Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([CH:4]=[C:5]1[NH:9][CH2:8][CH2:7][NH:6]1)([O-:3])=[O:2].[Cl:10]/[CH:11]=[CH:12]/[CH2:13]Cl>>[Cl:10]/[CH:11]=[CH:12]/[CH2:13][N:6]1[CH2:7][CH2:8][NH:9][C:5]1=[CH:4][N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])C=C1NCCN1
Reactant: Cl/C=C/CCl
Product: O=[N+]([O-])C=C1NCCN1C/C=C/Cl

Procedure:
Method B, reacting 2-(nitromethylene)imidazolidine with trans-1,3-dichloro-1-propene. Melting point: 134°-135°C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[CH3:15][S:16]([CH2:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](O)=[O:24])(=[O:18])=[O:17]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][CH:28]=[C:20]([CH2:19][S:16]([CH3:15])(=[O:18])=[O:17])[CH:21]=2)=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: CS(=O)(=O)Cc1cccc(C(=O)O)c1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: CS(=O)(=O)Cc1cccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c1

Procedure:
300 mg of methyl 3-(bromomethyl)benzoate was reacted via Procedure O to give methyl 3-(methylsulfonylmethyl)benzoate. 230 mg of methyl 3-(methylsulfonylmethyl)benzoate was reacted via Procedure M to give 3-(methylsulfonylmethyl)benzoic acid. 75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 3-(methylsulfonylmethyl)benzoic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield pure N-(4-chloro-3-(pyridin-2-yl)phenyl)-3-(methylsulfonylmethyl)benzamide. MS (Q1) 401 (M)+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH:21]1[C:30]2[N:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:24][CH2:23][CH2:22]1)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][NH2:20])=[CH:15][CH:14]=1.C(OC([N:38]1[CH2:45][CH2:44][CH2:43][C@H:39]1[C:40](O)=[O:41])=O)(C)(C)C.C(N(CC)C(C)C)(C)C.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][NH:20][C:40]([C@@H:39]2[CH2:43][CH2:44][CH2:45][NH:38]2)=[O:41])=[CH:17][CH:18]=1)[CH:21]1[C:30]2[N:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:24][CH2:23][CH2:22]1
Reactant: NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: O=C(NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1)[C@@H]1CCCN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 116.9 %

Procedure:
To a stirred solution of N′-(1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (148 mg, 0.37 mmol) in dry CH2Cl2 (5 mL) was added N-(tert-butoxycarbonyl)-L-proline (88 mg, 0.41 mmol), N,N-diisopropylethylamine (0.13 mL, 0.75 mmol), 1-hydroxybenzotriazole hydrate (68 mg, 0.50 mmol) and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide HCl (EDC) (99 mg, 0.52 mmol) and the mixture stirred at room temperature overnight. The reaction mixture was diluted with CH2Cl2 (25 mL) and saturated aqueous sodium bicarbonate (30 mL) and the aqueous layer was separated and extracted with CH2Cl2 (2×15 mL). The combined organic phases were dried (Na2SO4), filtered and evaporated in vacuo to give the crude product as a white foam. Purification by column chromatography on silica gel (CH2Cl2/MeOH, 96:4) gave the desired amide (214 mg, 85%) as a white foam.
Reaction SMILES: [Na].C([C:4]([CH2:11][CH3:12])([C:8]([O-:10])=[O:9])C([O-])=O)C.Cl[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22]/[CH:23]=[CH:24]\[CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30]CC>C(O)CCC>[C:8]([OH:10])(=[O:9])[CH2:4][CH2:11][CH2:12][CH2:30][CH2:29][CH2:28][CH2:27]/[CH:26]=[CH:25]\[CH2:24]/[CH:23]=[CH:22]\[CH2:21]/[CH:20]=[CH:19]\[CH2:18][CH2:17][CH2:16][CH2:15][CH3:14]
Reactant: CCCCC/C=C\C/C=C\C/C=C\CCCCCCCl
Reactant: CCC(CC)(C(=O)[O-])C(=O)[O-]
Agent: [Na]
Solvent: CCCCO
Product: CCCCC/C=C\C/C=C\C/C=C\CCCCCCCC(=O)O
Temperature: 140 °C
Reaction time: 20 h

Procedure:
To 15 ml. of n-butanol under nitrogen was added 211 mg. of sodium in pieces. The mixture was heated gently until all the sodium had dissolved, then 1.2 ml. of diethylmalonate was added and the mixture was refluxed one hour, then cooled, and a solution of 2.0 g. of 1-chloro-cis,cis,cis-7,10,13-nonadecatriene in 7.5 ml. of n-butanol was added. The resulting reaction mixture was refluxed for 3 hrs. under nitrogen, then allowed to stand for about 20 hrs., and concentrated under reduced pressure. The thus obtained residue was dissolved in a solution of 1.9 g. of potassium hydroxide in 38 ml. of 95% ethanol and heated under reflux for 3.5 hrs., then was concentrated to about 1/3 volume, diluted with water, and extracted with ether. The ether solution was extracted with 1N aqueous sodium hydroxide. The sodium hydroxide solution was made acid with 3N hydrochloric acid and extracted twice with ether. The ether extracts were washed with water, then with saturated aqueous sodium chloride, dried over sodium sulfate, and evaporated to give 1.72 g. of a pale yellow oil. The thus obtained oil was heated in a short path distillation tube at 140°C. under reduced pressure until decarboxylation was complete, then was distilled at a bath temperature of 180°-200°/0.006 mm., thus obtaining a distillate comprising cis,cis,cis-9,12,15-heneicosatrienoic acid.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:17][C:18]([C:20]2[N:24]([CH3:25])[N:23]=[CH:22][C:21]=2[C:26](O)=[O:27])=[O:19])=[CH:4][C:5]2[N:6]([N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.CCCP(=O)=O.C(N(C(C)C)CC)(C)C>O1CCCC1>[F:1][C:2]1[C:3]([NH:17][C:18]([C:20]2[N:24]([CH3:25])[N:23]=[CH:22][C:21]=2[C:26]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:27])=[O:19])=[CH:4][C:5]2[N:6]([N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1cc2nc(-c3ccccc3)nn2cc1F
Reactant: C1COCCN1
Agent: CCCP(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cn1ncc(C(=O)N2CCOCC2)c1C(=O)Nc1cc2nc(-c3ccccc3)nn2cc1F
Temperature: 70 °C
Reaction time: 60 h
Yield: 41.1 %

Procedure:
A mixture of 5-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid (138 mg, 363 μmol), morpholine (253 μl, 2.9 mmol), propylphosphonic anhydride (50% in ethyl acetate, 534 μl, 907 μmol) and diisopropylethylamine (190 μl, 1.09 mmol) in tetrahydrofuran (10 ml) was stirred for 2.5 days (weekend) at 70° C. under nitrogen atmosphere. The solvent was evaporated, the residue was triturated with saturated aqueous sodium hydrogencarbonate solution and the precipitated solid was filtered off and dried in vacuum. The crude material was applied on silica and purified by flash chromatography over a 20 g silica column using heptane/ethyl acetate 10-100% as eluent, affording 2-methyl-4-(morpholine-4-carbonyl)-2H-pyrazole-3-carboxylic acid (6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-amide (67 mg, 41.1%) as white solid. Mp.: 224-225° C. MS: m/z=450.0 (M+H+).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:12]([CH:13]([CH3:15])[CH3:14])=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2.[S:16](Cl)([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17].[NH4+].[Cl-]>C1COCC1>[Br:3][C:4]1[C:12]([CH:13]([CH3:15])[CH3:14])=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][N:8]2[S:16]([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)c1ccc2[nH]ncc2c1Br
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2ncc3c(Br)c(C(C)C)ccc32)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
NaH (60% dispersion in mineral oil, 241 mg, 6.02 mmol) was added to a solution of 4-bromo-5-isopropyl-1H-indazole (720 mg, 3.01 mmol) in THF (15 mL) at 0° C. After 10 min, TsCl (861 mg, 4.52 mmol) was added and the resulting mixture was stirred at 0° C. for 1 h, then at room temperature overnight. Saturated aqueous NH4Cl was added and the mixture was extracted with EtOAc (2×). The combined organics were washed with brine, dried (Na2SO4) and concentrated. Ther residue was purified by silica gel chromatography (0-30% EtOAc/heptanes) to provide 4-bromo-5-isopropyl-1-tosyl-1H-indazole. MS (ESI+) m/z 394.8 (M+H)+.
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]([CH3:26])[C:16]3[NH:21][C:20](=[O:22])[O:19][C:18]([CH3:24])([CH3:23])[C:17]=3[CH:25]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:27]O>>[C:1]1([S:7]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]([CH3:26])[C:16]3[NH:21][C:20](=[O:22])[O:19][C:18]([CH3:23])([CH3:24])[C:17]=3[CH:25]=2)=[O:27])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OO
Reactant: Cc1cc(OCCCCSc2ccccc2)cc2c1NC(=O)OC2(C)C
Product: Cc1cc(OCCCCS(=O)c2ccccc2)cc2c1NC(=O)OC2(C)C

Procedure:
Prepared analogously to Example 2 from 6-(4-phenylmercapto-butoxy)-4,4,8-trimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=3)[C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: O=[N+]([O-])c1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(Cl)nc2s1
Product: O=[N+]([O-])c1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-n3cncn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-6-nitro-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-nitro-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([CH:3]1[C:12](=[O:13])[N:11]2[C:6]([CH:7]=[CH:8][CH:9]=[CH:10]2)=[C:5]2[C:14]([CH2:17][CH2:18][CH3:19])=[N:15][N:16]=[C:4]12)#[N:2].[C:20](OC(=O)C)(=[O:22])[CH3:21]>>[C:20]([N:16]1[C:4]2=[C:3]([C:1]#[N:2])[C:12](=[O:13])[N:11]3[C:6]([CH:7]=[CH:8][CH:9]=[CH:10]3)=[C:5]2[C:14]([CH2:17][CH2:18][CH3:19])=[N:15]1)(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: CCCC1=NN=C2C1=C1C=CC=CN1C(=O)C2C#N
Product: CCCc1nn(C(C)=O)c2c(C#N)c(=O)n3ccccc3c12

Procedure:
A mixture of 80 g of 4-cyano-1-propyl-5H-pyrazolo-[4,3-a]quinolizin-5-one (S-1) and 2.0 l of acetic anhydride was heated under reflux for 18 hours. The solvent was evapolated under reduced pressure and the residual crystals were washed with water (0.5 l), methyl alcohol (0.5 l) and chloroform (0.5 l) successively to give 84 g of 3-acetyl-4-cyano-1-propyl-5H-pyrazolo-[4,3-a]quinolizin-5-one as pale yellow crystals.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:18][N:17]=[C:16]([C:19]3[N:24]=[C:23]([NH2:25])[N:22]=[C:21]([N:26]([CH3:33])[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:20]=3)[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:34]>O1CCOCC1.C(Cl)Cl>[ClH:34].[CH3:33][N:26]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[N:22]=[C:23]([NH2:25])[N:24]=[C:19]([C:16]2[N:15]=[C:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[O:18][N:17]=2)[N:20]=1
Reactant: CN(c1ccccc1)c1nc(N)nc(-c2noc(C3CCN(C(=O)OC(C)(C)C)CC3)n2)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CN(c1ccccc1)c1nc(N)nc(-c2noc(C3CCNCC3)n2)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
tert-Butyl-4-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-triazin-2-yl}-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate (Intermediate 106, 934 mg, 2.06 mmol) and 4M hydrogen chloride in 1,4-dioxane (5 mL) was combined in DCM (5 mL) at 0 C. The reaction was warmed to RT and left to stir for 18 h. The mixture was concentrated under reduced pressure to give title compound as a yellow solid (832 mg). Method B HPLC-MS: MH+ requires m/z=352 Found: m/z=353, Rt=1.23 min (100%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:23][C:24]1[C:32]([OH:33])=[CH:31][CH:30]=[C:29]2[C:25]=1[CH:26]=[CH:27][NH:28]2.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:23][C:24]1[C:32]([O:33][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:31][CH:30]=[C:29]2[C:25]=1[CH:26]=[CH:27][NH:28]2
Reactant: Oc1ccc2[nH]ccc2c1F
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]ccc4c3F)ncnc2cc1OCCCN1CCCC1
Temperature: 95 °C
Yield: 51.9 %

Procedure:
A solution of 4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (1.76 g, 5.47 mmol), (prepared as described for the starting material in Example 9), 4-fluoro-5-hydroxyindole (0.992 g, 6.57 mmol), (prepared as described for the starting material in Example 242), in DMF (25 ml) containing potassium carbonate (1.14 g; 8.21 mmol) was heated at 95° C. for 1 hour. After cooling, the mixture was filtered and washed with DMF. The filtrate was evaporated and the residue was purified by column chromatography eluting with methanol/methylene chloride (1/9) followed by methanol/methanol chloride/methanol (containing ammonia) (16/80/4). The fractions containing the expected product were combined and evaporated. The residue was repurified by column chromatography eluting with a gradient of methylene chloride/methanol (80/20 to 40/60). The fractions containing the expected product were combined and evaporated. The residue was triturated in cold methanol and the solid was filtered, washed with ether and dried under vacuum to give 4-(4-fluoroindol-5-yloxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (1.24 g, 52%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.[CH2:21](Br)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Reactant: BrCCc1ccccc1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(CCc3ccccc3)C2=O)cn1
Yield: 37 %

Procedure:
Prepared as in example 10-52 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and phenethylbromide. Yield: 37%. 1H NMR (DMSO-d6, 400 MHz): δ2.11 (s, 3H), 2.38 (s, 3H), 2.83 (t, J=6.4 Hz, 2H), 3.55 (t, J=7.4 Hz, 2H), 4.03 (s, 2H), 5.17 (s, 2H), 7.18-7.30 (m, 5H), 7.73 (s, 1H), 8.13 (s, 1H). MS M+H calculated 380.2; found 380.1. Melting point: 95-96° C. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.14 μM.
Reaction SMILES: [CH3:1][C:2]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:6])[C:3]([NH2:5])=O.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[CH3:6][C:2]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:1])[C:3]#[N:5]
Reactant: CC(C)(Oc1ccccc1)C(N)=O
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC(C)(C#N)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-methyl-2-phenoxypropanamide from Step C (0.01 mol) in dry CH2Cl2 (50 mL) and triethylamine (3.03 g, 0.03 mol) at 0° C. was added trifluoroacetic anhydride (3.15 g, 0.015 mol). After the addition was complete, the solution was allowed to warm to room temperature and stirring was continued at ambient temperature overnight. The reaction mixture was then refluxed for 3 hours. After cooling to room temperature and dilution with CH2Cl2 (100 mL), the solution was washed with saturated aqueous NaHCO3 (50 mL×3), water, and brine and dried over sodium sulfated. Evaporation gave the titled compound. 1H NMR (400 MHz, CDCl3) δ ppm 7.32˜7.36 (m, 2H), 7.14˜7.20 (m, 3H), 1.71 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([CH2:18][N:19]2[CH2:24][CH2:23][N:22](C(C)C)[CH:21]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:20]2)[CH:15]=[C:14]2[C:9]=1[CH2:10][NH:11][C:12](=[O:43])[N:13]2[C:35]1[C:40]([Cl:41])=[CH:39][CH:38]=[CH:37][C:36]=1[Cl:42].O>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([CH2:18][N:19]2[CH2:24][CH2:23][NH:22][CH:21]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:20]2)[CH:15]=[C:14]2[C:9]=1[CH2:10][NH:11][C:12](=[O:43])[N:13]2[C:35]1[C:40]([Cl:41])=[CH:39][CH:38]=[CH:37][C:36]=1[Cl:42]
Reactant: CC(C)N1CCN(Cc2cc(-c3ccccc3Cl)c3c(c2)N(c2c(Cl)cccc2Cl)C(=O)NC3)CC1C(=O)OC(C)(C)C
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)C1CN(Cc2cc(-c3ccccc3Cl)c3c(c2)N(c2c(Cl)cccc2Cl)C(=O)NC3)CCN1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To the solution of tert-butyl 4-{[5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl]methyl}-1-isopropylpiperazine-2-carboxylate (EXAMPLE AAA11, 30 mg, 0.047 mmol) in trifluoroacetic acid (0.6 mL) was added water (0.03 mL). The reaction was stirred at rt for 20 h. Removal of the solvent and subsequent addition of ether resulted in a white precipitate. Filtration of the precipitate followed by washing with ether provided the title compound. 1H NMR (CDCl3, 500 MHz): δ 1.22 (d, 3H, J=7.0 Hz), 1.24 (d, 3H, J=6.9 Hz), 3.12(m, 2H), 3.30 (m, 1H), 3.44 (m, 1H), 3.50 (abq, 2H, J=7.1 Hz), 3.74 (m, 1H), 3.81 (m, 1H), 3.96 (m, 1H), 4.07 (m, 1H), 4.28 (dd, 1H, J1=14.6 Hz, J2=5.7 Hz), 4.42 (dd, 1H, J1=14.9 Hz, J2=10.1 Hz), 5.80 (brs, 1H), 6.13 (d, 1H, J=9.8 Hz), 6.95 (s, 1H), 7.32-7.58 (m, 7H). MS (API-ES+): 589 (M+H).
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=1)#[C:2][CH3:3].C(N(CC)CC)C>CCO.[Pd]>[CH2:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=1)[CH2:2][CH3:3]
Reactant: CC#Cc1ccc(C(=O)O)cn1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCc1ccc(C(=O)O)cn1
Yield: 97.6 %

Procedure:
A solution of the product of Step A (0.25 g; 1.55 mmol), 10% Pd/C (0.15 g) and triethylamine (0.5 ml) in EtOH (15 ml) was stirred overnight at room temperature under H2 (Parr apparatus; 100 psi). The catalyst was removed by filtration, washed with fresh EtOH (2×10 ml), and combined filtrates were evaporated to dryness to give the title compound (0.25 g; 100%), as greyish solid, which was used in the next Step without further purification. 1H-NMR (CDCl3) 0.94 (tr, 3H, J=6 Hz); 1.69-1.81 (m, 2H); 2.83 (tr, 2H, J=6 Hz); 7.2 (d, 1H, J=9 Hz); 8.19 (s, 1H); 8.28 (d, 1H, J=9 Hz); 10.65 (broad s, 1H).
Reaction SMILES: [NH2:1][C@H:2]([C:12]1[O:13][C:14]([C:17]2[C:18]([O:27][CH3:28])=[N:19][C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:15][N:16]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8](=[O:11])[CH2:9][CH3:10].[CH3:29][O:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[NH:36][C:35]([CH3:40])=[C:34]2[CH2:41][C:42](O)=[O:43].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>CN(C=O)C.O.CC#N>[CH3:29][O:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[NH:36][C:35]([CH3:40])=[C:34]2[CH2:41][C:42]([NH:1][C@H:2]([C:12]1[O:13][C:14]([C:17]2[C:18]([O:27][CH3:28])=[N:19][C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:15][N:16]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8](=[O:11])[CH2:9][CH3:10])=[O:43]
Reactant: CCC(=O)CCCCC[C@H](N)c1nnc(-c2cc3ccccc3nc2OC)o1
Reactant: COc1ccc2[nH]c(C)c(CC(=O)O)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCC(=O)CCCCC[C@H](NC(=O)Cc1c(C)[nH]c2ccc(OC)cc12)c1nnc(-c2cc3ccccc3nc2OC)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(S)-9-amino-9-(5-(2-methoxyquinolin-3-yl)-1,3,4-oxadiazol-2-yl)nonan-3-one (0.05 mmol, 1 eq), prepared as described above, was treated with a solution of (5-methoxy-2-methyl-1H-indol-3-yl)acetic acid (1.3 eq), HOBT (1.3 eq) and EDC.HCl (1.3 eq) in DMF (premixed for 3 min), followed by DIPEA (1.3 eq). The mixture was stirred at room temperature for 2 h and the product was isolated by preparative RP-HPLC, using water (+0.01% TFA) and MeCN (+0.01% TFA) as eluents (column C18). The pooled product fractions were lyophilized and the product was obtained as a white solid. MS (ES) C33H37N5O5 requires: 583.68, found: 584.
Reaction SMILES: Br[C:2]1[N:3]([C:25]2[CH:26]=[N:27][N:28]([CH2:30][CH2:31][CH3:32])[CH:29]=2)[C:4]2[C:9]([C:10]=1[S:11][C:12]1[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:8][CH:7]=[C:6]([Cl:23])[C:5]=2[F:24].CC([O-])=O.[K+].[CH:38]1(B(O)O)[CH2:40][CH2:39]1>COCCOC.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:23][C:6]1[C:5]([F:24])=[C:4]2[C:9]([C:10]([S:11][C:12]3[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=3)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:2]([CH:38]3[CH2:40][CH2:39]3)[N:3]2[C:25]2[CH:26]=[N:27][N:28]([CH2:30][CH2:31][CH3:32])[CH:29]=2)=[CH:8][CH:7]=1
Reactant: CCCn1cc(-n2c(Br)c(Sc3cccc(C(=O)OCC)c3)c3ccc(Cl)c(F)c32)cn1
Reactant: OB(O)C1CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CCCn1cc(-n2c(C3CC3)c(Sc3cccc(C(=O)OCC)c3)c3ccc(Cl)c(F)c32)cn1
Temperature: 80 °C
Reaction time: 16 h
Yield: 15 %

Procedure:
To a stirred solution of compound 2 (360 mg, 0.67 mmol) in DME (5 mL) under inert atmosphere were added KOAc (197 mg, 2.01 mmol), Pd(dppf)Cl2 (98 mg, 0.13 mmol), cyclopropylboronic acid (57.8 mg, 0.67 mmol) at RT and degassed under Ar for 20 min; heated to 80° C. and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with EtOAc (40 mL), filtered through celite. The filtrate was washed with water (25 mL), brine (25 mL), dried over Na2SO4 and concentrated under reduced pressure to obtain the crude. This was purified by silica gel column chromatography and then preparative HPLC to afford pure compound 3 (50 mg, 15%) as a white solid. 1H NMR (500 MHz, CDCl3): δ 7.79 (s, 1H), 7.74 (d, J=7.5 Hz, 1H), 7.67 (s, 1H), 7.63 (s, 1H), 7.25-7.18 (m, 2H), 7.12 (d, J=8.0 Hz, 1H), 7.06-7.05 (m, 1H), 4.33 (q, J=7.5 Hz, 2H), 4.18 (t, J=7.5 Hz, 2H), 2.00-1.95 (m, 2H), 1.70-1.69 (m, 1H), 1.36 (t, J=7.5 Hz, 3H), 1.07-1.05 (m, 2H), 0.99-0.97 (t, J=7.5 Hz, 3H), 0.87-0.84 (m, 2H); LC-MS (ESI): 99.7%; m/z 498.5 (M+H+); (column: X Select CSH C-18, 50×3.0 mm, 3.5 μm); RT 5.11 min; 5 mM NH4OAc: ACN; 0.8 mL/min).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Br)ccc1Oc1ccccc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of 5-bromo-2-fluoronitrobenzene (1.10 g, 5.0 mmol), phenol (0.52 g, 5.5 mmol) and K2CO3 powder (0.83 g, 5.0 mmol) in DMF (10 mL) was stirred at 80° C. for 3 h. The mixture was concentrated under reduced pressure, and the residue was partitioned between AcOEt and water. The separated organic layer was washed with 1M aqueous HCl and saturated NaCl solution. After the organic layer was dried over Na2SO4, the solvent was removed to give desired product which was used for next step without further purification.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([NH:12][NH2:13])=[O:11].Cl.[N:15]([O-])=O.[Na+]>O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]=[N+:13]=[N-:15])=[O:11]
Reactant: NNC(=O)c1nc2ccccc2s1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=NC(=O)c1nc2ccccc2s1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 91.4 %

Procedure:
To a suspension of benzo[d]thiazole-2-carbohydrazide (9.3 g, 48.2 mmol) in aqueous HCl (1 N, 75 mL, 75 mmol) and water (200 mL) was added a solution of NaNO2 (6.9 g, 100 mmol) in water (50 mL) dropwise at 0-5° C. The mixture was stirred at 0-5° C. for 2 h and RT for 2 h. The precipitate was filtered, washed with cold water, and dried under high vacuum to give benzo[d]thiazole-2-carbonyl azide (9.0 g, 92%). LRMS (M+H+) m/z 205.1.