Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]([CH3:9])[C:7](=[O:10])[C:6]([CH2:11][CH2:12]O)=[C:5]([CH3:14])[N:4]=1.N1C=CC=CC=1.S(Cl)([Cl:23])=O>C(Cl)(Cl)Cl>[CH3:1][S:2][C:3]1[N:8]([CH3:9])[C:7](=[O:10])[C:6]([CH2:11][CH2:12][Cl:23])=[C:5]([CH3:14])[N:4]=1
Reactant: CSc1nc(C)c(CCO)c(=O)n1C
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CSc1nc(C)c(CCCl)c(=O)n1C
Reaction time: 0.25 h

Procedure:
To a solution of 2-methylthio-5-(2-hydroxyethyl)-3,6-dimethyl-3H-pyrimidin-4-one (20.3 g, 0.095 mol) in chloroform (200 ml) was added one equivalent of pyridine (7.6 ml), followed by slow addition of three equivalents of thionyl chloride (21 ml). After stirring for 15 minutes, the mixture was concentrated and water (300 ml) was added. The precipitate was collected and washed with water, isopropyl alcohol and petroleum ether. Yield 34.4 g (64%). Yield 20.3 g (92%). Mp. 135-137° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]1[N:19]=[CH:20][S:21][CH:22]=1>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]([S:8][CH2:17][C:18]2[N:19]=[CH:20][S:21][CH:22]=2)[N:5]=[C:4]([OH:9])[CH:3]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: BrCc1cscn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(O)nc(SCc2cscn2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 32.9 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (491 mg, 3.4 mmol) was dissolved in anhydrous DMF (25 mL), then potassium carbonate (1.43 g, 10.3 mmol) and 4-(bromomethyl)-1,3-thiazole (922 mg, 5.2 mmol) were added. The mixture was stirred for 4 hours at room temperature. The solid was removed by filtration and washed with methanol, and the filtrate was evaporated. The residue was dissolved in DCM/MeOH and purified on silica gel using 10% DCM in MeOH to afford to 6-methyl-2-[(1,3-thiazol-4-ylmethyl)sulfanyl]pyrimidin-4-ol (268 mg, 32% yield for 2 steps); 1H NMR (400 MHz, DMSO-d6): δ 2.21 (s, 3H), 4.53 (s, 2H), 6.00 (bs, 1H), 7.63 (d, J=2.0 Hz, 1H), 9.06 (d, J=2.0 Hz, 1H).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[N:15]=[C:14]([C@H:16]([CH2:25][CH2:26][CH2:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])[O:13][N:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([NH:8][C:9]([C:11]1[N:15]=[C:14]([C@H:16]([CH2:25][CH2:26][CH2:27][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]2)[CH2:17][C:18]([OH:20])=[O:19])[O:13][N:12]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(C(=O)NCc2ccccc2)no1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)C[C@@H](CCCC1CCCCC1)c1nc(C(=O)NCc2ccccc2)no1
Temperature: 25 °C
Reaction time: 17 h
Yield: 102.1 %

Procedure:
A solution of tert-butyl (3R)-3-{3-[(benzylamino)carbonyl]-1,2,4-oxadiazol-5-yl}6-cyclohexylhexanoate (Preparation 16b) (173 mg, 0.38 mmol) in dichloromethane (4 ml) was treated with trifluoroacetic acid (1 ml) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 17 hours. The solvent was removed under reduced pressure and the residue azeotroped from toluene to afford the title compound as a beige solid (155 mg).
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4](Cl)=[O:5].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([Cl:17])[CH:11]=1.O>C(#N)C>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:4](=[O:5])[CH2:3][C:2]([CH3:8])([CH3:7])[CH3:1])=[C:12]([Cl:17])[CH:11]=1
Reactant: Nc1ccc(Br)cc1Cl
Reactant: CC(C)(C)CC(=O)Cl
Solvent: CC#N
Solvent: O
Product: CC(C)(C)CC(=O)Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
3,3-Dimethylbutanoyl chloride (717 mg, 0.74 mL, 5.32 mmol) was added to a solution of 4-Bromo-2-chloro-phenylamine (1.0 g, 4.84 mmol) in acetonitrile (10 mL). The reaction mixture was stirred at room temperature overnight. Water was added to the mixture and the precipitate formed collected to give the title compound as a powder (1.04 g, 72% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N:11]2[CH2:14][CH:13]([N:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[CH2:12]2)[C:9]=1[Cl:10])[C:5]#[N:6].[CH2:22]([N:24](CC1C=CC(OC)=CC=1)[C:25]1[C:30]2=[N:31][CH:32]=[C:33]([C:34]#[N:35])[N:29]2[N:28]=[C:27](S(C)(=O)=O)[N:26]=1)[CH3:23].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Cl:10][C:9]1[C:8]([N:11]2[CH2:12][CH:13]([N:15]3[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]3)[CH2:14]2)=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[NH:1][C:27]1[N:26]=[C:25]([NH:24][CH2:22][CH3:23])[C:30]2=[N:31][CH:32]=[C:33]([C:34]#[N:35])[N:29]2[N:28]=1
Reactant: CN1CCN(C2CN(c3cc(C#N)cc(N)c3Cl)C2)CC1
Reactant: CCN(Cc1ccc(OC)cc1)c1nc(S(C)(=O)=O)nn2c(C#N)cnc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCNc1nc(Nc2cc(C#N)cc(N3CC(N4CCN(C)CC4)C3)c2Cl)nn2c(C#N)cnc12

Procedure:
3-amino-4-chloro-5-(3-(4-methylpiperazin-1-yl)azetidin-1-yl)benzonitrile (Example 151C) (40 mg, 0.131 mmol), 4-(ethyl(4-methoxybenzyl)amino)-2-(methylsulfonyl)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Intermediate 7) (50.5 mg, 0.131 mmol), and Cs2CO3 (128 mg, 0.392 mmol) in DMF were heated at 45° C. for 14 h. LC/MS showed product formation. The mixture was filtered and rinsed with CH2Cl2, then concentrated and the crude was taken forward to the next reaction.
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.[N:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[CH:14]([N:12]([CH3:13])[C:11]1[C:2]([C:24]2[CH:25]=[CH:26][N:21]=[CH:22][CH:23]=2)=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][C:7]([C:17]([O:19][CH3:20])=[O:18])=[CH:6][CH:5]=2)([CH3:16])[CH3:15]
Reactant: OB(O)c1ccncc1
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3ccncc3)c(N(C)C(C)C)nc2c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Into a 10-mL sealed tube, was placed methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (150 mg, 0.51 mmol, 1.00 equiv), pyridin-4-ylboronic acid (124.5 mg, 1.02 mmol, 1.99 equiv), Pd(PPh3)4 (59 mg, 0.05 mmol, 0.10 equiv), K3PO4 (433 mg, 2.04 mmol), 1,4-dioxane (4 mL). The resulting solution was stirred for overnight at 50° C. in an oil bath under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography with EA/PE (1:40). This resulted in 50 mg (29%) of methyl 3-(isopropyl(methyl)amino)-2-(pyridin-4-yl)quinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH2:8][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[OH:10])=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].Br[CH2:20][C:21]([O:23][CH3:24])=[O:22]>CN(C=O)C>[Br:1][C:2]1[C:7]([CH2:8][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:10][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: COC(=O)CBr
Reactant: OC(Cc1cccnc1Br)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COC(Cc1cccnc1Br)c1ccccc1
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-(2-bromopyridin-3-yl)-1-phenylethanol (2.5 g, 9.0 mmol) in anhydrous DMF (10 mL) was added dropwise to a suspension of sodium hydride (60% dispersion in mineral oil, 0.54 g, 13 mmol) in anhydrous DMF (10 mL) at 0° C., and the resulting mixture was stirred for 30 min. Methyl bromoacetate (1.03 mL, 10.7 mmol) was added, and the contents were warmed to 23° C. and stirred for 30 min, then partitioned between ethyl acetate and water (2×). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 20% ethyl acetate in petroleum ether to give the title compound. MS: m/z=352.0 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)\[CH3:7])[CH3:2].[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:17])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)\[CH2:7][Br:18])[CH3:2]
Reactant: CCOC(=O)/C=C(\C)Oc1cccc(OC)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)/C=C(\CBr)Oc1cccc(OC)c1
Yield: 55.2 %

Procedure:
To a stirred mixture of (E)-3-(3-methoxy-phenoxy)-but-2-enoic acid ethyl ester (5.50 g, 0.023 mol) in carbon tetrachloride (20 mL) under a nitrogen atmosphere was added N-bromosuccinimide (6.22 g, 0.035 mol) and benzoyl peroxide (563 mg, 0.002 mol). Nitrogen gas was bubbled through the mixture for 5 min, and the resulting mixture was heated to reflux for 4 h. The reaction mixture was then placed in the refrigerator overnight. The solids formed were removed by filtration and the filtrate concentrated in vacuo. The crude product obtained was purified using flash column chromatography (silica gel (100-200 mesh), ethyl acetate/hexanes) to afford (E)-4-bromo-3-(3-methoxy-phenoxy)-but-2-enoic acid ethyl ester (4.00 g, 55%) as a yellow oil.
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([N:9]1[CH2:16][CH:15]2[CH:11]([CH2:12][NH:13][CH2:14]2)[CH2:10]1)=[O:8].Cl[C:24]1[N:29]=[C:28]([C:30]2[O:31][CH:32]=[CH:33][CH:34]=2)[CH:27]=[CH:26][N:25]=1>>[C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([N:9]1[CH2:10][CH:11]2[CH:15]([CH2:14][N:13]([C:24]3[N:29]=[C:28]([C:30]4[O:31][CH:32]=[CH:33][CH:34]=4)[CH:27]=[CH:26][N:25]=3)[CH2:12]2)[CH2:16]1)=[O:8]
Reactant: O=C(c1ccccc1-c1ccccc1)N1CC2CNCC2C1
Reactant: Clc1nccc(-c2ccco2)n1
Product: O=C(c1ccccc1-c1ccccc1)N1CC2CN(c3nccc(-c4ccco4)n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 17 and 2-chloro-4-furan-2-yl-pyrimidine. MS (ESI) mass calcd. for C27H24N4O2, 436.52; m/z found, 437.2 [M+H]+.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Cl:5][C:6]1[CH:7]=[C:8]([O:12][CH3:13])[CH:9]=[CH:10][CH:11]=1.[C:14](Cl)([CH3:16])=[O:15]>C(Cl)Cl>[Cl:5][C:6]1[CH:7]=[C:8]([O:12][CH3:13])[CH:9]=[CH:10][C:11]=1[C:14](=[O:15])[CH3:16]
Reactant: COc1cccc(Cl)c1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(C)=O)c(Cl)c1
Temperature: -10 °C
Reaction time: 4 h
Yield: 64.9 %

Procedure:
To a mixture of AlCl3 (42.08 g; 315.60 mmol) in CH2Cl2 (300 mL) was added dropwise 3-chloroanisole (22.50 g; 157.80 mmol), at −30° C. To the resulting mixture was added dropwise a solution of AcCl (10.50 mL; 147.63 mmol) in CH2Cl2 (100 mL) at such a rate to keep the temperature below −15° C. The resulting mixture was stirred for 4 hours at −10° C. Subsequently, the mixture was poured onto ice and extracted with CH2Cl2. The combined organic layers, were dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Et2O/hexanes 1:9) to afford 1-(2-chloro-4-methoxy-phenyl)-ethanone (17.68 g).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:23][CH:24]2[CH2:26][CH2:25]2)[C:5]2[C:10]([C:11]#[N:12])=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:6]=2[N:7]=1.[NH2:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[NH:34][C:33](=[O:38])[CH2:32][CH2:31]2.C[Si](Cl)(C)C>C(O)CCC>[CH:24]1([NH:23][C:4]2[C:5]3[C:10]([C:11]#[N:12])=[CH:9][NH:8][C:6]=3[N:7]=[C:2]([NH:27][C:28]3[CH:29]=[C:30]4[C:35](=[CH:36][CH:37]=3)[NH:34][C:33](=[O:38])[CH2:32][CH2:31]4)[N:3]=2)[CH2:25][CH2:26]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(C#N)c3c(NC4CC4)nc(Cl)nc32)cc1
Reactant: Nc1ccc2c(c1)CCC(=O)N2
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: N#Cc1c[nH]c2nc(Nc3ccc4c(c3)CCC(=O)N4)nc(NC3CC3)c12
Temperature: 135 °C
Reaction time: 20 h
Yield: 37.6 %

Procedure:
A mixture of 2-chloro-4-(cyclopropylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (145 mg, 0.374 mmol), 6-amino-3,4-dihydroquinolin-2(1H)-one (60 mg, 0.370 mmol) and trimethylsilyl chloride (0.200 mL, 1.58 mmol) in nBuOH (4 mL) was stirred at 135° C. for 20 h. It was concentrated in vacuo. The residue was purified by HPLC to give the titled compound (50 mg). MS 360.3 (M+H); UV 202.2, 292.7 nm.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([OH:10])(=[S:9])[CH3:8].[CH2:11]([O:14][C:15]([N:17]1[CH2:21][C@H:20](OS(C)(=O)=O)[CH2:19][C@H:18]1[CH2:27][CH2:28][C:29]1[N:30]([CH3:34])[CH:31]=[CH:32][N:33]=1)=[O:16])[CH:12]=[CH2:13]>CN(C)C=O>[C:7]([S:9][C@@H:20]1[CH2:21][N:17]([C:15]([O:14][CH2:11][CH:12]=[CH2:13])=[O:16])[C@H:18]([CH2:27][CH2:28][C:29]2[N:30]([CH3:34])[CH:31]=[CH:32][N:33]=2)[CH2:19]1)(=[O:10])[CH3:8]
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CCc1nccn1C
Reactant: CC(O)=S
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1CCc1nccn1C
Temperature: 0 °C

Procedure:
To a solution of potassium t-butoxide (2.32 g) in N,N-dimethylformamide (25 ml) was added dropwise thioacetic acid (1.48 ml) with stirring at -10°~-5° C. and the mixture was stirred at -5°~0° C. for 10 minutes. To a solution of (2R,4R)-1-allyloxycarbonyl-2-[2-(1-methylimidazol-2-yl)ethyl]-4-methanesulfonyloxypyrrolidine (5.69 g) in N,N-dimethylformamide (55 ml) was added the mixture obtained above with stirring at ambient temperature. The mixture was stirred at 80°-90° C. for 3 hours. The reaction mixture was poured into ice-water (100 ml) and extracted three times with ethyl acetate (100 ml). The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo, the resulting residue was chromatographed on silica gel (150 g) eluting with a mixture of chloroform and methanol (19:1, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2R,4S)-4-acetylthio-1-allyloxycarbonyl-2-[2-(1-methylimidazol-2-yl)ethyl]pyrrolidine (3.20 g).
Reaction SMILES: C[O:2][C:3]([C@H:5]1[NH:24][C:23](=[O:25])[C:22]2=[CH:26][C:18](=[C:19]([CH3:28])[CH:20]=[C:21]2[CH3:27])[C:17]2=[CH:29][C:13](=[N:14][C:15]([NH2:30])=[N:16]2)[S:12][CH2:11][CH2:10][C:9](=[O:31])[NH:8][CH2:7][CH2:6]1)=[O:4].[OH-].[Na+].O>CO>[NH2:30][C:15]1[N:14]=[C:13]2[CH:29]=[C:17]([C:18]3[CH:26]=[C:22]([C:23](=[O:25])[NH:24][C@H:5]([C:3]([OH:4])=[O:2])[CH2:6][CH2:7][NH:8][C:9](=[O:31])[CH2:10][CH2:11][S:12]2)[C:21]([CH3:27])=[CH:20][C:19]=3[CH3:28])[N:16]=1
Reactant: COC(=O)[C@@H]1CCNC(=O)CCSc2cc(nc(N)n2)-c2cc(c(C)cc2C)C(=O)N1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(C)c2cc1C(=O)N[C@H](C(=O)O)CCNC(=O)CCSc1cc-2nc(N)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 86.4 %

Procedure:
(S)-4-Amino-18,20-dimethyl-10,16-dioxo-7-thia-3,5,11,15-tetraazatricyclo[15.3.1.12,6]docosa-1(20),2(22),3,5,17(21),18-hexaene-14-carboxylic acid methyl ester (1.1 g) obtained in Example 2-12 was dissolved in methanol (24.8 ml), and then a 1N aqueous sodium hydroxide solution (2.7 ml) was added thereto at room temperature. The resulting mixture was stirred at room temperature for six hours, and then water (80 ml) was added thereto. The precipitate was collected by filtration, washed with water, and then dried under reduced pressure to yield (S)-4-amino-18,20-dimethyl-10,16-dioxo-7-thia-3,5,11,15-tetraazatricyclo[15.3.1.12,6]docosa-1(20),2(22),3,5,17(21),18-hexaene-14-carboxylic acid (Compound 64) (0.92 g) as a white solid material.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10](SC)[CH2:9][N:8]([CH3:14])[C:7](=[O:15])[C:6]=2[CH:16]=1.[Cl:17][C:18]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:19]=1[NH2:20]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:20][C:19]3[C:18]([Cl:17])=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:25])[CH2:9][N:8]([CH3:14])[C:7](=[O:15])[C:6]=2[CH:16]=1
Reactant: Nc1c(Cl)cccc1Cl
Reactant: CSC1=Nc2ccc(Cl)cc2C(=O)N(C)C1
Product: CN1CC(Nc2c(Cl)cccc2Cl)=Nc2ccc(Cl)cc2C1=O
Temperature: 25 °C

Procedure:
A mixture of 20.38 g (0.08 m) of 7-chloro-3,4-dihydro-4-methyl-2-methylthio-5H-1,4-benzodiazepine-5-one and 64.81 g (0.40 m) of 2,6-dichloroaniline is stirred and heated to 225° for 1 1/2 hr. The reaction mixture is cooled to room temperature and crystallized from ether to give the crude product, 7-chloro-2-(2',6'-dichloroanilino)-3,4-dihydro-4-methyl-5H-1,4-benzodiazepine-5-one, m.p. (230) 240° - 245°. Recrystallization from acetone-ether and from methanol-isopropanol gives white solid with m.p. 247° - 249.5°.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[C:12]([F:13])=[CH:11][C:10]([CH2:14][OH:15])=[CH:9][C:8]=2[F:16])=[CH:4][C:3]=1[F:19].Cl[C:21]1[CH:31]=[C:25]2[N:26]([CH3:30])[CH2:27][CH2:28][CH2:29][N:24]2[C:23](=[O:32])[N:22]=1>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[C:12]([F:13])=[CH:11][C:10]([CH2:14][O:15][C:21]3[CH:31]=[C:25]4[N:26]([CH3:30])[CH2:27][CH2:28][CH2:29][N:24]4[C:23](=[O:32])[N:22]=3)=[CH:9][C:8]=2[F:16])=[CH:4][C:3]=1[F:19]
Reactant: OCc1cc(F)c(Oc2ccc(Cl)c(F)c2)c(F)c1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Product: CN1CCCn2c1cc(OCc1cc(F)c(Oc3ccc(Cl)c(F)c3)c(F)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from (4-(4-chloro-3-fluorophenoxy)-3,5-difluorophenyl)methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[NH:12][C:13]([CH3:34])=[C:14]([C:17]2[NH:18][C:19]3[CH:25]=[C:24]([C:26](=[O:33])[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:23]=[CH:22][C:20]=3[N:21]=2)[C:15]=1[CH3:16])=[O:10])=[O:5])C.[OH-].[Na+].Cl>O1CCCC1.C(O)C>[C:4]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[NH:12][C:13]([CH3:34])=[C:14]([C:17]2[NH:18][C:19]3[CH:25]=[C:24]([C:26](=[O:33])[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:23]=[CH:22][C:20]=3[N:21]=2)[C:15]=1[CH3:16])=[O:10])([OH:5])=[O:3]
Reactant: CCOC(=O)CCNC(=O)c1[nH]c(C)c(-c2nc3ccc(C(=O)c4ccccc4)cc3[nH]2)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1[nH]c(C(=O)NCCC(=O)O)c(C)c1-c1nc2ccc(C(=O)c3ccccc3)cc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.9 %

Procedure:
The N-(2-ethoxycarbonylethyl)-4-(5-benzoylbenzimidazol-2-yl)-3,5-dimethylpyrrole-2-carboxamide (300 mg) obtained in Example 19 was dissolved in tetrahydrofuran (5 ml) and ethanol (5 ml), and a 4 N sodium hydroxide aqueous solution (10 ml) was added to the solution and stirred at room temperature for 1 hour. The reaction mixture was neutralized with a 4 N hydrochloric acid solution, and then the precipitate was collected by filtration. The solid was dried in vacuo to afford N-(2-carboxyethyl)-4-(5-benzoylbenzimidazol-2-yl)-3,5-dimethylpyrrole-2-carboxamide (211 mg, 75%) as a purple solid.
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]2[NH:9][N:10]=[CH:11][C:3]=12.[CH3:12]I>[OH-].[Na+].O>[OH:1][C:2]1[N:7]=[C:6]([S:8][CH3:12])[N:5]=[C:4]2[NH:9][N:10]=[CH:11][C:3]=12
Reactant: Oc1nc(S)nc2[nH]ncc12
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CSc1nc(O)c2cn[nH]c2n1
Temperature: 5 °C
Reaction time: 0.29 h

Procedure:
4-hydroxy-6-mercapto-pyrazolo[3,4-d]pyrimidine (14 g) was dissolved in a solution of sodium hydroxide (10 g) in water (300 mL). The solution was cooled to 5° C. and shaken with of methyl iodide (12 g). After 15-20 minutes the solution was charcoaled, filtered and acidified with acetic acid to yield crude product. Re-crystallization in acid gave the desired product MS (ES+): 183.0 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15]O)[CH:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C(=O)N([Br:44])C(=O)C1>C1COCC1>[CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][Br:44])[CH:10]=1
Reactant: COC(=O)CCCCCc1cccc(CO)c1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)CCCCCc1cccc(CBr)c1
Temperature: 0 °C
Yield: 91.9 %

Procedure:
To a solution of 6-(3-hydroxymethyl-phenyl)-hexanoic acid methyl ester (587 mg, 2.48 mmol) in THF (10 mL) is added triphenylphosphine (716 mg, 2.73 mmol), stirred until homogeneous then cooled to 0° C. NBS (486 mg, 2.73 mmol) is added portionwise and the reaction mixture stirred for 45 min. The mixture is concentrated and the residue is purified by flash chromatography (eluting with 10% ethyl acetate/hexanes) to give 682 mg of title compound. 1H NMR (300 MHz, CDCl3) δ 7.23 (m, 3H), 7.10 (m, 1H), 4.48 (s, 2H), 3.66 (s, 3H), 2.60 (t, 2H), 2.31 (t, 2H), 1.63 (m, 4H), 1.37 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([SH:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[C@:11]([OH:17])([CH3:16])[C:12]([F:15])([F:14])[F:13].I[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N+:26]([O-:28])=[O:27].C[O-].[Na+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[C:6]([S:8][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N+:26]([O-:28])=[O:27])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[C@:11]([OH:17])([CH3:16])[C:12]([F:15])([F:13])[F:14]
Reactant: O=[N+]([O-])c1ccccc1I
Reactant: C[C@@](O)(C(=O)Nc1ccc(S)cc1Cl)C(F)(F)F
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@](O)(C(=O)Nc1ccc(Sc2ccccc2[N+](=O)[O-])cc1Cl)C(F)(F)F
Temperature: 135 °C
Yield: 60.5 %

Procedure:
A mixture of (R)-N-(2-chloro-4-mercaptophenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (0.1 g), 1-iodo-2-nitrobenzene (0.086 g), sodium methoxide (0.021 g), and cuprous chloride (0.014 g) in DMF (1 ml) was stirred and heated to 135° C. for 2.5 hours then allowed to cool to room temperature. The reaction mixture was diluted with water (5 ml) and poured onto a Varian Chem Elut column. When the liquid had been adsorbed the column was eluted with ethyl acetate and the eluate was concentrated by evaporation. The residue was purified on a silica gel Mega Bond Elut column, eluting with 5-40% ethyl acetate/hexane to give the title compound (0.085 g) as a glass. MS: 419 (M−H)−.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([Br:13])[CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.[C-:14]#[N:15].[K+]>O>[Br:13][C:11]1[CH:12]=[C:3]([CH2:2][C:14]#[N:15])[CH:4]=[C:5]2[C:10]=1[N:9]=[CH:8][CH:7]=[CH:6]2
Reactant: [C-]#N
Reactant: BrCc1cc(Br)c2ncccc2c1
Agent: [K+]
Solvent: O
Product: N#CCc1cc(Br)c2ncccc2c1
Temperature: 100 °C

Procedure:
DMP (10 mL) and H2O (5 mL) were added to 6-bromomethyl-8-bromoquinoline (3 g) (described in International Patent Publication WO 94/22852) and potassium cyanide (1.6 g). After heating at 100° C. for 1 hour, the resulting mixture was quenched with H2O (100 mL) and extracted with EtOAc. The combined organic extracts were washed with water (3×), brine, dried over MgSO4, filtered and concentrated. Flash chromatography (hexane:EtOAc, 3:1) yielded the (8-Bromo-quinolin-6-yl)-acetonitrile compound as a white solid.
Reaction SMILES: [CH3:1][NH:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=4)[CH2:19][CH2:18]3)=[O:16])=[CH:10][CH:9]=2)[CH2:4]1.[CH3:30][N:31]1[CH2:36][CH2:35][CH2:34][CH:33]([C:37](O)=[O:38])[CH2:32]1>>[CH3:1][N:2]([C:37]([CH:33]1[CH2:34][CH2:35][CH2:36][N:31]([CH3:30])[CH2:32]1)=[O:38])[C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15]([N:17]3[CH2:18][CH2:19][CH:20]([C:23]4[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=4)[CH2:21][CH2:22]3)=[O:16])=[CH:12][CH:13]=2)[CH2:4]1
Reactant: CN[C@@H]1CCN(c2ccc(NC(=O)N3CCC(c4ccc(Cl)cc4)CC3)cc2)C1
Reactant: CN1CCCC(C(=O)O)C1
Product: CN1CCCC(C(=O)N(C)[C@@H]2CCN(c3ccc(NC(=O)N4CCC(c5ccc(Cl)cc5)CC4)cc3)C2)C1

Procedure:
(R)-4-(4-Chlorophenyl)piperidine-1-carboxylic acid [4-(3-methylamino-pyrrolidin-1-yl)phenyl]amide was reacted with 1-methylpiperidine-3-carboxylic acid by method E. This resulted in the product with the molecular weight of 538.14 (C30H40ClN5O2); MS (ESI): 538 (M+H+).