((3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexanol (80 mg, 32%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[NH:9][C:8](=O)[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:8]1[NH:7][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[C:10]=2[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c2cccc(Cl)c2[nH]1
Product: Clc1nc2c(Cl)cccc2[nH]1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 92 %

Procedure:
Phosphorus oxychloride (10 mL) was added to 4-chloro-1,3-dihydro-benzoimidazol-2-one (0.750 g, 4.45 mmol), and the mixture heated to 80° C. for 48 h. The mixture was cooled to 23° C. and POCl3 removed under reduced pressure. The residue was cooled to 0° C., and cold saturated aqueous NaHCO3 (20 mL) was added cautiously. After stirring at 23° C. for 15 min, the mixture was sonicated and the resulting residue was filtered to yield the titled compound (0.760 g, 92%), which was used in the next step without further purification. MS (ESI/CI): mass calcd. for C7H5Cl2N2, 186.0; m/z found, 187.0 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 13.68 (s, 1H), 7.51-7.42 (m, 1H), 7.32-7.25 (m, 1H), 7.22 (m, 1H).
Reaction SMILES: COC[O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)[CH:8]=[O:9].Cl.C(=O)([O-])O.[Na+]>CO>[OH:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)[CH:8]=[O:9]
Reactant: COCOc1cc(C=O)ccc1N1CCOCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: O=Cc1ccc(N2CCOCC2)c(O)c1
Temperature: 60 °C
Reaction time: 18 h
Yield: 100.5 %

Procedure:
3-Methoxymethoxy-4-(morpholin-4-yl)benzaldehyde (0.35 g) was dissolved in methanol (10 mL). To the mixture was added 2 mol/L hydrochloric acid (5 mL), and the mixture was stirred at 60° C. for 18 hours. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (0.29 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1C(C)(C)C.O.[C:19]([OH:23])(=O)[CH:20]=[O:21].O>ClCCCl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([C:6]([CH3:11])([CH3:7])[CH3:5])[C:9]2[O:12][C:20](=[O:21])[CH:19]([OH:23])[C:10]=2[CH:11]=1
Reactant: O=CC(=O)O
Reactant: COC(=O)CCc1ccc(O)cc1C(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCCl
Solvent: O
Product: COC(=O)CCc1cc2c(c(C(C)(C)C)c1)OC(=O)C2O
Yield: 200 %

Procedure:
23.6 g of 3-(2-tert-butyl-4-hydroxy-phenyl)-propionic acid methyl ester (U.S. Pat. No. 43070-A2), 10.1 g of glyoxylic acid monohydrate and 0.08 g of p-toluenesulfonic acid are boiled in 80 ml of 1,2-dichloroethane for 7 hours using a water separator. The reaction solution is then cooled, washed three times with 50 ml of water each time and freed of solvent using a rotary evaporator. 29.2 g of 3-(7-tert-butyl-3-hydroxy-2-oxo-2,3-dihydro-benzofuran-5-yl)-propionic acid methyl ester are obtained in the form of a yellowish oil. That yellowish oil is placed in 50 ml of toluene with 15 ml of thionyl chloride and 3 drops of DMF and the reaction mixture is then slowly heated to 100° C. at such a rate that the evolution of HCl and SO2 remains vigorous yet controllable. The reaction mixture is then stirred at that temperature for a further hour. Approximately 50 ml of liquid are then distilled off in order to remove the excess thionyl chloride. The residue is diluted with 160 ml of toluene and, at room temperature, 14 ml of triethylamine are added dropwise thereto. The thick, red reaction mixture is then heated under reflux for 30 min. After cooling to room temperature, the triethylamine hydrochloride which has precipitated is filtered off and the filtrate is concentrated to an oily consistency using a rotary evaporator. The isoxindigo is crystallised out by adding 100 ml of acetonitrile, is filtered off, washed with acetonitrile and dried. 7.4 g (27% of the theoretical yield) of 3-[7,7′-di-tert-butyl-2,2′-dioxo-[3,3′]bibenzofuranyliden-5-yl]-5,5′-propionic acid methyl ester (LVIa) are obtained.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][N:10]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[S:11]([NH:14][C:15](=[O:30])[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)(=[O:13])=[O:12])[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:45](Cl)(=[O:52])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>ClCCl>[CH2:31]([N:10]([CH2:9][CH:6]1[CH2:5][CH2:4][CH:3]([CH2:2][NH:1][C:45](=[O:52])[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:8][CH2:7]1)[S:11]([NH:14][C:15](=[O:30])[C:16]1[CH:17]=[C:18]([C:26]([F:27])([F:28])[F:29])[CH:19]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:21]=1)(=[O:12])=[O:13])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCC1CCC(CN(Cc2ccccc2)S(=O)(=O)NC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCC1CCC(CN(Cc2ccccc2)S(=O)(=O)NC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1)c1ccccc1
Reaction time: 0.5 h

Procedure:
Amine (22) (23.5mg, 40 μmole, 1.0 eq) was suspended in dichloromethane, then triethylamine (16.7 μL, 120 μmole, 3.0 eq) and benzoyl chloride (4.7 μL, 40 μmole, 1.0 eq) were added and the reaction stirred 30 minutes. Silica gel chromatography provided the title compound. 1H NMR (500 MHz, DMSO-d6): δ 8.45 (s, 2H), 8.32 (t, 1H), 8.18 (s, 1H), 7.77 (d, 2H), 7.47 (t, 1H), 7.37 (m, 4H), 7.25 (d, 2H), 7.18 (t, 1H), 4.40 (s, 2H), 3.30 (water), 2.98 (t, 4H), 2.48 (DMSO), 1.61 (m, 4H), 1.36 (m, 1H), 1.28 (m, 1H), 0.62 (m, 4H).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].C(=O)(O)[O-].[Na+].[Cl:18][C:19]1[C:20](Cl)=[N:21][CH:22]=[C:23]([CH:26]=1)[C:24]#[N:25]>O1CCOCC1>[Cl:18][C:19]1[C:20]([NH:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[N:21][CH:22]=[C:23]([C:24]#[N:25])[CH:26]=1
Reactant: N#Cc1cnc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)CCCN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CCCNc1ncc(C#N)cc1Cl
Temperature: 50 °C

Procedure:
A mixture of tert-butyl 4-aminobutanoate hydrochloride (Bachem F-3755, 8.54 g, 28.9 mmol), sodium bicarbonate (6.0 g, 72.2 mmol) and 5,6-dichloronicotinonitrile (Bionet GC-0755, 5.0 g, 28.9 mmol) was prepared in dioxane under nitrogen, and then heated at 50° C. for 16 hours. The reaction mixture was filtered to remove inorganic solids and filtrate was concentrated under reduced pressure. After purification by flash chromatography (silica, pet ether/EtOAc), the title compound was obtained as a white powder. 1H NMR (DMSO-d6, 400 MHz) δ 8.40 (1H, d), 8.05 (1H, d), 7.58 (1H, t), 3.42 (2H, m), 2.21 (2H, t), 1.76 (2H, m), 1.37 (9H, s).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:16])[C@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:17]([CH2:20][C:21]1[N:26]=[C:25]([CH2:27][C:28]([OH:30])=O)[CH:24]=[CH:23][CH:22]=1)([OH:19])=O>CO.CCOC(C)=O>[CH2:2]([O:9][C:10]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:17](=[O:19])[CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]([CH2:27][C:28]([N:12]2[CH2:13][CH2:14][CH2:15][C@@H:11]2[C:10]([O:9][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:16])=[O:30])[N:26]=1)=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)Cc1cccc(CC(=O)O)n1
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(OCc1ccccc1)[C@H]1CCCN1C(=O)Cc1cccc(CC(=O)N2CCC[C@@H]2C(=O)OCc2ccccc2)n1
Yield: 7.8 %

Procedure:
Using General Procedure A with 9.7 g (40 mmol) D-Proline benzyl ester hydrochloride and 3.9 g (20 mmol) (6-carboxymethyl-pyridin-2-yl)-acetic acid afforded, after flash chromatography (gradient: 0-10% MeOH/EtOAc), 890 mg (8%) of the title compound as a yellow oil. MS m/e (%): 570 (M+H+, 100).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([CH3:14])[C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][C:16]1([CH3:24])[O:21][C:20](=[O:22])[CH2:19][C:18](=[O:23])[O:17]1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH:10]([CH3:14])[C:11]([CH:19]1[C:20](=[O:22])[O:21][C:16]([CH3:24])([CH3:15])[O:17][C:18]1=[O:23])=[O:13])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CC(CNC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(CNC(=O)OC(C)(C)C)C(=O)C1C(=O)OC(C)(C)OC1=O
Temperature: 0 °C
Reaction time: 18 h

Procedure:
The 3-[(tert-butoxycarbonyl)amino]-2-methylpropanoic acid (3.0 g, 14.76 mmol) was dissolved in CH2Cl2 (73.8 ml), cooled to 0° C. and treated with 2,2-dimethyl-1,3-dioxane-4,6-dione (2.55 g, 17.71 mmol) and DMAP (2.71 g, 22.14 mmol) and EDC (3.40 g, 17.71 mmol) and allowed to stir at room temperature for 18 hrs. The reaction mixture was diluted with CH2Cl2, washed with 5% KHSO4 (×3), dried (Na2SO4), filtered and evaporated in vacuo to give the title compound: 1H NMR (400 MHz, CDCl3) δ 4.78 (bs, 1H), 4.23 (bs, 1H), 3.42 (m, 2H), 1.75 (s, 6H), 1.41 (s, 9H), 1.23 (d, J=6.8 Hz, 3H).
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[CH:5]=[C:6]([C:14]([C:27]#[N:28])([CH2:21][CH2:22][C:23](OC)=[O:24])[CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12].[H-].[Na+]>COCCOC>[C:17]([CH:16]1[CH2:15][C:14]([C:6]2[CH:7]=[CH:8][C:9]([O:10][CH:11]([F:12])[F:13])=[C:4]([O:3][CH:2]([F:29])[F:1])[CH:5]=2)([C:27]#[N:28])[CH2:21][CH2:22][C:23]1=[O:24])([O:19][CH3:20])=[O:18]
Reactant: COC(=O)CCC(C#N)(CCC(=O)OC)c1ccc(OC(F)F)c(OC(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)C1CC(C#N)(c2ccc(OC(F)F)c(OC(F)F)c2)CCC1=O
Temperature: 25 °C
Yield: 46.8 %

Procedure:
To a solution of dimethyl 4-(3,4-bisdifluoromethoxyphenyl)-4-cyanopimelate (45.32 g, 107 mmol) in dry 1,2-dimethoxyethane (450 mL) under an argon atmosphere was added sodium hydride (80% dispersion in mineral oil, 13 g, 432 mmol). The resulting mixture was refluxed for 1 h, was cooled to room temperature was quenched with water and was concentrated. The mixture was partitioned between ether and acidic brine, was extracted twice with ether, the organic layer was dried (magnesium sulfate) and the solvent was removed in vacuo. The residue was purified by flash chromatography, eluting with 3:1 hexanes/ethyl acetate, to provide a pale-orange oil (19.5 g, 46.6%).
Reaction SMILES: N#N.[C:3]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])(=[O:5])[CH3:4].OS(O)(=O)=O.[C:18]([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.CO>[CH3:18][O:11][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][C:3](=[O:5])[CH3:4]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)CCCCC(=O)O
Agent: N#N
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)CCCCC(C)=O
Temperature: 25 °C

Procedure:
In a flame dried round-bottomed flask under inert atmosphere (N2), a solution of 5-acetylvaleric acid (7.54 g, 50.21 mmol) in a mixture of CH2Cl2 (35 mL) and MeOH (14 mL) was treated with conc. H2SO4 (0.14 mL, 2.51 mmol) and the reaction mixture was stirred at reflux for 24 h. The mixture was cooled to rt and sat. aq. Na2CO3 was added. The aq. layer was extracted with CH2Cl2 and the combined organic layers were washed with water, dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (50:1→1:2 hept-EA) gave the title compound as an orange oil.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]1=[O:14])=[O:5].[C:20]1(C)[CH:25]=[CH:24]C(S(O)(=O)=O)=[CH:22][CH:21]=1>CN(C=O)C>[CH2:21]([C:22]1[N:6]([CH:7]2[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]2=[O:14])[C:4](=[O:5])[C:3]2[C:2](=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:19])[N:1]=1)[CH2:20][CH2:25][CH3:24]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1cccc(N)c1C(=O)NC1CCC(=O)NC1=O
Solvent: CN(C)C=O
Product: CCCCc1nc2cccc(C)c2c(=O)n1C1CCC(=O)NC1=O
Yield: 30.1 %

Procedure:
A solution of 2-amino-N-(2,6-dioxo-piperidin-3-yl)-6-methyl-benzamide (0.65 g, 2.5 mmol) and trimethyl orthopentionate (0.66 mL, 3.8 mmol) and p-toluenesulfonic acid (140 mg) in DMF (7 mL) was heated at 150° C. in a microwave oven for 20 minutes. The mixture was extracted with ethyl acetate (50 mL) and water (50 mL). The aqueous layer was extracted with ethyl acetate (50 mL). The combined organic layers was washed with water (50 mL), HCl (1N, 50 mL) and brine (50 mL). The solvent was removed in vacuo to give an oil, which was purified with column chromatography (Silica Gel, methanol/methylene chloride 0% gradient to 5% 15 min), and followed by reversed layer column chromatography (C-18, acetonitrile/water 0% gradient to 100% 15 min) to give 3-(2-butyl-5-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as a white solid (80 mg, 10% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 grad 90/10 in 5 min CH3CN/0.1% H3PO4, 6.59 min (95.4%); mp: 190-192° C.; 1H NMR (DMSO-d6) δ 0.95 (t, J=8 Hz, 3H, CH3), 1.40-1.49 (m, 2H, CH2), 1.67-1.75 (m, 2H, CH2), 2.05-2.09 (m, 1H, CHH), 2.51-2.67 (m, 3H, CH2, CHH), 2.69 (s, 3H, CH3), 2.81-2.90 (m, 3H, CH2, CHH), 5.20 (dd, J=5, 11 Hz, 1H, NCH), 7.25 (d, J=7 Hz, 1H, Ar), 7.44 (d, J=8 Hz, 1H, Ar), 7.64 (t, J=8 Hz, 1H, Ar), 10.98 (s, 1H, NH); 13C NMR (DMSO-d6) δ 13.80, 21.11, 21.72, 22.48, 28.60, 30.50, 34.42, 55.41, 118.63, 124.98, 128.83, 133.70, 139.81, 148.25, 156.95, 161.17, 169.75, 172.65; LCMS: MH=328; Anal Calcd for C18H21N3O3: C, 66.04; H, 6.47; N, 12.84. Found: C, 65.87; H, 6.61; N, 12.89.
Reaction SMILES: C1(C[O:8][C:9]2[CH:10]=[C:11]([CH2:23][CH2:24][N:25]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][S:38][CH2:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)C(=O)C(F)(F)F)[CH:12]=[CH:13][C:14]=2[O:15]CC2C=CC=CC=2)C=CC=CC=1.[OH-].[Na+]>C(O)C>[C:41]1([CH2:40][CH2:39][S:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][NH:25][CH2:24][CH2:23][C:11]2[CH:10]=[C:9]([OH:8])[C:14]([OH:15])=[CH:13][CH:12]=2)[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: O=C(N(CCCCCCSCCc1ccccc1)CCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Oc1ccc(CCNCCCCCCSCCc2ccccc2)cc1O

Procedure:
The product from step (b) (7.0 g, 0.011 mole) was heated to reflux for 2 hr with a solution of sodium hydroxide (0.93 g, 0.023 mole) in 90% ethanol (100 ml). The cooled solution was concentrated in vacuo and the residue diluted with water and extracted with dichloromethane. The extracts were washed with water, dried (MgSO4) and evaporated. The residue was dissolved in ether and treated with ethereal-HCl to give the sub-title compound as the hydrochloride salt, a white solid (5.5 g) mp 89°-91°.