Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20](O)=[O:21])[C:15]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:29][CH:30]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH:31]([OH:36])[C:32]([F:35])([F:34])[F:33].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:29][CH:30]([CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:31]([OH:36])[C:32]([F:33])([F:34])[F:35])=[O:21])[C:15]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:29][CH:30]([CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:31](=[O:36])[C:32]([F:34])([F:35])[F:33])=[O:21])[C:15]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2cccnc2)ncc(NC(=O)OCc2ccccc2)c1=O
Reactant: NC(Cc1ccccc1)C(O)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Cn1c(-c2cccnc2)ncc(NC(=O)OCc2ccccc2)c1=O)NC(Cc1ccccc1)C(=O)C(F)(F)F
Product: O=C(Cn1c(-c2cccnc2)ncc(NC(=O)OCc2ccccc2)c1=O)NC(Cc1ccccc1)C(O)C(F)(F)F

Procedure:
2-[5-Benzyloxycarbonylamino-6-oxo-2-(3-pyridyl)-1,6-dihydro-1-pyrimidyl]-N-(1-benzyl-3,3,3-trifluoro-2-hydroxypropyl)acetamide was synthesized in the same manner as in Example 1. That is, [5-benzyloxycarbonylamino-6-oxo-2-(3-pyridyl)-1,6-dihydro-1-pyrimidinyl]acetic acid (title compound in Reference Example 17, 2.50 g, 6.57 mmol) was treated with 3-amino-1,1,1-trifluoro-4-phenyl-2-butanol (title compound in Reference Example 1, 1.51 g, 6.89 mmol), WSCI hydrochloride (1.51 g, 7.88 mmol) and HOBT (1.77 g, 13.1 mmol) in DMF (25 mL) to give 3.58 g (94%) of the target compound as colorless crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:16][C:10]2[S:11][C:12](C=O)=[CH:13][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl.[NH2:18][OH:19].C(O)C.CCOC(C)=O>O>[CH2:1]([O:3][C:4]([CH:6]1[CH2:16][C:10]2[S:11][C:12](=[N:18][OH:19])[CH2:13][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCc2cc(C=O)sc2C1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCC2=C(C1)SC(=NO)C2
Yield: 56.7 %

Procedure:
A mixture of 6-ethoxycarbonyl-2-formyl-4,5,6,7-tetrahydrobenzo[b]thiophene (3.23 g), hydroxylamine hydrochloride (0.92 g), and ethanol (EtOH) (30 ml) was stirred at reflux for 30 minutes. The reaction mixture was added into a mixture of AcOEt and water. The separated organic layer was washed with water, and brine, and dried over MgSO4. After evaporation of the filtrate, the resulting precipitate was washed with a mixture of n-hexane and isopropyl ether to give 6-ethoxycarbonyl-2-hydroxyimino-4,5,6,7-tetrahydrobenzo[b]thiophene (1.81 g).
Reaction SMILES: [CH3:1][N:2]([CH3:36])[C:3]([C:5]1[N:30]([CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([N:22]4[CH2:28][CH:27]5[CH2:29][CH:24]([CH2:25][NH:26]5)[CH2:23]4)=[O:21])=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].CCN(C(C)C)C(C)C.C(=O)([O-])[O-].[K+].[K+].[F:52][C:53]([F:64])([F:63])[CH2:54]OS(C(F)(F)F)(=O)=O>O1CCOCC1.C(Cl)Cl>[CH3:1][N:2]([CH3:36])[C:3]([C:5]1[N:30]([CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([N:22]4[CH2:28][CH:27]5[CH2:29][CH:24]([CH2:25][N:26]5[CH2:54][C:53]([F:64])([F:63])[F:52])[CH2:23]4)=[O:21])=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CNC(C5)C4)cn3)nc2n1C1CCCC1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1COCCO1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CC(C4)N(CC(F)(F)F)C5)cn3)nc2n1C1CCCC1
Temperature: 50 °C
Yield: 58.4 %

Procedure:
In a 100 ml round bottom flask was combined 7-Cyclopentyl-2-[5-(3,6-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (165 mg, 0.294 mmol) and DIPEA (0.128 ml, 0.735 mmol) which were diluted in Dioxane (6.00 ml) gave a yellowish heterogeneous solution. To this mixture was then added potassium carbonate (406 mg, 2.94 mmol) and trifluoroethyltriflate (0.106 ml, 0.735 mmol). The reaction was heated to 50° C. for 18 h. LCMS showed 100% conversion. The mixture was diluted in DCM, and washed with sat'd aq solution of NaHCO3, followed by a brine wash. The organic layer was then separated, dried over MgSO4 and evaporated to give a yellowish solid. This solid was triturated with EtOAc to give 98 mg of 7-Cyclopentyl-2-{5-[6-(2,2,2-trifluoro-ethyl)-3,6-diaza-bicyclo[3.2.1]octane-3-carbonyl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide in 58% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.95 (1H, s), 8.84 (1H, s), 8.30-8.40 (2H, m), 7.81-7.83 (1H, d), 6.65 (1H, s), 4.71-4.78 (1H, quin.), 3.23-3.42 (7H, m), 3.06 (7H, br. s.), 2.30-2.45 (2H, br. s.), 1.99 (4H, br. s.), 1.55-1.75 (4H, d), 1.24-1.35 (2H, br. s). MS (ESI) m/e (M+H+): 570.9
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH2:11][C@H:10]([NH:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[Cl:22])[CH2:9]2)=[N:6][CH:7]=1.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>CO>[CH3:14][CH:15]([CH2:16][CH2:17][CH3:18])[CH3:20].[Cl:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=1[CH2:14][NH:13][C@H:10]1[CH2:11][CH2:12][N:8]([C:5]2[CH:4]=[CH:3][C:2]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:7][N:6]=2)[CH2:9]1
Reactant: Clc1ccc(CN[C@H]2CCN(c3ccc(Br)cn3)C2)c(Cl)c1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CO
Product: CCCC(C)C
Product: Clc1ccc(CN[C@H]2CCN(c3ccc(-c4ccccc4)cn3)C2)c(Cl)c1

Procedure:
Dissolve a mixture of (S)-[1-(5-bromopyridin-2-yl)-pyrrolidin-3-yl]-(2,4-dichlorobenzyl)-amine (330 mg, 0.82 mmol), phenylboronic acid (100 mg, 0.82 mmol), tetakis(triphenylphosphine)palladium (0) (50 mg, 0.04 mmol), 2 N sodium carbonate solution (0.5 mL, 3.3 mmol) in 15:85 ethylene glycol dimethyl ether:methanol (8 mL) and heat in microwave (CEM Discover, 200W) at 80° C. for 20 min. Concentrate to a residue and dissolve in chloroform and wash with saturated aqueous sodium chloride, dry (magnesium sulfate), concentrate, and chromatograph on silica gel, eluting with 0:100 to 10:90 methanol:chloroform, then second column eluting with 0:100 to 50:50 ethyl acetate:2-methylpentane) to give the title compound as a residue. Treatment of the residue essentially as described in Example 1 gives the title compound as its hydrochloride. 1H NMR (400 MHz, DMSO-d6) δ 8.32 (1H, d, J=1.96 Hz), 8.12 (1H, dd, J=9.05, 2.20 Hz), 7.71-7.77 (2H, m), 7.64 (2H, d, J=7.58 Hz), 7.54 (1H, dd, J=8.31, 2.20 Hz), 7.47 (2H, t, J=7.58 Hz), 7.37 (1H, d, J=7.34 Hz), 6.93 (1H, d, J=9.05 Hz), 4.36 (2H, d, J=4.65 Hz), 4.09-4.16 (1H, m), 3.91-4.00 (2H, m), 3.82-3.89 (1H, m), 3.71-3.80 (1H, m), 2.50-2.56 (1H, m), 2.37-2.45 (1H, m), MS (ES): m/z=398 [M+].
Reaction SMILES: [CH:1]1([N:7]([C@H:24]2[CH2:29][CH2:28][C@H:27]([CH3:30])[CH2:26][CH2:25]2)[C:8](=[O:23])[NH:9][C:10]2[S:14][C:13]([S:15]([NH:18][CH2:19][C:20]([OH:22])=[O:21])(=[O:17])=[O:16])=[N:12][N:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:31]1(N[C@H]2CC[C@H](C)CC2)CCCCC1.C(OC(=O)CN(S(C1SC(N)=NN=1)(=O)=O)C)C>>[CH:1]1([N:7]([C@H:24]2[CH2:29][CH2:28][C@H:27]([CH3:30])[CH2:26][CH2:25]2)[C:8](=[O:23])[NH:9][C:10]2[S:14][C:13]([S:15]([N:18]([CH2:19][C:20]([OH:22])=[O:21])[CH3:31])(=[O:17])=[O:16])=[N:12][N:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[C@H]1CC[C@H](NC2CCCCC2)CC1
Reactant: C[C@H]1CC[C@H](N(C(=O)Nc2nnc(S(=O)(=O)NCC(=O)O)s2)C2CCCCC2)CC1
Agent: CCOC(=O)CN(C)S(=O)(=O)c1nnc(N)s1
Product: CN(CC(=O)O)S(=O)(=O)c1nnc(NC(=O)N(C2CCCCC2)[C@H]2CC[C@H](C)CC2)s1

Procedure:
Prepared in a similar manner to {5-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl)-ureido]-[1,3,4]thiadiazole-2-sulfonylamino}-acetic acid via cyclohexyl-(trans-4-methyl-cyclohexyl)-amine and [(5-amino-1,3,4-thiadiazole-2-sulfonyl)-methyl-amino]-acetic acid ethyl ester to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:12])[C:9](O)=O)[CH:5]=[CH:6][CH:7]=1.[F:13][C:14]1[C:19]([F:20])=[CH:18][C:17]([NH2:21])=[C:16]([NH2:22])[CH:15]=1.[OH-].[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([C:9]2[NH:21][C:17]3[CH:18]=[C:19]([F:20])[C:14]([F:13])=[CH:15][C:16]=3[N:22]=2)[OH:12])[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cc(F)c(F)cc1N
Reactant: O=C(O)C(O)c1cccc(Br)c1
Agent: [Na+]
Agent: [OH-]
Product: OC(c1cccc(Br)c1)c1nc2cc(F)c(F)cc2[nH]1
Temperature: 25 °C

Procedure:
A mixture of (3-bromophenyl)hydroxyacetic acid (809 mg) and 4,5-difluoro-ortho-phenylenediamine (500 mg) in 5N aqueous hydrochloric solution (2 mL) is heated under reflux for 15 h and cooled back to room temperature. The mixture is basified with concentrated sodium hydroxide and extracted with ethyl acetate. The organic phase is then dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by trituration in dichloromethane to afford the pure 3-bromophenyl(5,6-difluoro-1H-benzimidazol-2-yl)methanol.
Reaction SMILES: [O:1]1[CH2:18][C@H:2]1[CH2:3][O:4][C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=1[CH:7]=[C:8]1[CH2:13][CH2:12][O:11][C:9]1=[O:10].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][C:21]=1[C:32]([F:35])([F:34])[F:33].CO.Cl>CO>[OH2:1].[ClH:19].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[CH2:31][CH2:30][N:29]([CH2:18][C@H:2]([OH:1])[CH2:3][O:4][C:5]3[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=3[CH:7]=[C:8]3[CH2:13][CH2:12][O:11][C:9]3=[O:10])[CH2:28][CH2:27]2)=[CH:22][C:21]=1[C:32]([F:35])([F:33])[F:34]
Reactant: FC(F)(F)c1cc(C2CCNCC2)ccc1Cl
Reactant: O=C1OCCC1=Cc1ccccc1OC[C@@H]1CO1
Agent: Cl
Solvent: CO
Product: O
Product: O=C1OCCC1=Cc1ccccc1OC[C@@H](O)CN1CCC(c2ccc(Cl)c(C(F)(F)F)c2)CC1
Yield: 52.6 %

Procedure:
The reaction was performed in same manner as in Example 307 using (S)-α-(2′-(2,3-epoxypropan-1-yloxy)benzylidene)-γ-butyrolactone (1.0 g) and 4-(4-chloro-3-trifluoromethylphenyl)piperidine (0.8 g) in methanol (50 ml), and the obtained oil was treated with methanol/hydrochloric acid to give the title compound (0.45 g), melting point 172–174° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:18][C:17]2[C:12](=[CH:13][C:14]([C:19]3[CH:20]=[CH:21][N:22]4[C:27]([C:28]=3[CH3:29])=[C:26]([CH:30]3[CH2:32][CH2:31]3)[CH:25]=[C:24]([C:33]([O:35]C)=[O:34])[C:23]4=[O:37])=[CH:15][CH:16]=2)[NH:11][C:10]1=[O:38])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O>CO>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:18][C:17]2[C:12](=[CH:13][C:14]([C:19]3[CH:20]=[CH:21][N:22]4[C:27]([C:28]=3[CH3:29])=[C:26]([CH:30]3[CH2:32][CH2:31]3)[CH:25]=[C:24]([C:33]([OH:35])=[O:34])[C:23]4=[O:37])=[CH:15][CH:16]=2)[NH:11][C:10]1=[O:38])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc4c(c3)NC(=O)C(NC(=O)OC(C)(C)C)C4)ccn2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1c(-c2ccc3c(c2)NC(=O)C(NC(=O)OC(C)(C)C)C3)ccn2c(=O)c(C(=O)O)cc(C3CC3)c12
Temperature: 50 °C
Reaction time: 2 h
Yield: 69.4 %

Procedure:
Methyl 8-(3-(tert-butoxycarbonylamino)-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (43 mg, 0.083 mmol) was dissolved in methanol (2 mL) and sodium hydroxide 1M solution in water (0.5 mL, 0.5 mmol) was added. The mixture was stirred at 50° C. for 2 h. After cooling, the methanol was removed in vacuo. The residue was dissolved in water (5 mL) and then neutralized with 1M HCl (˜0.5 mL). The precipitate formed was stirred at room temperature overnight. The mixture was extracted with CH2Cl2 (3×4 mL). The organic layers were concentrated to afford the title compound as a yellow solid (29 mg, 69%). ESI-MS m/z: 504 (M+H)+.
Reaction SMILES: C([O:3][C:4]([CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[N+:16]([O-])=O)[CH:9]=[C:8]1[C:19]([O:21][CH2:22][CH3:23])=[O:20])=O)C.C1(C)C=CC=CC=1.C[O-].[Na+]>O1CCCC1.[C].[Pd]>[O:3]=[C:4]1[CH2:6][N:7]2[C:8]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:9][C:10]3[C:15]2=[C:14]([CH:13]=[CH:12][CH:11]=3)[NH:16]1
Reactant: CCOC(=O)Cn1c(C(=O)OCC)cc2cccc([N+](=O)[O-])c21
Agent: [Pd]
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2cccc3c2n1CC(=O)N3
Yield: 85.7 %

Procedure:
Ethyl 1-ethoxycarbonylmethyl-7-nitro-1H-indole-2-carboxylate (2.11 g, 6.59 mmol) was subjected to catalytic reduction in the presence of 10% palladium-carbon (0.20 g) in tetrahydrofuran (70 ml) at ordinary temperature and atmospheric pressure. After completion of the reaction, the catalyst was filtered off and the filtrate was concentrated under reduced pressure. Toluene (100 ml) and sodium methoxide (0.35 g, 6.48 mmol) were added to the residue, and the resulting mixture was heated under reflux for 2 hours. Then, the solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/8) to obtain ethyl 2,3-dihydro-2-oxo-1H-pyrrolo[1,2,3-de]quinoxaline-5-carboxylate (1.38 g).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(C(C)C)CC)(C)C.ClC(Cl)(O[C:37](=[O:43])OC(Cl)(Cl)Cl)Cl.[NH2:45][C:46]1[S:47][C:48]([CH2:51][CH3:52])=[N:49][N:50]=1>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:37]([NH:45][C:46]1[S:47][C:48]([CH2:51][CH3:52])=[N:49][N:50]=1)=[O:43]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: CCc1nnc(N)s1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nnc(NC(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2Cl)s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 14.3 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (100 mg) was dissolved in chloroform (5 ml) and diisopropylethylamine (0.5 ml) to prepare a solution. A solution of triphosgene (100 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 15 min. Next, 2-amino-5-ethyl-1,3,4-thiadiazole (41 mg) was added thereto, and the mixture was further stirred at room temperature overnight. Distilled water was added to the reaction solution, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine and was dried over sodium sulfate. The organic layer was concentrated under the reduced pressure, and the residue was purified by HPLC using chloroform/acetone for development to give 21 mg of the title compound.
Reaction SMILES: [Li][CH2:2]CCC.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14]([CH:20]=O)=[CH:15][CH:16]=[C:17]([Cl:19])[CH:18]=2)=[CH:9][CH:8]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[CH:20]=[CH2:2])=[CH:9][CH:8]=1
Reactant: O=Cc1ccc(Cl)cc1-c1ccc(Br)cc1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1ccc(Cl)cc1-c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.8 %

Procedure:
BuLi (2.5M in hexanes, 11.3 mL, 28.2 mmol) was added to a solution of methyltriphenylphosphonium bromide (10.1 g, 28.2 mmol) in THF (65 mL). The mixture was stirred at 0° C. for 1 hr. A solution of 4′-bromo-5-chlorobiphenyl-2-carbaldehyde (4.2 g, 14.11 mmol) in THF (65 mL) was added dropwise at 0° C. The mixture was stirred overnight from 0° C. to r.t. The reaction was filtered and evaporated. The residue was diluted with diethyl ether and washed with water and brine. The ether layer was collected, dried (MgSO4), filtered and evaporated to give the crude material. The crude material was purified on the Biotage (5-15% EtOAc:Hex) to give 4′-bromo-5-chloro-2-vinylbiphenyl (3.43 g, 11.68 mmol, 83% yield) as a clear oil.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:11]2[CH2:10][O:9][C:8](=[O:12])[C:7]=2[CH:6]=[CH:5][C:4]=1[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]1.[ClH:28]>O1CCOCC1>[Cl-:28].[CH3:1][S:2][C:3]1[C:11]2[CH2:10][O:9][C:8](=[O:12])[C:7]=2[CH:6]=[CH:5][C:4]=1[CH2:13][CH2:14][N:15]1[CH2:16][CH2:17][NH2+:18][CH2:19][CH2:20]1
Reactant: Cl
Reactant: CSc1c(CCN2CCN(C(=O)OC(C)(C)C)CC2)ccc2c1COC2=O
Solvent: C1COCCO1
Product: CSc1c(CCN2CC[NH2+]CC2)ccc2c1COC2=O
Product: [Cl-]
Reaction time: 18 h

Procedure:
In a 12 mL reaction vial, was added tert-butyl 4-(2-[4-(methylsulfanyl)-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazine-1-carboxylate (25 mg, 0.064 mmol) and 4 N HCl in dioxane (1 mL). The reaction was stirred at r. t. for 18 hr. The reaction mixture was concentrated to give the desired product.
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][CH:8]=[CH2:9])[C:3]([OH:5])=[O:4].[C:10]1(C)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1(C)C=CC(S(O)(=O)=[O:24])=CC=1>O>[CH2:6]([CH:2]1[O:1][C:15](=[O:24])[CH:14]([CH2:13][CH2:12][CH:11]=[CH2:10])[O:4][C:3]1=[O:5])[CH2:7][CH:8]=[CH2:9]
Reactant: C=CCCC(O)C(=O)O
Reactant: Cc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: C=CCCC1OC(=O)C(CCC=C)OC1=O
Yield: 41 %

Procedure:
In a 1-L flask equipped with a reflux condenser and a Dean-Stark trap, 3.0 g of 2-hydroxy-5-hexenoic acid, 400 ml of toluene and 30 mg of p-toluenesulfonic acid were added and refluxed under a nitrogen atmosphere. Water accumulated in the trap was eliminated from time to time. The mixture was cooled after refluxing for 72 hours. It was washed twice with 10 ml of a saturated aqueous solution of sodium hydrogencarbonate, and an obtained crude product was vacuum distilled in the presence of zinc oxide to obtain 1.06 g of desired 3,6-di(3-butenyl)-1,4-dioxane-2,5-dione (yield 41%).
Reaction SMILES: N[OH:2].CN(C)[C:5](Cl)=[O:6].[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CC(C)=O>[CH:5]([C:10]1[CH:11]=[CH:12][C:13]([OH:2])=[CH:14][N:9]=1)=[O:6]
Reactant: CN(C)C(=O)Cl
Reactant: NO
Reactant: c1ccncc1
Solvent: CC(C)=O
Product: O=Cc1ccc(O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
N-[5-(N',N'-Dimethylcarbamoyl)hydroxy-2-pyridine methylene] hydroxylamine. Dimethylcarbamoyl chloride (5.2 mL, 57 mmol) was added to a solution of N-(5-hydroxy-2-pyridinemethylene) hydroxylamine (6.53 g, 47 mmol) in 40 mL of pyridine. It was stirred at room temperature overnight and then the solvent was removed in vacuo, leaving a light green paste. The paste was dissolved in a minimum quantity of acetone and then triturated with ethyl acetate and placed in the freezer overnight. Glassy needles formed and were filtered and washed with ethyl acetate to yield 3.0 g of pure product (30%), m.p. 134°-135° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=O)[C:5](=[O:11])[NH:6]2.O.[NH2:14][NH2:15]>C(O)C>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[N:14][NH2:15])[C:5](=[O:11])[NH:6]2
Reactant: NN
Reactant: O=C1Nc2cccc(Cl)c2C1=O
Solvent: O
Solvent: CCO
Product: NN=C1C(=O)Nc2cccc(Cl)c21

Procedure:
To a stirred slurry of 43.3 g of 4-chloroisatin in 350 ml of ethanol was added 17.3 ml of hydrazine hydrate, and then the reaction mixture was heated under reflux for 2 hours. The reaction mixture was cooled, and the precipitate was recovered by filtration to give 43.5 g of 4-chloro-3-hydrazono-2-oxindole, mp 235°-236° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].O[CH2:13][C@@H:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1.C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])[O:11][CH2:15][C@@H:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])[CH3:13]
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C[C@@H](COc1ccc([N+](=O)[O-])c(F)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
To a mixture of 3-fluoro-4-nitrophenol (2.02 g), tert-butyl [(1S)-2-hydroxy-1-methylethyl]carbamate (5.62 g), triphenylphosphine (8.41 g) and THF (60 mL) was added dropwise a toluene solution (1.9 M, 16.9 mL) of diisopropyl azodicarboxylate at room temperature, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as a pale-yellow solid (4.03 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([NH:11]CC2OC(C3C=C4C(=CC=3)C(=NO)CC4)=C(C3C=CN=CC=3)C=2)[CH2:7][CH2:6]1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:6][CH2:7][CH:8]([NH2:11])[CH2:9][CH2:10]1
Reactant: COCCN1CCC(NCc2cc(-c3ccncc3)c(-c3ccc4c(c3)CCC4=NO)o2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCN1CCC(N)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.2 %

Procedure:
A solution of the product from Step 1 (500 mg, 1.94 mmol) in dichloromethane (5 ml) was cooled to 0° C. and treated with trifluoroacetic acid (2 ml). The mixture was allowed to warm to room temperature and stirred for a further 1 hour. After evaporation of the solvent in vacuo, the residue was partitioned between dichloromethane and an aqueous solution of sodium carbonate. After separation of the layers the aqueous phase was re-extracted six times with dichloromethane, dried and concentrated in vacuo to yield the title compound (145 mg, 47%); 1H NMR (CD3OD) 3.49 (2H, t, J 5.2 Hz), 3.35 (3H, s), 3.30 (2H, m), 3.10 (1H, s), 2.80 (2H, t, J 5.2 Hz), 2.68 (2H, m), 1.91 (2H, m), 1.30 (2H, m).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:27][CH2:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[N:35]=[C:34]([CH3:39])[N:33]([CH:40]1[CH2:45][CH2:44][C:43](=[O:46])[NH:42][C:41]1=[O:47])[C:32]2=[O:48]>CN(C=O)C>[O:47]=[C:41]1[CH:40]([N:33]2[C:32](=[O:48])[C:31]3[C:36](=[CH:37][CH:38]=[C:29]([CH2:28][NH:27][C:6](=[O:8])[C:5]4[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:1])([F:13])[F:12])[CH:4]=4)[CH:30]=3)[N:35]=[C:34]2[CH3:39])[CH2:45][CH2:44][C:43](=[O:46])[NH:42]1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Reactant: Cc1nc2ccc(CN)cc2c(=O)n1C1CCC(=O)NC1=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Cc1nc2ccc(CNC(=O)c3cccc(C(F)(F)F)c3)cc2c(=O)n1C1CCC(=O)NC1=O
Reaction time: 1 h
Yield: 56.9 %

Procedure:
To a stirred solution of 3-trifluoromethyl-benzoic acid (0.30 g, 1.6 mmol) in DMF (8 mL) in a 40° C. oil bath, was added 1,1′ carbonyldiimidazole (0.28 g, 1.7 mmol), and the mixture was stirred for one hour. Then 3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.53 g, 1.6 mmol) was added, and the mixture was stirred for 15 minutes. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-3-trifluoromethyl-benzamide as an off-white solid (430 mg, 59% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, grad. to 95/5 in 5 min, kept 5 min, 6.20 min (98.5%); mp, 220-222° C.; 1HNMR (DMSO-d6) 2.15-2.20 (m, 1H, CHH), 2.56-2.91 (m, 6H, CHCH2, CH3), 4.62 (d, J=5 Hz, 2H, CH2NH), 5.26 (dd, J=6, 11 Hz, 1H, CH), 7.59-8.25 (m, 7H, Ar), 9.42 (t, J=5 Hz, 1H, CH2NH), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.90, 23.41, 30.60, 42.45, 56.53, 120.02, 123.79 (q, JC-F=11 Hz), 123.79 (d, JC-F=3 Hz), 123.95 (q, JC-F=275 Hz), 124.04, 126.67, 127.96 (d, JC-F=3 Hz), 129.19 (d, JC-F=32 Hz), 129.74, 131.38, 134.18, 134.88, 137.81, 145.88, 154.65, 160.43, 164.73, 169.45, 172.59. LCMS MH=473; Anal Calcd For C23H19N4O4F3+0.3H2O: C, 57.81; H, 4.13; N, 11.73; F, 11.93. Found: C, 57.77; H, 4.11; N, 11.69; F, 11.97.