Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[CH:6][CH:7]=1.[CH2:9]([N:11](CC)CC)C.C[Si](C#N)(C)C.[OH-].[Na+]>C(#N)C>[Br:1][C:2]1[C:3]([C:9]#[N:11])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: [O-][n+]1cccc(Br)c1
Reactant: CCN(CC)CC
Agent: C[Si](C)(C)C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: N#Cc1ncccc1Br
Temperature: 100 °C
Reaction time: 16 h
Yield: 79 %

Procedure:
3-Bromo-pyridine 1-oxide (9.4 g, 54 mmol) is dissolved in acetonitrile (60 mL) and triethylamine (15 mL) is added followed by trimethylsilyl cyanide (21.7 mL, 163 mmol). The mixture is heated to 100° C. and stirred for 16 h. The mixture is cooled to 0° C., poured into 250 mL of 5 M aqueous NaOH, and extracted with dichloromethane. The combined extracts are washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting material is purified using flash chromatography (Biotage® Si65M, 20% AcOEt/hexane) yields 7.8 g (79%) of the title compound as a yellow solid. GCMS m/e 182 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[CH2:8][O:9][C:10]3[CH:33]=[C:32]4[C:13]([CH:14]=[CH:15][C:16]5[N:20]=[C:19]([C@@H:21]6[CH2:25][C@H:24]([O:26][CH2:27][CH3:28])[CH2:23][N:22]6C([O-])=O)[NH:18][C:17]=54)=[CH:12][C:11]=3[C:5]2=[CH:4][CH:3]=1.Cl.[CH3:35][O:36][C:37]([NH:39][C@@H:40]([CH:44]([CH3:46])[CH3:45])[C:41](O)=[O:42])=[O:38].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[C:6]2[CH2:8][O:9][C:10]3[CH:33]=[C:32]4[C:13]([CH:14]=[CH:15][C:16]5[N:20]=[C:19]([C@@H:21]6[CH2:25][C@H:24]([O:26][CH2:27][CH3:28])[CH2:23][N:22]6[C:41](=[O:42])[C@@H:40]([NH:39][C:37](=[O:38])[O:36][CH3:35])[CH:44]([CH3:46])[CH3:45])[NH:18][C:17]=54)=[CH:12][C:11]=3[C:5]2=[CH:4][CH:3]=1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: CCO[C@H]1C[C@@H](c2nc3ccc4cc5c(cc4c3[nH]2)OCc2cc(Cl)ccc2-5)N(C(=O)[O-])C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CCO[C@H]1C[C@@H](c2nc3ccc4cc5c(cc4c3[nH]2)OCc2cc(Cl)ccc2-5)N(C(=O)[C@@H](NC(=O)OC)C(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
To a solution of (2S,4S)-2-(9-chloro-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-ethoxypyrrolidine-1-carboxylate (0.46 g, 0.9 mmol) in a mixture of CH2Cl2 (9.0 mL) and MeOH (1.5 mL) was added HCl (in dioxanes, 4M, 6.5 mL, 26.0 mmol). The resulting solution was stirred at room temperature for 2 h. The solution was concentrated to dryness under reduced pressure. To the crude intermediate in CH2Cl2 (10.0 mL) was added (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (0.17 g, 0.9 mmol), HATU (0.41 g, 1.1 mmol), and DIPEA (0.5 mL, 2.9 mmol). The resulting solution was stirred at room temperature for 48 h and diluted with CH2Cl2. The solution was washed with aqueous HCl (1N) and brine. The aqueous layers were back extracted with CH2Cl2 (2×). The resulting organic layers were combined, dried (Na2SO4), and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (20% to 100% EtOAc (w/5% MeOH)/Hexanes to 80% MeOH/EtOAc) to afford methyl {(2S)-1-[(2S,4S)-2-(9-chloro-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-ethoxypyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate (0.46 g, 90%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][C:4]([C:7]#[N:8])=[N:3]1.C[O-].[Na+].[Cl-:12].[NH4+:13]>>[ClH:12].[CH3:1][N:2]1[CH:6]=[N:5][C:4]([C:7](=[NH:13])[NH2:8])=[N:3]1
Reactant: Cn1cnc(C#N)n1
Reactant: [NH4+]
Reactant: [Cl-]
Agent: C[O-]
Agent: [Na+]
Product: Cl
Product: Cn1cnc(C(=N)N)n1
Yield: 78.4 %

Procedure:
1-methyl-1H-1,2,4-triazole-3-carbonitrile (20 g, 185 mmol) was reacted with sodium methoxide (14 g, 295 mmol) and ammonium chloride (14.8 g, 277.5 mmol) according to the procedure as described in Example 61, Step B to give the title compound as a white solid (23.44 g, 78.8%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH:1]1([N:7]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16]C#N)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.SC[C@@H]([C@@H](CS)O)O.[N:33](=[CH:41][CH2:42]Cl)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]Cl>>[N:33]1([CH2:41][CH2:42][S:16][C:13]2[S:12][C:11]([NH:10][C:8](=[O:9])[N:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[N:15][CH:14]=2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: ClCC=NCCCCCCCl
Reactant: N#CSc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Agent: O[C@H](CS)[C@@H](O)CS
Product: O=C(Nc1ncc(SCCN2CCCCCC2)s1)N(C1CCCCC1)C1CCCCC1

Procedure:
Prepared as described in general procedure (H) using 1,1-dicyclohexyl-3-(5-thiocyanato-thiazol-2-yl)-urea, dithioerythritol and 2-(hexamethyleneimino) ethylchloride
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][NH:17][S:18]([C:21]2[CH:22]=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=2)(=[O:20])=[O:19])O[C:10]=1[C:28]([OH:30])=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(S(C(N)C2[N:46](C)[C:45](C(O)=O)=C(OCC3C=CC=CC=3)C(=O)C=2)(=O)=O)C=CC=CC=1>>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][NH:17][S:18]([C:21]2[CH:22]=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=2)(=[O:20])=[O:19])[N:46]([CH3:45])[C:10]=1[C:28]([OH:30])=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c(C(N)S(=O)(=O)c2ccccc2)cc(=O)c(OCc2ccccc2)c1C(=O)O
Reactant: Cc1cccc(S(=O)(=O)NCc2cc(=O)c(OCc3ccccc3)c(C(=O)O)o2)c1
Product: Cc1cccc(S(=O)(=O)NCc2cc(=O)c(OCc3ccccc3)c(C(=O)O)n2C)c1
Yield: 78.77 %

Procedure:
3-Benzyloxy-1-methyl-4-oxo-6-[(toluene-3-sulfonylamino)-methyl]-1,4-dihydro-pyridine-2-carboxylic acid (13-04) (1.3 g, 78.77%) was synthesized as a white solid from 3-benzyloxy-4-oxo-6-[(toluene-3-sulfonylamino)-methyl]-4H-pyran-2-carboxylic acid (12-04) (1.6 g, 3.73 mmol) following the procedure described for 6-(benzenesulfonylamino-methyl)-3-benzyloxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid (13-01).
Reaction SMILES: [OH:1][C@@H:2]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:3]([NH:5][C@H:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH2:7]1)=[O:4].[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:15][C@H:6]([NH:5][C:3](=[O:4])[C@@H:2]([OH:1])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:7]2)=[CH:25][CH:24]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: O=C(N[C@@H]1CNc2ccccc2C1)[C@@H](O)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: ClCCCl
Product: O=C(N[C@H]1Cc2ccccc2N(Cc2ccc(F)cc2)C1)[C@@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (S)-2-hydroxy-2-phenyl-N—((S)-1,2,3,4-tetrahydroquinolin-3-yl)acetamide (355 mg, 1.26 mmol) in 1,2-dichloroethane (20 mL) was added 4-fluorobenzaldehyde (160 μL, 1.51 mmol) followed by glacial acetic acid (86 μL) and sodium triacetoxyborohydride (533 mg, 2.51 mmol). The reaction was stirred at room temperature for 16 hours. The reaction was diluted with DCM (20 mL) and quenched by addition of water (20 mL). The organic layer was separated and the aqueous layer was once again extracted with DCM (20 mL). The combined organic extracts were washed with water (2×50 mL) and brine (50 mL), dried over anhydrous sodium sulfate and evaporated to dryness. The crude product was purified by flash chromatography using a gradient (20-40% EtOAc in hexanes). The desired product (S)—N—((S)-1-(4-fluorobenzyl)-1,2,3,4-tetrahydroquinolin-3-yl)-2-hydroxy-2-phenylacetamide was obtained as a beige solid (351 mg, 72% yield). 1H NMR (DMSO-d6) 400 MHz δ 7.67 (d, J=7.8 Hz, 1H), 7.39-7.34 (m, 2H), 7.33-7.22 (m, 5H), 7.12-7.07 (m, 2H), 6.96-6.90 (m, 2H), 6.58-6.52 (m, 2H), 6.07 (d, J=5.1 Hz, 1H), 4.91 (d, J=4.7 Hz, 1H), 4.45 (d, J=16.8 Hz, 1H for AB system), 4.41 (d, J=16.4 Hz, 1H for AB system), 4.24-4.15 (m, 1H), 3.34 (ddd, J=11.3, 3.5, 1.2 Hz, 1H), 3.22 (dd, J=11.0, 7.0 Hz, 1H), 2.95 (dd, J=15.7, 4.7 Hz, 1H), 2.80 (dd, J=16.0, 7.8 Hz, 1H). LCMS m/e 391 (M+H).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].N([O-])=O.[Na+].[S:14](=[O:16])=[O:15].[ClH:17]>O.CC(O)=O.[Cu]Cl>[C:5]([C:4]1[CH:3]=[C:2]([S:14]([Cl:17])(=[O:16])=[O:15])[CH:9]=[CH:8][CH:7]=1)#[N:6]
Reactant: N#Cc1cccc(N)c1
Reactant: O=S=O
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1cccc(S(=O)(=O)Cl)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 45 %

Procedure:
3-Aminobenzonitrile (2.5 g, 21 mmol) was dissolved in conc. HCl (20 mL) and water (20 mL), cooled to 0° C. and a solution of sodium nitrite (1.5 g, 22 mmol) in water (5 mL) was added dropwise. The reaction mixture was stirred for 10 min to complete the diazonium salt formation. In a separate flask was added copper(I) chloride (0.2 g) over a saturated solution of sulfur dioxide in AcOH (25 mL) and stirred at 0° C. for 10 min. The resulting solution was added dropwise to the diazonium salt and stirred at 0° C. for 1 h. The reaction mixture poured into ice water and the product was extracted with tert-butylmethylether. The combined organic layer was washed with water and brine. The crude product was purified by column chromatography (silica gel 60-120 mesh using 5% EtOAc in petroleum ether) to get the pure 3-cyanobenzene-1-sulfonyl chloride (1.9 g, yield 45%) as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 8.35 (t, J=1.5 Hz, 1H), 8.31-8.27 (m, 1H), 8.06-8.02 (m, 1H), 7.82 (t, J=7.9 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]([Cl:21])([Cl:20])[CH:3]1[O:8][CH:7]([C:9]([Cl:12])([Cl:11])[Cl:10])[C:6]2[CH:13]=[C:14]([C:17](Cl)=[O:18])[CH:15]=[CH:16][C:5]=2[O:4]1.[Cl:22][C:23]([Cl:27])([Cl:26])[CH2:24]O.[OH2:28]>>[Cl:21][C:2]([Cl:1])([Cl:20])[CH:3]1[O:8][CH:7]([C:9]([Cl:10])([Cl:11])[Cl:12])[C:6]2[CH:13]=[C:14]([C:17]([O:18][CH2:24][C:23]([Cl:27])([Cl:26])[Cl:22])=[O:28])[CH:15]=[CH:16][C:5]=2[O:4]1
Reactant: O
Reactant: O=C(Cl)c1ccc2c(c1)C(C(Cl)(Cl)Cl)OC(C(Cl)(Cl)Cl)O2
Reactant: OCC(Cl)(Cl)Cl
Product: O=C(OCC(Cl)(Cl)Cl)c1ccc2c(c1)C(C(Cl)(Cl)Cl)OC(C(Cl)(Cl)Cl)O2

Procedure:
A mixture of 2,4-bis(trichloromethyl)benzo[1,3]dioxin-6-carbonyl chloride (5.0 g.) and 2,2,2-trichloroethanol (25 ml.) was warmed on a steam bath for 2 hours. The reaction mixture was cooled, and water was added to produce a white precipitate which was filtered off and crystallised from a mixture of ether and petroleum ether (b.p. 60°-80° C.) to give 2,2,2-trichloroethyl 2,4-bis(trichloromethyl)benzo[1,3]dioxin-6-carboxylate, m.p. 129°-130° C.
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3]1([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:8][CH2:7][C:6](=[CH:9][C:10]([NH:12][CH2:13][CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)=[O:11])[CH2:5][CH2:4]1.[Cl:32][Si](C)(C)C>CC(CC)=O>[ClH:32].[CH3:31][N:2]([CH3:1])[C:3]1([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:8][CH2:7][C:6](=[CH:9][C:10]([NH:12][CH2:13][CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)=[O:11])[CH2:5][CH2:4]1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)C1(c2ccc(F)cc2)CCC(=CC(=O)NCCc2c[nH]c3ccccc23)CC1
Solvent: CCC(C)=O
Product: Cl

Procedure:
2-[4-Dimethylamino-4-(4-fluorophenyl)cyclo hexylidene)-N-[2-(1H-indol-3-yl)ethyl]acetamide (871 mg, 2.08 mmol) was dissolved in ethyl methyl ketone (35 ml), and chlorotrimethylsilane (0.39 ml, 3.11 mmol) was added. After 1.5 h the hydrochloride was isolated as a beige-coloured solid with an m.p. of 217-221° C. in a yield of 85% (810 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:32])=[C:4]([CH2:8][N:9]2[C:13]3[CH:14]=[C:15]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:16]=[C:17]([C:18]([O:20]C)=[O:19])[C:12]=3[N:11]=[C:10]2[C:28]([F:31])([F:30])[F:29])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].Cl>CO.O1CCCC1.CS(C)=O>[Cl:1][C:2]1[C:3]([CH3:32])=[C:4]([CH2:8][N:9]2[C:13]3[CH:14]=[C:15]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[CH:16]=[C:17]([C:18]([OH:20])=[O:19])[C:12]=3[N:11]=[C:10]2[C:28]([F:31])([F:29])[F:30])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(N2CCOCC2)cc2c1nc(C(F)(F)F)n2Cc1cccc(Cl)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Cc1c(Cl)cccc1Cn1c(C(F)(F)F)nc2c(C(=O)O)cc(N3CCOCC3)cc21
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
A suspension of methyl 1-[(3-chloro-2-methylphenyl)methyl]-6-(4-morpholinyl)-2-(trifluoromethyl)-1H-benzimidazole-4-carboxylate, prepared as described in Example 49 (1.09 g, 2.330 mmol) in Methanol (12 mL) and Tetrahydrofuran (THF) (4 mL) was treated with 1 M aq. sodium hydroxide (12 mL, 12.00 mmol) and stirred at 70° C. for 1.5 h (mixture turned homogeneous). The reaction was cooled to room temperature, the volume reduced to half and the residue was acidified (pH 4) by the addition of 1 N HCl. The precipitate was collected, washed with water and dried to give crude desired product (918.6 mg, 2.024 mmol, 87% yield) as a yellow solid. A portion of it (140 mg) was suspended in 3.5 mL of DMSO. After sonication and heating, the solid went into solution but it crashed out. The precipitate was collected and washed with DMSO, but it still showed impurities by LC/MS. Another aliquot (132 mg) was dissolved with heating in 5 mL of DMSO and purified by reverse phase-HPLC (15 to 95% AcCN in water plus 0.1% TFA). The desired product was isolated by evaporation of the organic solvent: the precipitate was collected by filtration, washed with water and dried in a vacuum oven to afford pure desired product (89 mg, 0.192 mmol, 8.25% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.09 (s, 1H), 7.63 (d, J=2.27 Hz, 1H), 7.36 (d, J=7.83 Hz, 1H), 7.30 (d, J=2.27 Hz, 1H), 7.05 (t, J=7.96 Hz, 1H), 5.98 (d, J=7.58 Hz, 1H), 5.70 (s, 2H), 3.66-3.83 (m, 4H), 3.08-3.24 (m, 4H), 2.47 (s, 3H). MS (ES+) m/e 453.9 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]([OH:14])=O)=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[NH2:26][C:27]1[C:32]([Cl:33])=[CH:31][C:30]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:29]([F:40])[CH:28]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:33][C:32]1[C:27]([NH:26][C:12]([C:6]2[C:5]3[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=3)[N:8]([CH3:11])[CH:7]=2)=[O:14])=[CH:28][C:29]([F:40])=[C:30]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:31]=1
Reactant: CCOC(=O)Cc1cc(Cl)c(N)cc1F
Reactant: Cn1cc(C(=O)O)c2ccc(F)cc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cc1cc(Cl)c(NC(=O)c2cn(C)c3cc(F)ccc23)cc1F
Temperature: 25 °C
Yield: 63.1 %

Procedure:
To a suspension of 6-fluoro-1-methylindole-3-carboxylic acid (500 mg, 2.59 mmol) and DMF (0.02 ml, 0.26 mmol) in methylene chloride (15 ml) was added dropwise oxalyl chloride (0.25 ml, 2.85 mmol) under stirring at room temperature. After completion of the dropwise addition, the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then distilled under reduced pressure to remove the solvent. The residue was dissolved in methylene chloride (10.0 ml), followed by the dropwise addition to a solution of ethyl (4-amino-5-chloro-2-fluorophenyl)acetate (600 mg, 2.59 mmol) and triethylamine (1.08 ml, 7.77 mmol) in methylene chloride (5.0 ml). After completion of the dropwise addition, the reaction mixture was heated under reflux for 10 hours. After the reaction mixture was cooled to room temperature, the precipitated crystals were removed under reduced pressure. The filtrate was distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from n-hexane:ethyl acetate (2:1, v/v) eluate fractions, ethyl (5-chloro-2-fluoro-4-((6-fluoro-1-methyl-3-indolylcarbonyl)amino)phenyl)acetate (665 mg, 63%) was obtained as a yellow solid.
Reaction SMILES: [C:1]([Mg]Br)([CH3:4])([CH3:3])[CH3:2].[C:7]([O:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:27]2[C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30]([CH:36]=[O:37])[N:29]=[C:28]2[CH2:38][CH2:39][CH2:40][CH3:41])=[CH:22][CH:21]=1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>O1CCCC1.C(OCC)(=O)C.[Cl-].[NH4+]>[C:7]([O:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:27]2[C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30]([CH:36]([OH:37])[C:1]([CH3:4])([CH3:3])[CH3:2])[N:29]=[C:28]2[CH2:38][CH2:39][CH2:40][CH3:41])=[CH:22][CH:21]=1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[Mg]Br
Reactant: CCCCc1nc(C=O)c(C(=O)OC)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCc1nc(C(O)C(C)(C)C)c(C(=O)OC)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reaction time: 0.5 h

Procedure:
2.77 ml of-a 2M solution of t-butylmagnesium bromide in tetrahydrofuran were added at -55° C. and under an atmosphere of nitrogen to a solution of 1.32 g of methyl 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-4-formylimidazole-5-carboxylate [prepared as described in step (a) above] in 26 ml of tetrahydrofuran, and the resulting mixture was stirred at a temperature of -55° C. to -50° C. for 30 minutes. At the end of this time, the reaction mixture was diluted with 50 ml of ethyl acetate and with a saturated aqueous solution of ammonium chloride. The organic layer was separated and dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, using a 2:1 by volume mixture of hexane and ethyl acetate as the eluent, to afford 0.87 g of the title compound as an amorphous solid.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:21]=[CH:20][C:7]([N:8]([CH3:19])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[C:6]([N+:22]([O-:24])=[O:23])[CH:5]=1.[CH3:25][CH2:26][CH2:27]Br.O>CN(C=O)C>[CH3:19][N:8]([S:9]([C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=1)(=[O:10])=[O:11])[C:7]1[CH:20]=[CH:21][C:4]([O:3][CH2:25][CH2:26][CH3:27])=[CH:5][C:6]=1[N+:22]([O-:24])=[O:23]
Reactant: CCCBr
Reactant: Cc1ccc(S(=O)(=O)N(C)c2ccc(O)cc2[N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1ccc(N(C)S(=O)(=O)c2ccc(C)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 41.6 %

Procedure:
To a suspension of sodium hydride (60%, 0.05 g (1.25 mmol)) in 1.0 ml of DMF, 4′-hydroxy-N-methyl-2′-nitro-p-toluenesulfonanilide (0.32 g (0.99 mmol)) was added with stirring at room temperature. To the resulting mixture, after 15 minutes' stirring at room temperature, n-propyl bromide (0.20 g (2.20 mmol)) was added dropwise and the mixture was stirred at room temperature for 15 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. Diisopropyl ether was added to the residue and crystals separated were filtered and washed to give 0.15 g (42%) of the title compound as pale yellow crystals.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][C:10]=1[N+:18]([O-])=O.CN(C=O)C.[F:26][C:27]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:28]=1[NH2:29]>CCCCCC>[NH2:18][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:9]=1[O:8][CH3:7])[C:13]([NH:29][C:28]1[CH:30]=[CH:31][C:32]([F:34])=[CH:33][C:27]=1[F:26])=[O:15]
Reactant: Nc1ccc(F)cc1F
Reactant: COc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2ccc(F)cc2F)cc1N
Yield: 86 %

Procedure:
Prepared according to the procedure described for Example 1 using oxalyl chloride (3.0 mL, 34.39 mmol), 4-methoxy-3-nitrobenzoic acid (5.00 g, 25.36 mmol), DMF (1.0 mL, 12.92 mmol), and 2,4-difluoroaniline (5.2 mL, 51.07 mmol) to afford the product (6.07 g), m.p. 166-168° C. after trituration in hexane.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:30])=[C:8]2[C:13](=[CH:14][C:15]=1[CH3:16])[N:12]=[C:11]([CH2:17][CH2:18][C:19](O)=[O:20])[N:10]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:28])[C:9]2=[O:29])=[O:5])[CH3:2].C(OC(C1C(C)=[C:38]2C(=CC=1C)N=C(CCC(OCC)=O)[N:40](C1C=CC=CC=1Cl)[C:39]2=O)=O)C>C(O)C.[OH-].[Na+]>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:30])=[C:8]2[C:13](=[CH:14][C:15]=1[CH3:16])[N:12]=[C:11]([CH2:17][CH2:18][C:19](=[O:20])[NH:40][CH2:39][CH3:38])[N:10]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:28])[C:9]2=[O:29])=[O:5])[CH3:2]
Reactant: CCOC(=O)CCc1nc2cc(C)c(C(=O)OCC)c(C)c2c(=O)n1-c1ccccc1Cl
Reactant: CCOC(=O)c1c(C)cc2nc(CCC(=O)O)n(-c3ccccc3Cl)c(=O)c2c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCNC(=O)CCc1nc2cc(C)c(C(=O)OCC)c(C)c2c(=O)n1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 96 h

Procedure:
2-(2-Carboxyethyl)-3-(2-chlorophenyl)-5,7-dimethyl-4-oxo-3,4-dihydroquinazoline-6-carboxylic acid ethyl ester: A solution of 3-(2-chlorophenyl)-2-(2-ethoxycarbonylethyl)-5,7-dimethyl-4-oxo-3,4-dihydroquinazoline-6-carboxylic acid ethyl ester (0.1 g, 0.22 mmol) in absolute ethanol (6 mL) is treated with 2M sodium hydroxide solution (12 drops) and the reaction mixture is stirred at room temperature for 4 days. The solvent is removed under reduced pressure, and the residue is dissolved in water and washed with ethyl acetate. The aqueous layer is acidified to pH2 with concentrated hydrochloric acid and this is extracted with ethyl acetate. The organic phases are combined, dried over anhydrous MgSO4 and the solvent is removed under reduced pressure to afford the title compound, which is used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]#[N:11].Br[CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1.CS(C)=O.[OH-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1)[C:10]#[N:11]
Reactant: BrCC1CCCCO1
Reactant: COc1ccccc1CC#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccccc1C(C#N)CC1CCCCO1
Reaction time: 2 h
Yield: 82 %

Procedure:
To a flask was added 20 g. (0.1346 mole) of (2-methoxyphenyl)acetonitrile, 25 g. (0.1346 mole) of 2-(bromomethyl)tetrahydro-2H-pyran, and 200 ml. of DMSO. The mixture was stirred for five minutes at room temperature and to the resultant solution was added 22 g. (0.2692 mole) of 50% aqueous sodium hydroxide over 30 minutes with the reaction temperature being allowed to exotherm to 60° C. The reaction was stirred an additional two hours, then cooled, water added and the organic material extracted with ether. The combined ether extracts were then washed with water, dried, filtered, and the ether distilled. The organic residue wss fractionally distilled to obtain 27 g. (82% yield) of the 2-(2-methoxyphenyl)-3-(tetrahydropyran-2-yl)propionitrile boiling 145°-160° C. at 5 mm of Hg.
Reaction SMILES: S1C2C(=NC=CC=2OC2C=CC(N)=CC=2)C=C1.F[C:19]1[CH:20]=[C:21]([NH:45][C:46]([NH:48][C:49](=[O:57])[CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[S:47])[CH:22]=[CH:23][C:24]=1[O:25][C:26]1[CH:31]=[CH:30][N:29]=[C:28]2[CH:32]=[C:33](C3C=CC(S(C)(=O)=O)=CC=3)[S:34][C:27]=12>>[C:51]1([CH2:50][C:49]([NH:48][C:46](=[S:47])[NH:45][C:21]2[CH:20]=[CH:19][C:24]([O:25][C:26]3[CH:31]=[CH:30][N:29]=[C:28]4[CH:32]=[CH:33][S:34][C:27]=34)=[CH:23][CH:22]=2)=[O:57])[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: CS(=O)(=O)c1ccc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4F)c3s2)cc1
Agent: Nc1ccc(Oc2ccnc3ccsc23)cc1
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3ccsc23)cc1
Yield: 34 %

Procedure:
Staring from the amine 213, following the procedure described above for the synthesis of compound 50 (scheme 10, example 55), title compound 170c was obtained in 34% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.35 (1H, s), 11.69 (1H, s), 8.47 (1H, d, J=5.28 Hz), 8.10 (1H, d, J=5.28 Hz), 7.70 (1H, s), 7.68 (1H, s), 7.54 (1H, d, J=5.28 Hz), 7.30-7.22 (7H, m), 6.61 (1H, d, J=5.28 Hz), 3.78 (2H, s). MS (m/z) 420.0 (M+H).